PBTC-017: PHASE I STUDY OF CLORETAZINE (VNP40101M) IN CHILDREN WITH RECURRENT,

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The specific aim of this study is to estimate the Maximum tolerated dose (MTD) and describe the Dose Limiting Toxicities (DLT) of CLORETAZINE¿ (VNP40101M) when administered intravenously daily for five days every six weeks to children and young adults with recurrent, progressive or refractory primary brain tumors. CLORETAZINE¿ is a novel alkylating agent with a broad spectrum of anti-tumor activity in murine tumor models. It is believed to specifically attack the O6 position of guanine, forming G-C DNA cross-links. CLORETAZINE¿ has demonstrated in vitro and in vivo anti-tumor activity against certain selected tumor cell lines that are resistant to currently approved alkylating agents. CLORETAZINE¿ will be given intravenously over 30 minutes for 5 consecutive days every 6 weeks. Six consecutive weeks will constitute one course of treatment. Every attempt will be made to avoid interruption of treatment during each course particularly during the DLT assessment phase. The first course of treatment should be completed in not more than 7 days. Patients are allowed to skip no more than one day of treatment during any course. This missed dose of drug can be made up within 7 days of starting treatment during any course. Dosing is based on the body surface area calculated at the beginning of each course of therapy. Adequate pulmonary and cardiac function assessed within 2 weeks prior to registration. Endpoints are estimated based on experience in PBTC-012 which showed that the average monthly accrual is about two patients. To investigate the seven dose levels with the plan to put 12 patients at the MTD, a maximum of 30 patients per stratum are expected to be needed, which will require patient accrual over a year to 18 months considering the times the study will be closed to accrual.