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

Rhabdomyosarcoma Clinical Trial

— FaR-RMS  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04625907
• Other study ID #: RG_17-247
• Secondary ID: 2018-000515-2445
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: September 17, 2020
• Est. completion date: June 2030

Study information

• Verified date: May 2023
• Source: University of Birmingham
• Contact: Bridget Shaw
• Phone: 0121 414 2996
• Email: farrms[@]trials.bham.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1672
• Est. completion date: June 2030
• Est. primary completion date: June 2030
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

Related Conditions & MeSH terms

• Rhabdomyosarcoma

Intervention

Drug:
• Irinotecan
antineoplastic enzyme inhibitor
• Actinomycin D
Antineoplastic agent that is a polypeptide antibiotic
• Doxorubicin
An anthracycline topoisomerase inhibitor isolated from streptpmyces peucetius var. casesius
• Ifosfamide
chemotherapeutic agent chemically related to the nitrogen mustards and is a synthetic analog of cyclophosphamide
• Vincristine
anti neoplastic vinca alkaloid agent
• Vinorelbine
vinca alkaloid with a role as an antineoplastic agent
• Cyclophosphamide
Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent
• Temozolomide
oral antineoplastic alkylating agent

Radiation:
• radiotherapy
Ionising radiation

Drug:
• Regorafenib
Oral multi-kinase inhibitor that targets a broad range of angiogenic, stromal and oncogenic kinases, including vascular endothelial growth factor receptors (VEFGR) 1, 2 and 3, tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptors (FGFR), c-KIT, RET, RAF-1 and BRAF (wild-type and V600E mutant).

Locations

Country	Name	City	State
Australia	Chris O'brien Lifehouse	Camperdown
Australia	Monash Children's Hospital	Clayton
Australia	Peter Maccallum Cancer Centre	Melbourne
Australia	Royal Childrens Hospital Melbourne	Melbourne
Australia	Perth Children's Hospital	Perth
Australia	The Childrens Hospital At Westmead	Sydney
Australia	Westmead Hospital	Westmead
Australia	Princess Alexandra Hospital	Woolloongabba
Austria	St Anna Childrens Hospital	Vienna
Belgium	Hopital Universitaire Des Enfants Reine Fabiola	Brussels
Czechia	Masaryk University Hospital Brno	Brno
Denmark	Aarhus University Hospital	Aarhus
Denmark	University Hospital Rigshospitalet	Copenhagen
France	Gustave Roussy	Villejuif
Greece	Children's General Hospital P and A Kyriakou	Athens
Greece	Department of Pediatric Hematology-oncology - Aghia Sophia Children's Hospital	Athens
Greece	Hellenic Society of Pediatric Hematology- Oncology	Athens
Greece	University Unit of Pediatric Oncology-hematology - Children's Hospital Agia Sophia	Athens
Greece	Children's and Adolescent's Oncology Clinic, "MITERA" Children's Hospital	Attikí
Greece	Hematology-oncology Children's Clinic, University General Hospital of Heraklion	Iraklio
Greece	Ippokratio General Hospital of Thessaloniki	Thessaloniki
Greece	Ahepa University General Hospital of Thessaloniki	Thessaloníki
Ireland	Our Lady's Children's Hospital	Crumlin
Israel	Rambam Health Care Campus	Haifa
Israel	Hadassah University Medical Centre	Jerusalem
Israel	Schneider Medical Centre	Petah Tikva
Israel	Dana Children's Hospital, Tel Aviv Sourasky Medical Center	Tel Aviv
