WO2014089004A1 - Methods for treating 5-fluorouracil prodrug non-responsive cancer patients - Google Patents

Abstract

Methods for treating a patient who had rapid disease progression on a 5-FU prodrug regimen comprising first administering to the patient a DPD inhibitor that substantially eliminates activity of the enzyme in both nervous and non-nervous tissues within the patient and thereafter administering 5-FU, wherein the level of 5- FU is in substantial excess of DPD inhibitor in the patient are envisioned. Also encompassed herein are a DPD inhibitor for use in a combined treatment with 5-FU, a combination for treating a patient having rapid disease progression on a 5-FU prodrug regimen comprising a DPD inhibitor and 5-FU, and use of eniluracil in combination with 5-FU for the manufacture of a medicament for treating a patient having rapid disease progression on a 5-FU prodrug regimen.

Description

METHODS FOR TREATING 5-FLUOROURACIL PRODRUG NON-RESPONSIVE CANCER PATIENTS

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority under 35 USC §119(e) from U.S Provisional Application Serial No. 61/733,204, filed December 4, 2012, which application is herein specifically incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] This invention relates generally to cancer therapy, and more particularly to methods for treating a subgroup of cancer patients characterized by rapid disease progression (fail) while undergoing 5-fluorouracil (5-FU) prodrug treatment, wherein the subgroup with rapid disease progression on 5-FU prodrug cancer patients is subsequently treated with eniluracil in combination with 5-FU, with or without leucovorin.

BACKGROUND OF THE INVENTION

[0003] 5-FU is rapidly inactivated by dihydropyrimidine dehydrogenase (DPD) and then converted to a-fluoro- -alanine (F-Bal). F-Bal is neurotoxic and the available evidence suggest that it contributes to hand-foot syndrome and interferes with antitumor activity of 5-FU. DPD levels in patients are highly variable, causing markedly variable 5-FU pharmacokinetics that significantly impact 5-FU efficacy and safety. Eniluracil irreversibly inactivates DPD, thereby eliminating the problems associated with 5-FU variability and the formation of F-Bal. Eniluracil confers linear, consistent pharmacokinetics, 100% oral bioavailability and a 5 hr half-life on 5-FU (Spector et al. 1994;19:565-71; Paff et al. Invest New Drugs. 2000 Nov;18(4):365-71), and markedly reduces the incidence of hand-foot syndrome (Schilsky et al. J Clin Oncol. 2002 Mar 15;20(6): 1519-26). In the year 2000, oral eniluracil/5-FU failed to achieve non-inferiority in overall survival vs. intravenous 5-FU/leucovorin for colorectal cancer (Schilsky et al. J Clin Oncol. 2002 Mar 15;20(6): 1519-26). Subsequently, a study in laboratory animals revealed that the high eniluracil: 5-FU ratio in those Phase 3 studies likely decreased antitumor activity (Spector et al. Clinical Colorectal Cancer. 2010;9(l):52-4).

SUMMARY OF THE INVENTION

[0004] According to one aspect, there is provided a method for treating a patient having rapid disease progression on a 5-FU prodrug regimen, the method comprising providing the patient having rapid disease progression (fail) on a 5-FU prodrug regimen and first administering eniluracil at a dose from about 16-40 mg/m² to the patient, and thereafter administering 5-FU, wherein the 5-FU is administered at a dose such that the 5-FU is present in the patient in substantial excess of the eniluracil and at a time when at least 3-5 elimination half-lives for the eniluracil have passed since the eniluracil was administered. In keeping with the present findings, a patient identified as having rapid disease progression (fail) on a 5-FU prodrug regimen is selected for treatment in accordance with the method described herein.

[0005] In another aspect, a DPD inhibitor for use in a combined treatment with 5-FU for treating a patient having rapid disease progression on a 5-FU prodrug regimen is encompassed herein, the combined treatment comprising first administering the DPD inhibitor, wherein the DPD inhibitor is eniluracil at a dose of 16-40 mg/m², and thereafter administering the 5-FU, wherein the 5-FU is administered at a dose such that the 5-FU is present in the patient in substantial excess of the eniluracil and at a time when at least 3-5 elimination half-lives for the eniluracil have passed since the eniluracil was administered. In keeping with the present findings, a patient provided as having rapid disease progression (fail) on a 5-FU prodrug regimen is identified and/or selected for the aforementioned combined treatment.

[0006] In yet another aspect, a combination for treating a patient having rapid disease progression on a 5-FU prodrug regimen is envisioned, the combination comprising eniluracil and 5-FU, characterized in that the eniluracil is first administered at a dose of about 16-40 mg/m², and the 5-FU is administered thereafter, characterized in that the 5-FU is administered at a dose such that the 5-FU is present in the patient in substantial excess of the eniluracil and at a time when at least about 3-5 elimination half-lives for the eniluracil have passed since the eniluracil was administered. In keeping with the present findings, the patient provided has been identified as having rapid disease progression (fail) on a 5-FU prodrug regimen is thus, selected for the aforementioned combination for treating as described herein.

[0007] In a still further aspect, use of eniluracil in combination with 5-FU for the manufacture of a medicament for treating a patient having rapid disease progression on a 5-FU prodrug regimen is encompassed, wherein the eniluracil is adapted to be administrable first at a dose of 16-40 mg/m², and thereafter the 5-FU, such that the 5-FU is present in the patient in substantial excess of the eniluracil and is adapted to be administrable at a time when at least 3-5 elimination half- lives for the eniluracil have passed since the eniluracil was administered. [0008] In an embodiment, the patient that rapidly fails 5-FU prodrug monotherapy fails within approximately 70 days of 5-FU prodrug administration. Evidence of 5-FU prodrug failure is demonstrated by significant tumor growth which reflects disease progression while being treated with a 5-FU prodrug such as, for example, capecitabine.

[0009] In one illustrative embodiment of an aspect of the method, the DPD inhibitor (e.g., eniluracil) for use in a combined treatment with 5-FU, the combination comprising eniluracil and 5-FU, or the use of eniluracil in combination with 5-FU for the manufacture of a medicament, a DPD inhibitor is administered at a dose sufficient to substantially eliminate DPD activity in both nervous and non-nervous tissues in a patient, such as a dose from about 14-40 mg/m² or from about 15-40 mg/m² or from about 16-40 mg/m² or from about 20-50 mg/m². In more specific embodiments, the DPD inhibitor is eniluracil and the dose of eniluracil is from about 14-30 mg/m² or from about 15-30 mg/m² or from about 16-30 mg/m² or from about 20-50 mg/m². In still other specific embodiments, the dose of eniluracil is from about 14-21 mg/m² or from about 15-21 mg/m² or from about 16-21 mg/m².

