Phase Ib Evaluation of Dinutuximab Beta with Induction Chemotherapy in Newly Diagnosed High-Risk Neuroblastoma Patients

The primary objective of this Phase Ib study is to assess the **safety** and tolerability of **dinutuximab beta** when combined with two different induction chemotherapy regimens, specifically GPOH or rapid COJEC, in the treatment of newly diagnosed high-risk **neuroblastoma** patients. This assessment aims to identify the recommended Phase 2 dose (RP2D) and the maximum tolerated dose (MTD) of dinutuximab beta. The clinical relevance of this objective lies in optimizing treatment regimens for high-risk neuroblastoma, a condition characterized by aggressive tumor growth and poor prognosis, thereby potentially improving patient outcomes.

Secondary objectives include: - Characterizing the toxicity of induction chemotherapy when combined with dinutuximab beta. - Determining the overall response, including primary tumor and metastases, during and at the end of induction chemotherapy with dinutuximab beta. - Determining the metastatic response rate to chemotherapy plus dinutuximab beta. These objectives are crucial for understanding the broader impact of the treatment regimen on tumor response and patient safety, which can inform future therapeutic strategies.

The clinical trial involves participants diagnosed with **neuroblastoma**, specifically Stage M, as defined by the SIOPEN modified International Neuroblastoma Risk Group (INRG) and the INSS criteria. The study population includes both male and female subjects aged 18 months to less than 18 years, with a body weight greater than 12 kg. Participants are required to have normal liver function, as indicated by alanine transaminase (ALT) and aspartate aminotransferase (AST) levels less than 10 times the upper limit of normal (ULN), and total bilirubin less than 1.5 times ULN, based on age-specific reference ranges. Renal function must be adequate, with a calculated glomerular filtration rate greater than 60 mL/min/1.73 m² or serum creatinine less than 1.5 times ULN corrected for age. Cardiac function is also assessed, requiring a shortening fraction of 27% or more and/or a left ventricular ejection fraction greater than 50%, as determined by echocardiography or MUGA. Participants must be able to comply with scheduled follow-up and study procedures. Written informed consent from parents or legal representatives, as well as age-appropriate assent from the patient, is mandatory before any study-specific screening procedures are conducted. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the safety and tolerability of **dinutuximab beta** in combination with induction chemotherapy regimens for patients with newly diagnosed high-risk **neuroblastoma**. This is a Phase Ib, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on June 1, 2024, and is estimated to conclude by June 1, 2030. Participants will be randomly assigned to receive either the GPOH or rapid COJEC induction chemotherapy regimens in combination with dinutuximab beta. The primary objective is to identify the recommended Phase 2 dose (RP2D) and maximum tolerated dose (MTD) of dinutuximab beta when used in these combinations.

The study will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. The screening visit will determine eligibility based on criteria such as age, weight, and specific laboratory values. Follow-up visits will occur at regular intervals to monitor the incidence of dose-limiting toxicities (DLTs) and adverse events (AEs), as well as to assess the overall response to treatment. The end-of-study visit will evaluate the cumulative incidence of treatment-related and disease-related mortality, as well as the overall response during and after induction therapy.

Participant involvement is expected to last throughout the duration of the trial, with specific timelines for each treatment cycle and follow-up assessment. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent by the participant or their legal representative. The trial will adhere to strict ethical guidelines, ensuring informed consent is obtained prior to any study-specific procedures.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Eldisine Powder for Solution for Injection 5.0 mg** is a pharmaceutical product in the form of a powder intended for solution for injection. It is administered as a concentrate for solution for infusion. The active substance is **vindesine**, and it is manufactured by Genus Pharmaceuticals Limited. The frequency and dosage are determined based on the trial protocol.

**Cyclophosphamide 1000 mg Powder for Solution for Injection or Infusion** is another experimental treatment used in this trial. It is provided as a powder for solution for injection or infusion, with the active substance being **cyclophosphamide**. The administration route is via concentrate for solution for infusion, and it is produced by Sandoz Ltd.

