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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04625907
Recruitment Status : Recruiting
First Posted : November 12, 2020
Last Update Posted : May 10, 2023
Sponsor:
Information provided by (Responsible Party):
University of Birmingham

Study Description
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Brief Summary:
FaR-RMS is an over-arching study for children and adults with newly diagnosed and relapsed rhabdomyosarcoma (RMS)

Condition or disease Intervention/treatment Phase
Rhabdomyosarcoma Drug: Irinotecan Drug: Actinomycin D Drug: Doxorubicin Drug: Ifosfamide Drug: Vincristine Drug: Vinorelbine Drug: Cyclophosphamide Drug: Temozolomide Radiation: radiotherapy Drug: Regorafenib Phase 1 Phase 2

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 Design
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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1672 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: FaR-RMS: An Overarching Study for Children and Adults With Frontline and Relapsed RhabdoMyoSarcoma
Actual Study Start Date : September 17, 2020
Estimated Primary Completion Date : June 2030
Estimated Study Completion Date : June 2030

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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
antineoplastic enzyme inhibitor

Drug: Actinomycin D
Antineoplastic agent that is a polypeptide antibiotic
Other Name: Dactinomycin

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

Drug: Vincristine
anti neoplastic vinca alkaloid agent
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
Antineoplastic agent that is a polypeptide antibiotic
Other Name: Dactinomycin

Drug: Doxorubicin
An anthracycline topoisomerase inhibitor isolated from streptpmyces peucetius var. casesius

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

Drug: Vincristine
anti neoplastic vinca alkaloid agent
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
antineoplastic enzyme inhibitor

Drug: Actinomycin D
Antineoplastic agent that is a polypeptide antibiotic
Other Name: Dactinomycin

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

Drug: Vincristine
anti neoplastic vinca alkaloid agent
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
Antineoplastic agent that is a polypeptide antibiotic
Other Name: Dactinomycin

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

Drug: Vincristine
anti neoplastic vinca alkaloid agent
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
antineoplastic enzyme inhibitor

Drug: Actinomycin D
Antineoplastic agent that is a polypeptide antibiotic
Other Name: Dactinomycin

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

Drug: Vincristine
anti neoplastic vinca alkaloid agent
Experimental: RT1A: Preoperative Radiotherapy
To be given either 41.4 Gy or 50.4 Gy prior to surgery
 Radiation: radiotherapy
Ionising radiation
Active Comparator: RT1A: Post operative radiotherapy
To be given either 41.4 Gy or 50.4 Gy following surgery
 Radiation: radiotherapy
Ionising radiation
Experimental: RT1B: Radiotherapy for resectable disease: dose escalated
To receive 50.4 Gy
 Radiation: radiotherapy
Ionising radiation
Active Comparator: RT1B: Radiotherapy for resectable disease: standard dose
To receive 41.4 Gy
 Radiation: radiotherapy
Ionising radiation
Experimental: RT1C: Radiotherapy for unresectable disease: dose escalated
To receive 59.4 Gy
 Radiation: radiotherapy
Ionising radiation
Active Comparator: RT1C: Radiotherapy for unresectable disease: standard dose
To receive 50.4 Gy
 Radiation: radiotherapy
Ionising radiation
Experimental: RT2: Radiotherapy to primary tumour and involved lymph nodes
Radiotherapy to the primary tumour and involved regional lymph nodes only
 Radiation: radiotherapy
Ionising radiation
Experimental: RT2: Radiotherapy to all metastatic sites
Radiotherapy given to all metastatic sites
 Radiation: radiotherapy
Ionising radiation
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
vinca alkaloid with a role as an antineoplastic agent

Drug: Cyclophosphamide
Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent
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
vinca alkaloid with a role as an antineoplastic agent

Drug: Cyclophosphamide
Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent
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
antineoplastic enzyme inhibitor

Drug: Vincristine
anti neoplastic vinca alkaloid agent

Drug: Temozolomide
oral antineoplastic alkylating agent
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
antineoplastic enzyme inhibitor

Drug: Vincristine
anti neoplastic vinca alkaloid agent

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


Outcome Measures
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Primary Outcome Measures :
  1. Event Free Survival (RT2) [ Time Frame: 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

  2. Event Free Survival (CT1A) [ Time Frame: 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

  3. Event Free Survival (CT1B) [ Time Frame: 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

  4. Event Free Survival (CT2A) [ Time Frame: 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

  5. Event Free Survival (CT2B) [ Time Frame: 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

  6. Event Free Survival (CT3) [ 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. ]

    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)


  7. Local Failure Free Survival (RT1A and RT1B) [ Time Frame: 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

  8. Local Failure Free Survival (RT1C) [ Time Frame: 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 :
  1. Recommended Phase II Dose (Phase 1b) [ Time Frame: 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).

