Rhabdomyosarcoma MedDRA version: 20.0 Level: PT Classification code 10039022 Term: Rhabdomyosarcoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Actinomycin D
Pharmaceutical Form: Lyophilisate for solution for injection
INN or Proposed INN: dactinomycin
CAS Number: 50-76-0
Concentration unit: µg microgram(s)
Concentration type: e
Sponsors
University of Birmingham
Oslo universitetssykehus
Eligibility
Sex/Gender
All
Inclusion criteria
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 t
Exclusion criteria
Exclusion criteria: Phase 1b specific exclusion • Weight 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 • 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objectives for this trial are related to each of the trial questions. For the Phase I Dose Finding Studies, the aim is to determine the recommended phase II dose (RP2D) of new systemic therapy regimens. The first combination to be tested is irinotecan in combination with ifosfamide, vincristine and actinomycin D (IrIVA). For the frontline chemotherapy questions, the objectives are: • To compare systemic therapy regimens for patients with Very High Risk (VHR) disease at diagnosis. The first new combination regimens to be compared are IVADo and IrIVA in a dose intense schedule. •To compare new systemic therapy regimens with standard chemotherapy for patients with High Risk (HR) disease at diagnosis. The standard chemotherapy is ifosfamide, vincristine, actinomycin D (IVA). The first new combination regime to be compared is irinotecan combined with IVA (IrIVA) in a dose intense schedule For the radiotherapy questions, the objectives are as follows: •To determine ;Secondary Objective: The secondary objectives for this trial are: •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. ;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 ti | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 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 and RT2 • 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 ;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 | — |
Countries
Australia, Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Netherlands, New Zealand, Norway, Portugal, Slovakia, Slovenia, Spain, Sweden, United Kingdom
Contacts
Public ContactLouise Moeller
The University of Birmingham
Outcome results
None listed