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RecruitingNCT04625907FaR-RMSUpdated May 23, 2024

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

A Phase 1/2 interventional study of Irinotecan and Actinomycin D in Rhabdomyosarcoma, sponsored by University of Birmingham. Recruiting at 128 sites in 20 countries. Per ClinicalTrials.gov, last updated 2024-05-23.

Sponsored by University of Birmingham · Phase 1/2, Interventional, and Treatment

From the registry’s dates

  • Started Sep 2020; still recruiting 6 years later.
Phase
Phase 1/2
Study type
Interventional
Enrollment
1,672
Allocation
Randomized
Sex
All
01

Study summary

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

Read the 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.

02

Conditions studied

  • Rhabdomyosarcoma

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03

In context

Rhabdomyosarcoma

238 studies on the registry are indexed under Rhabdomyosarcoma; 47 are open to participants now.

This study's planned enrollment of 1,672 is above the median of 40 across 191 interventional studies indexed under Rhabdomyosarcoma.

Browse Rhabdomyosarcoma studies →

Lead sponsor

University of Birmingham is the lead sponsor of 179 studies on the registry; 30 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
Child (0–17), Adult (18–64), Older adult (65+)
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

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
05

Study design

Phase
Phase 1 / Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
1,672 participants (estimated)

Study arms

  • 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 As per local practice: recommended as a short infusion (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 · Drug: Actinomycin D · Drug: Ifosfamide · Drug: Vincristine

  • 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 per local practice: recommended as a short infusion (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 · Drug: Doxorubicin · Drug: Ifosfamide · Drug: Vincristine

  • 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 per local practice: recommended as a short infusion (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 · Drug: Actinomycin D · Drug: Ifosfamide · Drug: Vincristine

  • 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 per local practice: recommended as a short infusion (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 · Drug: Ifosfamide · Drug: Vincristine

  • 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 per local practice: recommended as a short infusion (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 · Drug: Actinomycin D · Drug: Ifosfamide · Drug: Vincristine

  • Experimental
    RT1A: Preoperative Radiotherapy

    To be given either 41.4 Gy or 50.4 Gy prior to surgery

    Radiation: radiotherapy

  • Active comparator
    RT1A: Post operative radiotherapy

    To be given either 41.4 Gy or 50.4 Gy following surgery

    Radiation: radiotherapy

  • Experimental
    RT1B: Radiotherapy for resectable disease: dose escalated

    To receive 50.4 Gy

    Radiation: radiotherapy

  • Active comparator
    RT1B: Radiotherapy for resectable disease: standard dose

    To receive 41.4 Gy

    Radiation: radiotherapy

  • Experimental
    RT1C: Radiotherapy for unresectable disease: dose escalated

    To receive 59.4 Gy

    Radiation: radiotherapy

  • Active comparator
    RT1C: Radiotherapy for unresectable disease: standard dose

    To receive 50.4 Gy

    Radiation: radiotherapy

  • Experimental
    RT2: Radiotherapy to primary tumour and involved lymph nodes

    Radiotherapy to the primary tumour and involved regional lymph nodes only

    Radiation: radiotherapy

  • Experimental
    RT2: Radiotherapy to all metastatic sites

    Radiotherapy given to all metastatic sites

    Radiation: radiotherapy

  • 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 · Drug: Cyclophosphamide

  • 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 · Drug: Cyclophosphamide

  • No intervention
    CT2B: HR Maintenance - Stop Treatment

    To stop treatment at the point of randomisation

  • Active comparator
    CT3: Relpased Chemotherapy - VIRT

    Vincristine: 1.5 mg/m2 As per local practice: recommended as a short infusion (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 (Escalate to 150mg/m2/day in Cycle 2 if no toxicity \> grade 3) as an oral tablets prior to vincristine and irinotecan on days 1-5

    Drug: Irinotecan · Drug: Vincristine · Drug: Temozolomide

  • Experimental
    CT3: Relapsed Chemotherapy - VIRR

    Vincristine: 1.5 mg/m2 As per local practice: recommended as a short infusion (maximum dose 2mg) on days 1 and 8 Irinotecan: 50 mg/m2 as an i.v. infusion over 1 hour on days 1-5 Regorafenib: Children between 6 and 24 months = 65 mg/m2, children less than 12 and/or less than 40kg dose = 82 mg/m2 Maximum 120 mg, Fixed dose of 120 mg for patients over 12 years of age AND ≥ 40 kg, as an oral tablets on days 8 to 21.

    Drug: Irinotecan · Drug: Vincristine · Drug: Regorafenib

Interventions

  • DrugIrinotecan

    antineoplastic enzyme inhibitor

  • DrugActinomycin D

    Antineoplastic agent that is a polypeptide antibiotic

    Also known as: Dactinomycin

  • DrugDoxorubicin

    An anthracycline topoisomerase inhibitor isolated from streptpmyces peucetius var. casesius

  • DrugIfosfamide

    chemotherapeutic agent chemically related to the nitrogen mustards and is a synthetic analog of cyclophosphamide

  • DrugVincristine

    anti neoplastic vinca alkaloid agent

  • DrugVinorelbine

    vinca alkaloid with a role as an antineoplastic agent

  • DrugCyclophosphamide

    Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent

  • DrugTemozolomide

    oral antineoplastic alkylating agent

  • Radiationradiotherapy

    Ionising radiation

  • DrugRegorafenib

    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).

06

What researchers measure

Primary outcomes

  1. 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

    Time frame: From randomisation to first failure event, timeframe 36 months

  2. 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

    Time frame: From randomisation to first failure event, timeframe 36 months

  3. 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

    Time frame: From randomisation to first failure event, timeframe 36 months

  4. 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

    Time frame: From randomisation to first failure event, timeframe 36 months

  5. 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 frame: Time from randomisation to first failure event, timeframe 36 months

  6. 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)

    Time frame: 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.

  7. 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 frame: Time from randomisation to first local failure event, timeframe 36 months

  8. 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 frame: Time from randomisation to first local failure event, timeframe 36 months

Secondary outcomes

  1. Recommended Phase II Dose (Phase 1b)

    Based on tolerability, where tolerability is evaluated through the occurrence of dose limiting toxicity (DLT).

    Time frame: From first patient first visit in dose finding study until appropriate dose level found, estimated 9 months

  2. 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.

    Time frame: From first patient first visit in dose finding study until appropriate dose level

  3. Toxicity (All chemotherapy randomisations)

    Categorised and graded using Common Terminology Criteria for Adverse Events

    Time frame: From date of protocol defined treatment until 30 days after the administration of the last treatment

  4. 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

    Time frame: From commencement of treatment until 21 days after the start of cycle 2 (each cycle is 21 days)

  5. 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.

    Time frame: Response assessed after course 3 (63 days) and 6 (126 days)

  6. Tolerability (CT3)

    To determine the tolerability of the regimens.

    Time frame: From registration/randomisation until death/study endpoint

  7. Overall Survival (CT1A)

    Death from any cause

    Time frame: From randomisation to death from any cause, assessed for 36 months

  8. Overall Survival (CT1B)

    Death from any cause

    Time frame: From randomisation to death from any cause, assessed for 36 months

  9. Overall Survival (CT2A)

    Death from any cause

    Time frame: From randomisation to death from any cause, assessed for 36 months

  10. Overall Survival (CT2B)

    Death from any cause

    Time frame: From randomisation to death from any cause, assessed for 36 months

  11. Overall Survival (RT1A and RT1B)

    Death from any cause

    Time frame: From randomisation to death from any cause, assessed for 36 months

  12. Overall Survival (RT1C)

    Death from any cause

    Time frame: From RT1C randomisation to death from any cause, assessed for 36 months

  13. Overall Survival (RT2)

    Death from any cause

    Time frame: From RT2 randomisation to death from any cause, as assessed for 36 months

  14. Overall Survival (CT3)

    To evaluate the anti-tumour activity and effect on overall survival of VIRR when compared to standard therapy

    Time frame: 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.

  15. Overall Survival (all patients)

    Death from any cause

    Time frame: From randomisation/registration to death from any cause, assessed for 36 months

  16. 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

    Time frame: Within 120 days from surgery

  17. Acute post-radiotherapy complications (All radiotherapy randomisations)

    any grade 3 and above event according to CTCAE v 4

    Time frame: Within 120 days from start of radiotherapy

  18. Late complications (RT1A, RT1B. RT1C)

    specific grade 3 and above events according to CTCAE and Clavien-Dindo scale

    Time frame: After 120 days from last local therapy

  19. 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.

    Time frame: From randomisation to first local and/or regional failure event, assessed for 36 months

  20. 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.

    Time frame: 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

  21. 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.

    Time frame: 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

  22. 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.

    Time frame: 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

  23. 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.

    Time frame: 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

  24. Acceptability and Palatability of Regorafenib (CT3)

    "Acceptability and Palatability Questionnaire" To evaluate the acceptability and palatability of regorafenib formulations

    Time frame: 1 timepoint: Day 8 of cycle 1 (Each Cycle is 28 days)

  25. PET Response (if participating in PET Sub-study)

    assessed by PERCIST criteria and visual 'Deauville like' criteria

    Time frame: After three cycles of chemotherapy (each cycle is 21 days)

  26. 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

    Time frame: From date of randomisation/registration to death from any cause, assessed for 36 months

  27. 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

    Time frame: From date of randomisation/registration to death from any cause, assessed for 36 months

  28. 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

    Time frame: From date of randomisation/registration to first local failure event, assessed for 36 months

