CTP-09. Safety of frontline doxorubicin combined with standard treatment and valproic acid in pediatric malignant gliomas: results from a phase 2 study

Abstract BACKGROUND Pediatric high-grade gliomas (pHGGs) are aggressive central nervous system (CNS) tumors with poor prognosis and limited effective treatments. Doxorubicin (Dox), a widely used anthracycline, is rarely applied in CNS tumors due to blood-brain barrier (BBB) impermeability and dose-dependent cardiotoxicity. However, preclinical studies have demonstrated the efficacy of Dox against glioma cells, especially with prolonged exposure. Furthermore, it is known that radiotherapy transiently increases BBB permeability, allowing enhanced drug delivery. METHODS This is a monocentric, non-randomized, phase II trial (EudraCT 2015-002307-28) conducted at Meyer Children’s Hospital IRCCS in Florence. Twenty-one patients aged 3-22 years with newly diagnosed pHGGs received standard treatment (surgery if feasible, radiotherapy, temozolomide) in addition to valproic acid. 12 out of the 21 patients received 96-hour Dox infusion (100 mg/m²), for 1-3 cycles, 9 out of the 21 patients withdrew from the study because of disease progression or non-permissive clinical conditions before Dox administration.The primary endpoint was safety; the secondary endpoints included overall survival (OS) and response. RESULTS No cases of Dox-induced cardiotoxicity, nephrotoxicity, or neurotoxicity were observed. Adverse events were predominantly hematologic. No Dox related study withdrawals or deaths occurred. The median OS was 13.7 months in the Dox one cycle treated patients. CONCLUSIONS Prolonged infusion of Dox in pHGGs appears to be a safe and feasible therapeutic strategy, showing good overall tolerability. Notably, no signs of cardiotoxicity, nephrotoxicity, or neurotoxicity were observed, even in a high-risk pediatric population. These findings support the potential of this approach as a safe add-on regimen.