Phase II trial of nolatrexed dihydrochloride [ThymitaqTM, AG 337] in patients with advanced hepatocellular carcinoma
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Background: To evaluate the tolerability and efficacy of nolatrexed in patients with advanced hepatocellular carcinoma.
Patients and methods: Forty-eight patients were entered onto this study. Nolatrexed was administered every 3 weeks as a 24-h continuous intravenous infusion of 725 mg/m2/day for 5 days. Doses were adjusted to maintain a dose level that produced grade 2 toxicity. Response was assessed after every two cycles. Plasma pharmacokinetic samples were assayed using a validated high performance liquid chromatography ultraviolet method.
Results: Thirty-nine (81%) patients were evaluable for response. The mean number of cycles received was 2.8 (range 1–12). The mean dose intensity was 700 mg/m2/day (SD of 71). One patient had a partial response (2.6%) for 7 months. Eighteen (46%) patients had SD, 20 (51%) patients had progressive disease. The median duration of SD was 93 days. The median overall survival was 32 weeks [95% CI (22–37)]. The most frequent Grade 3 or 4 adverse events were stomatitis (25%), dehydration (23%) and asthenia (21%). There was no evidence of cumulative toxicity. The overall median plasma concentration (Cmax) was 14.20 μg/mL (range 1.41 to 119 μg /mL) with no accumulation observed between cycles 1–6.
Conclusion: This phase II study of nolatrexed in advanced HCC patients, demonstrated minimal activity and significant stomatitis. Hence, it does not warrant further study as a single agent for this disease.
KeywordsHepatocellular carcinoma Thymidylate synthase inhibitors Thymitaq Phase II clinical trial
We would like to thank all the physicians, patients and staff at Agouron Pharmaceuticals, Inc. La Jolla, CA and Eximias Pharmaceutical Corporation, Berwyn, PA involved in this study.
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