Cancer combination therapy using aza bicyclic compound and antiandrogen agent
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Filing Date
- 2024-08-23
- Publication Date
- 2026-05-11
Abstract
Description
Combination cancer therapy using azabicyclic compounds and antiandrogens
[0001] The present invention relates to a combination therapy for cancer patients using 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide or a salt thereof and an antiandrogen agent.
[0002] Prostate cancer is the most common cancer affecting men in Europe and the United States and the second leading cause of cancer-related death. In Japan, the number of prostate cancer patients is increasing year by year due to the Westernization of dietary habits and the aging of the population. Prostate cancer cell proliferation is generally stimulated by androgens. Therefore, androgen deprivation therapy, such as surgical or chemical castration, is primarily used to treat unresectable advanced prostate cancer. Androgen deprivation therapy reduces androgen levels in the body, and many patients experience therapeutic effects such as reduced prostate-specific antigen (PSA) levels and tumor regression. However, within several years, many patients may experience disease progression or recurrence despite castration-level androgen levels. This recurrent prostate cancer is called castration-resistant prostate cancer (CRPC). In CRPC patients, androgen receptor (AR) gene amplification and overexpression have been reported (Non-Patent Documents 1 to 3), and it is thought that due to AR overexpression, castration-resistant prostate cancer exhibits high sensitivity even to ultralow concentrations of androgen.
[0003] Antiandrogens such as abiraterone, enzalutamide, darolutamide, and apalutamide, as well as taxane antitumor agents such as docetaxel and cabazitaxel, have been approved and widely used in clinical settings for the treatment of CRPC. However, cross-resistance to antiandrogens due to mechanisms such as AR gene amplification has been reported, and the effectiveness of antiandrogens used as a second or subsequent agent is known to be limited (Non-Patent Document 4). Furthermore, taxane antitumor agents have a high incidence of hematotoxicity (neutropenia and anemia), which requires careful administration in prostate cancer patients, the majority of whom are elderly, and this is considered a clinical problem (Non-Patent Document 5). For these reasons, new treatments for CRPC, especially CRPC resistant to antiandrogens, are needed.
[0004] 3-Ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide (generic name: pimitespib, hereinafter also referred to as "Compound 1") is a compound that exhibits antitumor effects through its potent HSP90 inhibitory activity (Patent Document 1). HSP90 is a member of a group of proteins called molecular chaperones, and is known to perform multiple functions, including promoting and maintaining the functional structure of a wide range of client proteins, promoting correct assembly, inhibiting unnecessary aggregation, protecting against degradation, and promoting secretion (Non-Patent Document 6). Given the physiological function of HSP90, HSP90 inhibitors have the unique ability to simultaneously inhibit multiple signaling pathways involved in cancer survival and proliferation. Therefore, HSP90 inhibitors have long been expected to be drugs with broad and effective antitumor effects (Non-Patent Document 7). Compound 1 has been approved in Japan as a drug with efficacy or effectiveness for "gastrointestinal stromal tumors that have worsened after cancer chemotherapy" and is in clinical use (product name: Jesseri (registered trademark)). Patent documents 2 to 6 disclose the use of Compound 1 and its use in combination with other anticancer drugs. Because AR is one of the client proteins of HSP90, the combination of an HSP90 inhibitor such as NVP-AUY922 with an antiandrogen has been expected as a treatment for CRPC from the viewpoint of its mechanism of action (Non-Patent Document 8). However, in recent years, it has been reported that a clinical trial of the combination of AT13387 (onelespib), an HSP90 inhibitor, and abiraterone in CRPC patients did not show sufficient therapeutic effect (Non-Patent Document 9).
[0005] International Publication No. 2011 / 004610, International Publication No. 2015 / 046498, International Publication No. 2019 / 004417, International Publication No. 2019 / 054465, International Publication No. 2019 / 221086, International Publication No. 2021 / 025065
[0006] J Clin Oncol. 2012;30(6):644-646. Oncotarget. 2016;7(39):64447-64470. Nat Med. 2016;22(4):369-378. Lancet Oncol. 2019;20(12):1730-1739. Cancer Med. 2016;5(2):182-191. Nat Rev Cancer. 2005;5(10):761-772. Trends Mol Med. 2004;10(6):283-290. Endocr Relat Cancer. 2015;22(5):805-818. Clin Cancer Res. 2019;25(15):4624-4633.
[0007] An object of the present invention is to provide a new treatment for CRPC, particularly CRPC that has acquired resistance to antiandrogens.
[0008] The present inventors have conducted extensive research to solve the above problems and have found that the antitumor effect against CRPC is significantly enhanced by combining Compound 1 with an antiandrogen agent without increasing side effects.
[0009] That is, the present invention provides the following [1] to
[72] . [1] An antitumor agent characterized by administering Compound 1 or a salt thereof in combination with an antiandrogen. [2] The antitumor agent according to [1], wherein the antiandrogen is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide. [3] The antitumor agent according to [1], wherein the antiandrogen is enzalutamide. [4] The antitumor agent according to any one of [1] to [3], which is an antitumor agent for treating prostate cancer. [5] The antitumor agent according to any one of [1] to [3], which is an antitumor agent for treating castration-resistant prostate cancer. [6] The antitumor agent according to any one of [1] to [5], wherein Compound 1 or a salt thereof and the antiandrogen are administered to a cancer patient simultaneously or separately with an interval between them. [7] The antitumor agent according to any one of [1] to [6], wherein for compound 1 or a salt thereof, 120 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times. [8] The antitumor agent according to any one of [1] to [6], wherein for compound 1 or a salt thereof, 160 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times. [9] The antitumor agent according to any one of [1] to [8], further comprising concomitant administration of a taxane antitumor agent, a prostate-specific membrane antigen (PSMA) targeted therapeutic agent, or a PARP inhibitor.
[0010]
[10] An antitumor effect enhancer of an antiandrogen, comprising Compound 1 or a salt thereof as an active ingredient.
[11] The antitumor effect enhancer of
[10] , wherein the antiandrogen is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
[12] The antitumor effect enhancer of
[10] , wherein the antiandrogen is enzalutamide.
[13] The antitumor effect enhancer of any one of
[10] to
[12] , which is an antitumor agent for treating prostate cancer.
[14] The antitumor effect enhancer of any one of
[10] to
[12] , which is an antitumor agent for treating castration-resistant prostate cancer.
[15] The antitumor effect enhancer of any one of
[10] to
[14] , wherein Compound 1 or a salt thereof and the antiandrogen are administered to a cancer patient simultaneously or separately with an interval between them.
[16] The antitumor effect enhancer according to any one of
[10] to
[15] , characterized in that for compound 1 or a salt thereof, 120 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[17] The antitumor effect enhancer according to any one of
[10] to
[15] , characterized in that for compound 1 or a salt thereof, 160 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[18] The antitumor effect enhancer according to any one of
[10] to
[15] , characterized in that a taxane antitumor agent, a prostate-specific membrane antigen (PSMA) targeted therapeutic agent, or a PARP inhibitor is further administered in combination.
[0011]
[19] An antitumor agent comprising Compound 1 or a salt thereof as an active ingredient, which is administered in combination with an antiandrogen.
[20] The antitumor agent according to
[19] , wherein the antiandrogen is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
[21] The antitumor agent according to
[19] , wherein the antiandrogen is enzalutamide.
[22] The antitumor agent according to any one of
[19] to
[21] , which is an antitumor agent for treating prostate cancer.
[23] The antitumor agent according to any one of
[19] to
[21] , which is an antitumor agent for treating castration-resistant prostate cancer.
[24] The antitumor agent according to any one of
[19] to
[23] , wherein Compound 1 or a salt thereof and the antiandrogen are administered to a cancer patient simultaneously or separately with an interval between them.
