Combination of eniluracil and capecitabine for treating cancer

Abstract

The present invention relates to a method for treating cancer in a human subject, comprising: (a) orally administering to the subject eniluracil at a dose of 30-60 mg / day; (b) at least 10 hours after step (a), orally administering capecitabine to the subject at a dose of about 140-700 mg / day, or at a dose providing a 5-FU exposure (AUC) of about 1500 h*ng / mL or greater, for 2-14 consecutive days; and (c) 3-14 days after step (b), repeating steps (a) and (b). The present invention is suitable for treating colorectal cancer, gastrointestinal tumors, breast cancer, pancreatic cancer, head and neck cancer, lung cancer, or advanced biliary tract cancer.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 386,271, filed December 6, 2022, and 63 / 513,525, filed July 13, 2023, both of which are incorporated by reference in their entireties.

[0002] The present invention relates to a method for treating cancer by orally administering eniluracil and capecitabine to cancer patients, which method provides optimal dosing schedules and amounts of eniluracil and capecitabine to improve the efficacy-safety profile of capecitabine. [Background technology]

[0003] 5-Fluorouracil (5-FU) is one of the most widely used chemotherapy drugs in the treatment of various tumors. 5-FU must be activated by metabolic conversion to uridine and deoxyuridine nucleotides, which disrupt DNA synthesis and RNA function. Because 5-FU differs from its natural counterpart, uracil, only by a fluorine substitution at the 5-position, 5-FU is readily activated in cancer patients. Unfortunately, the structural similarity of 5-FU to uracil also contributes to its rapid and extensive conversion to degradation products that lack antitumor activity. The first step in 5-FU degradation is mediated by the drug-metabolizing enzyme dihydropyrimidine dehydrogenase (DPD:EC1312, uracil reductase).

[0004] DPD is a ubiquitous enzyme that is the first and rate-limiting step in the degradation (inactivation) of 5-FU. DPD is abundantly expressed in the gastrointestinal tract and liver, but is also present in other cells in the body and in cancer cells. Oral bioavailability of 5-FU is poor due to extensive and rapid first-pass metabolism that occurs from the abundant amount of DPD in the liver.

[0005] 5-Ethynyluracil, also known as eniluracil, is a DPD inhibitor that is an irreversible inactivator of DPD, thus reducing or eliminating the metabolic inactivation of 5-FU. The structural similarity between eniluracil and 5-FU makes it a substrate for DPD. Coadministration of eniluracil with 5-FU restores the oral bioavailability of 5-FU. Eniluracil has been shown to be safe at doses up to 50 g per day for 7 days [1].

[0006] Capecitabine, the first oral fluoropyrimidine, was introduced as a promising alternative therapy offering the benefits of 5-FU therapy without the need for intravenous infusion. Capecitabine is a prodrug that is converted to 5-FU through three enzymatic steps. Thymidine phosphorylase (TP) plays a key role in converting capecitabine to its active metabolite, which may be present at high concentrations in some malignant tissues. [2] Clinical trials have demonstrated an improved side effect profile when capecitabine therapy is compared with 5FU / LV therapy, including reduced stomatitis, diarrhea, nausea, and neutropenic sepsis. The FDA has approved capecitabine (Xeloda®) for the treatment of Dukes' stage C colon cancer, metastatic colorectal cancer, and metastatic breast cancer. However, the use of capecitabine at the approved dose has shown significantly higher rates of hyperbilirubinemia and hand-foot syndrome. [3] Capecitabine at 1255 mg / m 2 After oral dosing at 100 mg / dose, the pharmacokinetic (PK) parameters of capecitabine, 5-FU, 5-DFCR, and 5'-DFUR show rapid elimination (as shown in Table 1 below). The observed exposure (AUC) of 5-FU is approximately 1630 h*ng / mL. FBAL has a slightly prolonged PK profile with a half-life of 3.23 hours and an AUC of 30-35,000 h*ng / mL [4]. [Table 1] Descriptive statistics of estimated pharmacokinetic parameters 14 days after administration of capecitabine (1255 mg / m2) in eight cancer patients [4]. Summary of the Invention

[0007] In one aspect, the disclosure provides a method for treating cancer in a human subject, the method comprising: (a) orally administering to the subject eniluracil at a dose of 30-60 mg / day; (b) at least 10 hours after step (a), orally administering to the subject a fixed dose of capecitabine of about 140-700 mg / day for 2-14 consecutive days, or orally administering a dose of capecitabine providing a 5-FU exposure (AUC) of about 1500 h*ng / mL or greater; and (c) 3-14 days after step (b), repeating steps (a) and (b).

[0008] In a further embodiment, and in accordance with the above, eniluracil is administered at about 40 mg / day.

[0009] In a further embodiment, according to any of the above, capecitabine is administered at about 160-500 mg / day.

[0010] In further embodiments, according to any of the above, step (b) is performed at least 17 hours after step (a). In some other further embodiments, step (b) is performed 10 to 24 hours after step (a).

[0011] In a further embodiment, in accordance with any of the above, step (c) is performed 7 days after step (b).

