Clinical trial NCT04221035: High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)
Official title: High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: High-Risk Neuroblastoma
Patient With Insufficient Response Chemoimmunotherapy
Lead sponsor: Gustave Roussy, Cancer Campus, Grand Paris
Sponsor class: OTHER
First posted: 2020-01-09
Enrollment: 800
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

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