Pharmaceutical drug containing coumarin derivative for treating or preventing cell proliferative disease

Abstract

To provide a pharmaceutical drug for treating or preventing a cell proliferative disease, particularly cancer, which can be used safely over a long period based on a specific administration regimen.SOLUTION: The invention provides a pharmaceutical drug for treating or preventing a cell proliferative disease, comprising as an active ingredient a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, where (a) the compound or the salt is administered twice a week for three weeks, (b) administration of the compound or the salt is suspended for the following one week, and (c) thereafter, steps (a) and (b) are repeated at least once.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical agent for treating or preventing cell proliferative diseases, particularly cancer, which contains a coumarin derivative. [Background technology]

[0002] The 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 "the salt" in this specification) are known to have pharmacological effects such as antitumor activity (see Patent Documents 1 and 2). [ka]

[0003] Regarding the dosage and administration of compound (I) or a salt thereof, it is known that the potassium salt of compound (I) is administered at a dose of 4 mg twice a week to patients with solid cancers such as non-small cell lung cancer, ovarian cancer, endometrial cancer, and colorectal cancer (see Non-Patent Document 1). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO2007 / 091736 [Patent Document 2] WO2009 / 014100 [Non-patent literature]

[0005] [Non-Patent Document 1] Journal of Clinical Oncology 34, no.15_suppl(May 2016)2582-2582 Summary of the Invention [Problem to be solved by the invention]

[0006] When Compound (I) or a salt thereof was administered according to the above-mentioned administration regimen (4 mg once, twice a week), there were cases where administration was continued after unscheduled suspension and / or reduction due to, for example, worsening of the rash.

[0007] The present invention has been made in view of the above circumstances, and aims to provide a safe and long-term practicable administration regimen of compound (I) or a salt thereof, and a pharmaceutical for treating or preventing cell proliferative diseases (particularly cancer) to be used based on such an administration regimen. [Means for solving the problem]

[0008] The present invention provides pharmaceuticals described in the following items A1 to A15. Item A1: A pharmaceutical for treating or preventing a cell proliferative disease, comprising a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof as an active ingredient, (a) the compound or salt is administered twice weekly for three weeks; (b) the administration of the compound or salt is discontinued for one week; (c) Thereafter, steps (a) and (b) are repeated at least once. The medicine used as follows. Item A2: The pharmaceutical composition according to item A1, comprising the potassium salt of the compound represented by formula (I) as an active ingredient. Item A3: The pharmaceutical agent according to item A1 or A2, wherein the cell proliferative disorder is cancer. Item A4: The pharmaceutical agent according to any one of items A1 to A3, wherein the cell proliferative disease is a cancer with a KRAS mutation. Item A5: The pharmaceutical agent according to any one of items A1 to A4, wherein the cell proliferative disease is a solid cancer. Item A6: The pharmaceutical agent according to any one of items A1 to A5, wherein the single dose in step (a) is 3.2 mg. Item A7: Before step (a), (1) the compound or salt is administered at a dose of 3.2 mg twice a week; or (2) (2a) the compound or salt is administered at a dose of 4 mg twice a week for 3 weeks; (2b) the administration of the compound or salt is discontinued for one week; (2c) After that, steps (2a) and (2b) are repeated at least once. The pharmaceutical composition according to item A6, which is used as follows: Item A8: The pharmaceutical agent according to item A7, wherein, before step (1) or (2), the compound or salt is administered at a dose of 4 mg twice a week. Item A9: The pharmaceutical composition according to any one of items A1 to A5, (R1) (A) first, the compound or salt is administered twice weekly at a dose of 4 mg; (B1) then administering the compound or salt twice a week at a dose of 3.2 mg; (C) After that, (Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for 3 weeks; (Cb) the administration of the compound or salt is discontinued for one week; After (Cc), steps (Ca) and (Cb) are repeated at least once. It is used as follows: (R2) (A) first, the compound or salt is administered twice weekly at a dose of 4 mg; (B2) Next, (B2a) the compound or salt is administered at a dose of 4 mg twice a week for 3 weeks; (B2b) the administration of the compound or salt is discontinued for one week; After (B2c), steps (B2a) and (B2b) are repeated at least once. It is used as follows: (R3) (A) first, the compound or salt is administered twice weekly at a dose of 4 mg; (B2) Next, (B2a) the compound or salt is administered at a dose of 4 mg twice a week for 3 weeks; (B2b) the administration of the compound or salt is discontinued for one week; (B2c) After that, steps (B2a) and (B2b) are repeated at least once, (C) After that, (Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for 3 weeks; (Cb) the administration of the compound or salt is discontinued for one week; After (Cc), steps (Ca) and (Cb) are repeated at least once. The medicine used as follows. Item A10: The pharmaceutical agent according to any one of items A1 to A4, wherein the cell proliferative disease is multiple myeloma. Item A11: The pharmaceutical agent according to Item A10, wherein the dose per administration in step (a) is 4 mg. Item A12: The pharmaceutical agent according to item A10 or A11, wherein the cell proliferative disorder is a cancer with an NRAS mutation. Item A13: The pharmaceutical agent according to any one of items A10 to A12, which is used in combination with dexamethasone, wherein the compound or salt is administered before, simultaneously with, or after administration of dexamethasone. Item A14: The medicament according to item A13, wherein dexamethasone is administered at a dose of 20 mg once a week. Item A15: The medicament according to any one of items A1 to A14, wherein the compound or salt is administered orally.

