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

Abstract

Summary 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.

Pemetrexed pharmacokinetics and pharmacodynamics in a phase I/II study of doublet chemotherapy with vinorelbine: implications for further optimisation of pemetrexed schedules

“…Accumulation of dUMP occurs as a direct consequence of TS inhibition and also as a result of increased activity of other enzymes, including ribonucleotide reductase (RR) and deoxycytidylate (dCMP) deaminase (Maybaum et al, 1981). A number of studies have indicated that plasma dUrd is an important pharmacodynamic (PD) marker of TS inhibition (Mitchell et al, 1997;de Jonge et al, 2002;Ford et al, 2002;Rees et al, 2003) especially with the use of the TS inhibitors AG337 (Nolatrexed) (Jodrell et al, 1999;Estlin et al, 2001), ZD9331 (de Jonge et al, 2002;Ford et al, 2002;Rees et al, 2003) and ZD1964 (raltitrexed) (Ford et al, 2002;Horton et al, 2005); however, similar studies have not been performed with pemetrexed.…”

Professor Tom Connors and the development of novel cancer therapies by the Phase I/II Clinical Trials Committee of Cancer Research UK

“…and 10 day p.o. regimens (Rafi et al, 1995(Rafi et al, , 1998Jodrell et al, 1999;Hughes et al, 2000). The 5 day i.v.…”

The changing face of chemotherapy in colorectal cancer

“…The changing face of chemotherapy in colorectal cancer (Hughes et al, 1999;Jodrell et al, 1999), and phase II studies investigating this agent in a number of solid tumours including colorectal cancer are underway.…”