A phase I study evaluating a novel schedule of oral eniluracil (EU) combined with escalating doses of oral 5-fluorouracil (5- FU)

Abstract

13519 Background: 5-FU, a commonly utilized cytotoxic, is rapidly catabolized by dihydropyrimidine dehydrogenase (DPD), and requires anabolic conversion for anti-tumor activity. 5-FU has poor oral bioavailability due to DPD in the GI tract and liver, and toxicities such as hand-foot skin reaction. In addition, high levels of DPD are associated with 5-FU resistance. EU is a mechanism-based irreversible inactivator of DPD. Early studies in combination with oral 5-FU demonstrated activity; however, 3 Phase 3 studies were negative, due to an unrecognized inhibition of 5-FU anabolic activation by EU (Fourie et al; 2006 ASCO Proceedings; a 2058). Lower doses of EU given 12–20 hrs prior to 5-FU preserves the desired DPD inhibition, without inhibiting these anabolic enzymes. Methods: The objectives are to determine the dose limiting toxicities (DLTs) and maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK), and DPD activity in peripheral blood mononuclear cells following administration of a fixed dose of EU in combination with escalating doses of 5-FU. The combination of oral 5.0 mg EU 12 to 20 hours prior to oral 5-FU, is given qW for 3 weeks in 28 day cycles. Results: Thirty-five subjects with generally extensive prior therapy have been enrolled at eight 5-FU doses levels between 30 mg and 160 mg. A total of 90 cycles have been administered. The oral combination of EU and 5-FU has been well tolerated. Nearly all toxicities have been grade 1 or 2; two grade 3 dose limiting toxicities were reported at the 50mg dose (neutropenia) and the 160mg dose (diarrhea). 95–100% of DPD inhibition achieved at the time of 5-FU dosing and 5- FU PK demonstrate a dose proportional increase in 5-FU Cmax (mean at 160 mg = 4860 ng/mL) and AUC (mean at 160 mg = 22100 ng*hr/mL), and a plasma half life of ∼3.5 hours. Four patients (2 previously treated with 5-FU) have shown ≥4 cycles of SD. Conclusions: The oral combination of 5mg of EU given 12–20 hrs prior to 5-FU has been well tolerated and is enrolling at the 210 mg dose. EU in combination with 5-FU achieves full functional inhibition of DPD in all patients, predictable 5-FU PK and may provide a promising oral therapeutic option to overcome DPD mediated 5-FU resistance and hand-foot syndrome. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Adherex Technologies Adherex Adherex