Descrizione riassuntiva della sperimentazione (Fonte di dati: BASEC)
Le neuroblastome à haut risque est une maladie cancéreuse rare qui se présente sous forme de nodules ou de tumeurs dans l’abdomen ou près de la moelle épinière au niveau du thorax, du cou ou du bassin. En cas de propagation du cancer dans tout le corps (métastases) ou s’il présente certaines propriétés biologiques, le traitement chez l’enfant et l’adolescent peut être difficile. Les médecins parlent alors d’un neuroblastome à haut risque.
Les neuroblastomes à haut risque représentent le plus grand sous-groupe de neuroblastomes. Le pronostic des patients atteints de ce type de neuroblastome a été progressivement amélioré au fil des ans grâce à un traitement combinant chimiothérapie, chirurgie et radiothérapie. Toutefois, une amélioration des résultats pour les patients est toujours nécessaire. L’objectif de cette étude est donc de définir la meilleure stratégie thérapeutique pour augmenter les chances de guérison des patients atteints d’un neuroblastome à haut risque.
Malattie studiate(Fonte di dati: BASEC)
Neuroblastome à haut risque
Health conditions
(Fonte di dati: WHO)
Very High Risk Neuroblastoma
MedDRA version: 20.0Level: PTClassification code 10029260Term: NeuroblastomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: LLTClassification code 10029261Term: Neuroblastoma NOSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps);Therapeutic area: Diseases [C] - Cancer [C04]
Malattia rara
(Fonte di dati: BASEC)
No
Interventi esaminati (p. es. medicamento, terapia, campagna)
(Fonte di dati: BASEC)
Le programme de thérapie comprend quatre étapes. La première étape est la phase d’induction qui comprends deux schémas de chimiothérapie : l’un correspondant au traitement utilisé en Allemagne (GPOH), l’autre correspondant au traitement utilisé dans les autres pays Européens (RAPID COJEC). On ne sait pas, à l’heure actuelle, quel est le traitement d’induction le plus efficace et le mieux toléré, c’est-à-dire, qui est destiné à réduire le plus possible le nombre de cellules cancéreuses. C’est pourquoi, les patients sont randomisés. Ce qui signifie que deux groupes de patients similaires seront formés au hasard grâce à un tirage au sort par ordinateur.
Après l'achèvement de la thérapie d'induction et la chirurgie de la tumeur primaire, la deuxième étape sera la phase de consolidation par chimiothérapie à haute dose. Pour les patients avec une réponse insuffisante au traitement d’induction, un traitement intensifié avec deux médicaments anticancéreux supplémentaires sera proposé avant la chirurgie.
L’objectif de la phase de consolidation, pour les patients avec une réponse suffisante au traitement d’induction, est d’évaluer le bénéfice d’une intensification de la consolidation sur les chances de guérison du patient. Pour cela, on ajoute au traitement standard qui comprend deux médicaments anticancéreux (combinaison Busulfan-Melphalan), un troisième médicament, le Thiotepa. Pour comparer l’efficacité et la toxicité de ces deux traitements de chimiothérapies à haute dose (CHD), les patients seront attribués à l’un ou l’autre des traitements par tirage au sort (randomisation). Les patients auront autant de chances de recevoir l’une ou l’autre CHD.
Après la chirurgie de la tumeur et à l’issu de la phase de consolidation, la maladie du patient sera évaluée par plusieurs imageries (scanner et/ou IRM, etc.). Si l’imagerie montre la persistance d’une partie de la tumeur, le patient sera inclus dans l’un des deux groupes décrits ci-dessous pour comparer deux doses de radiothérapie et ainsi identifier la dose la plus efficace de radiothérapie :
• L’un recevra la dose standard de rayonnement (21.6 Grays).
• L’autre recevra le même traitement avec un complément d’irradiation à la dose de 14.4 Grays sur la zone résiduelle de la maladie.
Le tirage au sort sera effectué par un ordinateur qui déterminera au hasard quel traitement le patient recevra.
En l'absence de maladie résiduelle macroscopique, la dose standard de rayonnement sera administrée au lit tumoral préopératoire. La radiothérapie représente donc la troisième phase de cette étude et est toujours faite après la phase de consolidation par chimiothérapie à haute dose.
Enfin, un traitement d’entretien comportant de l’acide rétinoïque et de l’immunothérapie sera administré afin d’éliminer d’éventuelles cellules tumorales restantes. Ce traitement d’entretien comporte également l’administration d’un anticorps monoclonal Dinutuximab béta dirigé contre les cellules tumorales.
