High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)

High-Risk Neuroblastoma Clinical Trial

— HR-NBL2  

Official title:

High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04221035
• Other study ID #: 2019-001068-31
• Secondary ID: 2019/2894
• Status: Recruiting
• Phase: Phase 3
• Start date: November 5, 2019
• Est. completion date: November 2032

Study information

• Verified date: May 2024
• Source: Gustave Roussy, Cancer Campus, Grand Paris
• Contact: Claudia Pasqualini, MD PhD
• Phone: +33 (0)1 42 11 42 11
• Email: claudia.pasqualini[@]gustaveroussy.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an international multicenter, open-label, randomized phase III trial including three sequential randomizations to assess efficacy of induction and consolidation chemotherapies and radiotherapy for patients with high-risk neuroblastoma.

Description:

This is an international multicenter, open-label, randomized phase III trial including three sequential randomizations to assess efficacy of induction and consolidation chemotherapies and radiotherapy for patients with high-risk neuroblastoma.

The first randomization (R-I) will compare the efficacy of two induction chemotherapies (RAPID COJEC and GPOH regimens) in a phase III setting. The primary endpoint will be the 3-year EFS from date of randomization . The R-I randomization will be stratified on age, stage, MYCN status and countries.

The second randomization (R-HDC) will compare the efficacy of single HDC with Bu-Mel versus tandem HDC with Thiotepa followed by Bu-Mel. The primary endpoint is 3-year EFS calculated from the date of the R-HDC randomization. The R-HDC randomization will be stratified on the age, stage, MYCN status, induction chemotherapy regimen, response to induction phase and countries.

The impact of local treatment in this phase III setting will be assessed, according to the presence or not of a macroscopic residual disease after surgery and HDC.

In case of macroscopic residual disease, 21.6 Gy radiotherapy to the preoperative tumor bed will be randomized (R-RTx) versus the same treatment plus a sequential boost of additional 14.4 Gy to the residual tumor. The primary endpoint of R-RTx is 3-year EFS from the date of the R-RTx randomization. The R-RTx randomization will be stratified on age, stage, MYCN status, induction chemotherapy regimen, HDC regimen and countries.

In case of no macroscopic residual disease, 21.6 Gy radiotherapy will be delivered to the preoperative tumor bed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 800
• Est. completion date: November 2032
• Est. primary completion date: November 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 21 Years

Eligibility

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 R-I randomisation (RAPID COJEC/GPOH) low/intermediate risk neuroblastoma in Germany/Netherlands for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification

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.

2. No previous chemotherapy or up to 21 days after one cycle of Carboplatin-Etoposide chemotherapy 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

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

R-I eligibility criteria:

• Written informed consent to enter the R-I randomisation from patient or parents/legal representative, patient, and age- appropriate assent.

In case of parents'/patient's refusal to R-I, or Organ toxicity exclusion criteria at diagnosis, patients can still be enrolled in HR- NBL2 trial with parents'/patient's consent before or within 3 weeks from the beginning of chemotherapy

R-HDC randomisation (Single HDC Bu-Mel/ Tandem HDC Thiotepa+Bu-Mel) Etoposide or one course of the current protocol for low/intermediate risk neuroblastoma in Germany/Netherlands). Patients will be treated with the standard induction regimen per country (Rapid COJEC or GPOH) and will be potentially eligible for subsequent randomisations.

Randomisation for HDC strategy will be performed at the end of induction after the disease evaluation and after surgery of the primary tumour for those patients who will receive surgery before HDC.

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

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.

R-RTx randomisation (Local Radiotherapy) Chemoimmunotherapy arm

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.

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%

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 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. Concomitant use with yellow fever vaccine and with live virus or bacterial vaccines.

7. 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.

Related Conditions & MeSH terms

• High-Risk Neuroblastoma
• Neuroblastoma

Intervention

Drug:
• Vincristine
1.5 mg/m2 (max dose 2 mg)
• Carboplatin
750 mg/m2
• Etoposide
175 mg/m2
• Vindesine
3 mg/m2/day (max dose 6 mg)
• Dacarbazine
200 mg/m2/day
• Ifosfamide
1500 mg/m2/day
• Doxorubicin
30 mg/m2/dose
• Busulfan
< 9kg: 1.0 mg/kg/dose 9 kg to < 16 kg : 1.2 mg/kg/dose 16 kg to 23 kg : 1.1 mg/kg/dose >23 kg to 34 kg: 0.95 mg/kg/dose >34 kg: 0.8 mg/kg/dose Infusion IV over 2 hours Administration every 6 hours for a total of 16 doses
• Melphalan
140 mg/m2/dose IV short infusion (15'), at least 24 h after the last busulfan dose
• Thiotepa
300 mg/m2/day over 2 hours

Radiation:
• Radiotherapy
21.6 Gy 21.6 Gy + boost de 14.4 Gy

Drug:
• Dinutuximab Beta
Patients >12 kg are dosed based on the BSA: 10 mg/m^2/day Patients = 12 kg are dosed according to their body weight: 0.33 mg/kg/day
• Cisplatin
80 mg/m2/24h
• Temozolomide 100 MG
100 mg/m²/Day
• Irinotecan
50 mg/m²/jour de J0 à J4
• Cyclophosphamid
Cyclophosphamide has been demonstrated to have a cytostatic effect in many tumour types. The active metabolites of cyclophosphamide are alkylating agents which transfer alkyl groups to DNA during the process of cell division, thus preventing normal synthesis of DNA.