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

[0010] The present invention also provides the pharmaceuticals described in items A16 and A17 below. Item A16: Formula (I): [ka] or a pharmaceutically acceptable salt thereof, (i) a container for containing the medicament; and (ii) (a) the compound or salt is administered twice weekly for three weeks; (b) the administration of the compound or salt is discontinued for one week; (c) Thereafter, steps (a) and (b) are repeated at least once. Instructions for using said medicament The pharmaceutical packaged together with Item A17: The medicine is a medicine according to any one of items A1 to A15, the instructions are for using the medicament such that the compound or salt is administered according to a predetermined dosing regimen corresponding to the medicament; A medicament according to item A16.

[0011] The present invention also provides the methods described in the following items B1 to B15. Item B1: 1. A method for treating or preventing a cell proliferative disorder, comprising: (a) Formula (I): [ka] or a pharmaceutically acceptable salt thereof is administered twice a week for 3 weeks, (b) then withdrawing administration of the compound or salt for one week; (c) Thereafter, steps (a) and (b) are repeated at least once. The method comprising: Item B2: The method according to item B1, wherein the potassium salt of the compound of formula (I) is administered. Item B3: The method according to item B1 or B2, wherein the cell proliferative disorder is cancer. Item B4: The method according to any one of items B1 to B3, wherein the cell proliferative disease is a cancer with a KRAS mutation. Item B5: The method according to any one of items B1 to B4, wherein the cell proliferative disease is a solid cancer. Item B6: The method according to any one of items B1 to B5, wherein the single dose in step (a) is 3.2 mg. Item B7: Before step (a), (1) administering the compound or salt at a dose of 3.2 mg twice a week; or (2) (2a) administering the compound or salt at a dose of 4 mg twice a week for 3 weeks; (2b) then withdrawing administration of the compound or salt for one week; (2c) After that, repeat steps (2a) and (2b) at least once. The method according to item B6, comprising: Item B8: The method according to item B7, comprising administering the compound or salt at a dose of 4 mg twice a week before step (1) or (2). Item B9: The method according to any one of items B1 to B5, (R1) (A) first administering the compound or salt at a dose of 4 mg twice a week; (B1) then administering the compound or salt twice a week at a dose of 3.2 mg; (C) After that, (Ca) administering the compound or salt at a dose of 3.2 mg twice a week for 3 weeks; (Cb) then withdrawing administration of the compound or salt for one week; After (Cc), repeat steps (Ca) and (Cb) at least once. or (R2) (A) first administering the compound or salt at a dose of 4 mg twice a week; (B2) Next, (B2a) administering the compound or salt at a dose of 4 mg twice a week for 3 weeks; (B2b) suspending administration of the compound or salt for one week; (B2c) After that, steps (B2a) and (B2b) are repeated at least once. or (R3) (A) first administering the compound or salt at a dose of 4 mg twice a week; (B2) Next, (B2a) administering the compound or salt at a dose of 4 mg twice a week for 3 weeks; (B2b) suspending administration of the compound or salt for one week; (B2c) After that, steps (B2a) and (B2b) are repeated at least once, (C) After that, (Ca) administering the compound or salt at a dose of 3.2 mg twice a week for 3 weeks; (Cb) then withdrawing administration of the compound or salt for one week; After (Cc), repeat steps (Ca) and (Cb) at least once. The method comprising: Item B10: The method according to any one of items B1 to B4, wherein the cell proliferative disease is multiple myeloma. Item B11: The method according to item B10, wherein the dose per administration in step (a) is 4 mg. Item B12: The method according to item B10 or B11, wherein the cell proliferative disorder is a cancer with an NRAS mutation. Item B13: The method according to any one of items B10 to B12, wherein the compound or salt is used in combination with dexamethasone, the method comprising administering the compound or salt before, simultaneously with, or after administration of dexamethasone. Item B14: The method according to item B13, wherein dexamethasone is administered at a dose of 20 mg once a week. Item B15: The method according to any one of items B1 to B14, wherein the compound or salt is administered orally.

