FaR-RMS: An Overarching Study for Children and Adults With Frontline and Relapsed RhabdoMyoSarcoma
- Conditions
- Rhabdomyosarcoma
- Interventions
- Registration Number
- NCT04625907
- Lead Sponsor
- University of Birmingham
- Brief Summary
FaR-RMS is an over-arching study for children and adults with newly diagnosed and relapsed rhabdomyosarcoma (RMS)
- 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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 1672
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description RT1B: Radiotherapy for resectable disease: standard dose radiotherapy To receive 41.4 Gy RT1A: Post operative radiotherapy radiotherapy To be given either 41.4 Gy or 50.4 Gy following surgery RT1B: Radiotherapy for resectable disease: dose escalated radiotherapy To receive 50.4 Gy RT1C: Radiotherapy for unresectable disease: standard dose radiotherapy To receive 50.4 Gy RT2: Radiotherapy to primary tumour and involved lymph nodes radiotherapy Radiotherapy to the primary tumour and involved regional lymph nodes only RT2: Radiotherapy to all metastatic sites radiotherapy Radiotherapy given to all metastatic sites RT1A: Preoperative Radiotherapy radiotherapy To be given either 41.4 Gy or 50.4 Gy prior to surgery RT1C: Radiotherapy for unresectable disease: dose escalated radiotherapy To receive 59.4 Gy CT3: Relpased Chemotherapy - VIRT Irinotecan 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 Phase 1b Dose finding: VHR induction - IRIVA Irinotecan 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. Phase 1b Dose finding: VHR induction - IRIVA Actinomycin D 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. Phase 1b Dose finding: VHR induction - IRIVA Ifosfamide 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. Phase 1b Dose finding: VHR induction - IRIVA Vincristine 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. CT1A: VHR induction - IVADO Actinomycin D 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 CT1A: VHR induction - IVADO Doxorubicin 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 CT1A: VHR induction - IVADO Ifosfamide 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 CT1A: VHR Induction IRIVA Actinomycin D 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. CT1A: VHR Induction IRIVA Irinotecan 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. CT1A: VHR Induction IRIVA Ifosfamide 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. CT1A: VHR induction - IVADO Vincristine 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 CT1A: VHR Induction IRIVA Vincristine 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. CT1B: HR Induction IVA Ifosfamide 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. CT1B: HR Induction IVA Actinomycin D 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. CT1B: HR Induction IVA Vincristine 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. CT1B: HR Induction IRIVA Irinotecan 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. CT1B: HR Induction IRIVA Actinomycin D 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. CT1B: HR Induction IRIVA Vincristine 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. CT1B: HR Induction IRIVA Ifosfamide 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. CT2A: VHR Maintenance - VC Vinorelbine 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 CT2A: VHR Maintenance - VC Cyclophosphamide 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 CT3: Relpased Chemotherapy - VIRT Vincristine 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 CT2B: HR Maintenance - VC Vinorelbine Vinorelbine: 25 mg/m2 i.v. on days 1,8 and 15 Cyclophosphamide 25 mg/m2 orally daily for 28 days CT2B: HR Maintenance - VC Cyclophosphamide Vinorelbine: 25 mg/m2 i.v. on days 1,8 and 15 Cyclophosphamide 25 mg/m2 orally daily for 28 days CT3: Relpased Chemotherapy - VIRT Temozolomide 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 CT3: Relapsed Chemotherapy - VIRR Irinotecan 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. CT3: Relapsed Chemotherapy - VIRR Vincristine 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. CT3: Relapsed Chemotherapy - VIRR Regorafenib 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.
- Primary Outcome Measures
Name Time Method 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 neoplasmEvent 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 neoplasmEvent 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 neoplasmEvent 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 neoplasmEvent Free Survival (CT3) 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. 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)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 neoplasmLocal 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
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
- Secondary Outcome Measures
Name Time Method 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
Overall Survival (CT1A) 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
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
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
Overall Survival (CT1B) From 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) 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. To evaluate the anti-tumour activity and effect on overall survival of VIRR when compared to standard therapy
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
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.
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.
Tolerability (CT3) From registration/randomisation until death/study endpoint To determine the tolerability of the regimens.
Overall Survival (RT1A and RT1B) From randomisation to death from any cause, assessed for 36 months Death from any cause
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) self-reported questionnaire completed by the patient 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 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.
Health related quality of life (CT3) self-reported questionnaire completed by the patient 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 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.
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).
Overall Survival (CT2A) 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
Health related quality of life (RT1A and RT2) self-reported questionnaire completed by patient 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 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.
