Purpose: Lometrexol [(6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate] is the pro
totype folate antimetabolite that targets the de novo purine synthesis path
way. Early phase I trials were confounded by cumulative myelosuppression th
at prevented repetitive administration. Subsequent preclinical and clinical
studies suggested that coadministration of folic acid might favorably modu
late lometrexol toxicity without eliminating potential antitumor activity.
We set out to determine if concurrent folic acid would allow administration
of lometrexol on a weekly schedule, and, if so, to identify an appropriate
dose combination for phase II trials. Pharmacokinetic and metabolism studi
es were undertaken in an attempt to improve our understanding of lometrexol
pharmacodynamics. Methods: Patients with advanced cancer received daily or
al folic acid beginning 7 days before lometrexol and continuing for 7 days
beyond the last lometrexol dose. Lometrexol was administered by short i.v.
infusion weekly for 8 weeks. Scheduled lometrexol doses were omitted for to
xicity of more than grade 2 present on the day of treatment, and dose-limit
ing toxicity was prospectively defined in terms of frequency of dose omissi
on as well as the occurrence of severe toxic events. Plasma and whole blood
total lometrexol contents (lometrexol plus lometrexol polyglutamates) were
measured in samples taken just prior to each lometrexol dose. Results: A t
otal of 18 patients were treated at five lometrexol dose levels. The maximu
m tolerated dose was identified by frequent dose omission due to thrombocyt
openia and mucositis. The recommended phase II dose combination is lometrex
ol 10.4 mg/m(2) per week i.v. with folic acid 3 mg/m(2) per day orally. One
patient with melanoma experienced a partial response, and three patients,
two with melanoma and one with renal cell carcinoma, experienced stable dis
ease. Lometrexol was not detectable in any predose plasma sample tested. Th
e total red blood cell content of lometrexol increased over several weeks a
nd then appeared to plateau. Conclusions: Weekly administration of lometrex
ol is feasible and well-tolerated when coadministered with daily oral folic
acid.. The nature of the interaction between natural folates and lometrexo
l that renders this schedule feasible remains unclear. A definition of dose
-limiting toxicity that incorporated attention to dose omissions allowed ef
ficient identification of a recommended phase II dose that reflects the max
imum feasible dose intensity for a weekly schedule. Lometrexol is a promisi
ng, anticancer agent.