Locations

Country	Name	City	State
Australia	Children's Cancer Centre, Monash Children's Hospital	Clayton
Australia	Oncology/Haematology Department, Perth Children's Hospital	Nedlands
Australia	Children's Cancer & Haematology Services, John Hunter Children's Hospital	New Lambton Heights
Australia	Australian and New Zealand Children's Hematology/oncology Group	Sydney
Australia	sydney children Hospital	Sydney
Australia	Sydney children Hospital	Sydney	Randwick
Australia	Cancer Centre for Children, The Children's Hospital	Westmead
Belgium	Cliniques Universitaires Saint-Luc (UCL)	Brussel
Belgium	Hôpital Universitaire des Enfants Reine Fabiola (ULB)	Brussels
Belgium	University Hospital Gent	Gent
Belgium	University Hospitals Leuven	Leuven
Belgium	CHR Citadelle	Liège
Czechia	Klinika detské onkologie FN Brno	Brno
Czechia	University Hospital Motol	Prague,	Prague
Denmark	Aarhus University Hospital	Aarhus
Denmark	Department of Paediatrics and Adolescent Medicine, Rigshospitalet	Copenhagen
Denmark	The Hans Christian Andersen Children's Hospital, University of Southern Denmark	Odense
Finland	New Children's Hospital, Helsinki University Hospital, Helsinki and Uusimaa Hospital District	Helsinki
Finland	Kuopio University Hospital	Kuopio
Finland	Oulu University Hospital	Oulu
Finland	Tampere University Hospital	Tampere
Finland	Turku University Hospital	Turku
France	CHU d'AMIENS	Amiens
France	CHU angers	Angers
France	CHU-Pôle Médico-Chirurgical de l'Enfant et l'Adolescant	Besançon
France	CHU Bordeaux	Bordeaux
France	Groupe Hospitalier Pellegrin - Chu - Bordeaux	Bordeaux
France	CHU Brest	Brest
France	CHU Brest - Hôpital du Morvan	Brest
France	Centre François Baclesse	Caen
France	CHU de Caen	Caen
France	CHU Estaing	Clermont-Ferrand
France	Centre Georges-François Leclerc	Dijon
France	Hopital d'enfants Marechal de lattre	Dijon
France	Hôpital Couple-Enfant CHU de Grenoble	Grenoble
France	Chu de La Reunion - St Denis	La Réunion
France	centre Oscar lambert	Lille
France	Hôpital de la Mère et de l'Enfant - CHU Limoges	Limoges
France	Centre Léon Berard	Lyon
France	hopital la Timone	Marseille
France	CHRU Nancy-Hôpital Brabois Enfant	Nancy
France	Institut de cancérologie de Loraine	Nancy
France	Centre Antoine Lacassagne	Nice
France	CHU Nice-Hôpital d'Archet	Nice
France	Hôpital Armand Trousseau	Paris
France	institut Curie	Paris
France	CHU Poitiers	Poitiers
France	Hôpital Américain -CHU Reims	Reims
France	Centre Eugène Marquis	Rennes
France	CHU Rennes	Rennes
France	Hôpital des Enfants - CHU Rouen	Rouen
France	CHU Saint Etienne	Saint-Étienne
France	Institut de cancérologie de l'Ouest - Sité René Gauducheau	Saint-Herblain
France	CHU Haute Pierre	Strasbourg
France	Institut de Cancérologie Strasbourg	Strasbourg
France	Hopital des enfants-CHU Toulouse	Toulouse
France	IUCT Oncopole	Toulouse
France	CHU Tours Hôpital Clocheville	Tours
France	Gustave Roussy	Villejuif	Val De Marne
Germany	charite universitatsmedizin Berlin	Berlin
Germany	Uniklinik Köln, Klinik und Poliklinik für Kinder und Jugendmedizin	Köln
Greece	"MITERA" Private, General, Obstetrics - Gynaecology, Paediatric Clinic S.A.	Athens
Greece	Children's General Hospital "AGHIA SOFIA"	Athens
Greece	Children's General Hospital "I AGHIA SOFIA"	Athens
Greece	Children's General Hospital "P. & A. KYRIAKOU"	Athens
Greece	University General Hospital of Heraklion (UnGHH)	Heraklion
Greece	General Hospital of Thessaloniki "IPPOKRATIO"	Thessaloniki
Greece	University General Hospital of Thessaloniki "AHEPA"	Thessaloniki
Israel	RAMBAM Medical Center	Haifa
Italy	A.O.U Policlinico di Bari	Bari
Italy	Spedali civili Ospedale Dei Bambini Oncoematologia pediatrica e TMO	Brescia
Italy	policlinico rodolico San marco	Catania
Italy	Azienda ospedaliero universtaria Anna Meyer	Firenze
Italy	instituto Giannina Gaslini genova	Genova
Italy	IRCCS "Istituto Giannina Gaslini"	Genova
Italy	Azienda Policlinico di Modena	Modena
Italy	Azienda ospedaliero universitaria di Parma	Parma
Italy	Policlino San matteo di Pavia	Pavia
