Safety and efficacy of frontline doxorubicin in combination with temozolomide and valproic acid for the treatment of pediatric malignant gliomas: results of a phase 2 study.

Background: Despite innovative approaches, outcomes for pediatric high grade gliomas (HGGs) remain poor. Doxorubicin (Dox) is commonly used to treat many childhood cancers, with a well-known safety profile, although the blood-brain barrier limits its use in central nervous system tumors. However, its antineoplastic activity is reported in vitro and in vivo glioma models. We aimed to assess safety and activity of the addition of Dox to the standard treatment in this population. Methods: A monocentric, non-randomized, phase II interventional study was opened at Meyer Children's Hospital IRCCS in Florence (EudraCT 2015-002307-28), introducing Dox 100 mg/m2 over a 96-hour infusion following chemo-radiotherapy as a post-operative treatment, alongside valproic acid throughout the treatment. The endpoints were safety and efficacy of the add on Dox approach in prolonged infusion. Results: Twenty-one heterogeneous malignant pediatric HGGs patients were enrolled. However at the time of Dox administration, only twelve patients presented a performance status sufficient to receive the investigational drug. Dox single course-group (10 patients) exhibited a median overall survival (OS) of 13.7 months (6.9 months in non-Dox-treated patients). Analyzing a multivariate Cox regression, patients with diffuse midline glioma showed a significantly higher risk of events compared to those with other HGG (approximately 80%, p = 0.008). Dox-treated DMG shows a slight reduction in event rate (9.52 vs 12.55). Interestingly, all patients (6/12) with hemispheric malignant glioma, who had undergone Dox, relapsed at sites distant from the primary tumor. Currently, only one patient is alive (a Dox-treated grade 3 anaplastic pleomorphic xanthoastrocytoma), Considering the Dox-treated patients, despite 35 Serious Adverse Reactions related to Dox were reported, predominantly hematologic, the treatment after focal radiotherapy was well tolerated. No signs of cardiotoxicity, nephrotoxicity, or neurotoxicity following Dox infusion were reported. Conclusion: This preliminary study shows that a prolonged infusion Dox add-on to standard multimodal treatment for pediatric HGGs is well tolerated with no significant adverse events and with a positive impact in terms of survival, although not statistically significant.