Israel	Chaim Sheba Medical Centre	Tel HaShomer
Italy	University Hospital of Padova (azienda Ospedaliera of Padua)	Padova
Netherlands	University Medical Centre Groningen	Groningen
Netherlands	Prinses Maxima Centrum Voor Kinderoncologie	Utrecht
New Zealand	Starship Children's Health	Auckland
New Zealand	Christchurch Hospital	Christchurch
Norway	Haukeland University Hospital - Paediatric	Bergen
Norway	Oslo University Hospital - Paediatrics	Oslo
Norway	Oslo University Hospital - Radiumhospitalet	Oslo
Norway	University Hospital of North Norway - Paediatric	Tromso
Norway	St Olavs Hospital - Paediatric	Trondheim
Portugal	Instituto Portugues De Oncologia De Losbona Francisco Gentil, Epe	Lisbon
Slovakia	Bratislava, National Institute for Children's Diseases	Bratislava
Slovenia	University Childrens Hospital Ljubljana	Ljubljana
Spain	Hospital Sant Joan De Deu	Barcelona
Spain	Hospital Universitari Vall D'hebron	Barcelona
Spain	Hospital De Cruces	Bilbao
Spain	Hospital Del Nino Jesus	Madrid
Spain	Hospital Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Regional Universitario De Malaga	Malaga
Spain	Hospital Virgen Del Rocio	Seville
Spain	Hospital Politecnico U La Fe	Valencia
Spain	Hospital Universitario Miguel Servet Materno - infantil	Zaragoza
Switzerland	Kantonsspital Aarau	Aarau
Switzerland	Universitats-kinderspital Bieder Basel (UKBB)	Basel
Switzerland	Ospedale San Giovanni	Bellinzona
Switzerland	Inselspital Bern	Bern
Switzerland	Hug Hopitaux Universitaires De Geneve	Geneva
Switzerland	Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne	Lausanne
Switzerland	Luzerner Kantonspital - Kinderspital Luzern	Luzern
Switzerland	Ostschweizer Kinderspital	St Gallen
Switzerland	Universitaetsspital Zurich	Zurich
United Kingdom	Royal Aberdeen Children's Hospital	Aberdeen
United Kingdom	Belfast City Hospital	Belfast
United Kingdom	Royal Belfast Hospital for Sick Children	Belfast
United Kingdom	Birmingham Children's Hospital	Birmingham
United Kingdom	The Queen Elizabeth Hospital	Birmingham
United Kingdom	Bristol Haematology And Oncology Centre	Bristol
United Kingdom	Bristol Royal Hospital for Children	Bristol
United Kingdom	Addenbrooke's Hospital	Cambridge
United Kingdom	Noah's Ark Children's Hospital for Wales	Cardiff
United Kingdom	Velindre Hospital	Cardiff
United Kingdom	Royal Hospital for Children and Young People	Edinburgh
United Kingdom	Beatson West of Scotland Cancer Centre	Glasgow
United Kingdom	Royal Hospital for Children Glasgow	Glasgow
United Kingdom	Leeds General Infirmary	Leeds
United Kingdom	St James's University Hospital	Leeds
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Alder Hey Children's Hospital	Liverpool
United Kingdom	Great Ormond Street Hospital for Children	London
United Kingdom	University College London Hospital	London
United Kingdom	Christie Hospital	Manchester
United Kingdom	Royal Manchester Children's Hospital	Manchester
United Kingdom	Royal Victoria Infirmary	Newcastle Upon Tyne
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Queen's Medical Centre, Nottingham	Nottingham
United Kingdom	John Radcliffe Hospital	Oxford
United Kingdom	Sheffield Children's Hospital	Sheffield
United Kingdom	Weston Park Hospital	Sheffield
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	Royal Marsden Hospital	Sutton	Surrey
United Kingdom	Clatterbridge Cancer Centre	Wirral