[0012] In a further embodiment, in accordance with any of the above, the cancer is colon cancer, gastrointestinal tumor, breast cancer, pancreatic cancer, head and neck cancer, lung cancer, or advanced biliary tract cancer.

[0013] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "Fig.", "FIG.", "Figure," "Figures," "Figs.", and "FIGs."). [Brief explanation of the drawings]

[0014] [Figure 1] Figure 1 shows the antitumor effects of capecitabine and eniluracil in monotherapy and combination therapy. Figure 2 shows the median relative tumor volumes over time for groups 1 to 6 of the in vivo efficacy study. [Figure 2] The mean AUC0-∞ levels of 5-FU observed on day 2 after treatment with eniluracil and capecitabine are shown. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. The dashed line shows the corresponding PK parameter data from the EMA regulatory submission for Xeloda. [Figure 3] Figure 1 shows the Cmax data for 5-FU observed on day 2 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. The dashed line shows the corresponding PK parameter data from the EMA regulatory submission for Xeloda. [Figure 4] The mean AUC0-∞ levels of 5-FU observed at day 8 after treatment with eniluracil and capecitabine are shown. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. The dashed line shows the corresponding PK parameter data from the EMA regulatory submission for Xeloda. [Figure 5] Figure 1 shows the observed Cmax data for 5-FU at day 8 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. The dashed line shows the corresponding PK parameter data from the EMA regulatory submission for Xeloda. [Figure 6] Figure 1 shows the mean AUC0-∞ levels of FBAL observed on day 2 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. The dashed line shows the corresponding PK parameter data from the EMA regulatory submission for Xeloda. [Figure 7] Figure 1 shows the Cmax data for FBAL observed on day 2 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. The dashed line shows the corresponding PK parameter data from the EMA regulatory submission for Xeloda. [Figure 8] Figure 1 shows the mean AUC0-∞ levels of FBAL observed at day 8 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. The dashed line shows the corresponding PK parameter data from the EMA regulatory submission for Xeloda. [Figure 9] Figure 1 shows the Cmax data for FBAL observed at day 8 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. The dashed line shows the corresponding PK parameter data from the EMA regulatory submission for Xeloda. [Figure 10] Figure 1 shows the mean AUC levels of capecitabine observed on day 2 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. [Figure 11] Figure 1 shows the observed Cmax data for capecitabine on day 2 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. [Figure 12] Figure 1 shows the mean AUC0-∞ levels of DFCR observed on day 2 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. [Figure 13] Figure 1 shows the Cmax data for DFCR observed on day 2 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. [Figure 14] Figure 1 shows the mean AUC0-∞ levels of DFUR observed on day 2 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda. [Figure 15] Figure 1 shows the Cmax data for DFUR observed on day 2 after treatment with eniluracil and capecitabine. The solid line shows the corresponding PK parameter data from the FDA regulatory submission for Xeloda.

[0015] Brief description of the table Table 1 shows the descriptive statistics of the pharmacokinetic parameters estimated on day 14 after administration of capecitabine (1255 mg / m2) in eight cancer patients.

[0016] Table 2 shows the design of the in vivo efficacy experiments using patient-derived colon cancer xenograft CXF280 implanted subcutaneously in athymic nude mice.

[0017] Table 3 shows the antitumor effect of capecitabine (alone or in combination with eniluracil) expressed as the minimum T / C value in percent. The minimum T / C value recorded for the test group represents the maximum antitumor effect of the respective treatment.

[0018] Table 4 shows the mean T of 5-FU on day 2 after treatment with capecitabine (alone or in combination with eniluracil) for the various cohorts. max Data and T 1 / 2 The data shown is:

[0019] Table 5 shows the mean C of 5-FU on day 2 after treatment with capecitabine (alone or in combination with eniluracil) for the various cohorts. max Show the data.

[0020] Table 6 shows the mean AUC of 5-FU on day 2 after treatment with capecitabine (alone or in combination with eniluracil) for the various cohorts. last Show the data.

[0021] Table 7 provides an overview of the patient cohorts (1, 2A, 3, and 4), including gender, age, cancer type, PCS6422 dose, capecitabine dose, and number of cycles completed.

[0022] Table 8 provides an overview of ADRs reported in ≥5% of colon cancer patients studied with adjuvant Xeloda monotherapy or 5-FU / LV infusion.

[0023] Table 9 provides an overview of adverse events (grade 2 or higher) observed in cohorts 1, 2A, 3, and 4.

[0024] Table 10 presents data regarding the RECIST analysis of observed lesion(s) in patients enrolled in the clinical trial. DETAILED DESCRIPTION OF THE INVENTION

[0025] We compared the antitumor efficacy of the combination of eniluracil and capecitabine using a 7 / 7 (capecitabine 7 days on, 7 days off) dosing schedule with capecitabine alone using the conventional 14 / 7 (capecitabine 14 days on, 7 days off) schedule in a preclinical xenograft model. We found that pretreatment with eniluracil allowed complete clearance of eniluracil in mice before treatment with capecitabine, enhancing the antitumor activity of capecitabine without significantly affecting its safety and tolerability profile. Pretreatment with 10 mg / kg oral eniluracil before administration of 30 mg / kg or 15 mg / kg oral capecitabine resulted in efficacy comparable to that of 300 mg / kg oral capecitabine alone in mice. Notably, the total cumulative dose of capecitabine in the combination group was 13.3, which was 26.6 times lower than that in the capecitabine-only group.

