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

Overview

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.

Interventions

• Drug Irinotecan
  antineoplastic enzyme inhibitor
• Drug Actinomycin D
  Antineoplastic agent that is a polypeptide antibiotic
• 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
• Drug Vinorelbine
  vinca alkaloid with a role as an antineoplastic agent
• Drug Cyclophosphamide
  Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent
• Drug Temozolomide
  oral antineoplastic alkylating agent
• Radiation radiotherapy
  Ionising radiation
• 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).

Primary outcome measures

• Event Free Survival (RT2) [Time frame: From randomisation to first failure event, timeframe 36 months]
• Event Free Survival (CT1A) [Time frame: From randomisation to first failure event, timeframe 36 months]
• Event Free Survival (CT1B) [Time frame: From randomisation to first failure event, timeframe 36 months]
• Event Free Survival (CT2A) [Time frame: From randomisation to first failure event, timeframe 36 months]
• Event Free Survival (CT2B) [Time frame: Time from randomisation to first failure event, timeframe 36 months]
• 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.]
• Local Failure Free Survival (RT1A and RT1B) [Time frame: Time from randomisation to first local failure event, timeframe 36 months]
• Local Failure Free Survival (RT1C) [Time frame: Time from randomisation to first local failure event, timeframe 36 months]

Secondary outcome measures (12)

• 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]
• Maximum Tolerated Dose (Phase 1b) [Time frame: From first patient first visit in dose finding study until appropriate dose level]
• Toxicity (All chemotherapy randomisations) [Time frame: From date of protocol defined treatment until 30 days after the administration of the last treatment]
• 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)]
• Response (Phase 1b, CT1A, CT1B) [Time frame: Response assessed after course 3 (63 days) and 6 (126 days)]
• Tolerability (CT3) [Time frame: From registration/randomisation until death/study endpoint]
• Overall Survival (CT1A) [Time frame: From randomisation to death from any cause, assessed for 36 months]
• Overall Survival (CT1B) [Time frame: From randomisation to death from any cause, assessed for 36 months]
• Overall Survival (CT2A) [Time frame: From randomisation to death from any cause, assessed for 36 months]
• Overall Survival (CT2B) [Time frame: From randomisation to death from any cause, assessed for 36 months]
• Overall Survival (RT1A and RT1B) [Time frame: From randomisation to death from any cause, assessed for 36 months]
• Overall Survival (RT1C) [Time frame: From RT1C randomisation to death from any cause, assessed for 36 months]

Eligibility criteria

Inclusion Criteria for study entry - Mandatory at first point of study entry

• Histologically confirmed diagnosis of RMS (except pleomorphic RMS)
• Written informed consent from the patient and/or the parent/legal guardian

Phase 1b Dose Finding - IRIVA Inclusion

• Entered in to the FaR-RMS study at diagnosis
• Very High Risk disease
• Age >12 months and ≤25 years
• No prior treatment for RMS other than surgery
• Medically fit to receive treatment
• Adequate hepatic function:

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert's syndrome
• ALT or AST < 2.5 X ULN for age
• Absolute neutrophil count ≥1.0x 109/L
• Platelets ≥ 80 x 109/L
• Adequate renal function: estimated or measured creatinine clearance ≥60 ml/min/1.73 m2
• Documented negative pregnancy test for female patients of childbearing potential
• 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
• Written informed consent from the patient and/or the parent/legal guardian

Exclusion

• Weight <10kg
• Active > grade 2 diarrhoea
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter-current illness or active infection
• Pre-existing medical condition precluding treatment
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)
• Known hypersensitivity to any of the treatments or excipients
• Second malignancy
• Pregnant or breastfeeding women

Frontline chemotherapy randomisation Very High Risk - CT1a Inclusion

• Entered in to the FaR-RMS study at diagnosis
• Very High Risk disease
• Age ≥ 6 months
• Available for randomisation ≤60 days after diagnostic biopsy/surgery
• No prior treatment for RMS other than surgery
• Medically fit to receive treatment
• 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

• Absolute neutrophil count ≥1.0x 109/L (except in patients with documented bone marrow disease)
• Platelets ≥ 80 x 109/L (except in patients with documented bone marrow disease)
• Fractional Shortening ≥ 28%
• Documented negative pregnancy test for female patients of childbearing potential
• 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
• Written informed consent from the patient and/or the parent/legal guardian

Exclusion

• Active > grade 2 diarrhoea
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter-current illness or active infection
• Pre-existing medical condition precluding treatment
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)
• Known hypersensitivity to any of the treatments or excipients
• Second malignancy
• Pregnant or breastfeeding women

