Coumarin derivative for therapy or prophylaxis of a cell proliferative disorder

Abstract

N O N O N S N NHCHH F (I) manner that: 20 26 23 40 67 17 S ep 2 02 6 A B S T R A C T 1 7 S e p 2 0 2 6 N O O O N O N S N N H C H 2 0 2 6 2 3 4 0 6 7 F m a n n e r t h a t :

Description

Title of Invention COUMARIN DERIVATIVE FOR THERAPY OR PROPHYLAXIS OF A CELL PROLIFERATIVE DISORDER Cross Reference The present application is a divisional of Australian patent application no. 2024219534, which is a divisional of Australian application no. 2018369325, which was the national phase entry of PCT / EP2018 / 062805, the entire specifications of which are incorporated herein by cross-reference. Technical Field

[0001] The present invention relates to a therapeutic or prophylactic medicament for a cell proliferative disorder, particularly cancer, comprising a coumarin derivative. Background Art

[0002] The compound represented by formula (I) below (also referred to herein as “compound (I)”) and pharmaceutically acceptable salts thereof (also referred to herein simply as “salts thereof”) are known to have pharmacological activity such as antitumor activity (see patent document 1 or 2).

[0003] In regard to the usage and dosage of compound (I) or a salt thereof, a potassium salt of compound (I) is known to be administered to patients with solid cancers such as nonsmall-cell lung cancer, ovarian cancer, endometrial cancer, and colorectal cancer twice weekly at a dose of 4 mg per administration (see non patent document 1). Citation List 2026234067   17 Sep 2026 Patent Literature

[0004] Patent document 1: WO 2007 / 091736 Patent document 2: WO 2009 / 014100               ■ Non Patent Literature 5

[0005] Non patent document 1: Journal of Clinical Oncology 34, no. 15_suppl (May 2016) 2582-2582 Summary of Invention Technical Problem

[0006] When compound (I) or a salt thereof was administered 10 according to the dosing regimen described above (twice weekly, 4 mg per administration), there were some cases where worsening of skin rash, for example, resulted in. unplanned dose interruption and / or dose reduction before administration was further continued.

[0007] The present invention has been made in light of such 15 circumstances. It is an object of the present invention to provide a dosing regimen for compound (I) or a salt thereof that can be implemented safely and for long periods, as well as a therapeutic or prophylactic medicament for a cell proliferative disorder (particularly cancer) that is used based on such a dosing regimen. 20 Solution to Problem

[0008] The present invention provides medicaments according to the following items Al to Al5. Al: A medicament for the treatment or prevention of a cell proliferative disorder, the medicament comprising as an active 25 ingredient a compound represented by formula (I): 2026234067   17 Sep 2026 or a pharmaceutically acceptable salt thereof, wherein the medicament is used in such a maimer that: (a) said compound or salt is administered twice weekly for 3 weeks, (b) administration of said compound or salt is paused for the following 1 week, and (c) steps (a) and (b) are subsequently repeated at least once. A2: The medicament according to item Al, comprising a potassium salt of a compound represented by formula (I) as an active ingredient. A3: The medicament according to item Al or A2, wherein the cell proliferative disorder is cancer. A4; The medicament according to any one of items Al to A3, wherein the cell proliferative disorder is a KRAS mutant cancer. A5: The medicament according to any one of items Al to A4, wherein the cell proliferative disorder is a solid cancer. A6: The medicament according to any one of items Al to A5, wherein the dose per administration in step (a) is 3.2 mg. A7: The medicament according to item. A6, wherein the medicament is used in such a manner that prior to step (a): (1) said compound or salt is ad linistered twice weekly at a dose of 3.2 mg per administration; or (2) 2026234067   17 Sep 2026 10 15 20 25 (2a) said compound or salt is administered twice weekly for 3 weeks at a dose of 4 mg per administration, (2b) administration of said compound or salt is paused for the following 1 week, and (2c) steps (2a) and (2b) are subsequently repeated at least once. A8: The medicament according to item A7, wherein the medicament is used in such a manner that prior to step (1) or (2), said compound or salt is administered twice weekly at a dose of 4 mg per administration. A9:   The medicament according to any one of items Al to A5: (RI) wherein the medicament is used in such a manner that: (A) first, said compound or salt is administered twice weekly at a dose of 4 mg per administration, (Bl) next, said compound or salt is administered twice weekly at a dose of 3.2 mg per administration, (C) after which: (Ca) said compound or salt is administered twice weekly for 3 weeks at a dose of 3.2 mg per administration, (Cb) administration of said compound or salt is paused for the following 1 week, and (Cc) steps (Ca) and (Cb) are subsequently repeated at least once; or (R2) wherein the medicament is used in such a manner that: (A) first, said compound or salt is administered twice weekly at a dose of 4 mg per administration, (B2) following which: (B2a) said compound or salt is administered twice weekly for 3 2026234067   17 Sep 2026 weeks at a dose of 4 mg per administration, (B2b) administration of said compound or salt is paused for the following 1 week, and (B2c) steps (B2a) and (B2b) are subsequently repeated at least 5 once; or (R3) wherein the medicament is used in such a manner that: (A) first, said compound or salt is administered twice weekly at a dose of 4 mg per administration, (B2) following which: 10              (B2a) said compound or salt is administered twice weekly for 3 weeks at a dose of 4 mg per administration, (B2b) administration of said compound or salt is paused for the following 1 week, and (B2c) steps (B2a) and (B2b) are subsequently repeated at least 15       once, (C) after which: (Ca) said compound or salt is administered twice weekly for 3 .        weeks at a dose of 3.2 mg per administration, (Cb) administration of said compound or salt is paused for the 20 following 1 week, and (Cc) steps (Ca) and (Cb) are subsequently repeated at least once. A10: The medicament according to any one of items Al to A4, wherein the cell proliferative disorder is multiple myeloma. All: The medicament according to item A10, wherein the dose per 25 administration in step (a) is 4 mg. A12: The medicament according to item A10 or Al 1, wherein the cell 2026234067   17 Sep 2026 proliferative disorder is an NRAS mutant cancer. Al3: The medicament according to any one of items A10 to A12, wherein the medicament is used in combination with dexamethasone, and wherein the medicament is used in. such a manner that said 5 compound or salt is administered before, simultaneously with or after administration of dexamethasone. A14: The medicament according to item A13, wherein dexamethasone is administered once weekly at a dose of 20 mg per administration. 10 Al5: The medicament according to any one of items Al to A14, wherein the administration of said compound or salt is oral administration.