[25] The antitumor agent according to any one of
[19] to
[24] , wherein for compound 1 or a salt thereof, 120 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[26] The antitumor agent according to any one of
[19] to
[24] , wherein for compound 1 or a salt thereof, 160 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[27] The antitumor agent according to any one of
[19] to
[26] , wherein a taxane antitumor agent, a prostate-specific membrane antigen (PSMA) targeted therapeutic agent, or a PARP inhibitor is further administered in combination.
[0012]
[28] An antitumor agent comprising a combination of Compound 1 or a salt thereof and an antiandrogen.
[29] The antitumor agent according to
[28] , wherein the antiandrogen is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
[30] The antitumor agent according to
[28] , wherein the antiandrogen is enzalutamide.
[31] The antitumor agent according to any one of
[28] to
[30] , which is an antitumor agent for treating prostate cancer.
[32] The antitumor agent according to any one of
[28] to
[30] , which is an antitumor agent for treating castration-resistant prostate cancer.
[33] The antitumor agent according to any one of
[28] to
[32] , wherein Compound 1 or a salt thereof and the antiandrogen are administered to a cancer patient simultaneously or separately with an interval between them.
[34] The antitumor agent according to any one of
[28] to
[33] , wherein for compound 1 or a salt thereof, 120 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[35] The antitumor agent according to any one of
[28] to
[33] , wherein for compound 1 or a salt thereof, 160 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[36] The antitumor agent according to any one of
[28] to
[35] , wherein a taxane antitumor agent, a prostate-specific membrane antigen (PSMA) targeted therapeutic agent, or a PARP inhibitor is further administered in combination.
[0013]
[37] A method for treating cancer, comprising administering a therapeutically effective amount of compound 1 or a salt thereof and a therapeutically effective amount of an antiandrogen to a cancer patient.
[38] The method for treating cancer according to
[37] , wherein the antiandrogen is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
[39] The method for treating cancer according to
[37] , wherein the antiandrogen is enzalutamide.
[40] The method for treating cancer according to any one of
[37] to
[39] , wherein the cancer is prostate cancer.
[41] The method for treating cancer according to any one of
[37] to
[39] , wherein the cancer is castration-resistant prostate cancer.
[42] The method for treating cancer according to any one of
[37] to
[41] , wherein compound 1 or a salt thereof and the antiandrogen are administered to a cancer patient simultaneously or separately with an interval between them.
[43] The method for treating cancer according to any one of
[37] to
[42] , characterized in that for compound 1 or a salt thereof, 120 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[44] The method for treating cancer according to any one of
[37] to
[42] , characterized in that for compound 1 or a salt thereof, 160 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[45] The method for treating cancer according to any one of
[37] to
[44] , characterized in that a taxane antitumor agent, a prostate-specific membrane antigen (PSMA) targeted therapeutic agent, or a PARP inhibitor is further administered in combination.
[0014]
[46] Use of compound 1 or a salt thereof for the treatment of cancer, characterized in that compound 1 or a salt thereof is administered in combination with an antiandrogen to a cancer patient.
[47] The use according to
[46] , wherein the antiandrogen is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
[48] The use according to
[46] , wherein the antiandrogen is enzalutamide.
[49] The use according to any one of
[46] to
[48] , wherein the cancer is prostate cancer.
[50] The use according to any one of
[46] to
[48] , wherein the cancer is castration-resistant prostate cancer.
[51] The use according to any one of
[46] to
[50] , wherein compound 1 or a salt thereof and the antiandrogen are administered to a cancer patient simultaneously or separately with an interval between them.
[52] The use according to any one of
[46] to
[51] , wherein for compound 1 or a salt thereof, 120 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[53] The use according to any one of
[46] to
[51] , wherein for compound 1 or a salt thereof, 160 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[54] The use according to any one of
[46] to
[53] , wherein a taxane antitumor agent, a prostate-specific membrane antigen (PSMA) targeted therapeutic agent, or a PARP inhibitor is further administered in combination.
[0015]
[55] Use of compound 1 or a salt thereof for producing an antitumor agent, characterized by being administered in combination with an antiandrogen to a cancer patient.
[56] The use according to
[55] , wherein the antiandrogen is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
[57] The use according to
[55] , wherein the antiandrogen is enzalutamide.
[58] The use according to any one of
[55] to
[57] , wherein the cancer is prostate cancer.
[59] The use according to any one of
[55] to
[57] , wherein the cancer is castration-resistant prostate cancer.
[60] The use according to any one of
[55] to
[59] , wherein compound 1 or a salt thereof and the antiandrogen are administered to a cancer patient simultaneously or separately with an interval between them.
[61] The use according to any one of
[55] to
[60] , wherein for compound 1 or a salt thereof, 120 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[62] The use according to any one of
[55] to
[60] , wherein for compound 1 or a salt thereof, 160 mg of compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[63] The use according to any one of
[55] to
[62] , wherein a taxane antitumor agent, a prostate-specific membrane antigen (PSMA) targeted therapeutic agent, or a PARP inhibitor is further administered in combination.
[0016]
[64] Compound 1 or a salt thereof for use in treating cancer, characterized in that it is administered in combination with an antiandrogen to a cancer patient.
[65] Compound 1 or a salt thereof according to
[64] , wherein the antiandrogen is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
[66] Compound 1 or a salt thereof according to
[64] , wherein the antiandrogen is enzalutamide.
[67] Compound 1 or a salt thereof according to any one of
[64] to
[66] , wherein the cancer is prostate cancer.
[68] Compound 1 or a salt thereof according to any one of
[64] to
[66] , wherein the cancer is castration-resistant prostate cancer.
[69] Compound 1 or a salt thereof according to any one of
[64] to
[68] , wherein compound 1 or a salt thereof and an antiandrogen are administered to a cancer patient simultaneously or separately with an interval.
[70] Compound 1 or a salt thereof according to any one of
[64] to
[69] , characterized in that for Compound 1 or a salt thereof, 120 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[71] Compound 1 or a salt thereof according to any one of
[64] to
[69] , characterized in that for Compound 1 or a salt thereof, 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days, with this 7-day administration schedule being repeated once or twice or more times.
[72] Compound 1 or a salt thereof according to any one of
[64] to
[71] , characterized in that it is further administered in combination with a taxane antitumor agent, a prostate-specific membrane antigen (PSMA) targeted therapeutic agent, or a PARP inhibitor.
[0017] The antitumor agent of the present invention makes it possible to perform cancer treatment that exhibits high antitumor effects (e.g., extension of survival time (particularly, extension of overall survival time and progression-free survival time as determined by imaging diagnosis), tumor shrinkage, tumor growth delay, etc.) while suppressing the onset of side effects, thereby resulting in long-term survival of cancer patients. In particular, the antitumor agent of the present invention exhibits high antitumor effects against prostate cancer, HSPC, CRPC, and CRPC that has acquired resistance to antiandrogens.
[0018] 1 shows the results of an in vitro combination analysis of Compound 1 + abiraterone. 2 shows the results of an in vitro combination analysis of Compound 1 + enzalutamide. 3 shows the results of an in vitro combination analysis of Compound 1 + darolutamide. 4 shows the results of an in vitro combination analysis of Compound 1 + darolutamide. 5 shows the results of the combination of Compound 1 + enzalutamide in a castration-resistant model transplanted with the prostate cancer line LNCaP. 6 shows the results of the combination of Compound 1 + enzalutamide in a castration-resistant model transplanted with the prostate cancer line VCaP. 7 shows the results of the combination of Compound 1 + darolutamide in a castration-resistant model transplanted with the prostate cancer line LNCaP. 8 shows the results of the combination of Compound 1 + abiraterone in a castration-resistant model transplanted with the prostate cancer line VCaP. 9 shows an outline of the study design for the combination therapy of pimitespib and enzalutamide.
