Phase I study of AG2034, a targeted GARFT inhibitor, administered once every 3 weeks

Purpose: To identify a recommended phase II dose for the second generation glycinamide ribonucleotide transformylase (GARFT) inhibitor, AG2034, admini stered by intravenous bolus every 3 weeks without folate supplementation an d to describe AG2034 pharmacokinetics. Methods: Adults with advanced malign ancies were enrolled in cohorts of three per dose level with expansion to s ix upon observation of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was defined as the dose at which two of up to six patients exper ienced DLT. Upon identification of an MTD and evidence of cumulative toxici ty, a lower intermediate dose was explored as a candidate phase II dose. AG 2034 plasma concentrations were measured using an ELISA assay. Results and conclusions: The recommended phase II dose is 5.0 mg/m(2). DLTs were anemia , thrombocytopenia, mucositis, diarrhea, hyperbilirubinemia, fatigue, and i nsomnia. Toxicities were modestly cumulative over three courses. Pharmacoki netic analysis showed a dose-AUC(0-24) relationship and a progressive incre ase in AG2034 AUC(0-24) over three courses. Both pharmacokinetic and pharma codynamic factors may contribute to the modest cumulative toxicity observed with AG2034.