HR-NBL2: High-risk neuroblastoma study 2.0 of SIOP-Europe-Neuroblastoma/SIOPEN

Australia, Austria, Belgium, Croatia, Czech Republic, Czechia, Denmark, Finland, France, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Lithuania, Netherlands, New Zealand, Norway, Poland, Portugal, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom, Uruguay (ICTRP)

ICTRP Studien-ID
EUCTR2019-001068-31 (ICTRP)

Offizieller Titel (Genehmigt von der Ethikkommission)
High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN) (BASEC)

Wissenschaftlicher Titel
High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN) - HR-NBL2/SIOPEN (ICTRP)

Öffentlicher Titel
High-Risk Neuroblastoma Study (ICTRP)

Untersuchte Krankheit(en)
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] (ICTRP)

Untersuchte Intervention

Product Name: Cisplatino
Product Code: [Cisplatino]
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: CISPLATINO
CAS Number: 15663-27-1
Current Sponsor code: Cisplatino
Other descriptive name: Cisplatin
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: Vincristina
Product Code: [Vincristina]
Pharmaceutical Form: Solution for injection
INN or Proposed INN: VINCRISTINA
CAS Number: 57-22-7
Current Sponsor code: Vincristine
Other descriptive name: Vincristine
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 1-

Product Name: Tiotepa
Product Code: [Tiotepa]
Pharmaceutical Form: Powder for concentrate for solution for infusion
INN or Proposed INN: TIOTEPA
CAS Number: 52-24-4
Current Sponsor code: Thiotepa
Other descriptive name: Thiotepa
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Product Name: Etoposide
Product Code: [Etoposide]
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: ETOPOSIDE
CAS Number: 33419-42-0
Current Sponsor code: Etoposide
Other descriptive name: Etoposide
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Product Name: Vindesina
Product Code: [Vindesina]
Pharmaceutical Form: Powder for solution for injection
INN or Proposed INN: VINDESINA SOLFATO
CAS Number: 53643-48-4
Current Sponsor code: Vindesine
Other descriptive name: Vindesine
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Product Name: Carboplatino
Product Code: [Carboplatino]
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: CARBOPLATINO
CAS Number (ICTRP)

Studientyp
Interventional clinical trial of medicinal product (ICTRP)

Studiendesign
Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2 (ICTRP)

Ein-/Ausschlusskriterien
Gender:
Female: yes
Male: yes

Inclusion criteria:
R-I eligibility criteria:
- Established diagnosis of neuroblastoma according to the SIOPENmodified 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
- No previous chemotherapy (except one cycle of Etoposide-Carboplatin)
- 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 11). Female patients who are lactating must agree to stop breast-feeding.
- Written informed consent to enter the R-I randomization from patient or parents/legal representative, patient, and age-appropriate assent.
- Patient affiliated to a social security regimen or beneficiary of the same according to local requrements.
- 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 in (ICTRP)

Exclusion criteria:
Non-inclusion criteria specific to the R-I randomization (RAPID COJEC/GPOH) :
1) Urinary outflow obstruction
2) severe arrhythmia, heart failure, previous cardiac infarct, acute inflammatory heart disease
3) severe peripheral neuropathy
4) demyelinating form of Charcot-Marie-Tooth syndrome
5) hearing impairment
6) Concurrent prophylactic use of phenytoin
7) cardiorespiratory disease that contraindicates hyperhydration

Non-inclusion criteria common to all randomizations (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/1.73m? (toxicity = grade 2). If GFR < 60ml/min/1.73m?, 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
13) Concomitant use with St John?s Wort (Hypericum Perforatum).


Primäre und sekundäre Endpunkte
Main Objective: 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 Objective: Describe the EFS and OS from date of randomization of the whole cohort
Describe the effect of RAPID COJEC and GPOH induction regimens on metastatic disease during and after the end of induction
Assess the correlation of the response of metastatic disease during and after induction with survival (EFS and OS)
Describe the effect of HDC with Bu-Mel versus Thiotepa+Bu-Mel on PFS and OS
Describe and compare the toxicity associated with RAPID COJEC and GPOH induction therapy
Describe and compare the acute and long term toxicities of both HDC arms
Describe the long term toxicities of dinutuximab bet
Investigate the relationship between the quality of surgical resection of the primary tumor, local control and survival
Investigate the impact of the radiotherapy dose on local relapse rate
Collect data on selected circulating biomarkers, biological and genomic features to determine and compare the effect of these on response to treatment, EFS, incidence of relapse/progression and OS;Primary end point(s): R-I: 3-year EFS from date of R-I randomization
R-HDC: 3-year EFS from date of R-HDC randomization
R-RTx: 3-year EFS from date of RTx randomization;Timepoint(s) of evaluation of this end point: 3 years (ICTRP)

Secondary end point(s): For the whole population of high-risk neuroblastoma:
- 3- and 5-year EFS, PFS and OS calculated from date of randomization
For each treatment phase:
- 5-year EFS, 3- and 5-year PFS and OS calculated from date of
randomization
- Cumulative incidence of relapse/progression
- Cumulative incidence of treatment related mortality and of disease
related mortality
- Overall response as per the new INRG response criteria [Park JR, JCO
2017] (including primary tumor after induction), skeletal response on
MIBG, bone marrow response, local control
- Therapy-related toxicity;Timepoint(s) of evaluation of this end point: 5 years (ICTRP)

Registrierungsdatum
04.06.2021 (ICTRP)

Einschluss des ersten Teilnehmers
19.04.2021 (ICTRP)

Sekundäre Sponsoren
nicht verfügbar

Weitere Kontakte
Coordinatore Nazionale, albertogaraventa@gaslini.org, 01056362714, IRCCS ?Istituto Giannina Gaslini? (ICTRP)

Sekundäre IDs
HR-NBL2/SIOPEN, 2019-001068-31-FR (ICTRP)

Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
nicht verfügbar

Weitere Informationen zur Studie
https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2019-001068-31 (ICTRP)