[0009] The medicament of the present invention may consist of compound (I) or a salt thereof, or it may be a pharmaceutical 15      composition further comprising another component

[0010] According to the present invention, there are also provided medicaments according to the following items A16 and A17. Al 6: A medicament for the treatment or prevention of a cell proliferative disorder, the medicament comprising a compound 20 represented by formula (I): or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the medicament is packaged together with: 2026234067   17 Sep 2026 (i) a container for housing said medicament, and (ii) an instruction for using said medicament in such a manner that: (a) said compound or salt is administered twice weekly for 3 weeks, (b) administration of said compound or salt is paused for the following 1 week, and (c) steps (a) and (b) are subsequently repeated at least once. Al 7: The medicament according to item A16, wherein the medicament is a medicament according to any one of Al to A15, and wherein the instruction is an instruction for using said medicament in such a manner that said compound or salt is administered according to the prescribed dosing regimen corresponding to the medicament used.

[0011] According to the present invention, there are also provided methods according to the following items Bl to Bl5. Bl: A method for the treatment or prevention of a cell proliferative disorder, the method comprising: (a) administering a compound represented by formula (I): or a pharmaceutically acceptable salt thereof twice weekly for 3 weeks, (b) pausing administration of said compound or salt for the following 1 week, and (c) subsequently repeating steps (a) and (b) at least once. ■ 2026234067   17 Sep 2026 B2: The method according to item. Bl, wherein a potassium salt of a compound represented by formula (I) is administered. B3: The method according to item Bl or B2, wherein the cell proliferative disorder is cancer. 5      B4: The method according to any one of items Bl to B3, wherein the cell proliferative disorder is a KRAS mutant cancer. B5: The method according to any one of items B1 to B4, wherein the cell proliferative disorder is a solid cancer. B6: The method according to any one of items B1 to B5, wherein the 10 dose per administration in step (a) is 3.2 mg. B7: The method according to item B6, wherein the method comprises, prior to step (a): (1) administering said compound or salt twice weekly at a dose of 3.2 mg per administration; or 15               (2) (2a) administering said compound or salt twice weekly for 3 weeks at a dose of 4 mg per administration, (2b) pausing administration of said compound or salt for the following 1 week, and 20              (2c) subsequently repeating steps (2a) and (2b) at least once. B8: The method according to item B7, wherein the method comprises, prior to step (1) or (2), administering said compound or salt twice weekly at a dose of 4 mg per administration. B9: The method according to any one of items Bl to B5: 25             (RI) wherein the method comprises: (A) first, administering said compound or salt twice weekly at a 2026234067   17 Sep 2026 dose of 4 mg per administration, (Bl) next, administering said compound or salt twice weekly at a dose of 3.2 mg per administration, and (C) then: 5              (Ca) administering said compound or salt 'twice weekly for 3 weeks at a dose of 3.2 mg per administration, (Cb) pausing administration of said compound or salt for the following 1 week, and (Cc) subsequently repeating steps (Ca) and (Cb) at least once; or 10             (R2) wherein the method comprises: (A) first, administering said compound or salt twice weekly at a dose of 4 mg per administration, and (B2) next: (B2a) administering said compound or salt twice weekly for 3 15       weeks at a dose of 4 mg per administration, (B2b) pausing administration of said compound or salt for the following 1 week, and (B2c) subsequently repeating steps (B2a) and (B2b) at least once; or                                           ' 20             (R3 ) wherein the method comprises: (A) first, administering said compound or salt twice weekly at a dose of 4 mg per administration, (B2) next: (B2a) administering said compound or salt twice weekly for 3 25 weeks at a dose of 4 mg per administration, (B2b) pausing administration of said compound or salt for the 2026234067   17 Sep 2026 following 1 week, and (B2c) subsequently repeating steps (B2a) and (B2b) at least once, and (C) then: 5              (Ca) administering said compound or salt twice weekly for 3 weeks at a dose of 3.2 mg per administration, (Cb) pausing administration of said compound or salt for the following 1 week, and -            (Cc) subsequently repeating steps (Ca) and (Cb) at least once. 10 BIO: The method according to any one of items B1 to B4, wherein the cell proliferative disorder is multiple myeloma. Bll: The method according to item BIO, wherein the dose per administration in step (a) is 4 mg. B12: The method according to item BIO or Bll, wherein the cell. 15 proliferative disorder is an. NRAS mutant cancer. B13: The method according to any one of items BIO to B12, wherein said compound or salt is used in combination with dexamethasone, and wherein the method comprises administering said compound or salt before, simultaneously with or after administration of dexamethasone. 20 Bl4: The method according to item Bl3, wherein dexamethasone is administered once weekly at a dose of 20 mg per administration. B15: The method according to any one of items Bl to B14, wherein the administration of said compound or salt is oral administration.