[0019] The present invention relates to an antitumor agent, an antitumor effect enhancer, a kit preparation, use of these agents, a tumor treatment method, and a method for enhancing antitumor effect, which are characterized by administering Compound 1 or a salt thereof in combination with an antiandrogen agent.
[0020] [Compound 1 or a Salt Thereof] In the present invention, Compound 1 is 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide, also known as pimitespib by common name, and is a compound having the following structure:
[0021]
[0022] When Compound 1 has isomers such as optical isomers, stereoisomers, rotamers, and tautomers, unless otherwise specified, all isomers and mixtures thereof are encompassed in Compound 1. Furthermore, Compound 1 or a salt thereof may be a solvate (e.g., a hydrate) or a non-solvate, and in the present invention, both are encompassed in "Compound 1 or a salt thereof."
[0023] The "salt" of Compound 1 means a pharmaceutically acceptable salt, and specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, paratoluenesulfonic acid, and glutamic acid; inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; organic bases such as methylamine, ethylamine, meglumine, and ethanolamine; and basic amino acids such as lysine, arginine, and ornithine; and ammonium salts.
[0024] Compound 1 or a salt thereof is a known compound and can be synthesized, for example, according to the method described in Patent Document 1 (WO 2011 / 004610). Alternatively, a product sold in Japan (Jesseri (registered trademark)) can also be used.
[0025] [Antiandrogen] As described in the Examples below, when compound 1 or a salt thereof of the present invention is administered in combination with an antiandrogen, the antitumor effect is synergistically enhanced. The "antiandrogen" of the present invention refers to a drug that exhibits only antagonist activity without agonist activity against the androgen receptor (AR). The form of the drug is not particularly limited, and may be a low-molecular-weight drug, an antibody drug, a nucleic acid drug, or the like. Specific examples of the antiandrogen of the present invention include abiraterone, enzalutamide, darolutamide, and apalutamide. From the viewpoint of synergistic effects with compound 1 or a salt thereof of the present invention, the antiandrogen is preferably one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide, more preferably one or more selected from abiraterone, enzalutamide, and darolutamide, more preferably one or more selected from abiraterone and enzalutamide, and particularly preferably enzalutamide. These antiandrogens may be commercially available products or may be synthesized by well-known conventional methods.
[0026] In addition to the antiandrogen, other antitumor agents may be administered in combination. In this case, the other antitumor agents are not particularly limited as long as they do not inhibit the combined effect of Compound 1 or a salt thereof and the antiandrogen, and examples thereof include taxane antitumor agents, prostate-specific membrane antigen (PSMA) targeting therapeutic agents, and PARP inhibitors. Examples of taxane antitumor agents include docetaxel and cabazitaxel. Examples of PSMA targeting therapeutic agents include lutetium (177Lu) vipivotide tetraxetan (Pluvicto). Examples of PARP inhibitors include olaparib, rucaparib, talazoparib, niraparib, and veliparib.
[0027] [Target Disease] In the present invention, the target cancer is not particularly limited as long as it exhibits a synergistic effect between Compound 1 or a salt thereof and an antiandrogen, and specific examples thereof include head and neck cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder / bile duct cancer, etc.), pancreatic cancer, small intestine cancer, large intestine cancer (colorectal cancer, colon cancer, rectal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer, etc.), breast cancer, ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), kidney cancer, bladder cancer, prostate cancer, skin cancer (malignant melanoma, epidermal cancer, etc.), blood cancer (multiple myeloma, acute myeloid leukemia, etc.), sarcoma (osteosarcoma, soft tissue sarcoma, uterine sarcoma, gastrointestinal stromal tumor, etc.), etc. Among these, prostate cancer is preferred from the viewpoint of the combined effect of Compound 1 or a salt thereof and an antiandrogen. More preferably, the prostate cancer is hormone-sensitive prostate cancer (hereinafter also referred to as "HSPC"; it may also be called castration-sensitive prostate cancer (CSPC)) or castration-resistant prostate cancer (CRPC), and even more preferably, castration-resistant prostate cancer (CRPC), and even more preferably, castration-resistant prostate cancer that has acquired resistance to antiandrogens. Here, prostate cancer is not particularly limited in terms of the presence or absence of distant metastasis, and includes metastatic castration-resistant prostate cancer, non-metastatic castration-resistant prostate cancer, metastatic hormone-sensitive prostate cancer, non-metastatic hormone-sensitive prostate cancer, and the like. Here, "castration-resistant prostate cancer that has acquired resistance to antiandrogens" refers to castration-resistant prostate cancer that has worsened after cancer chemotherapy with antiandrogens. Here, examples of the "antiandrogen" include the antiandrogen agents mentioned above, with abiraterone being preferred.
[0028] [Dosage and Administration] In the present invention, the daily dose of Compound 1 or a salt thereof on the day of administration is preferably 50 to 150%, more preferably 50 to 125%, more preferably 50 to 100%, more preferably 75 to 100%, and particularly preferably 100%, of the recommended dose when Compound 1 or a salt thereof is administered alone, from the viewpoint of enhancing the antitumor effect. Specifically, the recommended dose when Compound 1 or a salt thereof is administered alone is 160 mg / day of Compound 1 for a typical adult. The usual administration method is to administer 160 mg of Compound 1 once daily. The dose may be increased or decreased as needed. In the present invention, the preferred daily dose is 80 to 240 mg / day of Compound 1, more preferably 80 to 200 mg / day, more preferably 80 to 160 mg / day, more preferably 120 to 160 mg / day, and particularly preferably 160 mg / day. Specifically, for Compound 1, 80 mg / day, 120 mg / day, 160 mg / day, 200 mg / day and 240 mg / day are preferred, 80 mg / day, 120 mg / day and 160 mg / day are more preferred, 120 mg / day and 160 mg / day are even more preferred, and 160 mg / day is particularly preferred.
[0029] In the present invention, the daily dose of the antiandrogen on the day of administration is preferably 50 to 150%, more preferably 50 to 100%, more preferably 75 to 100%, and particularly preferably 100%, of the recommended dose when the antiandrogen is administered alone, from the viewpoint of enhancing the antitumor effect. Specifically, the recommended dose when abiraterone is administered alone is 1000 mg / day of abiraterone acetate for a typical adult. The usual administration method is to administer 1000 mg of abiraterone acetate once daily. The dose may be increased or decreased as needed. In the present invention, the preferred daily dose is 500 to 1500 mg of abiraterone acetate, more preferably 500 to 1000 mg, more preferably 750 to 1000 mg, and particularly preferably 1000 mg.
[0030] The recommended dose of enzalutamide when administered alone is usually 160 mg / day for adults, and the usual administration method is 160 mg administered once daily. The dose may be increased or decreased as needed. In the present invention, the preferred daily dose of enzalutamide is 80 to 240 mg, more preferably 80 to 160 mg, more preferably 120 to 160 mg, and particularly preferably 160 mg.
[0031] The recommended dose of darolutamide when administered alone is usually 1200 mg / day for adults, and the usual administration method is 600 mg twice daily. The dose may be increased or decreased as needed. In the present invention, the preferred daily dose of darolutamide is 600 to 1800 mg, more preferably 600 to 1200 mg, even more preferably 900 to 1200 mg, and particularly preferably 1200 mg.
[0032] The recommended dose of apalutamide when administered alone is usually 240 mg / day for adults, and the usual administration method is 240 mg once daily. The dose may be increased or decreased as needed. In the present invention, the preferred daily dose of apalutamide is 120 to 360 mg, more preferably 120 to 240 mg, more preferably 180 to 240 mg, and particularly preferably 240 mg.