  2. Maximum Tolerated Dose (Phase 1b) [ Time Frame: 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.

  3. Toxicity (All chemotherapy randomisations) [ Time Frame: 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

  4. Dose Limiting Toxicity (Phase 1b) [ Time Frame: 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

  5. Response (Phase 1b, CT1A, CT1B) [ Time Frame: 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.

  6. Tolerability (CT3) [ Time Frame: From registration/randomisation until death/study endpoint ]
    To determine the tolerability of the regimens.

  7. Overall Survival (CT1A) [ Time Frame: From randomisation to death from any cause, assessed for 36 months ]
    Death from any cause

  8. Overall Survival (CT1B) [ Time Frame: From randomisation to death from any cause, assessed for 36 months ]
    Death from any cause

  9. Overall Survival (CT2A) [ Time Frame: From randomisation to death from any cause, assessed for 36 months ]
    Death from any cause

  10. Overall Survival (CT2B) [ Time Frame: From randomisation to death from any cause, assessed for 36 months ]
    Death from any cause

  11. Overall Survival (RT1A and RT1B) [ Time Frame: From randomisation to death from any cause, assessed for 36 months ]
    Death from any cause

  12. Overall Survival (RT1C) [ Time Frame: From RT1C randomisation to death from any cause, assessed for 36 months ]
    Death from any cause

  13. Overall Survival (RT2) [ Time Frame: From RT2 randomisation to death from any cause, as assessed for 36 months ]
    Death from any cause

  14. Overall Survival (CT3) [ 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. ]
    To evaluate the anti-tumour activity and effect on overall survival of VIRR when compared to standard therapy

  15. Overall Survival (all patients) [ Time Frame: From randomisation/registration to death from any cause, assessed for 36 months ]
    Death from any cause

  16. Acute wound complications and post-operative complications (RT1A and RT1B) [ Time Frame: 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

  17. Acute post-radiotherapy complications (All radiotherapy randomisations) [ Time Frame: Within 120 days from start of radiotherapy ]
    any grade 3 and above event according to CTCAE v 4

  18. Late complications (RT1A, RT1B. RT1C) [ Time Frame: After 120 days from last local therapy ]
    specific grade 3 and above events according to CTCAE and Clavien-Dindo scale

  19. Loco-regional failure-free survival (All radiotherapy randomisations) [ Time Frame: 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.

  20. Health related quality of life (RT1A and RT2) self-reported questionnaire completed by patient [ 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 ]
    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.

  21. Health related quality of life (RT1A and RT2) self-reported questionnaire completed by the patient [ 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 ]
    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.

  22. Health related quality of life (CT3) self-reported questionnaire completed by the patient [ 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 ]
    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.

  23. Health related quality of life (CT3) self-reported questionnaire completed by the patient [ 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 ]
    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.

  24. Acceptability and Palatability of Regorafenib (CT3) [ Time Frame: 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

  25. PET Response (if participating in PET Sub-study) [ Time Frame: After three cycles of chemotherapy (each cycle is 21 days) ]
    assessed by PERCIST criteria and visual 'Deauville like' criteria

  26. Event Free Survival (all patients) [ Time Frame: 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

  27. Event Free Survival (if participating in PET Sub-study) [ Time Frame: 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

  28. Local Failure Free Survival (if participating in PET Sub-study) [ Time Frame: 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


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04625907


Contacts
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Contact: Bridget Shaw 0121 414 2996 farrms@trials.bham.ac.uk
Contact: Emma Gray 0121 414 3799 farrms@trials.bham.ac.uk

Locations
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Sponsors and Collaborators
University of Birmingham
Investigators
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Principal Investigator: Meriel Jenney Chief Investigator
More Information
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
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Responsible Party: University of Birmingham
ClinicalTrials.gov Identifier: NCT04625907    
Other Study ID Numbers: RG_17-247
2018-000515-24 ( EudraCT Number )
45535982 ( Registry Identifier: ISRCTN )
First Posted: November 12, 2020    Key Record Dates
Last Update Posted: May 10, 2023
Last Verified: May 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Rhabdomyosarcoma
Myosarcoma
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Sarcoma
Dactinomycin
Cyclophosphamide
Temozolomide
Ifosfamide
Doxorubicin
Irinotecan
Vincristine
Vinorelbine
 Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Topoisomerase I Inhibitors
Antineoplastic Agents, Phytogenic