Eniluracil is an irreversible inhibitor of dihydropyrimidine dehydrogenase, or DPD, the enzyme responsible for the rapid breakdown of 5-fluorouracil, or 5-FU.  5-FU is one of the world’s most widely-used anti-cancer agents and is currently first or second line therapy for a variety of cancers, including colorectal and breast. 5-FU is only available in an IV formulation.

Adherex has studied an all oral regimen of eniluracil/5-FU/ leucovorin to improve the therapeutic benefit of 5-FU by making it orally-available, more effective, and better tolerated.

Adherex conducted Protocol AHX-03-202, an open-label, randomized study comparing the completely oral combination of eniluracil/5-FU/leucovorin to capecitabine monotherapy in metastatic breast cancer (the “main study”). The study design included a crossover arm that allowed patients who had radiologically documented disease progression on capecitabine monotherapy to crossover and take eniluracil/5-FU/leucovorin (the “Crossover Arm”).

Interim results for the main study show the two regimens, eniluracil/5-FU/leucovorin and capecitabine, to be similar in efficacy and tolerability. However, promising results were seen in the Crossover Arm which present rationale for further development.

Twenty-five patients entered the Crossover Arm from the capecitabine monotherapy arm to take eniluracil/5-FU/leucovorin. Twelve experienced rapid disease progression (within 70 days) on capecitabine. Nine of the 12 achieved subsequent benefit from the eniluracil regimen: 3 patients had partial tumor responses and 6 had stable disease (see publication Rivera et.al. 2014).

To confirm the results seen in the Crossover Arm of Study AHX-03-202 in metastatic breast cancer will require very large number of patients.  However, it is clear that eniluracil/5-FU/leucovorin is active and well tolerated in refractory iv 5-FU and Xeloda® populations.  Because of known patient preferences for oral regimens and the established safety profile of eniluracil/5-FU/leucovorin, this regimen may provide an option for the patients and physicians who prefer to continue with oral 5-FU.

Further Study in Colorectal Cancer

In 2000, oral eniluracil/5-FU failed to achieve equivalence in overall survival vs. intravenous 5‑FU/leucovorin for colorectal cancer in two Phase 3 trials conducted by GSK.  In 2004, a preclinical study showed that when the eniluracil:5‑FU ratio was high, the antitumor activity of 5‑FU was significantly diminished.  This finding presented a plausible explanation for the results seen in the Phase 3 trials where the eniluracil:5‑FU ratio was 10:1 (see publication Spector 2010).

In 2003, an Investigator-sponsored Phase 1 clinical study tested a weekly eniluracil/5-FU/leucovorin regimen (dosing eniluracil either 1 or 12 hours before 5‑FU) using lower eniluracil:5-FU ratios. This regimen produced durable objective tumor responses in 2 of 17 advanced colorectal cancer patients who were refractory to intravenous (IV) 5‑FU/leucovorin (see publications Grem 2000 and Guo 2003)

The regimen used in the Grem and Guo study was the basis for the regimen selected in the Adherex Phase 2 study in metastatic breast cancer (MBC). Based on the comparable efficacy and safety data seen in the Phase 2 MBC study completed in 2013, the new dosing regimen and schedule has been validated and presents opportunity for further study in metastatic colorectal cancer.

See Eniluracil Way Forward 2014


Spector T, Cao, S. A Possible Cause and Remedy for the Clinical Failure of 5-Fluorouracil plus Eniluracil. Clin Colorectal Cancer. 2010;9(1):52-54

Guo XD, Harold N, Saif MW, et al. Pharmacokinetic and pharmacodynamic effects of oral eniluracil, fluorouracil and leucovorin given on a weekly schedule. Cancer Chemother Pharmacol. 2003;52(1):79-85

Grem JL, Harold N, Shapiro J, et al. Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors. J Clin Oncol. 2000;18(23):3952-3963

Rivera E, Chang JC, Semiglazov V. Eniluracil Plus 5-Fluorouracil and Leucovorin: Treatment for Metastatic Breast Cancer Patients in Whom Capecitabine Treatment Rapidly Failed. Clin Breast Cancer. 2014;14(1):26-30