Frontline chemotherapy randomisation High Risk - CT1b Inclusion

• Entered in to the FaR-RMS study at diagnosis
• High Risk disease
• Age ≥ 6 months
• Available for randomisation ≤60 days after diagnostic biopsy/surgery
• No prior treatment for RMS other than surgery
• Medically fit to receive treatment
• 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

• Absolute neutrophil count ≥1.0x 109/L
• Platelets ≥ 80 x 109/L
• Documented negative pregnancy test for female patients of childbearing potential
• 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
• Written informed consent from the patient and/or the parent/legal guardian

Exclusion

• Active > grade 2 diarrhoea
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter-current illness or active infection
• Pre-existing medical condition precluding treatment
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)
• Known hypersensitivity to any of the treatments or excipients
• Second malignancy
• Pregnant or breastfeeding women

Frontline Radiotherapy Note: eligible patients may enter multiple radiotherapy randomisations.

Radiotherapy Inclusion - for all radiotherapy randomisations

• Entered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation)
• Very High Risk, High Risk and Standard Risk disease
• ≥ 2 years of age
• 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
• Patient assessed as medically fit to receive the radiotherapy
• Documented negative pregnancy test for female patients of childbearing potential
• 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
• Written informed consent from the patient and/or the parent/legal guardian

Radiotherapy Exclusion - for all radiotherapy randomisations

• Prior allo- or autologous Stem Cell Transplant
• Second malignancy
• Pregnant or breastfeeding women
• Receiving radiotherapy as brachytherapy

RT1a Specific Inclusion

• Primary tumour deemed resectable (predicted R0/ R1 resection feasible) after 3 cycles of induction chemotherapy (6 cycles for metastatic disease)
• Adjuvant radiotherapy required in addition to surgical resection (local decision).
• 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

• Primary tumour deemed resectable (predicted R0/R1 resection) after 3 cycles of induction chemotherapy (6 cycles for metastatic disease).
• Adjuvant radiotherapy required in addition to surgical resection (local decision)
• Higher Local Failure Risk (HLFR) based on presence of either of the following criteria:

• Unfavourable site
• Age ≥ 18yrs
• 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

• Primary radiotherapy indicated (local decision)
• Higher Local Failure Risk (HLFR) based on either of the following criteria:

• Unfavourable site
• Age ≥ 18yrs
• 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

• Available for randomisation after cycle 6 and before the start of cycle 9 of induction chemotherapy.
• 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.

• Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point)
• Very High Risk disease
• 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

• Completed 11 cycles of VnC maintenance treatment (either oral or IV regimens)
• No evidence of progressive disease
• Absence of severe vincristine neuropathy - i.e requiring discontinuation of vincristine treatment)
• Medically fit to continue to receive treatment
• 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
• Written informed consent from the patient and/or the parent/legal guardian

Exclusion

• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled intercurrent illness or active infection
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)
• Second malignancy
• Pregnant or breastfeeding women

Maintenance chemotherapy (High Risk) - CT2b Randomisation must take place during the 6th cycle of maintenance chemotherapy. Inclusion

• Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point)
• High Risk disease
• 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
• Completed 5 cycles of VnC maintenance treatment
• No evidence of progressive disease
• Absence of severe vincristine neuropathy i.e. requiring discontinuation of vincristine treatment
• Medically fit to continue to receive treatment
• 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
• Written informed consent from the patient and/or the parent/legal guardian

Exclusion

• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter current illness or active infection
• Urinary outflow obstruction that cannot be relieved prior to starting treatment
• Active inflammation of the urinary bladder (cystitis)
• Second malignancy
• Pregnant or breastfeeding women

CT3 Relapsed Chemotherapy

Inclusion:

• Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point)
• First or subsequent relapse of histologically verified RMS
• Age ≥ 6 months
• Measurable or evaluable disease
• No cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous three weeks: within two weeks for vinorelbine and cyclophosphamide maintenance chemotherapy
• Medically fit to receive trial treatment
• Documented negative pregnancy test for female patients of childbearing potential within 7 days of planned randomisation
• 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
• Written informed consent from the patient and/or the parent/legal guardian

Exclusion:

• Progression during frontline therapy without previous response (=Refractory to first line treatment)
• Prior regorafenib or temozolomide
• Active > grade 1 diarrhoea
• ALT or AST >3.0 x upper limit normal (ULN)
• Bilirubin, Total >1.5 x ULN; total bilirubin is allowed up to 3 x ULN if Gilbert's syndrome is documented
• 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)
• Uncontrolled hypertension > 95th centile for age and gender
• Prior allo- or autologous Stem Cell Transplant
• Uncontrolled inter-current illness or active infection
• Pre-existing medical condition precluding treatment
• Known hypersensitivity to any of the treatments or excipients
• Second malignancy
• Pregnant or breastfeeding women

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 31 centers

Center list to be confirmed — check the primary protocol.

France · 27 centers

• Centre Hospitalier Universitaire D'angers — Angers
• Centre Hospitalier Regional Universitaire Besancon - Hopital Jean Minjoz — Besançon
• Centre Hospitalier Universitaire De Bordeaux - Hopital Pellegrin — Bordeaux
• Centre Hospitalier Regional Universitaire Brest - Hopital Morvan — Brest
• Centre Francois Baclesse — Caen
• Centre Hospitalier Universitaire De Caen — Caen
• Centre Hospitalier Universitaire Dijon Bourgogne - Hopital D'enfants — Dijon
• Centre Hospitalier Universitaire De Grenoble — Grenoble
• … and 19 more centers

Australia · 11 centers

• Queensland Children's Hospital — Brisbane
• Chris O'brien Lifehouse — Camperdown
• Monash Children's Hospital — Clayton
• Peter Maccallum Cancer Centre — Melbourne
• Royal Childrens Hospital Melbourne — Melbourne
• John Hunter Children's Hospital — New Lambton Heights
• Perth Children's Hospital — Perth
• Sydney Children's Hospital — Sydney
• … and 3 more centers

Spain · 10 centers

• Hospital Sant Joan De Deu — Barcelona
• Hospital Universitari Vall D'hebron — Barcelona
• Hospital De Cruces — Bilbao
• … and 7 more centers

Switzerland · 9 centers

Center list to be confirmed — check the primary protocol.

Greece · 8 centers

• Children's General Hospital P and A Kyriakou — Athens
• Department of Pediatric Hematology-oncology - Aghia Sophia Children's Hospital — Athens
• Hellenic Society of Pediatric Hematology- Oncology — Athens
• University Unit of Pediatric Oncology-hematology - Children's Hospital Agia Sophia — Athens
• Children's and Adolescent's Oncology Clinic, "MITERA" Children's Hospital — Attiki
• Hematology-oncology Children's Clinic, University General Hospital of Heraklion — Heraklion
• Ahepa University General Hospital of Thessaloniki — Thessaloniki
• Ippokratio General Hospital of Thessaloniki — Thessaloniki

Belgium · 6 centers

• Cliniques Universitaires Saint Luc — Brussels
• Hopital Universitaire Des Enfants Reine Fabiola — Brussels
• Universitair Ziekenhuis Gent — Ghent
• Uz Leuven Campus Gasthuisberg — Leuven
• Centre Hospitalier Regional De La Citadelle — Liège
• Clinique Chc Montlegia — Liège

Israel · 5 centers

• Rambam Health Care Campus — Haifa
• Hadassah University Medical Centre — Jerusalem
• Schneider Medical Centre — Petah Tikva
• Dana Children's Hospital, Tel Aviv Sourasky Medical Center — Tel Aviv
• Chaim Sheba Medical Centre — Tel Litwinsky

Norway · 5 centers

• Haukeland University Hospital - Paediatric — Bergen
• Oslo University Hospital - Paediatrics — Oslo
• Oslo University Hospital - Radiumhospitalet — Oslo
• University Hospital of North Norway - Paediatric — Tromsø
• St Olavs Hospital - Paediatric — Trondheim

Austria · 2 centers

• Kepler University Clinic Linz — Linz
• St Anna Childrens Hospital — Vienna

Denmark · 2 centers

• Aarhus University Hospital — Aarhus
• University Hospital Rigshospitalet — Copenhagen

Netherlands · 2 centers

• University Medical Centre Groningen — Groningen
• Prinses Maxima Centrum Voor Kinderoncologie — Utrecht

New Zealand · 2 centers

• Starship Children's Health — Auckland
• Christchurch Hospital — Christchurch

Slovenia · 2 centers

• University Childrens Hospital Ljubljana — Ljubljana
• University Medical Centre Ljubjlana — Ljubljana

Czechia · 1 center

• Masaryk University Hospital Brno — Brno

Ireland · 1 center

• Our Lady's Children's Hospital — Crumlin

Italy · 1 center

• University Hospital of Padova (azienda Ospedaliera of Padua) — Padova

Portugal · 1 center

• Instituto Portugues De Oncologia De Losbona Francisco Gentil, Epe — Lisbon

Slovakia · 1 center

• Bratislava, National Institute for Children's Diseases — Bratislava

Sweden · 1 center

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT04625907 · RG_17-247 · 2018-000515-24 · 45535982

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