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

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 blocks de novo 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/m(2)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 AUC(0-24)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.

• Authors: D Bissett, H L McLeod, B Sheedy, M Collier, Y Pithavala, L Paradiso, M Pitsiladis, J Cassidy
• Journal: British journal of cancer (Br J Cancer) Vol. 84 Issue 3 Pg. 308-12 (Feb 02 2001) ISSN: 0007-0920 [Print] England
• PMID: 11161393 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Glutamates
• Pyrimidines
• AG 2034

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Area Under Curve
• Diarrhea (chemically induced)
• Dose-Response Relationship, Drug
• Female
• Glutamates (administration & dosage, adverse effects, pharmacokinetics)
• Humans
• Male
• Middle Aged
• Mouth Mucosa (drug effects, pathology)
• Nausea (chemically induced)
• Neoplasms (drug therapy, metabolism)
• Neutropenia (chemically induced)
• Pyrimidines (administration & dosage, adverse effects, pharmacokinetics)
• Stomatitis (chemically induced)
• Thrombocytopenia (chemically induced)
• Treatment Outcome