[00010] In another illustrative embodiment, the 5-FU is administered or adapted to be

administrable about 10.5-20 hours after the DPD inhibitor (e.g., eniluracil) is administered. In yet another embodiment, the 5-FU is administered or adapted to be administrable 11-16 hours after the DPD inhibitor is administered.

[00011] In still another illustrative embodiment, the 5-FU is administered or adapted to be administrable at a dose such that at its time of administration the 5-FU is present in the patient in at least 5-fold or 10-fold excess of the DPD inhibitor.

[00012] Generally, the DPD inhibitors useful in the methods, uses, combinations, and

medicaments described herein include, but are not limited to, irreversible DPD inhibitors. For example, certain illustrative DPD inhibitors comprise a 5-substituted uracil compound or a prodrug thereof. In a more specific embodiment, the DPD inhibitor comprises a uracil compound substituted in the 5-position by a halogen atom, a C_2-4 alkenyl group, a C_2-4 alkenyl group substituted by halogen, a C_2-6 alkynyl group, a C_2-6 alkynyl group substituted by a halogen, a cyano group, a C_1-4 alkyl group or a C_1-4 alkyl group substituted by halogen. In another specific embodiment, the DPD inhibitor comprises a uracil compound selected from the group consisting of eniluracil, 5-prop-l-ynyluracil, 5-cyanouracil, 5-prop-l-ynyluracil, 5- bromoethynyluracil, 5-(l-chlorovinyl)uracil, 5-iodouracil, 5-(2-bromovinyl)uracil, (E)-5-(2-bromovinyl)uracil 5-hex-l-ynyluracil, 5-vinyluracil, 5-trifluorouracil, 5-bromouracil and 5 -(2-bromo- 1 -chlorovinyl)uracil .

[00013] In a particular embodiment of the invention, the DPD inhibitor is eniluracil.

[00014] In another particular embodiment, the DPD inhibitor is eniluracil and the anticancer agent is 5-FU.

[00015] In one illustrative embodiment, the DPD inhibitor is eniluracil, the anticancer agent is 5- FU, the eniluracil is administered or adapted to be administrable at a dose between about 16-40 mg/m², or at another DPD inhibitor dose or range as described herein, and the 5-FU is administered or adapted to be administrable about 11-16 hours thereafter at a dose between about 15-50 mg/m².

[00016] In another illustrative embodiment, the DPD inhibitor is eniluracil, the anticancer agent is 5-FU, the eniluracil is administered or adapted to be administrable at a dose between about 16-40 mg/m², or at another DPD inhibitor dose or range as described herein, and the 5-FU is administered or adapted to be administrable at a dose between about 15-50 mg/m² at a time when at least about 3-5 elimination half-lives of the eniluracil have passed since the eniluracil was administered.

[00017] In another illustrative embodiment, the DPD inhibitor is eniluracil, the anticancer agent is 5-FU, the eniluracil is administered or adapted to be administrable at a dose between about 16-40 mg/m², or at another DPD inhibitor dose or range as described herein, and the 5-FU is administered or adapted to be administrable about 11-16 hours thereafter at a dose such that the 5-FU is present in the patient in at least 5-fold or 10-fold excess of the DPD inhibitor.

[00018] The method may further comprise identifying and/or selecting a patient or patients that rapidly fail 5-FU prodrug monotherapy within approximately 70 days of 5-FU prodrug administration. In a more particular embodiment, the patient or patients are afflicted by a cancer. In a more particular embodiment, the cancer is metastatic breast or colon cancer (e.g., Dukes' C colon cancer) and the patient or patients that rapidly fail 5-FU prodrug monotherapy within approximately 70 days of 5-FU prodrug administration are selected for treatment in accordance with methods set forth herein.

[00019] In another illustrative embodiment, the method further comprises administering leucovorin 11-16 hours after the DPD inhibitor (e.g., eniluracil) is administered. In yet another illustrative embodiment, the method further comprises administering a dose of leucovorin with 5-FU or with 5-FU and on the following day and/or on the day before 5-FU is administered.

[00020] These and other aspects of the invention will be apparent upon reference to the following detailed description and attached figures. Patent and other documents cited herein to more specifically set forth various aspects of this invention are hereby incorporated by reference in their entireties.

BRIEF DESCRIPTION OF THE DRAWINGS

[00021] Figure 1 shows the chemical structures of eniluracil and 5-FU.

[00022] Figure 2 shows the catabolic pathway for 5-FU and its blockade by eniluracil.

[00023] Figure 3 presents a Kaplan-Meier Progression-Free Survival graph. Patients with rapid disease progression on capecitabine were crossed over to treatment with eniluracil/5-FU/Lv.

DETAILED DESCRIPTION OF THE INVENTION

[00024] Results presented herein relate to a clinical study involving orally administering eniluracil, 5-FU, and leucovorin to breast cancer patients. More particularly, the therapeutic protocol calls for administering high dose eniluracil that is sufficient to eliminate all DPD, including DPD in nervous tissue. Accordingly, the protocol minimizes the potential for neurotoxicity associated with F-Bal accumulation in nervous tissue cells. The therapeutic protocol also requires a delay in time between initial administration of eniluracil and subsequent dosing with 5-FU, so as to allow clearance of excess eniluracil. The therapeutic protocol further requires that 5-FU is administered such that the eniluracil: 5-FU ratio is very low, so as to optimize efficacy of the 5-FU. The protocol also optionally calls for administering leucovorin with 5-FU and 24 hours afterwards to potentiate 5-FU efficacy.

