A study for children and adults with newly diagnosed or recurrent rhabdomyosarcoma (RMS)

Australia, Austria, Belgium, Canada, Croatia, Czech Republic, Czechia, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Netherlands, New Zealand, Norway, Portugal, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom (ICTRP)

ID di studio ICTRP
EUCTR2018-000515-24 (ICTRP)

Titolo ufficiale (approvato dal comitato etico)
FaR-RMS: An overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma (BASEC)

Titolo accademico
FaR-RMS: An overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma - FaR-RMS (ICTRP)

Titolo pubblico
FaR-RMS: An overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma (ICTRP)

Malattie studiate
Rhabdomyosarcoma
MedDRA version: 20.0Level: PTClassification code 10039022Term: RhabdomyosarcomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Cancer [C04] (ICTRP)

Intervento studiato

Trade Name: LYOVAC*-COSMEGEN
Product Name: Actinomycin D
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: dactinomycin
CAS Number: 50-76-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0,5-

Product Name: Doxorubicin
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: doxorubicin
CAS Number: 23214-92-8

Product Name: Ifosfamide
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: ifosfamide
CAS Number: 3778-73-2
Concentration number: -2

Product Name: Irinotecan
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Irinotecan
CAS Number: 97682-44-5
Concentration number: -20

Product Name: Vincristine
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Vincristine
CAS Number: 57-22-7

Product Name: Vinorelbine
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Vinorelbine
CAS Number: 71486-22-1

Product Name: Vinorelbine
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: Vinorelbine
CAS Number: 71486-22-1
Concentration number: -80

Product Name: Cyclophosphamide
Pharmaceutical Form: Powder for solution for injection/infusion
INN or Proposed INN: Cyclophosphamide
CAS Number: 50-18-0
Concentration number: -2000

Product Name: Cyclophosphamide
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: Cyclophosphamide
CAS Number: 50-18-0
Concentration number: -1000

Product Name: Cyclophosphamide
Pharmaceutical Form: Tablet
INN or Proposed INN: Cyclophosphamide
CAS Number: 50-18-0

Product Name: Temozolomide
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Temozolomide
CAS Number: 85622-93-1
Concentration number: -250

Product Name: Regorafenib
Ph (ICTRP)

Tipo di studio
Interventional clinical trial of medicinal product (ICTRP)

Disegno dello studio
Controlled: yes Randomised: yes Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: yes Other specify the comparator: radiotherapy dose Number of treatment arms in the trial: 19 (ICTRP)

Criteri di inclusione/esclusione
Gender:
Female: yes
Male: yes

Inclusion criteria:
Inclusion Criteria for study entry
1. Histologically confirmed diagnosis of RMS (except pleomorphic RMS)
2. Written informed consent from the patient and/or the parent/legal guardian
Inclusion criteria for all randomisations and registrations:
?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
?Medically fit to receive treatment
Frontline chemotherapy specific inclusion:
?Entered in to the FaR-RMS study at diagnosis
?No prior treatment for RMS other than surgery
?Documented negative pregnancy test for female patients of childbearing potential
?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
Phase 1b Specific Inclusion
?VHR disease
?Age >12 months and =25 years
?Adequate hepatic function: ALT or AST < 2.5 X ULN for age
?Adequate renal function: estimated or measured creatinine clearance =60 ml/min/1.73 m2
?Absolute neutrophil count =1.0x 10^9/L
?Platelets = 80 x 10^9/L

CT1a specific inclusion
?VHR disease
?Age = 6 months
?Available for randomisation =60 days after diagnostic biopsy/surgery
?Fractional Shortening = 28%
?Absolute neutrophil count =1.0x 10^9/L (except in patients with documented bone marrow disease)
?Platelets = 80 x 109/L (except in patients with documented bone marrow disease)

CT1b specific inclusion
?HR disease
?Age = 6 months
?Available for randomisation =60 days after diagnostic biopsy/surgery
?Absolute neutrophil count =1.0x 10^9/L
?Platelets = 80 x 10^9/L

Radiotherapy Inclusion
?Entered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation)
?VHR, HR and SR 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
?Documented negative pregnancy test for female patients of childbearing potential
?RT1a and RT1b 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 and RT1c Specific Inclusion
?Higher Local Failure Risk (HLFR) based on presence of either of the following criteria:
?Unfavourable site
?Age = 18yrs

RT1c Specific Inclusion
?Primary radiotherapy indicated (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

RT2 Specific Inclusion
?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

Maintenance specific Inclusion
?Received frontline induction chemotherapy as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy
?regimen
?Patients (ICTRP)

Exclusion criteria:
Phase 1b specific 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
?Known hypersensitivity to any of the treatments or excipients
?Second malignancy
?Pregnant or breastfeeding women
?Urinary outflow obstruction that cannot be relieved prior to starting treatment
?Active inflammation of the urinary bladder (cystitis)

CT1a and CT1b specific 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
?Known hypersensitivity to any of the treatments or excipients
?Second malignancy
?Pregnant or breastfeeding women
?Urinary outflow obstruction that cannot be relieved prior to starting treatment
?Active inflammation of the urinary bladder (cystitis)


Radiotherapy specific exclusion
?Prior allo- or autologous Stem Cell Transplant
?Second malignancy
?Pregnant or breastfeeding women
?Receiving radiotherapy as brachytherapy