**Human Albumin Baxalta 50 g/l Solution for Infusion** is utilized as a non-experimental treatment. This solution for infusion contains **human albumin solution** as the active substance and is administered intravenously. It is manufactured by Baxalta Innovations GmbH.

**Water for Injections Ph. Eur.** serves as a solvent for parenteral use in the trial. It is administered intravenously and contains **water for injection** as the active substance. This product is provided by Baxter Holding B.V.

**Qarziba 4.5 mg/mL concentrate for solution for infusion** is an experimental treatment containing **dinutuximab beta**. It is administered as a concentrate for solution for infusion and is produced by Recordati Netherlands B.V. This product is designated as an orphan drug.

**Doxorubicin Teva 2 mg/ml Concentrate for Solution for Infusion** is another experimental treatment. It is a concentrate for solution for infusion with **doxorubicin hydrochloride** as the active substance, manufactured by Teva Pharma B.V.

**Vincristine Sulfate 1 mg/ml Solution for Injection or Infusion** is administered as a solution for injection or infusion. The active substance is **vincristine sulfate**, and it is produced by Pfizer Healthcare Ireland.

**Glucose 5% Intravenous Infusion BP** is used as an auxiliary treatment. It is a solution for infusion containing **glucose** and is administered intravenously. This product is provided by Baxter Holding B.V.

**Cisplatin 1 mg/ml Concentrate for Solution for Infusion** is an experimental treatment administered as a concentrate for solution for infusion. The active substance is **cisplatin**, and it is manufactured by Pfizer Healthcare Ireland.

**Mitoxana 1 g Powder for Sterile Concentrate** is provided as a powder for sterile concentrate, with **ifosfamide** as the active substance. It is administered as a concentrate for solution for infusion and is produced by Baxter Holding B.V.

**Sodium Chloride 0.9% Intravenous Infusion BP** is used as an auxiliary treatment. It is a solution for infusion containing **sodium chloride** and is administered intravenously. This product is provided by Baxter Holding B.V.

**Dacarbazine Lipomed 200 mg powder for solution for injection or infusion** is an experimental treatment. It is a powder for solution for injection or infusion with **dacarbazine** as the active substance, manufactured by Lipomed GmbH.

**Etoposide 20 mg/ml Concentrate for Solution for Infusion** is administered as a concentrate for solution for infusion. The active substance is **etoposide**, and it is produced by Accord Healthcare Ireland Limited.

**Carboplatin 10 mg/ml concentrate for solution for infusion** is another experimental treatment. It is a concentrate for solution for infusion with **carboplatin** as the active substance, manufactured by Fresenius Kabi Deutschland GmbH.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint focuses on the incidence of dose-limiting toxicities (DLTs) associated with the combination of **dinutuximab beta** with two different induction chemotherapy regimens: GPOH and rapid COJEC. The evaluation will occur over two DLT evaluation cycles for each regimen. Secondary endpoints include the type, incidence, severity, seriousness, and relationship to study medications for Grade 3 and 4 adverse events (AEs), including laboratory abnormalities and severe adverse events (SAEs). Additionally, the cumulative incidence of treatment-related mortality and disease-related mortality will be monitored.

Overall response during and after induction treatment will be evaluated, focusing on the primary tumor and metastases. The trial will also assess the modified complete response (mCR) after induction treatment and the modified partial response (mPR) according to eligibility criteria to proceed to consolidation by high-dose chemotherapy/autologous stem cell transplantation (HDC/ASCT). Specific criteria for mPR include MIBG uptake resolution or reduction in bone disease, complete response (CR) or minimal disease (MD) in bone marrow disease, and mPR for other metastatic sites. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the overall effectiveness of the treatment regimens in patients with newly diagnosed high-risk neuroblastoma.