Interventions
(Fonte di dati: WHO)
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: BUSULFAN
Other descriptive name: BUSULFAN
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: CARBOPLATIN
Other descriptive name: CARBOPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50-18-0
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: CISPLATIN
Other descriptive name: CISPLATIN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: DACARBAZINE
CAS Number: 4342-03-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: DOXORUBICIN
CAS Number: 23214-92-8
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: ETOPOSIDE
Other descriptive name: ETOPOSIDE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: IFOSFAMIDE
CAS Number: 3778-73-2
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 80-
Pharmaceutical Form: Powder and solvent for solution for injection/infusion
INN or Proposed INN: MELPHALAN
CAS Number: 148-82-3
Pharmaceutical Form:
Criteri per la partecipazione alla sperimentazione
(Fonte di dati: BASEC)
Au moment du diagnostic ou jusqu'à 21 jours après un cycle de chimiothérapie pour les patients atteints d'un neuroblastome localisé avec amplification du gène MYCN.
Les patients de moins de 18 ans au moment du diagnostic.
Criteri di esclusione
(Fonte di dati: BASEC)
Une maladie existante qui ne permet pas le traitement selon le protocole.
Femme enceinte ou allaitante.
Participation à une autre étude clinique
Inclusion/Exclusion Criteria
(Fonte di dati: WHO)
Gender:
Female: yes
Male: yes
Inclusion criteria:
Enrollment in HR-NBl2 will be performed:
- at diagnosis before the beginning of chemotherapy
or
- up to 21 days after one course of Carboplatin-Etoposide for patients with localized neuroblastoma or infants with metastatic neuroblastoma with
MYCN amplification or patients with metastatic neuroblastoma treated in emergency
or
- up to 21 days after one course of the current protocol for low/intermediate risk neuroblastoma in Germany/Netherlands for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification
R-I eligibility criteria:
1) Established diagnosis of neuroblastoma according to the SIOPEN-modified International Neuroblastoma Risk Group (INRG) criteria, High-risk neuroblastoma defined as:
? Stage M neuroblastoma above 365 days of age at diagnosis (no upper age limit) and Ms neuroblastoma 12-18 months old, any MYCN status* OR
-L2, M or Ms neuroblastoma any age with MYCN amplification, or focal high level MYC or MYCL amplification
2) No previous chemotherapy or up to 21 days after one cycle of Carboplatin-Etoposide for patients with localized neuroblastoma with MYCN amplification or patients with metastatic neuroblastoma treated in emergency)
3) Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment.
4) Written informed consent to enter the R-I randomization from patient or parents/legal representative, patient, and age-appropriate assent.
5) Patient affiliated to a social security regimen or beneficiary of the same according to local requrements.
6) Patients should be able and willing to comply with study visits and procedures as per protocol.
R-HDC eligibility criteria:
1) Stage M neuroblastoma above 365 days of age at diagnosis, any MYCN status, EXCEPT patients with stage M or Ms 12-18 months old with numerical chromosomal alterations only, and in complete metastatic response at the end of induction: in this case, patients will have surgery but will not be eligible for R-HDC and will not be able to pursue the trial.
OR
- L2, M or Ms neuroblastoma with MYCN amplification or focal high level MYC or MYCL amplification
2) Age < 21 years
3) Complete response (CR) or partial response (PR) at metastatic sites
- Bone marrow disease
- Other metastatic sites
4) Acceptable organ function and performance status
- Performance status = 50%.
- Hematological status: ANC>0.5x109/L, platelets > 20x 109/L
- Cardiac function (< grade 2)
- Normal chest X-ray and oxygen saturation.
- Absence of any toxicity = grade 3.
5) Sufficient collected stem cells available; minimum required: 6 x 106 CD34+ cells/kg body weight stored in 3 separate fractions.
6) Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-HDC randomization.
7) Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
8) Patients should be able and willing to comply with study visits and procedures as per protocol.
In case of parents'/patient's refusal, or insufficient stem cells, collection for tandem HDC but with a minimum of 3 x 106 CD34+ cells/kg body weight, or in case of patients older than 21 years, or organ toxicity, HDC will consist on the standard HD Bu-Mel and patients will be eligible for the subsequent randomisation.
R-RTx eligibility criteria:
An evaluation of the local disease will be performed after HDC/ASCR and surgery:
- In case of no loca
Exclusion criteria:
Non-inclusion criteria for HR-NBL2:
1.Any negative answer concerning the HR-NLB2 inclusion criteria
2.Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving his consent.
