E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Very High Risk neuroblastoma |
Bambini e adolescenti con neuroblastoma ad altissimo rischio |
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E.1.1.1 | Medical condition in easily understood language |
Neuroblastoma |
Neuroblastoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008126 |
E.1.2 | Term | Cerebral neuroblastoma |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of two intensified consolidation strategies in very-high risk neuroblastoma (VHR-NBL) patients in terms of event-free survival from randomisation date. This evaluation will follow a hierarchical testing procedure: each experimental treatment will be first evaluated as a single-arm phase 2 study, and in case of positive conclusion, the relative efficacy of both arms will then be evaluated comparatively. |
Valutare l’efficacia di due tipi di strategia di consolidamento intensificata in pazienti con neuroblastoma ad altissimo rischio (VHR-NBL) in termini di risultati di Sopravvivenza libera da progressione (PFS) dalla data della randomizzazione. |
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E.2.2 | Secondary objectives of the trial |
•To estimate and compare the overall survival (OS) of patients treated in the two treatment strategies
•To evaluate and compare the safety of the two treatment strategies in terms of toxic death and non-fatal toxicities rates.
•To estimate and compare the disease response after BuMel and at the end of treatment of the two treatment strategies
•To evaluate the between-treatment differences in Quality adjusted Time WIthout Symptoms and Toxicity (Q-TWiST approach)
•To evaluate the feasibility and document the logistical issues raised by 131I-mIBG and topotecan therapy in a multicenter setting
•To estimate and compare the Event-Free Survival of the two treatment strategies from the start of the intensified consolidation chemotherapy
•To estimate and compare the Event-Free Survival of the two treatment strategies from the date of the neuroblastoma diagnosis
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•Valutare e comparare la sopravvivenza globale (OS) dei pazienti trattati con le due strategie
•Valutare e comparare la sicurezza delle due strategie di trattamento in termini di percentuale tossicità letale e tossicità non letali
•Valutare e stimare la risposta di malattia dopo trattamento con busulfano e melphalan con entrambe le strategie terapeutiche
•Valutare le differenze tra i trattamenti in termini di Quality adjusted Time Without Symptoms and Toxicity (Q-TWiST approach)
•Valutare la fattibilità e documentare gli aspetti logistici legati alla somministrazione di radioterapia metabolica e chemioterapia concomitante in un setting multicentrico
•Valutazione della combinazione di 131I-mIBG e topotecan in un setting multicentrico
•Valutare e comparare la sopravvivenza libera da eventi delle due strategie di trattamento dall’inizio della terapia di consolidamento
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1 - Metastatic neuroblastoma (NBL)
2 - Patient previously treated within the ongoing High Risk Neuroblastoma SIOPEN study
3 - mIBG scintigraphy positive at diagnosis and after induction chemotherapy (pre BuMel evaluation).
4 - Metastatic response after induction chemotherapy lower than the ongoing High Risk Neuroblastoma SIOPEN trial criteria to be eligible for High Dose Chemotherapy (metastatic response worse than partial response (< PR) or SIOPEN score ≥ 3)
5 - Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation of treatment. Sexually active patients must agree to use acceptable and appropriate contraception while on study drug and for one year after stopping the study drug.
6 -Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines.
7 - Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
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1.Neuroblastoma metastatico
2.Pazienti in trattamento secondo il protocollo High Risk Neuroblastoma SIOPEN study
3.Scintigrafia mIBG positiva alla diagnosi e dopo la chemioterapia di induzione
4.Risposta metastatica dopo la chemioterapia di induzione minore rispetto ai criteri del protocollo High Risk Neuroblastoma SIOPEN trial per essere eligibile alla chemioterapia mieloablativa con busulfano + melphalan (cioè risposta metastatica inferiore a Remissione Parziale, o score scintigrafico SIOPEN score ≥ 3)
5.Le femmine in età fertile devono avere un test di gravidanza negativo nella settimana precedente la inclusione nel protocollo. I partner sessualmente attivi devono accettare di utilizzare metodi contraccettivi appropriati ed accettabili durante la fase dello studio e per 1 anno dopo la conclusione del trattamento. I metodi appropriati ed accettabili sono indicati nelle CTFG Guidelines “Recommendations related to contraception and pregnancy testing in clinical trials”. Le femmine che sono in fase di allattamento devono accettare di interrompere l’allattamento.