[0026] Based on the efficacy results of our xenograft model, combined with knowledge of previous preclinical and clinical antitumor efficacy using eniluracil and 5-FU combination therapy, we have found the optimal dosing schedule and amounts of eniluracil and capecitabine for treating cancer in patients in whom fluoropyrimidine therapy alone is preferred.

[0027] The present application provides a method for treating cancer in a patient, the cancer being a type for which 5-FU or a 5-FU prodrug, such as capecitabine, is active. The method includes: (a) initially administering eniluracil to the patient at a dose of about 30-60 mg / day; (b) at least 10 hours after step (a), orally administering capecitabine to the patient at a dose of about 140-700 mg / day for 6-14 consecutive days, or orally administering capecitabine at a dose that provides a 5-FU exposure (AUC) of about 1500 h*ng / mL or greater; and (c) repeating steps (a) and (b) 7-14 days after step (b).

[0028] In step (a) of the method, at least about 30 mg / day or at least about 40 mg / day of eniluracil is administered to the patient. For example, about 40 mg / day, about 50 mg / day, or about 60 mg / day of eniluracil is administered to the patient. The eniluracil is administered first to the patient (i.e., administered prior to capecitabine) to substantially eliminate DPD activity in both neuronal and non-neuronal tissues of the patient prior to administration of the 5-FU prodrug capecitabine. "Substantially eliminate" means that the level of DPD activity in both neuronal and non-neuronal tissues of the patient is reduced to less than 10%, and preferably less than 5% or less than 1%, of the baseline DPD activity in the patient prior to administration of eniluracil.

[0029] In step (b) of the method, capecitabine is administered between 10 and 24 hours after administration of eniluracil. For example, capecitabine is administered at least 10, 12, 16, or 17 hours, but not more than 24 hours, after administration of eniluracil. The dosing schedule and amount of capecitabine are selected to allow eniluracil to be substantially cleared from the patient before administration of capecitabine, such that capecitabine is present in molar excess (e.g., at least 5-fold, at least 10-fold, at least 25-fold, at least 50-fold, or at least 100-fold) relative to the level of eniluracil remaining in the patient upon administration of capecitabine. Thus, potential interference by eniluracil with the metabolic activation of capecitabine is minimized, thereby preventing interference by eniluracil with the antitumor effects of capecitabine.

[0030] Capecitabine is administered to patients at doses between about 140 and 700 mg / day. For example, capecitabine is administered at doses of 140 to 700 mg / day, 160 to 700 mg / day, 140 to 500 mg / day, 150 to 500 mg / day, 200 to 500 mg / day, 140 to 450 mg / day, 150 to 450 mg / day, 160 to 450 mg / day, 140 to 400 mg / day, 150 to 400 mg / day, or 300 to 400 mg / day.

[0031] Capecitabine will also be administered at a dose that provides a 5-FU exposure (AUC) of about 1500 h*ng / mL or greater.

[0032] Lower doses of capecitabine are ineffective or only partially effective, and higher doses are expected to cause toxicity.

[0033] Capecitabine can be administered to a patient once a day or more than once a day. Preferably, capecitabine is administered twice a day. Capecitabine is administered to a patient for 2 to 14 consecutive days, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days.

[0034] In step (c) of the method, after the patient has rested, for example, for at least 3 to 14 days, or after 3, 4, 5, 6, or 7 days, or after 7 to 14 days, the patient receives the next cycle of eniluracil and capecitabine following steps (a) and (b).

[0035] Steps (a)-(c) are repeated at the discretion of the physician's assessment of response and side effects. The physician may often stop treating the patient if the patient experiences a complete remission or when the patient's disease progresses. A complete remission means that the tumor is no longer present. Progression of the disease means that the tumor begins to grow or is no longer stable. A stable tumor means that the tumor is not progressing or regressing.

[0036] The present invention is useful in treating all cancers for which capecitabine can be used, including, but not limited to, colon cancer, gastrointestinal tumors, breast cancer, pancreatic cancer, head and neck cancer, lung cancer, and advanced biliary tract (biliary) cancer.

[0037] The present invention is useful in treating mammalian subjects, including humans, horses, and dogs. The present invention is particularly useful in treating humans.

[0038] This method uses optimal dosing schedules and optimal amounts of both eniluracil and capecitabine to provide effective treatment and is safe. The total cumulative dose of capecitabine administered in this manner is less than the effective dose of capecitabine when used alone without eniluracil. This is beneficial because high-dose capecitabine treatment can cause side effects that necessitate dose reduction or treatment discontinuation and can lead to resistance to therapy, as evidenced by shorter patient progression-free survival and lower response rates. [5] This method is also useful for treating patients whose cancer is resistant to either 5-FU or capecitabine therapy. [Example]

[0039] The following examples further illustrate the present invention. These examples are intended merely to illustrate the invention and should not be construed as limiting.