[0012] The present invention also provides the uses described in the following items C1 to C15. Item C1: A compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, The pharmaceutical (a) the compound or salt is administered twice weekly for three weeks; (b) the administration of the compound or salt is discontinued for one week; (c) Thereafter, steps (a) and (b) are repeated at least once. The above-mentioned use is used as follows. Item C2: The use according to item C1, which is the use of the potassium salt of the compound of formula (I). Item C3: The use according to paragraph C1 or C2, wherein the cell proliferative disorder is cancer. Item C4: The use according to any one of items C1 to C3, wherein the cell proliferative disease is a cancer with a KRAS mutation. Item C5: The use according to any one of items C1 to C4, wherein the cell proliferative disorder is a solid cancer. Item C6: The use according to any one of items C1 to C5, wherein the single dose in step (a) is 3.2 mg. Item C7: The medicament, prior to step (a), (1) the compound or salt is administered at a dose of 3.2 mg twice a week; or (2) (2a) the compound or salt is administered at a dose of 4 mg twice a week for 3 weeks; (2b) the administration of the compound or salt is discontinued for one week; (2c) After that, steps (2a) and (2b) are repeated at least once. The use according to item C6, Item C8: The use according to item C7, wherein the medicament is used such that, before step (1) or (2), the compound or salt is administered at a dose of 4 mg twice a week. Item C9: The use according to any one of items C1 to C5, (R1) The medicine is (A) first, the compound or salt is administered twice weekly at a dose of 4 mg; (B1) then administering the compound or salt twice a week at a dose of 3.2 mg; (C) After that, (Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for 3 weeks; (Cb) the administration of the compound or salt is discontinued for one week; After (Cc), steps (Ca) and (Cb) are repeated at least once. It is used as follows: (R2) The medicine is (A) first, the compound or salt is administered twice weekly at a dose of 4 mg; (B2) Next, (B2a) the compound or salt is administered at a dose of 4 mg twice a week for 3 weeks; (B2b) the administration of the compound or salt is discontinued for one week; After (B2c), steps (B2a) and (B2b) are repeated at least once. It is used as follows: (R3) The medicine is (A) first, the compound or salt is administered twice weekly at a dose of 4 mg; (B2) Next, (B2a) the compound or salt is administered at a dose of 4 mg twice a week for 3 weeks; (B2b) the administration of the compound or salt is discontinued for one week; (B2c) After that, steps (B2a) and (B2b) are repeated at least once, (C) After that, (Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for 3 weeks; (Cb) the administration of the compound or salt is discontinued for one week; After (Cc), steps (Ca) and (Cb) are repeated at least once. The above-mentioned use is used as follows. Item C10: The use according to any one of items C1 to C4, wherein the cell proliferative disorder is multiple myeloma. Item C11: The use according to item C10, wherein the dose per administration in step (a) is 4 mg. Item C12: The use according to item C10 or C11, wherein the cell proliferative disorder is a cancer with an NRAS mutation. Item C13: The use according to any one of items C10 to C12, wherein the medicament is used in combination with dexamethasone, wherein the compound or salt is administered before, simultaneously with, or after administration of dexamethasone. Item C14: The use described in item C13, wherein dexamethasone is administered at a dose of 20 mg once a week. Item C15: The use according to any one of items C1 to C14, wherein the administration of the compound or salt is oral administration.

