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 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

1. Primary tumour deemed resectable (predicted R0/R1 resection) after 3 cycles of induction chemotherapy (6 cycles for metastatic disease).
2. Adjuvant radiotherapy required in addition to surgical resection (local decision)
3. Higher Local Failure Risk (HLFR) based on presence of either of the following criteria:

   1. Unfavourable site
   2. Age ≥ 18yrs
4. 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

1. Primary radiotherapy indicated (local decision)
2. Higher Local Failure Risk (HLFR) based on either of the following criteria:

   1. Unfavourable site
   2. Age ≥ 18yrs
3. 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

1. Available for randomisation after cycle 6 and before the start of cycle 9 of induction chemotherapy.
2. 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.

1. Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point)
2. Very High Risk disease
3. 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
4. Completed 11 cycles of VnC maintenance treatment (either oral or IV regimens)
5. No evidence of progressive disease
6. Absence of severe vincristine neuropathy - i.e requiring discontinuation of vincristine treatment)
7. Medically fit to continue to receive treatment
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

Exclusion

1. Prior allo- or autologous Stem Cell Transplant
2. Uncontrolled intercurrent illness or active infection
3. Urinary outflow obstruction that cannot be relieved prior to starting treatment
4. Active inflammation of the urinary bladder (cystitis)
5. Second malignancy
6. Pregnant or breastfeeding women

Maintenance chemotherapy (High Risk) - CT2b Randomisation must take place during the 6th cycle of maintenance chemotherapy. Inclusion

1. Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point)
2. High Risk disease
3. 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
4. Completed 5 cycles of VnC maintenance treatment
5. No evidence of progressive disease
6. Absence of severe vincristine neuropathy i.e. requiring discontinuation of vincristine treatment
7. Medically fit to continue to receive treatment
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

Exclusion

1. Prior allo- or autologous Stem Cell Transplant
2. Uncontrolled inter current illness or active infection
3. Urinary outflow obstruction that cannot be relieved prior to starting treatment
4. Active inflammation of the urinary bladder (cystitis)
5. Second malignancy
6. Pregnant or breastfeeding women

CT3 Relapsed Chemotherapy

Inclusion:

1. Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point)
2. First or subsequent relapse of histologically verified RMS
3. Age ≥ 6 months
4. Measurable or evaluable disease
5. No cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous three weeks: within two weeks for vinorelbine and cyclophosphamide maintenance chemotherapy
6. Medically fit to receive trial treatment
7. Documented negative pregnancy test for female patients of childbearing potential within 7 days of planned randomisation
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

Exclusion:

1. Progression during frontline therapy without previous response (=Refractory to first line treatment)
2. Prior regorafenib or temozolomide
3. Active \> grade 1 diarrhoea
4. ALT or AST \>3.0 x upper limit normal (ULN)
5. Bilirubin, Total \>1.5 x ULN; total bilirubin is allowed up to 3 x ULN if Gilbert's syndrome is documented
6. Patients with unstable angina or new onset angina (within 3 months of planned date of randomisation), recent myocardial infarction (within 6 months of randomisation) and those with cardiac failure New York Heart Association (NYHA) Classification 2 or higher Cardiac abnormalities such as congestive heart failure (Modified Ross Heart Failure Classification for Children = class 2) and cardiac arrhythmias requiring antiarrhythmic therapy (beta blockers or digoxin are permitted)
7. Uncontrolled hypertension \> 95th centile for age and gender
8. Prior allo- or autologous Stem Cell Transplant
9. Uncontrolled inter-current illness or active infection
10. Pre-existing medical condition precluding treatment
11. Known hypersensitivity to any of the treatments or excipients
12. Second malignancy
13. Pregnant or breastfeeding women