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

2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochl oride (nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor o f thymidylate synthase, was developed using protein structure-based drug de sign. Intravenously administered nolatrexed is active clinically. As oral b ioavailability is high (70-100%), nolatrexed was administered orally, 6 hou rly for In 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 toxici ties included nausea, vomiting, stomatitis and liver function test (LFT) ab normalities. Thrombocytopenia (grade I or 2) occurred at doses greater than or equal to 318 mg m(-2) day-l and neutropenia (grade 2) at 429 and 572 mg m-2 day(-1). An erythematous maculopapular rash occurred at dosages greate r than or equal to 318 mg m(-2) day(-1) (7 out of 19 patients). LFT abnorma lities occurred in two out of six patients (grade 3 or 4 bilirubin and grad e 3 alanine transaminase) at 572 mg m(-2) day(-1). Nolatrexed plasma concen trations 1 h after dosing were 6-16 mu g ml(-1), and trough 3-8 mu g ml(-1) , at 572 mg m(-2) day(-1). Inhibition of thymidylate synthase was demonstra ted by elevation of plasma deoxyuridine. Six-hourly oral nolatrexed for In 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 4 29 mg m(-2) day(-1); three out of nine experienced grade 3 nausea, but 17 o ut of 22 treatment courses were completed (with the cc-administration of pr ophylactic antiemetics) and this dose lever could be considered for phase I I testing.