A Phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid

Abstract

Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities. Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance. The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.

Selective expression of folate receptor ? and its possible role in methotrexate transport in synovial macrophages from patients with rheumatoid arthritis

“…In fact, toxicity has been a more common reason for discontinuation of MTX than poor efficacy (43). Some folate antagonists with a high affinity for FR-␤ are in phase I or phase II trials for the treatment of cancer (44,45). In conclusion, the present findings strongly suggest a role for FR-␤ in the transport of folic acid and folate derivatives in RA SMC and imply that folic acid antagonists with a high affinity for FR-␤ may be useful in the treatment of RA.…”

Mutations in the Reduced Folate Carrier Gene Which Confer Dominant Resistance to 5,10-Dideazatetrahydrofolate

“…Preclinical (21) and clinical therapeutic trials (22,24) 3 have shown that the toxicity of (6R)-DDATHF to animals and man can be substantially decreased by the co-administration of oral folic acid. Animal studies have shown that the toxicity of (6R)-DDATHF can be shifted by a surprising 1000-fold by the administration of rather small doses of oral folic acid to animals on a low folate diet (21).…”

A phase I study of pemetrexed (LY231514) supplemented with folate and vitamin B12 in Japanese patients with solid tumours

“…Clinical experience and nonclinical studies with methotrexate and lometrexol indicated that severe toxicity may be associated with nutritional folate status (Morgan et al, 1990;Alati et al, 1996;Mendelsohn et al, 1996). In fact, in the study of lometrexol, a significant effect of folate supplementation on toxicity was observed (Laohavinij et al, 1996). Based on these experiences, Niyikiza et al (2002a) investigated relationships between toxicity and baseline patient characteristics for early pemetrexed studies.…”