[0033] In the present invention, the term "recommended dose" refers to a dose that brings about the maximum therapeutic effect within the range of safe use, as determined by clinical trials or the like. Specifically, this refers to a dose approved, recommended, or advised by public institutions or organizations such as the Pharmaceuticals and Medical Devices Agency (PMDA; Pharmaceuticals and Medical Devices Agency), the U.S. Food and Drug Administration (FDA; Food and Drug Administration), the European Medicines Agency (EMA; European Medicines Agency), etc., and is described in package inserts, interview forms, treatment guidelines, etc., and a dose approved by any of the public institutions, PMDA, FDA, or EMA, is preferred.
[0034] The administration schedule of Compound 1 or a salt thereof and antiandrogen agents of the present invention can be appropriately selected depending on the type of cancer, stage of disease, etc. In the case of Compound 1 or a salt thereof, an administration schedule of 5 consecutive days of administration followed by 2 days of rest is preferred, and an administration schedule of 4 weeks of administration using an administration method of 5 days of administration followed by 2 days of rest per week is most preferred, with this cycle being repeated. In the case of antiandrogens, the administration schedule recommended for each drug is preferred. As the administration schedule for abiraterone, enzalutamide, darolutamide, and apalutamide, daily administration is the most preferred.
[0035] The order of administration of Compound 1 or a salt thereof and an antiandrogen agent can be appropriately selected depending on the type of cancer, stage of disease, etc., but it does not matter which agent is administered first, or they can be administered simultaneously. When the two agents are not administered simultaneously, the administration interval between the two agents can be appropriately selected as long as the antitumor effect is enhanced, but is preferably 1 to 7 days, more preferably 1 to 5 days, and particularly preferably 1 to 2 days.
[0036] Suitable combinations of daily doses of Compound 1 or a salt thereof and an antiandrogen in the present invention on the day of administration include, for normal adults, the following: for Compound 1 or a salt thereof, 50 to 100% of the recommended dose when administered alone, and for antiandrogens, 100% of the recommended dose when administered alone. for Compound 1 or a salt thereof, 75 to 100% of the recommended dose when administered alone, and for antiandrogens, 100% of the recommended dose when administered alone. for Compound 1 or a salt thereof, 50% of the recommended dose when administered alone, and for antiandrogens, 100% of the recommended dose when administered alone. for Compound 1 or a salt thereof, 75% of the recommended dose when administered alone, and for antiandrogens, 100% of the recommended dose when administered alone. for Compound 1 or a salt thereof, 100% of the recommended dose when administered alone, and for antiandrogens, 100% of the recommended dose when administered alone.
[0037] For Compound 1 or a salt thereof, 50-100% of the recommended dose when administered alone, and for abiraterone, 100% of the recommended dose when administered alone. For Compound 1 or a salt thereof, 50-100% of the recommended dose when administered alone, and for enzalutamide, 100% of the recommended dose when administered alone. For Compound 1 or a salt thereof, 50-100% of the recommended dose when administered alone, and for darolutamide, 100% of the recommended dose when administered alone. For Compound 1 or a salt thereof, 50-100% of the recommended dose when administered alone, and for apalutamide, 100% of the recommended dose when administered alone.
[0038] For Compound 1 or a salt thereof, 75-100% of the recommended dose when administered alone, and for abiraterone, 100% of the recommended dose when administered alone. For Compound 1 or a salt thereof, 75-100% of the recommended dose when administered alone, and for enzalutamide, 100% of the recommended dose when administered alone. For Compound 1 or a salt thereof, 75-100% of the recommended dose when administered alone, and for darolutamide, 100% of the recommended dose when administered alone. For Compound 1 or a salt thereof, 75-100% of the recommended dose when administered alone, and for apalutamide, 100% of the recommended dose when administered alone.
[0039] For Compound 1 or a salt thereof, 50% of the recommended dose when administered alone, and for abiraterone, 100% of the recommended dose when administered alone.For Compound 1 or a salt thereof, 50% of the recommended dose when administered alone, and for enzalutamide, 100% of the recommended dose when administered alone.For Compound 1 or a salt thereof, 50% of the recommended dose when administered alone, and for darolutamide, 100% of the recommended dose when administered alone.For Compound 1 or a salt thereof, 50% of the recommended dose when administered alone, and for apalutamide, 100% of the recommended dose when administered alone.
[0040] For Compound 1 or a salt thereof, 75% of the recommended dose when administered alone, and for abiraterone, 100% of the recommended dose when administered alone.For Compound 1 or a salt thereof, 75% of the recommended dose when administered alone, and for enzalutamide, 100% of the recommended dose when administered alone.For Compound 1 or a salt thereof, 75% of the recommended dose when administered alone, and for darolutamide, 100% of the recommended dose when administered alone.For Compound 1 or a salt thereof, 75% of the recommended dose when administered alone, and for apalutamide, 100% of the recommended dose when administered alone.
[0041] For Compound 1 or a salt thereof, 100% of the recommended dose when administered alone, and for abiraterone, 100% of the recommended dose when administered alone.For Compound 1 or a salt thereof, 100% of the recommended dose when administered alone, and for enzalutamide, 100% of the recommended dose when administered alone.For Compound 1 or a salt thereof, 100% of the recommended dose when administered alone, and for darolutamide, 100% of the recommended dose when administered alone.For Compound 1 or a salt thereof, 100% of the recommended dose when administered alone, and for apalutamide, 100% of the recommended dose when administered alone.
[0042] For Compound 1 or a salt thereof, 80 to 160 mg / day as Compound 1, and for abiraterone, 1000 mg / day as abiraterone acetate. For Compound 1 or a salt thereof, 80 to 160 mg / day as Compound 1, and 160 mg / day as enzalutamide. For Compound 1 or a salt thereof, 80 to 160 mg / day as Compound 1, and 1200 mg / day as darolutamide. For Compound 1 or a salt thereof, 80 to 160 mg / day as Compound 1, and 240 mg / day as apalutamide.
[0043] For Compound 1 or a salt thereof, 120 to 160 mg / day as Compound 1, and for abiraterone, 1000 mg / day as abiraterone acetate. For Compound 1 or a salt thereof, 120 to 160 mg / day as Compound 1, and 160 mg / day as enzalutamide. For Compound 1 or a salt thereof, 120 to 160 mg / day as Compound 1, and 1200 mg / day as darolutamide. For Compound 1 or a salt thereof, 120 to 160 mg / day as Compound 1, and 240 mg / day as apalutamide.
[0044] For Compound 1 or a salt thereof, 80 mg / day as Compound 1, and for abiraterone, 1000 mg / day as abiraterone acetate. For Compound 1 or a salt thereof, 80 mg / day as Compound 1, and 160 mg / day as enzalutamide. For Compound 1 or a salt thereof, 80 mg / day as Compound 1, and 1200 mg / day as darolutamide. For Compound 1 or a salt thereof, 80 mg / day as Compound 1, and 240 mg / day as apalutamide.
[0045] For Compound 1 or a salt thereof, 120 mg / day as Compound 1, and for abiraterone, 1000 mg / day as abiraterone acetate. For Compound 1 or a salt thereof, 120 mg / day as Compound 1, and 160 mg / day as enzalutamide. For Compound 1 or a salt thereof, 120 mg / day as Compound 1, and 1200 mg / day as darolutamide. For Compound 1 or a salt thereof, 120 mg / day as Compound 1, and 240 mg / day as apalutamide.