[0013] The administration regimen used in the present invention involves repeating a cycle including a certain rest period, which enables long-term administration of Compound (I) or a salt thereof while suppressing side effects and maintaining efficacy, and also enables treatment or prevention of cell proliferative disorders, particularly cancer, while minimizing the burden on patients. [Effects of the Invention]

[0014] The present invention provides a safe and long-term practicable administration regimen of compound (I) or a salt thereof, and a pharmaceutical for treating or preventing cell proliferative diseases (particularly cancer) that is used based on such an administration regimen. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 is a graph showing the progression of tumor size over time in patients with KRAS-mutated non-small cell lung cancer treated with the pharmaceutical agent of the present invention. The horizontal axis (X axis) represents the treatment cycle number, and the vertical axis (Y axis) represents the percentage change in tumor size from baseline. Tumor size was measured using CT scans. [Figure 2] Figure 2 provides a summary of the dosing regimens used in patients with HRAS-mutated apocrine adenocarcinoma and the observed efficacy and safety of these regimens. [Figure 3] FIG. 3 shows an example of the administration guidance for the medicine of the present invention. DETAILED DESCRIPTION OF THE INVENTION

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

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

[0018] The active ingredient used in the present invention is preferably a pharmaceutically acceptable salt of Compound (I). Examples of such salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate; sulfonates such as methanesulfonate, benzenesulfonate, and toluenesulfonate; carboxylates such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, and glutarate; alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, and rubidium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. Among these, 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 potassium salts of compound (I) include salts represented by the following formula (Ia): [ka]

[0019] Cell proliferative diseases that can be treated or prevented by the medicament or method of the present invention include cancer, rheumatism, and inflammation, with cancer being preferred.

[0020] Examples of cancer include leukemia (acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, etc.), malignant lymphoma (Hodgkin's disease, non-Hodgkin's lymphoma, etc.), multiple myeloma, and myelodysplastic syndromes and other cancers of the blood and lymphatic system, brain tumors and gliomas and other cancers of the central nervous system, as well as head and neck cancers (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, stomach cancer, and colorectal cancer (appendicitis, colon cancer, rectal cancer). Examples of cancers that can be treated include solid cancers such as ovarian cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (endometrial cancer, cervical cancer, etc.), testicular cancer, renal cell carcinoma, bladder cancer, renal pelvis / ureter cancer, malignant melanoma, and skin cancer (basal cell carcinoma, squamous cell carcinoma, extramammary Paget's disease, Merkel cell carcinoma, sweat gland carcinoma (e.g., apocrine gland carcinoma or eccrine gland carcinoma), sebaceous gland carcinoma, trichoepithelioma, etc.). As a cancer of the blood or lymph, multiple myeloma is preferred. As a solid cancer, for example, ovarian cancer, breast cancer, uterine cancer, colon cancer, and lung cancer are preferred, with non-small cell lung cancer being particularly preferred. As a cancer, multiple myeloma and solid cancers are preferred, with multiple myeloma and non-small cell lung cancer being particularly preferred.

