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- Title
Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034.
- Authors
Bissett, D; McLeod, H L; Sheedy, B; Collier, M; Pithavala, Y; Paradiso, L; Pitsiladis, M; Cassidy, J
- 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[SUP2] 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[SUP2] 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[SUP2]. Most side effects occurred more frequently with cumulative dosing. In keeping with this, pharmacokinetic analysis revealed evidence of drug accumulation. The AG2034 AUC[SUB0-24] (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.
- Subjects
NUCLEOTIDES; TRANSFERASES; CANCER patients
- Publication
British Journal of Cancer, 2001, Vol 84, Issue 3, p308
- ISSN
0007-0920
- Publication type
Article
- DOI
10.1054/bjoc.2000.1601