[0040] Example 1. Antitumor effects of eniluracil and capecitabine in mice A.Purpose The present study was to evaluate the antitumor efficacy of eniluracil in combination with different doses of capecitabine in patient-derived colon xenografts CXF280 implanted subcutaneously in immunodeficient athymic nude mice.

[0041] B. Mouse Model Human tumor explants, termed patient-derived tumor xenografts (PDXs), implanted directly from patients into nude mice and passaged subcutaneously retain most of the characteristics of the parent patient tumor, including histology and sensitivity to anticancer drugs. Studies have shown that PDXs passaged in nude mice accurately recapitulate the donor patient's response to standard cytotoxic anticancer drugs in >90% of cases [6], [7], [8].

[0042] C. Research design The present study consisted of an in vivo efficacy experimental design using patient-derived colon cancer xenograft CXF280 implanted subcutaneously in athymic nude mice.

[0043] The study consisted of six groups of six animals each. For monotherapy, animals received capecitabine at 300 or 30 mg / kg / day daily for two weeks, followed by a one-week break and then daily for two more weeks (14 days on, 7 days off). For combination therapy, animals received capecitabine at 30, 15, or 7.5 mg / kg / day on days 1–7, 15–21, and 29–35 (7 days on, 7 days off). Eniluracil was also administered at 10 mg / kg / day on days 1, 3, 5, 15, 17, 19, 29, 31, and 33.

[0044] Combination treatment with capecitabine and eniluracil scheduled for the same dosing day was administered with a 6-hour delay after eniluracil dosing to ensure that all eniluracil had been cleared in the mice before capecitabine administration.

[0045] All treatments were administered by oral gavage (po) for 35 days, followed by a 1-week observation period until day 42 of the study.

[0046] Table 2 shows the experimental design. [Table 2] D. Results

[0047] Figure 1 shows the antitumor effects of capecitabine and eniluracil in monotherapy and combination therapy. Median relative tumor volumes over time are shown for groups 1 to 6. Relative tumor volume on day x (RTV) was calculated by dividing the absolute volume of an individual tumor on day x (Tx) by the absolute volume of an individual tumor of the same tumor on the day of randomization (Tr) and multiplying by 100%.

[0048] Tumor growth inhibition was determined by comparing the median RTV of the test group (T) with the vehicle control group (C) and expressed as the minimum T / C value in percent. The minimum T / C value recorded for a test group during an experiment indicates the maximum antitumor effect of the respective treatment.

[0049] The antitumor effect is also shown in Table 3 by calculating the minimum T / C value (%) on day 35. [Table 3]

[0050] These results demonstrate that monotherapy with 300 mg / kg / day capecitabine achieved high antitumor activity in mice and was significantly more effective than 30 mg / kg / day monotherapy. Combination therapy with capecitabine and eniluracil was most effective with 30 mg / kg / day or 15 mg / kg / day capecitabine, achieving very high levels of tumor growth inhibition at much lower cumulative doses due to the addition of eniluracil and higher capecitabine exposure than the 7.5 mg / kg / day group. All combinations of capecitabine with eniluracil (30, 15, and 7.5 mg / kg / day) were more effective than 30 mg / kg / day capecitabine monotherapy, despite the much lower cumulative doses achieved by the modified dosing schedule.

[0051] Example 2. Clinical Study Protocol A.Purpose To evaluate the safety, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD) of capecitabine administered using a 7-day-on, 7-day-off regimen approximately 24 hours after a single fixed oral 40-mg dose of eniluracil in patients with advanced, refractory gastrointestinal (GI) tumors.

[0052] B. Research design: This is an open-label, multicenter study in patients with advanced, recurrent, or refractory GI cancer, or patients who are not recurrent / refractory but intolerant to other therapies who, in the investigator's judgment, are candidates for fluoropyrimidine monotherapy.

