부산대학교 도서관

Simple Summary: This study tested the repurposing of two rationally selected, non-anticancer drugs as a way to address the need for less toxic therapeutic options in children with gliomas. The determined recommended phase II dose of fluvastatin in combination with celecoxib in children with gliomas is 6 mg/kg/day (in 14 days on, 14 days off schedule) with a fixed daily dose of celecoxib (from 200 mg to 800 mg depending on weight). The combination is not active in HGG but could be explored as a maintenance treatment in LGG patients to avoid or delay a possible tumor recurrence, which would require a more toxic treatment. This oral strategy with very limited toxicity may be used to gain time and therefore limit treatment-related toxicities in growing children. Given its good safety profile, its low cost and all-oral administration, we think that it could be considered as an option for children with LGG living in low- and middle-income countries. Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries. [ABSTRACT FROM AUTHOR]