[0046] For Compound 1 or a salt thereof, 160 mg / day as Compound 1, and for abiraterone, 1000 mg / day as abiraterone acetate. For Compound 1 or a salt thereof, 160 mg / day as Compound 1, and 160 mg / day as enzalutamide. For Compound 1 or a salt thereof, 160 mg / day as Compound 1, and 1200 mg / day as darolutamide. For Compound 1 or a salt thereof, 160 mg / day as Compound 1, and 240 mg / day as apalutamide.
[0047] Suitable 7-day administration schedules in the present invention for typical adults include the following, and this 7-day administration schedule is repeated once or twice or more times: For Compound 1 or a salt thereof, 80 to 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period; for abiraterone, 1000 mg of abiraterone acetate is administered once daily for 7 consecutive days; for Compound 1 or a salt thereof, 80 to 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period; for enzalutamide, 160 mg is administered once daily for 7 consecutive days; for Compound 1 or a salt thereof, 80 to 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period; and for darolutamide, 600 mg is administered twice daily for 7 consecutive days. For Compound 1 or a salt thereof, 80 to 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for apalutamide, 240 mg is administered once daily for 7 consecutive days. For Compound 1 or a salt thereof, 120 to 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for abiraterone, 1000 mg of abiraterone acetate is administered once daily for 7 consecutive days. For Compound 1 or a salt thereof, 120 to 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days. For Compound 1 or a salt thereof, 120 to 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for darolutamide, 600 mg is administered twice daily for 7 consecutive days. Compound 1 or a salt thereof is administered at 120 to 160 mg as Compound 1 once daily for 5 consecutive days followed by a 2-day drug holiday, and apalutamide is administered at 240 mg once daily for 7 consecutive days.
[0048] For Compound 1 or a salt thereof, 80 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for abiraterone, 1000 mg of abiraterone acetate is administered once daily for 7 consecutive days. For Compound 1 or a salt thereof, 80 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days. For Compound 1 or a salt thereof, 80 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for darolutamide, 600 mg is administered twice daily for 7 consecutive days. For Compound 1 or a salt thereof, 80 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for apalutamide, 240 mg is administered once daily for 7 consecutive days.
[0049] For Compound 1 or a salt thereof, 120 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for abiraterone, 1000 mg of abiraterone acetate is administered once daily for 7 consecutive days. For Compound 1 or a salt thereof, 120 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days. For Compound 1 or a salt thereof, 120 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for darolutamide, 600 mg is administered twice daily for 7 consecutive days. For Compound 1 or a salt thereof, 120 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for apalutamide, 240 mg is administered once daily for 7 consecutive days.
[0050] For Compound 1 or a salt thereof, 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for abiraterone, 1000 mg of abiraterone acetate is administered once daily for 7 consecutive days. For Compound 1 or a salt thereof, 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for enzalutamide, 160 mg is administered once daily for 7 consecutive days. For Compound 1 or a salt thereof, 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for darolutamide, 600 mg is administered twice daily for 7 consecutive days. For Compound 1 or a salt thereof, 160 mg of Compound 1 is administered once daily for 5 consecutive days followed by a 2-day rest period, and for apalutamide, 240 mg is administered once daily for 7 consecutive days.
[0051] The combined administration of Compound 1 or a salt thereof and an antiandrogen brings about a superior therapeutic effect compared to the administration of each agent alone. Items that can be used to evaluate the therapeutic effect of the present invention include, but are not limited to, the following: radiological progression-free survival (rPFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), prostate-specific antigen (PSA) response rate (PSA30 and PSA50) and time to progression, time to symptomatic skeletal-related event (SSRE) onset, change in bone scan index (BSI), and brief pain inventory-short Changes in the BPI-SF score, changes in bone metabolic markers, time to start of next treatment for prostate cancer (TTNT), time to start of next chemotherapy with a cytotoxic drug for prostate cancer (TTNC), time from registration to progression or death after next treatment (PFS2), overall survival (OS), best overall response (BOR) based on RECIST (which may include complete response (CR), partial response (PR), stable disease (SD))
[0052] In the present invention, Compound 1 or a salt thereof, and the antiandrogen agent may be formulated so that each active ingredient is divided into multiple dosage forms, or may be formulated together into a single dosage form (i.e., formulated as a combination drug), depending on the dosage form and administration schedule of each active ingredient. Furthermore, each formulation may be manufactured and sold together in a single package suitable for combined use, or each formulation may be manufactured and sold separately in separate packages.
[0053] The administration form of the antitumor agent of the present invention is not particularly limited and can be appropriately selected depending on the purpose of treatment, and specific examples include oral preparations (tablets, coated tablets, powders, granules, capsules, liquid preparations, etc.), injections, suppositories, patches, ointments, etc. Oral preparations are preferred.
[0054] These various dosage forms of preparations can be prepared by commonly known methods using pharmaceutically acceptable carriers as needed, including various carriers commonly used in conventional pharmaceutical preparations, such as excipients, binders, disintegrants, lubricants, diluents, solubilizers, suspending agents, isotonicity agents, pH adjusters, buffers, stabilizers, colorants, flavoring agents, and odorants.
[0055] The present invention also relates to an agent for enhancing the antitumor effect of an antiandrogen, comprising Compound 1 or a salt thereof as an active ingredient. Here, "enhancement of the antitumor effect of an antiandrogen" by Compound 1 or a salt thereof means that the combined use of Compound 1 or a salt thereof with an antiandrogen produces an antitumor effect that exceeds the antitumor effect of the antiandrogen alone. The antitumor effect enhancer has the formulation of the antitumor agent described above.
[0056] The present invention also relates to an antitumor agent comprising Compound 1 or a salt thereof, which is administered in combination with an antiandrogen agent. The antitumor agent has the above-mentioned formulation.
[0057] The present invention also relates to an antitumor agent comprising Compound 1 or a salt thereof in combination with an antiandrogen agent, the antitumor agent having the above-mentioned formulation.
[0058] The present invention also relates to a kit formulation including instructions for use describing the coadministration of Compound 1 or a salt thereof with an antiandrogen. Here, the "instructions" may be any instructions that describe the above-mentioned dosage, and may be legally binding or not, but preferably recommend the above-mentioned dosage. Specific examples include package inserts, pamphlets, etc. Furthermore, the kit formulation including instructions for use may be one in which the instructions for use are printed and attached to the package of the kit formulation, or one in which the instructions for use are enclosed in the package of the kit formulation together with the antitumor agent.
[0059] The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples, and many modifications can be made by those skilled in the art within the technical scope of the present invention.
[0060] Example 1: In vitro combination analysis of Compound 1 and abiraterone Human prostate cancer cells VCaP (American Type Culture Collection) were grown in RPMI-1640 medium (Fujifilm Wako Pure Chemical Industries) containing 10% fetal bovine serum (FBS). The cells were maintained at 37°C and 5% CO2 and subcultured every 4 to 10 days at a ratio of 1:2 to 1:5. The viable cell count was measured using CellTiter-Glo 2.0® Reagent (Promega). Cells were harvested by standard methods, suspended in medium, and seeded into 384-well plates. The seeding density was 900 cells / 40 μL per well. 37°C, 5% CO2 ２ After overnight incubation at 4°C, abiraterone and compound 1 dissolved in DMSO were added using a D300e digital dispenser (Tecan). Abiraterone was added at nine concentrations (0, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, and 30 μM), and compound 1 was added at six concentrations (0, 0.1, 0.3, 1, 3, and 10 μM), for a total of 54 combinations. Four wells were allocated to each combination. In addition, the cell number at the start of drug treatment (Day 0) was measured using 40 μL of CellTiter-Glo 2.0 per well. ＴＭ The reagent was added, and the mixture was incubated at room temperature for 10 minutes. Chemiluminescence was then measured using a plate reader, Spark 10M (Tecan). The compound-added cells were then further incubated at 37°C, 5% CO ２ The cells were incubated at RT for 5 days and the number of viable cells was measured in the same manner as on Day 0. As a control, the cells were cultured with the addition of only the evaluation medium (both drug concentrations were 0 μM), and the number of viable cells was measured (control group).
