FaR-RMS: An Overarching Study for Children and Adults With Frontline and Relapsed RhabdoMyoSarcoma

Inclusion Criteria for study entry - Mandatory at first point of study entry 1. Histologically confirmed diagnosis of RMS (except pleomorphic RMS) 2. Written informed consent from the patient and/or the parent/legal guardian Phase 1b Dose Finding - IRIVA Inclusion 1. Entered in to the FaR-RMS study at diagnosis 2. Very High Risk disease 3. Age \>12 months and ≤25 years 4. No prior treatment for RMS other than surgery 5. Medically fit to receive treatment 6. Adequate hepatic function: 1. Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert's syndrome 2. ALT or AST \< 2.5 X ULN for age 7. Absolute neutrophil count ≥1.0x 109/L 8. Platelets ≥ 80 x 109/L 9. Adequate renal function: estimated or measured creatinine clearance ≥60 ml/min/1.73 m2 10. Documented negative pregnancy test for female patients of childbearing potential 11. 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 12. Written informed consent from the patient and/or the parent/legal guardian Exclusion 1. Weight \<10kg 2. Active \> grade 2 diarrhoea 3. Prior allo- or autologous Stem Cell Transplant 4. Uncontrolled inter-current illness or active infection 5. Pre-existing medical condition precluding treatment 6. Urinary outflow obstruction that cannot be relieved prior to starting treatment 7. Active inflammation of the urinary bladder (cystitis) 8. Known hypersensitivity to any of the treatments or excipients 9. Second malignancy 10. Pregnant or breastfeeding women Frontline chemotherapy randomisation Very High Risk - CT1a Inclusion 1. Entered in to the FaR-RMS study at diagnosis 2. Very High Risk disease 3. Age ≥ 6 months 4. Available for randomisation ≤60 days after diagnostic biopsy/surgery 5. No prior treatment for RMS other than surgery 6. Medically fit to receive treatment 7. Adequate hepatic function : a. Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert's syndrome 8. Absolute neutrophil count ≥1.0x 109/L (except in patients with documented bone marrow disease) 9. Platelets ≥ 80 x 109/L (except in patients with documented bone marrow disease) 10. Fractional Shortening ≥ 28% 11. Documented negative pregnancy test for female patients of childbearing potential 12. 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 13. Written informed consent from the patient and/or the parent/legal guardian Exclusion 1. Active \> grade 2 diarrhoea 2. Prior allo- or autologous Stem Cell Transplant 3. Uncontrolled inter-current illness or active infection 4. Pre-existing medical condition precluding treatment 5. Urinary outflow obstruction that cannot be relieved prior to starting treatment 6. Active inflammation of the urinary bladder (cystitis) 7. Known hypersensitivity to any of the treatments or excipients 8. Second malignancy 9. Pregnant or breastfeeding women Frontline chemotherapy randomisation High Risk - CT1b Inclusion 1. Entered in to the FaR-RMS study at diagnosis 2. High Risk disease 3. Age ≥ 6 months 4. Available for randomisation ≤60 days after diagnostic biopsy/surgery 5. No prior treatment for RMS other than surgery 6. Medically fit to receive treatment 7. Adequate hepatic function : a. Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, except if the patient is known to have Gilbert's syndrome 8. Absolute neutrophil count ≥1.0x 109/L 9. Platelets ≥ 80 x 109/L 10. Documented negative pregnancy test for female patients of childbearing potential 11. 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 12. Written informed consent from the patient and/or the parent/legal guardian Exclusion 1. Active \> grade 2 diarrhoea 2. Prior allo- or autologous Stem Cell Transplant 3. Uncontrolled inter-current illness or active infection 4. Pre-existing medical condition precluding treatment 5. Urinary outflow obstruction that cannot be relieved prior to starting treatment 6. Active inflammation of the urinary bladder (cystitis) 7. Known hypersensitivity to any of the treatments or excipients 8. Second malignancy 9. Pregnant or breastfeeding women Frontline Radiotherapy Note: eligible patients may enter multiple radiotherapy randomisations. Radiotherapy Inclusion - for all radiotherapy randomisations 1. Entered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation) 2. Very High Risk, High Risk and Standard Risk disease 3. ≥ 2 years of age 4. Receiving frontline induction treatment as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy regimen patients for whom. Note that patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible 5. Patient assessed as medically fit to receive the radiotherapy 6. Documented negative pregnancy test for female patients of childbearing potential 7. 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 8. Written informed consent from the patient and/or the parent/legal guardian Radiotherapy Exclusion - for all radiotherapy randomisations 1. Prior allo- or autologous Stem Cell Transplant 2. Second malignancy 3. Pregnant or breastfeeding women 4. Receiving radiotherapy as brachytherapy RT1a Specific Inclusion 1. Primary tumour deemed resectable (predicted R0/ R1 resection feasible) after 3 cycles of induction chemotherapy (6 cycles for metastatic disease) 2. Adjuvant radiotherapy required in addition to surgical resection (local decision). 3. Available for rando