A medicament for treating or preventing cell proliferative diseases, containing a coumarin derivative

Abstract

To provide a medicament for the treatment or prevention of cell proliferative disorder.SOLUTION: The medicament contains, as an active ingredient, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The medicament is used such that (a) the compound or salt is administered twice weekly for 3 weeks, (b) the administration of the compound or salt is paused for the following 1 week, and (c) subsequently the steps (a) and (b) are repeated at least once.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a medicament for treating or preventing cell proliferative diseases, particularly cancer, containing a coumarin derivative.

Background Art

[0002] A compound represented by the following formula (I) (also referred to as "compound (I)" in this specification) and a pharmaceutically acceptable salt thereof (also simply referred to as "its salt" in this specification) are known to have pharmacological actions such as antitumor activity (see Patent Document 1 or 2).

Chemical Formula

[0003] Regarding the usage and dosage of compound (I) or its salt, it is known that for patients with solid cancers such as non-small cell lung cancer, ovarian cancer, endometrial cancer, colorectal cancer, etc., the potassium salt of compound (I) is administered twice a week at a dose of 4 mg per time. (See Non-Patent Document 1).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0005]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] When the compound (I) or a salt thereof was administered according to the above-described dosing regimen (4 mg once, twice a week), there were cases where administration was continued after an unscheduled drug withdrawal and / or dose reduction, for example, due to exacerbation of a rash.

[0007] The present invention has been made in view of such circumstances, and aims to provide a dosing regimen of the compound (I) or a salt thereof that is safe and can be implemented long-term, and a medicament for treating or preventing a cell proliferative disease (particularly cancer) used based on such a dosing regimen.

Means for Solving the Problems

[0008] The present invention provides a medicament described in the following items A1 to A15. Item A1: A medicament for treating or preventing a cell proliferative disease, comprising, as an active ingredient, a compound represented by formula (I):

Chemical formula

[0009] The medicament of the present invention may consist of the compound (I) or a salt thereof, or may be a pharmaceutical composition further containing other components.

[0010] The present invention also provides a medicament as described in the following items A16 and A17. Item A16: Formula (I):

Chemical formula

[0011] The present invention also provides a method as described in the following Items B1 to B15. Item B1: A method for treating or preventing a cell proliferative disease, (a) Formula (I):

Chemical formula

[0012] The present invention also provides the uses described in the following Items C1 to C15. Item C1: For the manufacture of a medicament for the treatment or prevention of a cell proliferative disease, a compound represented by formula (I):

Chemical formula

[0013] The dosing regimen used in the present invention involves repeating cycles that include a certain rest period, which enables long-term administration of compound (I) or a salt thereof while suppressing side effects and maintaining the medicinal efficacy. Further, it enables treatment or prevention of cell proliferative diseases, particularly cancer, while suppressing the burden on the patient.

Advantages of the Invention

[0014] The present invention provides a safe and long-term applicable dosing regimen for compound (I) or a salt thereof, and a medicament for treating or preventing a cell proliferative disease (particularly cancer) used based on such a dosing regimen.

Brief Description of the Drawings

[0015]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0016] Exemplary embodiments of the present invention will be described below.

[0017] Compound (I) and salts thereof can be produced by the methods described in WO2007 / 091736 or WO2013 / 035754.

[0018] As the active ingredient used in the present invention, a pharmaceutically acceptable salt of compound (I) is preferred. Such salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.; sulfonate salts such as methanesulfonate, benzenesulfonic acid, toluenesulfonate, etc.; carboxylate salts such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, glutarate, etc.; alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, rubidium salt, etc.; alkaline earth metal salts such as magnesium salt, calcium salt, etc.; ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc. Among them, alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, rubidium salt, etc. are preferred, sodium salt and potassium salt are more preferred, and potassium salt is particularly preferred. Specific examples of the potassium salt of compound (I) include, for example, the salt represented by the following formula (Ia).

Chemical formula

[0019] Cell proliferative diseases treated or prevented by the medicament or method of the present invention include cancer, rheumatism and inflammation, preferably cancer.

