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.

Autor: de Lima Lopes G Jr; Department of Oncology, Johns Hopkins Singapore International Medical Centre, 11 Jalan Tan Tock Seng, Level 1, Singapore, 308433, Singapore. glopes@imc.jhmi.edu, Dicksey JS, Peters WP, Palalay M, Chang AY
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2011 Oct; Vol. 68 (4), pp. 1067-73. Date of Electronic Publication: 2011 Feb 23.
DOI: 10.1007/s00280-011-1588-x
Abstrakt: 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.
Databáze: MEDLINE
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