07

Study locations

120 of 128 sites recruiting
  • Queensland Children's Hospital
    Brisbane, 4101, Australia
    • R Walker · Contact
    Recruiting
  • Chris O'brien Lifehouse
    Camperdown, Australia
    • Angela Hong · Contact
    Recruiting
  • Monash Children's Hospital
    Clayton, Australia
    • Paul Wood · Contact
    Recruiting
  • Peter Maccallum Cancer Centre
    Melbourne, Australia
    • Jeremy Lewin · Contact
    Recruiting
  • Royal Childrens Hospital Melbourne
    Melbourne, Australia
    • Marty Campbell · Contact
    Recruiting
  • John Hunter Children's Hospital
    New Lambton Heights, 2310, Australia
    • E Hesketh · Contact
    Recruiting
  • Perth Children's Hospital
    Perth, Australia
    • Marianne Phillips · Contact
    Recruiting
  • Sydney Children's Hospital
    Sydney, Australia
    • Timothy Trahair · Contact
    Recruiting
  • The Childrens Hospital At Westmead
    Sydney, Australia
    • Jessica Ryan · Contact
    Recruiting
  • Westmead Hospital
    Westmead, Australia
    • Jennifer Chard · Contact
    Recruiting
  • Princess Alexandra Hospital
    Woolloongabba, Australia
    • Rick Walker · Contact
    Recruiting
  • Kepler University Clinic Linz
    Linz, Austria
    • B Aistleitner · Contact
    • B Aistleitner · Principal investigator
    Recruiting
  • St Anna Childrens Hospital
    Vienna, Austria
    • Ruth Ladenstein · Contact
    Recruiting
  • Hopital Universitaire Des Enfants Reine Fabiola
    Brussels, Belgium
    • Christine Devalck · Contact
    Recruiting
  • Cliniques Universitaires Saint Luc
    Bruxelles, Belgium
    • B Brichard · Contact
    Recruiting
  • Universitair Ziekenhuis Gent
    Gent, Belgium
    • C Dhooge · Contact
    Recruiting
  • Uz Leuven Campus Gasthuisberg
    Leuven, Belgium
    • M Renard · Contact
    Recruiting
  • Centre Hospitalier Regional De La Citadelle
    Liège, Belgium
    • S Gatineau-Sailliant · Contact
    Recruiting
  • Clinique Chc Montlegia
    Liège, Belgium
    • L Roufiange · Contact
    Recruiting
  • Masaryk University Hospital Brno
    Brno, 625 00, Czechia
    • Peter Mudry · Contact
    Recruiting
  • Aarhus University Hospital
    Aarhus, Denmark
    • Pernille Wendtland · Contact
    Recruiting
  • University Hospital Rigshospitalet
    Copenhagen, Denmark
    • Lisa Hjalgrim · Contact
    Recruiting
  • Centre Hospitalier Universitaire D'angers
    Angers, France
    • S Proust · Contact
    Recruiting
  • Centre Hospitalier Regional Universitaire Besancon - Hopital Jean Minjoz
    Besançon, France
    • S Klein · Contact
    Recruiting
  • Centre Hospitalier Universitaire De Bordeaux - Hopital Pellegrin
    Bordeaux, France
    • C Verite · Contact
    Recruiting
  • Centre Hospitalier Regional Universitaire Brest - Hopital Morvan
    Brest, France
    • L Carausu · Contact
    Recruiting
  • Centre Francois Baclesse
    Caen, France
    • F Missohou · Contact
    Recruiting
  • Centre Hospitalier Universitaire De Caen
    Caen, France
    • D Bodet · Contact
    Recruiting
  • Centre Hospitalier Universitaire Dijon Bourgogne - Hopital D'enfants
    Dijon, France
    • C Briandet · Contact
    Recruiting
  • Centre Hospitalier Universitaire De Grenoble
    Grenoble, France
    • D Plantaz · Contact
    Recruiting
  • Centre Hospitalier Universitaire La Reunion
    La Réunion, France
    • Y Reguerre · Contact
    Recruiting
  • Centre Oscar Lambret
    Lille, France
    • A Defachelles · Contact
    Recruiting
  • Centre Leon Berard
    Lyon, France
    • N Corradini · Contact
    Recruiting
  • Hopital De La Timone (ap-hm)
    Marseille, France
    • A Rome · Contact
    Recruiting
  • Centre Hospitalier Universitaire De Nancy
    Nancy, France
    • L Mansuy · Contact
    Recruiting
  • Centre Hospitalier Universitaire De Nantes
    Nantes, France
    • M Cleirec · Contact
    Recruiting
  • Hopital Armand Trousseau
    Paris, France
    • H Boutroux · Contact
    Recruiting
