International clinical research programme to improve outcomes in newly diagnosed Ewing sarcoma – Trial 1 (INTER-EWING-1)

ACTRN 12624000532505

Brief Summary

Ewing Sarcomacancer arising from bones and/or soft tissue is a cancera disease where abnormal cells split without control and spread to other nearby body tissue and/or organs of bone or soft tissuetissue/the material that joins, holds up or surrounds inside body parts such as fat, muscle, ligaments and lining around joints that occurs in children and adults. Treatment usually includes chemotherapya cancer treatment that uses drugs to kill or slow the growth of cancer cells, while minimising damage to healthy cells, surgerytreatment involving removal of cancerous tissue and/or tumours and a margin of healthy tissue around it to reduce recurrence and/or radiotherapy. This is an international clinical trial (INTER-EWING-1) that will assess multiple combinations of these treatment types to determine whether different combinations are better able to improve survival for patients with Ewing Sarcoma.

Intervention/Treatment

• Drug: Regorafenib.

Inclusion Criteria

1. Any histologically and genetically confirmed Ewing sarcoma of bone or soft tissuea group of cells that work together to perform a function, or round cell sarcomas which are ‘Ewing’s-like’ but negative for EWSR1-Fli gene rearrangement.
2. Age > 2 years.
3. Written informed consenta process in which a patient receives detailed information about a procedure or treatment, including its potential risks, benefits, and alternatives. The patient then has the opportunity to understand the information and voluntarily agree to the procedure or treatment. from the patient and/or the parent/legal guardian

Inclusion criteria for randomisation A will be defined on completion of the externally sponsored phase 1b study (ClinicalTrials.gov Identifier: NCT05830084, EudraCT No: 2022-002874-10). A substantial amendment will be submitted to the relevant competent authority and ethics committee(s) to include these details prior to the opening of Randomisation A.

Radiotherapy Randomisations – B1 and B2
Inclusion Criteria

1. Entered into the INTER-EWING-1 study.
2. Received induction/consolidation chemotherapy with a VDC/IE/VC/VAI/BuMel based regimen.
3. Patient assessed as medically fit to receive the radiotherapy.
4. Documented negative pregnancy test for female patients of childbearing potential.
5. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active.
6. Written informed consent from the patient and/or the parent/legal guardian.

Randomisation B1 specific Inclusion criteria– Definitive radical radiotherapy dosethe amount of medication taken finding randomisation

1. Patients requiring definitive radical radiotherapy to primary tumoura tissue mass that forms from groups of unhealthy cells site as sole local therapy following discussion by local multidisciplinary teama team of health specialists such as medical oncologists, surgical oncologists, radiation oncologists, nurses, allied health and pharmacists who work together to treat patients.
2. Patients who have undergone an R2 resectionsurgical removal of tissue or part/all of an organ of the primary tumour (macroscopic residual tumour), requiring definitive radical radiotherapy.

Randomisation B2 specific Inclusion criteria– Post-operative radiotherapy dose finding randomisation

1. Patients requiring post-operative radiotherapy following discussion by local multidisciplinary team
   according to multidisciplinary team meeting.

Randomisation C – Maintenance chemotherapy randomisation
Inclusion Criteria

1. Entered into the INTER-EWING-1 study.
2. Received induction/ consolidation chemotherapy with a VDC/IE/VC/VAI/BuMel based regimen.
3. Have responded to induction treatment and not progressed.
4. Medically fit to receive treatment.
5. Absence of severe vincristine neuropathy – i.e. requiring discontinuation of vincristine treatment.
6. Adequate liver function: bilirubin <3 x ULN and ALT or AST < 5 x ULN
7. Documented negative pregnancy test for female patients of childbearing potential.
8. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active.
9. Written informed consent from the patient and/or the parent/legal guardian.