Drug & Device Development

Investigational antitumor agent nolatrexed fails in phase III study of liver cancer

Last Updated: 2007-08-01 16:51:04 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Nolatrexed (Eximias Pharmaceutical Corp.) showed "minimal activity" for the treatment of unresectable hepatocellular carcinoma (HCC) in an international phase III trial, researchers report in the July 20th issue of the Journal of Clinical Oncology.

Dr. Robert G. Gish of the California Pacific Medical Center in San Francisco and colleagues compared nolatrexed, a novel thymidylate synthase inhibitor, with doxorubicin in 445 patients with unresectable HCC. In the absence of an approved treatment, doxorubicin is frequently used as first-line therapy.

Nolatrexed is unlike other thymidylate synthase inhibitors, such as fluorouracil, because it does not require active uptake into cells, the researchers note.

Patients had Karnofsky scores of 60% or greater, Cancer of the Liver Italian Program scores of 3 or less and adequate organ function.

After nearly 5 years, 377 patients had died. Median overall survival was 22.3 weeks for nolatrexed and 32.3 weeks with doxorubicin, with a hazard ratio of 0.753 in favor of doxorubicin.

The objective response rate, which consisted of partial responders plus complete responders, was 1.4% for nolatrexed and 4.0% for doxorubicin.

Median progression-free survival was 12 weeks for nolatrexed and 10 weeks for doxorubicin. Median time to treatment failure was 8.4 weeks for nolatrexed and 9.1 weeks for doxorubicin.

Grade 3 and 4 stomatitis, vomiting, diarrhea and thrombocytopenia were more common in nolatrexed-treated patients. Alopecia was more common with doxorubicin. Treatment discontinuation rates were higher with nolatrexed than doxorubicin.

"The extended survival in the doxorubicin arm was unexpected, based on the information available at the time of the origination of the phase III trial," Dr. Gish and colleagues write. "To our knowledge, this is the largest randomized controlled trial utilizing doxorubicin as a control arm ... for the treatment of unresectable HCC with chemotherapy."

The team concludes, "Nolatrexed should not be tested again in this disease at this dose and schedule. However, nolatrexed does have high bioavailability, has the potential to be effective in other tumors, and may have potential in pancreatic or head and neck cancer based on phase II data."

On the other hand, "The survival rates demonstrated in the doxorubicin-treated patients are of interest and could support further licensing trials that may lead to the approval by regulatory authorities as a primary treatment of HCC," the investigators propose.

J Clin Oncol 2007;25:3069-3075.