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 neoplasmOverall Survival (RT1C) From RT1C randomisation to death from any cause, assessed for 36 months Death from any cause
Acceptability and Palatability of Regorafenib (CT3) 1 timepoint: Day 8 of cycle 1 (Each Cycle is 28 days) "Acceptability and Palatability Questionnaire" To evaluate the acceptability and palatability of regorafenib formulations
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 (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
Trial Locations
- Locations (128)
University Unit of Pediatric Oncology-hematology - Children's Hospital Agia Sophia
🇬🇷Athens, Greece
Rambam Health Care Campus
🇮🇱Haifa, Israel
Hadassah University Medical Centre
🇮🇱Jerusalem, Israel
Schneider Medical Centre
🇮🇱Petah Tikva, Israel
Department of Pediatric Hematology-oncology - Aghia Sophia Children's Hospital
🇬🇷Athens, Greece
Hospital Virgen Del Rocio
🇪🇸Seville, Spain
Uppsala University Childrens Hospital
🇸🇪Uppsala, Sweden
The Queen Elizabeth Hospital
🇬🇧Birmingham, United Kingdom
Hospital Regional Universitario De Malaga
🇪🇸Malaga, Spain
Hospital De Cruces
🇪🇸Bilbao, Spain
Hospital Politecnico U La Fe
🇪🇸Valencia, Spain
Royal Aberdeen Children's Hospital
🇬🇧Aberdeen, United Kingdom
Royal Belfast Hospital for Sick Children
🇬🇧Belfast, United Kingdom
Hospital Universitario Gregorio Maranon
🇪🇸Madrid, Spain
Starship Children's Health
🇳🇿Auckland, New Zealand
Hospital Sant Joan De Deu
🇪🇸Barcelona, Spain
Inselspital Bern
🇨🇭Bern, Switzerland
Belfast City Hospital
🇬🇧Belfast, United Kingdom
Addenbrooke's Hospital
🇬🇧Cambridge, United Kingdom
Hospital Universitari Vall D'hebron
🇪🇸Barcelona, Spain
Birmingham Children's Hospital
🇬🇧Birmingham, United Kingdom
Noah's Ark Children's Hospital for Wales
🇬🇧Cardiff, United Kingdom
Hospital Universitario Miguel Servet Materno - infantil
🇪🇸Zaragoza, Spain
Christchurch Hospital
🇳🇿Christchurch, New Zealand
Universitaetsspital Zurich
🇨🇭Zurich, Switzerland
Bristol Haematology And Oncology Centre
🇬🇧Bristol, United Kingdom
Beatson West of Scotland Cancer Centre
🇬🇧Glasgow, United Kingdom
St James's University Hospital
🇬🇧Leeds, United Kingdom
Leicester Royal Infirmary
🇬🇧Leicester, United Kingdom
Royal Hospital for Children and Young People
🇬🇧Edinburgh, United Kingdom
Royal Marsden Hospital London
🇬🇧London, United Kingdom
University College London Hospital
🇬🇧London, United Kingdom
Nottingham City Hospital
🇬🇧Nottingham, United Kingdom
John Radcliffe Hospital
🇬🇧Oxford, United Kingdom
Queensland Children's Hospital
🇦🇺Brisbane, Australia
Peter Maccallum Cancer Centre
🇦🇺Melbourne, Australia
Royal Childrens Hospital Melbourne
🇦🇺Melbourne, Australia
John Hunter Children's Hospital
🇦🇺New Lambton Heights, Australia
Perth Children's Hospital
🇦🇺Perth, Australia
Sydney Children's Hospital
🇦🇺Sydney, Australia
The Childrens Hospital At Westmead
🇦🇺Sydney, Australia
Westmead Hospital
🇦🇺Westmead, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Australia
Kepler University Clinic Linz
🇦🇹Linz, Austria
St Anna Childrens Hospital
🇦🇹Vienna, Austria
Hopital Universitaire Des Enfants Reine Fabiola
🇧🇪Brussels, Belgium
Cliniques Universitaires Saint Luc
🇧🇪Bruxelles, Belgium
Uz Leuven Campus Gasthuisberg
🇧🇪Leuven, Belgium
Clinique Chc Montlegia
🇧🇪Liège, Belgium
Masaryk University Hospital Brno
🇨🇿Brno, Czechia
Aarhus University Hospital
🇩🇰Aarhus, Denmark
Centre Hospitalier Universitaire D'angers
🇫🇷Angers, France
Centre Hospitalier Regional Universitaire Besancon - Hopital Jean Minjoz
🇫🇷Besançon, France
Centre Hospitalier Universitaire De Bordeaux - Hopital Pellegrin
🇫🇷Bordeaux, France
Centre Francois Baclesse
🇫🇷Caen, France
Centre Hospitalier Regional Universitaire Brest - Hopital Morvan
🇫🇷Brest, France
Centre Hospitalier Universitaire De Caen
🇫🇷Caen, France
Centre Hospitalier Universitaire Dijon Bourgogne - Hopital D'enfants
🇫🇷Dijon, France
Centre Hospitalier Universitaire De Grenoble
🇫🇷Grenoble, France
Centre Hospitalier Universitaire La Reunion
🇫🇷La Réunion, France
Centre Oscar Lambret
