International Phase I Trial of Dinutuximab Beta With VDC/IE in GD2-Positive Ewing Sarkoma

Immunotherapeutic approaches have emerged as an effective therapeutic approach in cancer. We will investigate the cell-surface ganglioside GD2 as a target since it is expressed on the cell surface of Ewing Sarcoma cells and clinical trials support the safety and efficacy of anti-GD2 antibodies in pediatric solid cancers. Dinutuximab beta is a chimeric antibody that targets the disialoganglioside GD2. GD2 is expressed on a number of solid malignancies and was clinically investigated in pediatric patients with neuroblastoma. Expression in normal tissues is restricted to cerebellar neurons, skin melanocytes and peripheral pain fibers. Due to this expression pattern, anti-GD2 antibodies have been studied as targeted immunotherapy for neuroblastoma. With the results of these clinical trials, combination therapies with dinutuximab beta became a standard component of high-risk neuroblastoma therapy. GD2 expression is found in several EWS samples with variable expression-levels, and it is expected that anti-GD2 treatment is best suited as biomarker?biomarker Something measurable in the body, such as a blood test result or an imaging finding, that indicates how a condition or treatment is behaving.-driven approach. The administration of vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) has been shown to be an effective systemic therapy and is therefore currently part of the standard treatment?standard treatment Treatment generally considered appropriate for a condition in a particular clinical setting. It can vary by patient, place and over time. In many studies the new treatment is added to, or compared with, standard of care. in Ewing Sarcoma. The international newest standard induction chemotherapy in the standard- and high-risk group consists of alternating VDC/IE. High-risk patients with a GD2 positive tumor could benefit from an addition of dinutuximab beta to the standard chemotherapy with VDC/IE. The rationale for this trial is to investigate the feasibility, toxicity, and biological activity of dinutuximab beta in combination with standard chemotherapy in EWS. This is a multi-center, phase 1?phase 1 An early-stage study, usually small, mainly to check safety, side effects and how much of a treatment can be given. Whether it works is not the main question yet., open-label?open-label No masking is used, so the assigned intervention is not deliberately hidden from participants or study staff., dose escalation study enrolling high-risk Ewing sarcoma patients that have been tested with GD2-positivity in a classical 3+3 design. The decision to initiate treatment with 50% of the approved dosage for neuroblastoma in this dose-escalation study is grounded in both scientific literature and safety considerations. Starting at a lower dosage allows for the careful monitoring of patient response and minimizes the risk of adverse effects, particularly in a dose-sensitive adult population. A risk assessment further supports this approach, indicating that starting at 50% of the approved neuroblastoma dose provides a safe baseline?baseline Measurements taken at the start of the study, before any study treatment, so that later results can be compared with them. from which to escalate. The assessment outlines that a stepwise increase to 75% and subsequently to 100% of the approved dose allows for the identification of any dose-limiting toxicities?dose-limiting toxicities A side effect, defined in advance, that is severe enough to limit how far the dose can be raised in a dose-escalation study. How many such events stop escalation is set by the study's rules. (DLTs) in a controlled manner, thus optimizing patient safety. The choice of 100 mg/m2 as the maximum dosage per cycle, equivalent to the dosage used in standard neuroblastoma treatment, is justified by its established efficacy and safety profile in this specific indication. The literature supports that doses up to 100 mg/m2 per cycle are well-tolerated in the majority of patients, with the therapeutic benefits outweighing the risks when administered within a carefully monitored clinical framework.