[0012] According to the present invention, there are also provided, uses 25 according to the following items Cl to Cl5. C1:   Use of a compound represented by formula (I): 2026234067   17 Sep 2026 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a cell proliferative disorder, wherein the medicament is used in such a manner that: 5              (a) said compound or salt is administered twice weekly for 3 weeks, (b) administration of said compound or salt is paused for the ' following 1 week, and (c) steps (a) and (b) are subsequently repeated at least once. 10       C2: The use according to item Cl, which is use of a potassium salt of a compound represented by formula (I). C3: The use according to item Cl or C2, wherein the cell proliferative disorder is cancer. C4: The use according to any one of items Cl to C3, wherein the 15       cell proliferative disorder is a KRAS mutant cancer. C5: The use according to any one of items Cl to C4, wherein the cell proliferative disorder is a solid cancer. C6: The use according to any one of items Cl to C5, wherein 'the dose per administration in step (a) is 3.2 mg. 20      C7: The use according to item C6, wherein the medicament is used in such a manner that prior to step (a): (1) said compound or salt is administered twice weekly at a dose of 3.2 mg per administration; or 2026234067   17 Sep 2026 (2) (2a) said compound or salt is administered twice weekly for 3 weeks at a dose of 4 mg per administration, (2b) administration of said compound or salt is paused for the 5 following 1 week, and (2c) steps (2a) and (2b) are subsequently repeated at least once. 0g. The use according to item C7, wherein the medicament is used in such a manner that prior to step (1) or (2), said compound or salt is administered twice weekly at a dose of 4 mg per administration. 10      C9: The use according to any one of items C1 to C5: (RI) wherein the medicament is used in such a manner that: (A) first, said compound or salt is administered twice weekly at a dose of 4 mg per administration, (Bl) next, said compound or salt is administered twice weekly at 15       a dose of 3.2 mg per administration, (C) after which: (Ca) said compound or salt is administered twice weekly for 3 weeks at a dose of 3.2 mg per administration, (Cb) administration of said compound or salt is paused for the 20 following 1 week, and (Cc) steps (Ca) and (Cb) are subsequently repeated at least once; or (R2) wherein the medicament is used in such a manner that: (A) first, said compound or salt is administered twice weekly at 25 a dose of 4 mg per administration, (B2) following which: 2026234067   17 Sep 2026 (B2a) said compound or salt is administered twice weekly for 3 weeks at a dose of 4 mg per administration, (B2b) administration of said compound or salt is paused for the following 1 week, and 5              (B2c) steps (B2a) and (B2b) are subsequently repeated at least once; or (R3) wherein the medicament is used in such a manner that: (A) first, said compound or salt is administered twice weekly at a dose of 4 mg per administration, 10              (B2) following which: (B2a) said compound or salt is administered twice weekly for 3 weeks at a dose of 4 mg per administration, (B2b) administration of said compound or salt is paused for the following 1 week, and 15              (B2c) steps (B2a) and (B2b) are subsequently repeated at least once, (C) after which: (Ca) said compound or salt is administered twice weekly for 3 weeks at a dose of 3.2 mg per administration, 20              (Cb) administration of said compound or salt is paused for the following 1 week, and (Cc) steps (Ca) and (Cb) are subsequently repeated at least once. CIO: The use according to any one of items Cl. to C4, wherein the cell proliferative disorder is multiple myeloma. 25 Cll: The use according to item CIO, wherein the dose per administration in step (a) is 4 mg. 2026234067   17 Sep 2026 C12: The use according to item CIO or Cll, wherein the cell proliferative disorder is an NRAS mutant cancer. C13: The use according to any one of items CIO to C12, wherein the medicament is used in combination with dexamethasone, and wherein 5 the medicament is used in such a manner that said compound or salt is administered before, simultaneously with or after administration of dexamethasone. Cl4: The use according to item C13, wherein dexamethasone is administered once weekly at a dose of 20 mg per administration. 10      C15: The use according to any one of items Cl to C14, wherein the administration of said compound or salt is oral administration. [00'13] The dosing regimen that is used in the present invention comprises repeating a cycle comprising a prescribed rest period, and makes it possible to administer compound (I) or a salt thereof for long 15       periods while minimizing side effects and maintaining the drug efficacy. In addition, the dosing regimen makes it possible to treat or prevent cell proliferative disorders, particularly cancer, while minimizing the burden on patients. Advantageous Effects of Invention 20

[0014] According to the present invention, there is provided a dosing regimen for compound (I) or a salt 'thereof 'that can be implemented safely and for long periods, as well as a therapeutic or prophylactic medicament for a cell proliferative disorder (particularly cancer) that is used based on such a dosing regimen. 25 Brief Description of Drawings

[0015] Fig. 1 is a graph showing change in tumor size over time in a 2026234067   17 Sep 2026 KRAS mutant non-small-cell lung cancer patient who received treatment by the medicament of the present invention. 'The horizontal axis (X-axis) represents the treatment cycle number and the vertical axis (Y-axis) represents the rate of change of tumor size from baseline. The 5      tumor size was measured by CT scan. Fig. 2 summarizes: a dosing regimen that was used for a HRAS mutant apocrine adenocarcinoma patient; and the observed efficacy and safety of the dosing regimen. Fig. 3 shows an example of a dosing guidance for the 10       medicament of the present invention. Description of Embodiments

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

[0017] Compound (I) and salts thereof can be prepared by the method 15 described in WO 2007 / 091736 or WO 2013 / 035754.