Italy	U.O Pediatria, SS Oncoematologia pediatrica	Rimini
Italy	IRCCS Burlo Garoflo oncoematologia	Trieste
Italy	U.O.C oncoematologia pediatrica ospedale Donna Bambino	Verona
Lithuania	National Cancer Institute	Vilnius
Lithuania	Vilnius University Hospital Santaros Klinikos	Vilnius
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Princess Maxima center	Utrecht
Norway	Haukeland University Hospital	Haukeland
Norway	Oslo University Hospital	Oslo
Norway	University Hospital Northern Norway, Tromsoe	Tromsø
Norway	St Olavs Hospital,	Trondheim
Slovakia	Children's University Hospital Banská Bystrica	Banská Bystrica
Slovakia	NÚDCH- National Institute of Children's Diseases,	Bratislava
Slovakia	Children's University Hospital Košice	Košice
Slovenia	University medical center Ljubljana, University Children's Hospital Ljubljana, Slovenia	Ljubljana
Spain	Hospital Universitario Son Espases	Balea
Spain	Hospital Universitario Vall D´Hebron	Barcelona
Spain	Hospital Universitario Cruces	Cruces
Spain	Hospital Clínico Universitario Virgen de la Arrixaca	El Palmar
Spain	Hospital Universitario Infantil Niño Jesús	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Regional Universitario de Málaga	Málaga
Spain	Hospital Universitario Donostia	San Sebastián
Spain	Hospital Clínico Universitario de Santiago	Santiago De Compostela
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Universitario Politécnico de La FE	Valence
Sweden	Sahlgrenska University Hospital	Gothenburg
Sweden	Linköping University Hospital	Linköping
Sweden	Skåne University Hospital	Lund
Sweden	Karolinska University Hospital, Stockholm	Stockholm
Sweden	Norrland University Hospital	Umeå
Sweden	Uppsala University Hospital	Uppsala
Switzerland	Kantonsspital Aarau AG Klinik für Kinder und Jugendliche	Aarau
Switzerland	Universitäts-Kinderspital beider Basel (UKBB)	Basel
Switzerland	Ospedale San Giovanni Pediatria, Emato-oncologia pediatrica	Bellinzona
Switzerland	Inselspital, Universitätsklinik für Kinderheilkunde	Bern
Switzerland	HUG Hôpitaux Universitaires de Genève Unité d'Hémato-Oncologie Pédiatrique	Geneva
Switzerland	CHUV - Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	Luzerner Kantonsspital, Kinderspital pädiatrische Hämatologie/Onkologie	Lucerne
Switzerland	Ostschweizer Kinderspital Hämatologie/Onkologie Claudiusstrasse 6	Saint Gallen
Switzerland	Division of Pediatric Oncology Universitäts-Kinderspital Zürich	Zürich
United Kingdom	Royal Aberdeen Children's Hospital	Aberdeen
United Kingdom	Royal Belfast Hospital for Sick Children	Belfast
United Kingdom	Birmingham children's Hospital	Birmingham
United Kingdom	University Hospitals Birmingham Queen Elisabeth Hospital(UHB)	Birmingham
United Kingdom	University Hospitals Bristol and Weston NHS Foundation Trust	Bristol
United Kingdom	Addenbrookes Hospital, Cambridge	Cambridge
United Kingdom	Noah's Ark Children's Hospital for Wales - Cardiff	Cardiff
United Kingdom	Royal Hospital for Sick Children - Edinburgh	Edinburgh
United Kingdom	Royal Hospital for Children Glasgow	Glasgow
United Kingdom	Leeds General Infirmary	Leeds
United Kingdom	Alder Hey Children's Hospital - Liverpool	Liverpool
United Kingdom	Great Ormond Street Hospital - London	London
United Kingdom	Royal Manchester Children's Hospital	Manchester
United Kingdom	Royal Victoria Infirmary, Newcastle	Newcastle
United Kingdom	Nottingham Children's Hospital	Nottingham
United Kingdom	Sheffield Children's Hospital	Sheffield
United Kingdom	Southampton General Hospital	Southampton
United Kingdom	Royal Marsden Hospital	Sutton

Sponsors (1)

Lead Sponsor	Collaborator
Gustave Roussy, Cancer Campus, Grand Paris

Countries where clinical trial is conducted

Australia,  Belgium,  Czechia,  Denmark,  Finland,  France,  Germany,  Greece,  Israel,  Italy,  Lithuania,  Netherlands,  Norway,  Slovakia,  Slovenia,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event free survival (EFS)	Event free survival	Assessed at each end of randomization sequences up to one year