Evaluation of Melphalan-Based Chemotherapy Regimens in Low and Intermediate Risk Neuroblastoma: A Multicenter, Prospective Study
- Trial ID
- 2024-517295-37-00
- Protocol
- Uni-Koeln-4299
- Sponsor
- University Of Cologne
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is the **improvement of event-free survival (EFS)** in patients with low and intermediate risk neuroblastoma. This is achieved by employing gene expression-based risk stratification to allocate treatment. The aim is to enhance EFS in patients receiving intensified treatment while ensuring no impairment of EFS in those receiving reduced treatment. This objective is clinically relevant as it seeks to optimize treatment efficacy and minimize unnecessary exposure to intensive therapies, thereby improving patient outcomes and quality of life.
Secondary objectives include the implementation of an RNA expression-based classifier for risk prediction in low- and intermediate-risk neuroblastoma patients. This secondary goal is significant as it aims to refine risk assessment, potentially leading to more personalized and effective treatment strategies.
Participants
The clinical trial focuses on patients diagnosed with **low and intermediate risk neuroblastoma**. The study population includes both male and female subjects, with an age range from infancy to 21 years. Participants are selected based on specific criteria, including a histological diagnosis of neuroblastoma, non-amplified MYCN, and sufficient tumor tissue available for RNA expression analysis. The trial involves a vulnerable population, as it includes children and young adults. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **randomized**, **controlled**, and **double-blind** study aimed at evaluating the efficacy of treatment stratification in patients with low and intermediate risk **neuroblastoma**. The primary objective is to improve event-free survival (EFS) through intensified treatment without impairing EFS in patients receiving reduced treatment, based on gene expression-based risk stratification. The trial is expected to commence recruitment on December 1, 2024, and conclude by December 1, 2035, with an estimated duration of 11 years.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histological diagnosis, age, and stage of neuroblastoma. Subsequent visits will include regular follow-up assessments to monitor treatment response, adverse events, and overall health status. The end-of-study visit will evaluate the final outcomes, including EFS and overall survival (OS). The expected length of participant involvement varies depending on the treatment group, with some treatments lasting up to 70 days.
Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The trial will utilize a range of medicinal products, including **melphalan**, **dinutuximab beta**, and **filgrastim**, administered via intravenous infusion or subcutaneous injection, depending on the specific treatment regimen. The study will also assess secondary endpoints such as OS, risk factors impacting EFS and OS, response to treatment, and incidence rates of toxic events, providing a comprehensive evaluation of the treatment's efficacy and safety.
Treatment
The clinical trial involves the administration of several **experimental medications** and auxiliary treatments. **Melphalan** is provided as a powder and solvent for solution for infusion, administered via **intravenous infusion**. The dosage is calculated at 140 mg/m², with a maximum treatment period of 1 day. **Dinutuximab beta**, an orphan drug, is administered as a solution for infusion, also via intravenous infusion, with a dosage of 10 mg/m² and a maximum total dose of 5000 mg/m² over a 50-day period.
**Filgrastim** is used as a concentrate for solution for infusion, administered through **subcutaneous injection**. The dosage is 10 µg/kg, with a maximum total dose of 400 µg/kg over 70 days. **Vindesine sulfate** is provided as a powder for solution for injection, administered via intravenous infusion, with a dosage of 3 mg/m² and a maximum total dose of 9 mg/m² over 3 days. **Vincristine sulfate** is administered as a solution for injection/infusion via intravenous infusion, with a dosage of 1.5 mg/m² and a maximum total dose of 9 mg/m² over 6 days.
**Clonazepam** is used as a concentrate for solution for injection/infusion, administered intravenously, with a dosage of 0.1 mg/kg and a maximum total dose of 0.7 mg/kg over 7 days. **Busulfan** is administered as a concentrate for solution for infusion via intravenous infusion, with a dosage of 4.8 mg/kg and a maximum total dose of 19.2 mg/kg over 4 days. **Cyclophosphamide** is provided in two forms: as a coated tablet for oral administration with a dosage of 150 mg/m² and a maximum total dose of 4800 mg/m² over 32 days, and as a powder for solution for infusion via intravenous infusion with a dosage of 300 mg/m² and a maximum total dose of 8400 mg/m² over 28 days.
**Etoposide** is administered as a concentrate for solution for infusion via intravenous infusion, with a dosage of 100 mg/m² and a maximum total dose of 1200 mg/m² over 12 days. **Carboplatin** is provided as a concentrate for solution for infusion, administered via intravenous infusion, with a dosage of 160 mg/m² and a maximum total dose of 640 mg/m² over 8 days. **Lenograstim** is used as a powder and solvent for solution for injection, administered through subcutaneous injection, with a dosage of 10 µg/kg and a maximum total dose of 400 µg/kg over 70 days.
**Mesna** is administered as a solution for injection via intravenous infusion, with a dosage of 900 mg/m² and a maximum total dose of 18900 mg/m² over 21 days. **Doxorubicin hydrochloride** is provided as a concentrate for solution for infusion, administered via intravenous infusion, with a dosage of 30 mg/m² and a maximum total dose of 180 mg/m² over 12 days. **Etoposide phosphate** is administered as a powder for solution for injection via intravenous infusion, with a dosage of 100 mg/m² and a maximum total dose of 1200 mg/m² over 12 days.