[0020] Examples of cancers include cancers of the blood and lymph such as leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (e.g., Hodgkin's disease, non-Hodgkin lymphoma, etc.), multiple myeloma, and myelodysplastic syndrome; cancers of the central nervous system such as brain tumors and gliomas; and solid cancers such as head and neck cancers (e.g., pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, gastric cancer, colorectal cancer (e.g., cecal cancer, colon cancer, rectal cancer, etc.), lung cancer (e.g., small cell carcinoma, non-small cell carcinoma, etc.), thyroid cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (e.g., endometrial cancer, cervical cancer, etc.), testicular cancer, renal cell carcinoma, bladder cancer, renal pelvis / ureteral cancer, malignant melanoma, and skin cancer (e.g., basal cell carcinoma, squamous cell carcinoma, extramammary Paget's disease, Merkel cell carcinoma, sweat gland cancer (e.g., apocrine adenocarcinoma or eccrine adenocarcinoma), sebaceous adenocarcinoma, hair follicle epithelioma, etc.). Multiple myeloma is preferred as a cancer of the blood or lymph. As solid cancers, for example, ovarian cancer, breast cancer, uterine cancer, colorectal cancer, and lung cancer are preferred, and non-small cell lung cancer is particularly preferred. As cancers, multiple myeloma and solid cancers are preferred, and multiple myeloma and non-small cell lung cancer are particularly preferred.

[0021] The cancer may or may not have a gene mutation, or it may be unknown whether it has a gene mutation or not, but those having a gene mutation are preferred. Examples of genes in which mutations occur include EGFR, FGFR, ALK, ROS1, PI3K, BRAF, HRAS, KRAS, and NRAS. As cancers, those having a KRAS mutation and / or an NRAS mutation are preferred, and multiple myeloma having a KRAS mutation and an NRAS mutation, as well as solid cancers (particularly non-small cell lung cancer) having a KRAS mutation are particularly preferred. As cancers having a gene mutation, for example, HRAS-mutated apocrine adenocarcinoma is also preferred.

[0022] The subject to which compound (I) or a salt thereof is administered is an animal, preferably a mammal (e.g., mouse, rat, rabbit, dog, monkey (e.g., cynomolgus monkey), and human), and particularly preferably a human. The human may be an adult (18 years old or older) or a child (less than 18 years old). The child is preferably, for example, 6 months old or older after birth.

[0023] As a method of administering to a subject, for example, systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intravesical administration, vaginal administration, intraperitoneal administration, intravesical administration, inhalation administration, etc., and local administration with ointments, gels, creams, etc. can be mentioned, but oral administration is preferred.

[0024] Compound (I) or a salt thereof is usually formulated into a certain preparation (dosage form) and used. Such preparations include, for example, tablets, capsules, granules, powders, fine granules, pills, and aqueous or non-aqueous solutions and suspensions. Solutions and suspensions can be stored by filling them into containers suitable for dividing into individual doses.

[0025] The above various preparations can be produced by mixing compound (I) or a salt thereof with pharmaceutically acceptable additives by a well-known method. Such additives include excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring and odor-correcting agents, bases, dispersants, diluents, surfactants, emulsifiers, etc.

[0026] Examples of excipients include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and calcium hydrogen phosphate.

[0027] Examples of lubricants (coating agents) include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.

[0028] Examples of binders include polyvinylpyrrolidone and macrogol, as well as compounds similar to the above excipients.

[0029] Examples of disintegrants include crosscarmellose sodium, carboxymethyl starch sodium, crosslinked polyvinylpyrrolidone, etc., chemically modified starches and celluloses, as well as compounds similar to the above excipients.

[0030] Examples of stabilizers include paraoxybenzoic acid esters such as methyl paraben and propyl paraben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

[0031] Examples of flavoring and odor-masking agents include, for example, commonly used sweeteners, acidulants, fragrances, and the like.

[0032] Examples of bases include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetyl alcohol; animal oils; lanolinic acid; petrolatum; paraffin; bentonite; glycerin; and glycol oil.

[0033] Examples of dispersants include cellulose derivatives (such as gum arabic, tragacanth, methyl cellulose, etc.), polyesters of stearic acid, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters.

[0034] Examples of solvents or diluents in liquid preparations include phenol, chlorocresol, purified water, and distilled water.

[0035] Examples of surfactants or emulsifiers include polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.

[0036] The preferred content ratio of compound (I) or its salt in the preparation varies depending on the dosage form, but generally it is 0.01 to 100% by weight based on the total weight of the preparation.

