A phase I study evaluating a novel schedule of oral eniluracil (EU) combined with escalating doses of oral 5-fluorouracil (5- FU)
2560 Background: 5-FU, a commonly utilized cytotoxic, is rapidly catabolized by dihydropyrimidine dehydrogenase (DPD), and requires anabolic conversion for anti-tumor activity. It 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 eniluracil 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 (PBMCs) 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: Twenty subjects have been enrolled, at 5-FU doses of 30, 40, 50, 60, and 70 mg. A total of 39 cycles have been administered, with 4 patients currently on study. The oral combination of EU and 5-FU has been well tolerated. All toxicities have been grade 1 or 2 with the exception of two grade 3 toxicities reported at the 50mg dose (anemia and neutropenia). The grade 3 neutropenia is the only observed DLT and resulted in a 1 week delay in initiation of cycle 2. No CR or PR noted, but 4 patients (2 previously treated with 5-FU) with 4 cycles of SD. 95–100% of DPD inhibition achieved at the time of 5-FU dosing and PK results demonstrate a dose proportional increase in 5-FU Cmax and AUC, and a half life of ∼3.5 hours. Conclusions: The oral combination of 5mg of EU given 12–20 hrs prior to 5-FU has been well tolerated and achieves full functional inhibition of DPD in all patients. The MTD is not yet defined and the next cohort is enrolling at the 80mg dose. EU in combination with 5-FU may provide a promising therapeutic option for patients with tumors known to be resistant to 5-FU due to high levels of DPD. No significant financial relationships to disclose.