Phase I study of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed malignant tumors

13553 Background: New drugs are strongly needed in childhood cancers, particularly in metastatic tumors. Temozolomide (TMZ) and Topotecan (TPT) have shown activity in several pediatric cancers. Resistance to alkylating agents due to MGMT expression, MMR deficiency or microsatellite instability may be overcome through the combination with topoisomerase I inhibitors. The combination of TPT with TMZ has never been given in patients and our objective was to determine the recommended dose (RD) in children. Methods: The study was conducted in 9 centers of the SFCE Pharmacology Group. TMZ was administered orally followed by TPT as a 30 minutes intravenous infusion for 5 consecutive days every 28 days. Dose escalation was performed in a classical 3+3 methodology starting at 100 mg/m2 TMZ and 0.75 mg/m2 TPT. Dose-limiting toxicity (DLT) was evaluated after the first cycle. Pharmacokinetic parameters were studied during the 1st cycle Results: Sixteen patients, median age 8.5 years (range 3–19), were enrolled betwee...