[0021] Cancers may or may not have a genetic mutation, or it may be unclear whether they have a genetic mutation, but those with a genetic mutation are preferred. Examples of genes that may be mutated include EGFR, FGFR, ALK, ROS1, PI3K, BRAF, HRAS, KRAS, and NRAS. Cancers with a KRAS mutation and / or an NRAS mutation are preferred, with multiple myeloma with a KRAS mutation and NRAS mutation and solid cancers (particularly non-small cell lung cancer) with a KRAS mutation being particularly preferred. Cancers with a genetic mutation, such as HRAS-mutated apocrine adenocarcinoma, are 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 of age or older) or a child (under 18 years of age). The child is preferably, for example, 6 months of age or older.

[0023] Methods of administration to a subject include, for example, systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intracisternal administration, intravaginal administration, intraperitoneal administration, intravesical administration, and inhalation administration, and local administration using ointments, gels, creams, etc., with oral administration being preferred.

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

[0025] The above-mentioned various formulations can be produced by well-known methods by mixing Compound (I) or a salt thereof with pharmaceutically acceptable additives, such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring 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] Lubricants (coating agents) include, for example, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, shellac, talc, carnauba wax, and paraffin.

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

[0029] Examples of disintegrants include chemically modified starches and celluloses such as croscarmellose sodium, carboxymethyl starch sodium, cross-linked polyvinylpyrrolidone, and the same compounds as the above-mentioned excipients.

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

[0031] Examples of flavoring agents include commonly used sweeteners, acidulants, fragrances, etc.

[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 cetanol; animal oils; lanolin; petrolatum; paraffin; bentonite; glycerin; and glycolic oil.

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

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

[0035] Surfactants or emulsifiers include, for example, polysorbate 80, polyoxyl 40 stearate, and lauromacrogol.

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

[0037] The content of Compound (I) or a salt thereof in the preparation can be appropriately determined depending on the intended dose. A preferred content is, for example, 0.01 mg to 10 mg, and when the preparation is a capsule, 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 three weeks; (b) the administration of Compound (I) or a salt thereof is discontinued for one week; (c) Thereafter, steps (a) and (b) are repeated at least once.

[0039] In the present invention, administration "twice a week" means that Compound (I) or a salt thereof is administered twice within a one-week period. The administration may be performed twice on the same day, or once a day on different days (which may be consecutive days), preferably on different days. It is more preferable to administer Compound (I) or a salt thereof at intervals of 3 to 4 days, for example, on days 1 and 4 or 3 and 6 of the period, so that the administration intervals are as even as possible. The one-week period may start, for example, on Monday or Wednesday. When the two administrations are performed on different days, each administration may be performed at any time, preferably 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. When the cancer is multiple myeloma, 4 mg is preferred, and when the cancer is a solid cancer (particularly non-small cell lung cancer), 3.2 mg or 4 mg is preferred.

[0041] A 4-week cycle consisting of steps (a) and (b) is repeated, for example, 2 times (8 weeks) to 60 times (approximately 4 years and 8 months), more specifically, for example, 8 times (32 weeks) or 18 times (72 weeks). 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 depending on the condition of the subject, etc. Furthermore, administration can also be discontinued midway through a cycle based on the judgment of a physician or veterinarian depending on the condition of the subject, etc.

[0042] In one embodiment, before step (a), (1) Compound (I) or a salt thereof is administered twice a week at a dose of 3.2 mg, or (2) (2a) Compound (I) or a salt thereof is administered at a dose of 4 mg twice a week for 3 weeks; (2b) the administration of compound (I) or a salt thereof is discontinued for one week; (2c) After that, steps (2a) and (2b) are repeated at least once. Additionally, optionally, before step (1) or (2), (3) Compound (I) or a salt thereof is administered twice a week at a dose of 4 mg.

[0043] The cell proliferative disorder to be treated or prevented based on the administration regimen of this embodiment is preferably a solid tumor, and particularly preferably non-small cell lung cancer.

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

[0045] In step (3), one cycle of administration lasts for four weeks, and the cycle is usually repeated two times (eight weeks) to 30 times (approximately two years and four months), preferably eight times (32 weeks), for example.