[00025] To evaluate the efficacy of the eniluracil/5-FU/leucovorin regimen described herein, the clinical study compares the efficacy and safety of the eniluracil/5-FU/leucovorin regimen to capecitabine (XELODA^®), an oral prodrug of 5-FU, for treatment of metastatic breast cancer. Patients with disease progression on capecitabine could crossover to take eniluracil/5-FU/ leucovorin. Patients having rapid disease progression on a 5-FU prodrug regimen (e.g., capecitabine), as documented by disease progression within approximately 70 days, were identified as a specific sub-group of patients and were selected to cross over to take

eniluracil/ 5 -FU/leucovorin. [00026] Currently capecitabine (XELODA®) is the only oral form of 5-FU approved in the United States. Capecitabine monotherapy is approved for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing

chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated. Capecitabine is also indicated as a single agent monotherapy for adjuvant treatment in patients with Dukes' C colon cancer who have undergone complete resection of the primary tumor when treatment with fluoropyrimidine therapy alone is preferred (see XELODA® package insert).

[00027] As described in WO2006/060697, DPD inhibitors such as eniluracil in excess ratios to 5- FU and 5-FU generated from prodrugs can compromise their antitumor activity, possibly by inhibiting one or more of the metabolic activating steps. Therefore, by ensuring that 5-FU levels are in sufficient excess of DPD inhibitor levels at the time the 5-FU is administered to a patient, the extent to which the DPD inhibitor may interfere with the antitumor activity of the 5-FU is advantageously minimized, and antitumor efficacy of these agents is thereby improved. Thus, WO2006/060697 discloses that an irreversible DPD inhibitor such as eniluracil should be dosed at the lowest dose that effectively inactivates DPD in nervous tissues as well as non-nervous tissues and sufficient time should lapse to allow extra DPD inhibitor not bound to DPD to be partially cleared such that at its time of administration the 5-FU is present in excess of the DPD inhibitor.

[00028] Further to the above and as described in WO2011/047195, subsequent studies revealed that if eniluracil and 5-FU are not administered in accordance with particular dosing and administration timing parameters, patients experience unexpected and unacceptable levels of neurotoxicity, both with respect to frequency and severity.

[00029] The methods described herein benefit from the earlier disclosure of WO2011/047195, as well as that of Guo et al. (Cancer Chemother Pharmacol. 2003 Jul;52(l):79-85), both of which are incorporated herein in their entireties.

[00030] Results presented herein reveal that a sub-group or sub-population of patients identified as rapid capecitabine failures, as evidenced by rapid disease progression (significant tumor growth; Disease Progression; PD) while being treated with capecitabine, exhibited unexpectedly superior clinical benefit when subsequently treated with the eniluracil/5-FU/leucovorin (Lv) protocol described herein. More particularly, as described in greater detail herein below, ten evaluable patients with radiologically documented rapid disease progression (PD) within 70 days on capecitabine were subsequently treated with a modified oral weekly eniluracil/5-FU/Lv regimen. After switching to eniluracil/5-FU/Lv, three (30%) patients had partial tumor response (PR) and six (60%) had stable disease (SD), producing a total of 90% with PR or SD. The median progression- free survival (PFS) on the eniluracil/5-FU/Lv regimen was 140 days (vs. 42.5 days while on capecitabine). Four (40%) patients had >7months progression free survival (PFS). Results presented herein, moreover, reveal that eniluracil/5-FU/Lv was well-tolerated with mild to moderate diarrhea and nausea as the most common side effects.

[00031] Given these promising results, eniluracil/5-FU/Lv may enable patients identified as rapid capecitabine failures to continue with oral 5-FU rather than switching to the generally less well- tolerated intravenous microtubule-interfering agents. Further underscoring the surprising nature of these findings, it is important to note that 5-FU is the active agent in both the capecitabine and eniluracil/5-FU/Lv therapies. Accordingly, the present findings identify a sub-group or sub- population of patients based on defined clinical criteria that can be treated efficaciously with the methods described herein. The present results also reveal that the rapid capecitabine failure subgroup is distinct from those patients who fail capecitabine but with delayed timing (after 70 days of capecitabine treatment), since patients that exhibit delayed capecitabine failure do not respond favorably to the eniluracil/5-FU/Lv regimen described herein.

[00032] The methods described herein are applicable to the treatment of essentially any cancer type in which 5-FU and/or 5-FU prodrugs have activity (e.g., any 5-FU-responsive cancer type or 5-FU prodrug-responsive cancer type), including, by way of illustration but not by way of limitation, breast cancer, colon cancer (e.g., Dukes' C colon cancer), lung cancer, pancreatic cancer, gastric cancer, bladder cancer, renal cancer, head and neck cancer, esophageal cancer, hepatocellular cancer, and all malignant leukemias and lymphomas. Moreover, because the present findings identify a population of breast cancer patients as rapid capecitabine failures that derive particular benefit from the eniluracil/5-FU or eniluracil/5-FU/leucovorin regimen as described herein, the present findings can be applied to cancer patients afflicted with other cancers that are generally considered to be responsive to 5-FU and/or 5-FU prodrugs. Thus, with regard to a cancer such as Dukes' C colon cancer, for example, which is routinely treated with capecitabine monotherapy, a sub-population of rapid capecitabine failures may be identified that, in accordance with the present findings, should be switched over to the eniluracil/5-FU or eniluracil/5-FU/leucovorin therapeutic regimen described herein since this patient sub-group or sub-population is expected to benefit from same.

[00033] It will be understood on the part of the skilled artisan, in view of this disclosure, that a multitude of administration and dosing schedules exist that can be used in the methods described herein while ensuring that the DPD inhibitor is administered at a level sufficient to adequately inhibit DPD activity in both nervous and non-nervous tissues in the patient and that levels of the 5-FU at its time of administration are in a therapeutically effective amount and are in sufficient excess of DPD inhibitor level in the patient to minimize or eliminate inhibition of 5-FU antitumor activity. All such administration and dosing schedules are considered within the scope of the present invention.

[00034] In one illustrative embodiment of the invention, a DPD inhibitor is first administered (i.e., pre-dosed) to a patient in need thereof at a dose sufficient to substantially eliminate DPD activity in the patient in both nervous and non-nervous tissue, followed by administration of 5- FU or a 5-FU prodrug. By "substantially eliminate", it is meant that the level of DPD activity in both nervous and non-nervous tissues in the patient is reduced to less than 10%, and preferably to less than 5%, of the baseline level of DPD activity in the patient prior to administration of the DPD inhibitor. See, for example, WO2011/047195, the entire content of which is incorporated herein by reference. A baseline level of DPD activity for a patient can be readily determined in biological samples taken from a patient using known techniques (e.g., Baker et al, J Clin Oncol 18: 915-926 2000; Schilsky et al, J Clin Oncol 4: 1450-7, 1998). It is, however, understood that assays of DPD inhibition in non- nervous tissues, such as circulating blood cells, may

overestimate the degree of DPD inhibition in nervous tissues.

