Patent Application
20240180910
The present invention relates to a method of treating cancer, by orally administering eniluracil and capecitabine to a cancer patient. The method provides optimal dosing schedules and amounts of eniluracil and capecitabine to improve the efficacy-safety profile of capecitabine.
5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutic drugs in the treatment of a variety of tumors. 5-FU must be activated by metabolic conversion to fraudulent uridine nucleotides and deoxyuridine nucleotides that interfere with DNA synthesis and RNA functions. Because 5-FU differs from uracil, its natural counterpart, by only a fluorine substitution in the 5-position, it is readily activated in cancer patients. Unfortunately, its structural similarity to uracil also accounts for its rapid and extensive conversion to breakdown products that have no antitumor activity. The first step in the breakdown of 5-FU is through the drug metabolizing enzyme, dihydropyrimidine dehydrogenase (DPD: EC 1312, uracil reductase).
DPD is a ubiquitous enzyme that is the first and the rate-limiting step in the degradation (inactivation) of 5-FU. DPD is abundantly expressed in the gastrointestinal tract and the liver but also exists in other cells within the body and in cancer cells. The oral bioavailability of 5-FU is poor because of the extensive and rapid first-pass metabolism that occurs from the abundant amounts of DPD in the liver.
5-Ethynyluracil, also referred to as eniluracil, is a DPD inhibitor that is an irreversible inactivator of DPD thus reducing or eliminating the metabolic inactivation of 5-FU. Due to the structural similarity between eniluracil and 5-FU, eniluracil is a substrate for DPD. The co-administering of eniluracil with 5-FU restores the oral bioavailability of 5-FU. Eniluracil has been shown to be safe when doses up to 50 g per day were administered for seven days. [1]
Capecitabine, the first oral fluoropyrimidine, was introduced as a promising alternative therapy that does not require infusion and yet provides the benefits of 5-FU therapy. Capecitabine is a prodrug, which is converted to 5-FU via three enzymatic steps. Thymidylate phosphorylase (TP) plays a key role in the conversion of capecitabine to its active metabolite and may be present in higher concentrations in some malignant tissues [2]. Clinical trials have shown an improved side effect profile when comparing capecitabine therapy to 5FU/LV therapy and includes decreased stomatitis, diarrhea, nausea and neutropenic sepsis. The FDA approved capecitabine (Xeloda®) for the treatment of Dukes' stage C colon cancer, metastatic colorectal cancer and metastatic breast cancer. However, use of capecitabine at the approved doses has shown substantially higher rates of hyperbilirubinemia and hand-foot syndrome [3]. After capecitabine oral dosing at 1255 mg/m2, the PK parameters for capecitabine, 5-FU, 5-DFCR and 5′-DFUR indicate a rapid elimination (as shown below in Table 1). The observed exposure (AUC) of 5-FU is approximately 1630 h*ng/mL. FBAL has slightly extended PK profile with a half-life of 3.23 hours and an AUC of 30-35,000 h*ng/ml [4].
Descriptive Statistics on the Pharmacokinetic Parameters Estimated on Day 14 after Administration of Capecitabine (1255 mg/m2) in 8 Cancer Patients [4].
In one aspect, the present disclosure provides a method for treating cancer in a human subject, the method comprising: (a) orally administering eniluracil at a dose of 30-60 mg/day to the subject; (b) at least after 10 hours of step (a), orally administering a fixed dose of capecitabine at about 140-700 mg/day to the subject for 2 to 14 consecutive days or a dose of capecitabine providing a 5-FU exposure (AUC) of approximately 1500 h*ng/ml or higher; and (c) 3 to 14 days after step (b), repeat the steps (a) and (b).
In a further embodiment and in accordance with the above, eniluracil is administered at about 40 mg/day.
In a further embodiment and in accordance with any of the above, capecitabine is administered at about 160-500 mg/day.
In a further embodiment and in accordance with any of the above, step (b) occurs at least after 17 hours of step (a). In some other further embodiments, step (b) occurs 10-24 hours after step (a).
In a further embodiment and in accordance with any of the above, step (c) occurs 7 days after step (b).
In a further embodiment and in accordance with any of the above, the cancer is colorectal cancer, gastrointestinal tract tumor, breast cancer, pancreatic cancer, head and neck cancer, lung cancer, or advanced biliary tract cancer.
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 “Fig.”, “FIG.”, “Figure”, “Figures”, “Figs.”, and “FIGs.” herein) of which:
Table 1 depicts descriptive statistics on the pharmacokinetic parameters estimated on Day 14 after administration of capecitabine (1255 mg/m2) in 8 cancer patients.
Table 2 depicts the design of an in vivo efficacy experiment with patient-derived colon cancer xenograft CXF 280 implanted subcutaneously in athymic nude mice.
Table 3 depicts the anti-tumor efficacy of capecitabine (alone, or in combination with eniluracil) expressed as minimum T/C value in percent. The minimum T/C value recorded for a test group represents the maximum antitumor efficacy for the respective treatment.
Table 4 depicts mean Tmax and T1/2 data for 5-FU at day 2 following treatment with capecitabine (alone, or in combination with eniluracil) for the various cohorts.
Table 5 depicts mean Cmax data for 5-FU at day 2 following treatment with capecitabine (alone, or in combination with eniluracil) for the various cohorts.
Table 6 depicts mean AUClast data for 5-FU at day 2 following treatment with capecitabine (alone, or in combination with eniluracil) for the various cohorts.
Table 7 depicts a summary of the patient cohorts (1, 2A, 3, and 4), including: gender, age, cancer type, dose of PCS6422, dose of capecitabine, and number of cycles completed.
Table 8 depicts a summary of ADRs reported in ≥5% of patients with colon cancer tested with Xeloda monotherapy or i.v. 5-FU/LV in the adjuvant setting.
Table 9 depicts a summary of adverse events (Grade 2 or higher) observed in cohorts 1, 2A, 3, and 4.
Table 10 depicts data regarding the RECIST analysis of the observed lesion(s) for patients enrolled in the clinical trial.
The inventors have compared the anti-tumor efficacy of the combination of eniluracil and capecitabine using a 7/7 (capecitabine 7 days on and 7 days off) dosing schedule with capecitabine alone using the conventional 14/7 (capecitabine 14 days on and 7 days off) schedule in a preclinical xenograft model. The inventors discovered that pretreatment with eniluracil allows for the complete elimination of eniluracil in the mice prior to treatment with capecitabine and enhances the anti-tumor activity of capecitabine without a gross impact on its safety and tolerability profile. Pretreatment with 10 mg/kg oral eniluracil prior to administration of 30 mg/kg or 15 mg/kg of oral capecitabine resulted in comparable efficacy to that of 300 mg/kg of oral capecitabine alone in mice. Notably, the total cumulative dose of capecitabine in the combination groups was 13.3 and 26.6-fold lower compared to the capecitabine alone group.
Based on inventors' xenograft model efficacy results, in conjunction with the knowledge of previous preclinical and clinical antitumor efficacy using eniluracil and 5-FU combination therapy, the inventors discovered optimal dosing schedules and amounts of eniluracil and capecitabine for treating cancers in patients where fluoropyrimidine therapy alone is preferred.
The present application provides a method for treating cancer in a patient, wherein the cancer is a cancer type in which 5-FU or 5-FU prodrugs such as capecitabine have activity. The method comprises the steps of: (a) first orally administering eniluracil at a dose about 30-60 mg/day to the patient, (b) at least after 10 hours of step (a), orally administering capecitabine at a dose about 140-700 mg/day to the patient for 6-14 consecutive days or orally administering capecitabine at a dose providing a of 5-FU exposure (AUC) of approximately 1500 h*ng/ml or higher; and (c) 7-14 days after step (b), repeat the steps (a) and (b).
In step (a) of the method, at least about 30 mg/day or at least about 40 mg/day of eniluracil is administered to a patient. For example, about 40 mg/day, or about 50 mg/day, or about 60 mg/day, of eniluracil is administered to a patient. Eniluracil is first administered (i.e., pre-dosed prior to capecitabine) to a patient to substantially eliminate the DPD activity in both nervous and non-nervous tissues in the patient, before administration of the 5-FU prodrug capecitabine. By “substantially eliminate”, it means 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%, or less than 1% of the baseline DPD activity in the patient prior to administration of eniluracil.
In step (b) of the method, capecitabine is administered between 10-24 hours after administering eniluracil. For example, at least after 10 hours, after 12 hours, after 16 hours, after 17 hours, and no longer than 24 hours after administering eniluracil, capecitabine is administered. The dosing schedule and the capecitabine amount are selected to allow eniluracil to be substantially cleared from the patient prior to capecitabine administration, so 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 at the time capecitabine is administered. Accordingly, the potential interference by eniluracil with the metabolic activation of capecitabine is minimized, and the anti-tumor efficacy of capecitabine is thereby not interfered by eniluracil.
Capecitabine at a dose between approximately 140 to 700 mg/day, is administered to the patient. For example, capecitabine is administered at a dose of 140-700 mg/day, 160-700 mg/day, 140 to 500 mg/day, 150-500 mg/day, 200-500 mg/day, 140-450 mg/day, 150-450 mg/day, 160-450 mg/day, 140-400 mg/day, 150-400 mg/day, or 300-400 mg/day.
Capecitabine could also be administered at a dose providing 5-FU exposure (AUC) of approximately 1500 h*ng/ml or higher.
Lower amount of capecitabine is non-efficacious or only partially efficacious. Higher amount of capecitabine is expected to cause toxicity.
Capecitabine can be administered once a day, or more than once a day to the patient. Preferably, capecitabine is administered twice a day. Capecitabine is administered to the patient for 2-14 consecutive days, for example, for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 consecutive days.
In step (c) of the method, after the patient is rested for at least 3 to 14 days, for example, or after 3, 4, 5, 6, or 7 days, or after any of 7-14 days, the patient receives the next cycle of eniluracil and capecitabine which follows the steps (a) and (b).
The steps (a)-(c) are repeated based on the discretion of the physician evaluation of response and side effects. A physician may often stop treating a patient if the patient either has a complete response or when the disease progresses in the patient. A complete response means that the tumor is no longer present. The progress of the disease means that the tumor starts to enlarge or the tumor is no longer stable. A tumor is stable means that the tumor is not progressing and not regressing.
The present invention is useful in treating all cancers that capecitabine is used, including but not limited to colorectal cancer, gastrointestinal tract tumor, breast cancer, pancreatic cancer, head and neck cancer, lung cancer, and advanced biliary (bile) tract cancer.
The present invention is useful in treating a mammal subject, such as humans, horses, and dogs. The present invention is particularly useful in treating humans.
The present method uses an optimal dosing schedule and optimal amounts of both eniluracil and capecitabine, which provide an efficacious treatment and is safe. The total cumulative dose of capecitabine administered in the present method is lower than the effective dose of capecitabine if used alone without eniluracil. This is beneficial because high doses of capecitabine treatment may cause side effects resulting in the need to decrease the dose or discontinue treatment as well as resistance to therapy as evidenced by shorter progress-free survival and lower response rate in patients [5]. The present method is also useful in treating patients with tumor resistance to either 5-FU or capecitabine therapy.
The following examples further illustrate the present invention. These examples are intended merely to be illustrative of the present invention and are not to be construed as being limiting.
This study was to assess the antitumor efficacy of eniluracil in combination with different doses of capecitabine in the patient-derived colon xenograft CXF 280 subcutaneously implanted in immunodeficient athymic nude mice.
Human tumor explants directly transplanted from patients to nude mice, and passaged subcutaneously termed patient-derived tumor xenografts (PDXs), retain most of the characteristics of the parental patient tumors including histology and sensitivity to anti-cancer drugs. Studies have shown that PDXs passaged in nude mice correctly replicate the response of the donor patient to standard cytotoxic anti-cancer drugs in >90% of cases. [6], [7], [8].
The study consisted of an in vivo efficacy experiment with the patient-derived colon cancer xenograft CXF 280 implanted subcutaneously in athymic nude mice.
This experiment consisted of six groups with six animals each. Animals were dosed in monotherapy with capecitabine at 300 or at 30 mg/kg/day daily for 2 weeks with a one-week dosing break followed by another 2 weeks of daily dosing (14 days ON and 7 days OFF). In combination therapies, capecitabine was dosed at 30, 15 or 7.5 mg/kg/day on days 1-7, 15-21 and 29-35 (7 days ON and 7 days OFF) as well as with eniluracil at 10 mg/kg/day on days 1, 3, 5, 15, 17, 19, 29, 31, and 33.
Combination therapies with capecitabine and eniluracil scheduled for the same dosing day were administered with a six-hour dosing delay after dosing with eniluracil in order to ensure that all the eniluracil is eliminated in the mouse prior to capecitabine administration.
All therapies were administered via oral gavage (p.o.) over the course of 35 days followed by an observation period of one week until day 42 of the experiment.
Table 2 shows the design of the experiment.
Tumor growth inhibition was determined by comparison of the median RTV of the test groups (T) with the vehicle control group (C) and was expressed as minimum T/C value in percent. The minimum T/C value recorded for a test group during an experiment represents the maximum antitumor efficacy for the respective treatment.
The anti-tumor efficacy is also shown in Table 3 by calculating minimum T/C value (%) at Day 35.
The above results show that monotherapy with capecitabine at 300 mg/kg/day in mice achieved high antitumor activity and was significantly more efficacious than monotherapy with 30 mg/kg/day. Combination therapies of capecitabine with eniluracil were most efficacious with 30 or 15 mg/kg/day of capecitabine, reaching very high levels of tumor growth inhibition at a much lower cumulative dose due to the addition of eniluracil and a higher level of capecitabine exposure than the 7.5 mg/kg/day group. All combination therapies of capecitabine (30, 15 and 7.5 mg/kg/day) with eniluracil were more efficacious than the monotherapy of capecitabine with 30 mg/kg/day, at a much lower cumulative dose due to the modified dosing schedule.
To evaluate the safety, dose-limiting toxicities (DLTs), and maximum tolerated dose (MTD) of capecitabine administered to patients with advanced, refractory gastrointestinal tract (GI) tumors using a 7 days on +7 days off capecitabine regimen ˜24 hours after a single, fixed, oral 40 mg dose of eniluracil.
This study is an open label, multi-center study in patients who have advanced, relapsed refractory GI cancer or are not relapsed/refractory but are intolerant to other therapies who, in the judgment of investigators, are candidates for fluoropyrimidine monotherapy.
Patients meeting the following criteria will be eligible for the study:
Patients meeting any of the following criteria will not be allowed to enroll in this study:
Eniluracil (40-50 mg) is orally administrated at Day 1. After 12-24 hours, capecitabine is orally administered. Capecitabine is given twice a day at 140-600 mg/day for a total of 7 days. Then the patient is rested for 7 days before receiving the next cycle which follows the above-described procedures. The cycles are repeated until either the patient has a complete response or when the disease progresses in the patient. A complete response means that the tumor is no longer present. Progression of the cancer means that the tumor starts enlarging or the tumor is no longer stable.
Disease assessment according to the standard of care by the investigator every 8 weeks according to RECIST criteria (Version 1.1).
The following PK parameters will be determined for eniluracil, 5-acetyluracil, capecitabine, 5 FU, and the main metabolites FBAL, 5′-DFCR, and 5′-DFUR, data permitting:
A clinical trial was performed as is generally described above (see, e.g., Example 2) to assess various pharmacokinetic parameters and the safety of capecitabine (discussed below in Example 4) in an effort to corroborate the effects observed in the PDX mouse model (see, e.g., Example 1). Briefly, capecitabine was administered to patients with advanced, refractory gastrointestinal tract (GI) tumors using a 7 days on +7 days off capecitabine regimen ˜24 hours after a single, fixed, oral 40 mg dose of eniluracil. Results obtained in the clinical trial were compared against the data reported in the new drug application for Xeloda used by Roche to obtain FDA market approval (sometimes referred to herein as “the Xeloda study”), which are summarized above in Table 1.
In the Xeloda study, 1255 mg/m2 capecitabine was administered twice daily (b.i.d.) and various pharmacokinetic (PK) parameters were assessed in plasma at steady-state (day 14) following administration of the recommended dose of capecitabine (1255 mg/m2 b.i.d.) in 8 cancer patients. Specifically, Cmax (μg/mL), tmax (h), AUC0-t (μg*h/mL), AUC0-∞(μg*h/mL), and t1/2 (h) were estimated for capecitabine, 5′-DFCR, 5′-DFUR, 5-FU, FUH2, and FBAL in the Xeloda study.
The results from the Xeloda study are similar to those described in the EMA 2005 Scientific Discussion for Registration of Xeloda in Europe. Briefly, peak plasma concentrations (Cmax in μg/mL) for capecitabine, 5′-DFCR, 5′-DFUR, 5-FU, and FBAL were 4.67, 3.05, 12.1, 0.95, and 5.46, respectively, in the 2005 EMA for Xeloda. The time to peak plasma concentrations (tmax in hours) were 1.50, 2.00, 2.00, 2.00, and 3.34, respectively, in the 2005 EMA for Xeloda. The AUC0-∞values in μg*h/mL were 7.75, 7.24, 24.6, 2.03, and 36.3, respectively, in the 2005 EMA for Xeloda.
It was determined that 5-FU levels were greatly increased in patients that received a pre-treatment with eniluracil at day 1 followed by treatment with increasing doses of capecitabine at day 2. Both AUC and Cmax levels of 5-FU (as shown in
Assuming an average body surface of 1.6 m2, when capecitabine is given at a dosage of 1255 mg/m2, the daily dose for such an average individual is 4016 mg. A single dose of 1250 mg/m2 is equivalent to 2000 mg per patient. The AUC0-∞ levels observed with capecitabine alone were 1630 h*ng/ml for the 1255 mg/m2 b.i.d. dosing and 2030 h*ng/ml for the 1250 mg/m2 dosing. The mean AUC0-∞ levels observed for the combination of eniluracil and capecitabine at 450 mg daily dose (225 mg b.i.d.) was 5691 h*ng/ml. Therefore, a single dose of 225 mg of capecitabine (in combination with pretreatment with eniluracil) provided between 2.8- to 3.5-fold higher AUC at a total dose that is 8.9-fold lower. Based on the AUC comparison, eniluracil pretreatment amplified the efficacy of capecitabine by a factor of 25- to 30-fold.
Eniluracil potentiation was also observed when analyzing the Cmax data, although not as strong as with the AUC data. A dose of 225 mg of capecitabine (in combination with eniluracil pretreatment) yielded a Cmax of 1082 ng/mL compared to 709 and 950 ng/ml for capecitabine alone.
Another major difference observed in the PK of 5-FU at day 2 when eniluracil was given in combination with capecitabine was the extension of the half-life (T1/2). The half-life increased from 0.76 hours (capecitabine alone) up to 5.71 hours (capecitabine in combination with eniluracil pretreatment). Extension of the half-life of 5-FU contributed to the increase in the AUC observed for the combination treatment.
However, at day 8, the effects of eniluracil on the AUC and Cmax of 5-FU were no longer observed (as shown in
The effect of the pre-treatment with eniluracil on the metabolism of capecitabine into FBAL were, generally, the opposite of those observed for 5-FU. Essentially, while 5-FU exposure was greatly increased by eniluracil, FBAL levels were almost undetectable at day 2. Both AUC and Cmax parameters showed that eniluracil completely blocked the metabolism of capecitabine into FBAL, even for the highest doses assessed (as shown in
Pre-treatment with eniluracil also resulted in an increase in Tmax of FBAL at day 2 (7-8 hours compared to 3.24 hours for capecitabine treatment alone).
Similar to the results obtained for 5-FU, the effects of eniluracil on FBAL metabolism was no longer apparent at day 8. At day 8, the AUC and Cmax and parameters for FBAL were proportional to the levels observed with capecitabine therapy alone (as shown in
D. Capecitabine and other Metabolites:
Pretreatment with eniluracil did not significantly affect the PK values of capecitabine, 5—DCFR, and 5′DFUR, since the AUC and Cmax values (Capecitabine—
As mentioned in the FDA and EMA regulatory submissions for Xeloda, the variability of PK parameters (e.g., AUC and Cmax) for capecitabine and its metabolites was very high. This high variability occurred in patients in which capecitabine had been dose-adjusted based on their body surface (body surface adjustment (BSA)). One problem associated with capecitabine in clinical practice is the need to individualize the treatment doses for each patient.
In the current clinical trial, capecitabine was given to patients as a fixed dose, and as such was not individually adjusted. The data generated for 5-FU at day 2 shows a remarkably low level of variability (15-30%).
A clinical trial was performed as is generally described above (see, e.g., Example 2) to assess various pharmacokinetic parameters (discussed above in Example 3) and the safety of capecitabine in an effort to corroborate the effects observed in the PDX mouse model (see, e.g., Example 1). Briefly, capecitabine was administered to patients with advanced, refractory gastrointestinal tract (GI) tumors using a 7 days on +7 days off capecitabine regimen ˜24 hours after a single, fixed, oral 40 mg dose of eniluracil.
A summary of the patient cohorts (1, 2A, 3, and 4) is shown below in Table 7. All patients had late-stage cancers and, with the exception of one patient in cohort 3, completed more than 2 cycles of treatment at the cutoff used for data collection.
C. Adverse Events with Xeloda/Capecitabine:
The Xeloda label contains the following warnings and precautions:
Furthermore, it contains the following statement: “If toxicity on therapy occurs, XELODA should be interrupted until the event resolves, or the severity decreases when the following toxicities occur at a severity of grade 2 or greater: diarrhea, hand-foot syndrome, nausea, hyperbilirubinemia, vomiting or stomatitis . . . .”
Table 8 below details the most frequently observed adverse drug reactions in the clinical trial for registration of Xeloda.
Table 9 below shows adverse events (grade 2 or higher) observed in cohorts 1, 2A, 3, and 4.
Although the number of patients treated for each dose was limited, making 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 assessed. These grade 2 AEs are indicated in the Xeloda label and are the main reason for treatment delay, interruption, and dose reduction for Xeloda (capecitabine). Since HFS was observed in about 60% of the patients and diarrhea in about 46% of the patients in the Xeloda clinical trials, the total absence of grade 2 AEs in the current clinical trial was very encouraging in view of the fact that many patients were treated for multiple cycles of therapy.
Table 10 below contains some data regarding the RECIST analysis of the observed lesion(s) for patients enrolled in the clinical trial.
As the clinical trial is still ongoing, it was too early to make any meaningful consideration on clinical efficacy. The patient in cohort 1 (102-101), dosed with 75 mg capecitabine daily for the first 7 cycles and then 75 mg b.i.d. for the remaining cycles, has been treated for a total of 24 cycles, corresponding to almost 1 year of therapy. During this time, the patient exhibited stable disease. Further, patients 107-115 and 107-116 were treated for multiple cycles and showed stable disease.
The invention, and the manner and process of making and using it, 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 is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude the specification.
This application claims the benefit of priority from U.S. Provisional Patent Application Nos. 63/386,271, filed on Dec. 6, 2022, and 63/513,525, filed on Jul. 13, 2023, which are both hereby incorporated by reference in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63386271 | Dec 2022 | US | |
| 63513525 | Jul 2023 | US |
