Phase II trial of nolatrexed dihydrochloride [Thymitaq, AG 337] in patients with advanced hepatocellular carcinoma.

Abstract

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/m(2)/day for 5 days. Doses were adjusted to maintain a dose level that produced > or = 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/m(2)/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 microg/mL (range 1.41 to 119 microg /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.

• Authors: Minaxi Jhawer, Lee Rosen, Janet Dancey, Howard Hochster, Solomon Hamburg, Margaret Tempero, Neil Clendeninn, Sridhar Mani
• Journal: Investigational new drugs (Invest New Drugs) Vol. 25 Issue 1 Pg. 85-94 (Feb 2007) ISSN: 0167-6997 [Print] United States
• PMID: 16957834 (Publication Type: Clinical Trial, Phase II, Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• Quinazolines
• nolatrexed

Topics

• Adult
• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (adverse effects, pharmacokinetics, therapeutic use)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Drug Administration Schedule
• Exanthema (chemically induced)
• Female
• Humans
• Infusions, Intravenous
• Liver Neoplasms (drug therapy, pathology)
• Male
• Metabolic Clearance Rate
• Middle Aged
• Nausea (chemically induced)
• Quinazolines (blood, pharmacokinetics, therapeutic use)
• Stomatitis (chemically induced)
• Survival Analysis
• Time Factors
• Treatment Outcome