Clinical Development of Eniluracil: Current Status

ABSTRACT: Eniluracil is a potent inactivator of dihydropyrimidine dehydrogenase (DPD), which is the first enzyme in the degradative pathway of systemically administered 5-fluorouracil (5-FU). Two completely oral regimens of eniluracil plus 5-FU are being evaluated in clinical trials: (1) a chronic schedule with both agents administered BID in a 10:1 ratio for 28 days of a 5-week course, and (2) a 5-day schedule of eniluracil once daily on days 1 through 7 and 5-FU once daily on days 2 through 6. The clinical development of eniluracil is being pursued in several tumor types, including colorectal cancer, breast cancer, and pancreatic cancer. Response rates achieved in a phase II study of the chronic schedule of oral eniluracil/5-FU in patients with colorectal cancer compare favorably with those obtained in trials of intravenous 5-FU and leucovorin, while results from other trials are awaited. Safety analysis for the 28-day schedule has revealed a low incidence of severe toxicities, particularly as compared with standard 5-FU regimens. [ONCOLOGY 12(Suppl 7):52-56, 1998]

Introduction

Until recently, strategies aimed at modulating 5-fluorouracil (5-FU) have focused on 5-FU activation pathways. However, the recent recognition of the clinical importance of dihydropyrimidine dehydrogenase (DPD)—the first enzyme in a degradative pathway that rapidly catabolizes more than 80% of systemically administered 5-FU—has led to new potentials for improving the efficacy and safety of 5-FU.[1] The limited antitumor activity of 5-FU may be due in part to its pharmacokinetic characteristics, which are dependent on DPD and have been well described.[2] It has also been reported that intratumoral DPD expression is an independent determinant of tumor response to 5-FU-based chemotherapy.[3]

Eniluracil (776C85, 5-ethynyluracil) is a potent inactivator of DPD.[4] The chemical structure of eniluracil in comparison with that of 5-FU is shown in Figure 1. In preclinical studies, doses of eniluracil sufficient to inactivate more than 99% of endogenous DPD were nontoxic and exhibited no antiproliferative activity. In animal models, pretreatment with eniluracil significantly increased the bioavailability and reduced the pharmacokinetic variability of oral 5-FU. In three rodent tumor models, eniluracil also increased the antitumor efficacy of 5-FU and increased the therapeutic index of 5-FU by up to sixfold.[5,6] Preclinical evidence suggests that eniluracil may improve the efficacy of 5-FU by preventing the formation of 5-FU catabolites that may impair antitumor activity and increase 5-FU toxicity.[7] It was also demonstrated in vitro that DPD activity was an independent factor significantly related to 5-FU sensitivity and that eniluracil enhanced 5-FU cytotoxicity in six cell lines expressing high basal DPD activity.[8] By inhibiting DPD, eniluracil may eliminate one potential mechanism for 5-FU chemoresistance.

Clinical Trials of Eniluracil

Eniluracil is currently in phase III clinical development. Baker et al reported that the oral bioavailability of 5-FU is excellent and is approximately 100% in the presence of eniluracil at a dose of 3.7 mg/m².[9] This study paved the way for the development of two completely oral 5-FU regimens, which are currently under clinical investigation: The first regimen involves a chronic dosing schedule in which eniluracil and 5-FU are administered orally BID in a 10:1 ratio for 28 days of a 5-week course. The 5-FU dose is 1.0 or 1.15 mg/m². In the second regimen, eniluracil is given orally once daily on days 1 through 7 and 5-FU given orally once daily on days 2 through 6. Results of the initial phase I trial for this schedule showed that it was well tolerated and demonstrated antitumor activity.[10]

The phase II/III development of eniluracil has focused on three important tumor types: colorectal cancer, breast cancer, and pancreatic cancer.

