| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Rhabdomyosarcoma
|
| rabdomiosarkom |
|
| E.1.1.1 | Medical condition in easily understood language |
Rhabdomyosarcoma: cancer of soft tissue (such as muscle), connective tissue (such as tendon or cartilage), or
bone.
|
| Rabdomiosarkom: rak mehkih tkiv (kot je mišica), vezivnega tkiva (kot je hrustanec ali kita) ali kosti |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To compare systemic therapy regimens for patients with Very High Risk (VHR) disease at diagnosis.
•To compare new systemic therapy regimens with standard chemotherapy for patients with High Risk (HR) disease at
diagnosis.
•To determine whether pre-operative or standard post-operative radiotherapy is better for patients with resectable
disease
•To determine whether dose escalation of radiotherapy improves the outcome in patients with a higher local failure risk
•To determine whether radiotherapy treatment of all sites of disease, including metastatic sites, when compared to
radiotherapy treatment to the primary site and involved regional lymph nodes alone, improves the outcome for patients
with unfavourable metastatic disease
•Maintainance chemotherapy
The objectives for the relapsed disease
|
prva testirana kombinacija bo dodatek irinotekana v kombinaciji
ifosfamida, vinkristina in aktinomicina D (IRIVA)
primerjava sistemske kemoterapije v skupini VHR bolnikov (CT1A). Prva
kombinacija, ki bo randomizirana nasproti standradnemu zdravljenju (IVADo,
Doxorubicin) je IRIVA.
primerjava sistemske kemoterapije v skupini HR bolnikov (CT1B).
ugotoviti ali dodatnih 12 ciklusov vzdrževalne kemoterapije z vinorelbinom in
ciklofosfamidom (VnC) v primerjavi s standrdnimi 12 ciklusi (skupno 24
ciklusov) izboljša izhod VHR bolnikov (CT2A)
ugotoviti ali dodatnih 6 ciklusov vzdrževalne kemoterapije z vinorelbinom in
ciklofosfamidom (VnC) v primerjavi s standrdnimi 6 ciklusi (skupno 12 ciklusov)
izboljša izhod HR bolnikov (CT2B)
Randomizirana vprašanja ob relapsu bolezni
ugotoviti ali dodatek novih sistemskih zdravil izboljša izhod
začetna kombinacija bo temozolamid, vinkristin in irinotekan
|
|
| E.2.2 | Secondary objectives of the trial |
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.
|
Sekundarni cilji
dokazati, da uporaba fuzijskega statusa namesto klasične histologije izboljša
razvrščanje bolnikov v skupine tveganja
ugotovita ali je določitev fuzijskega statusa nujna pri bolnikih s histološko sliko
embrionalnega RMS
ugotoviti ali je imunohistokemični dokaz beljakovine, ki je posledica ekspresije
fuzijskega transkripta, ustrezen nadomestek za opredelitev fuzijskega statusa ugotoviti ali je ocena odgovora po indukcijski kemoterapiji s FDG PET-CT
prognostični kazalec za lokalno ponovitev/preživetje |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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:
o 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
CT1a specific inclusion
• VHR disease
• Age ≥ 6 months
• Available for randomisation ≤60 days after diagnostic biopsy/surgery
• Fractional Shortening ≥ 28%
CT1b specific inclusion
• HR disease
• Age ≥ 6 months
• Available for randomisation ≤60 days after diagnostic biopsy/surgery
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:
o Unfavourable site
o 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
o Patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible
• No evidence of progressive disease
• Absence of severe vincristine neuropathy – i.e requiring discontinuation of vincristine treatment)
CT2a specific inclusion
• VHR disease
• Completed 11 cycles of VnC maintenance treatment (either oral or IV regimens)
CT2b specific Inclusion
• HR disease
• Completed 5 cycles of VnC maintenance treatment
Relapse CT3 specific Inclusion
1. Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point including at relapse)
2. Age ≥ 6 months
3. First or subsequent relapse of RMS
4. No cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous two weeks
5. Documented negative pregnancy test for female patients of childbearing potential |
VKLJUČITVENI KRITERIJI
Vključitev v raziskavo FaR-RMS
VHR bolniki
Starost > 12 mesecev in < 25 let
Brez predhodnega zdravljenja, razen operacije
Sposobni prejeti terapijo
Normalna jetrna funkcija (celokupni bilirubin < 1.5-krat zgornja normalna vrednost za
starost, razen pri bolnikih z Gilbertovim sindromom, AST ali ALT < 2.5-krat zgornja
normalna vrednost za starost)
Negativen test nosečnosti pri plodnih ženskah
Bolnik se strinja s kontracepcijo med terapijo in še 12 mesecev (ženske) oziroma 6
mesecev (moški) po koncu terapije, če so spolno aktivni
Podpisano pisno privoljenje bolnika ali staša/skrbnika |
|
| E.4 | Principal exclusion criteria |
Phase 1b specific 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. Known hypersensitivity to any of the treatments or excipients
7. Second malignancy
8. Pregnant or breastfeeding women
CT1a, CT1b and CT3 specific 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. Known hypersensitivity to any of the treatments or excipients
6. Second malignancy
7. Pregnant or breastfeeding women
Radiotherapy specific exclusion
1. Prior allo- or autologous Stem Cell Transplant
2. Second malignancy
3. Pregnant or breastfeeding women
4. Receiving radiotherapy as brachytherapy
CT2a and CT2b specific Exclusion
1. Prior allo- or autologous Stem Cell Transplant
2. Uncontrolled inter current illness or active infection
3. Second malignancy
4. Pregnant or breastfeeding women |
IZKLJUČITVENI KRITERIJI
Teža < 10 kg
Aktivna driska gradus > 2
Predhodna avtologna ali alogena presaditev krvotvornih matičnih celic
Neobvladana druga bolezen ali okužba
Stanje, ki preprečuje zdravljenje
Preobčutljivost na zdravilo
Sekundarna maligna bolezen
Noseče ženske ali doječe matere |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Event Free Survival for randomisations CT1a, CT1b, CT2, RT2 and CT3.
Local failure free survival for randomisations RT1a, RT1b and RT1c
|
Preživetje brez dogodka
Lokalna ponovitev
|
|
| E.5.1.1 | 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. |
| definirano v angleškem jeziku |
|
| E.5.2 | 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
|
| najboljši odgovor |
|
| E.5.2.1 | 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 |
| definirano v angleškem jeziku |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| obsevalna doza |
| radiotherapy dose |
|
| E.8.2.4 | Number of treatment arms in the trial | 19 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Czech Republic |
| Denmark |
| France |
| Italy |
| Netherlands |
| New Zealand |
| Norway |
| Slovenia |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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