[0046] In steps (1) and (3), even if the number of cycles to be repeated is once determined, the number of cycles may be changed based on the judgment of a physician or veterinarian depending on the condition of the subject, etc. Furthermore, administration may also be discontinued midway through a cycle based on the judgment of a physician or veterinarian depending on the condition of the subject, etc.

[0047] In one embodiment, Compound (I) or a salt thereof is administered as follows: (R1) (A) First, compound (I) or a salt thereof is administered at a dose of 4 mg twice a week; (B1) Compound (I) or a salt thereof is then administered twice a week at a dose of 3.2 mg; (C) After that, (Ca) Compound (I) or a salt thereof is administered at a dose of 3.2 mg twice a week for 3 weeks; (Cb) the administration of compound (I) or a salt thereof is suspended for one week; After (Cc), steps (Ca) and (Cb) are repeated at least once, or (R2) (A) First, compound (I) or a salt thereof is administered at a dose of 4 mg twice a week; (B2) Next, (B2a) Compound (I) or a salt thereof is administered at a dose of 4 mg twice a week for 3 weeks; (B2b) the administration of compound (I) or a salt thereof is suspended for one week; After (B2c), steps (B2a) and (B2b) are repeated at least once, or (R3) (A) First, compound (I) or a salt thereof is administered at a dose of 4 mg twice a week; (B2) Next, (B2a) Compound (I) or a salt thereof is administered at a dose of 4 mg twice a week for 3 weeks; (B2b) the administration of compound (I) or a salt thereof is suspended for one week; (B2c) After that, steps (B2a) and (B2b) are repeated at least once, (C) After that, (Ca) Compound (I) or a salt thereof is administered at a dose of 3.2 mg twice a week for 3 weeks; (Cb) the administration of compound (I) or a salt thereof is suspended for one week; After (Cc), steps (Ca) and (Cb) are repeated at least once. Which of (R1) to (R3) should be selected can be determined according to the severity or grade of the adverse event observed in the subject, for example, according to the administration guidance shown in FIG. 3.

[0048] The cell proliferative disease to be treated or prevented based on the administration regimen of this embodiment is preferably cancer, more preferably solid cancer, and among solid cancers, non-small cell lung cancer is preferred, and KRAS-mutated non-small cell lung cancer is particularly preferred.

[0049] In step (A), one cycle consists of 4 weeks of administration, and the cycle is usually repeated 2 times (8 weeks) to 30 times (approximately 2 years and 4 months), preferably 13 times (52 weeks), for example.

[0050] In step (B1), one cycle of administration lasts for four weeks, and the cycle is usually repeated 2 times (8 weeks) to 30 times (approximately 2 years and 4 months), preferably 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 may be changed based on the judgment of a physician or veterinarian depending on the condition of the subject, etc. Furthermore, administration may also be discontinued midway through a cycle based on the judgment of a physician or veterinarian depending on the condition of the subject, etc.

[0052] Compound (I) or a salt thereof can be used alone or in combination with other drugs. When used in combination with other drugs, the 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, proteosome 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 preferable to use Compound (I) or a salt thereof alone.

[0054] When compound (I) or a salt thereof is used in combination with another drug for the treatment of multiple myeloma, the other drug is preferably, for example, dexamethasone, which is included in the standard treatment for multiple myeloma.

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

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

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

[0058] Formula (I): [ka] or a pharmaceutically acceptable salt thereof as an active ingredient, (i) a container for containing the medicine; and (ii) (a) Compound (I) or a salt thereof is administered twice a week for three weeks; (b) the administration of Compound (I) or a salt thereof is discontinued for one week; (c) Thereafter, steps (a) and (b) are repeated at least once. Instructions for using the medicine It may be packaged together with

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

[0060] Packaging can be performed using, for example, a wrapping material (e.g., a paper box), and the package can further include, for example, a label, a pamphlet, or a pharmaceutically acceptable cushioning material.