Eniluracil/5-FU in Colorectal Cancer

Because 5-FU-based chemotherapy has been the mainstay of therapy for advanced gastrointestinal and upper aerodigestive cancers, colorectal cancer was an obvious choice for phase II development of eniluracil. Mani et al recently reported preliminary results of a multicenter phase II trial evaluating the chronic dosing regimen of eniluracil/5-FU in patients with previously untreated metastatic colorectal cancer (Table 1).[11] Eligible patients had measurable lesions and had received no previous chemotherapy or only adjuvant chemotherapy completed at least 12 months prior to study entry. A Karnofsky performance status (KPS) ³ 70 and adequate organ function were also required. After 28 patients were treated with 5-FU 1.0 mg/m² BID, the protocol was amended to increase the 5-FU dose to 1.15 mg/m² because of the minimal toxicity observed at the lower dose. The response rates were 25% and 29% for the 1.0 and 1.15 mg/m² dose groups, respectively. In addition, there appeared to be a higher percentage of stable disease for the higher-dose group compared with the lower- dose group (57% vs 36%). These promising results compare favorably to those reported with regimens of intravenous 5-FU and leucovorin.[12,13]

These preliminary results prompted randomized phase III comparative trials in previously untreated patients with metastatic colorectal cancer. Currently, two large multicenter phase III studies are under way. In the United States, a phase III trial (FUMA3008) is comparing eniluracil/5-FU given on the chronic 28-day schedule vs a commonly used 5-day intravenous regimen of leucovorin 20 mg/m²/day and 5-FU 425 mg/m²/day. The sample size is approximately 900 patients and the primary end point is survival. A similar trial (FUMB3002) is under way in Europe. It has the same two treatment arms as the US trial but the sample size is approximately 500 patients and the primary end point is response rate. Survival is a secondary end point. Both trials will also evaluate progression-free survival and quality of life. Enrollment in these trials is expected to be completed by early 1999.

Eniluracil/5-FU in Breast Cancer

The combination of eniluracil/5-FU is also being evaluated as a treatment for advanced breast cancer. An overall response rate of 29% was reported in a series of small phase II studies of continuous intravenous 5-FU in heavily pretreated advanced breast cancer patients.[14] Based on these results, exploratory phase II trials in previously treated breast cancer patients were initiated. In the United States, patients with metastatic breast cancer who are resistant to or not candidates for further treatment with anthracyclines and taxanes are currently being enrolled in two multicenter phase II trials of eniluracil/5-FU. Preliminary results from one of these trials were recently reported by Rivera et al.[15] Of 31 evaluable patients, 5 had partial responses for a response rate of 16%. Additional phase II/III studies are planned, as are phase I studies of eniluracil combined with commonly used chemotherapy agents such as paclitaxel, docetaxel, and vinorelbine.

Eniluracil/5-FU in Pancreatic Cancer

Although continuous intravenous 5-FU has not been widely used for the treatment of metastatic pancreatic cancer, Hansen et al reported on 16 patients with metastatic pancreatic cancer who received continuous infusion 5-FU (200-300 mg/m²/day).[16] In a disease in which objective responses are rare, three partial responses were observed, for an overall response rate of 19%. An additional eight patients had stable disease, with a median duration of disease stabilization of 5 months (range, 3 to 10 months). As a result of these preliminary findings and the lack of effective therapy for this difficult-to-treat tumor, phase II and phase III trials of eniluracil/5-FU were started simultaneously. The non-controlled multicenter phase II trial in previously untreated patients with advanced pancreatic cancer was conducted in Europe and has completed accrual. Results have not yet been reported. In the United States, a large phase III trial is comparing eniluracil/5-FU given on the chronic 28-day schedule vs gemcitabine, a recently approved agent for this disease. Accrual is nearly complete, and results are expected in 1999.

