, Volume 25, Issue 1, pp 85-94
Date: 07 Sep 2006

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 (C max) 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.