[0061] The container (i) above is, for example, a bottle or a PTP sheet, and can be made of a material such as glass, plastic, aluminum, etc. Preferably, the container has printed thereon, or has attached thereto, for example, characters indicating that the medicine is for the treatment or prevention of a specific disease.

[0062] The container (i) above may or may not contain the medicine, but it is preferable that the medicine is contained therein.

[0063] The instructions (ii) above include information necessary for using the drug according to a predetermined dosing regimen, and may further include, for example, information regarding the efficacy and effectiveness of the drug.

[0064] The instructions (ii) above may be in the form of a document. An example of a document containing the instructions is a pharmaceutical package insert. The instructions may be printed on a label or on a packaging material (e.g., a paper box). The instructions may also be printed on paper or plastic, or electronically stored on a storage medium such as a CD-ROM or 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 at a dose of 4 mg twice a week (Tuesdays and Fridays) to patients with KRAS-mutated and NRAS-mutated IgG λ-type multiple myeloma in a 4-week cycle consisting of 3 weeks on followed by 1 week off (3 weeks on / 1 week off). IMP was not administered concomitantly with dexamethasone.

[0067] The patient began treatment on November 29, 2016. Adverse events included intermittent grade 1 diarrhea, possibly related to IMP, which persisted from the beginning. A grade 2 rash, also related to IMP, also occurred. The patient's progress was excellent, with a continuous partial response according to the International Myeloma Working Group (IMWG) criteria (FLCλ: 325 mg / L (baseline), 161 mg / L (after cycle 1), and 264 mg / L (after cycle 2)).

[0068] The patient had previously received the following treatments: ·Autologous hematopoietic stem cell transplantation Proteosome inhibitors Immunomodulators Cyclophosphamide + dexamethasone + thalidomide Melphalan Lenalidomide Cyclophosphamide + Bortezomib Dexamethasone ·Spine T3-T12, 5 divisions (radiotherapy)

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

[0070] The patient's treatment began on September 1, 2014. IMP was initially administered at a dose of 4 mg twice weekly in 4-week cycles (4 mg 4 weeks on). During cycle 9, the dose was reduced to 3.2 mg twice weekly in 4-week cycles (3.2 mg 4 weeks on). During cycle 22, the dose was reduced again to 3.2 mg twice weekly on a 3-week on / 1-week off schedule (3.2 mg 3 weeks on / 1 week off) due to grade 3 facial rash. These dose reductions reduced the rash to only grade 1, and it remained well controlled as of cycle 40. Regarding treatment efficacy, a partial response (PR) was achieved by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, which was maintained as of cycle 40.

[0071] Figure 1 shows the change in tumor size over the first 40 cycles (approximately 3 years). The horizontal axis (X axis) represents the treatment cycle number, and the vertical axis (Y axis) represents the percentage change in tumor size from baseline. Tumor size was measured using CT scans. The highest responses achieved with the 4 mg 4-week, 3.2 mg 4-week, and 3.2 mg 3-week on / 1-week off dosing schedules were 58%, 61%, and 68% reductions in target lesions according to RECIST 1.1, respectively. As of April 18, 2018 (Cycle 48) (corresponding to 3.6 years), the patient's treatment with IMP is ongoing, and no rashes of grade 2 or higher have 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-mutated apocrine gland carcinoma of the scalp. Apocrine gland carcinoma of the scalp is a carcinoma of the sweat glands of the skin. The patient was diagnosed in 2014 and had undergone radiation therapy and two surgeries prior to treatment with IMP.

[0074] The patient's treatment with IMP began on January 8, 2018, at a dose of 4 mg twice weekly in 4-week cycles. During week 3 of cycle 1, a grade 2 acneiform rash and grade 2 diarrhea occurred, leading to a dose reduction to 4 mg twice weekly on a 3-week on / 1-week off schedule. The acneiform rash was graded 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 maintained at 4 mg rather than reduced to 3.2 mg. The patient's tumor size, measured by CT scan, demonstrated a partial response (PR) per 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 and its observed efficacy and safety are summarized in Figure 2. The dosing guidance used in this example is provided in Figure 3. As of April 30, 2018 (Day 1 of Cycle 5), patient treatment with IMP is ongoing, with no observed Grade 2 or higher rash or diarrhea.

