FaR-RMS: An Overarching Study for Children and Adults With Frontline and Relapsed RhabdoMyoSarcoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 1,672
- 试验地点
- 128
- 主要终点
- Event Free Survival (RT2)
研究概览
简要总结
FaR-RMS is an over-arching study for children and adults with newly diagnosed and relapsed rhabdomyosarcoma (RMS)
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
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.
干预措施: Irinotecan (Drug)
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.
干预措施: Actinomycin D (Drug)
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.
干预措施: Ifosfamide (Drug)
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.
干预措施: Vincristine (Drug)
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
干预措施: Actinomycin D (Drug)
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
干预措施: Doxorubicin (Drug)
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
干预措施: Ifosfamide (Drug)
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
干预措施: Vincristine (Drug)
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.
干预措施: Irinotecan (Drug)
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.
干预措施: Actinomycin D (Drug)
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.
干预措施: Ifosfamide (Drug)
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.
干预措施: Vincristine (Drug)
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.
干预措施: Actinomycin D (Drug)
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.
干预措施: Ifosfamide (Drug)
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.
干预措施: Vincristine (Drug)
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.
干预措施: Irinotecan (Drug)
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.
干预措施: Actinomycin D (Drug)
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.
干预措施: Ifosfamide (Drug)
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.
干预措施: Vincristine (Drug)
RT1A: Preoperative Radiotherapy
To be given either 41.4 Gy or 50.4 Gy prior to surgery
干预措施: radiotherapy (Radiation)
RT1A: Post operative radiotherapy
To be given either 41.4 Gy or 50.4 Gy following surgery
干预措施: radiotherapy (Radiation)
RT1B: Radiotherapy for resectable disease: dose escalated
To receive 50.4 Gy
干预措施: radiotherapy (Radiation)
RT1B: Radiotherapy for resectable disease: standard dose
To receive 41.4 Gy
干预措施: radiotherapy (Radiation)
RT1C: Radiotherapy for unresectable disease: dose escalated
To receive 59.4 Gy
干预措施: radiotherapy (Radiation)
RT1C: Radiotherapy for unresectable disease: standard dose
To receive 50.4 Gy
干预措施: radiotherapy (Radiation)
RT2: Radiotherapy to primary tumour and involved lymph nodes
Radiotherapy to the primary tumour and involved regional lymph nodes only
干预措施: radiotherapy (Radiation)
RT2: Radiotherapy to all metastatic sites
Radiotherapy given to all metastatic sites
干预措施: radiotherapy (Radiation)
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
干预措施: Vinorelbine (Drug)
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
干预措施: Cyclophosphamide (Drug)
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
干预措施: Vinorelbine (Drug)
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
干预措施: Cyclophosphamide (Drug)
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
干预措施: Irinotecan (Drug)
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
干预措施: Vincristine (Drug)
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
干预措施: Temozolomide (Drug)
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.
干预措施: Irinotecan (Drug)
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.
干预措施: Vincristine (Drug)
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.
干预措施: Regorafenib (Drug)
结局指标
主要结局
Event Free Survival (RT2)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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
次要结局
- Toxicity (All chemotherapy randomisations)(From date of protocol defined treatment until 30 days after the administration of the last treatment)
- Overall Survival (CT1A)(From randomisation to death from any cause, assessed for 36 months)
- Overall Survival (CT2B)(From randomisation to death from any cause, assessed for 36 months)
- Acute wound complications and post-operative complications (RT1A and RT1B)(Within 120 days from surgery)
- Acute post-radiotherapy complications (All radiotherapy randomisations)(Within 120 days from start of radiotherapy)
- Local Failure Free Survival (if participating in PET Sub-study)(From date of randomisation/registration to first local failure event, assessed for 36 months)
- Overall Survival (CT1B)(From randomisation to death from any cause, assessed for 36 months)
- Overall Survival (RT2)(From RT2 randomisation to death from any cause, as assessed for 36 months)
- 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.)
- Late complications (RT1A, RT1B. RT1C)(After 120 days from last local therapy)
- Maximum Tolerated Dose (Phase 1b)(From first patient first visit in dose finding study until appropriate dose level)
- Dose Limiting Toxicity (Phase 1b)(From commencement of treatment until 21 days after the start of cycle 2 (each cycle is 21 days))
- Response (Phase 1b, CT1A, CT1B)(Response assessed after course 3 (63 days) and 6 (126 days))
- Tolerability (CT3)(From registration/randomisation until death/study endpoint)
- Overall Survival (RT1A and RT1B)(From randomisation to death from any cause, assessed for 36 months)
- Loco-regional failure-free survival (All radiotherapy randomisations)(From randomisation to first local and/or regional failure event, assessed for 36 months)
- 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)
- 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)
- Recommended Phase II Dose (Phase 1b)(From first patient first visit in dose finding study until appropriate dose level found, estimated 9 months)
- Overall Survival (CT2A)(From randomisation to death from any cause, assessed for 36 months)
- Overall Survival (all patients)(From randomisation/registration to death from any cause, assessed for 36 months)
- 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)
- Event Free Survival (all patients)(From date of randomisation/registration to death from any cause, assessed for 36 months)
- Overall Survival (RT1C)(From RT1C randomisation to death from any cause, assessed for 36 months)
- Acceptability and Palatability of Regorafenib (CT3)(1 timepoint: Day 8 of cycle 1 (Each Cycle is 28 days))
- PET Response (if participating in PET Sub-study)(After three cycles of chemotherapy (each cycle is 21 days))
- Event Free Survival (if participating in PET Sub-study)(From date of randomisation/registration to death from any cause, assessed for 36 months)