🇫🇷Lille, France
Centre Leon Berard
🇫🇷Lyon, France
Hopital De La Timone (ap-hm)
🇫🇷Marseille, France
Centre Hospitalier Universitaire De Nancy
🇫🇷Nancy, France
Institut Curie
🇫🇷Paris, France
Centre Hospitalier Universitaire De Nantes
🇫🇷Nantes, France
Hopital Armand Trousseau
🇫🇷Paris, France
Centre Hospitalier Universitaire Haut Levque
🇫🇷Pessac, France
Chu De Reims
🇫🇷Reims, France
Centre Eugne Marquis De Rennes
🇫🇷Rennes, France
Centre Hospitalier Universitaire De Rennes - Hopital Pontchaillou
🇫🇷Rennes, France
Centre Hospitalier Universitaire De Rouen
🇫🇷Rouen, France
Centre Hospitalier Universitaire Saint-etienne
🇫🇷Saint-Étienne, France
Centre Hospitalier Universitaire De Toulouse - Hopital Des Enfants
🇫🇷Toulouse, France
Gustave Roussy
🇫🇷Villejuif, France
Children's General Hospital P and A Kyriakou
🇬🇷Athens, Greece
Clatterbridge Cancer Centre
🇬🇧Wirral, United Kingdom
University Hospital Rigshospitalet
🇩🇰Copenhagen, Denmark
University Hospital of Padova (azienda Ospedaliera of Padua)
🇮🇹Padova, Italy
Bristol Royal Hospital for Children
🇬🇧Bristol, United Kingdom
Velindre Hospital
🇬🇧Cardiff, United Kingdom
Royal Hospital for Children Glasgow
🇬🇧Glasgow, United Kingdom
Leeds General Infirmary
🇬🇧Leeds, United Kingdom
Alder Hey Children's Hospital
🇬🇧Liverpool, United Kingdom
Great Ormond Street Hospital for Children
🇬🇧London, United Kingdom
Royal Manchester Children's Hospital
🇬🇧Manchester, United Kingdom
Christie Hospital
🇬🇧Manchester, United Kingdom
Royal Victoria Infirmary
🇬🇧Newcastle Upon Tyne, United Kingdom
Queen's Medical Centre, Nottingham
🇬🇧Nottingham, United Kingdom
Sheffield Children's Hospital
🇬🇧Sheffield, United Kingdom
Weston Park Hospital
🇬🇧Sheffield, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
Centre Hospitalier Universitaire De Poitiers
🇫🇷Poitiers, France
Strasbourg Hautepierre
🇫🇷Strasbourg, France
Centre Hospitalier Regional Universitaire De Tours - Hopital Clocheville
🇫🇷Tours, France
Chris O'brien Lifehouse
🇦🇺Camperdown, Australia
Monash Children's Hospital
🇦🇺Clayton, Australia
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Hospital Del Nino Jesus
🇪🇸Madrid, Spain
Children's and Adolescent's Oncology Clinic, "MITERA" Children's Hospital
🇬🇷Attikí, Greece
Ippokratio General Hospital of Thessaloniki
🇬🇷Thessaloniki, Greece
Ahepa University General Hospital of Thessaloniki
🇬🇷Thessaloníki, Greece
Prinses Maxima Centrum Voor Kinderoncologie
🇳🇱Utrecht, Netherlands
Haukeland University Hospital - Paediatric
🇳🇴Bergen, Norway
Oslo University Hospital - Radiumhospitalet
🇳🇴Oslo, Norway
Hematology-oncology Children's Clinic, University General Hospital of Heraklion
🇬🇷Iraklio, Greece
Dana Children's Hospital, Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
Instituto Portugues De Oncologia De Losbona Francisco Gentil, Epe
🇵🇹Lisbon, Portugal
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
Hellenic Society of Pediatric Hematology- Oncology
🇬🇷Athens, Greece
Oslo University Hospital - Paediatrics
🇳🇴Oslo, Norway
University Hospital of North Norway - Paediatric
🇳🇴Tromso, Norway
Chaim Sheba Medical Centre
🇮🇱Tel HaShomer, Israel
Kantonsspital Aarau
🇨🇭Aarau, Switzerland
Ospedale San Giovanni
🇨🇭Bellinzona, Switzerland
Luzerner Kantonspital - Kinderspital Luzern
🇨🇭Luzern, Switzerland
Royal Marsden Hospital
🇬🇧Sutton, Surrey, United Kingdom
Centre Hospitalier Regional De La Citadelle
🇧🇪Liège, Belgium
Our Lady's Children's Hospital
🇮🇪Crumlin, Ireland
University Medical Centre Groningen
🇳🇱Groningen, Netherlands
St Olavs Hospital - Paediatric
🇳🇴Trondheim, Norway
Universitats-kinderspital Bieder Basel (UKBB)
🇨🇭Basel, Switzerland
Bratislava, National Institute for Children's Diseases
🇸🇰Bratislava, Slovakia
University Medical Centre Ljubjlana
🇸🇮Ljubljana, Slovenia
University Childrens Hospital Ljubljana
🇸🇮Ljubljana, Slovenia
Hug Hopitaux Universitaires De Geneve
🇨🇭Geneva, Switzerland
Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne
🇨🇭Lausanne, Switzerland
Ostschweizer Kinderspital
🇨🇭St Gallen, Switzerland