3.Participating in another clinical study with an IMP while on study treatment.
4.Chronic inflammatory bowel disease and/or bowel obstruction.
5.Pregnant or breastfeeding women.
6.Known hypersensitivity to the active substance or to any of the excipients of the study drugs
7.Concomitant self-medication medicine that in the investigator opinion could interact with study treatments, including herbal medicine (e.g. St John's Wort (Hypericum Perforatum).
Non-inclusion criteria specific to the R-I randomisation (RAPID COJEC/GPOH):
1.Urinary tract obstruction = grade 3
2.Heart failure or myocarditis = grade 2, any arrhythmia or myocardial infection
3.Peripheral motor or sensory neuropathy = grade 3
4.Demyelinating form of Charcot-Marie-Tooth syndrome
5.Hearing impairment = grade 2
6.Concurrent prophylactic use of phenytoin
7.Cardiorespiratory disease that contraindicates hyperhydration
Non-inclusion criteria common to all randomisations (R-I, R-HDC, and R-RTx
1) Any negative answer concerning the inclusion criteria of R-I or R-HDC or R-RTx will render the patient ineligible for the corresponding therapy
phase randomization. However, these patients may remain on study and be considered to receive standard treatment of the respective therapy
phase, and may be potentially eligible for subsequent randomizations.
2) Liver function: Alanine aminotransferase (ALT) > 3.0 x ULN and blood bilirubin > 1.5 x ULN (toxicity = grade 2). In case of toxicity = grade 2, call national principal investigator study coordinator to discuss the feasibility.
3) Renal function: Creatinine clearance and/or GFR < 60 ml/min/1.73m? (toxicity = grade 2). If GFR < 60ml/min/1.73m?, call national principal investigator study coordinator to discuss about the treatment.
4) Dyspnea at rest and/or pulse oximetry <95% in air (only for R-HDC,a nd R-RTx)
5) Any uncontrolled intercurrent illness or infection that in the investigator opinion would impair study participation.
7) Concomittant use with yellow fever vaccine and with live virus or bacterial vaccines.
8) Patient allergic to peanut or soya.
Non-inclusion criteria to R-HDC:
?Any negative answer concerning the R-HDC inclusion criteria
Non-inclusion criteria to chemoimmunotherapy arm:
?Any negative answer concerning the inclusion criteria of chemoimmunotherapy arm.
-
Altre informazioni sulla sperimentazione
Data di registrazione della sperimentazione
6 mar 2023
Inserimento del primo partecipante
7 lug 2023
Stato di reclutamento
Authorised-recruitment may be ongoing or finished
Titolo scientifico
(Fonte di dati: WHO)
High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)Randomized, international and multicentric phase 3 study that evaluates and compares 2 treatment strategies in 3 therapeutic phases (induction, high-dose chemotherapy and radiotherapy) for patients with high-risk neuroblastoma and introduces chemoimmunotherapy for patients with insufficient metastatic response after induction chemotherapy. - HR-NBL2
Tipo di sperimentazione
(Fonte di dati: WHO)
Interventional clinical trial of medicinal product
Disegno della sperimentazione
(Fonte di dati: WHO)
Controlled: yes Randomised: yes Open: yes 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: no Number of treatment arms in the trial: 2
Fase
(Fonte di dati: WHO)
Human pharmacology (Phase I): noTherapeutic exploratory (Phase II): noTherapeutic confirmatory - (Phase III): yesTherapeutic use (Phase IV): no
Punti finali primari
(Fonte di dati: WHO)
Main Objective: R-I:
Comparison of the 3 year EFS rate of 2 induction regimens, GPOH and RAPID COJEC, in patients with high-risk neuroblastoma.
R-HDC:
Comparison of the 3 year EFS rate of single HDC with busulphan and melphalan (Bu-Mel) versus tandem HDC with Thiotepa followed by Bu-Mel in patients with high-risk neuroblastoma and a sufficient response to induction chemotherapy.
R-RTx:
Comparison of the 3 years EFS rate of 21.6 Gy radiotherapy to the preoperative tumor bed versus 21.6 Gy radiotherapy and a sequential boost up to 36 Gy to the residual tumor in patients with macroscopic residual disease after HDC and surgery.
Chemoimmunotherapy arm:
Metastatic response rate after 4 courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic reponse at the end of induction chemotherapy (TEMIRI/DB).
