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

Bissett, D., McLeod, H., Sheedy, B., Collier, M., Pithavala, Y., Paradiso, L., Pitsiladis, M. and Cassidy, J. (2001) Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034. British Journal of Cancer, 84(3), pp. 308-312. (doi: 10.1054/bjoc.2000.1601)

Abstract

The novel folate analogue AG2034, which was designed as an inhibitor of GARFT (glycinamide ribonucleotide formyltransferase), was evaluated in this phase 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. AG2034 was administered as a short intravenous infusion once every 3 weeks. 8 dose 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, diarrhoea and vomiting were observed at doses of 6 mg/m2 and above. Significant levels of thrombocytopenia, neutropenia and anaemia were also recorded. Other sporadic toxicities included fatigue and myalgia. The MTD with this schedule 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 objective antitumour responses were observed in the study.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cassidy, Professor James
• Authors: Bissett, D., McLeod, H., Sheedy, B., Collier, M., Pithavala, Y., Paradiso, L., Pitsiladis, M., and Cassidy, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: British Journal of Cancer
• ISSN: 0007-0920