title: 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.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, Johns Hopkins Singapore International Medical Centre, 11 Jalan Tan Tock Seng, Level 1, Singapore, 308433, Singapore. glopes@imc.jhmi.edu
authors.forename: Gilberto
authors.initials: G
authors.lastname: de Lima Lopes
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Dicksey
authors.forename: William P
authors.initials: WP
authors.lastname: Peters
authors.forename: Melvin
authors.initials: M
authors.lastname: Palalay
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Chang
mesh_terms: D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D044466:Asian People; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016896:Treatment Outcome; D014498:Uracil / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: C073482:eniluracil; D014498:Uracil; D005472:Fluorouracil