Claims

1. A pharmaceutical for treating or preventing a cell proliferative disease, comprising a compound represented by formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof as an active ingredient, (a) the compound or salt is administered twice a week for three weeks; (b) the administration of the compound or salt is discontinued for one week; (c) Thereafter, steps (a) and (b) are repeated at least once. The medicine used as follows.

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

3. The pharmaceutical composition according to claim 1 or 2, wherein the cell proliferative disease is cancer.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cell proliferative disease is a cancer with a KRAS mutation.

5. The pharmaceutical agent according to any one of claims 1 to 4, wherein the cell proliferative disease is a solid cancer.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the dose per administration in step (a) is 3.2 mg.

7. Before step (a), (1) the compound or salt is administered twice a week at a dose of 3.2 mg; or （２） (2a) the compound or salt is administered at a dose of 4 mg twice a week for 3 weeks; (2b) the administration of the compound or salt is discontinued for one week; (2c) Thereafter, steps (2a) and (2b) are repeated at least once. The pharmaceutical composition according to claim 6, which is used as follows:

8. The pharmaceutical composition according to claim 7, wherein, before step (1) or (2), the compound or salt is administered at a dose of 4 mg twice a week.

9. The pharmaceutical composition according to any one of claims 1 to 5, (A) first, the compound or salt is administered at a dose of 4 mg twice a week; (B1) The compound or salt is then administered twice a week at a dose of 3.2 mg; (C) After that, (Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for 3 weeks; (Cb) the administration of the compound or salt is discontinued for one week; (Cc) After that, steps (Ca) and (Cb) are repeated at least once. It is used as follows: (A) first, the compound or salt is administered at a dose of 4 mg twice a week; (B2) Next, (B2a) the compound or salt is administered at a dose of 4 mg twice a week for 3 weeks; (B2b) the administration of the compound or salt is discontinued for one week; (B2c) After that, steps (B2a) and (B2b) are repeated at least once. It is used as follows: (A) first, the compound or salt is administered at a dose of 4 mg twice a week; (B2) Next, (B2a) the compound or salt is administered at a dose of 4 mg twice a week for 3 weeks; (B2b) the administration of the compound or salt is discontinued for one week; (B2c) Thereafter, steps (B2a) and (B2b) are repeated at least once, (C) After that, (Ca) the compound or salt is administered at a dose of 3.2 mg twice a week for 3 weeks; (Cb) the administration of the compound or salt is discontinued for one week; (Cc) After that, steps (Ca) and (Cb) are repeated at least once. The medicine used as follows.

10. The pharmaceutical composition according to any one of claims 1 to 4, wherein the cell proliferative disease is multiple myeloma.

11. The pharmaceutical composition according to claim 10, wherein the dose per administration in step (a) is 4 mg.

12. The pharmaceutical composition according to claim 10 or 11, wherein the cell proliferative disease is a cancer with an NRAS mutation.

13. The pharmaceutical agent according to any one of claims 10 to 12, which is used in combination with dexamethasone, wherein the compound or salt is administered before, simultaneously with, or after administration of dexamethasone.

14. The pharmaceutical composition of claim 13, wherein dexamethasone is administered at a dose of 20 mg once a week.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the compound or salt is administered orally.

16. Formula (I): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, (i) a container for containing the medicament; and (ii) (a) the compound or salt is administered twice a week for three weeks; (b) the administration of the compound or salt is discontinued for one week; (c) Thereafter, steps (a) and (b) are repeated at least once. Instructions for using said medicament The pharmaceutical packaged together with

17. The pharmaceutical is a pharmaceutical according to any one of claims 1 to 15, the instructions are for using the medicament such that the compound or salt is administered according to a predetermined dosing regimen corresponding to the medicament; The pharmaceutical composition of claim 16.

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