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

• Published in: British journal of cancer 2001-02, Vol.84 (3), p.308-312
• Main Authors: Bissett, D, McLeod, H L, Sheedy, B, Collier, M, Pithavala, Y, Paradiso, L, Pitsiladis, M, Cassidy, J
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chemotherapy; Diarrhea - chemically induced; Dose-Response Relationship, Drug; Drug Resistance; Epidemiology; Female; Glutamates - administration & dosage; Glutamates - adverse effects; Glutamates - pharmacokinetics; Humans; Male; Medical sciences; Middle Aged; Molecular Medicine; Mouth Mucosa - drug effects; Mouth Mucosa - pathology; Nausea - chemically induced; Neoplasms - drug therapy; Neoplasms - metabolism; Neutropenia - chemically induced; Oncology; Pharmacology. Drug treatments; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Regular; regular-article; Stomatitis - chemically induced; Thrombocytopenia - chemically induced; Treatment Outcome
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1054/bjoc.2000.1601

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. © 2001 Cancer Research Campaign http://www.bjcancer.com