**Dacarbazine** is provided as a powder for solution for infusion, administered via intravenous infusion, with a dosage of 200 mg/m² and a maximum total dose of 3000 mg/m² over 15 days. **Ifosfamide** is administered as a powder for solution for infusion via intravenous infusion, with a dosage of 1500 mg/m² and a maximum total dose of 22500 mg/m² over 15 days. **Cisplatin** is provided as a concentrate for solution for infusion, administered via intravenous infusion, with a dosage of 40 mg/m² and a maximum total dose of 480 mg/m² over 12 days.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Event-Free Survival (EFS)**, which is defined as the time from diagnosis to an event or last follow-up for patients without an event. An event is characterized by death from any cause, progression, relapse following previous complete remission, or secondary malignant disease. Secondary endpoints include **Overall Survival (OS)**, which is crucial for individual patient outcomes, and the impact of risk factors such as age at diagnosis, stage according to INSS and INRG, and copy number alterations of selected genes on EFS and OS. These factors will be evaluated through multivariate and subgroup analysis.
Additional secondary endpoints involve the response to trial treatment compared to historical controls, particularly focusing on the cohort with reduced treatment. The percentage of spontaneous regression in patients where the residual primary is observed without cytotoxic treatment will also be compared to historical controls. Incidence rates of toxic events will be assessed by comparing the kind and intensity of side effects to historical controls and between patient groups A-C. Furthermore, additional molecular analyses will be conducted to evaluate the impact of clinical and molecular risk factors, such as copy number alterations, telomere maintenance status, and mutation status of candidate genes on EFS and OS. The outcome of patients with relapse or progression of neuroblastoma diagnosed at age less than 18 months with unfavorable classification will also be analyzed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Neuroblastoma diagnosed according to the accepted criteria: histological diagnosis from tumor tissue or presence of distinct neuroblastoma cells in the bone marrow and elevated catecholamine metabolites (HVA, VMA) in blood or urine
- MYCN not amplified
- Stage and age either: a. localized neuroblastoma INRGSS stage L1/L2/INSS stage 1-3 and age at diagnosis ≥18 months and < 21 years b. INSS Stage 4S/INRGSS stage MS c. INSS Stage 4/INRGSS stage M and age at diagnosis <18 months d. INRGSS stage L1/L2 and age at first diagnosis <18 months with relapse or progression of neuroblastoma
- Sufficient tumor tissue available from initial diagnosis available for analysis of RNA expression array
- Guardians’ informed consent and/ or patient’s informed consent if appropriate according to age and status of psycho-intellectual development
Exclusion Criteria
- Participation in other clinical trials
- Pregnancy or lactation
- Insufficient contraception for sexually active study participants as well as female partners of sexually active male trial participants. Patients must be informed about the need of adequate contraception. Moreover, this need for contraception must be understood by the trial participants. Only contraception with a Pearl index <1% are considered as sufficient. For the purpose of this trial, these are long-term parenteral hormones, progesterone releasing implants, intramuscular progesterone, and intrauterine hormone releasing devices, tubal ligation, and vaginal hormonal contraception. This also holds true for adolescents who are at risk to become sexually active during trial participation
- Any concomitant non-protocol anticancer therapy
- Incomplete initial staging
- Known allergy/hypersensitivity to the scheduled drugs
- Impaired cardiac function such as insufficiency, heart rate abnormalities and blood pressure abnormalities corresponding to CTCAE 5.0 grade 2 or higher. Hypertension according to age specific reference values clearly due to neuroblastoma is no exclusion criterion
- Impaired renal function defined by a reduced glomerular filtration rate <30 ml/min*1,73 m2 determined by serum creatinine (Schwartz formula) or serum cystatin C
- Impaired liver function corresponding to CTCAE 5.0 grade 3 or higher unless liver impairment is clearly caused by neuroblastoma in stage 4S/MS patients. Isolated elevation of the transaminases without evidence of impaired liver function is not an exclusion criterion
- History of earlier VOD/SOS of the liver
- Impaired bone marrow function defined by granulocytes <500/μl and/or thrombocytes <50.000/μl unless clearly caused by bone marrow involvement proven by bone marrow cytology or diffuse abnormal osteomedullary signal in the mIBG scintigraphy
- HIV infection because of the antiretroviral medication which potentially interferes with the metabolism of the scheduled investigational drugs
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Yet Recruiting | 01 Dec 2024 | 280 |
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 |
|---|---|---|---|---|---|---|
MELPHALAN | Test | — | INTRAVENOUS INFUSION | 140 | 1 | SUB08728MIG |
DINUTUXIMAB BETA | Test | — | INTRAVENOUS INFUSION | 10 | 50 | SUB174757 |
FILGRASTIM | Other | — | SUBCUTANEOUS INJECTION | 10 | 70 | SUB07627MIG |
VINDESINE SULFATE | Test | — | INTRAVENOUS INFUSION | 3 | 3 | SUB05102MIG |
VINCRISTINE SULFATE | Test | — | INTRAVENOUS INFUSION | 1.5 | 6 | SUB05101MIG |
CLONAZEPAM | Other | — | INTRAVENOUS | 0.1 | 7 | SUB06728MIG |
BUSULFAN | Test | — | INTRAVENOUS INFUSION | 4.8 | 4 | SUB05993MIG |
CYCLOPHOSPHAMIDE | Test | — | ORAL | 150 | 32 | SUB06859MIG |
ETOPOSIDE | Test | — | INTRAVENOUS INFUSION | 100 | 12 | SUB07337MIG |
CARBOPLATIN | Test | — | INTRAVENOUS INFUSION | 160 | 8 | SUB06614MIG |