[0037] The content of compound (I) or its salt in the preparation can be appropriately set according to the intended dosage. The preferred content is, for example, 0.01 mg to 10 mg, and when the preparation is a capsule, it is, for example, 0.1 mg to 4 mg. A more preferred content is, for example, 0.8 mg.

[0038] In the dosing regimen used in the present invention, compound (I) or a salt thereof is administered as follows. (a) Compound (I) or a salt thereof is administered twice a week for 3 weeks, (b) Administration of compound (I) or a salt thereof is discontinued for the following 1 week, (c) Thereafter, steps (a) and (b) are repeated at least once.

[0039] In the present invention, "administered twice a week" means that compound (I) or a salt thereof is administered twice within a period of one week. The administrations may be carried out twice on the same day, or once a day on different days (which may be consecutive days), but it is preferred to carry them out on different days. It is more preferred that the dosing intervals are as even as possible, i.e., compound (I) or a salt thereof is administered at dosing intervals of 3 to 4 days, for example, on the 1st and 4th days or the 3rd and 6th days of the period. The one-week period may start, for example, on a Monday or on a Wednesday. When the two administrations are carried out on different days, each administration may be carried out at any time, but it is preferred to carry them out at approximately the same time (e.g., after breakfast).

[0040] The dose of compound (I) or a salt thereof per administration is preferably 3.2 mg or 4 mg. 4 mg is preferred when the cancer is multiple myeloma, and 3.2 mg or 4 mg is preferred when the cancer is a solid cancer (especially non-small cell lung cancer).

[0041] The 4-week cycle consisting of steps (a) and (b) is repeated, for example, 2 times (8 weeks) to 60 times (about 4 years and 8 months), and more specifically, for example, 8 times (32 weeks) or 18 times (72 weeks). Even once the number of cycles to be repeated is determined, the number of cycles can be changed based on the judgment of a physician or veterinarian according to the condition of the subject, etc. Also, based on the judgment of a physician or veterinarian according to the condition of the subject, etc., administration can be discontinued during the cycle.

[0042] In one embodiment, before step (a), (1) The compound (I) or a salt thereof is administered twice a week at a dose of 3.2 mg per administration, or (2) (2a) The compound (I) or a salt thereof is administered twice a week at a dose of 4 mg per administration for 3 weeks, (2b) Subsequently, the administration of the compound (I) or a salt thereof is suspended for 1 week, (2c) Thereafter, steps (2a) and (2b) are repeated at least once. Furthermore, optionally, before step (1) or (2), (3) The compound (I) or a salt thereof is administered twice a week at a dose of 4 mg per administration.

[0043] As the cell proliferative disease to be treated or prevented based on the administration regimen of this embodiment, solid cancer is preferred, and non-small cell lung cancer is particularly preferred.

[0044] In step (1), taking 4-week administration as one cycle, the cycle is usually repeated 2 times (8 weeks) to 30 times (about 2 years and 4 months), preferably for example 13 times (52 weeks).

[0045] In step (3), taking 4-week administration as one cycle, the cycle is usually repeated 2 times (8 weeks) to 30 times (about 2 years and 4 months), preferably for example 8 times (32 weeks).

[0046] In steps (1) and (3), even if the number of cycles to be repeated is once determined, the number of cycles can be changed based on the judgment of a physician or veterinarian according to the condition of the subject, etc. Also, according to the condition of the subject, etc., the administration can be stopped during the cycle based on the judgment of a physician or veterinarian.

[0047] Also, in one embodiment, the compound (I) or a salt thereof is administered as follows. (R1) (A) First, the compound (I) or a salt thereof is administered twice a week at a dose of 4 mg per administration, (B1) Then, the compound (I) or a salt thereof is administered twice a week at a dose of 3.2 mg per administration, (C) Thereafter, (Ca) Compound (I) or a salt thereof is administered twice a week at a dose of 3.2 mg per administration for 3 weeks, (Cb) Subsequently, the administration of compound (I) or a salt thereof is suspended for 1 week, (Cc) Thereafter, steps (Ca) and (Cb) are repeated at least once, or (R2) (A) First, compound (I) or a salt thereof is administered twice a week at a dose of 4 mg per administration, (B2) Then, (B2a) Compound (I) or a salt thereof is administered twice a week at a dose of 4 mg per administration for 3 weeks, (B2b) Subsequently, the administration of compound (I) or a salt thereof is suspended for 1 week, (B2c) Thereafter, steps (B2a) and (B2b) are repeated at least once, or (R3) (A) First, compound (I) or a salt thereof is administered twice a week at a dose of 4 mg per administration, (B2) Then, (B2a) Compound (I) or a salt thereof is administered twice a week at a dose of 4 mg per administration for 3 weeks, (B2b) Subsequently, the administration of compound (I) or a salt thereof is suspended for 1 week, (B2c) Thereafter, steps (B2a) and (B2b) are repeated at least once, (C) Thereafter, (Ca) Compound (I) or a salt thereof is administered twice a week at a dose of 3.2 mg per administration for 3 weeks, (Cb) Subsequently, the administration of compound (I) or a salt thereof is suspended for 1 week, (Cc) Thereafter, steps (Ca) and (Cb) are repeated at least once. (R1) to (R3) should be selected according to, for example, the severity or grade of adverse events observed in the subject, in accordance with the dosing guidance shown in Figure 3.

