Crisnatol mesylate : phase I dose escalation by extending infusion duration

• Published in: Investigational new drugs 1991-02, Vol.9 (1), p.41-47
• Main Authors: POPLIN, E. A, CHABOT, G. G, TUTTLE, R. L, WARGIN, W. A, BAKER, L. H
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Chemotherapy; Chrysenes - administration & dosage; Chrysenes - adverse effects; Chrysenes - pharmacokinetics; Chrysenes - therapeutic use; Colonic Neoplasms - drug therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Female; Humans; Infusions, Intravenous; Kidney Neoplasms - drug therapy; Lung Neoplasms - drug therapy; Male; Medical sciences; Middle Aged; Neoplasms - drug therapy; Ovarian Neoplasms - drug therapy; Pharmacology. Drug treatments; Propylene Glycols - administration & dosage; Propylene Glycols - adverse effects; Propylene Glycols - pharmacokinetics; Propylene Glycols - therapeutic use; Sarcoma - drug therapy
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/BF00194543

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 (T1/2 beta) was 3.3 hours with a total body clearance (CL) of 22.8 L/hr/m2 and a volume of distribution (Vdss) of 53 L/m2. The median steady-state peak plasma concentration (Css) at 2700 mg/m2/72 hours was 2.7 micrograms/ml and at 3400 mg/m2/72 hours was 3.8 micrograms/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.