Sponsors (1)

Lead Sponsor	Collaborator
University of Birmingham

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  Czechia,  Denmark,  France,  Greece,  Ireland,  Israel,  Italy,  Netherlands,  New Zealand,  Norway,  Portugal,  Slovakia,  Slovenia,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event Free Survival (RT2)	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	From randomisation to first failure event, timeframe 36 months
Primary	Event Free Survival (CT1A)	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	From randomisation to first failure event, timeframe 36 months
Primary	Event Free Survival (CT1B)	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	From randomisation to first failure event, timeframe 36 months
Primary	Event Free Survival (CT2A)	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	From randomisation to first failure event, timeframe 36 months
Primary	Event Free Survival (CT2B)	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	Time from randomisation to first failure event, timeframe 36 months
Primary	Event Free Survival (CT3)	To determine whether new systemic therapy regimens improve event free survival in relapsed RMS compared to standard therapy (VIRT) (CT3): Initial new systemic therapy combination to be tested: o Regorafenib (R) added to vincristine and irinotecan (VIR) (VIRR)	Patients will be followed up for a minimum of 6 years from trial entry (or 5 years from end of relapsed trial treatment, whichever comes later). Patients will be followed up for progression and death until the end of trial definition has been met.
Primary	Local Failure Free Survival (RT1A and RT1B)	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	Time from randomisation to first local failure event, timeframe 36 months
Primary	Local Failure Free Survival (RT1C)	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	Time from randomisation to first local failure event, timeframe 36 months
Secondary	Recommended Phase II Dose (Phase 1b)	Based on tolerability, where tolerability is evaluated through the occurrence of dose limiting toxicity (DLT).	From first patient first visit in dose finding study until appropriate dose level found, estimated 9 months
Secondary	Maximum Tolerated Dose (Phase 1b)	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.	From first patient first visit in dose finding study until appropriate dose level
Secondary	Toxicity (All chemotherapy randomisations)	Categorised and graded using Common Terminology Criteria for Adverse Events	From date of protocol defined treatment until 30 days after the administration of the last treatment
Secondary	Dose Limiting Toxicity (Phase 1b)	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	From commencement of treatment until 21 days after the start of cycle 2 (each cycle is 21 days)
Secondary	Response (Phase 1b, CT1A, CT1B)	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 assessed after course 3 (63 days) and 6 (126 days)
Secondary	Tolerability (CT3)	To determine the tolerability of the regimens.	From registration/randomisation until death/study endpoint
Secondary	Overall Survival (CT1A)	Death from any cause	From randomisation to death from any cause, assessed for 36 months
Secondary	Overall Survival (CT1B)	Death from any cause	From randomisation to death from any cause, assessed for 36 months
Secondary	Overall Survival (CT2A)	Death from any cause	From randomisation to death from any cause, assessed for 36 months
Secondary	Overall Survival (CT2B)	Death from any cause	From randomisation to death from any cause, assessed for 36 months
Secondary	Overall Survival (RT1A and RT1B)	Death from any cause	From randomisation to death from any cause, assessed for 36 months
Secondary	Overall Survival (RT1C)	Death from any cause	From RT1C randomisation to death from any cause, assessed for 36 months
Secondary	Overall Survival (RT2)	Death from any cause	From RT2 randomisation to death from any cause, as assessed for 36 months
Secondary	Overall Survival (CT3)	To evaluate the anti-tumour activity and effect on overall survival of VIRR when compared to standard therapy	Patients will be followed up for a minimum of 6 years from trial entry (or 5 years from end of relapsed trial treatment, whichever comes later). Patients will be followed up for progression and death until the end of trial definition has been met.
Secondary	Overall Survival (all patients)	Death from any cause	From randomisation/registration to death from any cause, assessed for 36 months
Secondary	Acute wound complications and post-operative complications (RT1A and RT1B)	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	Within 120 days from surgery
Secondary	Acute post-radiotherapy complications (All radiotherapy randomisations)	any grade 3 and above event according to CTCAE v 4	Within 120 days from start of radiotherapy
Secondary	Late complications (RT1A, RT1B. RT1C)	specific grade 3 and above events according to CTCAE and Clavien-Dindo scale	After 120 days from last local therapy
Secondary	Loco-regional failure-free survival (All radiotherapy randomisations)	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.	From randomisation to first local and/or regional failure event, assessed for 36 months
Secondary	Health related quality of life (RT1A and RT2) self-reported questionnaire completed by patient	will be assessed using Pediatric quality of life questionnaire (PedsQL) for the paediatric population (under 18 years). The minimum score is 0 where quality of life is completely unaffected by the intervention to 4 where quality of life is severely affected.	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
Secondary	Health related quality of life (RT1A and RT2) self-reported questionnaire completed by the patient	will be assessed using European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire 30 (EORTC QLQ-C30) for patients 18 years of age and over. The minimum score is 0 where quality of life is completely unaffected by the intervention to 4 where quality of life is severely affected.	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
Secondary	Health related quality of life (CT3) self-reported questionnaire completed by the patient	will be assessed using Pediatric quality of life questionnaire (PedsQL) for the paediatric population (under 18 years). The minimum score is 0 where quality of life is completely unaffected by the intervention to 4 where quality of life is severely affected.	3 timepoints: Each Cycle is 28 days. Timepoint 1: Day 0 of cycle 1 (prior to starting treatment), Timepoint 2 day 0 cycle 3, Timepoint 3) day 0 cycle 5
Secondary	Health related quality of life (CT3) self-reported questionnaire completed by the patient	will be assessed using European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire 30 (EORTC QLQ-C30) for patients 18 years of age and over. The minimum score is 0 where quality of life is completely unaffected by the intervention to 4 where quality of life is severely affected.	3 timepoints: Each Cycle is 28 days. Timepoint 1: Day 0 of cycle 1 (prior to starting treatment), Timepoint 2 day 0 cycle 3, Timepoint 3) day 0 cycle 5
Secondary	Acceptability and Palatability of Regorafenib (CT3)	"Acceptability and Palatability Questionnaire" To evaluate the acceptability and palatability of regorafenib formulations	1 timepoint: Day 8 of cycle 1 (Each Cycle is 28 days)
Secondary	PET Response (if participating in PET Sub-study)	assessed by PERCIST criteria and visual 'Deauville like' criteria	After three cycles of chemotherapy (each cycle is 21 days)
Secondary	Event Free Survival (all patients)	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	From date of randomisation/registration to death from any cause, assessed for 36 months
Secondary	Event Free Survival (if participating in PET Sub-study)	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	From date of randomisation/registration to death from any cause, assessed for 36 months
Secondary	Local Failure Free Survival (if participating in PET Sub-study)	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	From date of randomisation/registration to first local failure event, assessed for 36 months