[0048] Among the cell proliferative diseases to be treated or prevented based on the administration regimen of this embodiment, cancer is preferred, and solid cancer is more preferred. Among solid cancers, non-small cell lung cancer is preferred, and non-small cell lung cancer having a KRAS mutation is particularly preferred.

[0049] In step (A), taking a 4-week administration as one cycle, the cycle is usually repeated 2 times (8 weeks) to 30 times (about 2 years and 4 months), preferably repeated 13 times (52 weeks) for example.

[0050] In step (B1), taking a 4-week administration as one cycle, the cycle is usually repeated 2 times (8 weeks) to 30 times (about 2 years and 4 months), preferably repeated 8 times (32 weeks) for example.

[0051] In steps (A), (B1), (B2) and (C), even if the number of cycles to be repeated is once determined, the number of cycles can be changed based on the judgment of a doctor or veterinarian according to the condition of the subject etc. Also, according to the condition of the subject etc., based on the judgment of a doctor or veterinarian, the administration can be stopped during the cycle.

[0052] Compound (I) or a salt thereof can be used alone or in combination with other drugs. When used in combination with other drugs, examples of other drugs include, for example, antiemetics and anticancer drugs, and anticancer drugs are preferred. Examples of anticancer drugs include thalidomide-based anticancer drugs such as thalidomide and lenalidomide, proteasome inhibitors such as bortezomib and ixazomib, and steroid-based anticancer drugs such as dexamethasone and prednisolone.

[0053] When the cancer is, for example, non-small cell lung cancer, it is preferred to use compound (I) or a salt thereof alone.

[0054] When compound (I) or a salt thereof is used in combination with other drugs for the treatment of multiple myeloma, dexamethasone is preferred as the other drug. Dexamethasone is a drug included in the standard treatment of multiple myeloma.

[0055] When the compound (I) or a salt thereof is used in the treatment of multiple myeloma in combination with dexamethasone, dexamethasone is preferably administered once a week, and the dose of dexamethasone per administration is preferably, for example, 20 mg.

[0056] When the compound (I) or a salt thereof is used in combination with dexamethasone, the order and timing of their administrations are not particularly limited, and the compound (I) or a salt thereof can be administered before, simultaneously with, or after the administration of dexamethasone. For example, in step (a), when the compound (I) or a salt thereof and dexamethasone are administered within a one-week period, preferably, for example, the compound (I) or a salt thereof is administered on the 1st and 4th days of the period, dexamethasone is administered on the 2nd day, or the compound (I) or a salt thereof is administered on the 3rd and 6th days of the period, dexamethasone is administered on the 4th day, or the compound (I) or a salt thereof is administered on the 2nd and 5th days of the period, dexamethasone is administered on the 1st day, or the compound (I) or a salt thereof is administered on the 4th and 7th days of the period, dexamethasone is administered on the 2nd day. The one-week period may start, for example, on a Monday or on a Wednesday. Each administration can be performed at any time, but it is preferably performed at approximately the same time (for example, after dinner).

[0057] The period during which the compound (I) or a salt thereof is used in combination with dexamethasone can be determined based on the judgment of a physician or veterinarian according to the condition of the subject, etc. Also, based on the judgment of a physician or veterinarian according to the condition of the subject, etc., the administration of one or both of the compound (I) or a salt thereof and dexamethasone can be discontinued.

