BACKGROUND.
Inoperable hepatocellular carcinoma is an incurable malignancy with no accepted standard therapy. Chemotherapy has demonstrated occasional responses and the need is great for a new and effective agent. Therefore the authors conducted this Phase II trial of a novel thymidylate synthase inhibitor, nolatrexed dihydrochloride (designed using structure-based computer modeling), in patients with advanced hepatocellular carcinoma.
METHODS.
Forty-one patients with unresectable or metastatic hepatocellular carcinoma were treated with nolatrexed, which was administered as a 24-hour outpatient intravenous infusion for 5 days at a dose of 795 mg/m 2 /day as free base (1000 mg/m 2 /day as salt) during each 21-day cycle. Prophylactic treatment was given for emesis and rash.
RESULTS.
Twenty-eight patients received at least 2 courses of treatment and 26 patients were evaluable. Two patients (8%) achieved a partial response and 2 additional patients achieved a minor response that was significant enough to allow surgical resection with curative intent. Fourteen patients (54%) achieved stable disease. The overall median survival was 7 months (10 months among patients who completed 2 cycles) and 1 patient remained free of disease at last follow-up, 37 months after surgery. Toxicity was modest and generally was comprised of stomatitis, nausea, malaise, and rash.
CONCLUSIONS.
Nolatrexed appears to have modest biologic activity in hepatocellular carcinoma. Due to the lack of alternative treatments, further study of this drug or an oral equivalent may be warranted.