A PHASE-I CLINICAL-STUDY OF THE ANTIPURINE ANTIFOLATE LOMETREXOL (DDATHF) GIVEN WITH ORAL FOLIC-ACID

Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synt hesis. Extensive experimental and limited clinical data have shown tha t lometrexol has activity against tumours which are refractory to othe r drugs, notably methotrexate. However, the initial clinical developme nt of lometrexol was curtailed because of severe and cumulative antipr oliferative toxicities. Preclinical murine studies demonstrated that t he toxicity of lometrexol can be prevented by low dose folic acid admi nistration, i.e. for 7 days prior to and 7 days following a single bol us dose. This observation prompted a Phase I clinical study of lometre xol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid suppleme ntation. Thrombocytopenia and mucositis were the major toxicities. The re was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lomet rexol plasma pharmacokinetics were not altered by folic acid administr ation indicating that supplementation is unlikely to reduce toxicity b y enhancing lometrexol plasma clearance. The work described in this re port has identified for the first time a clinically acceptable schedul e for the administration of st GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.