International and multicentric 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

Phase 1

• Conditions: 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]

• Registration Number: EUCTR2019-001068-31-DK
• Lead Sponsor: Gustave Roussy

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-04-14
• Last Update Posted: 3 June 2024

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 800

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

HR-NBL2 eligibility criteria: (...)
R-I eligibility criteria: (...)
R-HDC eligibility criteria: (...)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 local macroscopic disease, all patients will receive 21,6-Gy radiotherapy to the pre-operative tumour bed
- In case of local macroscopic residual disease, patients will be eligible to R-RTx if the following criteria are met:
(...)
In case of parents’/patient’s refusal of the randomisation, the patient will receive 21.6 Gy radiotherapy to the pre-operative tumour bed.

Chemoimmunotherapy arm eligibility criteria:
1.Insufficient metastatic response at the end of induction chemotherapy, defined as:
•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 tumours)
OR
•Bone marrow disease: SD according to International Neuroblastoma Response Criteria OR
•Other metastatic sites: PR or SD. For distant lymph nodes : PR and not resectable or SD.
2.Performance status = 50%.
3.Hematological status: ANC>0.75x109/L without G-CSF for at least 48 hours (or ANC = 0.50 x 109 /L in case of bone marrow involvement), platelets > 50x 109/L and rising, without platelets transfusion for 72 hours.
4.AST or ALT =7.5 ULN and total bilirubin =1.5 ULN. In patients with liver metastases, total bilirubin =2.5 ULN is allowed.
5.No active infection;
6.No grade >2 gastrointestinal toxicity.
7.No grade = 3 toxicity related to previous treatment.
8.Oxygen saturation > 94%

Are the trial subjects under 18? yes
Number of subjects for this age range: 790
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 10
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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/1.73m² (toxicity = grade 2). If GFR < 60ml/min/1.73m², 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.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified