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

Inclusion Criteria164

• Histologically confirmed diagnosis of RMS (except pleomorphic RMS)
• Written informed consent from the patient and/or the parent/legal guardian
• Phase 1b Dose Finding - IRIVA Inclusion
• Entered in to the FaR-RMS study at diagnosis
• Very High Risk disease
• Age \>12 months and ≤25 years
• No prior treatment for RMS other than surgery
• Medically fit to receive treatment
• Adequate hepatic function:
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert's syndrome
• ALT or AST \< 2.5 X ULN for age
• Absolute neutrophil count ≥1.0x 109/L
• Platelets ≥ 80 x 109/L
• Adequate renal function: estimated or measured creatinine clearance ≥60 ml/min/1.73 m2
• Documented negative pregnancy test for female patients of childbearing potential
• 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
• Written informed consent from the patient and/or the parent/legal guardian
• Exclusion
• Weight \<10kg
• Active \> grade 2 diarrhoea
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter-current illness or active infection
• Pre-existing medical condition precluding treatment
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)
• Known hypersensitivity to any of the treatments or excipients
• Second malignancy
• Pregnant or breastfeeding women
• Frontline chemotherapy randomisation Very High Risk - CT1a Inclusion
• Entered in to the FaR-RMS study at diagnosis
• Very High Risk disease
• Age ≥ 6 months
• Available for randomisation ≤60 days after diagnostic biopsy/surgery
• No prior treatment for RMS other than surgery
• Medically fit to receive treatment
• 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
• Absolute neutrophil count ≥1.0x 109/L (except in patients with documented bone marrow disease)
• Platelets ≥ 80 x 109/L (except in patients with documented bone marrow disease)
• Fractional Shortening ≥ 28%
• Documented negative pregnancy test for female patients of childbearing potential
• 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
• Written informed consent from the patient and/or the parent/legal guardian
• Exclusion
• Active \> grade 2 diarrhoea
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter-current illness or active infection
• Pre-existing medical condition precluding treatment
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)
• Known hypersensitivity to any of the treatments or excipients
• Second malignancy
• Pregnant or breastfeeding women
• Frontline chemotherapy randomisation High Risk - CT1b Inclusion
• Entered in to the FaR-RMS study at diagnosis
• High Risk disease
• Age ≥ 6 months
• Available for randomisation ≤60 days after diagnostic biopsy/surgery
• No prior treatment for RMS other than surgery
• Medically fit to receive treatment
• 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
• Absolute neutrophil count ≥1.0x 109/L
• Platelets ≥ 80 x 109/L
• Documented negative pregnancy test for female patients of childbearing potential
• 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
• Written informed consent from the patient and/or the parent/legal guardian
• Exclusion
• Active \> grade 2 diarrhoea
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter-current illness or active infection
• Pre-existing medical condition precluding treatment
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)
• Known hypersensitivity to any of the treatments or excipients
• Second malignancy
• Pregnant or breastfeeding women
• Frontline Radiotherapy Note: eligible patients may enter multiple radiotherapy randomisations.
• Radiotherapy Inclusion - for all radiotherapy randomisations
• Entered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation)
• Very High Risk, High Risk and Standard Risk disease
• ≥ 2 years of age
• 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
• Patient assessed as medically fit to receive the radiotherapy
• Documented negative pregnancy test for female patients of childbearing potential
• 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
• Written informed consent from the patient and/or the parent/legal guardian
• Radiotherapy Exclusion - for all radiotherapy randomisations
• Prior allo- or autologous Stem Cell Transplant
• Second malignancy
• Pregnant or breastfeeding women
• Receiving radiotherapy as brachytherapy
• RT1a Specific Inclusion
• Primary tumour deemed resectable (predicted R0/ R1 resection feasible) after 3 cycles of induction chemotherapy (6 cycles for metastatic disease)
• Adjuvant radiotherapy required in addition to surgical resection (local decision).
• Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease
• RT1b Specific Inclusion
• Primary tumour deemed resectable (predicted R0/R1 resection) after 3 cycles of induction chemotherapy (6 cycles for metastatic disease).
• Adjuvant radiotherapy required in addition to surgical resection (local decision)
• Higher Local Failure Risk (HLFR) based on presence of either of the following criteria:
• Unfavourable site
• Age ≥ 18yrs
• Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease
• RT1c Specific Inclusion
• Primary radiotherapy indicated (local decision)
• Higher Local Failure Risk (HLFR) based on either of the following criteria:
• Unfavourable site
• Age ≥ 18yrs
• Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease
• RT2
• Available for randomisation after cycle 6 and before the start of cycle 9 of induction chemotherapy.
• Unfavourable metastatic disease, defined as Modified Oberlin Prognostic Score 2-4
• Note: Definition of metastatic lesions for RT2 eligibility
• Modified Oberlin Prognostic Score (1 point for each adverse factor):
• Age ≥10y
• Extremity, Other, Unidentified Primary Site
• Bone and/ or Bone Marrow involvement
• ≥3 metastatic sites
• Unfavourable metastatic disease: 2- 4 adverse factors Favourable metastatic disease: 0-1 adverse factors
• Maintenance chemotherapy (Very High Risk) - CT2a Inclusion Randomisation must take place during the 12th cycle of maintenance chemotherapy.
• Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point)
• Very High Risk disease
• Received frontline induction chemotherapy as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy regimen
• a. Patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible
• Completed 11 cycles of VnC maintenance treatment (either oral or IV regimens)
• No evidence of progressive disease
• Absence of severe vincristine neuropathy - i.e requiring discontinuation of vincristine treatment)
• Medically fit to continue to receive treatment
• 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
• Written informed consent from the patient and/or the parent/legal guardian
• Exclusion
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled intercurrent illness or active infection
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)
• Second malignancy
• Pregnant or breastfeeding women
• Maintenance chemotherapy (High Risk) - CT2b Randomisation must take place during the 6th cycle of maintenance chemotherapy. Inclusion
• Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point)
• High Risk disease
• Received frontline induction chemotherapy as part of the FaR-RMS trial or with a IVA based chemotherapy regimen. Note that patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible
• Completed 5 cycles of VnC maintenance treatment
• No evidence of progressive disease
• Absence of severe vincristine neuropathy i.e. requiring discontinuation of vincristine treatment
• Medically fit to continue to receive treatment
• 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
• Written informed consent from the patient and/or the parent/legal guardian
• Exclusion
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter current illness or active infection
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)
• Second malignancy
• Pregnant or breastfeeding women
• CT3 Relapsed Chemotherapy
• Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point)
• First or subsequent relapse of histologically verified RMS
• Age ≥ 6 months
• Measurable or evaluable disease
• No cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous three weeks: within two weeks for vinorelbine and cyclophosphamide maintenance chemotherapy
• Medically fit to receive trial treatment
• Documented negative pregnancy test for female patients of childbearing potential within 7 days of planned randomisation
• 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
• Written informed consent from the patient and/or the parent/legal guardian