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

Abstract

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.