Phase 2 Randomized Study of Radiotherapy with Nimotuzumab and Vinorelbine in Pediatric Diffuse Intrinsic Pontine Glioma

The primary objective of this study is to compare the best response, defined as complete response (CR) and partial response (PR), up to 36 weeks between conventional and experimental irradiation in patients with **diffuse intrinsic pontine glioma**. This objective is clinically relevant as it aims to determine the efficacy of different irradiation strategies in improving treatment outcomes for this aggressive pediatric brain tumor.

Secondary objectives include:

• Comparing the disease stabilization rate, considering stable disease (SD) only, up to week 36 between the two arms, evaluated according to radiological and clinical criteria.
• Comparing progression-free survival (PFS) and overall survival (OS) between the two arms.
• Assessing the safety of radiotherapy.
• Evaluating the quality of life and life situation of patients.
• Assessing PFS and OS of diffuse midline glioma with K27 mutation using the standard arm of the main protocol.

The clinical trial focuses on **diffuse intrinsic pontine glioma** and involves a study population comprising both male and female participants aged between 2 to 21 years. The sponsor did not provide information regarding the total number of participants. The trial population includes individuals who have not undergone previous treatments, except for the use of steroids. Participants are required to have a radiologically verified diagnosis of diffuse intrinsic pontine glioma, with symptoms persisting for less than six months and a life expectancy of at least four weeks. The study includes a vulnerable population, and participants must have a Karnowski/Lansky performance status of 40% or higher, with no organ dysfunction, and must not be pregnant or breastfeeding. Baseline cranial MRI with gadolinium is mandatory, and spinal MRI is required due to the potential for metastatic cases at diagnosis. Written informed consent from parents or legal guardians is necessary before treatment initiation. The trial also includes an observational arm for diffuse midline glioma, requiring central pathology review according to standard Italian procedures.

The clinical trial is designed as a **randomized**, open-label, Phase 2 study aimed at evaluating the efficacy of radiotherapy combined with **nimotuzumab** and **vinorelbine tartrate** in patients with newly diagnosed childhood and adolescence **diffuse intrinsic pontine glioma** (DIPG). The trial will compare the best response rates up to 36 weeks between conventional and experimental irradiation methods. Participants will be randomly assigned to either the experimental arm, which includes re-irradiation at relapse, or the control arm, which involves multiple elective radiotherapy courses. The study is expected to conclude by October 2025, with recruitment having commenced in November 2015.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (2 to 21 years), radiologically-verified DIPG, and a performance status of at least 40%. Baseline cranial MRI with gadolinium and spinal MRI will be conducted to assess the presence of metastatic cases. Follow-up visits will occur regularly to monitor treatment response and any adverse events. The end-of-study visit will evaluate the primary endpoint, which is the number of complete and partial responses up to week 36, as well as secondary endpoints including disease progression, recurrence, secondary malignancy, and mortality.

The expected duration of participant involvement is up to 24 months, with treatment administered intravenously. Conditions that may lead to early termination from the study include significant adverse reactions, disease progression, or withdrawal of consent. The trial's methodology ensures rigorous assessment of the therapeutic potential of the investigational regimen, with the primary aim of improving outcomes for patients with this rare and aggressive brain tumor.

The clinical trial involves the administration of **Nimotuzumab**, a monoclonal antibody, as an experimental treatment. Nimotuzumab is provided in the form of a **solution for injection** and is administered intravenously. The dosage is calculated based on body surface area, with a maximum daily dose of 150 mg/m². The treatment period for Nimotuzumab is set to a maximum of 24 weeks. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to Nimotuzumab, the trial also includes the administration of **Vinorelbine Tartrate**, marketed as NAVELBINE 10 mg/ml concentrato per soluzione per infusione. This chemotherapy drug is provided as a **solution for infusion** and is also administered intravenously. The maximum daily dose for Vinorelbine Tartrate is 25 mg/m², with a treatment period extending up to 24 weeks. As with Nimotuzumab, participant compliance with the dosing schedule for Vinorelbine Tartrate will be closely monitored to maintain protocol integrity.

The study does not include any non-experimental treatments such as placebo or comparator treatments. The focus is on evaluating the efficacy of the combined administration of Nimotuzumab and Vinorelbine Tartrate in the treatment of newly diagnosed childhood and adolescence diffuse intrinsic pontine glioma (DIPG). The trial aims to compare the best response up to 36 weeks between conventional and experimental irradiation methods.

The efficacy of the clinical trial will be assessed by comparing the best response rates, specifically the number of complete and partial responses (**CR+PR**), up to 36 weeks between the conventional and experimental irradiation arms. This primary endpoint will involve calculating the number of best responses in both arms and performing a comparison of the response rates. Secondary endpoints will include the assessment of first progression of disease, first recurrence, secondary malignancy, and death. These efficacy parameters will be measured and collected at specified timepoints, with the primary focus on the 36-week mark. The trial aims to evaluate the therapeutic effects of the treatment regimen involving radiotherapy, concomitant **nimotuzumab** and **vinorelbine**, and re-irradiation at relapse in patients with newly diagnosed childhood and adolescence diffuse intrinsic pontine glioma (DIPG). The study will utilize radiological assessments, including cranial MRI with gadolinium, to monitor disease progression and response to treatment.