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

Sponsor

University of Birmingham (Other)

Overall Status

Recruiting

CT.gov ID

NCT04625907

Collaborator

(none)

1,672

Enrollment

Locations

Arms

116.4

Anticipated Duration (Months)

836

Patients Per Site

7.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

FaR-RMS is an over-arching study for children and adults with newly diagnosed and relapsed rhabdomyosarcoma (RMS)

Condition or Disease	Intervention/Treatment	Phase
Rhabdomyosarcoma	Drug: Irinotecan Drug: Actinomycin D Drug: Doxorubicin Drug: Ifosfamide Drug: Vincristine Drug: Vinorelbine Drug: Cyclophosphamide Drug: Temozolomide Radiation: radiotherapy	Phase 1/Phase 2

Detailed Description

FaR-RMS is an over-arching study for children and adults with newly diagnosed and relapsed rhabdomyosarcoma (RMS). It is a multi-arm, multi-stage format, involving several different trial questions. FaR-RMS is intended to be a rolling programme of research with new treatment arms being introduced dependant on emerging data and innovation. This study has multiple aims. It aims to evaluate the impact of new agent regimens in both newly diagnosed and relapsed RMS; whether changing the duration of maintenance therapy affects outcome; and whether changes to dose, extent (in metastatic disease) and timing of radiotherapy improve outcome and quality of life. In addition the study will evaluate risk stratification through the use of PAX-FOXO1 fusion gene status instead of histological subtyping and explore the use of FDG PET-CT response assessment as a prognostic biomarker for outcome following induction chemotherapy.

Newly diagnosed patients should, where possible, be entered into the FaR-RMS study at the time of first diagnosis prior to receiving any chemotherapy. However, patients can enter at the point of radiotherapy or maintenance, and those with relapsed disease can enter the study even if not previously entered at initial diagnosis. Patients may be entered into more than one randomisation/registration, dependant on patient risk group and disease status.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1672 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 17, 2020

Anticipated Primary Completion Date :

Jun 1, 2030

Anticipated Study Completion Date :