[0018] The active ingredient to be used in the present invention is preferably a pharmaceutically acceptable salt of compound (I). Examples of such salts include: inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates; 20 sulfonates such as methanesulfonates, benzenesulfonates and toluenesulfonates; carboxylates such as formates, acetates, oxalates, maleates, 'fumarates, citrates, .malates, succinates, malonates, gluconates, mandelates, benzoates, salicylates, fluoroacetates, trifluoroacetates, tartrates, propionates and glutarates; alkali metal salts 25 such as lithium salts, sodium salts, potassium salts, cesium salts and rubidium salts; alkaline earth metal salts such as magnesium salts and 2026234067   17 Sep 2026 calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts. Among them, alkali metal salts such as lithium salts, sodium, salts, potassium salts, cesium salts and rubidium salts are preferred, sodium salts and potassium salts are more preferred, and potassium salts are particularly preferred. Specific examples of potassium salts of compound (I) include a salt represented by the following formula (la). io 15 20

[0019] Examples of cell proliferative disorders to be treated or prevented by the medicament or method of the present invention include cancer, rheumatism and inflammation, among which cancer is preferred.

[0020] Examples of cancers include: blood and lymphoid cancers, such as leukemias (acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelocytic leukemia, chrome lymphocytic leukemia, and the like), malignant lymphomas (Hodgkin’s disease, non-Hodgkin’s lymphoma, and 'the like), multiple myeloma, and myelodysplastic syndrome; central nervous system cancers, such as brain tumor and glioma; and solid cancers, such as head and neck cancers (pharyngeal cancer, laryngeal cancer, tongue cancer, and the like), esophageal cancer, gastric cancer, colorectal cancer (cecal cancer, colon cancer, rectal, cancer, or the like), lung cancer (small cell lung cancer, non-small cell lung cancer, or the like), thyroid cancer, breast cancer, gallbladder 2026234067   17 Sep 2026 cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer (endometrial cancer, cervical cancer, or the like), testicular cancer, renal cell carcinoma, bladder cancer, renal pelvic and ureteral cancer, malignant melanoma, and skin cancer (basal cell 5 carcinoma, squamous cell carcinoma, Paget’s disease affecting the scrotum and penis, Merkel cell carcinoma, sweat gland carcinoma (for example, apocrine adenocarcinoma or eccrine adenocarcinoma), sebaceous carcinoma, trichoepithelioma, or the like). A preferred blood or lymphoid cancer is multiple myeloma. Examples of preferred 10 solid cancers include ovarian cancer, breast cancer, uterine cancer, colorectal cancer, and lung cancer, among which non-small cell lung cancer is particularly preferred. Preferred cancers are multiple myeloma and solid cancers, among which multiple myeloma and non-small cell lung cancer are particularly preferred. 15

[0021] The cancer may be one with a gene mutation or without a gene mutation, or one where die presence or absence of mutation is unclear, but it is preferably one with a gene mutation. Examples of genes to be mutated include EGFR, FGFR, ALK, ROS1, PI3K, BRAF, HRAS, KRAS and NRAS. The cancer is preferably a KRAS mutant and / or 20 NRAS mutant one, and more preferably it is KRAS mutant and NRAS mutant multiple myeloma or a KRAS mutant solid cancer (particularly non-small-cell lung cancer). Examples of preferred cancers with gene mutations also include HRAS mutant apocrine adenocarcinoma.

[0022] The subject to be administered compound (I) or a salt thereof is 25 an animal, preferably a mammal (for example, a mouse, a rat, a rabbit, a dog, a monkey (for example, a cynomolgus monkey), or a human), and 2026234067   17 Sep 2026 io 15 20 25 most preferably a human. The human may be an adult (18 years or older) or a child (younger than 18). In the case of a child, it is preferably one of age at least 6 months or older, for example.

[0023] With regard to the route of administration to a subject, there may be used: systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intracistemal administration, vaginal administration, intraperitoneal, administration, intravesical administration or inhalation administration; or topical administration in the form of an ointment, gel, cream or the like. Oral inistration is preferred.

[0024] Compound (I) or a salt thereof is generally prepared as a certain formulation (dosage form). The formulation may be, for example, a tablet, a capsule, a granule, a powder, a fine granule, a pill, or an aqueous or nonaqueous solution or suspension. The solution or suspension may be stored filled in a container suited for the preparation of an individual dose.

[0025] Each of such formulations as the ones mentioned above may be produced by a known method, by mixing the compound (I) or salt thereof with a pharmaceutically acceptable additive. Examples of such additives include excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, emulsifiers, and the like.

[0026] Examples of excipients include starches (starch, potato starch, maize starch and the like), lactose, crystalline cellulose, and calcium hydrogen phosphate. 2026234067 • 17 Sep 2026

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

[0028] Examples of binders include polyvinylpyrrolidone and 5 macrogol, as well as the same compounds as mentioned for the excipient.

[0029] Examples of disintegrants include chemically modified starches and celluloses, such as croscaimellose sodium, sodium carboxymethyl starch, and crosslinked polyvinylpyrrolidone, as well as the same 10 compounds as mentioned for the excipient.

[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. 15

[0031] Examples of flavoring agents include sweeteners, acidulants and fragrances which are commonly used.

[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 acid; vaseline; paraffins; bentonite; 20 glycerine; and glycol oils.

[0033] Examples of dispersants include cellulose derivatives (gum arabic, tragacanth, methyl cellulose and the like), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbates, and sorbitan fatty acid esters. 25

[0034] Examples of solvents and diluents in liquid formulations include phenol, chlorocresol, purified water and distilled water. 2026234067   17 Sep 2026

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

[0036] The preferred percentage of the compound (I) or salt thereof contained in the formulation will differ depending on the dosage form, 5 but it is generally 0.01% to 100% by weight with respect to the total weight of the formulation.

[0037] The content of the compound (I) or salt thereof in the formulation may be set as appropriate for the predetermined dosage. The preferred content is 0.01 mg to 10 mg, for example; for a capsule, it 10 may be 0.1 mg to 4 mg, for example. A more preferred content is 0.8 mg, for example.

[0038] According to the dosing regimen that is used in the present invention, compound (I) or a salt thereof is administered in the following manner: 15              (a) the compound (I) or salt thereof is administered twice weekly for 3 weeks, (b) administration of the compound (I) or salt thereof is paused for the following 1 week, and (c) steps (a) and (b) are subsequently repeated at least once. 20

[0039] In the present invention, to be administered “twice weekly” means that the compound (I) or salt thereof is administered two times during a one-week period. Administration may be performed twice on the same day, or once a day on different days (which may be consecutive), but it is preferably performed on different days. More 25 preferably, administration is performed on the 1st and 4th days or the 3rd and 6th days of the period, for example, so that the compound (I) or 2026234067   17 Sep 2026 salt thereof is administered at dose intervals as 'uniform as possible, i.e., at dose intervals of 3 to 4 days. The one-week period may start on a Monday, for example, or it may start on a Wednesday, for example. When two administrations are performed on different days, each may be 5 performed at any time of day, but they are preferably performed at the same tune of day (for example, after breakfast).

[0040] The dose of the compound (I) or salt thereof per administration is preferably 3.2 mg or 4 mg. When the cancer is multiple myeloma, the dose is preferably 4 mg, and when the cancer is a solid cancer 10 (particularly non-small-cell lung cancer), it is preferably 3.2 mg or 4 mg.

[0041] The 4-week cycle consisting of steps (a) and (b) is repeated two times (8 weeks) to 60 times (approximately 4 years and 8 months), for example, and more specifically, it is repeated 8 times (32 weeks) or 18 15 times (72 weeks), for example. Even if the number of cycles to be repeated has previously been determined, the number of cycles may be changed based on the judgment of the physician or veterinarian depending on, for example, the condition of the subject. Moreover, administration may even be stopped during the cycle based on the 20 judgment of the physician or veterinarian depending on, for example, the condition of the subject.

[0042] In one embodiment, prior to step (a): (1) the compound (I) or salt thereof is administered twice weekly at a dose of 3.2 mg per administration; or 25               (2) (2a) the compound (I) or salt thereof is administered twice 2026234067   17 Sep 2026 weekly for 3 weeks at a dose of 4 mg per administration, (2b) administration of the compound (I) or salt thereof is paused for the following 1 week, and (2c) steps (2a) and (2b) are subsequently repeated at least once. Moreover, optionally, prior to step (1) or (2), (3) the compound (I) or salt thereof is administered twice weekly at a dose of 4 mg per administration.

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

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

[0045] In step (3), a cycle consisting of 4 weeks of administration is usually repeated two times (8 weeks) to 30 times (approximately 2 years and 4 months), and it is preferably repeated 8 times (32 weeks), for example.

[0046] In. steps (1) and (3), even if the number of cycles to be repeated has previously been determined, the number of cycles may be changed based on the judgment of the physician or veterinarian depending on, for example, the condition of the subject. Moreover, administration may even be stopped during the cycle based on the judgment of the physician or veterinarian, depending on, for example, the condition of the subject.

[0047] In one embodiment, compound (I.) or a salt thereof is 2026234067   17 Sep 2026 io 15 20 25 administered in the following manner: (RI) (A) First, the compound (I) or salt thereof is administered twice weekly at a dose of 4 mg per administration, (Bl) next, the compound (I) or salt thereof is administered twice weekly at a dose of 3.2 mg per administration, (C) after which: (Ca) the compound (I) or salt thereof is administered twice weekly for 3 weeks at a dose of 3.2 mg per administration, (Cb) administration of the compound (I) or salt thereof is paused for the following 1 week, and (Cc) steps (Ca) and (Cb) are subsequently repeated at least once; or (R2) (A) First, the compound (I) or salt thereof is administered twice weekly at a dose of 4 mg per a linistration, (B2) following which: (B2a) the compound (I) or salt thereof is administered twice weekly for 3 weeks at a dose of 4 mg per administration, (B2b) administration of the compound (I) or salt thereof is paused for the following 1 week, and (B2c) steps (B2a) and (B2b) are subsequently repeated at least once; or (R3) (A) First, the compound (I) or salt thereof is administered twice weekly at a dose of 4 mg per administration, 2026234067   17 Sep 2026 (B2) following which: (B2a) the compound (I) or salt thereof is administered twice weekly for 3 weeks at a dose of 4 mg per administration, (B2b) administration of the compound (I) or salt thereof is 5 paused for the following 1 week, and (B2c) steps (B2a) and (B2b) are subsequently repeated at least once, (C) after which: (Ca) the compound (I) or salt thereof is administered twice 10 weekly for 3 weeks at a dose of 3.2 mg per administration, (Cb) administration of the compound (I) or salt thereof is paused for the following 1 week, and                        ■ (Cc) steps (Ca) and (Cb) are subsequently repeated at least once. Which of (RI) to (R3) should be selected may be determined 15 according to, for example, the dosing guidance shown in Fig. 3 depending on, for example, the severity or grade of an adverse event observed in the subject.

[0048] The cell proliferative disorder to be treated or prevented based on the dosing regimen of this embodiment is preferably cancer and 20 more preferably a solid cancer. Among solid cancers, non-small cell lung cancer is preferred, and KRAS mutant non-small cell lung cancer is particularly preferred.

[0049] In step (A), a cycle consisting of 4 weeks of administration is usually repeated two times (8 weeks) to 30 times (approximately 2 years 25 and 4 months), and it is preferably repeated 13 times (52 weeks), for example. 2026234067   17 Sep 2026

[0050] In step (Bl), a cycle consisting of 4 weeks of administration is usually repeated two times (8 weeks) to 30 times (approximately 2 years and 4 months), and it is preferably repeated 8 times (32 weeks), for example. 5

[0051] In steps (A), (B1), (B2) and (C), even if the number of cycles to be repeated has previously been determined, the number of cycles may be changed based on the judgment of the physician or veterinarian depending on, for example, the condition of the subject. Moreover, administration may even be stopped during the cycle based on the 10 judgment of the physician or veterinarian depending on, for example, the condition of the subject.