[0061] From the measured viable cell counts, the rate of increase or decrease in cell count after the start of drug treatment at each drug treatment concentration was calculated as follows: (1) In the case of a concentration where the number of cells after drug treatment (Day 5) was greater than the number of cells at the start of drug treatment (Day 0) (growth inhibition), the cell growth inhibition rate was calculated compared to the control group on Day 5. Cell growth inhibition rate (%) = (number of viable cells in test group - number of viable cells in control group) / (number of viable cells in control group) x 100
[0062] (2) In the case of a concentration where the number of cells after drug treatment (Day 5) is smaller than the number of cells at the start of drug treatment (Day 0) (cell death), the cell reduction rate on Day 5 compared to the number of cells at the start of drug treatment (Day 0) was calculated. Cell proliferation rate (%) = (number of viable cells in the test group - number of viable cells at the start of drug treatment) / (number of viable cells in the control group - number of viable cells at the start of drug treatment) x 100
[0063] An example of the results is shown in Figure 1. The obtained cell proliferation inhibition rates (%) were analyzed by Aspin-Welch t-test, and the results showed that the compound 1 + abiraterone combination treatment group had a significantly higher cell proliferation inhibition rate than the compound 1 single-drug treatment group or abiraterone single-drug treatment group and the control group, indicating a stronger cell proliferation inhibitory effect.
[0064] Example 2: In Vitro Combination Analysis of Compound 1 and Enzalutamide. Human prostate cancer cells, VCaP, were grown in RPMI-1640 medium containing 10% FBS, and human prostate cancer cells, 22Rv1 (European Collection of Cell Cultures), were grown in phenol red-free RPMI 1640 medium containing 10% FBS (Thermo Scientific). Cells were maintained at 37°C and 5% CO2 and passaged every 4–10 days at a ratio of 1:2 to 1:5. Cells were harvested using standard methods, suspended in phenol red-free RPMI 1640 containing 10% charcoal-stripped fetal bovine serum (DCC-FBS), and seeded into 384-well plates. 22Rv1 cells were seeded at 400 cells / 40 μL per well, and VCaP cells were seeded at 900 cells / 40 μL per well. 37°C, 5% CO ２ After overnight incubation at 4°C, enzalutamide dissolved in DMSO, Compound 1, and dihydrotestosterone (DHT) (final concentration 0.1 nmol / L) were added using a D300e digital dispenser (Tecan), and the same analysis as for abiraterone was performed.
[0065] An example of the results is shown in Figure 2. The obtained cell proliferation inhibition rates (%) were analyzed by Aspin-Welch t-test, and the results showed that the compound 1 + enzalutamide combination treatment group had a significantly higher cell proliferation inhibition rate than the compound 1 single agent treatment group, the enzalutamide single agent treatment group, and the control group, indicating a stronger cell proliferation inhibitory effect.
[0066] Example 3: In Vitro Combination Analysis of Compound 1 and Darolutamide Human prostate cancer cells VCaP were grown in RPMI-1640 medium containing 10% FBS, human prostate cancer cells LNCaP (Microbial Chemistry Institute) were grown in RPMI-1640 medium containing 5% FBS, and 22Rv1 cells were grown in phenol red-free RPMI 1640 medium containing 10% FBS. Cells were maintained at 37°C in 5% CO2 and passaged every 4 to 10 days at a ratio of 1:2 to 1:5. Cells were harvested by standard methods, suspended in phenol red-free RPMI 1640 containing 5% DCC-FBS (for LNCaP) or 10% (for 22Rv1 and VCaP), and seeded into 384-well plates. The seeding number was 400 cells / 40 μL per well for LNCaP and 22Rv1, and 900 cells / 40 μL per well for VCaP. ２ After overnight incubation at 4°C, darolutamide, Compound 1, and DHT (final concentration: 0.1 nmol / L) dissolved in DMSO were added using a D300e digital dispenser (Tecan), and the same analysis as for abiraterone was performed.
[0067] Examples of the results are shown in Figures 3-1 and 3-2. The obtained cell proliferation inhibition rates (%) were analyzed by Aspin-Welch t-test. As a result, the group treated with Compound 1 and darolutamide in combination showed a significantly higher cell proliferation inhibition rate than the group treated with Compound 1 alone or darolutamide alone, and the control group, indicating a stronger cell proliferation inhibitory effect.
[0068] Example 4: Evaluation of the antitumor effect of the combination of Compound 1 and enzalutamide in a castration-resistant prostate cancer LNCaP subcutaneously xenografted model. Castration-resistant prostate cancer LNCaP-Xeno-IL-6 cells (reported as LNCaP-IL-6+ cells in the paper) were established from human prostate cancer LNCaP cells based on a paper report (Clin Cancer Res, 2001 7:2941-8) and used in the study. LNCaP-Xeno-IL-6 cells were cultured in RPMI 1640 medium containing 5% FBS and human recombinant IL-6 (final concentration 5 ng / mL). Normal human lung fibroblasts (NHLF) were cultured as feeder cells in FBM medium (LONZA). LNCaP-Xeno-IL-6 cells and NHLF were cultured at 37°C and 5% CO ２ The cells were subcultured in an incubator at a ratio of 1:3 to 1:5 every 4 to 10 days. 2 × 10 LNCaP-Xeno-IL-6 cells were injected subcutaneously into 6-week-old C.B-17 SCID mice (Jackson Laboratory Japan) near the right hind rib. ６ cells / 0.1 mL, NHLF 1 x 10 ６ A cell suspension was prepared in 50% Matrigel (Corning) solution containing DHT (final concentration 10 nmol / L) so that the cell suspension was 0.1 mL per 100 mm of the mouse. 3 The tumors were allowed to grow until they reached a tumor volume (TV) of 100 mm, after which they were castrated. The tumor diameter was measured using a Digimatic caliper to measure the long and short diameters of the tumor, and the TV was calculated using the following formula: TV (mm ３ ) = major axis (mm) × minor axis (mm) × minor axis (mm) / 2
[0069] Three days after castration surgery, animals were assigned to each group (6 animals per group) using a stratified random allocation method with TV as an index. The day when the groups were assigned (n=6) was designated as Day 1. The relative tumor volume change rate (T / C) was calculated from the TV using the following formula: T / C (%) = (average TV of each drug-administered group) / (average TV of the control group) x 100
[0070] Body weight was measured using an electronic animal balance. The weight change rate on day n (BWCn) was calculated from the weight on day n (BWn) using the following formula: Weight change rate BWCn (%) = (BWn - BW1) / BW1 x 100
[0071] An appropriate amount of Japanese Pharmacopoeia water for injection was added to achieve a hypromellose concentration of 0.5 w / v%, followed by stirring with a stirrer to completely dissolve the mixture, thereby preparing a 0.5% hypromellose aqueous solution. Compound 1 was ground using a rotation / revolution mixer (Thinky), suspended in a 0.5% hypromellose aqueous solution to a predetermined concentration, and sonicated to obtain a homogeneous suspension. This suspension was orally administered once daily at 10 mg / kg / day or 14 mg / kg / day of Compound 1 for 5 consecutive days, followed by a 2-day drug-free period, three times. Enzalutamide was ground using a rotation / revolution mixer, suspended in a 0.5% hypromellose aqueous solution to a predetermined concentration, and sonicated to obtain a homogeneous suspension. This suspension was orally administered once daily for 21 consecutive days at 10 mg / kg / day of enzalutamide. DMSO was added to NVP-AUY922 to a concentration of 71.4 mg / mL. A homogeneous solution was then obtained by sonication. This solution was diluted 20-fold with a Tween 20 / physiological saline mixture (Tween 20:physiological saline = 1:18). This solution was administered intravenously three times at 35.7 mg / kg / day, once daily every other day, followed by a one-day rest period. This cycle was repeated three times. An appropriate amount of Japanese Pharmacopoeia water for injection was added to achieve a 17.5 w / v% hydroxypropyl-β-cyclodextrin (HP-β-CD) concentration, and the mixture was stirred with a stirrer to completely dissolve the solution, preparing a 17.5% HP-β-CD aqueous solution. A 17.5% HP-β-CD aqueous solution was added to AT13387 monolactate to a concentration of 9 mg / mL of AT13387, and the mixture was sonicated to form a homogeneous solution. This solution was intraperitoneally administered at 90 mg / kg / day once a day, once a week, three times. The results are shown in Figure 4 and Table 1.
