A phase I study of the combination of benznidazole and CCNU in man

The 2-nitroimidazole benznidazole (BENZO) has previously been shown to be an effective potentiator of the cytotoxicity of CCNU in mice, at levels which are achievable in man. This enhancement is greater than that for normal tissues, resulting in a therapeutic gain. In this study BENZO has been given to 46 patients in oral doses of 4 mg/kg to 30 mg/kg, and drug concentrations measured in plasma, urine, tumor and normal brain by HPLC. The mean plasma t 1/2 was 12.8 +/- 0.5 h and plasma peak concentration and AUC0-infinity were linearly related to dose over the whole range. Approximately 60% of the drug was bound to plasma proteins and 6% excreted unchanged in urine. Mean tumor/plasma ratios of 88% (range 54 to 122%) for 11 gliomas and 72% (range 46 to 103%) for 6 superficially accessible non-brain tumors were obtained while that for normal brain was 69% (range 53 to 75%). Doses of more than 17 mg/kg BENZO produce changes in the plasma pharmacokinetics of CCNU (130 mg/m2 p.o.), increasing the half life of active hydroxylated metabolites. In addition, CCNU parent compound is present. This is not seen when CCNU is given alone. Such changes may result in improved response rates as it is possible to achieve in man, plasma and tumor levels of BENZO, which in the mouse model produce effective enhancement of the response to CCNU. No evidence was seen that BENZO enhanced wither the acute gastrointestinal toxicity or the hematological toxicity of CCNU over the dose range studied.