[0058] Formula (I):

Chemical formula

[0059] Preferably, for example, the packaged medicament is the medicament described in any of the foregoing items A1 to A15, and the above instructions are instructions for using the medicament such that the compound (I) or a salt thereof is administered according to a predetermined dosing regimen corresponding to the medicament. The "predetermined dosing regimen corresponding to the medicament" refers to, for example, in the case of the medicament described in item A9, any of the dosing regimens (R1) to (R3) described in item A9.

[0060] The packaging can be carried out, for example, using a packaging material (such as a cardboard box). Further, the package may further contain, for example, a label, a pamphlet, or a pharmaceutically acceptable cushioning material.

[0061] The container in (i) above is, for example, a bottle or a PTP sheet and can be manufactured from materials such as glass, plastic, aluminum, etc. Preferably, the container has, for example, characters indicating that the medicament is for the treatment or prevention of a predetermined disease printed thereon, or a label with such characters attached thereto.

[0062] The container in (i) above may or may not contain the medicament, but preferably contains it.

[0063] The instructions in (ii) above contain the information necessary for using the medicament based on a predetermined dosing regimen. Further, the instructions may further contain, for example, information regarding the efficacy and effects of the medicament.

[0064] The instruction in (ii) above may exist, for example, in the form of a document. Examples of the document containing the above instruction include pharmaceutical package inserts. The document containing the above instruction may be printed on a label or on a packaging material (e.g., a cardboard box). Further, the above instruction may be in a form printed on paper or plastic, or may be in a form electronically stored on a storage medium such as a CD-ROM or a flash memory.

Example

[0065] Hereinafter, exemplary embodiments of the present invention will be described based on examples.

[0066] Example 1: The potassium salt of compound (I) (also referred to as "IMP" in this example) was orally administered to patients with KRAS - mutated and NRAS - mutated IgGλ - type multiple myeloma at a dose of 4 mg twice a week (Tuesday and Friday) in a 4 - week cycle consisting of 3 - week administration followed by 1 - week rest (3 - week administration / 1 - week rest). IMP was not used in combination with dexamethasone.

[0067] The administration to the patient started on November 29, 2016. As adverse events, intermittent grade 1 diarrhea that may be related to IMP was continuously observed from the beginning. Also, grade 2 rash related to IMP occurred. The patient's course was extremely good, and a partial response was continuously obtained according to the criteria of the International Myeloma Working Group (IMWG) (FLCλ: 325 mg / L (before the start of administration), 161 mg / L (after 1 cycle), 264 mg / L (after 2 cycles)).

[0068] The patient had previously received the following treatments. · Autologous hematopoietic stem cell transplantation · Proteasome inhibitor · Immunomodulatory agent · Cyclophosphamide + dexamethasone + thalidomide · Melphalan · Lenalidomide · Cyclophosphamide + Bortezomib · Dexamethasone · Vertebral T3-T12, divided into 5 parts (radiation therapy)

[0069] Example 2: The potassium salt of compound (I) (also referred to as "IMP" in this example) was orally administered to patients with KRAS mutant non-small cell lung cancer.

[0070] The treatment of the patient started on September 1, 2014. IMP was initially administered at a dose of 4 mg twice a week (4 mg administered for 4 weeks) in a 4-week cycle consisting of 4 weeks of administration. In cycle 9, due to grade 3 punctate papules, the dose was reduced to 3.2 mg twice a week (3.2 mg administered for 4 weeks) in a 4-week cycle. In cycle 22, due to grade 3 facial rash, the dose was reduced again to 3.2 mg twice a week (3.2 mg administered for 3 weeks / 1 week rest) on a 3-week administration / 1-week rest schedule. These dose reductions reduced the rash to a slight grade 1 and were well controlled even at the time of cycle 40. Regarding the treatment effect, a partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 was obtained in solid tumors and was maintained even at the time of cycle 40.

[0071] The change in the tumor size of the patient in the first 40 cycles (about 3 years) is shown in Figure 1. The horizontal axis (X-axis) represents the treatment cycle number, and the vertical axis (Y-axis) represents the change rate of the tumor size from the baseline. The tumor size was measured using a CT scan. The highest effects obtained in the administration schedules of 4 mg administered for 4 weeks, 3.2 mg administered for 4 weeks, and 3.2 mg administered for 3 weeks / 1 week rest were, respectively, a 58% reduction, a 61% reduction, and a 68% reduction in the target lesions according to RECIST 1.1. As of April 18, 2018 (cycle 48) (corresponding to the 3.6th year), the treatment of the patient with IMP is ongoing, and no rash of grade 2 or higher has been observed.

