DAY101 Monotherapy vs. Standard-of-Care Chemotherapy in Children and Adolescents with Low-Grade Gliomas

Gliomas are tumors of the brain or spinal cord (CNS tumors) that arise from the supporting cells of the nervous system (glial cells) and can grow slowly or aggressively, depending on the type. The World Health Organization (WHO) classifies gliomas into four grades. These can be summarized as low-grade (Grades 1 and 2) and high-grade (Grades 3 and 4) gliomas. Low-grade gliomas generally have a better prognosis because they grow more slowly. Nevertheless, their growth is unpredictable, and the course of the disease can be life-threatening. The most common low-grade gliomas in children include pilocytic astrocytomas (Grade 1), glioneural tumors (Grade 1), and diffuse astrocytomas (Grade 2), which differ in cell composition, growth patterns, and demarcation from surrounding tissue. The diagnosis can often be made through magnetic resonance imaging (MRI) of the head, but is confirmed by an additional biopsy (removal of a tissue sample). During this process, molecular biomarkers—that is, specific genetic alterations—are examined to classify the tumor more precisely and determine possible treatment options. Potential genetic alterations can occur, for example, in the RAF gene. An activating RAF mutation causes the RAF protein to remain constantly active. Since it regulates cell growth, if it remains permanently “switched on,” it can lead to uncontrolled growth of tumor cells.

The standard treatment for such low-grade gliomas with an activating RAF mutation is, initially, complete surgical removal of the tumor. For patients in whom this is not possible because the tumor is located in hard-to-reach or sensitive areas of the brain or spinal cord, systemic chemotherapy is often used as first-line treatment to slow tumor growth. Conventional chemotherapies such as vincristine (VCR) and carboplatin or vinblastine (VBL) are used for this purpose. Targeted drugs that specifically target RAF mutations are already approved for other cancers, but not for these low-grade gliomas. Tovorafenib is a new drug that directly interferes with the altered signaling pathway and is intended to block the persistently active RAF protein in order to slow or stop tumor growth. However, it has not yet been approved in Germany outside of clinical trials.

The goal of the study is to evaluate the efficacy and safety of the new drug tovorafenib compared to the current standard of care. To do this, patients will be randomly assigned to two groups. In the experimental group, participants will receive the study drug tovorafenib. It is administered every 28 days via an intravenous line as long as the treatment is effective and well tolerated. This treatment is not yet approved in Germany and is experimental. In the control group, patients will receive one of the four approved standard chemotherapy options. In this arm, the treating physicians select one of the four approved options (vincristine/carboplatin according to the COG-V/E or SIOPe protocol, vinblastine (VBL), or carboplatin monotherapy). Depending on the protocol, chemotherapy is continued for a fixed period until the end of treatment or is discontinued if the disease progresses or severe side effects occur. Assignment is open-label; both treating physicians and patients know which study arm they are in and which treatment is being administered. Follow-up as part of the study lasts for up to 5 years.

Patients under the age of 25 with a low-grade glioma and a confirmed activating RAF mutation who require initial systemic treatment are eligible to participate in the study. Patients with certain other tumor types, such as schwannomas or specific gliomas, as well as those with additional genetic alterations such as IDH or histone H3 mutations, are excluded. Participation in the study is not possible if the patient has already undergone cancer treatment in the form of chemotherapy, radiation, or targeted therapy.