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

Donald Bissett, H. L. McLeod, B. Sheedy, M. Collier, Y. Pithavala, M. Pitsiladis, J. Cassidy, L. Paradiso

    Research output: Contribution to journalArticle

    21 Citations (Scopus)

    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. (C) 2001 Cancer Research Campaign.

    Original languageEnglish
    Pages (from-to)308-312
    Number of pages4
    JournalBritish Journal of Cancer
    Volume84
    Issue number3
    DOIs
    Publication statusPublished - 2001

    Keywords

    • folate analogue
    • AG2034
    • GARFT inhibitor
    • ANTIFOLATE LOMETREXOL DDATHF
    • ORAL FOLIC-ACID

    Cite this

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

    Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034. / Bissett, Donald; McLeod, H. L.; Sheedy, B.; Collier, M.; Pithavala, Y.; Pitsiladis, M.; Cassidy, J.; Paradiso, L.

    In: British Journal of Cancer, Vol. 84, No. 3, 2001, p. 308-312.

    Research output: Contribution to journalArticle

    Bissett, D, McLeod, HL, Sheedy, B, Collier, M, Pithavala, Y, Pitsiladis, M, Cassidy, J & Paradiso, L 2001, 'Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034', British Journal of Cancer, vol. 84, no. 3, pp. 308-312. https://doi.org/10.1054/bjoc.2000.1601
    Bissett D, McLeod HL, Sheedy B, Collier M, Pithavala Y, Pitsiladis M et al. Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034. British Journal of Cancer. 2001;84(3):308-312. https://doi.org/10.1054/bjoc.2000.1601
    Bissett, Donald ; McLeod, H. L. ; Sheedy, B. ; Collier, M. ; Pithavala, Y. ; Pitsiladis, M. ; Cassidy, J. ; Paradiso, L. / Phase I dose-escalation and pharmacokinetic study of a novel folate analogue AG2034. In: British Journal of Cancer. 2001 ; Vol. 84, No. 3. pp. 308-312.
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