[0072]
[0073] Analysis of the TV on Day 22 for each group using Dunnett's test showed that the AT13387 or enzalutamide monotherapy groups, and the compound 1 + enzalutamide, NVP-AUY922 + enzalutamide, or AT13387 + enzalutamide combination groups had significantly lower TVs compared to the control group, demonstrating antitumor efficacy. The compound 1 and NVP-AUY922 monotherapy groups tended to have lower TVs, but no significant differences were observed compared to the control group. Furthermore, analysis using the Aspin-Welch t-test showed that the compound 1 + enzalutamide combination group had significantly lower TVs compared to the compound 1 or enzalutamide monotherapy groups, demonstrating a stronger antitumor effect. The mean weight change rate of the combination therapy group was not associated with increased toxicity compared to the compound 1 or enzalutamide monotherapy groups. On the other hand, no significant difference was observed between the NVP-AUY922 + enzalutamide or AT13387 + enzalutamide combination administration groups and the enzalutamide single drug group.
[0074] Example 5: Evaluation of the antitumor effect of a combination of Compound 1 and enzalutamide in a castration-resistant prostate cancer VCaP subcutaneous transplant model Human prostate cancer VCaP cells were cultured in RPMI 1640 medium containing 10% FBS. The cells were passaged at a ratio of 1:2 to 1:5 every 4 to 10 days in a 37°C, 5% CO2 incubator. 5 x 10 VCaP cells were subcutaneously injected into 7-week-old C.B-17 SCID mice (Jackson Laboratory Japan, Inc.) near the right posterior rib. 6 A cell suspension was prepared with 50% Matrigel (Corning) solution at a cell / 0.1 mL concentration and transplanted. 3 After the tumors were allowed to grow, they were castrated until they reached a tumor volume (TV) of 220-390 mm. 3 The tumors were allowed to grow (2-3 weeks) until they reached a tumor volume (TV) of 1000 mg / kg. Animals were assigned to each group (n=6) by stratified randomization using TV as an index, with 6 animals assigned to each group, and the day on which the groups were assigned (n=6) was designated Day 0. Measurement of tumor diameter and body weight, and preparation of suspensions of Compound 1 or enzalutamide were performed in the same manner as in Example 4. The results are shown in Figure 5 and Table 2.
[0075]
[0076] Analysis of the TV on Day 29 for each group using Dunnett's test showed that the group administered the combination of Compound 1 and enzalutamide had a significantly lower TV than the control group, indicating an antitumor effect. On the other hand, the Compound 1 group tended to have a lower TV, but no significant difference was observed compared to the control group, and the enzalutamide monotherapy group showed no antitumor effect. Furthermore, analysis using the Aspin-Welch t-test showed that the group administered the combination of Compound 1 and enzalutamide had a significantly lower TV than the Compound 1 or enzalutamide monotherapy groups, indicating a stronger antitumor effect. The mean weight change rate for the combination therapy group was not associated with increased toxicity compared to the Compound 1 or enzalutamide monotherapy groups.
[0077] Example 6: Evaluation of antitumor activity of a combination of Compound 1 and darolutamide in a castration-resistant prostate cancer LNCaP subcutaneous transplant model The model was the same as in Example 4. However, in this case, five animals were assigned to each group. The day on which the animals were assigned to the groups (n=5) was designated Day 0. Measurement of tumor diameter, weight, and preparation of a suspension of Compound 1 were performed in the same manner as in Example 4.
[0078] A 0.5% hypromellose aqueous solution was prepared by adding an appropriate amount of Japanese Pharmacopoeia water for injection to achieve a hypromellose concentration of 0.5 w / v%, followed by stirring using a stirrer to completely dissolve the mixture. Darolutamide was ground using a rotation / revolution mixer, suspended in a 0.5% hypromellose aqueous solution to a predetermined concentration, and then sonicated to obtain a homogeneous suspension. This suspension was orally administered twice daily for 21 consecutive days at 50 mg / kg / day of darolutamide. The results are shown in Figure 6 and Table 3.
[0079]
[0080] Analysis of TV on Day 22 for each group using Dunnett's test showed that the darolutamide monotherapy group and the Compound 1 + darolutamide combination group had significantly lower TVs compared to the control group, indicating antitumor effects. The Compound 1 monotherapy group tended to have lower TVs, but no significant difference was observed compared to the control group. Furthermore, analysis using the Aspin-Welch t-test showed that the Compound 1 + darolutamide combination group had significantly lower TVs compared to the Compound 1 monotherapy group, indicating a stronger antitumor effect. The Compound 1 (10 mg / kg / day) + darolutamide combination group had significantly lower TVs compared to the darolutamide monotherapy group, indicating a stronger antitumor effect. The mean weight change rate in the combination therapy group was not associated with increased toxicity compared to the Compound 1 or darolutamide monotherapy groups.
[0081] Example 7: Evaluation of antitumor activity of a combination of Compound 1 and abiraterone in a castration-resistant prostate cancer VCaP subcutaneous transplant model The model was the same as in Example 5. However, here, the day on which grouping (n=6) was performed was designated as Day 1. Measurement of tumor diameter, measurement of body weight, and preparation of a suspension of Compound 1 and a solution of AT13387 were the same as in Example 4.
[0082] A 0.5% hypromellose aqueous solution was prepared by adding an appropriate amount of Japanese Pharmacopoeia water for injection to a hypromellose concentration of 0.5 w / v%, followed by stirring using a stirrer to completely dissolve the solution. Abiraterone acetate was ground using a rotation / revolution mixer, suspended in a 0.5% hypromellose aqueous solution to the desired concentration, and sonicated to obtain a homogeneous suspension. This suspension was orally administered once daily for 21 consecutive days at 200 mg / kg / day of abiraterone. The results are shown in Figure 7 and Table 4.
[0083]
[0084] Analysis of the TV on Day 29 for each group using Dunnett's test showed that the AT13387 group, the Compound 1 14 mg / kg / day group, or the abiraterone group (single-drug groups), and the Compound 1 + abiraterone or AT13387 + abiraterone combination groups had significantly lower TVs compared to the control group, demonstrating antitumor efficacy. The Compound 1 10 mg / kg / day group (single-drug group) tended to have lower TVs, but no significant difference was observed compared to the control group. Furthermore, analysis using the Aspin-Welch t-test showed that the Compound 1 + abiraterone combination group had significantly lower TVs compared to the Compound 1 or abiraterone single-drug groups, demonstrating a stronger antitumor effect. The mean weight change rate of the combination-administered group was not associated with increased toxicity compared to the Compound 1 or abiraterone single-drug groups. On the other hand, the AT13387 + abiraterone combination group had a significantly lower TV than the abiraterone single drug group, indicating a stronger antitumor effect, but no significant difference was observed compared to the AT13387 single drug group.
