Phase I evaluation of 773U82.HCl, a member of a new class of DNA intercalators.

Abstract

The arylmethylaminopropanediols (AMAPs) are a new class of DNA intercalators. 773U82.HCl is the second of these compounds to enter clinical trial. Significant antitumor activity for 773U82.HCl was documented in a variety of murine and human tumor models. This phase I study examined a 1-, 2- and 6-hour infusion given every 28 days. Thirty-six patients received 58 courses of drug at doses ranging from 15 mg/m2 to 980 mg/m2. The dose-limiting toxicity of 773U82.HCl was hemolysis noted at 980 mg/m2. Change in color of the plasma and decreases in haptoglobin were correlated with drug concentrations of the infusate greater than or equal to 3 mg/ml. Clinically significant changes in hemoglobin levels requiring blood transfusions did not occur. Neurologic toxicity occurred at 720 mg/m2 with the most severe neurologic toxicity occurring in a patient with the highest peak plasma concentration (4.1 micrograms/ml). With an increase in duration of the infusion and amount of fluid administered, the neurologic toxicity resolved. Other toxicities included mild nausea and vomiting and a dose-related phlebitis. Pharmacokinetic studies were completed in 22 patients. The mean terminal t1/2 beta was 4.4 h with a mean apparent volume of distribution at steady state (Vdss) of 314 l/m2. The mean total body clearance was 72 l/h/m2. Peak plasma levels ranged from 0.04 to 4.14 micrograms/ml. Further studies with 773U82.HCl on this schedule at the doses studied are not recommended. Hematologic monitoring for evidence of intravascular hemolysis should be included in future studies with 773U82.HCl.

• Authors: K A Havlin, J G Kuhn, J B Craig, G R Weiss, J Koeller, J N Turner, J S Luther, G Clark, K W Bair, W Wargin
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 2 Issue 4 Pg. 357-63 (Aug 1991) ISSN: 0959-4973 [Print] England
• PMID: 1797191 (Publication Type: Clinical Trial, Controlled Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Fluorenes
• Intercalating Agents
• Propylene Glycols
• 1,3-propanediol, 2-((3-fluoranthenylmethyl)amino)-2-methyl-

Topics

• Adult
• Aged
• Drug Evaluation
• Female
• Fluorenes (pharmacokinetics, therapeutic use, toxicity)
• Hemolysis (drug effects)
• Humans
• Intercalating Agents (pharmacokinetics, therapeutic use, toxicity)
• Male
• Middle Aged
• Nausea (chemically induced)
• Neoplasms (drug therapy)
• Nervous System Diseases (chemically induced)
• Phlebitis (chemically induced)
• Propylene Glycols (pharmacokinetics, therapeutic use, toxicity)
• Vomiting (chemically induced)