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Etude : HR-NBL2 /



ATTENTION : pour chaque essai clinique, les éléments affichés ci-dessous ne sont pas exhaustifs, et le protocole fourni par le promoteur reste l’unique document à consulter pour mener à bien un essai clinique sur centre. Pour plus d'informations, contactez le référent du territoire concerné.


Acronyme
Nom
Traitement
Type d'étude
MÀJ
Présentation de l'étude
Acronyme : HR-NBL2

Nom :

Traitement : Métastatique ou localement avancé

Type d'étude : Ciblage moléculaire / Innovation thérapeutique

Dernière MÀJ : 17/02/2020
Titre
Spécialité(s)
CIM10 - Localisation(s)
Informations principales
Titre : High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN) Etude internationale multicentrique de phase 3 randomisée qui évalue et compare 2 stratégies de traitement dans 3 phases thérapeutiques (induction, chimiothérapie à haute dose et radiothérapie) pour les patients atteints de neuroblastome de haut-risque

Spécialité : Oeil, cerveau et autres parties du système nerveux central
Localisation : C.9 - Oeil, cerveau et autres parties du système nerveux central : autres et non précisés
Schéma
Phase
Stade
Ligne(s)
Informations complémentaires
Schéma : Le protocole HRNBL2 est un protocole destiné aux patients porteurs d’un neuroblastome de haut risque (maladie métastatique chez des enfants de plus de un an ou maladie avec une amplification de l’oncogène NMYC). Il repose sur l’expérience du groupe européen SIOPEN et les informations issues de l’expérience internationale. Il comporte quatre phases de traitement.

La phase d’induction consiste en de la chimiothérapie conventionnelle dont l’objectif est de réduire au maximum l’envahissement métastatique. Ce protocole va comparer deux types de chimiothérapie, le protocole issu de l’expérience du groupe SIOPEN et celui utilisé jusqu’à maintenant par le groupe allemand.

La phase de consolidation consiste en l’administration d’une chimiothérapie à haute dose dont la toxicité hématologique est contrôlée grâce à une greffe de cellules souches hématopoïétiques prélevés auparavant par cytaphérèse chez le patient. Le protocole évalue le bénéfice potentiel de deux cures de chimiothérapie à haute doses par rapport à une cure qui est le traitement classique.

Le traitement local consiste en une chirurgie de la tumeur primitive
généralement réalisée entre la phase d’induction et celle de consolidation et une radiothérapie du site de cette tumeur primitive faite après la phase de consolidation. Pour les patients pour lesquels la tumeur n’aura pas pu être totalement enlevée sera posée la question d’un bénéfice d’une réirradiation plus importante à ce niveau.

Enfin le traitement est complété par une phase d’entretien comprenant un agent «matûrant» donné en gélule l’acide rétinoïque avec six cures et une immunothérapie avec un anticorps administré par voie intra veineuse en cinq cures de dix jours.


Main objective of the trial:

R-I:
Comparison of the EFS rate of 2 induction regimens, GPOH and RAPID COJEC, in patients with high-risk neuroblastoma.

R-HDC:
Comparison of the 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.

R-RTx:
Comparison of the 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 objectives of the trial:
To describe the EFS 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 progression-free survival (PFS) and OS,To describe and compare the toxicity associated with RAPID COJEC and GPOH induction therapy,To describe and compare the acute and long term toxicities of both HDC arms,To describe the long term toxicities of dinutuximab beta,To investigate the relationship between the quality of surgical resection of the primary tumor, local control and survival,To investigate the impact of the radiotherapy dose on local relapse rate etc.

Phase : III

Stade : Métastasique

1
Informations libres de droit
Critères d'inclusion
Critères de non-inclusion
Informations libres de droit
Critères d'inclusion et de non-inclusion
Critères d'inclusion : 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
* 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 (except one cycle of Etoposide-Carboplatin or, in Germany and Nertherlands, one course of the current protocol for low/intermediate risk neuroblastoma)
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 study drug and for one year after stopping the study drug. Acceptable contraception is defined in CTFG Guidelines “Recommendations related to contraception and pregnancy testing in clinical trials” (Appendix 12). 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
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 [Park JR, JCO 2017; Burchill S, Cancer 2017].
 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: Shortening fraction ≥ 28% or ejection fraction ≥ 55% by echocardiogram, no clinical congestive heart failure. Normal pulmonary artery pressure.
 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 following criteria are met:
1) No evidence of disease progression after HDC/ASCR.
2) Interval between the last ASCR and radiotherapy start between 60 and 90 days.
3) Performance status greater or equal 50%.
4) Hematological status: ANC >0.5x109/L, platelets > 20x109/L.
5) Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-RTx randomization.
6) Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
7) Patients should be able and willing to comply with study visits and procedures as per protocol.

Critères de non-inclusion : 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/1.73m² (toxicity ≥ grade 2). If GFR < 60ml/min/1.73m², call national principal investigator to discuss.the feasibility.
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).
NCT
Promoteur
Coordonnateur
Informations relatives au promoteur
NCT :
NCT04221035
Promoteur :
INSTITUT GUSTAVE ROUSSY
Type de sponsor : Institutionnel
114 Rue Edouard Vaillant -
94800 VILLEJUIF

Coordonnateur :
Docteur Dominique VALTEAU-COUANET
Centre investigateur
Investigateur
TEC / ARC / IDE
État
MÀJ
Informations relatives aux investigateurs
Centre investigateur :
Centre Oscar Lambret - 3 Rue Frédéric Combemale - 59000 LILLE

Investigateur :
Docteur Anne-Sophie DEFACHELLES

TEC / ARC / IDE :
Unité Intégrée de Recherche Clinique
investigation@
o-lambret.fr
03.20.29.59.35

Statut de l'essai : OUVERT

MAJ : 17/02/2020