  • Institut Curie
    Paris, France
    • D Orbach · Contact
    Recruiting
  • Centre Hospitalier Universitaire Haut Levque
    Pessac, France
    • A Huchet · Contact
    Recruiting
  • Centre Hospitalier Universitaire De Poitiers
    Poitiers, France
    • F Millot · Contact
    Recruiting
  • Chu De Reims
    Reims, France
    • C Pluchart · Contact
    Recruiting
  • Centre Eugne Marquis De Rennes
    Rennes, France
    • J Leseur · Contact
    Recruiting
  • Centre Hospitalier Universitaire De Rennes - Hopital Pontchaillou
    Rennes, France
    • S Taque · Contact
    Recruiting
  • Centre Hospitalier Universitaire De Rouen
    Rouen, France
    • A Marie Cardine · Contact
    Recruiting
  • Centre Hospitalier Universitaire Saint-etienne
    Saint-Étienne, France
    • C Berger · Contact
    Recruiting
  • Strasbourg Hautepierre
    Strasbourg, France
    • S Jannier · Contact
    Recruiting
  • Centre Hospitalier Universitaire De Toulouse - Hopital Des Enfants
    Toulouse, France
    • MP Castex · Contact
    Recruiting
  • Centre Hospitalier Regional Universitaire De Tours - Hopital Clocheville
    Tours, France
    • J Serre · Contact
    Recruiting
  • Gustave Roussy
    Villejuif, 94805, France
    • Veronique Minard-Colin · Contact
    Recruiting
  • Children's General Hospital P and A Kyriakou
    Athens, 115 27, Greece
    • Marina Servitzoglou · Contact
    Recruiting
  • Department of Pediatric Hematology-oncology - Aghia Sophia Children's Hospital
    Athens, Greece
    • Vasiliki Tzotzola · Contact
    Recruiting
  • Hellenic Society of Pediatric Hematology- Oncology
    Athens, Greece
    • Apostolos Pourtsidis · Contact
    Recruiting
  • University Unit of Pediatric Oncology-hematology - Children's Hospital Agia Sophia
    Athens, Greece
    • Antonis Kattamis · Contact
    Recruiting
  • Children's and Adolescent's Oncology Clinic, "MITERA" Children's Hospital
    Attikí, 151 23, Greece
    • Apostolos Pourtsidis · Contact
    Recruiting
  • Hematology-oncology Children's Clinic, University General Hospital of Heraklion
    Iraklio, 715 00, Greece
    • Nikolaos Katzilakis · Contact
    Recruiting
  • Ippokratio General Hospital of Thessaloniki
    Thessaloniki, Greece
    • Evgenia Papakonstantinou · Contact
    Recruiting
  • Ahepa University General Hospital of Thessaloniki
    Thessaloníki, Greece
    • Emmanouil Chatzipantelis · Contact
    Recruiting
  • Our Lady's Children's Hospital
    Crumlin, Ireland
    • Cormac Owens · Contact
    Not yet recruiting
  • Rambam Health Care Campus
    Haifa, Israel
    • Shifra Ash · Contact
    Recruiting
  • Hadassah University Medical Centre
    Jerusalem, Israel
    • Dror Raviv · Contact
    Recruiting
  • Schneider Medical Centre
    Petah Tikva, Israel
    • Shira Amar · Contact
    Recruiting
  • Dana Children's Hospital, Tel Aviv Sourasky Medical Center
    Tel Aviv, Israel
    • Dror Levin · Contact
    Recruiting
  • Chaim Sheba Medical Centre
    Tel HaShomer, Israel
    • Iris Kvenstel · Contact
    Recruiting
  • University Hospital of Padova (azienda Ospedaliera of Padua)
    Padova, Italy
    • Gianni Bisogno · Contact
    Not yet recruiting
  • University Medical Centre Groningen
    Groningen, Netherlands
    • Wim Tissing · Contact
    Recruiting
  • Prinses Maxima Centrum Voor Kinderoncologie
    Utrecht, Netherlands
    • Hans Merks · Contact
    Recruiting
  • Starship Children's Health
    Auckland, New Zealand
    • Mandy De Silva · Contact
    Recruiting
  • Christchurch Hospital
    Christchurch, New Zealand
    • Tristan Pettitt · Contact
    Recruiting
  • Haukeland University Hospital - Paediatric
    Bergen, Norway
    • Ingrid Kristin Torsvik · Contact
    Recruiting
  • Oslo University Hospital - Paediatrics
    Oslo, Norway
    • Heidi Glosli · Contact
    Recruiting
  • Oslo University Hospital - Radiumhospitalet
    Oslo, Norway
    • Kjetil Boye · Contact
    Recruiting
  • University Hospital of North Norway - Paediatric