Jun 1, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1b Dose finding: VHR induction - IRIVA Irinotecan: an i.v. infusion over 1 hour on days 8,9,10,11 and 12 . For the phase 1b registration, starting dose of 20 mg/m2. Ifosfamide: 3g/m2 as an i.v. infusion over 3 hours on days 1 and 2 Vincristine: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg). Administered days 1,8,15 on cycles 1-2 and on days 1 and 8 on cycles 3-9. Actinomycin: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on day 1.	Drug: Irinotecan antineoplastic enzyme inhibitor Drug: Actinomycin D Antineoplastic agent that is a polypeptide antibiotic Other Names: Dactinomycin Drug: Ifosfamide chemotherapeutic agent chemically related to the nitrogen mustards and is a synthetic analog of cyclophosphamide Drug: Vincristine anti neoplastic vinca alkaloid agent
Active Comparator: CT1A: VHR induction - IVADO Ifosfamide: 3g/m2 as an i.v. infusion over 3 hours on days 1 and 2 Vincristine: 1.5 mg/m2 as an i.v. bolus (maximum dose 2mg). Administered days 1,8,15 on cycles 1-2 and on day 1 on cycles 3-9. Actinomycin: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on day 1. Doxorubicin: 30 mg/m2 as an i.v infusion over 1 hour on days 1 and 2 on cycles 1-4	Drug: Actinomycin D Antineoplastic agent that is a polypeptide antibiotic Other Names: Dactinomycin Drug: Doxorubicin An anthracycline topoisomerase inhibitor isolated from streptpmyces peucetius var. casesius Drug: Ifosfamide chemotherapeutic agent chemically related to the nitrogen mustards and is a synthetic analog of cyclophosphamide Drug: Vincristine anti neoplastic vinca alkaloid agent
Experimental: CT1A: VHR Induction IRIVA Irinotecan: an i.v. infusion over 1 hour on days 8,9,10,11 and 12 . Phase 2 recommended dose as determined by IRIVA dose finding arm Ifosfamide: 3g/m2 as an i.v. infusion over 3 hours on days 1 and 2 Vincristine: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg). Administered days 1,8,15 on cycles 1-2 and on days 1 and 8 on cycles 3-9. Actinomycin: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on day 1.	Drug: Irinotecan antineoplastic enzyme inhibitor Drug: Actinomycin D Antineoplastic agent that is a polypeptide antibiotic Other Names: Dactinomycin Drug: Ifosfamide chemotherapeutic agent chemically related to the nitrogen mustards and is a synthetic analog of cyclophosphamide Drug: Vincristine anti neoplastic vinca alkaloid agent
Active Comparator: CT1B: HR Induction IVA Ifosfamide: 3g/m2 as an i.v. infusion over 3 hours on days 1 and 2 Vincristine: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg). Administered days 1,8,15 on cycles 1-2 and on day 1 on cycles 3-9. Actinomycin: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on day 1.	Drug: Actinomycin D Antineoplastic agent that is a polypeptide antibiotic Other Names: Dactinomycin Drug: Ifosfamide chemotherapeutic agent chemically related to the nitrogen mustards and is a synthetic analog of cyclophosphamide Drug: Vincristine anti neoplastic vinca alkaloid agent
Experimental: CT1B: HR Induction IRIVA Irinotecan: an i.v. infusion over 1 hour on days 8,9,10,11 and 12 . Phase 2 recommended dose as determined by IRIVA dose finding arm Ifosfamide: 3g/m2 as an i.v. infusion over 3 hours on days 1 and 2 Vincristine: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg). Administered days 1,8,15 on cycles 1-2 and on days 1 and 8 on cycles 3-9. Actinomycin: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on day 1.	Drug: Irinotecan antineoplastic enzyme inhibitor Drug: Actinomycin D Antineoplastic agent that is a polypeptide antibiotic Other Names: Dactinomycin Drug: Ifosfamide chemotherapeutic agent chemically related to the nitrogen mustards and is a synthetic analog of cyclophosphamide Drug: Vincristine anti neoplastic vinca alkaloid agent
Experimental: RT1A: Preoperative Radiotherapy To be given either 41.4 Gy or 50.4 Gy prior to surgery	Radiation: radiotherapy Ionising radiation
Active Comparator: RT1A: Post operative radiotherapy To be given either 41.4 Gy or 50.4 Gy following surgery	Radiation: radiotherapy Ionising radiation
Experimental: RT1B: Radiotherapy for resectable disease: dose escalated To receive 50.4 Gy	Radiation: radiotherapy Ionising radiation
Active Comparator: RT1B: Radiotherapy for resectable disease: standard dose To receive 41.4 Gy	Radiation: radiotherapy Ionising radiation
Experimental: RT1C: Radiotherapy for unresectable disease: dose escalated To receive 59.4 Gy	Radiation: radiotherapy Ionising radiation
Active Comparator: RT1C: Radiotherapy for unresectable disease: standard dose To receive 50.4 Gy	Radiation: radiotherapy Ionising radiation
Experimental: RT2: Radiotherapy to primary tumour and involved lymph nodes Radiotherapy to the primary tumour and involved regional lymph nodes only	Radiation: radiotherapy Ionising radiation
Experimental: RT2: Radiotherapy to all metastatic sites Radiotherapy given to all metastatic sites	Radiation: radiotherapy Ionising radiation
Experimental: CT2A: VHR Maintenance - VC Vinorelbine: 25 mg/m2 i.v. or 60 mg/m2 orally on days 1,8 and 15 Cyclophosphamide 25 mg/m2 orally daily for 28 days	Drug: Vinorelbine vinca alkaloid with a role as an antineoplastic agent Drug: Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent
No Intervention: CT2A: Maintenance -Stop treatment To stop treatment at the point of randomisation
Experimental: CT2B: HR Maintenance - VC Vinorelbine: 25 mg/m2 i.v. on days 1,8 and 15 Cyclophosphamide 25 mg/m2 orally daily for 28 days	Drug: Vinorelbine vinca alkaloid with a role as an antineoplastic agent Drug: Cyclophosphamide Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent
No Intervention: CT2B: HR Maintenance - Stop Treatment To stop treatment at the point of randomisation
Active Comparator: Relpased Chemotherapy - VIR Vincristine: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on days 1 and 8 Irinotecan: 50 mg/m2 as an i.v. infusion over 1 hour on days 1-5	Drug: Irinotecan antineoplastic enzyme inhibitor Drug: Vincristine anti neoplastic vinca alkaloid agent
Experimental: Relapsed Chemotherapy - VIRT Vincristine: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on days 1 and 8 Irinotecan: 50 mg/m2 as an i.v. infusion over 1 hour on days 1-5 Temozolomide: 125 mg/m2 given orally on days 1-5	Drug: Irinotecan antineoplastic enzyme inhibitor Drug: Vincristine anti neoplastic vinca alkaloid agent Drug: Temozolomide oral antineoplastic alkylating agent

Outcome Measures

Primary Outcome Measures

Event Free Survival (RT2) [From randomisation to first failure event, timeframe 36 months]
Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm
Event Free Survival (CT1A) [From randomisation to first failure event, timeframe 36 months]
Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm
Event Free Survival (CT1B) [From randomisation to first failure event, timeframe 36 months]
Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm
Event Free Survival (CT2A) [From randomisation to first failure event, timeframe 36 months]
Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm
Event Free Survival (CT2B) [Time from randomisation to first failure event, timeframe 36 months]
Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm
Event Free Survival (CT3) [Time from randomisation to first failure event, timeframe 36 months]
Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm
Local Failure Free Survival (RT1A and RT1B) [Time from randomisation to first local failure event, timeframe 36 months]
A local failure event is relapse or progression of tumour at the primary site at any time even if there has been a prior /concurrent, regional or distant failure
Local Failure Free Survival (RT1C) [Time from randomisation to first local failure event, timeframe 36 months]
A local failure event is relapse or progression of tumour at the primary site at any time even if there has been a prior /concurrent, regional or distant failure

