Phase 3 Randomized Trial of Tovorafenib Monotherapy vs. Standard Chemotherapy in Pediatric Low-Grade Glioma with RAF Alteration

The primary objective of this study is to compare the **objective response rate (ORR)** assessed per RANO-LGG criteria by an Independent Review Committee (IRC) of tovorafenib monotherapy versus standard of care (SoC) chemotherapy in patients with pediatric low-grade glioma harboring an activating RAF alteration requiring first-line systemic therapy. This is clinically relevant as it aims to determine the efficacy of tovorafenib, a targeted therapy, in improving response rates compared to traditional chemotherapy, potentially offering a more effective treatment option for this patient population.

Secondary objectives include:

• Comparing the progression-free survival (PFS) assessed by IRC of tovorafenib monotherapy versus SoC chemotherapy per RANO-LGG criteria.
• Comparing the duration of response (DOR) assessed by IRC of tovorafenib monotherapy versus SoC chemotherapy per RANO-LGG criteria.
• Comparing the overall survival (OS) of tovorafenib monotherapy versus SoC chemotherapy.

The clinical trial involves a total of **155 participants** diagnosed with **pediatric low-grade glioma** harboring an activating RAF alteration, requiring first-line systemic therapy. The study population includes both male and female subjects, with an age range of less than 25 years. Participants are selected based on specific criteria, including a histopathologic diagnosis of glioma or glioneuronal tumor and the presence of at least one measurable lesion as defined by RANO criteria. The trial population is characterized by individuals who meet the indication for first-line systemic therapy. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, reflecting the pediatric nature of the condition under investigation.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy, safety, and tolerability of **tovorafenib** monotherapy compared to standard of care chemotherapy in patients with pediatric low-grade glioma harboring an activating RAF alteration. The trial aims to assess the overall response rate (ORR) as the primary endpoint, with secondary endpoints including progression-free survival (PFS), duration of response (DOR), and overall survival (OS). The trial is expected to run from October 31, 2022, to March 31, 2030, with an estimated duration of participant involvement of up to 81 weeks, depending on the treatment arm and individual response.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histopathologic diagnosis, and the presence of a measurable lesion. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety. These visits will include clinical assessments, imaging studies, and laboratory tests as per the protocol. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent.

Throughout the trial, participants will receive either tovorafenib or standard chemotherapy, with the latter including agents such as **vincristine sulfate**, **vinblastine sulfate**, and **carboplatin**. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, with safety monitoring conducted by an independent review committee. Conditions for early termination from the study include adverse events, protocol non-compliance, or any other reason deemed necessary by the investigator. The trial's design and methodology aim to provide robust data on the comparative effectiveness of tovorafenib in this patient population.

The clinical trial involves the administration of **tovorafenib**, a chemical-origin medication, in two pharmaceutical forms: **powder for oral suspension** and **tablet**. Tovorafenib is administered orally with a maximum daily dose of 600 mg and a total dose not exceeding 600 mg over a treatment period of 60 days. The medication is provided by DAY ONE BIOPHARMACEUTICALS INC. and is designated as an orphan drug for this study. The trial aims to evaluate the efficacy of tovorafenib monotherapy compared to standard-of-care chemotherapy in patients with pediatric low-grade glioma harboring an activating RAF alteration.

**Vincristine sulfate** is utilized in the trial as a comparator treatment. It is available in the form of a **solution for injection** and is administered intravenously. The maximum daily dose is 2 mg, with a total dose limit of 83 mg over a treatment period of 81 days. This medication is supplied by STADAPHARM GMBH, TEVA B.V, and TEVA PHARMA BELGIUM N.V./S.A. Vincristine sulfate is a chemical-origin substance and is used in the trial to compare its efficacy against tovorafenib.

**Vinblastine sulfate** is another comparator treatment in the study, provided in the form of a **solution for injection**. It is administered intravenously with a maximum daily dose of 10 mg and a total dose not exceeding 700 mg over a 70-day treatment period. The medication is supplied by STADAPHARM GMBH, STADA ARZNEIMITTEL GMBH, and PHARMACHEMIE BV. Vinblastine sulfate is of chemical origin and serves as a standard-of-care chemotherapy in the trial.

**Carboplatin** is included as a comparator treatment in the form of a **solution for infusion**. It is administered intravenously with a maximum daily dose of 1050 mg and a total dose limit of 42,000 mg over an 81-day treatment period. The medication is provided by HIKMA FARMACÊUTICA (PORTUGAL), S.A. and is of chemical origin. Carboplatin is used in the trial to assess its efficacy in comparison to tovorafenib monotherapy.

The efficacy of the clinical trial will be assessed by comparing the Overall Response Rate (ORR) of **tovorafenib** monotherapy versus standard of care chemotherapy in patients with pediatric low-grade glioma harboring an activating RAF alteration. The ORR will be evaluated according to the RANO-LGG criteria by an Independent Review Committee (IRC). The primary endpoint is defined as the proportion of patients achieving an overall confirmed response, which includes complete response (CR) or partial response (PR).

Secondary endpoints include Progression-Free Survival (PFS), Duration of Response (DOR), and Overall Survival (OS). PFS is defined as the time from randomization to progression of disease (PD) or death from any cause, whichever occurs first. DOR is measured from the first imaging of tumor response (CR or PR) that is subsequently confirmed, to PD or death from any cause. OS is defined as the time from randomization to death from any cause.

The trial is a Phase 3, randomized, international multicenter study, and the efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration. The trial aims to provide a comprehensive evaluation of the therapeutic potential of tovorafenib in this patient population.