Safety of Eniluracil

Preliminary results of studies of eniluracil suggest that this agent produces antitumor efficacy with a low incidence of severe toxicities. A preliminary safety analysis for the chronic 28-day dosing regimen, involving data from 108 patients treated in three different studies, was recently conducted (see Table 2). The three studies included in the analysis are FUMA1003 (phase I dose-escalation trial for the 28-day dose regimen), FUMA2003 (phase II breast cancer trial reported by Rivera et al[15]), and FUMA2006 (phase II colorectal cancer trial reported by Mani et al[11]). Table 3 lists the most frequently occurring nonhematologic toxicities for the 28-day regimen of eniluracil/5-FU, most of which are gastrointestinal in nature. Severe (grade 3 and 4) diarrhea occurred in fewer than 10% of patients and completely resolved with treatment discontinuation. After cessation of diarrhea, patients could usually resume therapy. In contrast, up to 27% of patients treated with the common 5-day regimen of 5-FU and leucovorin may experience severe diarrhea. Severe nausea and vomiting occurred in 5% and 2% of patients, respectively.

Hand-foot syndrome, also known as palmar-plantar erythrodysaesthesia, is observed in 24% of patients who receive continuous-infusion 5-FU.[17] While the causative mechanism for this toxicity is unknown, it usually resolves with discontinuation of treatment. Fewer than 5% of patients have experienced this adverse reaction when treated with the chronic 28-day dosing schedule of eniluracil/5-FU. The relative lack of hand-foot syndrome is clearly a potential advantage for the eniluracil/5-FU combination.

The hematologic toxicity of the eniluracil/5-FU combination is summarized in Table 4. Grade 4 granulocytopenia occurred in 1% of patients. Severe thrombocytopenia requiring platelet transfusion was rare. The incidence of marked myelosuppression with the chronic 28-day regimen was low, pointing to the observation that diarrhea usually occurs in the absence of marked myelosuppression. The relative lack of concomitant diarrhea and granulocytopenia lowers the risk of sepsis or morbidity that would require hospitalization, as occurs in some patients treated with intravenous regimens of 5-FU/leucovorin.

The toxicity profile for eniluracil/5-FU is similar for patients with different types of cancer. However, breast cancer patients appear to have a higher incidence of granulocytopenia than colorectal cancer patients: Granulocytopenia ³ grade 2 occured in 14% and 5.5% of patients with breast cancer and colorectal cancer, respectively. This difference is probably related more to the effects of previous chemotherapy than to the tumor type itself, because all breast cancer patients had previously received anthracyclines and taxanes, whereas those with colorectal cancer had not received any previous chemotherapy for metastatic disease. Interestingly, the incidence of diarrhea ³ grade 2 was higher in the colorectal cancer population than in the breast cancer population (25% vs 14%); this difference may be related to previous surgical procedures but a disease effect cannot be ruled out. No hand-foot syndrome was observed in the two phase II studies involving breast and colorectal cancer patients.

The effect of dose on toxicity was also evaluated. Table 5 lists common toxicities according to initial 5-FU dose (ie, 1.0 or 1.15 mg/m²). The incidences of ³ grade 2 diarrhea, nausea, vomiting and granulocytopenia were similar in the two dose groups, which supports the hypothesis (based on preclinical data) that eniluracil increases the therapeutic index of 5-FU.

Other adverse experiences that have been reported include cholestatic jaundice, deep vein thrombosis, and nystagmus. The first two events may be related to metastatic cancer, but a relationship to eniluracil/5-FU cannot be eliminated because the patients were receiving treatment at the time of the event. Nystagmus has been observed previously in patients receiving 5-FU-based chemotherapy.

Summary

In summary, eniluracil is a promising new agent with a novel mechanism of 5-FU modulation. Extensive phase II/III trials in patients with colorectal, breast, and pancreatic cancers as well as other solid tumors are ongoing. Preliminary results of a phase II study in colorectal cancer are encouraging. The chronic 28-day regimen is well tolerated with a relatively low incidence of severe toxicities (in particular, hand-foot syndrome) as compared with that of standard 5-FU-based regimens. The combination of eniluracil/5-FU may prove to be a convenient, well tolerated and effective alternative to intravenous 5-FU-based chemotherapy regimens.

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