Phase 3 Study of Busulfan, Melphalan, and Chemoimmunotherapy in High-Risk Neuroblastoma Patients with Insufficient Metastatic Response
- Trial ID
- 2024-514917-36-00
- Protocol
- 2019/2894
- Sponsor
- Institut Gustave Roussy
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the 3-year event-free survival (**EFS**) rate of two induction regimens, GPOH and RAPID COJEC, in patients with high-risk neuroblastoma. This comparison is clinically relevant as it aims to identify the more effective induction regimen, potentially improving survival outcomes for this high-risk patient population. Additionally, the study seeks to compare the 3-year EFS rate of single high-dose chemotherapy (**HDC**) with busulfan and melphalan (Bu-Mel) versus tandem HDC with Thiotepa followed by Bu-Mel in patients with a sufficient response to induction chemotherapy. Furthermore, the study evaluates the 3-year EFS rate of 21.6 Gy radiotherapy to the preoperative tumor bed versus 21.6 Gy radiotherapy with a sequential boost up to 36 Gy to the residual tumor in patients with macroscopic residual disease after HDC and surgery. The chemoimmunotherapy arm assesses the metastatic response rate after four courses of irinotecan-temozolomide (TEMIRI) combined with dinutuximab beta (DB) in patients with insufficient metastatic response at the end of induction chemotherapy.
Secondary objectives include:
- Describing the EFS, progression-free survival (**PFS**), and overall survival (**OS**) from diagnosis.
- Describing the effect of RAPID COJEC and GPOH induction regimens on metastatic disease during and after induction.
- Assessing the correlation of the response of metastatic disease during and after induction with survival (EFS, PFS, and OS).
- Describing the effect of HDC with Bu-Mel versus Thiotepa + Bu-Mel on PFS and OS.
- Describing and comparing the toxicity associated with RAPID COJEC and GPOH induction therapy.
- Describing and comparing the acute and long-term toxicities of both HDC arms.
- Describing the long-term toxicities of dinutuximab beta.
- Investigating the relationship between the quality of surgical resection of the primary tumor, local control, and survival.
- Investigating the impact of the radiotherapy dose on local relapse rate.
- Collecting data on selected circulating biomarkers, biological and genomic features to determine and compare their effect on response to treatment, EFS, PFS, and OS.
- Describing, for each randomization, 5-year EFS, 3 and 5-year PFS, and 3 and 5-year OS since the date of randomization.
- Describing the 3 and 5-year EFS and OS of patients treated in the chemoimmunotherapy arm with TEMIRI/DB, Thio, and Bu-Mel and current high-risk neuroblastoma local/maintenance treatment.
- Evaluating circulating tumor DNA (**ctDNA**) to monitor the tumor status.
- Validating prospectively the new international criteria for response assessment in neuroblastoma.
- Monitoring the emergence in plasma of other targetable genomic alterations to inform the next generation of studies.
- Describing the metastatic response rate after two courses of TEMIRI/DB for patients with insufficient metastatic response at the end of induction chemotherapy.
- Describing acute toxicities of the combination of TEMIRI/DB.
Participants
The clinical trial involves a total of **81 participants** diagnosed with **high-risk neuroblastoma**, a condition characterized by aggressive cancer in nerve tissues. The study population includes both male and female subjects, with an age range extending from infants to young adults under 21 years. Participants were selected based on specific criteria, including the presence of high-risk neuroblastoma as defined by the SIOPEN-modified International Neuroblastoma Risk Group criteria. The trial includes individuals with varying MYCN status and those with specific chromosomal alterations. Participants are required to have no prior chemotherapy or limited exposure to certain chemotherapy regimens. The study population is considered vulnerable due to the inclusion of minors and individuals with a serious health condition. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial ensures that participants are able and willing to comply with study visits and procedures, and all participants or their legal representatives have provided informed consent. The trial does not specify any particular lifestyle modifications or restrictions for participants during the study period.
Plans and Procedures
The clinical trial is designed to evaluate and compare two treatment strategies in three therapeutic phases for patients with **high-risk neuroblastoma**. This is a randomized, international, and multicentric phase 3 study. The trial will assess the efficacy of different induction regimens, high-dose chemotherapy, and radiotherapy, as well as introduce chemoimmunotherapy for patients with insufficient metastatic response after induction chemotherapy. The trial is structured as a randomized, double-blind, controlled study, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias.
The trial is expected to run from November 5, 2019, to November 5, 2031, with participant involvement lasting up to one year. The study includes several key visits: an initial screening visit to determine eligibility, multiple follow-up visits to monitor treatment response and side effects, and an end-of-study visit to assess overall outcomes. Participants will be required to attend these visits as per the protocol to ensure accurate data collection and patient safety.
Inclusion criteria for the study involve a confirmed diagnosis of high-risk neuroblastoma according to the SIOPEN-modified International Neuroblastoma Risk Group criteria. Participants must not have received previous chemotherapy, except under specific conditions, and must provide written informed consent. Exclusion criteria are not explicitly detailed in the provided data. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent by the participant or their legal representative.
The primary endpoint of the trial is the 3-year event-free survival (EFS) rate from the date of randomization for each treatment phase. Secondary endpoints include overall survival (OS), progression-free survival (PFS), and response rates, among others. The trial will employ intention-to-treat analysis, ensuring that all randomized participants are included in the analysis according to their assigned treatment group, regardless of whether they completed the treatment as per the protocol.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and administration routes. **Etoposide** is provided as a 20 mg/mL concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 175 mg/m². The treatment period is limited to one day.
**Melphalan** is available as a 50 mg concentrate and solvent for solution for injection/infusion. This medication is also administered intravenously, with a maximum daily dose of 140 mg/m², and the treatment period is one day.