[0085] Example 8: Conducting a Phase 2 Clinical Trial to Evaluate Combination Therapy of Pimitespib (Compound 1) and Enzalutamide in Patients with CRPC
[0086]
[0087]
[0088] Methods: A clinical trial will be conducted to evaluate the combination of pimitespib and enzalutamide in patients with metastatic castration-resistant prostate cancer who have previously received one regimen of a novel hormonal agent. The study will consist of two parts. ・ Feasibility part: The primary objective is to evaluate the tolerability and safety of pimitespib combination therapy and determine the maximum tolerated dose (MTD). This will be a non-randomized design. ・ Expansion part: The primary objective is to evaluate the efficacy of pimitespib combination therapy (radiographic progression-free survival (rPFS) by independent imaging review based on RECIST v1.1 and PCWG3). Enrollment will begin after the completion of dose-limiting toxicity (DLT) evaluation in the feasibility part. Target number of cases (planned): In the feasibility part, up to 12 patients will be evaluated as DLT-evaluable patients, and in the expansion part, 20 patients (10 patients per group) will be enrolled as the efficacy analysis population. Diagnosis and main inclusion criteria: - Patients aged 18 years or older with metastatic CRPC. - Patients have a history of treatment with one new hormone agent (abiraterone in the feasibility part, and new hormone agents including abiraterone in the expansion part) for metastatic or non-metastatic CRPC or metastatic castration-sensitive prostate cancer. - Patients have no history of chemotherapy (cytotoxic anticancer agents, etc.) or Ra-223 administration for metastatic CRPC, and the most recent drug therapy was a new hormone agent with confirmed disease progression. Note that "disease progression" here refers to the following: 1. 1. PSA progression: An increase in PSA levels in two or more consecutive measurements spaced at least one week apart, with the PSA level increasing by 1 ng / mL or more (based on PCWG3), 2. Soft tissue lesion progression: Disease progression determined according to the definition of RECIST v1.1, 3. Bone lesion progression: The appearance of two or more new lesions on bone scintigraphy (based on PCWG3). Dosage and administration method: - Feasibility part: Pimitespib is administered orally at 160 mg (Level 1) or 120 mg (Level -1) once daily on an empty stomach (avoid 1 hour before and 2 hours after meals) for five consecutive days followed by two days off. Enzalutamide is administered orally at 160 mg once daily.- Expansion part: Pimitespib will be orally administered once daily on an empty stomach (avoiding administration 1 hour before and 2 hours after meals) at a dose not exceeding the MTD determined in the feasibility part, on a schedule of 5 consecutive days of administration followed by 2 days of rest. Enzalutamide will be orally administered at 160 mg once daily. - Pimitespib and enzalutamide may be taken simultaneously. Treatment period: One cycle is 28 days, and treatment will continue until the discontinuation criteria for study treatment are met. Evaluation criteria: Efficacy: RECIST Version 1.1, PCWG3 Safety: CTCAE Version 5.0.
[0089] Statistical methods: The analysis populations for this study are as follows:
[0090]
[0091] Analysis of primary endpoints - Feasibility part: For patients evaluable for DLT, the number of patients who experienced DLT in cycle 1, the incidence rate, and the 95% confidence interval (CI) for the incidence rate will be calculated for each dose level. All DLTs will be listed by patient. - Expansion part: Efficacy will be analyzed for the efficacy analysis population. Using the Cox proportional hazards model, the hazard ratio and 95% CI for rPFS by independent imaging review will be estimated for the pimitespib and enzalutamide combination therapy group compared to the enzalutamide monotherapy group. Using the log-rank test, a two-sided p-value will be calculated comparing rPFS by independent imaging review. The rPFS curve by independent imaging review will be presented using the Kaplan-Meier method. The median and 95% CI, as well as the bounded mean survival time and 95% CI will be estimated. The risk set number and event-free rate per month will be estimated. An overview of the study design is shown in Figure 8. Results from the feasibility part showed that no dose-limiting toxicity was observed when pimitespib was administered at 160 mg (Level 1) and enzalutamide was administered at 160 mg, which are the recommended doses for monotherapy, and that tolerability was confirmed. The expansion part is currently underway.
Claims
1. An antitumor agent characterized by the co-administration of 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazole-4-yl)-1H-imidazole-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}benzamide or a salt thereof with an antiandrogen agent.
2. The antitumor agent according to claim 1, wherein the antiandrogen agent is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
3. The antitumor agent according to claim 1, wherein the antiandrogen agent is enzalutamide.
4. An antitumor agent for treating prostate cancer, as described in any one of claims 1 to 3.
5. An antitumor agent according to any one of claims 1 to 3, which is an antitumor agent for treating castration-resistant prostate cancer.
6. An antitumor agent according to any one of claims 1 to 3, characterized in that 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazole-4-yl)-1H-imidazole-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}benzamide or a salt thereof and an antiandrogen are administered to a cancer patient simultaneously or separately at intervals.
7. An antitumor enhancer for antiandrogens, comprising 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazole-4-yl)-1H-imidazole-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}benzamide or a salt thereof as an active ingredient.
8. The antitumor effect enhancer according to claim 7, wherein the antiandrogen agent is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
9. The antitumor effect enhancer according to claim 7, wherein the anti-androgen agent is enzalutamide.
10. An antitumor effect enhancer according to any one of claims 7 to 9, which is an antitumor agent for treating prostate cancer.
11. An antitumor effect enhancer according to any one of claims 7 to 9, which is an antitumor agent for treating castration-resistant prostate cancer.
12. An antitumor effect enhancer according to any one of claims 7 to 9, characterized in that 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazole-4-yl)-1H-imidazole-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}benzamide or a salt thereof and an antiandrogen are administered to a cancer patient simultaneously or separately at intervals.
13. An antitumor agent comprising 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazole-4-yl)-1H-imidazole-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}benzamide or a salt thereof as an active ingredient, characterized by being administered in combination with an antiandrogen.
14. The antitumor agent according to claim 13, wherein the antiandrogen agent is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
15. The antitumor agent according to claim 13, wherein the antiandrogen agent is enzalutamide.
16. An antitumor agent according to any one of claims 13 to 15, which is an antitumor agent for treating prostate cancer.
17. An antitumor agent according to any one of claims 13 to 15, which is an antitumor agent for treating castration-resistant prostate cancer.
18. An antitumor agent according to any one of claims 13 to 15, characterized in that 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazole-4-yl)-1H-imidazole-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}benzamide or a salt thereof and an antiandrogen are administered to a cancer patient simultaneously or separately at intervals.
19. An antitumor agent comprising 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazole-4-yl)-1H-imidazole-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}benzamide or a salt thereof, combined with an antiandrogenic agent.
20. The antitumor agent according to claim 19, wherein the antiandrogen agent is one or more selected from abiraterone, enzalutamide, darolutamide, and apalutamide.
21. The antitumor agent according to claim 19, wherein the antiandrogen agent is enzalutamide.
22. An antitumor agent according to any one of claims 19 to 21, which is an antitumor agent for treating prostate cancer.
23. An antitumor agent according to any one of claims 19 to 21, which is an antitumor agent for treating castration-resistant prostate cancer.
24. An antitumor agent according to any one of claims 19 to 21, characterized in that 3-ethyl-4-{4-[4-(1-methyl-1H-pyrazole-4-yl)-1H-imidazole-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-1-yl}benzamide or a salt thereof and an antiandrogen are administered to a cancer patient simultaneously or separately at intervals.