[00035] After first administering at least one DPD inhibitor, and thereby substantially eliminating DPD activity in the patient, in both nervous and non-nervous tissues, 5-FU is then administered to the patient after sufficient time has passed to allow the DPD inhibitor to be substantially, but not completely, cleared from the patient by elimination. In this respect, it may be desirable in certain embodiments that a low level of DPD inhibitor remain in the system leading up and/or during 5-FU administration in order to inactivate the activity of de novo synthesized DPD.

[00036] The delay in time between administration of the DPD inhibitor and the 5-FU can vary provided that upon administration of the 5-FU, it is present in the patient in substantial excess relative to the level of DPD inhibitor remaining in the patient at that time. In one illustrative embodiment, the 5-FU is administered at a dose such that the level of 5-FU is present in the patient at least in molar excess of the DPD inhibitor remaining in the patient, for example at least about 2-fold, at least about 3-fold, at least about 5-fold, at least about 10-fold, at least about 25- fold, at least about 50-fold, or at least about 100-fold excess relative to the level of DPD inhibitor remaining in the patient at the time the 5-FU is administered. The skilled artisan will recognize that any of a number of known and available techniques may be used for calculating and/or determining the level of excess of 5-FU in a patient relative to DPD inhibitor in accordance with the embodiments described herein. Such techniques may include, for example, FIPLC, LC-MS, ELISA, and others. As noted above, it is believed that by ensuring that the 5-FU is present in sufficient excess relative to the level of DPD inhibitor in the patient at the time the 5-FU is administered, interference by the DPD inhibitor with the 5-FU antitumor activity is thereby minimized, and the efficacy of the 5-FU is thereby improved.

[00037] In a further embodiment, the 5-FU is administered to the patient only after at least about 3, 4, 5, 6, 7, 8, 9, or 10 elimination half-lives of the DPD inhibitor have passed since the DPD inhibitor was administered. In a more particular embodiment, the 5-FU is administered to the patient only after at least about 3-5 elimination half-lives of the DPD inhibitor have passed since the DPD inhibitor was administered. The elimination half-lives for certain DPD inhibitors have been determined and, for those that have not, elimination half-lives can be readily determined using well known and established gas-chromatography/mass spectrometry and UPLC techniques (referenced in Baker et al., J Clin Oncol 18: 915-926 2000; Schilsky et al., J Clin Oncol 4: 1450- 7, 1998). The elimination half-life for eniluracil in humans has been reported to be about 3.5 hours (e.g., Baker et al. , J Clin Oncol 18: 915-926 2000; Ochoa et al, Ann Oncol 11 : 1313-22, 2000), however, it is possible that the half-life for DPD inhibitors may be dose-dependent and this dose dependency should be considered when determining an appropriate time delay between the administration of DPD inhibitor and 5-FU.

[00038] For certain embodiments of the invention that employ eniluracil as the DPD inhibitor, in order to allow the level of eniluracil to be sufficiently decreased by elimination prior to administration of the 5-FU, the 5-FU is administered about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, or about 16 hours, or any minute interval in between, after administration of the eniluracil. In certain related embodiments of the present invention, the 5- FU is administered at a time between about 11-16 hours after administration of the eniluracil. In still other embodiments of the invention, the 5-FU is not administered until, at its time of administration, the ratio of eniluracil to 5-FU in the patient, will be less than about 1 : 10, less than about 1 :5, less than about 1 :4, or less than about 1 :3. Of course, it will be understood that these ranges and ratios are illustrative in nature and can be varied as necessary or desired for a particular dosing schedule provided that the presence of eniluracil is minimized or absent when 5-FU is dosed, and further provided that DPD activity has been substantially eliminated to a desired extent in both nervous and non-nervous tissue at the time the 5-FU is dosed.

[00039] The DPD inhibitor used according to the present invention is preferably one that irreversibly inactivates DPD. Thus, the inhibitor, such as eniluracil, will inactivate the enzyme and the extra inhibitor not covalently bound to the enzyme is partially cleared before 5-FU is administered. Illustrative irreversible DPD inhibitors include, but are not limited to, DPD inhibitors comprising a 5-substituted uracil compound, or a prodrug thereof, particularly a uracil compound substituted in the 5-position by a halogen atom, a C_2-4 alkenyl group (e.g. , vinyl) optionally substituted by halogen (e.g,. 2-bromovinyl, 1-chlorovinyl or 2-bromo-l-chlorovinyl), a C_2-6 alkynyl group optionally substituted by a halogen atom, a cyano group, or a Ci_-4 alkyl group substituted by halogen (e.g. , trifluoromethyl).

[00040] In a more particular embodiment of the invention, the DPD inhibitor is selected from the group consisting of eniluracil, 5-prop-l-ynyluracil, 5-cyanouracil, 5-propynyluracil, 5- bromoethynyluracil, 5-(l-chlorovinyl)uracil, 5-iodouracil, 5-(l-bromovinyl)uracil,

(E)-5-(2-bromovinyl)uracil, 5-hex-l-ynyluracil, 5-vinyluracil, 5-trifluorouracil, 5-bromouracil, and 5-(2-bromo-l-chlorovinyl)uracil, or a prodrug thereof.

[00041] In another illustrative embodiment, the DPD inhibitor is a prodrug of 5-bromovinyluracil, one illustrative compound being represented by the compound l-P-D-arabinofuranosyl-(£)-5-(2- bromovinyl)uracil (also referred to as BV-araU or sorivudine). Certain illustrative prodrug compounds in this regard are described, for example, in U. S. Patent No. 4,386,076, the disclosure of which is incorporated herein by reference.

[00042] In a particular embodiment, the DPD inhibitor is eniluracil or a prodrug of eniluracil, such as 5-ethynyl-2(lH)-pyrimidinone (eniluracil missing the 4-oxygen) (Porter, et al , Biochem. Pharmacol 47: 1 165-1 171, 1994), a nucleoside or deoxynucleoside derivative of eniluracil, a compound that is converted to eniluracil in vivo, and/or a derivative of a DPD inactivator that is converted to the inactivator in vivo. By way of example, such compounds can include nucleoside derivatives which contain a nucleobase corresponding to the above 5-substituted uracil compounds, for example nucleoside derivatives containing a ribose, 2'-deoxyribose, 2',3'- dideoxyribose, arabinose or other cleavable sugar portion, which may additionally contain a 2'- or 3'-substituent such as a halogen or a 5'substituent such as an ester. More particular examples of such nucleoside derivatives include l-(B-D-arabinofuranosyl)-5-prop-l-ynyluracil and 2',3'- dideoxy-5-ethynyl-3'-fluorouridine.