[0053] C. Inclusion criteria Patients who meet the following criteria will be eligible for this study: 1. Have advanced, metastatic, or unresectable GI tract tumors that are refractory or intolerant to existing available therapies and for which the investigator recommends fluoropyrimidine monotherapy. 2. Have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1). 3. ≥ 18 years old. 4. Not having received treatment with intravenous (IV) 5FU analogues or oral 5FU analogues in the 4 weeks prior to enrollment. 5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 / 2 at the time of study entry. 6. Have adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements performed within 7 days prior to starting study treatment. a. Peripheral ANCE ≥ 1.5 × 109 / L b. Platelet count ≥ 75 x 109 / L without growth factors / transfusions C. Hemoglobin ≥ 8.5 g / dL without growth factors / transfusions d. Estimated glomerular filtration rate >50 mL / min e. Total bilirubin <2 x upper limit of normal (ULN) if the patient has liver metastases, biliary tract cancer, <5 x ULN, or ≤3 x ULN if the patient has Gilbert's disease f. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <2.5 × ULN, liver metastasis <5 × ULN g. International normalized ratio (INR) < 1.5 7. Have a life expectancy of at least 12 weeks. 8. Female patients of childbearing potential and male patients with reproductive partners must agree to use effective contraception as described below from the time of screening until 60 days after the last dose of capecitabine. highly effective methods of birth control, including hormonal contraception (e.g., combined oral control pills, patches, vaginal rings, injectable solutions, and implants), intrauterine devices or systems, vasectomy, or tubal ligation; or ·An effective double-barrier method of contraception (two of the following: male condom, female condom, cervical cap, diaphragm, or contraceptive sponge), or -Abstain from sexual activity while participating in the study and for 60 days after your last dose of capecitabine. 9. Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin pregnancy test result within 3 days prior to the first dose of study treatment. Female patients who have been surgically sterilized by hysterectomy and / or bilateral oophorectomy or who are postmenopausal (amenorrhea ≥ 12 months, at least 55 years of age) may be exempt from the beta-human chorionic gonadotropin pregnancy test. 10. Actively provide written informed consent. 11. Acute toxicities from prior therapy have resolved or stabilized to grade <2 (excluding grade 2 neuropathy). 12. If the patient has human immunodeficiency virus (HIV) infection, the HIV infection is controlled with an undetectable viral load through antiretroviral therapy. 13. If the patient has hepatitis C infection and has received antiviral treatment, have a negative viral load at screening. 14. If the patient has chronic hepatitis B infection and is receiving antiviral treatment, have a negative viral load at screening. 15. Willing and able to attend all visits and evaluations required by protocol.

[0054] D. Exclusion criteria Patients who meet any of the following criteria will not be permitted to enroll in this study: 1. Malabsorption syndrome that prevents oral medication or may interfere with medication absorption (e.g., short bowel syndrome or chronic partial intestinal obstruction). 2. Has a history of clinically significant 12-lead ECG results or has clinically significant 12-lead ECG results in the opinion of the investigator. 3.Has ongoing brain metastasis. 4. Prolonged corrected QT interval (by Fridericia correction) of >480 msec in both men and women performed at screening. 5. Patients with a history of prolonged corrected QT interval, ventricular tachycardia / fibrillation, or significant ventricular arrhythmia, or torsade de pointes, or a history of ventricular ablation due to arrhythmia. 6. Congenital long QT syndrome or family history of long QT syndrome. 7. Have other clinically significant cardiac disease, including but not limited to uncontrolled angina, myocardial ischemia or infarction within 6 months, congestive heart failure > Class II according to the New York Heart Association, or a history of myocarditis. 8. Have electrolyte imbalances such as uncorrected hypokalemia / hyperkalemia, hypomagnesemia, or hypocalcemia. Patients who successfully correct their electrolyte imbalances can be enrolled. 9.Currently using any drug on the protocol's prohibited drug list (including drugs that may prolong the corrected QT interval) that cannot be discontinued. 10. Have known hypersensitivity to any of the components of the study treatment. 11. Have any other primary cancer requiring treatment within the past 3 years, except for cervical intraepithelial neoplasia, ductal carcinoma in situ, or completely resected squamous cell carcinoma or basal cell carcinoma. 12. Pregnant or breastfeeding women. 13. Had major surgery, open biopsy, or significant trauma within 4 weeks prior to the first dose of study treatment. 14. Currently receiving or has received investigational treatment within 4 weeks prior to the start of the study, or participating in another clinical study. 15. Known DPD deficiency.

[0055] E. Drug Administration and Duration: On day 1, eniluracil (40-50 mg) is administered orally. 12-24 hours later, capecitabine is administered orally. Capecitabine is administered at 140-600 mg twice daily for a total of 7 days. The patient then receives a 7-day rest period before undergoing the next cycle following the procedure described above. Cycles are repeated until either the patient achieves complete remission or the patient's disease progresses. Complete remission means that the tumor is no longer present. Cancer progression means that the tumor begins to grow or is no longer stable. F. The purpose of the test is to: 1.Main purpose: To evaluate the safety, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD) of capecitabine administered approximately 24 hours after a single fixed oral dose of 40 mg eniluracil, using a 7-day on, 7-day off regimen of capecitabine in patients with advanced, refractory gastrointestinal (GI) tumors. To characterize the plasma pharmacokinetic (PK) profiles of capecitabine, 5-fluorouracil (5FU), and the major quantifiable metabolites α-fluoro-β-alanine (FBAL), 5'-deoxy-5-fluorocytidine (5'DFCR), and doxifluridine (5'DFUR). 2. Secondary Objectives · To characterize the PK profiles of eniluracil and its major metabolite, 5-acetyluracil. To assess dihydropyrimidine dehydrogenase (DPD) enzyme activity over time after a single dose of eniluracil, using the dihydrouracil-to-uracil ratio as a surrogate for enzyme activity or a future method for analyzing DPD activity. To assess the effect of eniluracil on QT corrected for heart rate (QTc). To assess the incidence of adverse events (AEs) of particular importance (AESI), including the incidence of hand-foot syndrome (HFS). 3. Preliminary Objectives: To obtain preliminary evidence of the antitumor activity of eniluracil and capecitabine in advanced GI tumors. G. The evaluation items of the test are as follows: 1. Primary endpoint: Incidence of DLTs and adverse events according to NCI CTCAE 5.0. Plasma capecitabine, 5FU, FBAL, 5'DFCR, and 5'DFUR concentrations and PK parameters will be estimated from concentration-time data using non-compartmental methods, where data permit. For plasma eniluracil concentrations, PK parameters will be estimated from concentration-time data using non-compartmental methods, where data permit. 2. Secondary endpoints To evaluate the incidence of AESI, including the incidence of HFS. To assess dihydropyrimidine dehydrogenase (DPD) enzyme activity using the dihydrouracil to uracil ratio as a surrogate for enzyme activity or a future method for analyzing DPD activity. The effect of eniluracil treatment on QTc will be assessed by comparing baseline ECGs before the first dose of eniluracil on Day 1, 2 hours ± 30 minutes after the first dose of eniluracil (at the maximum observed concentration [Cmax] level), and immediately before the dose of capecitabine on Day 2. 3. Preliminary endpoints:

