Very High Risk Neuroblastoma MedDRA version: 20.0 Level: PT Classification code 10029260 Term: Neuroblastoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: LLT Classification code 10029261 Term: Neuroblastoma NOS System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Pharmaceutical Form: Concentrate for solution for injection
INN or Proposed INN: BUSULFAN
Other descriptive name: BUSULFAN
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
C
Sponsors
Gustave Roussy
Eligibility
Sex/Gender
All
Inclusion 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 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
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 RRTx) 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 funtion: 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: R-I: Comparison of the 3 years EFS rate of 2 induction regimens, GPOH and RAPID COJEC, in patients with high-risk neuroblastoma. R-HDC: Comparison of the 3 years 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 and sufficient response to induction chemotherapy. R-RTx: Comparison of the 3 years 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. Chemoimmunotherapy arm Metastatic response rate 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 Objective: To describe the EFS, PFS and overall survival (OS) from diagnosis, To describe the effect of RAPID COJEC and GPOH induction regimens on metastatic disease during and after the end of induction, To assess the correlation of the response of metastatic disease during and afterinduction with survival (EFS and OS), To describe the effect of HDC with Bu-Mel versus Thiotepa + Bu-Mel on OS, To describe, for each randomisation, 5-year EFS, 3 and 5-year PFS, and 3 and 5-year OS since date of randomization, To describe the 3 and 5-year EFS and OS of patients treated in the intensified arm with TEMIRI, Thio and Bu-Mel because of insufficient response at the end of induction treatment, To evaluate ctDNA to monitor the tumour status To describe the metastatic response rate after 2 courses of TEMIRI/DB for patients with insufficient metastatic response at the end of induction chemotherapy To describe acute toxicities of the combination of TEMIRI/DB;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 R | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 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;Timepoint(s) of evaluation of this end point: 5 years | — |
Countries
Australia, Austria, Belgium, Croatia, Czechia, Czech Republic, 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
Contacts
Public ContactAqsa YAR
Gustave Roussy
Outcome results
None listed