[0052] Compound (I) or a salt thereof may be used either alone or in combination with another drug. When used in combination with another drug, the other drug may be an antiemetic drug or anticancer 15       agent, for example, and is preferably an anticancer agent. Examples of anticancer agents include thalidomide-based anticancer agents such as thalidomide and lenalidomide, proteasome inhibitors such as bortezomib and ixazomib, and steroidal anticancer agents such as dexamethasone and prednisolone. 20

[0053] 'When the cancer is non-small-cell lung cancer, for example, compound (I) or a salt thereof is preferably used alone.

[0054] When compound (I) or a salt thereof is used for treatment of multiple myeloma in combination with another drug, the other drag is preferably dexamethasone, for example. Dexamethasone is a drug that 25 is part of the standard of care for multiple myeloma.

[0055] When compound (I) or a salt thereof is used for treatment of 2026234067   17 Sep 2026 multiple myeloma in combination with dexamethasone, dexamethasone is preferably administered once weekly 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 5 dexamethasone, the order and timing of their administrations are not particularly restricted, and the compound (I) or salt thereof may be administered before, simultaneously with or after administration of dexamethasone. For example, in step (a), when the compound (I) or salt thereof and dexamethasone are administered in a one-week period, 10 'it is preferred, for example, that: the compound (I) or salt thereof is administered on the 1st and 4th days and dexamethasone on the 2nd day of the period, or the compound (I) or salt thereof is administered on the 3rd and 6th days and dexamethasone on the 4th day of the period, or the compound (I) or salt thereof is administered on the 2nd and 5th days 15       and dexamethasone on the 1st day of the period, or the compound (I) or salt thereof is administered on the 4th and 7th days and dexamethasone on the 2nd day of the period. The one-week period may start on a Monday, for example, or it may start on a Wednesday, for example. Each administration may be performed at any time of day, but the 20 administrations are preferably performed at the same time of day (for example, after dimer).

[0057] The period during which the compound (I) or salt thereof is used in combination with dexamethasone may be determined based on the judgment of the physician or veterinarian depending on, for example, 25 the condition of the subject. .Also, administration of either or both the compound (I) or salt thereof and dexamethasone may be stopped based 2026234067   17 Sep 2026 on the judgment of the physician or veterinarian depending on, for example, the condition of the subject.

[0058] A medicament for the treatment or prevention of a cell proliferative disorder that comprises a compound represented by 5 formula (I): or a pharmaceutically acceptable salt thereof as an. active ingredient may be packaged together with: (i) a container for housing the medicament, and 10              (ii) an instruction(s) for using the medicament in such a manner that: (a) the compound (I) or salt thereof is administered twice weekly for 3 weeks, (b) administration of the compound (I) or salt thereof is paused 15 for the following 1 week, and (c) steps (a) and (b) are subsequently repeated at least once.

[0059] It is preferred, for example, that the packaged medicament is a medicament according to any one of items Al to Al 5 above and that the instruction(s) above is / are an instruction(s) for using the medicament in 20 such a manner that the compound (I) or salt thereof is administered according to the prescribed dosing regimen corresponding to the medicament used. The phrase “prescribed dosing regimen corresponding to 'the medicament used” means, in the case of the 2026234067   17 Sep 2026 medicament of item. A9, for example, any of the dosing regimens (RI) to (R3) prescribed in item A9.

[0060] The packaging may be performed using a packaging material (such as a carton), for example. The package may also include a label, 5 a pamphlet or a pharmaceutically acceptable cushioning material, for example.

[0061] The container of (i) above is, for example, a bottle or a PTP sheet, and it may be produced from a material such as glass, plastic or aluminum, for example. Preferably, the container is printed with 10 letters indicating, for example, that the medicament is to be used for treatment or prevention of the prescribed disease, or it has a label attached on which such letters are printed.

[0062] The medicament may or may not be housed in the container of (i), but is preferably housed in it. 15

[0063] The instructions) of (ii) above include(s) information necessary for use of the medicament based on the prescribed dosing regimen. The instructions) may also include information relating to the efficacy and effects of the medicament, for example.

[0064] The instruction(s) of (ii) may be in the form of a document, for 20 example. The document containing the instructions) may be a package insert, for example. The document containing the instruction^) may also be printed on a label, or printed on a packaging material (such as a carton), for example. The instruct!on(s) may also be in the form of printing on paper or plastic, for example, or in the 25 form of electronic storage in a storage medium such as a CD-ROM or flash memory. 2026234067   17 Sep 2026 Examples

[0065] Exemplary embodiments of the present invention are described below based on examples.

[0066] Example 1: A potassium salt of compound (I) (the potassium salt being also referred to as the WIMF’ in this example) was orally administered to a patient with KRAS mutant and NRAS mutant IgG lambda multiple myeloma at a dose of 4 mg twice weekly (Tuesday and Friday) in 4-week cycles consisting of 3 weeks of treatment followed by 1 week of rest (3 weeks on / 1 week off). Dexamethasone was not used in combination with the IMP.

[0067] The patient started dosing on 29th November, 2016. His initial and ongoing toxicity was intermittent Grade 1 diarrhoea that may be related to the IMP. He also had a Grade 2 rash related to the IMP. He had been faring very well since, with an ongoing partial response as per the international myeloma working group (IMWG) criteria (FLCX: 325 mg / L (pre), 161 mg / L (after 1 cycle), and 264 mg / L (after 2 cycles)).

