Crisnatol mesylate: Phase I dose escalation by extending infusion duration

Crisnatol mesylate is a rationally designed cytotoxic arylmethylamino-propanediol with broad spectrum cytotoxic activity. A phase I study with an unconventional escalation scheme was developed using a constant drug infusion rate (mg/m²/hr) and prolonging the infusion duration from 6 to 96 hours. Sixty-five patients received crisnatol at doses from 18 mg/m² in 6 hrs to 3400 mg/m² in 72 hours. The dose-limiting toxicity in two of five patients at 2700 mg/m² and two of three patients at 3400 mg/m² was neurologic and consisted of a syndrome of confusion, agitation, and disorientation. Phlebitis mandated the use of a central line. The mean terminal phase half-life (T_{1/2 β}) was 3.3 hours with a total body clearance (CL) of 22.8 L/hr/m² and a volume of distribution (Vd_ss) of 53 L/m². The median steady-state peak plasma concentration (C_ss) at 2700 mg/m²/72 hours was 2.7 μg/ml and at 3400 mg/m²/72 hours was 3.8 μg/ml. No responses were seen. The maximum tolerated dose (MTD) on this schedule is 2700 mg/m²/72 hours in patients with no liver disease and good performance status.