[0056] Investigator-performed disease assessment with standard of care every 8 weeks according to RECIST criteria (version 1.1).

[0057] 4. Pharmacokinetic endpoints: The following PK parameters will be determined (data permitting) for eniluracil, 5-acetyluracil, capecitabine, 5FU, and the major metabolites FBAL, 5'-DFCR, and 5'-DFUR. Cmax: maximum observed plasma concentration tmax: time to reach peak plasma concentration AUC∞: Area under the plasma concentration-time curve from time 0 to infinity AUC0-t: Area under the plasma concentration-time curve from time zero to the last sample with a quantifiable concentration AUC9: Area under the plasma concentration-time curve from time 0 to 9 hours CL / F: Apparent total body clearance (calculated for eniluracil and capecitabine only) Vd / F: Apparent volume of distribution (calculated for eniluracil and capecitabine only) ·MRT: Average residence time ·λz: terminal disappearance rate constant t1 / 2: terminal elimination half-life, and Other PK parameters will be determined as deemed necessary and data permit.

[0058] Example 3. Pharmacokinetic (PK) Results A. Introduction: The clinical trial was conducted generally as described above (see, e.g., Example 2) to evaluate various pharmacokinetic parameters and the safety of capecitabine (described below in Example 4) in an attempt to corroborate the effects observed in the PDX mouse model (see, e.g., Example 1). Briefly, patients with advanced, refractory gastrointestinal (GI) tumors received a single, fixed oral 40 mg dose of eniluracil approximately 24 hours later, followed by capecitabine using a 7-day on, 7-day off regimen. Results from the clinical trial were compared to data reported in the Xeloda New Drug Application (sometimes referred to herein as the "Xeloda Study") used by Roche to obtain FDA market approval, as summarized above in Table 1.

[0059] In the Xeloda study, 1255 mg / m 2 capecitabine twice daily (bid), and various pharmacokinetic (PK) parameters were evaluated in 8 patients with cancer at the recommended dose of capecitabine (1255 mg / m bid). 2 ) were assessed in plasma at steady state (day 14) after administration. Specifically, capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, FUH2, and FBAL in the Xeloda study were assessed at C max (μg / mL), t max (h), AUC 0-t (μg*h / mL), AUC 0-∞ (μg*h / mL), and t 1 / 2 (h) was estimated.

[0060] The results of the Xeloda study are similar to those described in the EMA 2005 Scientific Discussion for Registration of Xeloda in Europe. Briefly, peak plasma concentrations (C in μg / mL) of capecitabine, 5'-DFCR, 5'-DFUR, 5-FU, and FBAL were measured. max) were 4.67, 3.05, 12.1, 0.95, and 5.46, respectively, in the 2005 EMA for Xeloda. Time to peak plasma concentration (t max ) were 1.50, 2.00, 2.00, 2.00, and 3.34, respectively, in the 2005 EMA for Xeloda. AUC in μg*h / mL 0-∞ The values ​​were 7.75, 7.24, 24.6, 2.03, and 36.3, respectively, for Xeloda's 2005 EMA.

[0061] B.5-FU: It was determined that 5-FU levels were significantly elevated in patients treated with eniluracil on day 1 followed by increased doses of capecitabine on day 2. Compared to the levels observed in patients receiving capecitabine alone, the AUC and C of 5-FU were significantly elevated in patients pretreated with eniluracil (as shown in Figures 2 and 3, respectively). max Both were at a high level.

[0062] Average body surface is 1.6m 2 Assuming that capecitabine is 1255 mg / m 2 If administered at a dosage of 1250 mg / m, the daily dose for such an average individual would be 4016 mg. 2 A single dose of 2000 mg corresponds to 2000 mg per patient. AUC observed with capecitabine alone 0-∞ The level is 1255 mg / m twice daily. 2 For medications of 1630h*ng / mL, 1250mg / m 2 The mean AUC observed for the combination of eniluracil and capecitabine at a daily dose of 450 mg (225 mg twice daily) was 2030 h*ng / mL. 0-∞ The level was 5691 h*ng / mL. Thus, a single dose of 225 mg of capecitabine (combined with pretreatment with eniluracil) provided a 2.8- to 3.5-fold higher AUC at an 8.9-fold lower total dose. Based on the AUC comparison, pretreatment with eniluracil amplified the efficacy of capecitabine by 25- to 30-fold.

