Phase II Randomized Controlled Trial of Trametinib vs. Vinblastine in Pediatric and AYA Patients with Newly Diagnosed Low-Grade Glioma with Wild-Type BRAF

The primary objective of this study is to improve the current standard treatment regimen for non-NF1 pediatric and adolescent and young adult (AYA) patients with newly diagnosed low-grade glioma characterized by a wild-type BRAF gene. The study aims to demonstrate the superiority of the experimental arm, which involves a daily oral **MEK inhibitor** (Trametinib), compared to the standard therapy of weekly intravenous Vinblastine over 18 courses, each lasting 4 weeks, totaling 72 weeks. The expected superiority is quantified as a 20% improvement in 3-year progression-free survival (PFS). This objective is clinically relevant as it seeks to enhance treatment outcomes for this patient population, potentially offering a more effective therapeutic option.

Secondary objectives include:

• Evaluating tumor objective response rate (ORR) at 24 and 72 weeks based on RANO criteria.
• Estimating overall survival (OS) for each treatment arm at 3 years.
• Monitoring the toxicity and safety of the new experimental compound compared to the control arm during treatment and at 3 years post-treatment initiation.
• Comparing the quality of life (QoL) between the two arms, specifically a daily oral compound versus weekly intravenous chemotherapy administration.
• Assessing the treatment effect across molecular strata in each treatment group.
• Correlating visual outcomes with treatment response in patients with optic pathway glioma (OPG).
• Collecting data on patients receiving the experimental drug after first progression or relapse on therapy.

The clinical trial involves a study population comprising both **male** and **female** participants, ranging in age from 1 month to 25 years. The trial focuses on individuals diagnosed with grade 1 glioma, mixed glio-neuronal tumors, or pleomorphic xanthoastrocytoma (PXA). Participants are required to have a Karnofsky or Lansky performance status of 50% or higher, indicating a moderate level of general health. The trial population includes vulnerable groups, such as infants and young adults, and requires participants to have adequate bone marrow, liver, renal, and cardiac function. Lifestyle considerations, such as diet and physical activity, are not specified. The selection criteria emphasize the absence of a BRAFv600 mutation and the presence of specific genetic markers, such as 7q34 duplication or KIAA1549-BRAF fusion. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized**, controlled, phase II study aimed at evaluating the efficacy of a daily oral **MEK inhibitor** (Trametinib) compared to weekly intravenous Vinblastine in pediatric and adolescent patients with newly diagnosed low-grade glioma characterized by a wild-type BRAF gene. The trial will span 18 months, divided into 18 courses of 4 weeks each, totaling 72 weeks. The primary objective is to assess the superiority of the experimental arm in terms of 3-year progression-free survival (PFS) rates. The trial will include participants aged 1 month to 25 years, with specific inclusion criteria such as adequate bone marrow, liver, and renal function, and a negative BRAFv600 mutation.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria. This will be followed by regular follow-up visits every 4 weeks to monitor treatment response and adverse events. The end-of-study visit will occur at the conclusion of the 18-month treatment period. The expected length of participant involvement is approximately 18 months, with conditions for early termination including significant disease progression, unacceptable toxicity, or withdrawal of consent.

The trial will employ a double-blind methodology to ensure unbiased results, with both participants and investigators unaware of the treatment allocation. The primary endpoint is the comparison of 3-year PFS rates between the two treatment arms, while secondary endpoints include overall response rate, overall survival (OS) rate, and the frequency of adverse events. The trial will also assess quality of life using specific questionnaires at baseline, 24 weeks, the end of treatment, and 3 years post-treatment. The study aims to improve the current standard treatment regimen, with an anticipated 20% improvement in 3-year PFS for the experimental arm.

The clinical trial involves the administration of **Mekinist** (trametinib) in two different formulations. The first formulation is Mekinist 2 mg film-coated tablets, which are administered orally. The maximum daily dose is 2 mg, with a total maximum dose of 1095 mg over a treatment period of 18 months. The tablets are produced by Novartis Europharm Limited and are intended for use in non-NF1 pediatric and adolescent patients with newly diagnosed low-grade glioma characterized by a wild-type BRAF gene. The pharmaceutical form is a film-coated tablet, ensuring ease of oral administration.

The second formulation of Mekinist is 0.5 mg film-coated tablets, also administered orally. Similar to the 2 mg tablets, the maximum daily dose is 2 mg, with a total maximum dose of 1095 mg over the same treatment period of 18 months. This formulation is also produced by Novartis Europharm Limited and shares the same therapeutic indications and administration route as the 2 mg tablets. Both formulations of Mekinist are chemically derived and are not pediatric-specific formulations.

In addition to the experimental treatment, the trial includes a comparator treatment with **Vinblastine sulfate**. Vinblastine is provided as Velbe 10 mg, a powder for solution for injection, and is administered via intravenous infusion. The maximum daily dose is 2 mg, with a total maximum dose of 780 mg over a treatment period of 78 weeks. This comparator treatment is intended to serve as the standard therapy against which the efficacy of trametinib is measured. The pharmaceutical form is a powder for solution for injection, and it is produced by EG Labo Laboratoires Eurogenerics.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the superiority of the experimental arm, which involves daily administration of trametinib, compared to the standard therapy of weekly vinblastine, over the course of 18 months.

Efficacy in this clinical trial will be assessed primarily through the measurement of the 3-year **Progression-Free Survival (PFS)** rates, comparing the experimental arm using the MEK inhibitor **Trametinib** with the standard therapy of weekly intravenous **Vinblastine**. PFS will be measured from the time of the first treatment administration up to the first event within the first three years of follow-up. An event is defined as death from any cause, progression of a residual tumor, reappearance of a tumor, or the appearance of new tumor locations in the brain and spine.

Secondary endpoints include the tumor response at 24 and 72 weeks, assessed using the international RANO criteria. The analysis will focus on the overall response rate (ORR) by central independent radiological review, classifying patients into two groups: progressive disease (PD) versus complete response (CR), partial response (PR), or stable disease (SD). Additionally, the 3-year overall survival (OS) rate will be calculated from the time of first treatment administration to death.

Further assessments will include the frequency and description of adverse events (AEs) and serious adverse events (SAEs) based on CTCAE criteria, focusing on visual disturbances, skin, intestinal, and cardiac side effects. Quality of life (QoL) will be evaluated using specific questionnaires (PEDs-QoL) at baseline, 24 weeks, end of treatment, and three years post-treatment, with analysis based on EORTC adapted QoL questionnaires.

The trial will also analyze the 3-year PFS and OS rates according to molecular biomarkers obtained through routine molecular analyses and centralized tumor histology review. For patients with optic pathway glioma, visual outcomes will be assessed using the LoqMAR scale at baseline, 24 weeks, end of treatment, and three years post-treatment. Data from patients benefiting from the crossover strategy will be collected to gather information on response rate, PFS, and OS for those progressing or relapsing on standard arm treatment.