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

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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, 45, and 60 mg. DLT in evaluable pts was myelosuppression (grade IV neutropenia for > 7 days or any grade IV thrombocytopenia) and occurred in 4/16 pts in stratum I [45 mg (n=1/12), 60 mg (n=1/2), 78 mg (n= 2/2)] and 3/19 pts in stratum II [45 mg (n= 3/4), 60 mg (n=0/1), 30 mg (n= 0/12), and 20 mg (n= 0/2)] respectively. Other significant toxicities post first course included renal failure (n=2), pulmonary (n=2), and fatal infection (n=1). PK studies showed median (range) terminal half-life of 62 mins (7.3 to 522 min). The MTDs in stratum I and II were 45 mg/m2/day and 30 mg/m2/day daily for 5 days q 6 weeks, respectively. Objective responses were observed in one pt each with brain stem glioma and medulloblastoma respectively. PBMC AGT levels did not decrease following VNP40101M treatment. Conclusions: The recommended pediatric phase II dose of VNP40101M given i.v daily for 5 days q 6 weeks is 45 mg/m2/day in less-heavily treated and 30 mg/m2/day in heavily treated pts. [Table: see text]