[0063] C max At the time of data analysis, synergistic effects of eniluracil were also observed, although not as strong as in the AUC data. Capecitabine at a dose of 225 mg (combined with pretreatment eniluracil) resulted in a C of 1082 ng / mL compared with 709 ng / mL and 950 ng / mL for capecitabine alone. max This resulted in the following.

[0064] Another major difference observed in the PK of 5-FU on day 2 when eniluracil was administered in combination with capecitabine was the half-life (T 1 / 2 The half-life increased from 0.76 hours (capecitabine alone) to a maximum of 5.71 hours (capecitabine in combination with eniluracil pretreatment). The prolonged half-life of 5-FU contributed to the increased AUC observed with combination treatment. [Table 4]

[0065] However, on day 8, the AUC and C of 5-FU max The effect of eniluracil on 5-FU was no longer observed (as shown in Figures 4 and 5, respectively). max The level of max Values ​​were comparable to capecitabine treatment alone.

[0066] C.FBAL: The effect of pretreatment with eniluracil on the metabolism of capecitabine to FBAL was generally opposite to that observed with 5-FU. Essentially, 5-FU exposure was significantly increased by eniluracil, whereas FBAL levels were nearly undetectable by day 2. AUC and C max Both parameters indicated that eniluracil completely blocked the metabolism of capecitabine to FBAL, even at the highest dose evaluated (as shown in Figures 6 and 7, respectively).

[0067] In addition, pretreatment with eniluracil resulted in a significant increase in the T of FBAL. max increased on day 2 (7–8 h compared with 3.24 h with capecitabine treatment alone).

[0068] Similar to the results obtained with 5-FU, the effect of eniluracil on FBAL metabolism was no longer evident at day 8. At day 8, the AUC and C of FBAL max and parameters were proportional to the levels observed with capecitabine therapy alone (as shown in Figures 8 and 9, respectively).

[0069] D. Capecitabine and other metabolites: AUC and C when capecitabine was administered at a daily dose of 450 mg max The values ​​(capecitabine - Figures 10 and 11, respectively; DFCR - Figures 12 and 13, respectively; DFUR - Figures 14 and 15, respectively) were approximately 4000 to 4500 mg (1255 mg / m twice daily). 2 ) was approximately 10-15 times lower than capecitabine treatment (alone) at the estimated daily dose of eniluracil, so pretreatment with eniluracil did not significantly affect the PK values ​​of capecitabine, 5-DFCR, and 5'DFUR.

[0070] E. Variability of PK parameters: As noted in the FDA and EMA regulatory submissions for Xeloda, PK parameters (e.g., AUC and C max ) was very variable. This variability occurred in patients who received capecitabine dose-adjusted based on body surface area (body surface area adjustment (BSA)). One issue associated with capecitabine in clinical practice is the need to individualize the treatment dose for each patient.

[0071] In this clinical trial, capecitabine was administered to patients as a fixed dose and therefore not individually adjusted. The data generated for 5-FU on day 2 show a remarkably low level of variability (15–30%). [Table 5] [Table 6]

[0072] Example 4. Safety and Efficacy Results A. Introduction: Clinical trials were conducted generally as described above (see, e.g., Example 2) to evaluate various pharmacokinetic parameters and safety of capecitabine (described above in Example 3) in an attempt to corroborate the effects observed in PDX mouse models (see, e.g., Example 1). Briefly, patients with advanced and refractory gastrointestinal (GI) tumors received a single fixed oral 40 mg dose of eniluracil approximately 24 hours followed by capecitabine using a 7-day on, 7-day off regimen of capecitabine.

[0073] B. Patient Demographics, Cancer Type, and Cycle Number: An overview of the patient cohorts (1, 2A, 3, and 4) is shown below in Table 7. All patients had late-stage cancer and, except for one patient in Cohort 3, had completed more than two cycles of treatment at the time of the cutoff used for data collection. [Table 7]

[0074] C. Adverse events with Xeloda / Capecitabine: Xeloda labeling includes the following warnings and precautions: "Acute renal failure secondary to dehydration can be fatal. If grade 2 (or higher) dehydration occurs, XELODA treatment should be discontinued immediately and rehydration should be performed..." "As with other fluorinated pyrimidines, sudden death due to cardiac toxicity has been observed with XELODA..." "XELODA may induce severe skin reactions, including hand-foot syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. If a Grade 2 (or higher) event occurs, administration of XELODA should be immediately discontinued..." "Rarely, unexpected severe 5-FU-associated toxicities (e.g., stomatitis, diarrhea, mucosal inflammation, neutropenia, and neurotoxicity) are attributed to a lack of DPD activity. Fatalities have also been reported..." "Alterations in coagulation parameters and / or bleeding have been reported in patients taking XELODA in combination with coumarin-derived anticoagulants, such as warfarin. Patients taking a coumarin-derived anticoagulant in combination with XELODA should be monitored regularly for changes in coagulation parameters (PT or INR) and the anticoagulant dose adjusted accordingly..."

[0075] The Xeloda label further states: "If toxicity occurs during treatment, XELODA should be interrupted until the event has resolved or, if the following toxicities occur with a severity of Grade 2 or greater: diarrhea, hand-foot syndrome, nausea, hyperbilirubinemia, vomiting, or stomatitis, until the severity has decreased..."

[0076] Table 8 below details the most frequently observed adverse drug reactions in clinical trials for the registration of Xeloda. [Table 8]

[0077] D. Adverse Events in Clinical Trials: Table 9 below shows the adverse events (grade 2 or higher) observed in cohorts 1, 2A, 3, and 4. [Table 9]

[0078] Although the limited number of patients treated at each dose made any safety analysis difficult, it was notable that no grade 2 HFS, diarrhea, nausea, vomiting, or stomatitis were observed in the 11 patients treated with the combination of eniluracil and capecitabine at the various doses evaluated. These grade 2 adverse events are indicated on the Xeloda label and are the leading reason for delays, interruptions, and dose reductions of Xeloda (capecitabine). In clinical trials of Xeloda, HFS was observed in approximately 60% of patients and diarrhea was observed in approximately 46% of patients. The complete absence of grade 2 adverse events in this study was very encouraging, given the fact that many patients were treated with multiple cycles of therapy.

[0079] E. Preliminary reaction rate: Table 10 below provides some data regarding the RECIST analysis of the observed lesion(s) in patients enrolled in the clinical trial. [Table 10]

[0080] Because the clinical trial is still ongoing, it is premature to make any meaningful observations regarding clinical efficacy. Patients in Cohort 1 (102-101), who received capecitabine at 75 mg daily for the first seven cycles, followed by 75 mg twice daily for the remaining cycles, were treated for a total of 24 cycles, corresponding to approximately 1 year of treatment. During this time, patients demonstrated stable disease. Additionally, patients 107-115 and 107-116 were treated for multiple cycles and demonstrated stable disease.

[0081] References [1]Schilsky et al., 1998, J. Clin Oncol 4:1450-7.

[0082] [2] Schuller J, et al., 2000, Cancer Chemother Pharmacol.291-7.

[0083] [3]FDA,US2001.Drug Approval Package:Xeloda.4 30. www.accessdata.fda.gov / drugsatfda_docs / nda / 2001 / 20896s6_Xeloda.cfm

[0084] [4]Roche Canada.2017.「Xeloda capecitabine)Product Monograph.」1-59.

[0085] [5]Rivera E,et al,2014、Clin.Breast Cancer 14(1):26-30.

[0086] [6]Fiebig HH Comparison of Tumor Response in Nude Mice and in Patients.In:Winograd B,Peckham MJ,Pinedo HM(eds.),Human Tumour Xenografts in Anticancer Drug Development.Berlin、Springer、1988、25-30.

[0087] [7]Fiebig HH,et al:Combined in Vitro / in Vivo Test Procedure with Human Tumor Xenografts for New Drug Development.In:Fiebig HH、Berger DP(eds.)、Immunodeficient MICE in Oncology.Contrib.Oncol.Basel,Kanger、1992、42:321-351。

[0088] [8] Schueler J, et al: Patient-derived renal cell carcinoma xenografts exhibit distinct sensitivity patterns in response to antiangiogenic therapy and constitute a suitable tool for biomarker development. Oncotarget, 2018, 9(57):30946-30961.

[0089] The invention, and the manner and process of making and using the same, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains to make and use the same. It will be understood that the foregoing describes preferred embodiments of the invention, and that modifications can be made without departing from the scope of the invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Claims

1. 1. A method for treating cancer in a human subject, comprising: (a) orally administering to said subject eniluracil at a dose of 30-60 mg / day; (b) at least 10 hours after step (a), orally administering to said subject a fixed dose of capecitabine of about 140-700 mg / day for 2-14 consecutive days, or a dose of capecitabine that provides a 5-FU exposure (AUC) of about 1500 h*ng / mL or greater; (c) repeating steps (a) and (b) 3 to 14 days after step (b); The method comprising:

2. 10. The method of claim 1, wherein eniluracil is administered at about 40 mg / day.

3. 10. The method of claim 1, wherein capecitabine is administered at about 160-500 mg / day.

4. 10. The method of claim 1, wherein step (b) occurs at least 17 hours after step (a).

5. 10. The method of claim 1, wherein step (b) occurs at least 10 to 24 hours after step (a).

6. 10. The method of claim 1, wherein step (c) is performed 7 days after step (b).

7. 10. The method of claim 1, wherein the cancer is colon cancer, gastrointestinal tumor, breast cancer, pancreatic cancer, head and neck cancer, lung cancer, or advanced biliary tract cancer.

Images