[00043] In addition to 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine (capecitabine, marketed by Roche Laboratories Inc. as XELODA®), numerous 5-FU prodrugs are known which may also be used in accordance with the present invention to select a rapid 5-FU prodrug failure population identified as being particularly responsive to eniluracil/5-FU or

eniluracil/5-FU/leucovorin therapeutic regimens as described herein. A prodrug of 5-FU is a compound which is metabolized in vivo to 5-fluorouracil and may include, by way of illustration, 5-fluorouridine, 5-fluorocytidine, 5-fluoro-2-deoxyuridine, 5-fluoro-2-deoxycytidine,

5-fluoroarabinosyluracil, and their 5'-esters, including phosphate esters. Other illustrative compounds include 5'-deoxy-4',5-fluorouridine, 5'-deoxy-5-fluorouridine, l-(2- tetrahydrofuranyl)-5-fluorouracil, a l-Ci-8 alkylcarbamoyl-5-fluorouracil derivative, l-(2- tetrahydrofuryl)-5-fluorouracil, and Ftorafur (Tegafur, an oral 5-FU prodrug that is widely used in Asian countries), or a compound that is converted to 5-FU in vivo.

[00044] In particular embodiments, the methods described herein employ the administration of the DPD inhibitor, eniluracil, in combination with 5-FU and optionally leucovorin. For example, in exemplary embodiments, an administration schedule may be used which comprises a 28 day cycle wherein the following is taken weekly for three consecutive weeks, followed by one week off treatment: 40 mg of eniluracil is taken on the first day; 30 mg/m² 5-FU is taken 11-16 hr after eniluracil, with or without 30 mg leucovorin; and if the option to supplement with leucovorin is exercised, 30 mg leucovorin is also taken on third day and/or the first day.

[00045] It will be understood that suitable doses of eniluracil can vary provided that a sufficient amount is administered to a patient to substantially inhibit DPD activity in both nervous and non- nervous tissues, as described herein. In certain embodiments, for example, eniluracil is administered at a dose from about 14-40 mg/m² or from about 15-40 mg/m² or from about 16-40 mg/m². In more specific embodiments, the dose of eniluracil is from about 14-30 mg/m² or from about 15-30 mg/m² or from about 16-30 mg/m². In still other specific embodiments, the dose of eniluracil is from about 14-21 mg/m² or from about 15-21 mg/m² or from about 16-21 mg/m² or from about 16-25 mg/m² or from about 12-35 mg/m². In still other embodiments of the invention, eniluracil can be dosed at about 14-50 mg/m², about 15-50 mg/m², about 16-50 mg/m², about 20-50 mg/m² or about 30-50 mg/m². In still further embodiments, eniluracil can be dosed at 25, 30, 35, 40, 45, or 50 mg.

[00046] Of course, preferably, a DPD inhibitor dosage selected for administration to a patient according to the present invention is one that is at least sufficient to ensure that DPD activity in both nervous and non-nervous tissue of the patient is substantially eliminated. Moreover, it will be understood that any of the DPD inhibitor dose ranges described above, and elsewhere herein, may be used in the context of the various embodiments of the invention described herein.

[00047] In certain other embodiments of the invention, the 5-FU is administered about 11-16 hours after the eniluracil, thereby ensuring that the ratio of eniluracil to 5-FU will be

considerably less than 1.0, as desired in order to avoid the decreased antitumor activity caused by high eniluracil to 5-FU ratios.

[00048] In other particular embodiments, eniluracil is dosed at about 16-40 mg/m², or at another DPD inhibitor dose or range as described herein, and 5-FU is administered only after about 3-5 eniluracil elimination half-lives have passed.

[00049] In yet other particular embodiments, eniluracil is dosed at about 16-40 mg/m², or at another DPD inhibitor dose or range as described herein, and 5-FU is administered only after sufficient time is allowed to pass such that, at the time of 5-FU administration, the ratio of eniluracil to 5-FU is < 1 : 10.

[00050] Eniluracil doses of 14-21 mg/m2 have been previously used (Schilsky et al, J Clin Oncol 1998;16: 1450-7; Baker et al., J Clin Oncol 2000;18:915-26), however the eniluracil was administered one hour before, or simultaneously with the 5-FU dose. In contrast, the present invention doses eniluracil about 11-16 hours before 5-FU, in particular embodiments, and employs doses of DPD inhibitor sufficient to inactivate DPD in both nervous tissue and non- nervous tissue, in order to avoid the unexpected neurotoxicity observed in human patients.

[00051] The amounts of eniluracil shown in Table 1 below may be used to achieve doses in the 16-20 mg/m² range. The calculated amount of eniluracil remaining in the body after 10.5 hours (approximately three elimination half-lives) is also presented. Thus, if weekly or 5-day dosing schedules employ doses of 5-FU ranging between about 15-50 mg/m², the ratio of eniluracil to 5-FU will always be less than about 1 :6 when 5-FU is administered. For example, when the commonly used 25 mg/m² dose of 5-FU is administered 10.5 hours after eniluracil, the ratio of eniluracil to 5-FU will be about 1 : 10 or less.

Table 1 - The dose of eniluracil that delivers 16-20 mg/m² for patients of the indicated body surface area (BSA), and the calculated amount of eniluracil remaining in the body after 10.5 hours (approximately three elimination half-lives). Also encompassed herein are patients having less than or equal to the specific BSAs indicated in Table 1.

[00052] For another example, if patients less than 1.9 m² received 30 mg eniluracil, and patients > 1.9 m² received 45 mg eniluracil, these two doses would produce about 16-23 mg/m² over a wide range of body sizes. Furthermore, because eniluracil is nontoxic and has been shown to be safe with doses up to 50 mg per day for seven days (Schilsky et al, J Clin Oncol 4: 1450-7, 1998), illustrative administration schemes can be simplified even further. For example, if all patients were dosed with 40 mg eniluracil, the dosing range would encompass about 15-31 mg/m². In addition, if all patients received 50 mg eniluracil, the dosing range would be about 18-39 mg/m².