CT2a and CT2b specific Exclusion
?Prior allo- or autologous Stem Cell Transplant
?Uncontrolled inter current illness or active infection
?Second malignancy
?Pregnant or breastfeeding women
?Urinary outflow obstruction that cannot be relieved prior to starting treatment
?Active inflammation of the urinary bladder (cystitis)

CT3 specific 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


Endpoint primari e secondari
Main Objective: Phase I Dose Finding Studies:
determine the recommend. phase II dose (RP2D) of new systemic therapy regimens: irinotecan with IVA (IrIVA).
Frontline chemoth.:
? To compare syst. ther. reg. for pat. with VHR. First combination: IVADo and IrIVA
?To compare new syst. ther. reg. for pat. with HR. First combin.: IrIVA with IVA.
Radiotherapy (RT):
?Whether pre-OP or standard post-OP RT is better for pat. with resectable disease
?Whether dose escalation of RT improves outcome in pat. with a HLFR
?Whether RT of all sites +metast. sites or RT to primary site+involved lymph nodes is better for pat. with unfav. metast. dis.
Maintenance chemoth.:
?Whether addition of 12 cycles of VnC to standard 12C improves outcome for pat. with VHR
?Whether addition of 6 cycles of VnC to standard 6C improves outcome for pat. with localised HR
Relapsed dis.:
?Whether new systemic therapy regimens improve outcome in relapsed RMS. First combination: Regorafenib (R) + VIr (VIrR) compared with VIrT;Secondary Objective:
?To validate whether the use of fusion status (PAX3/PAX7-FOXO1) in place of histopathological diagnosis improves risk stratification
?To determine whether assessment of fusion status is necessary in tumours classified as Embryonal Rhabdomyosarcoma by histopathology
?To determine whether immunohistochemistry assessment for protein expression driven by the fusion protein is an accurate surrogate for fusion status
?To determine whether FDG PET- CT response assessment following induction chemotherapy is a prognostic biomarker for local failure and/ or survival.

Secondary Objectives (CT3 arm Relapse)
?To determine the tolerability of the regimens
?To evaluate the anti-tumour activity and effect on overall survival of VIrR when compared to standard therapy
?To evaluate the effect on quality of life of VIRR when compared to standard therapy
?To evaluate the acceptability and palatability of regorafenib formulations
?To examine the pharmacokinetics of regorafenib;Primary end point(s): The primary outcome measures for this study are as follows:

Recommended Phase 2 Dose (RP2D) - Phase 1b
Event Free Survival for randomisations CT1a, CT1b, CT2, RT2 and CT3.
Local failure free survival for randomisations RT1a, RT1b and RT1c
;Timepoint(s) of evaluation of this end point: Event-free survival (EFS) time is defined as the time from the each relevant randomisation to first failure event.
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 (LFFS) time is defined as time from randomisation to first local failure event. 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. (ICTRP)

Secondary end point(s): ?Best Response for randomisation CT3
?Dose Limiting Toxicity for registration phase 1b
?Event Free Survival for all patients, randomisations RT1a, RT1b, RT1c, CT3 and also the PET sub-study
?Local failure free survival for the PET sub-study
?Loco-regional failure-free survival for randomisations RT1a, RT1b, RT1c and RT2
?Health Related Quality of Life for randomisations RT1a, RT2 and CT3
?Maximum Tolerated Dose for registration phase 1b
?Overall Survival for all patients, randomisations CT1a, CT1b, CT2, CT3, RT1a, RT1b, RT1c and also RT2
?Response for registration phase 1b and also randomisations CT1a, CT1b, and CT3
?Recommended Phase II Dose for registration phase 1b
?Toxicity for registration phase 1b and also randomisations CT1a, CT1b, and CT3
?Duration of response for randomisation CT3
?Acute post-radiotherapy complications for randomisations RT1a, RT1b, RT1c and RT2
?Late complications for randomisations RT1a, RT1b and RT1c
?Acute post-operative complications for randomisations RT1a and RT1b
?Wound complications for randomisations RT1a and RT1b
?PET response for the PET sub-study
? Acceptability/palatability of regorafenib
? Duration of Best response for randomisation CT3
? Objective response for randomisation CT3
? Pharamcodynamics, Pharmacokinetics and biomarker for ranomisation CT3
;Timepoint(s) of evaluation of this end point: first failure event
death from any cause
first local failure event
first local or regional failure event.
30 days after the last treatment
within 120 days from surgery
completion of radiotherapy
Progression
Relapse
after 120 days from last local therapy.
at the start of radiotherapy,
At completion of radiotherapy,
3 months following the end of radiotherapy,
24 months following radiotherapy
after course 2 and 6 for the newly diagnosed chemotherapy
after course 2 and 4 for the relapse randomisation.
End of any Phase 1b study
time point 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 cycles of induction chemotherapy
(ICTRP)

Data di registrazione
08.07.2022 (ICTRP)

Inclusione del primo partecipante
03.10.2022 (ICTRP)

Sponsor secondari
Gustave Roussy (ICTRP)

Contatti aggiuntivi
Bridget Shaw, farrms@trials.bham.ac.uk, +4401214142996, The University of Birmingham (ICTRP)

ID secondari
RG_17-247, 2018-000515-24-IE (ICTRP)

Risultati-Dati individuali dei partecipanti
non disponibile

Ulteriori informazioni sullo studio
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-000515-24 (ICTRP)