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

Phase 1

Recruiting

• Conditions: Rhabdomyosarcoma
• Interventions: Radiation: radiotherapy; Drug: Irinotecan; Drug: Vinorelbine; Drug: Actinomycin D; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Ifosfamide; Drug: Temozolomide; Drug: Regorafenib; Drug: Vincristine

• 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.

Study Timeline

• Study First Submitted: 2019-11-22
• Study Start: 2020-09-17
• Study First Submitted QC: 2020-11-10
• Study First Posted: 2020-11-12
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-22
• Last Update Posted: 2024-05-23
• Primary Completion: 2030-06
• Study Completion: 2030-06

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1672

Inclusion Criteria

Not provided

Exclusion Criteria

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

Queensland Children's Hospital; 🇦🇺 Brisbane, 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

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

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