[0072] The patient had previously received the following treatments. · Carboplatin / pemetrexed · Pemetrexed · Docetaxel · Pleurodesis (October 2012) (surgery)

[0073] Example 3: The potassium salt of compound (I) (also referred to as "IMP" in this example) was orally administered to a patient with HRAS - mutant apocrine adenocarcinoma of the scalp. Apocrine adenocarcinoma of the scalp is a skin sweat gland cancer. The patient was diagnosed in 2014 and had received radiotherapy and surgery twice before treatment with IMP.

[0074] The treatment of the patient with IMP was started on January 8, 2018, at a dose of 4 mg twice a week in 4 - week cycles. On the third week of cycle 1, grade 2 acneiform rash and grade 2 diarrhea occurred, so the dose was reduced to 4 mg twice a week on a 3 - week administration / 1 - week rest schedule. The grade of the acneiform rash was 1 on day 1 of cycle 2, 3 on day 22 of cycle 2, and 2 on day 1 of cycle 3. Therefore, the dose on day 1 of cycle 3 was not reduced to 3.2 mg but remained at 4 mg. The change in the patient's tumor size measured by CT scan showed a partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (54% reduction on day 22 of cycle 2 and 58% reduction on day 15 of cycle 4).

[0075] The dosing regimen used in this example, along with an overview of its observed efficacy and safety, is shown in Figure 2. The dosing guidance used in this example is shown in Figure 3. As of April 30, 2018 (day 1 of cycle 5), the treatment of the patient with IMP is ongoing, and no grade 2 or higher rash and diarrhea have been observed.

Claims

1. A medicament for the treatment or prevention of cancer, comprising, as an active ingredient, a compound represented by formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein (a) the compound or salt is administered twice a week for 3 weeks, (b) administration of the compound or salt is suspended for the following 1 week, (c) thereafter, steps (a) and (b) are repeated at least once, and is used in such a manner that the cancer is selected from the group consisting of non-small cell lung cancer, ovarian cancer, malignant melanoma, pancreatic cancer, colorectal cancer, brain tumor, glioma, gastric cancer, thyroid cancer, breast cancer, endometrial cancer, and cervical cancer, said medicament.

2. The medicament according to claim 1, comprising, as an active ingredient, a potassium salt of the compound represented by formula (I).

3. The medicament according to claim 1 or 2, wherein the dose per administration in step (a) is 3.2 mg.

4. The medicament according to claim 1 or 2, wherein the dose per administration in step (a) is 4 mg.

5. The medicament according to any one of claims 1 to 4, wherein, before step (a), the compound or salt is used such that it is administered twice a week at a dose of 3.2 mg per administration for at least 4 weeks.

6. The medicament according to any one of claims 1 to 4, wherein, before step (a), the compound or salt is used such that it is administered twice a week at a dose of 4 mg per administration for at least 4 weeks.

7. The medicament according to any one of claims 1 to 6, wherein the administration of the compound or salt is oral administration.

8. The medicament according to any one of claims 1 to 7, wherein the cancer is non-small cell lung cancer.

9. The medicament according to any one of claims 1 to 7, wherein the cancer is ovarian cancer.

10. The medicament according to any one of claims 1 to 7, wherein the cancer is pancreatic cancer.

11. The medicament according to any one of claims 1 to 7, wherein the cancer is colorectal cancer.

12. The medicament according to any one of claims 1 to 7, wherein the cancer is malignant melanoma.

13. The medicament according to any one of claims 1 to 7, wherein the cancer is a brain tumor.

14. The medicament according to any one of claims 1 to 7, wherein the cancer is glioma.

15. The medicament according to any one of claims 1 to 7, wherein the cancer is gastric cancer.

16. The medicament according to any one of claims 1 to 7, wherein the cancer is thyroid cancer.

17. The medicament according to any one of claims 1 to 7, wherein the cancer is breast cancer. The pharmaceutical according to any one of claims 1 to 7, wherein the cancer is endometrial cancer. The pharmaceutical according to any one of claims 1 to 7, wherein the cancer is cervical cancer.

20. The pharmaceutical according to any one of claims 1 to 19, which is used such that the compound or salt is administered in combination with an anticancer agent.

Images