[0068] The patient had previously been treated with: - Autologous stem cell transplant - Proteasome inhibitor - Immunomodulatoiy drug - Cyclophosphamide + Dexamethasone + Thalidomide - Melphalan - Lenalidomide - Cyclophosphamide + Bortezomib - Dexamethasone 2026234067   17 Sep 2026 - Spine T3-T12, 5 fractions (radiotherapy)

[0069] Example 2: A potassium salt of compound (I) (the potassium salt being also referred to as the “IMP” in this example) was orally administered to a 5 patient with KRAS mutant non-small-cell lung cancer.

[0070] The patient started treatment on 1st September, 2014. The IMP was first administered at a dose of 4 mg twice weekly in 4-week cycles consisting of 4 weeks of treatment (4mg 4wk on). In Cycle 9, due to Grade 3 maculopapular rash, the dosage was reduced to 3.2 mg twice 10 weekly in. 4-week cycles (3.2mg 4wk on). In Cycle 22, due to Grade 3 facial rash, the dosage was reduced again to a 3 weeks on / 1 week off schedule with 3.2 mg twice weekly (3.2mg 3wk on / Iwk off). These reductions resulted in a reduction of their rash, which was only Grade 1 and being managed well with responding with a maintained partial 15 response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at Cycle 40.

[0071] The change in tumor size in the patient over the first 40 cycles (approximately 3 years) is shown in Fig, 1. The horizontal axis (X-axis) represents the treatment cycle number and the vertical axis 20 (Y-axis) represents the rate of change of tumor size from baseline. The tumor size was measured by CT scan. The best responses of the dosing schedules 4mg 4wk on, 3.2mg 4wk on, and 3.2mg 3wk on / Iwk off were 58% reduction, 61% reduction, and 68% reduction in target lesions by RECIST 1.1, respectively. Treatment of the patient by the 25 IMP is being continued as of 18th April, 2018 (at Cycle 48, equivalent to 3.6 years) without any Grade 2 or higher rash being observed. 2026234067   17 Sep 2026

[0072] The patient had previously been treated with: - Carboplatin / Pemetrexed - Pemetrexed - Docetaxel 5                - Pleurodesis (October 2012) (surgery)

[0073] Example 3: A potassium salt of compound (I) (the potassium salt being also referred to as the “IMP” in this example) was orally administered to a patient with HRAS mutant apocrine adenocarcinoma of the scalp. 10 Apocrine adenocarcinoma of the scalp is a cutaneous sweat gland carcinoma. The patient was diagnosed in 2014, and had radiotherapy and surgery twice before treatment with the IMP.

[0074] Treatment of the patient by the IMP was started on 8th January, 2018 at a dose of 4 mg twice weekly in 4-week cycles. In Cycle 1 15 Week 3, the patient had Grade 2 acneiform rash and Grade 2 diarrhoea and thus the dosage was reduced to a 3 weeks on / 1 week off schedule with 4 mg twice weekly. The grade of acneiform rash was one (1) in Cycle 2 Day 1, three (3) in Cycle 2 Day 22, and two (2) in Cycle 3 Day 1. Thus, the dose at Cycle 3 Day 1 was not reduced to 3.2 mg and was 20 determined as 4 mg. The change in tumor size in the patient measured by CT scan demonstrated partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (54% reduction at Cycle 2 Day 22 and 58% reduction at Cycle 4 Day 15).

[0075] The dosing regimen used in this example and the observed 25 efficacy and safety thereof are summarized in Fig. 2. The dosing guidance used in this example is shown in Fig. 3. Treatment of the 2026234067   17 Sep 2026 patient by the IMP is ongoing as of 30th April, 2018 (Cycle 5 Day 1) without any Grade 2 or higher rash or diarrhoea being observed. 2026234067   17 Sep 2026 Forms: 1.       A medicament for the treatment or prevention of a cell proliferative disorder, the medicament comprising as an active ingredient a compound represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein the medicament is used in such a manner that: (a) said compound or salt is administered twice weekly for 3 weeks, (b) administration of said compound or salt is paused for the following 1 week, and (c) steps (a) and (b) are subsequently repeated at least once. 2.      The medicament according to form 1, comprising a potassium salt of a compound represented by formula (I) as an active ingredient. 3.      The medicament according to form 1 or 2, wherein the cell proliferative disorder is cancer. 4.      The medicament according to any one of forms 1 to 3, wherein the cell proliferative disorder is a KRAS mutant cancer. 5.      The medicament according to any one of forms 1 to 4, wherein the cell proliferative disorder is a solid cancer. 6.      The medicament according to any one of forms 1 to 5, wherein the dose per administration in step (a) is 3.2 mg. 7.      The medicament according to form 6, wherein the medicament is used in such a manner that prior to step (a): (1) said compound or salt is administered twice weekly at a dose of 3.2 mg per administration; or (2) (2a) said compound or salt is administered twice weekly for 3 weeks at a dose of 4 mg per administration, 2026234067   17 Sep 2026 (2b) administration of said compound or salt is paused for the following 1 week, and (2c) steps (2a) and (2b) are subsequently repeated at least once. 8.      The medicament according to form 7, wherein the medicament is used in such a manner that prior to step (1) or (2), said compound or salt is administered twice weekly at a dose of 4 mg per administration. 9.      The medicament according to any one of forms 1 to 5: wherein the medicament is used in such a manner that: (A) first, said compound or salt is administered twice weekly at a dose of 4 mg per administration, (B1) next, said compound or salt is administered twice weekly at a dose of 3.2 mg per administration, (C) after which: (Ca) said compound or salt is administered twice weekly for 3 weeks at a dose of 3.2 mg per administration, (Cb) administration of said compound or salt is paused for the following 1 week, and (Cc) steps (Ca) and (Cb) are subsequently repeated at least once; or wherein the medicament is used in such a manner that: (A) first, said compound or salt is administered twice weekly at a dose of 4 mg per administration, (B2) following which: (B2a) said compound or salt is administered twice weekly for 3 weeks at a dose of 4 mg per administration, (B2b) administration of said compound or salt is paused for the following 1 week, and (B2c) steps (B2a) and (B2b) are subsequently repeated at least once; or wherein the medicament is used in such a manner that: (A) first, said compound or salt is administered twice weekly at a dose of 4 mg per administration, (B2) following which: (B2a) said compound or salt is administered twice weekly for 3 weeks at a dose of 4 mg per administration, (B2b) administration of said compound or salt is paused for the following 1 week, and 2026234067   17 Sep 2026 (B2c) steps (B2a) and (B2b) are subsequently repeated at least once, (C) after which: (Ca) said compound or salt is administered twice weekly for 3 weeks at a dose of 3.2 mg per administration, (Cb) administration of said compound or salt is paused for the following 1 week, and (Cc) steps (Ca) and (Cb) are subsequently repeated at least once. 10.     The medicament according to any one of forms 1 to 4, wherein the cell proliferative disorder is multiple myeloma. 11.     The medicament according to form 10, wherein the dose per administration in step (a) is 4 mg. 12.     The medicament according to form 10 or 11, wherein the cell proliferative disorder is an NRAS mutant cancer. 13.     The medicament according to any one of forms 10 to 12, wherein the medicament is used in combination with dexamethasone, and wherein the medicament is used in such a manner that said compound or salt is administered before, simultaneously with or after administration of dexamethasone. 14.     The medicament according to form 13, wherein dexamethasone is administered once weekly at a dose of 20 mg per administration. 15.     The medicament according to any one of forms 1 to 14, wherein the administration of said compound or salt is oral administration. 16.     A medicament for the treatment or prevention of a cell proliferative disorder, the medicament comprising a compound represented by formula (I): or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the medicament is packaged together with: (i) a container for housing said medicament, and 2026234067   17 Sep 2026 (ii) an instruction for using said medicament in such a manner that: (a) said compound or salt is administered twice weekly for 3 weeks, (b) administration of said compound or salt is paused for the following 1 week, and (c) steps (a) and (b) are subsequently repeated at least once. 17.     The medicament according to form 16, wherein the medicament is a medicament according to any one of forms 1 to 15, and wherein the instruction is an instruction for using said medicament in such a manner that said compound or salt is administered according to the prescribed dosing regimen corresponding to the medicament used.

