Study on New Treatment Strategies for Recurrent High-Risk Neuroblastoma

A neuroblastoma is a malignant tumor of the nervous system that arises from immature nerve cells, which normally develop into functioning nerve cells or adrenal cells during development. The tumor is usually found in the abdomen, primarily in the adrenal gland, but also along the spine, in the chest, or in the neck. Symptoms depend heavily on the tumor’s location. Neuroblastomas can follow very different courses: Some disappear on their own, while others grow rapidly and form tumor metastases in the bones, bone marrow, lymph nodes, or liver. Treatment for patients with neuroblastoma is based on their individual clinical situation and the likelihood of disease recurrence (recurrence). Patients are therefore assigned to a specific risk or treatment group at the start of treatment. Current treatment guidelines call for classification into three treatment groups: low-risk group, intermediate-risk group, and high-risk group. Different treatment plans apply to each of these therapy groups. Most patients with neuroblastoma are treated as part of clinical trials, meaning that many different, trial-specific treatment regimens are used. However, neuroblastoma is usually treated with a combination of induction chemotherapy and, possibly, surgery and/or radiation therapy. This is typically followed by high-dose chemotherapy and a stem cell transplant as consolidation therapy. In most cases, this is followed by maintenance therapy with immunotherapeutic agents. However, the disease may not respond to treatment (treatment refractoriness) or may recur after treatment (relapse).

The goal of this multi-arm, multi-stage platform study is to investigate the efficacy and safety of various new treatment strategies. In Phase 1 (Tier 1) of the study, patients with a first-time recurrence will be randomly assigned to two treatment arms. Arm A receives temozolomide (Days 1–5), dinutuximab beta (Days 1–7), and irinotecan (Days 1–5) as part of a 3-week cycle for up to 12 cycles. Arm B receives temozolomide (Days 1–5), bevacizumab (Day 1), and irinotecan (Days 1–5), also as part of a 3-week cycle for up to 12 cycles. The study is open-label, meaning that both the medical staff and the patient know which treatment is being administered. The primary endpoint for Tier 1 is progression-free survival (PFS), defined as the time from the start of the study until the first occurrence of disease progression, recurrence, or death from any cause.

In Phase 2 (Tier 2) of the study, patients with multiple recurrences or who are ineligible for Tier 1 will receive combination therapy consisting of temozolomide (Days 1–5), bevacizumab (Day 1), dinutuximab beta (Days 1–5), and irinotecan (Days 1–5) as part of a 3-week cycle for up to 12 cycles. New treatment arms may be integrated into Tier 2 as the study progresses. The primary endpoint of Phase 2 is to identify a safe and well-tolerated combination therapy. The study will last approximately 36 weeks (treatment phase), followed by a follow-up period of at least 5 years. Patients aged 1 year and older with recurrent or refractory high-risk neuroblastoma are eligible to participate in this study. The disease must be measurable (e.g., CT/MRI) or detectable via MIBG scintigraphy; diseases detectable only in the bone marrow are excluded.