6.Consenso informato del paziente se maggiorenne, altrimenti consenso informato dei genitori/tutore legale. Assenso del paziente minorenne in accordo con le regole locali, regionali o nazionali prima delle procedure di screening
7.Paziente affiliato ad un regime di previdenza sociale o beneficiario dello stesso secondo i requisiti locali.
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E.4 | Principal exclusion criteria |
1 - Parenchymal brain metastasis (even one)
2 - Progressive disease at study entry
3 - Previous high-dose therapy and PBSCT
4 - Performance status (Karnofsky, Lansky) <70%
5 - Patient having received other therapy for cancer treatment than those allowed as per the ongoing High Risk Neuroblastoma SIOPEN trial or as defined in the future frontlines protocol (for HRNBL1 trial : after induction + 2 TVD)
6 - Impaired organ function (liver, kidney, heart, lungs)
7 - Any uncontrolled intercurrent illness or infection that in the investigator’s opinion would impair study participation
8 - Concomitant use with yellow fever vaccine and with live virus and bacterial vaccines
9 - Patient allergic to peanut or soya
10 - Chronic inflammatory bowel disease and/or bowel obstruction
11 - Pregnant or breastfeeding women
12 - Known hypersensitivity to the active substance or to any of the excipients of study drugs
13 - Known hypersensitivity to dacarbazine
14 - Concomitant use with St John's Wort
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1.Presenza di metastasi al sistema nervosa centrale
2.Malattia in progressione al momento di ingresso nello studio
3.Precedente terapia mieloablativa
4.Performance status (Karnofsky o Lansky) <70%
5.Trattamento precedente secondo programmi differenti dallo studio SIOPEN per neuroblastoma ad alto rischio
6.Funzione d’organo alterata (epatica, renale, cardiaca, polmonare)
7.Frazione di eiezione <28%, o <55% se accompagnata da segni di insufficienza cardiaca congestizia, o alterazioni del ritmo non controllate
8.Dispnea a riposo o saturazione O2 <95% in aria ambiente
9.Qualsiasi malattia incontrollata che potrebbe pregiudicare la aderenza al protocollo a giudizio dello sperimentatore
10.Ipersensibilità nota ad uno o più medicinali o eccipienti in sperimentazione.
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E.5 End points |
E.5.1 | Primary end point(s) |
Event Free Survival (EFS) from the date of randomisation into the VERITAS trial |
Valutazione dell’event Free Survival (EFS) nei 3 anni successivi dalla data di randomizzazione |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
•Overall survival
•Adverse events, evaluated using NCI-CTCAE v4.0 toxicity grading system, reported by treatment phase and overall over the whole treatment duration (maximum grade).
•Disease response after BuMel and at the end of treatment
•For the Q-TWiST analysis: time spent with severe toxicity after randomization and before progression/relapse (duration of hospitalisation will be used as a surrogate of time with toxicity); time spent without progression/relapse and without toxicity; and time from progression until death.
•Feasibility of each strategy of intensified consolidation chemotherapy
•Event-Free Survival from the date of start of the consolidation phase
•Event-Free Survival from the date of the neuroblastoma diagnosis
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Valutazione della sopravvivenza globale
• Valutazione dell’insorgenza degli eventi avversi valutati attraverso il NCI-CTCAE v4.0 system. La stopping rule per tossicità sarà basata sugli effetti collaterali che portano a ventilazione assistita in UTI e su eventi con tossicità letale. Questi eventi verranno monitorati nei 6 mesi successivi alla randomizzazione
•Risposta della malattia al ciclo BuMel e alla fine delle cure
•Per la Q-TWiST analysis: tempo intercorso tra tossicità severa dopo la randomizzazione e prima della progressione/ricaduta (con durata della ospedalizzazione come surrogate di tempo di tossicità); tempo trascorso in assenza di progressione/recidiva e senza tossicità; e tempo tra la progressione/ricaduta e il decesso.
•Event-Free Survival dalla data di inizio della fase di consolidamento
•Event-Free Survival dalla data di diagnosi di neuroblastoma |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
*By treatment phase and on the whole treatment duration
*At disease progression / relapse
*At death |
8 anni |
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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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 30 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 |
Austria |
France |
Israel |
Italy |
Spain |
United Kingdom |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 8 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 8 |