[00053] Accordingly, in other embodiments, an eniluracil dose range used according to the invention may advantageously comprise from about 14-50 mg/m², 16-23 mg/m², 15-31 mg/m², 18-39 mg/m², 19-39 mg/m² and 20-50 mg/m².

[00054] In still other embodiments of the invention, the time interval between administration of eniluracil and 5-FU can be between about 11-16 hours, about 8-20 hours, about 8-24 hours, about 8-30 hours, about 6-36 hours, about 3-48 hours, or about 3-72 hours.

[00055] In other embodiments, at least about 3-5, about 2.5-7, about 2-10, about 1-14, or 1-21 eniluracil elimination half-lives are allowed to pass before administration of 5-FU.

[00056] In further embodiments, eniluracil is administered the day before 5-FU is administered, or is administered on multiple days before 5-FU is administered.

[00057] In still other embodiments, 5-FU is administered at a dose of about 15-40 mg/m², 10-50 mg/m², 5-60 mg/m², or 5-70 mg/m² particularly for weekly and 5-day dosing schedules.

[00058] In still further embodiments of the present invention, the 5-FU administration schedule used according to the invention is a weekly schedule; a five-day schedule; a daily schedule; a daily schedule where 5-FU is dosed for more than one day following the administration of eniluracil, which is dosed prior to 5-FU and on every day, every other day, or every third day during 5-FU therapy.

[00059] In one illustrative embodiment, eniluracil may be administered at a dose of about 16-40 mg/m², or at another DPD inhibitor dose range described herein, the night before 5-FU or, alternatively, can be administered in the morning followed by 5-FU administration in the evening. Using an illustrative dose for 5-FU of about 20 to 30 mg/m² for these schedules (Levin et al., Invest New Drugs 18:383-90, 2000; Schilsky et al., J Clin Oncol 4: 1450-7, 1998; Guo et al, Cancer Chemother Pharmacol 52:79-85, 2003), for example, 5-FU should always be in substantial excess relative to eniluracil.

[00060] The present invention includes as a further feature pharmaceutical formulations comprising at least one pharmaceutically acceptable carrier or excipient and further comprising a DPD inhibitor and/or 5-FU, present as separate formulations to be administered at separate time points in accordance with the present invention. A carrier or excipient is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Formulations include, for example, those adapted for oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the pharmaceutical arts. Such methods include the step of bringing into association the active ingredient with the carrier that constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

[00061] Formulations according to the present invention may be prepared and/or administered using essentially any available technique. Formulations of the present invention adapted for oral administration, for example, may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of an active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. An active ingredient may also be presented as a bolus, electuary or paste. Oral administration will typically be a preferred route of

administration.

[00062] A tablet may be made, for example, by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropyl-methylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycollate, cross-linked povidone, cross- linked sodium carboxymethylcellulose) surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide controlled release of the active ingredient therein using, for example,

hydroxypropyl-methylcellulose in varying proportions to provide the desired release profile.

[00063] Formulations for topical administration in the mouth, for example, include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. Formulations for rectal administration, for example, may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulation for vaginal administration, for example, may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

[00064] Formulations for parenteral administration, for example, include aqueous and nonaqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers,

bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried

(lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[00065] Typically, liquid formulations including one or more active agents are preferably buffered to a pH of 7 to 11, generally 9.5 to 10.5. Certain unit dosage formulations may include those containing a daily dose or unit, daily sub-dose, as hereinabove recited, or an appropriate fraction thereof, of an active ingredient.

[00066] Methods for making DPD inhibitors described herein are known and may be carried out using conventional methodology. For example, DPD inhibitors referred to above may be prepared by the methods described in Heterocycl. Chem. 19(3) 463-4 (1982) for the preparation of 5-ethynyluracil.

[00067] In another embodiment, the methods described herein further comprise the administration of leucovorin. Leucovorin, or isovorin, the active isomer of leucovorin, is commonly used in conjunction with 5-FU for treating cancer patients. It may also be added to the above-described dosing regimens for eniluracil and 5-FU. Leucovorin has been shown to improve the antitumor efficacy of eniluracil and 5-FU in tumor-bearing rats and in tissue culture (Cao et al, Cancer Res 90: 1507-1510, 1993; Fischel et al, Biochem Pharmacol 53 : 1703-1709, 1997) and has been administered to patients receiving eniluracil and 5-FU (Schilsky et al, J Clin Oncol 4: 1450-7, 1998; Guo et al, Cancer Chemother Pharmacol 52:79-85, 2003). Leucovorin is also

advantageously available in an oral formulation. [00068] The invention can be further understood upon consideration of the following non-limiting Example.

EXAMPLE I

Patients and Methods

[00069] Patients

[00070] Adult women needing first- or second-line treatment for MBC and having previous treatment with an anthracycline and a taxane were randomized into the comparative study.

Patients must have measurable disease by RECIST 1.1, an Eastern Cooperative Oncology Group (EGOG) = 0 or 1, adequate renal function (Creatinine Clearance > 50 mL/min), no prior capecitabine treatment, and be willing to avoid any other dose or form (iv, oral, or topical) of 5- FU or related derivatives during treatment and for 8 weeks following the last dose of eniluracil. Prior treatment with 5-FU, but not capecitabine was allowed. The protocol was approved by the local ethics boards. Informed consent was obtained for all participants. The study

(NCT01231802) was registered on ClinicalTrials.gov.

[00071] Study Design

[00072] Up to 140 evaluable patients were randomized in a 4:3 ratio to receive eniluracil/5-FU/Lv or capecitabine (Xeloda®), an oral prodrug of 5-FU. Patients with radiologically documented PD [Disease Progression (Significant tumor growth)] after at least two cycles of capecitabine were allowed to crossover to take eniluracil/5-FU/Lv, provided that no more than 21 days have passed between their last tumor assessment on the Capecitabine Arm and the first dose of eniluracil/5-FU/Lv. Patients are evaluable if they had a tumor assessment after being on study for at least 6 weeks ± 1 week and had taken the scheduled eniluracil/5-FU/leucovorin during that time period.

[00073] The primary objective was progression-free survival (PFS) and the secondary objectives were safety, antitumor response rate, disease control rate, duration of response, and time to treatment response. The completed final results for crossover patients are reported here.

