A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq™ (nolatrexed dihydrochloride) given by 10-day oral administration

2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design. Intravenously administered nolatrexed is active clinically. As oral bioavailability is high (70–100%), nolatrexed was administered orally, 6 hourly for 10 days, at 3-week intervals, and dose escalated from 80 to 572 mg m(−2)day(−1)in 23 patients. Common toxicity criteria (CTC) grade 3 toxicities included nausea, vomiting, stomatitis and liver function test (LFT) abnormalities. Thrombocytopenia (grade 1 or 2) occurred at doses ≥ 318 mg m(−2)day(−1)and neutropenia (grade 2) at 429 and 572 mg m(−2)day(−1). An erythematous maculopapular rash occurred at dosages ≥ 318 mg m(−2)day(−1)(7 out of 19 patients). LFT abnormalities occurred in two out of six patients (grade 3 or 4 bilirubin and grade 3 alanine transaminase) at 572 mg m(−2)day(−1). Nolatrexed plasma concentrations 1 h after dosing were 6–16 μg ml(−1), and trough 3–8 μg ml(−1), at 572 mg m(−2)day(−1). Inhibition of thymidylate synthase was demonstrated by elevation of plasma deoxyuridine. Six-hourly oral nolatrexed for 10 days was associated with antiproliferative effects, but nausea and vomiting was dose limiting at 572 mg m(−2)day(−1). Nine patients were treated at 429 mg m(−2)day(−1); three out of nine experienced grade 3 nausea, but 17 out of 22 treatment courses were completed (with the co-administration of prophylactic antiemetics) and this dose level could be considered for phase II testing. 1999 Cancer Research Campaign