Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034

The novel folate analogue AG2034, which was designed as an inhibitor of GAR FT (glycinamide ribonucleotide formyltransferase), was evaluated in this ph ase I study under the auspices of The Cancer Research Campaign. UK. AG2034 blacks de nova purine synthesis through inhibition of GARFT. A total of 28 patients with histologically proven intractable cancers were enrolled. AG20 34 was administered as a short intravenous infusion once every 3 weeks. 8 d ose levels ranging from 1-11 mg/m(2) were evaluated with patients receiving up to 6 cycles. Dose-limiting toxicities in the form of mucositis, diarrho ea and vomiting were observed at doses of 6 mg/m2 and above. Significant le vels of thrombocytopenia, neutropenia and anaemia were also recorded. Other sporadic toxicities included fatigue and myalgia. The MTD with this schedu le of AG2034 was 5 mg/m(2). Most side effects occurred more frequently with cumulative dosing. In keeping with this, pharmacokinetic analysis revealed evidence of drug accumulation. The AG2034 AUG,,, increased by a median of 184% (range 20-389%) from cycle 1 to 3 in all 10 patients examined. No obje ctive antitumour responses were observed in the study. (C) 2001 Cancer Rese arch Campaign.