Phase I trial and pharmacokinetics of aziridinylbenzoquinone (NSC 182986) in humans

2,5-Diaziridinyl-3,6-(carboethoxyamino)-1,4-benzoquinone (AZQ) is a rationally designed antitumor agent which possesses sufficient lipid solubility to allow central nervous system penetration as well as adequate aqueous solubility for drug formulation and administration. We have conducted a Phase I trial of AZQ in 40 previously treated patients with advanced cancer. The drug was given as a 15-min i.v. infusion on Days 1 and 8 of a 28-day cycle. Seven dose levels ranging from 1 to 25 mg/sq m were studied with 3 to 11 patients treated at each level. Sixty-nine evaluable cycles of AZQ were administered. The major toxicity was myelosuppression, with the nadir in white blood cells and/or platelet count occurring at Days 15 to 20 of the cycle and first appearing at doses greater than 10 mg/sq m. The highest tolerated dose was 20 mg/sq m, and this dose is recommended for Phase II trials. Other toxicities were mild nausea, slight alopecia, and anemia. Plasma pharmacokinetics was studied in 11 patients by a high-performance liquid chromatography assay. Plasma decay curves could be fitted to a two-compartment open model of drug disappearance with a dose-independent terminal half-life of 33.3 +/- 4.5 (S.D.) min. Cerebrospinal fluid AZQ levels were determined in three patients and revealed readily detectable levels of AZQ.