Final results of a prematurely discontinued Phase 1/2 study of eniluracil with escalating doses of 5-fluorouracil administered orally in patients with advanced hepatocellular carcinoma

Gilberto De Lima Lopes, Jennifer S. Dicksey, William P. Peters, Melvin Palalay, Alex Y. Chang

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Eniluracil (EU) is a potent dihydropyrimidine (DPD) inhibitor, which improves the oral bio-availability of 5-fluorouracil (5-FU) and may overcome fluoropyrimidine (FP) resistance in hepatocellular carcinoma (HCC). Based on preclinical evidence, we aimed at studying a new dosing schedule for the combination with sequential administration, a lower dose of EU and higher doses of 5-FU than previously investigated. Methods: Patients with a diagnosis of hepatocellular carcinoma were eligible for this Phase 1/2 study. The primary endpoint for the Phase 1 was the determination of dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of oral 5-FU when given 14 h after oral EU 5 mg, weekly for 3 out of 4 weeks. The starting dose of 5-FU was 20 mg, followed by 30 mg and 80 mg. Secondary endpoints were anti-tumor activity, pharmacokinetics, and DPD activity in peripheral blood mononuclear cells. RECIST was used for assessment of efficacy and NCI CTC-AE version 3.0 for describing toxicity. Results: Nine patients enrolled in the trial. Median age was 53 years. All patients were Asian (one from Hawaii, 8 from Singapore). Prior treatment was as follows: liver surgery, 2 patients; chemo-embolization, 2 patients; thalidomide, 3 patients; adriamycin, 3 patients. Patients received a median of 2 cycles (range, 1-14) of therapy. No DLTs were seen up to the 80-mg 5-FU cohort. Out of 3 patients in the 80-mg cohort, one had pancytopenia. One patient at the 20-mg cohort had stable disease that lasted for 14 months. Conclusion: EU, at a 5.0-mg weekly dose, was well tolerated. There was no evidence of dose-related safety effects. This trial did not define the MTD for oral 5-FU. No objective responses by RECIST were noted but one patient had stable disease and a decrease of 28% in the sum of the largest diameters of her target lesions. The study was terminated early because of CNS-related toxicities noted in the single higher dose levels in a companion study, AHX-03-104.

Original languageEnglish (US)
Pages (from-to)1067-1073
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume68
Issue number4
DOIs
StatePublished - Oct 2011

Keywords

  • Chemotherapy
  • Eniluracil
  • Fluoropyrimidine
  • Fluorouracil
  • Hepatocellular carcinoma

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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