**Thiotepa** is supplied as a 15 mg powder for solution for injection. It is administered intravenously, with a maximum daily dose of 300 mg/m², and the treatment period is one day.
**Cisplatin** is provided as a 1 mg/mL concentrate for solution for infusion. It is administered intravenously, with a maximum daily dose of 80 mg/m², and the treatment period is one day.
**Busulfan** is available as a 6 mg/mL concentrate for solution for infusion. It is administered intravenously, with a maximum daily dose of 1.2 mg/kg, and the treatment period is one day.
**Dacarbazine** is supplied as a 200 mg powder for solution for injection/infusion. It is administered intravenously, with a maximum daily dose of 200 mg/m², and the treatment period is one day.
**Eldisine** is provided as a powder for solution for injection, with a dosage of 5.0 mg. It is administered intravenously, with a maximum daily dose of 3 mg/m², and the treatment period is one day.
**Irinotecan Hydrochloride** is available as a 20 mg/mL concentrate for solution for infusion. It is administered intravenously, with a maximum daily dose of 50 mg/m², and the treatment period is one day.
**Cyclophosphamide** is supplied as a 500 mg injection. It is administered intravenously, with a maximum daily dose of 1050 mg/m², and the treatment period is one day.
**Temozolomide** is provided in the form of 100 mg hard capsules. It is administered orally, with a maximum daily dose of 100 mg/m², and the treatment period is one day.
**Carboplatin** is available as a 10 mg/mL solution for infusion. It is administered intravenously, with a maximum daily dose of 750 mg/m², and the treatment period is one day.
**Doxorubicin Hydrochloride** is supplied as a 2 mg/mL solution for infusion. It is administered intravenously, with a maximum daily dose of 30 mg/m², and the treatment period is one day.
**Vincristine Sulfate** is provided as a 1 mg/mL solution for injection. It is administered intravenously, with a maximum daily dose of 1.5 mg/m², and the treatment period is one day.
**Dinutuximab Beta** is available as a 4.5 mg/mL concentrate for solution for infusion. It is administered intravenously, with a maximum daily dose of 10 mg/m², and the treatment period is one day.
**Ifosfamide** is supplied as a 2g injection. It is administered intravenously, with a maximum daily dose of 1500 mg/m², and the treatment period is one day.
All medications are administered intravenously, except for Temozolomide, which is administered orally. Participant compliance is monitored through regular assessments and adherence to dosing schedules. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment.
Efficacy
The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the 3-year event-free survival (EFS) rate from the date of randomization for each treatment phase: induction regimens (R-I), high-dose chemotherapy (R-HDC), and radiotherapy (R-RTx). Additionally, the metastatic response rate after four cycles of irinotecan-temozolomide combined with **dinutuximab beta** (TEMIRI/DB) will be evaluated for patients in the chemoimmunotherapy arm. All analyses for randomized trials will be conducted on an intention-to-treat basis, with control for stratification factors.
Secondary endpoints for the entire high-risk neuroblastoma population include 3- and 5-year EFS, progression-free survival (PFS), and overall survival (OS) calculated from diagnosis. For each treatment phase, 5-year EFS, 3- and 5-year PFS, and OS will be calculated from the date of each randomization or arm inclusion. Additional secondary endpoints include the cumulative incidence of relapse/progression, treatment-related mortality, disease-related mortality, overall response according to the new International Neuroblastoma Risk Group (INRG) response criteria, skeletal response on mIBG, bone marrow response, local control, and therapy-related toxicity. For patients in the chemoimmunotherapy arm, the metastatic response rate after two cycles of TEMIRI/DB and 3- and 5-year EFS/PFS/OS from the date of initial diagnosis will also be assessed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- 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.
- 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%
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.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 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.
- Non-inclusion criteria to chemoimmunotherapy arm: Any negative answer concerning the inclusion criteria of chemoimmunotherapy arm.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 05 Nov 2019 | 30 |
 Belgium | Recruiting | 05 Nov 2019 | 20 |
 Czechia | Recruiting | 05 Nov 2019 | 10 |
 Denmark | Recruiting | 05 Nov 2019 | 20 |
 Finland | Not Yet Recruiting | 05 Nov 2019 | 20 |
 France | Recruiting | 05 Nov 2019 | 274 |
 Germany | Recruiting | 05 Nov 2019 | 160 |
 Greece | Recruiting | 05 Nov 2019 | 40 |
 Hungary | Not Yet Recruiting | 05 Nov 2019 | 10 |
 Italy | Recruiting | 05 Nov 2019 | 156 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Busulfan 6 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1.2 | 1 | PRD4025397 |
Qarziba 4.5 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 10 | 1 | PRD9795090 |
Melphalan 50 mg concentrate and solvent for solution for injection/infusion | Test | CONCENTRATE AND SOLVENT FOR SOLUTION FOR INJECTION/INFUSION | INTRAVENOUS USE | 140 | 1 | PRD10567579 |
Irinotecan Hydrochloride 20 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 50 | 1 | PRD1165463 |
Temodal 100 mg hard capsules | Test | HARD CAPSULES | INTRAVENOUS USE | 100 | 1 | PRD2864123 |
Vincristine Sulfate 1 mg/ml solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS USE | 1.5 | 1 | PRD993268 |
Thiotepa 15 mg Powder for solution for injection | Test | POLVO PARA CONCENTRADO PARA SOLUCIÓN PARA PERFUSIÓN | INTRAVENOUS USE | 300 | 1 | PRD10516314 |
Cisplatin 1 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 80 | 1 | PRD4670319 |
Cyclophosphamide Injection 500 mg. | Test | INJECTION | INTRAVENOUS USE | 1050 | 1 | PRD347229 |
Etoposide 20 mg/ml Concentrate for Solution for Infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 175 | 1 | PRD11213470 |