Weekly lometrexol with daily oral folic acid is appropriate for phase II evaluation.
OBJECTIVE
Lometrexol [(6R)-5,10-dideaza-5,6,7,8-tetrahydrofolate] is the prototype folate antimetabolite that targets the de novo purine synthesis pathway. Early phase I trials were confounded by cumulative myelosuppression that prevented repetitive administration. Subsequent preclinical and clinical studies suggested that coadministration of folic acid might favorably modulate 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 studies were undertaken in an attempt to improve our understanding of lometrexol pharmacodynamics.


METHODS
Patients with advanced cancer received daily oral 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 toxicity of more than grade 2 present on the day of treatment, and dose-limiting toxicity was prospectively defined in terms of frequency of dose omission 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 total of 18 patients were treated at five lometrexol dose levels. The maximum tolerated dose was identified by frequent dose omission due to thrombocytopenia and mucositis. The recommended phase II dose combination is lometrexol 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 disease. Lometrexol was not detectable in any predose plasma sample tested. The total red blood cell content of lometrexol increased over several weeks and then appeared to plateau.


CONCLUSIONS
Weekly administration of lometrexol is feasible and well-tolerated when coadministered with daily oral folic acid. The nature of the interaction between natural folates and lometrexol that renders this schedule feasible remains unclear. A definition of dose-limiting toxicity that incorporated attention to dose omissions allowed efficient identification of a recommended phase II dose that reflects the maximum feasible dose intensity for a weekly schedule. Lometrexol is a promising, anticancer agent.
Roberts
J D
JD
Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0037, USA. roberts@mcc1.mcc.vcu.edu
Poplin
E A
EA
Tombes
M B
MB
Kyle
B
B
Spicer
D V
DV
Grant
S
S
Synold
T
T
Moran
R
R
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced* / Q000517:prevention & control; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D004906:Erythrocyte Count; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000009:adverse effects* / Q000493:pharmacokinetics; D006397:Hematinics / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D013763:Tetrahydrofolates / Q000009:adverse effects* / Q000493:pharmacokinetics
D005493:Folic Acid Antagonists; D006397:Hematinics; D013763:Tetrahydrofolates; C045894:lometrexol; D005492:Folic Acid