[00074] Tumors were evaluated by CT or MRI every six weeks using RECIST 1.1. Routine safety, laboratory, and hand-foot syndrome assessments were performed every clinic visit. The Kaplan-Meier method was used to estimate median PFS. The associated 95% confidence intervals are also presented.

[00075] Chemotherapy [00076] All agents were self-administered as oral tablets. Patients taking eniluracil/5-FU/Lv started with 40 mg eniluracil, followed 11-16 hr later with 30 mg/m² 5-FU plus 30 mg Lv. The Lv dose was repeated 24 hr later. The regimen was taken for three consecutive weeks followed by one week off treatment. Patients receiving capecitabine ingested 1000 mg/m² capecitabine twice a day for two weeks followed by one week off treatment. Patients received regular telephone calls reminding them to take their study drugs. Capecitabine administration compliance was verified for patients who entered the Crossover Arm.

Results

[00077] Antitumor Efficacy

[00078] Twenty-five patients with progressive disease on capecitabine crossed over to take eniluracil/5-FU/Lv. Twelve patients had rapid (within 70 days) disease progression on capecitabine. Ten of the 12 were evaluable. Of those not evaluable, one experienced clinical PD before the scheduled tumor assessment at 6 weeks and one was ineligible because more than 21 days passed between the last tumor assessment on the Capecitabine Arm and first dose of eniluracil/5-FU/leucovorin. The characteristics of the 10 evaluable patients who experienced disease progression within 70 days of capecitabine treatment are presented in Table 2. They ranged from 39-70 years in age. Seventy percent had one or two previous 5-FU treatments in the adjuvant or neoadjuvant setting. Capecitabine had been administered as first-line for three patients and as second-line for the remaining seven patients.

[00079] These patient's clinical responses are presented in Table 3. Disease progression was detected at the first tumor assessment, 39-43 days for 8 patients while on capecitabine treatment. The other two patients had disease progression at 63 and 64 days, respectively (Figure 3). Their median PFS (progression free survival) was 42.5 days (95% CI 39-43) on capecitabine. None of these patients had a tumor response while on capecitabine.

[00080] However, after switching to eniluracil/5-FU/Lv, these 10 patients had a median PFS of 140 days (95% CI 37-268) (Figure 3). Four patients had >7 months PFS. Three (30%) patients had partial tumor responses (PR). Six (60%) had SD (stable disease), producing a total PR + SD in 9 patients (90%). Their tumor response durations were 43, 78, and 84 days. Two of the 3 responders had 63% reductions in the sum of the diameters of their target lesions and had confirmed responses at subsequent tumor evaluation. The third responder had 100% reduction in the sum of the diameters of target lesions, but a new non-target tumor lesion was detected at the subsequent scan.

[00081] In contrast to the patients with disease progression within 70 days on capecitabine, the 13 patients who crossed over to take eniluracil/5-FU/Lv when disease progression occurred after 70 days (87-422 days) on capecitabine received little benefit. Three of the 13 had SD, lasting from 66 to 93 days, but none had any tumor responses.

[000821 Definitions

CR = Complete Tumor Response (no detectable tumor lesions)

PR = Partial Tumor Response (Significant tumor shrinkage)

PD = Disease Progression (Significant tumor growth)

SD = Stable Disease (no PR, CR, or PD)

Clinical Benefit = (PR + CR + SD)

Best Response = Most favorable response to treatment (from best to worse: CR> PR>SD>PD) PFS = Progression Free Survival (Number of days from the first dose of study drug to disease progression (PD) or death)

[00083] Table 2. Clinical Characteristics

Number of Evaluable Patients: 10

Age

Average ± std dev: 56 ± 9

Range: 39-70

39-50 years: 3

>50 years: 7

Hormone Receptor Status

ER⁺ and PR^+: 2

PR⁺ 1

HER2^+: 2

ER⁺, PR⁺ and HER2^+: 2

ER^", PR^" and HERT 3

Neoadjuvant/Adjuvant 5-FU Treatments

None: 3

One: 5

Two: 2

Previous Treatments for Metastatic Breast Cancer (before capecitabine)

None: 3

One: 7 [00084] Table 3. Antitumor Results for Evaluable Patients with Rapid Disease Progression on Capecitabine Followed by Eniluracil/5-FU/Lv Treatment*

• PR = Partial Response, SD = Stable Disease, PFS = Progression-Free Survival

[00085] Safety

The unique eniluracil/5-FU/Lv-related adverse events (AEs) for all patients who crossed over from capecitabine treatment are presented in Table 4. The most common side effects are mild to moderate diarrhea and nausea. Two drug-related SAEs occurred in these patients; a pulmonary embolism and one death due to progressive disease.

[00086] Table 4. Summary of All Unique Eniluracil/5-FU/Lv-Related Adverse Events for All Crossover Patients

Conclusions

[00087] Ninety percent of the evaluable patients who had rapid disease progression on capecitabine had PR or SD with eniluracil/5-FU/Lv treatment. This result is striking because 5-FU is the active agent of both oral regimens. Clearly, these patients had rapid disease progression on capecitabine for reasons other than inherent resistance to 5-FU. The different pharmacokinetic properties of the two treatments provide likely explanations for rapid capecitabine failure and subsequent benefit from eniluracil /5-FU/Lv. [00088] In light of the above, a therapeutic regimen as set forth herein comprising

eniluracil/5-FU/leucovorin could potentially allow metastatic breast cancer patients who rapidly fail capecitabine, for example, to continue with another oral 5-FU therapy rather than switching to the less well-tolerated intravenous microtubule-interfering agents, ixabepilone (Ixempra^®) and eribulin mesylate (Halaven^®).

[00089] Based on the above, it is reasonable to expect that a therapeutic regimen of

eniluracil/5-FU/leucovorin as described herein also offers colon cancer patients, such as Dukes' C colon cancer patients, who rapidly fail capecitabine monotherapy an option to continue with another oral 5-FU therapy, rather than switching to an intravenous approach. Moreover, given the surprising response rate of rapid capecitabine failure breast cancer patients, Dukes' C colon cancer patients, for example, who rapidly fail capecitabine monotherapy may also experience significant clinical benefit.

