PHASE-I TRIAL OF THE THYMIDYLATE SYNTHASE INHIBITOR AG331 AS A 5-DAY CONTINUOUS-INFUSION

AG331 yl)benzyl]-N-6-methyl-2,6-diaminobenz-[c,d]-indole glucuronate) is a lipophilic thymidylate synthase inhibitor with activity in solid tumor models, On the basis of preclinical data supporting regimens of frequent drug administration, we performed a Phase I trial of AG331 as a 5-day continuous infusion repeated every 3 weeks, Twenty-nine patie nts were entered at doses ranging from 25 to 1000 mg/m(2)/day, The maj or side effects were mild to moderate fatigue, nausea, vomiting, diarr hea, and fever, At doses greater than or equal to 400 mg/m(2), acute r eversible elevation of bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltranspeptidase was observed, All p atients who received greater than or equal to 600 mg/m(2)/day experien ced elevated alanine aminotransferase. Elevated liver function tests w ere evident by day 3 of the infusion and had resolved by day 8 in the majority, This toxicity was dose limiting at 1000 mg/m(2)/day, at whic h dose two of two patients developed grade 4 reversible hyperbilirubin emia in addition to the enzyme elevations, Serum and urine samples wer e analyzed by a novel high-pressure liquid chromatography method for t he determination of the pharmacokinetics of AG331, Over the 50-1000 mg /m(2)/day dose range, mean total clearance ranged from 11.6 to 30.0 li ters/h/m(2), and volume of distribution at steady state ranged from 27 9.5 to 758.7 liters/m(2). These parameters were dose independent over the dose range tested, The harmonic mean terminal half-life of AG331 w as 20.2 h, Less than 5% of an AG331 dose is eliminated unchanged in th e urine, Both the administered dose and exposure to the drug were rela ted to the changes in bilirubin and aminotransferase blood levels, Evi dence for inhibition of thymidylate synthase was obtained at doses ran ging from 100 to 1000 mg/m(2) in seven patients; plasma deoxyuridine c oncentrations at end-infusion were 1.8-3.8-fold higher than pretreatme nt values, Because of the nature of toxicity on this schedule, more ex tensive Phase LI evaluation is not recommended, although an AG331 dose of 800 mg/m(2)/day for 5 days is tolerable, Exploration of less frequ ent dose administration is under way.