    Tromso, Norway
    • Tove Anita Nystad · Contact
    Recruiting
  • St Olavs Hospital - Paediatric
    Trondheim, Norway
    • Bendik Lund · Contact
    Recruiting
  • Instituto Portugues De Oncologia De Losbona Francisco Gentil, Epe
    Lisbon, Portugal
    • Cristina Mendes · Contact
    Not yet recruiting
  • Bratislava, National Institute for Children's Diseases
    Bratislava, Slovakia
    • Martina Mileskova · Contact
    Not yet recruiting
  • University Childrens Hospital Ljubljana
    Ljubljana, Slovenia
    • Maja Cesen Mazic · Contact
    Recruiting
  • University Medical Centre Ljubjlana
    Ljubljana, Slovenia
    • Cesen Mazic · Contact
    Recruiting
  • Hospital Sant Joan De Deu
    Barcelona, Spain
    • Moira Garraus Oneca · Contact
    Recruiting
  • Hospital Universitari Vall D'hebron
    Barcelona, Spain
    • Raquel Hladun Alvaro · Contact
    Recruiting
  • Hospital De Cruces
    Bilbao, 48903, Spain
    • Ricardo Lopez Almaraz · Contact
    Recruiting
  • Hospital Del Nino Jesus
    Madrid, 28009, Spain
    • David Ruano · Contact
    Recruiting
  • Hospital Universitario Gregorio Maranon
    Madrid, 28009, Spain
    • Cristina Mata · Contact
    Recruiting
  • Hospital Universitario La Paz
    Madrid, Spain
    • Pedro Rubio · Contact
    Recruiting
  • Hospital Regional Universitario De Malaga
    Malaga, Spain
    • Guiomar Gutierrez Schiaffino · Contact
    Recruiting
  • Hospital Virgen Del Rocio
    Seville, Spain
    • Gema Ramirez Villar · Contact
    Recruiting
  • Hospital Politecnico U La Fe
    Valencia, 46026, Spain
    • Antonio Juan Ribelles · Contact
    Recruiting
  • Hospital Universitario Miguel Servet Materno - infantil
    Zaragoza, Spain
    • Ascensión Muñoz · Contact
    Recruiting
  • Uppsala University Childrens Hospital
    Uppsala, Sweden
    • G Ljungman · Contact
    Recruiting
  • Kantonsspital Aarau
    Aarau, Switzerland
    • Andreas Klein-Franke · Contact
    Recruiting
  • Universitats-kinderspital Bieder Basel (UKBB)
    Basel, Switzerland
    • Nicolas von der Weld · Contact
    Recruiting
  • Ospedale San Giovanni
    Bellinzona, Switzerland
    • Pierluigi Brazzola · Contact
    Recruiting
  • Inselspital Bern
    Bern, Switzerland
    • Jochen Roessler · Contact
    Recruiting
  • Hug Hopitaux Universitaires De Geneve
    Geneva, Switzerland
    • Andre Von Buren · Contact
    Recruiting
  • Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne
    Lausanne, Switzerland
    • Manuel Diezi · Contact
    Recruiting
  • Luzerner Kantonspital - Kinderspital Luzern
    Luzern, Switzerland
    • Freimut Schilling · Contact
    Recruiting
  • Ostschweizer Kinderspital
    St Gallen, Switzerland
    • Jeanette Greiner · Contact
    Recruiting
  • Universitaetsspital Zurich
    Zurich, Switzerland
    • Willemijn Breunis · Contact
    Recruiting
  • Royal Marsden Hospital
    Sutton, Surrey SM2 5PT, United Kingdom
    • Julia Chisholm · Contact · 020 8642 6011
    Recruiting
  • Royal Aberdeen Children's Hospital
    Aberdeen, United Kingdom
    • Hugh Bishop · Contact
    Recruiting
  • Belfast City Hospital
    Belfast, United Kingdom
    • Robert Johnston · Contact
    Not yet recruiting

Showing the first 100 of 128 sites across 20 countries.

08

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on May 23, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
09

Registry details

Key details

Study ID
NCT04625907
Lead sponsor
University of Birmingham
Responsible party
Sponsor
First posted
Nov 12, 2020
Start date
Sep 17, 2020
Primary completion
Jun 2030 (estimated)
Completion
Jun 2030 (estimated)
Last update
May 23, 2024

Study contacts

Bridget Shaw
Contact
farrms@trials.bham.ac.uk
0121 414 2996
Emma Gray
Contact
farrms@trials.bham.ac.uk
0121 414 3799
Meriel Jenney
principal investigator · Chief Investigator

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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