title: Phase I clinical and pharmacology study of 502U83 given as a 24-h continuous intravenous infusion.
abstract: 502U83 is an arylmethylaminopropanediol that displays significant antitumor activity in a number of murine and human tumor-model systems. In the present phase I study, a 24-h continuous intravenous infusion of this agent was given every 28 days to patients with advanced or refractory solid tumors. In all, 46 patients received a total of 96 cycles of 502U83 at doses ranging from 25 to 8,000 mg/m2. No significant hematologic, gastrointestinal, or neurologic toxicity was observed. At doses of 2,000 mg/m2 and higher, prolongation of the corrected QT interval on ECG was evident in most patients but was completely reversible, was not associated with arrhythmias, and was not dose-limiting. Dose-limiting pulmonary toxicity characterized by acute onset of dyspnea, severe hypoxemia, interstitial pulmonary edema, and death occurred in three patients treated at the highest dose levels. Plasma concentrations of 502U83 and its metabolites were measured by high-performance liquid chromatography. The 502U83 maximal concentration (Cmax) and area under the concentration-time curve (AUC) were proportional to the delivered dose; however, substantial interpatient variability in total body clearance was noted at all dose levels. Significant conversion of 502U83 to two glucuronide metabolites was detected. Metabolite concentrations were highest in the three patients who succumbed to pulmonary toxicity, although the precise contribution of these metabolites to the observed toxic effects is unknown. In view of the unfavorable clinical profile of QTc prolongation and pulmonary toxicity produced by 502U83, further clinical development of this agent has been suspended.
authors.affiliation: Department of Medicine, Committee on Clinical Pharmacology, University of Chicago, IL 60637-1470.
authors.forename: R L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: L
authors.initials: L
authors.lastname: Janisch
authors.forename: N J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: V S
authors.initials: VS
authors.lastname: Lucas
authors.forename: J
authors.initials: J
authors.lastname: Ravitch
authors.forename: J A
authors.initials: JA
authors.lastname: Hohneker
authors.forename: N J
authors.initials: NJ
authors.lastname: Clendeninn
authors.forename: R L
authors.initials: RL
authors.lastname: Tuttle
mesh_terms: D000328:Adult; D000368:Aged; D000873:Anthracenes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D012131:Respiratory Insufficiency / Q000139:chemically induced
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; C066521:502U83