Phase I trial of VNP40101M in children with recurrent brain tumors—A Pediatric Brain Tumor Consortium (PBTC) study

2059 Background: VNP40101M, a novel DNA alkylating agent and a potent inhibitor of alkylguanine alkyl transferase (AGT) in pre- clinical studies, was evaluated in a phase I study in children with recurrent brain tumors. Methods: VNP40101M was given intravenously (i.v) daily for 5 days q 6 weeks up to 8 cycles. Using the continual reassessment method, dose escalation was performed independently in pts stratified based on intensity of prior therapy (stratum I-less-heavily pre-treated; stratum II- heavily pre-treated). Dose limiting toxicities (DLTs) and responses were assessed at the end of the first and 2nd cycles of treatment, respectively. Correlative studies included pharmacokinetics and measurement of AGT activity in peripheral blood mononuclear cells (PBMC) before and after treatment. Results: 41 eligible pts (stratum I- 19, stratum II- 22; median age 9.3 yrs, range 0.9 to 21.5) were enrolled on this study. Dose levels (in mg/m2/day) evaluated in Stratum I were 45, 60, and 78 mg; In Stratum II 20, 30,...