Claims

2026234067   17 Sep 20261.      A method for the treatment of cancer in a subject in need thereof, wherein thecancer is selected from the group consisting of multiple myeloma, malignant melanoma, brain tumor, glioma, gastric cancer, thyroid cancer, breast cancer, and cervical cancer, the method comprising:(a) administering a compound represented by formula (I):or a pharmaceutically acceptable salt thereof twice weekly for 3 weeks,(b) pausing administration of said compound or salt for the following 1 week, and(c) subsequently repeating steps (a) and (b) at least once.

2. Use of a compound represented by formula (I):or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the cancer is selected from the group consisting of multiple myeloma, malignant melanoma, brain tumor, glioma, gastric cancer, thyroid cancer, breast cancer, and cervical cancer, wherein the medicament is administered to the subject according to the following dosage regime:(a) administering the compound represented by formula (I):or a pharmaceutically acceptable salt thereof twice weekly for 3 weeks,(b) pausing administration of said compound or salt for the following 1 week, and2026234067   17 Sep 2026(c) subsequently repeating steps (a) and (b) at least once.

3. The method according to claim 1, or use according to claim 2, wherein a potassiumsalt of a compound represented by formula (I) is administered to the subject.

4. The method according to claim 1 or 3, or use according to claim 2 or 3, whereinthe dose per administration in step (a) is 3.2 mg.

5. The method according to claim 1 or 3, or use according to claim 2 or 3, whereinthe dose per administration in step (a) is 4 mg.

6. The method according to any one of claims 1 and 3 to 5, or use according to anyone of claims 2 to 5, which comprises, prior to step (a), administering said compound or salt twice weekly at a dose of 3.2 mg per administration for at least 4 weeks.

7. The method according to any one of claims 1 and 3 to 5, or use according to anyone of claims 2 to 5, which comprises, prior to step (a), administering said compound or salt twice weekly at a dose of 4 mg per administration for at least 4 weeks.

8. The method according to any one of claims 1 and 3 to 7, or use according to anyone of claims 2 to 7, wherein the administration of said compound or salt is oral administration.

9. The method according to any one of claims 1 and 3 to 8, or use according to anyone of claims 2 to 8, wherein the cancer is multiple myeloma.

10. The method according to any one of claims 1 and 3 to 8, or use according to anyone of claims 2 to 8, wherein the cancer is malignant melanoma.

11. The method according to any one of claims 1 and 3 to 8, or use according to anyone of claims 2 to 8, wherein the cancer is brain tumor.

12. The method according to any one of claims 1 and 3 to 8, or use according to anyone of claims 2 to 8, wherein the cancer is glioma.

13. The method according to any one of claims 1 and 3 to 8, or use according to anyone of claims 2 to 8, wherein the cancer is gastric cancer.

14. The method according to any one of claims 1 and 3 to 8, or use according to anyone of claims 2 to 8, wherein the cancer is thyroid cancer.2026234067   17 Sep 202615.     The method according to any one of claims 1 and 3 to 8, or use according to anyone of claims 2 to 8, wherein the cancer is breast cancer.

16. The method according to any one of claims 1 and 3 to 8, or use according to anyone of claims 2 to 8, wherein the cancer is cervical cancer.

17. The method according to any one of claims 1 and 3 to 16, or use according to anyone of claims 2 to 16, wherein said compound or salt is administered in combination with an anticancer agent.The Institute of Cancer Research: Royal Cancer Hospital;The Royal Marsden NHS Foundation TrustPatent Attorneys for the Applicant / Nominated Person SPRUSON & FERGUSON

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