Long-term Safety Assessment of Dabrafenib Mesylate and Trametinib in Pediatric Patients with Cancers Harboring V600 Mutation: A Multi-center Roll-over Study

The primary objective of this study is to assess the long-term **safety** of treatment with dabrafenib, trametinib, or their combination in pediatric patients with cancers harboring the V600 mutation. This is clinically relevant as it aims to ensure that these treatments do not pose significant long-term health risks to children and adolescents, thereby supporting their safe use in this vulnerable population.

Secondary objectives include:

• Assessing the long-term effect of treatment on general health, growth, and development, which is crucial for understanding the broader impact of these therapies on pediatric patients' overall well-being.
• Evaluating efficacy as determined by institutional standard of care procedures, which helps in determining the effectiveness of the treatment in real-world clinical settings.

The clinical trial involves a total of **98 participants** who are children and adolescents diagnosed with cancers harboring the **V600 mutation**. The study population includes both male and female subjects, with an age range that encompasses young children to adolescents. Participants were selected based on their current or prior involvement in a Novartis-sponsored study, demonstrating treatment compliance, and the likelihood of benefiting from continued treatment with dabrafenib, trametinib, or their combination. The trial population is characterized by its inclusion of a vulnerable group, necessitating careful ethical considerations. Participants are required to have provided written informed consent, and they must not require treatment with prohibited concomitant medications. Lifestyle factors such as diet and physical activity are not specified, but participants must be willing and able to comply with scheduled visits and treatment plans.

The clinical trial is designed to assess the long-term safety of treatment with **dabrafenib** and **trametinib** in pediatric patients with cancers harboring the V600 mutation. This is a phase IV, open-label, multi-center roll-over study. The trial is not categorized as low intervention and aims to evaluate the long-term effects on growth, development, and general health. The study is expected to conclude by May 26, 2026, with recruitment having started on November 4, 2019. Participants are required to have been involved in a prior Novartis-sponsored study and must currently be receiving treatment with dabrafenib and/or trametinib. The trial will involve oral administration of the investigational products, which include DRB436 in various formulations and Mekinist in film-coated tablets.

The trial involves several key visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as prior participation in relevant studies and current treatment status. Follow-up visits will be scheduled to monitor adverse events (AEs), serious adverse events (SAEs), and clinically significant changes in laboratory values and vital signs. Secondary endpoints include serial measurements of height, weight, skeletal maturation, sexual maturation, and cardiac function. The end-of-study visit will conclude the participant's involvement, assessing the overall clinical benefit as determined by the investigator using institutional standards of care.

Participant involvement is expected to last up to 84 days, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the need for prohibited concomitant medications. The trial is conducted under strict adherence to ethical guidelines, ensuring informed consent is obtained from participants or their legal guardians. The study's primary objective is to ensure the safety and efficacy of the treatment regimen, contributing valuable data to the understanding of long-term outcomes in this patient population.

The clinical trial involves the administration of several experimental medications, primarily focusing on **dabrafenib mesylate** and **trametinib**. The experimental medication **DRB436**, containing the active substance dabrafenib mesylate, is available in two pharmaceutical forms: dispersible tablets and hard capsules. The dispersible tablet form is specifically designed as a pediatric formulation, while the hard capsule form is intended for general use. Both forms are administered orally with a maximum daily dose of 300 mg and a maximum treatment period of 84 days. The dispersible tablet is accompanied by a dosing cup to ensure accurate administration. Participant compliance is monitored through regular assessments of dosing adherence.

Another experimental medication used in the trial is **Mekinist**, which contains the active substance trametinib. Mekinist is available in two forms: film-coated tablets and powder for oral solution. The film-coated tablets are available in 2 mg and 0.5 mg dosages, while the powder for oral solution is a pediatric formulation. Both forms are administered orally with a maximum daily dose of 2 mg and a maximum treatment period of 84 days. The powder for oral solution is provided with an oral dosing syringe and a press-in bottle adapter to facilitate accurate dosing. The film-coated tablets have specific differences from the commercial product, including variations in packaging sites, bottle fill-count, storage conditions, shelf-life, and labeling.

The trial also includes the experimental medication **TMT212**, which contains the active substance trametinib dimethyl sulfoxide. TMT212 is available as a film-coated tablet and is administered orally with a maximum daily dose of 2 mg and a maximum treatment period of 84 days. The trial ensures that all medications are administered under controlled conditions, with participant compliance monitored through regular follow-ups and assessments. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are mentioned in the trial data provided.

The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the evaluation of adverse events (AEs), serious adverse events (SAEs), and clinically significant changes in laboratory values and vital signs. These parameters will be systematically monitored to ensure the safety and effectiveness of the treatment regimen involving **dabrafenib** and **trametinib**.

Secondary endpoints will focus on serial measurements of height, weight, skeletal maturation, sexual maturation, and cardiac function. Additionally, disease-specific clinical benefits will be determined by the investigator using the institutional standard of care. These assessments will provide a comprehensive evaluation of the long-term effects of the treatment in pediatric patients.