HR-NBL2: High-risk neuroblastoma study 2.0 of SIOP-Europe- Neuroblastoma/SIOPEN: Randomised, international and multicentric phase 3 study that evaluates 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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Gustave Roussy

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Nov 2024 → ongoing

Decision date (initial)

2024-11-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-514917-36-00

EudraCT number

2019-001068-31

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Pharmacodynamic, Pharmacogenomic, Pharmacogenetic, Therapy, Safety

R-HDC:Comparison of the 3-year EFS rate of single HDC with busulfan andmelphalan (Bu-Mel) versus tandem HDC with Thiotepa followed by Bu-Mel in patients with high-risk neuroblastoma and a sufficient response toinduction chemotherapy.
R-RTx:Comparison of the 3-year-EFS rate of 21.6 Gy radiotherapy to thepreoperative tumour bed versus 21.6 Gy radiotherapy and a sequentialboost up to 36 Gy to the residual tumour in patients with macroscopicresidual disease after HDC and surgery.

Chemoimmunotherapy arm Metastatic response rate as per International Neuroblastoma Response
Criteria (INRC) 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 objectives 17

1. To describe the EFS, progression-free survival (PFS) and overallsurvival (OS) from diagnosis,
2. To describe the disease response (primary tumour and metastatic sites) as per INRC during and at the end of induction
3. To assess the correlation of the response of metastatic disease as per INRC during and after induction with survival (EFS, PFS and OS),
4. To describe the effect of HDC with Bu-Mel versus Thiotepa + Bu-Mel on PFS and OS
5. To describe and compare the toxicity associated with RAPID COJECand GPOH induction therapy,
6. To describe and compare the acute and long-term toxicities of bothHDC arms,
7. To describe the long-term toxicities of dinutuximab beta,
8. To investigate the relationship between the quality of surgicalresection of the primary tumour, local control and survival,
9. To investigate the impact of the radiotherapy dose on local relapserate
10. To collect data on selected circulating biomarkers, biological andgenomic features to determine and compare the effect of these onresponse to treatment, EFS, PFS and OS,
11. To describe, for each randomisation, 5-year EFS, 3 and 5-year PFS,and 3 and 5-year OS since the date of randomization,
12. To describe the 3 and 5-year EFS and OS of patients treated in thechemoimmunotherapy arm with TEMIRI/DB, Thio and Bu-Mel andcurrent high-risk neuroblastoma local/maintenance treatment
13. To evaluate ctDNA to monitor the tumour status,
14. To validate prospectively the new international criteria for response assessment in neuroblastoma,
15. To monitor the emergence in plasma of other targetable genomic alterations to inform the next generation of studies,
16. To describe the metastatic response rate after 2 courses of TEMIRI/DB for patients with insufficient metastatic response at the end of induction chemotherapy
17. To describe acute toxicities of the combination of TEMIRI/DB

Conditions and MedDRA coding

Patients with High Risk Neuroblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. HR-NBL2 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**. * In Germany, patients aged less than 18 months with stage M and without MYCN amplification will not be enrolled in HR-NBL2 trial. ** see section 8 (Biology) for details 2) No previous chemotherapy or up to 21 days after one cycle of Carboplatin-Etoposidechemotherapy 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 OR after the first cycle A of Rapid COJEC and before the beginning of cycle B (2nd course) of Rapid COJEC induction regimen 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 HR-NBL2 study 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 HR-NBL2 protocol 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 requirements. 6) Patients should be able and willing to comply with study visits and procedures as per protocol
2. 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 and no further treatment. OR - L2, M or Ms neuroblastoma, any age, with MYCN amplification, or focal high level MYC or MYCL amplification** ** see section 8 (Biology) for details 2) Age < 21 years at the time of randomization 3) Complete response (CR) or partial response (PR) at metastatic sites:  Bone disease: mIBG uptake 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 tumours).  Bone marrow disease: CR and/or minimal disease (MD) according to International Neuroblastoma Response Criteria  Other metastatic sites: CR. (after induction chemotherapy +/- surgery), except For distant lymph nodes for which PR is accepted with a possible secondary surgery 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. 4) Sufficient collected stem cells available; a total harvest of at least 6 x 106/kg CD34+ cells, to be stored in at least 4 separate bags to administer at least 3 x 106/kg CD34+ cells per rescue. 5) Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-HDC randomisation. 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. 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.5) Cellules souches autologues collectées ≥ 6 x 106 CD34+ cellules/kg et stockées avec un minimum de 4 fractions distinctes. 6) Consentement signé par le patient ou les parents / représentants légaux et accord de l’enfant en fonction de son âge pour l’entrée dans la randomisation R-HDC. 7) Les patients doivent être affiliés à un régime de sécurité sociale ou l’équivalent selon les exigences locales. 8) Les patients doivent être capables et disposés à participer aux visites d'étude et aux procédures conformément au protocole. Dans le cas d’un refus de participation des parents ou du patient à la randomisation R-HDC, ou d’un nombre insuffisant de cellules souches autologues collectées pour la double greffe mais avec un minimum de 3 x 106 CD34+ cellules/kg ou si le patient est âgé de plus de 21 ans ou en cas de toxicités viscérales alors la CHD sera réalisée avec le traitement standard par Bu-Mel et le patient sera éligible à la randomisation suivante. L’évaluation de la maladie locale sera réalisée après la CHD et la chirurgie.
3. 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: 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 randomisation. 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. In case of parents’/patient’s refusal of the randomisation, the patient will receive 21.6 Gy radiotherapy to the pre-operative tumour bed.
4. 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%

Exclusion criteria 3

1. 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.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)
2. Non-inclusion criteria common to all randomisations R-HDC, and R-RTx : 1. Any negative answer concerning the inclusion criteria of R- HDC or R-RTx will render the patient ineligible for the corresponding therapy phase randomisation. 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 randomisations. 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, and R-RTx) 5. Any uncontrolled intercurrent illness or infection that in the investigator opinion would impair study participation. 6. Concomittant use with yellow fever vaccine and with live virus or bacterial vaccines.
3. Non-inclusion criteria to chemoimmunotherapy arm: Any negative answer concerning the inclusion criteria of chemoimmunotherapy arm.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. R-HDC: 3-year EFS from the date of R-HDC randomisation R-RTx: 3-year EFS from the 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

Secondary endpoints 3

1. For the whole population of high-risk neuroblastoma: - 3- and 5-year EFS, PFS and OS calculated from diagnosis
2. For each randomized treatment: -5-year EFS, 3- and 5-year PFS and OS calculated from the date of each randomisation/ arm inclusion - Cumulative incidence of relapse/progression -Cumulative incidence of treatment related mortality and of disease related mortality - Overall and metastatic response as per the new INRG response criteria (including primary tumour after induction), skeletal response on mIBG, bone marrow response, local control - Therapy-related toxicity
3. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 11

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Gustave Roussy

Sponsor organisation

Institut Gustave Roussy

Address

114 Rue Edouard Vaillant

City

Villejuif

Postcode

94800

Country

France

Scientific contact point

Organisation

Institut Gustave Roussy

Contact name

Bureau projet Promotion- DRC

Public contact point

Organisation

Institut Gustave Roussy

Contact name

Bureau projet Promotion- DRC

Third parties 2

Locations

13 EU/EEA countries · 156 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 239 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications