JP2015199676A - Antitumor agent and antitumor effect enhancer comprising regorafenib - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel cancer therapeutic method using a trifluridine (FTD)-tipiracil hydrochloride (TPI) compounding agent which shows significantly excellent antitumor effect and has little adverse effect.SOLUTION: An antitumor agent is characterized in that a trifluridine (FTD)-tipiracil hydrochloride (TPI) compounding agent and regorafenib are administered in combination.

Description

  The present invention relates to an antitumor agent comprising a combination of trifluridine and tipiracil hydrochloride and regorafenib, and an antitumor effect potentiator of regorafenib.

Trifluridine (also known as α, α, α-trifluorothymidine; hereinafter also referred to as “FTD”) exerts an antitumor effect by inhibiting DNA synthesis by inhibiting thymidylate production and by DNA dysfunction by incorporation into DNA. On the other hand, tipiracil hydrochloride (chemical name: 5-chloro-6-[(2-iminopyrrolidin-1-yl) methyl] pyrimidine-2,4 (1H, 3H) -dione hydrochloride, hereinafter also referred to as “TPI”. ) Has a thymidine phosphorylase inhibitory action. It is known that the antitumor effect of FTD is enhanced when TPI suppresses the degradation of FTD in vivo by thymidine phosphorylase (Patent Document 1). Currently, an antitumor agent containing FTD and TPI at a molar ratio of 1: 0.5 (hereinafter also referred to as “FTD / TPI combination agent”) is under development as a therapeutic agent for solid cancers such as colorectal cancer, and relapses. It has been approved as a therapeutic agent for colorectal cancer (Non-patent Documents 1 and 2).
Furthermore, in order to enhance the antitumor effect of the FTD / TPI combination drug, combination therapy has been studied, and the effect of the combined use of the combination drug with irinotecan or oxaliplatin has been suggested so far. (Non-Patent Documents 3 and 4).

Regorafenib is a multikinase inhibitor and is known to inhibit VEGFR, TIE2, c-KIT, RET, B-RAF, PDGFR, FGFR, and the like. By inhibiting these kinases, signal transduction related to angiogenesis and tumor formation is inhibited to exert an antitumor effect. Regorafenib is used for advanced or recurrent colorectal cancer (colon / rectal cancer) that cannot be curatively resected, and is also being developed for gastric cancer, small cell lung cancer, renal cell cancer, and hepatocellular carcinoma. Development of FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) and regorafenib is also under development (Non-patent Document 5).
As described above, a therapeutic method including an FTD / TPI combination and a therapeutic method including regorafenib have been vigorously developed, but no combination therapy using an FTD / TPI combination and regorafenib has been performed.

International Publication No. 96/30346

Invest New Drugs 26 (5): 445-54, 2008. Lancet Oncol. 13 (10): 993-1001, 2012. Eur J Cancer. 43 (1): 175-83, 2007. Br J Cancer. 96 (2): 231-40, 2007. Ann Oncol. 24 (6): 1560-1567, 2013.

  It is an object of the present invention to provide a novel cancer treatment method using an FTD / TPI combination agent that exhibits a remarkably excellent antitumor effect and has few side effects.

  Therefore, the present inventor examined the combined therapy of the FTD / TPI combination drug and regorafenib, and by using the FTD / TPI combination drug and regorafenib, it was further possible to use the combination of the FTD / TPI combination drug or the regorafenib alone. It was found that the antitumor effect was significantly enhanced.

  That is, the present invention provides the following [1] to [15].

[1] An antitumor agent comprising a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 and regorafenib.
[2] The antitumor agent according to [1], wherein regorafenib is 0.175 to 1.76 mol per mol of trifluridine.
[3] The daily dose of trifluridine in the combination day containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 is 50 to 100% of the recommended dose when administered alone. The antitumor agent according to [1] or [2].
[4] The daily dosage on the day of administration of trifluridine of the combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 is 35 to 70 mg / m ² / day [1] to [3 ] The antitumor agent of any one of.
[5] The antitumor agent according to any one of claims 1 to 4, wherein the daily dose on the day of administration of regorafenib is 20 to 100% of the maximum tolerated dose when administered alone.
[6] The antitumor agent according to any one of [1] to [5], wherein the daily dose on the day of administration of regorafenib is 32-160 mg / body / day.
[7] The antitumor agent according to any one of [1] to [6], wherein the target cancer is digestive organ cancer.
[8] The antitumor agent according to any one of [1] to [7], wherein the target cancer is colon cancer.
[9] An antitumor effect potentiator comprising a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 for enhancing the antitumor effect of regorafenib.
[10] An antitumor effect potentiator comprising regorafenib for enhancing the antitumor effect of a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5.
[11] An antitumor agent comprising a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 for treating a cancer patient to whom regorafenib has been administered.
[12] An antitumor agent comprising regorafenib for treating a cancer patient to whom a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 is administered.
[13] An antitumor agent comprising a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5, which is used in combination with regorafenib.
[14] An antitumor agent comprising regorafenib, which is used in combination with a compounding agent containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5.
[15] A kit preparation comprising a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 and instructions for use.

  According to the antitumor agent of the present invention, it is possible to perform cancer treatment that exhibits high antitumor effects (particularly, tumor reduction effect, growth delay effect (life extension effect)) while suppressing the onset of side effects. In turn, it leads to long-term survival of cancer patients.

A regorafenib monohydrate with a dose of 75 mg / kg / day and a dose of 10 mg / kg / day as FTD of the FTD / TPI combination drug (trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5) in mice The antitumor effect at the time of using together. A regorafenib monohydrate with a dose of 75 mg / kg / day and a dose of 50 mg / kg / day as FTD of the FTD / TPI combination drug (trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5) in mice The antitumor effect at the time of using together. Regorafenib monohydrate with dosage of 150 mg / kg / day and dosage of 10 mg / kg / day as FTD of FTD / TPI combination drug (trifluridine and tipiracil hydrochloride in molar ratio 1: 0.5) in mice The antitumor effect at the time of using together. FTD / TPI combination dose (trifluridine and tipiracil hydrochloride 1: 0.5 molar ratio) and regorafenib monohydrate at a dose of 50 mg / kg / day as FTD in mice The antitumor effect at the time of using together.

  FTD and TPI in the present invention are each known compounds and can be synthesized, for example, according to the method described in WO96 / 30346 pamphlet. A compounding agent containing FTD and TPI at a molar ratio of 1: 0.5 is also known (Non-Patent Documents 1 and 2). In addition, the FTD / TPI combination drug has been approved in Japan as a treatment for advanced / recurrent colorectal cancer, and its dosage is “70 mg / m2 / day as FTD, twice a day for 5 consecutive days. After the administration, the drug is withdrawn for 2 days. This is repeated twice, and then the drug is withdrawn for 14 days.

  Legorafenib (chemical name: 4- [4-({[4-chloro-3- (trifluoromethyl) phenyl] carbamoyl} amino) -3-fluorophenoxy] -N-methylpyridine-2-carboxamide) is also a known compound. is there. Regorafenib can be synthesized according to the method described in International Publication No. 2008/043446 pamphlet. In the present invention, “regorafenib” includes hydrates such as regorafenib monohydrate as long as the effects of the present invention are exhibited. In addition, regorafenib is marketed as a monohydrate and the commercial item (Stivaga tablet (registered trademark), Bayer Yakuhin) may be used.

The daily dose on the administration day of the FTD / TPI combination agent (when the molar ratio of FTD and TPI is 1: 0.5, for example) in the antitumor agent of the present invention is FTD / TPI combination agent. From the viewpoint of potentiating the antitumor effect of regorafenib by, 50 to 100% of the recommended dose when the FTD / TPI combination drug is administered alone is preferable, and more preferably 100%. Specifically, the recommended dose when administering the FTD / TPI combination drug alone in humans is 70 mg / m ² / day as FTD, which is the approved dose in Japan as described above. the daily dosage of the administration day of FTD · TPI formulation in anti-tumor agent of the invention, 35~70mg / m ² / day is preferred as FTD, more preferably from 70mg / m ² / day. In addition, since the human body surface area is about 1.6 m ² in a standard male and female adult, the daily dose on the administration day of the FTD / TPI combination agent in the antitumor agent of the present invention is 56 to 112 mg / body / day is preferable, and 112 mg / body / day is more preferable.
In the present invention, the “recommended dose” is a dose that is determined by clinical trials and the like and provides the maximum therapeutic effect within a range that can be safely used without causing serious side effects. Are Japan Pharmaceuticals and Medical Devices Agency (PMDA), US Food and Drug Administration (FDA), European Medicines Agency (EMA), European Medicines Agency, etc. Dose approved, recommended, and recommended by organizations and listed in package inserts, interview forms, treatment guidelines, etc., and doses approved by any PMDA, FDA, or EMA public organization are preferred.

  The daily dose of the administration of regorafenib in the antitumor agent of the present invention is 20 to 20 times the recommended dose when regorafenib is administered alone from the viewpoint of enhancing the antitumor effect of regorafenib by the FTD / TPI combination agent. 100% is preferable and 100% is more preferable. Specifically, the recommended dose when regorafenib is administered alone in humans is 160 mg / body / day (for example, when orally administered for 3 weeks and then withdrawn for 1 week from the approval information in the package insert / interview form) , Colorectal cancer, and gastrointestinal stromal tumor are preferable), the daily dose of regorafenib in the antitumor agent of the present invention is preferably 32 to 160 mg / body / day, and 160 mg / body. / Day is more preferable.

These molar ratios can be calculated from the doses of the FTD / TPI combination drug and regorafenib.
In the antitumor agent of the present invention, the molar ratio of the FTD / TPI combination drug and regorafenib is preferably 0.175 to 1.76 moles of regorafenib, preferably 0.175 to 0.878 moles per mole of FTD. Is more preferable.

  The administration schedule of the antitumor agent of the present invention can be appropriately selected according to the carcinoma, the stage, and the like. The FTD / TPI combination drug is preferably administered on a daily basis for 5 days, followed by a 2-day rest twice, followed by a 2-week rest. Regorafenib is preferably administered on a daily schedule for 3 weeks and then withdrawn for 1 week. In addition, the administration schedule may be appropriately provided with a drug holiday according to side effects and the like.

  The number of daily administrations of the antitumor agent of the present invention can be appropriately selected according to the cancer type, stage, etc., but FTD / TPI combination is preferably twice a day, and legolefenib is preferably once a day. .

  The administration order of the FTD / TPI combination drug and legolefenib of the present invention can be appropriately selected according to the cancer type, stage, etc., either of which may be administered first or simultaneously.

  Specific examples of the cancer that is the target of the antitumor agent of the present invention include head and neck cancer, digestive organ cancer (esophageal cancer, stomach cancer, gastrointestinal stromal tumor, duodenal cancer, liver cancer, biliary tract cancer (gallbladder / bile duct) Cancer), pancreatic cancer, small intestine cancer, colon cancer (colorectal cancer, colon cancer, rectal cancer, etc.), lung cancer, breast cancer, ovarian cancer, uterine cancer (cervical cancer, endometrial cancer, etc.), renal cancer, Examples include bladder cancer and prostate cancer. Here, the cancer includes not only the primary lesion but also cancer that has metastasized to other organs (eg, liver). Among these, from the viewpoint of antitumor effects and side effects, digestive organ cancer, breast cancer, renal cancer, and small cell lung cancer are preferable, digestive organ cancer is more preferable, colon cancer, gastrointestinal stromal tumor, and stomach cancer are more preferable, and large intestine Cancer is particularly preferred. In addition, the antitumor agent of the present invention is used in advance to surgically remove the tumor, even if it is used for postoperative adjuvant chemotherapy for preventing recurrence after surgically removing the tumor. It may be preoperative adjuvant chemotherapy.

  In the present invention, each active ingredient may be formulated into one dosage form. The antitumor agent of the present invention is preferably formulated by dividing each active ingredient into a plurality of dosage forms. That is, it is preferable to formulate FTD and TPI as a compounding agent and regorafenib as a single agent.

  In addition, as long as each active ingredient is administered according to the dose of the present invention, each preparation may be manufactured and sold in one package suitable for combined administration, and each preparation is divided into separate packages. May be sold.

  There is no restriction | limiting in particular as an administration form of the antitumor agent of this invention, According to the therapeutic purpose, it can select suitably, Specifically, an oral agent (a tablet, a coated tablet, a powder, a granule, a capsule, a liquid agent etc.), injection Examples include suppositories, suppositories, patches, ointments and the like. The combination of FTD and TPI is preferably an oral preparation. Examples of the preparation containing regorafenib include the above-mentioned administration forms, and oral preparations are preferable.

  The antitumor agent in the present invention can be prepared by a generally known method using a pharmaceutically acceptable carrier for both FTD / TPI combination drug and regorafenib depending on its administration form. Examples of such carriers include various types commonly used for ordinary drugs, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonic agents, pH. Examples include regulators, buffers, stabilizers, colorants, flavoring agents, and flavoring agents.

The present invention also relates to an antitumor effect potentiator comprising an FTD / TPI combination agent for enhancing the antitumor effect of regorafenib for cancer patients (particularly colorectal cancer patients). The antitumor effect potentiator has a preparation form of the antitumor agent.
The present invention also relates to an antitumor effect enhancer comprising regorafenib for enhancing the antitumor effect of an FTD / TPI combination drug for cancer patients (particularly colorectal cancer patients). The antitumor effect potentiator has a preparation form of the antitumor agent.

The present invention also relates to an antitumor agent comprising an FTD / TPI combination agent for treating cancer patients (particularly colorectal cancer patients) administered with regorafenib. The antitumor agent has the above-described preparation form.
The present invention also relates to an antitumor agent comprising regorafenib for treating cancer patients (particularly colorectal cancer patients) administered with an FTD / TPI combination. The antitumor agent has the above-described preparation form.
The present invention also relates to an antitumor agent containing an FTD / TPI combination drug, which is used in combination with regorafenib for cancer patients (particularly colorectal cancer patients). The antitumor agent has the above-described preparation form.
The present invention also relates to an antitumor agent containing regorafenib, which is used in combination with an FTD / TPI combination agent for cancer patients (particularly colorectal cancer patients). The antitumor agent has the above-described preparation form.

  The present invention also relates to a kit preparation comprising an FTD / TPI combination and instructions for use that describe the combined administration of the FTD / TPI combination and regorafenib to cancer patients (particularly colorectal cancer patients). Here, the “instruction for use” may be anything that describes the above-mentioned dose, and it does not matter whether there is a legal binding force. Specifically, an attached document, a pamphlet, etc. are illustrated. In addition, a kit preparation including instructions for use includes instructions for use printed together with the antitumor agent even if the instructions for use are printed and attached to the kit preparation package. It may be a thing.

  Next, the present invention will be described in more detail with reference to examples and reference examples. The present invention is not limited in any way by these examples, and many variations are possible by those having ordinary knowledge in the art within the technical idea of the present invention.

Reference example 1
Cultured cells (1 × 10 ⁷ cells / mouse) of a human colon cancer strain (KM20C) were transplanted into the peritoneal cavity of 5-6 week old BALB / cA Jcl-nu mice. Mice were allocated so that the average body weight of each group was equal, and the day when grouping (n = 10) was performed was defined as Day 0.
FTD / TPI combination agents (mixtures having a molar ratio of FTD to TPI of 1: 0.5) were prepared so that the FTD was 75, 100, 150, 300, and 450 mg / kg / day. The administration of the drug was started from Day 3, and the FTD / TPI combination drug was orally administered for 5 days and suspended for 2 days for 6 weeks.
As an index of the antitumor effect, the number of surviving mice in each group was confirmed, and the survival time and survival rate of each group were compared. The life extension rate (ILS; Increased Life Span) was calculated as follows.

  The results are shown in Table 1.

As shown in Table 1, the FTD / TPI combination was effective in extending the survival time in all groups of 75 to 450 mg / kg / day as FTD, and the most viable in the 150 mg / kg / day group. Since the period was long, the recommended dose (RD; Recommended Dose) of the FTD / TPI combination drug in mice is 150 mg / kg / day as FTD. That is, it was shown that the FTD / TPI combination drug exerts an effect of extending the survival time at a dose of 50% to 300% of RD.
On the other hand, it is known that the recommended dose of the FTD / TPI combination drug in humans is 70 mg / m ² / day as FTD, and the survival time is significantly prolonged at this dose (Non-patent Document 2). Therefore, the recommended dose of FTD / TPI combination as FTD corresponds to 150 mg / kg / day in mice and 70 mg / m ² / day in humans.

Reference example 2
Day 0 was defined as the day when 8 week old non-tumor bearing nude mice (BALB / cAJcl-nu / nu) were grouped into 6 groups (n = 3). The dose volume of the drug was 10 mL / kg, and regorafenib was prepared as a monohydrate at 50, 100, 200 mg / kg / day. Among them, one group was treated as an untreated group, and regorafenib monohydrate was orally administered once daily for 14 days (Day 1 to Day 14) at doses of 50, 100, and 200 mg / kg / day to the remaining 5 groups.
Then, from Day 4 to Day 29, the number of survivors and body weight change (body weight change: BWC) of each group of mice were confirmed. Groups with deaths were considered toxic. A change in body weight was judged to be toxic when it showed -20% or less during the test period (Day 0 to Day 29).
The change in body weight was calculated as follows.

  Table 2 shows the dose, the number of deaths, and the onset date of death in each group. In addition, the weight change in each group did not become lower than -20% in the period until the onset date of death.

As shown in Table 2, in non-cancer-bearing nude mice, death was confirmed by Day 14 in the group administered regorafenib monohydrate at 100 mg / kg / day or more, but at 29 mg at 50 mg / kg / day Until then there were no confirmed deaths.
As is apparent from this result, the recommended dose of regorafenib monohydrate in mice is 50 mg / kg / day. That is, the recommended dose in mice as regorafenib is 48.2 mg / kg / day. On the other hand, the recommended dose of regorafenib in humans is 160 mg / body / day (166 mg / body / day as a hydrate) according to the interview form. Therefore, the recommended dose of regorafenib monohydrate is equivalent to 50 mg / kg / day in mice and 166 mg / body / day in humans.

Example (combination of FTD / TPI combination and regorafenib in COLO205)
A human colon cancer-derived strain (COLO205) was transplanted in the vicinity of the rightmost rearmost rib of a 5-week-old mouse, BALB / cAJcl-nu / nu (nude mouse). After tumor transplantation, the major axis (mm) and minor axis (mm) of the tumor were measured, and the tumor volume (TV) was calculated by the following formula.

When the average TV of each group reached about 100 mm ³ , the mice were divided into groups (n = 6), and the day was defined as Day 0. Among them, 1 group was an untreated group, 2 group was a single agent administration group of FTD / TPI combination agent, 3 group was a single agent administration group of regorafenib, and 6 group was a combination administration group of FTD / TPI combination agent and regorafenib. .

  The dose volume of the drug was 10 mL / kg, and the FTD / TPI combination drug (mixture of FTD and TPI at a molar ratio of 1: 0.5) was prepared to have an FTD of 75 and 150 mg / kg / day. Regorafenib monohydrate was prepared to be 10, 50 mg / kg / day. The FTD / TPI combination was orally administered to Day 1-14 twice daily. Legorafenib monohydrate was orally administered to Day 1-14 once daily. In the combination administration group, the FTD / TPI combination drug and regorafenib monohydrate were administered at the same dosage and administration schedule as the single agent administration group.

  In order to show the index of the antitumor effect by RTV, Day 0, 4, 7, 11, 15, 18, 22, 25, 29 are set as TV measurement days, and the TV of each group at that time is calculated. Relative tumor volume (RTV) was determined.

  The above RTV was plotted for each measurement day, and the RTV days of the non-treatment group, the FTD / TPI combination administration group, the regorafenib monohydrate administration group, and the FTD / TPI combination formulation and regorafenib monohydrate administration group We compared the trend. Table 3 shows the results of the RTV untreated group and the single agent administration group in Day 29. In addition, the FTD / TPI combination agent in the table is a dose converted in humans, and the same applies to regorafenib monohydrate.

Table 4 shows the results of the combination administration group. In RTV, regarding the presence or absence of an effect enhancing effect by combined administration, the maximum value (Overall maximum P) of significance obtained by each comparison by a closed procedure (Intersection-Union Test) is less than 0.01. In the case of antitumor effect enhancement. In the table, “#” of RTV indicates that the maximum value of the above significant probability was 0.01 or less.
The “regorafenib molar ratio” in the table means the FTD / TPI combination drug (mixture of FTD and TPI at a molar ratio of 1: 0.5) and regorafenib monohydrate in each group. It is the number of equivalents of regorafenib relative to 1 equivalent of FTD at this time. As in Reference Examples, 150 mg / kg / day in mice corresponds to 70 mg / m ² / day in humans for the FTD dose of the FTD / TPI combination drug. It was multiplied by a human body surface area of 1.6 m ² and converted to 112 mg / body / day. That is, for the FTD / TPI combination, the FTD human dose (mg / body / day) is calculated by multiplying the FTD mouse dose (mg / kg / day) by 0.747.
Further, as in the Reference Example, 50 mg / kg / day in mice corresponds to 166 mg / body / day in humans for the dose of regorafenib monohydrate. That is, by multiplying the regorafenib monohydrate mouse dose (mg / kg / day) by 3.32, the regorafenib monohydrate human dose (mg / body / day) is calculated, and FTD and regorafenib • The unit of human dosage of monohydrate can be adjusted to “mg / body / day”. From these calculation results, the number of equivalents of regorafenib relative to 1 equivalent of FTD in humans was described as “regorafenib molar ratio” in the table. In addition, the FTD / TPI combination agent in the table is a dose converted in humans, and the same applies to regorafenib monohydrate.

  Moreover, the result of the daily change of RTV is shown in FIGS. In addition, not only the human colorectal cancer-derived strain (COLO205) but also the human colorectal cancer-derived strain (SW620) was tested in the same manner, and the antitumor effect enhancing action was confirmed.

  Next, tumor growth delaying effects were confirmed (Clin Cancer Res. 2000; 6 (2): 701-8 .; J Radiat Res. 2007; 48 (3): 187-95 .; Invest New Drugs. 2008; 26 (1): 1-5 .; J Radiat Res. 2011; 52 (5): 646-54.). The period from the time when the tumor volume was Day 0 to 1.5 times larger (that is, the RTV was 1.5) was predicted from the single agent administration group to the combined administration group in FIGS. Table 5 summarizes the “number of days when RTV actually reached 1.5” in the single agent administration group. “The number of days when RTV actually reached 1.5” was calculated on the assumption that the RTV first exceeded the measurement date of 1.5 and the RTV on the measurement date immediately before the transition was in accordance with a linear function. . In addition, the FTD / TPI combination agent in the table is a dose converted in humans, and the same applies to regorafenib monohydrate.

  Table 6 summarizes the “expected number of days” when the RTV of the combination administration group reached 1.5 and the “actual number of days” when the RTV reached 1.5. In addition, the FTD / TPI combination agent in the table is a dose converted in humans, and the same applies to regorafenib monohydrate.

In the combined administration group of FTD / TPI combination at 75 mg / kg / day and regorafenib at 10 mg / kg / day, the “actual number of days” when the RTV in each single agent administration group reached 1.5 was 1.8 days And 6.3 days. Therefore, assuming that the effects of the FTD / TPI combination drug and legofenib do not antagonize, in the combined administration group, the total of 8.1 days is “expected when RTV reaches 1.5. Days ". Surprisingly, however, the “actual number of days” when the RTV reached 1.5 was 21.4 days.
Similarly, in the combined administration group of 75 mg / kg / day for FTD / TPI and 50 mg / kg / day for regorafenib, the “expected number of days” was 19.2 days when RTV reached 1.5. However, the “actual number of days” was 26.7 days. In addition, in the combined administration group of FTD / TPI combination at 150 mg / kg / day and regorafenib at 10 mg / kg / day, the “expected number of days” is 8.5 days when RTV reaches 1.5. However, “actual days” was 26.9 days. Furthermore, in the combined administration group of FTD / TPI combination at 150 mg / kg / day and regorafenib at 50 mg / kg / day, the “expected number of days” was 19.6 days for RTV to reach 1.5. However, the “actual number of days” was 29 days or more.
In addition, the body weight change in each group did not become lower than -20% in the period of Day0-29.

From the above, when the FTD / TPI combination drug and regorafenib were used in combination, a remarkable tumor growth delay effect exceeding the expected effect was observed while suppressing the occurrence of side effects within an allowable range.
Moreover, the same effect was confirmed also in the antitumor effect test using colon cancer strain SW620.

Claims (15)

  An antitumor agent comprising a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 and regorafenib.   The antitumor agent according to claim 1, wherein the amount of regorafenib is 0.175 to 1.76 mol per mol of trifluridine.   2. The daily dose on the day of administration of trifluridine of a combination preparation containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is 50 to 100% of the recommended dose when administered alone. Or 2. The antitumor agent according to 2. The daily dose on the day of administration of trifluridine of a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 is 35 to 70 mg / m ² / day. Item antitumor agent.   The antitumor agent according to any one of claims 1 to 4, wherein the daily dose of regorafenib on the day of administration is 20 to 100% of the maximum tolerated dose when administered alone.   The antitumor agent according to any one of claims 1 to 5, wherein the daily dose of regorafenib on the administration day is 32 to 160 mg / body / day.   The antitumor agent according to any one of claims 1 to 6, wherein the target cancer is digestive organ cancer.   The anticancer agent according to any one of claims 1 to 7, wherein the target cancer is colon cancer.   An antitumor effect potentiator comprising a combination agent containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 for enhancing the antitumor effect of regorafenib.   An antitumor effect potentiator comprising regorafenib for enhancing the antitumor effect of a combination preparation containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5.   An antitumor agent comprising a combination drug containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5 for treating a cancer patient to which regorafenib has been administered.   An antitumor agent comprising regorafenib for treating a cancer patient administered with a combination comprising trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5.   An antitumor agent comprising a combination drug containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5, which is used in combination with regorafenib.   An antitumor agent comprising regorafenib, which is used in combination with a compounding agent containing trifluridine and tipiracil hydrochloride at a molar ratio of 1: 0.5.   A kit preparation comprising a combination preparation containing trifluridine and tipiracil hydrochloride in a molar ratio of 1: 0.5 and instructions for use.

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