;Secondary Objective: To describe the EFS, PFS, OS from diagnosis; the effect of RAPID COJEC & GPOH induction regimens on metastatic disease during & after the end of induction; the correlation of the response of metastatic disease during & after induction with survival (EFS&OS); the effect of HDC with Bu-Mel vs. Thiotepa + Bu-Mel on OS, To describe, for each randomisation, 5-year EFS, 3 & 5-year PFS, and 3 & 5-year OS since date of randomization; the 3 & 5-year EFS and OS of patients treated in the intensified arm with TEMIRI, Thio and Bu-Mel; ctDNA to monitor the tumour status, To validate prospectively new international criteria for response assessment, to monitor the emergence in plasma of other targetable genomic alterations to inform the next generation of studies, To describe the metastatic response rate after TEMIRI/DB for patients with insufficient metastatic response at the end of induction chemotherapy, To describe acute toxicities of the combination of TEMIRI/DB;Primary end point(s): R-I: 3-year EFS from date of R-I randomization
R-HDC: 3-year EFS from date of R-HDC randomization
R-RTx: 3-year EFS from date of RTx randomization
Chemoimmunotherapy arm: Metastatic response rate after 4 cycles of TEMIRI/DB.
All analyses for randomized trials will be performed considering patients in the treatment group defined by randomization (intention to treat).
The primary analysis will be controlled for stratification factors. ;Timepoint(s) of evaluation of this end point: 3 years
Punti finali secondari
(Fonte di dati: WHO)
Secondary end point(s): For the whole population of high-risk neuroblastoma:
- 3- and 5-year EFS, PFS and OS calculated from date of randomization
For each treatment phase:
- 5-year EFS, 3- and 5-year PFS and OS calculated from date of randomization
- Cumulative incidence of relapse/progression
- Cumulative incidence of treatment related mortality and of disease related mortality
- Overall response as per the new INRG response criteria [Park JR, JCO 2017] (including primary tumor after induction), skeletal response on MIBG, bone marrow response, local control
- Therapy-related toxicity
For patients in the chemoimmunotherapy arm:
?Metastatic reponse rate after 2 cycles TEMIRI/DB and 3- and 5- year EFS/PFS/OS from the date of initial diagnosis;Timepoint(s) of evaluation of this end point: 5 years
Contatto per informazioni
(Fonte di dati: WHO)
PHRC
Risultati della sperimentazione
(Fonte di dati: WHO)
Sintesi dei risultati
ancora nessuna informazione disponibile
Collegamento ai risultati nel registro primario
ancora nessuna informazione disponibile
Informazioni sulla disponibilità dei dati dei singoli partecipanti
ancora nessuna informazione disponibile
Siti di esecuzione della sperimentazione
Siti di esecuzione in Svizzera
(Fonte di dati: BASEC)
Aarau, Basilea, Bellinzona, Berna, Ginevra, Losanna, Luzern, San Gallo, Zurigo
Paesi di esecuzione
(Fonte di dati: WHO)
Australia, Austria, Belgium, Croatia, Czech Republic, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Lithuania, Netherlands, New Zealand, Norway, Poland, Portugal, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom
Contatto per maggiori informazioni sulla sperimentazione
Dati della persona di contatto in Svizzera
(Fonte di dati: BASEC)
PD Dr. med. Dr. sc. nat. Raffaele Renella
+41 21 314 14 33
raffaele.renella@chuv.ch
Contatto per informazioni generali
(Fonte di dati: WHO)
Aqsa YAR
114 rue Edouard Vaillant
Gustave Roussy
0033142116717
bpp.regulatory@gustaveroussy.fr
Contatto per informazioni scientifiche
(Fonte di dati: WHO)
Aqsa YAR
114 rue Edouard Vaillant
Gustave Roussy
0033142116717
bpp.regulatory@gustaveroussy.fr
Autorizzazione da parte della commissione d’etica (Fonte di dati: BASEC)
Nome della commissione d’etica che rilascia l’autorizzazione (nel caso di studi multicentrici solo la commissione direttiva)
Commission
cantonale d’Éthique de la Recherche sur l’être humain Vaud (CER-VD)
Data di autorizzazione da parte della commissione d’etica
02.06.2021
Altri numeri di identificazione delle sperimentazioni
Numero di identificazione della sperimentazione della commissione d’etica (BASEC-ID)
(Fonte di dati: BASEC)
2021-00661
Secondary ID (Fonte di dati: WHO)
2019/2894
2019-001068-31-FR
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