[00090] Further to the above, because capecitabine is a prodrug that generates 5-FU as the active agent, eniluracil/5-FU (with or without leucovorin) could potentially allow cancer patients who have rapid disease progression on any 5-FU prodrug monotherapy to continue with another oral 5-FU therapy.

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[00092] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

CLAIMS What is claimed is:

1. A method for treating a patient having rapid disease progression on a 5-FU prodrug regimen, the method comprising providing the patient having rapid disease progression on a 5-FU prodrug regimen and first administering eniluracil at a dose from about 16-40 mg/m² to the patient, and thereafter administering 5-FU, wherein the 5-FU is administered at a dose such that the 5-FU is present in the patient in substantial excess of the eniluracil and at a time when at least 3-5 elimination half- lives for the eniluracil have passed since the eniluracil was administered.

2. A DPD inhibitor for use in a combined treatment with 5-FU for treating a patient having rapid disease progression on a 5-FU prodrug regimen, the combined treatment comprising first administering the DPD inhibitor, wherein the DPD inhibitor is eniluracil at a dose of 16-40 mg/m², and thereafter administering the 5-FU, wherein the 5-FU is administered at a dose such that the 5-FU is present in the patient in substantial excess of the eniluracil and at a time when at least 3-5 elimination half- lives for the eniluracil have passed since the eniluracil was administered.

3. A combination for treating a patient having rapid disease progression on a 5- FU prodrug regimen comprising eniluracil and 5-FU, characterized in that the eniluracil is first administered at a dose of about 16-40 mg/m², and the 5-FU is administered thereafter, characterized in that the 5-FU is administered at a dose such that the 5-FU is present in the patient in substantial excess of the eniluracil and at a time when at least about 3-5 elimination half-lives for the eniluracil have passed since the eniluracil was administered.

4. The use of eniluracil in combination with 5-FU for the manufacture of a medicament for treating a patient having rapid disease progression on a 5-FU prodrug regimen, wherein the eniluracil is adapted to be administrable first at a dose of 16-40 mg/m², and thereafter the 5-FU, such that the 5-FU is present in the patient in substantial excess of the eniluracil and is adapted to be administrable at a time when at least 3-5 elimination half-lives for the eniluracil have passed since the eniluracil was administered.

5. The method of claim 1 , the eniluracil for use according to claim 2, the combination of claim 3, or the use of eniluracil according to claim 4, wherein the patient having rapid disease progression exhibited the rapid disease progression within approximately 70 days of the 5-FU prodrug regimen.

6. The method of claim 1 , the eniluracil for use according to claim 2, the combination of claim 3, or the use of eniluracil according to claim 4, wherein the eniluracil is administered or adapted to be administrable at a dose from about 16-25 mg/m²

7. The method of claim 1 , the eniluracil for use according to claim 2, the combination of claim 3, or the use of eniluracil according to claim 4, wherein the 5- FU is administered or adapted to be administrable about 11-16 hours after the eniluracil is administered.

8. The method of claim 1 , the eniluracil for use according to claim 2, the combination of claim 3, or the use of eniluracil according to claim 4, wherein the 5- FU is administered or adapted to be administrable at a dose such that at its time of administration the 5-FU is present in the patient in at least 5-fold or 10-fold excess of the eniluracil.

9. The method of claim 1 , the eniluracil for use according to claim 2, the combination of claim 3, or the use of eniluracil according to claim 4, wherein the patient having rapid disease progression on the 5-FU prodrug regimen was treated with a 5-FU prodrug selected from the group consisting of 5-fluorouridine,

5-fluorocytidine, 5-fluoro-2-deoxyuridine, 5-fluoro-2-deoxycytidine, 5'-deoxy-4',5- fluorouridine, 5-fluoroarabinosyluracil, 5'-Deoxy-5-fluorouridine, l -(2- tetrahydrofuranyl)-5-fluorouracil, l-C_1-8 alkylcarbamoyl-5-fluorouracil derivative, 1 - (2-tetrahydrofuryl)-5-fluorouracil, and 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]- cytidine (capecitabine), or a 5'-ester thereof or a 5'-phosphate ester thereof.

10. The method of claim 1 , the eniluracil for use according to claim 2, the combination of claim 3, or the use of eniluracil according to claim 4, wherein the 5- FU is administered or adapted to be administrable at a dose between about 15-50 mg/m²

1 1. The method of claim 1 , the eniluracil for use according to claim 2, the combination of claim 3, or the use of eniluracil according to claim 4, wherein the 5- FU is administered or adapted to be administrable about 11-16 hours thereafter at a dose between about 15-50 mg/m².

12. The method of claim 1 , the eniluracil for use according to claim 2, the combination of claim 3, or the use of eniluracil according to claim 4, wherein the 5- FU is administered or adapted to be administrable about 11-16 hours thereafter at a dose such that the 5-FU is present in the patient in at least 5-fold or 10-fold excess of the eniluracil.

13. The method of claim 1 , the eniluracil for use according to claim 2, the combination of claim 3, or the use of eniluracil according to claim 4, further comprising administering leucovorin with the 5-FU dose or use of leucovorin in combination with the 5-FU dose or wherein leucovorin is adapted to be administrable in combination with the 5-FU dose.

14. The method of claim 13, the eniluracil for use according to claim 13, the combination of claim 13, or the use of eniluracil according to claim 13, further comprising administering another dose of leucovorin the day after the 5-FU dose is administered, or use of leucovorin the day after the 5-FU dose, or wherein leucovorin is adapted to be administrable the day after the 5-FU dose.

15. The method of claim 14, the eniluracil for use according to claim 14, the combination of claim 14, or the use of eniluracil according to claim 14, further comprising administering a dose of leucovorin the day before 5-FU is administered, or use of leucovorin the day before the 5-FU dose, or wherein leucovorin is adapted to be administrable the day before the 5-FU dose.

16. The method of claim 1 , the eniluracil for use according to claim 2, the combination of claim 3, or the use of eniluracil according to claim 4, wherein the patient having rapid disease progression on the 5-FU prodrug regimen is afflicted by cancer.

17. The method of claim 16, the eniluracil for use according to claim 16, the combination of claim 16, or the use of eniluracil according to claim 16, wherein the cancer is metastatic breast cancer or colon cancer.

18. The method of claim 17, the eniluracil for use according to claim 17, the combination of claim 17, or the use of eniluracil according to claim 17, wherein the colon cancer is Dukes' C colon cancer.