Secondary Outcome Measures

Recommended Phase II Dose (Phase 1b) [From first patient first visit in dose finding study until appropriate dose level found, estimated 9 months]
Based on tolerability, where tolerability is evaluated through the occurrence of dose limiting toxicity (DLT).
Maximum Tolerated Dose (Phase 1b) [From first patient first visit in dose finding study until appropriate dose level]
Dose level at which no or one participant experiences a DLT when at least two of three to six participants experience a DLT at the next highest dose.
Toxicity (All chemotherapy randomisations) [From date of protocol defined treatment until 30 days after the administration of the last treatment]
Categorised and graded using Common Terminology Criteria for Adverse Events
Dose Limiting Toxicity (Phase 1b) [From commencement of treatment until 21 days after the start of cycle 2 (each cycle is 21 days)]
Diarrhoea: Grade 3 for >3 days despite loperamide therapy Diarrhoea: Grade 4 despite loperamide therapy. Enterocolitis: Grade 3 or above Ileus: Grade 3 or above for more than 3 days Oral mucositis: Grade 3 above for >3 days despite optimal supportive care Persistent neutropenia or thrombocytopenia leading to delay of start of next course by >7 days; i.e. starting > day 28 Any grade 3 or 4 toxicity resulting in discontinuation of the new combination Any grade 5 toxicity
Response (Phase 1b, CT1A, CT1B) [Response assessed after course 3 (63 days) and 6 (126 days)]
defined as complete (CR) or partial response (PR) and is clinically defined. Patients who are not assessable for response - e.g. because of early stopping of treatment or death - will be assumed to be non-responders.
Response (CT3) [Response assessed after cycle 2 and 4 (each cycle is 21 days)]
defined as complete (CR) or partial response (PR) and is clinically defined. Patients who are not assessable for response - e.g. because of early stopping of treatment or death - will be assumed to be non-responders.
Overall Survival (CT1A) [From randomisation to death from any cause, assessed for 36 months]
Death from any cause
Overall Survival (CT1B) [From randomisation to death from any cause, assessed for 36 months]
Death from any cause
Overall Survival (CT2A) [From randomisation to death from any cause, assessed for 36 months]
Death from any cause
Overall Survival (CT2B) [From randomisation to death from any cause, assessed for 36 months]
Death from any cause
Overall Survival (RT1A and RT1B) [From randomisation to death from any cause, assessed for 36 months]
Death from any cause
Overall Survival (RT1C) [From RT1C randomisation to death from any cause, assessed for 36 months]
Death from any cause
Overall Survival (RT2) [From RT2 randomisation to death from any cause, as assessed for 36 months]
Death from any cause
Overall Survival (CT3) [From randomisation to death from any cause, assessed for 36 months]
Death from any cause
Overall Survival (all patients) [From randomisation/registration to death from any cause, assessed for 36 months]
Death from any cause
Acute wound complications and post-operative complications (RT1A and RT1B) [Within 120 days from surgery]
specific grade 3 and above complications according to CTCAE v 4 and Clavien Dindo scale. Specific wound complications within the same time frame will also be collected
Acute post-radiotherapy complications (All radiotherapy randomisations) [Within 120 days from start of radiotherapy]
any grade 3 and above event according to CTCAE v 4
Late complications (RT1A, RT1B. RT1C) [After 120 days from last local therapy]
specific grade 3 and above events according to CTCAE and Clavien-Dindo scale
Loco-regional failure-free survival (All radiotherapy randomisations) [From randomisation to first local and/or regional failure event, assessed for 36 months]
A local failure event is relapse or progression of tumour at the primary site at any time even if there has been a prior concurrent local, regional or distant failure. A regional event is relapse or progression of tumour at regional lymph nodes at any time even if there has been a prior distant failure.
Health related quality of life (RT1A and RT2) [4 timepoints: 1) 1 day of start of radiotherapy, 2) at completion of radiotherapy, average 5 weeks after start of radiotherapy, 3) 3 months and 4) 24 months following radiotherapy]
will be assessed using PedsQL for the paediatric population (under 18 years) and EORTC QLQ-C30 for patients 18 years of age and over
Best Response (CT3) [Throughout the treatment for CT3, for 12 cycles (each cycle is 21 days)]
Best Response
Duration of response (CT3) [From the date of first response to date of relapse, progression or death from any cause, assessed for 36 months]
Duration of response
PET Response (if participating in PET Sub-study) [After three cycles of chemotherapy (each cycle is 21 days)]
assessed by PERCIST criteria and visual 'Deauville like' criteria
Event Free Survival (all patients) [From date of randomisation/registration to death from any cause, assessed for 36 months]
Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm
Event Free Survival (if participating in PET Sub-study) [From date of randomisation/registration to death from any cause, assessed for 36 months]
Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm
Local Failure Free Survival (if participating in PET Sub-study) [From date of randomisation/registration to first local failure event, assessed for 36 months]
A local failure event is relapse or progression of tumour at the primary site at any time even if there has been a prior /concurrent, regional or distant failure

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria for study entry - Mandatory at first point of study entry

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 :

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 :

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

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

Relapse randomisation CT3 Inclusion

Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point including at relapse)
Age ≥ 6 months
First or subsequent relapse of RMS
No cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous two weeks
Medically fit to receive trial treatment
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