Zusammenfassende Beschreibung der Studie (Datenquelle: 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.
Untersuchte Krankheiten(Datenquelle: BASEC)
Neuroblastome à haut risque
Health conditions
(Datenquelle: 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]
Seltene Krankheit
(Datenquelle: BASEC)
Nein
Untersuchte Intervention (z.B. Medikament, Therapie, Kampagne)
(Datenquelle: 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
(Datenquelle: WHO)
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: BUSULFAN
Other descriptive name: BUSULFAN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 0.5-
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 sol
Kriterien zur Teilnahme an der Studie
(Datenquelle: 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.
Ausschlusskriterien
(Datenquelle: 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
(Datenquelle: WHO)
Gender:
Female: yes
Male: yes
Inclusion criteria:
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 with MYCN amplification, any age with MYCN amplification, or focal high level MYC or MYCL amplification
* In Germany, patients aged less than 18 months with stage M and without MYCN amplification will not be enrolled in HR-NBL2 trial.
2) No previous chemotherapy or up to 21 days after one cycle of chemotherapy 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. Sexually active patients must agree to use acceptable and appropriate contraception while on HRNBL2 study drug and for one year after stopping the study. Acceptable contraception is defined in CTFG Guidelines ?Recommendations related to contraception and pregnancy testing in clinical trials? (Appendix 11). Female patients who are lactating must agree to stop breast-feeding.
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 (see section 8 (Biology) for details)
2) Age < 21 years
3) Complete response (CR) or partial response (PR) at metastatic sites:
? Bone disease: MIBG uptake (or FDG-PET uptake for MIBG-nonavid tumors) completely resolved or SIOPEN score = 3 and at least 50% reduction in mIBG score (or = 3 bone lesions and at least 50% reduction in number of FDG-PET-avid bone lesions for MIBG-nonavid tumors).
? Bone marrow disease: CR and/or minimal disease (MD) according to International Neuroblastoma Response Criteria [61;15].
? Other metastatic sites: complete response after induction chemotherapy +/- surgery.
4) Acceptable organ function and performance status
? Performance status = 50%.
? Hematological status: ANC>0.5x109/L, platelets > 20x 109/L
? Cardiac function: (? 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.
R-RTx if the follow
Exclusion criteria:
Non-inclusion criteria specific to the R-I randomization (RAPID COJEC/GPOH) :
1)Urinary outflow obstruction
2)severe arrhythmia, heart failure, previous cardiac infarct, acute inflammatory heart disease
3)severe peripheral neuropathy
4)demyelinating form of Charcot-Marie-Tooth syndrome
5)hearing impairment
6)Concurrent prophylactic use of phenytoin
7)cardiorespiratory disease that contraindicates hyperhydration
Non-inclusion criteria common to all randomizations (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 to discuss about the treatment
4) Dyspnea at rest and/or pulse oximetry <95% in air.
5) Any uncontrolled intercurrent illness or infection that in the investigator opinion would impair study participation.
6) Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving his consent.
7) Participating in another clinical study with an IMP while on study treatment.
8) Concomittant use with yellow fever vaccine and with live virus or 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 known
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13) Concomitant use with St John?s Wort (Hypericum Perforatum).
Non-inclusion criteria to R-HDC:
Patients with insufficient metastatic response at the end of induction SIOPEN score >3 or less than 50% reduction in MIBG score or >3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG non-avid tumor, will not be elegible for R-HDC
-
Weitere Informationen zur Studie
Datum der Studienregistrierung
02.02.2022
Einschluss der ersten teilnehmenden Person
05.09.2022
Rekrutierungsstatus
Not Recruiting
Wissenschaftlicher Titel
(Datenquelle: 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. - HR-NBL2
Studientyp
(Datenquelle: WHO)
Interventional clinical trial of medicinal product
Design der Studie
(Datenquelle: 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
Phase
(Datenquelle: WHO)
Human pharmacology (Phase I): noTherapeutic exploratory (Phase II): noTherapeutic confirmatory - (Phase III): yesTherapeutic use (Phase IV): no
Primäre Endpunkte
(Datenquelle: 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 year 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.
;Secondary Objective: To describe the EFS, PFS and overall survival (OS) from date of randomization of the whole cohort,To describe the effect of RAPID COJEC and GPOH induction regimens on metastatic disease during and after the end of induction,To assess the correlation of the response of metastatic disease during and after induction with survival (EFS and OS),To describe the effect of HDC with Bu-Mel versus Thiotepa + Bu-Mel on OS. To describe, for each randomisation,5-year EFS, 3 and 5-year PFS, and 3 and 5-year OS since date of randomisation.To describe the 3 and 5-year EFS and OS of patients treated in the intensified arm with TEMIRI, Thio and Bu-Mel because of insufficient response at the end of induction treatment.To evaluate ctDNA to monitor the tumor status.To validate prospectively the new international criteria for response assessment in neuroblastoma,To monitor the emergence in pasma of other targetable genomic alterations to inform the next generation of studies. ;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
;Timepoint(s) of evaluation of this end point: 3 years
Sekundäre Endpunkte
(Datenquelle: 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
;Timepoint(s) of evaluation of this end point: 5 years
Kontakt für Auskünfte
(Datenquelle: WHO)
PHRC
Ergebnisse der Studie
(Datenquelle: WHO)
Zusammenfassung der Ergebnisse
noch keine Angaben verfügbar
Link zu den Ergebnissen im Primärregister
noch keine Angaben verfügbar
Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
noch keine Angaben verfügbar
Studiendurchführungsorte
Durchführungsorte in der Schweiz
(Datenquelle: BASEC)
Aarau, Basel, Bellinzona, Bern, Genf, Lausanne, Luzern, St Gallen, Zürich
Durchführungsländer
(Datenquelle: 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
Kontakt für weitere Auskünfte zur Studie
Angaben zur Kontaktperson in der Schweiz
(Datenquelle: BASEC)
PD Dr. med. Dr. sc. nat. Raffaele Renella
+41 21 314 14 33
raffaele.renella@chuv.ch
Kontakt für allgemeine Auskünfte
(Datenquelle: WHO)
Aqsa YAR
114 rue Edouard Vaillant
Gustave Roussy
0033142116717
bpp.regulatory@gustaveroussy.fr
Kontakt für wissenschaftliche Auskünfte
(Datenquelle: WHO)
Aqsa YAR
114 rue Edouard Vaillant
Gustave Roussy
0033142116717
bpp.regulatory@gustaveroussy.fr
Bewilligung durch Ethikkommission (Datenquelle: BASEC)
Name der bewilligenden Ethikkommission (bei multizentrischen Studien nur die Leitkommission)
Commission
cantonale d’Éthique de la Recherche sur l’être humain Vaud (CER-VD)
Datum der Bewilligung durch die Ethikkommission
02.06.2021
Weitere Studienidentifikationsnummern
Studienidentifikationsnummer der Ethikkommission (BASEC-ID)
(Datenquelle: BASEC)
2021-00661
Secondary ID (Datenquelle: WHO)
2019/2894
2019-001068-31-FR
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