Combination drug compositions of CDK4 / 6 inhibitors and their uses.

Abstract

This disclosure relates to combination pharmaceutical compositions of CDK4 / 6 inhibitors and their uses, specifically to combination pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant. This disclosure also relates to the use of such combination pharmaceutical compositions for the treatment of breast cancer. The combination pharmaceutical compositions of this disclosure produce better efficacy in reducing tumor growth or even eliminating tumors.

Description

[0001] This application is a divisional application of application filed on March 3, 2022, with application number 202280017434.5 and entitled "Combination Pharmaceutical Composition of CDK4 / 6 Inhibitor and Its Use Thereof".

[0002] Cross-reference to related applications

[0003] This disclosure claims the benefit and priority of Chinese Patent Application No. 202110236331.5, filed with the State Intellectual Property Office of the People's Republic of China on March 3, 2021, the entire contents of which are hereby incorporated herein by reference. Technical Field

[0004] This disclosure pertains to the field of pharmaceutical technology and relates to a combination pharmaceutical composition of CDK4 / 6 inhibitors and its use in the treatment of breast cancer. Background Technology

[0005] Cyclin-dependent kinases (CDKs) 4 / 6 are key regulators of the cell cycle, triggering the transition from the growth phase (G1 phase) to the DNA replication phase (S1 phase). During cell proliferation, the complex formed by CDKs 4 / 6 and cyclin D phosphorylates retinoblastoma protein (Rb). Once phosphorylated, the tumor suppressor protein Rb releases its tightly bound transcription factor E2F in its unphosphorylated state. E2F activates further transcription, propelling the cell cycle through the restriction point (R point) and progressing from G1 to S phase. Therefore, inhibiting CDKs 4 / 6 to prevent the formation of the Cyclin D-CDKs 4 / 6 complex can halt the cell cycle progression from G1 to S phase, thereby inhibiting tumor proliferation. WO2016141881 discloses a 2-hydropyrazole derivative as a selective CDKs 4 / 6 inhibitor, specifically disclosing a compound of formula (I) with the following structure.

[0006]

[0007] Fulvestrant, chemically known as 7-α-[9-(4,4,5,5,5-pentafluoropentanesulfinyl)nonyl]estrogens-1,3,5-(10)-trien-3,17-β-diol, has a relative molecular mass of 606.77. It is a white or off-white powder, insoluble in water. Fulvestrant is a novel estrogen receptor antagonist—an estrogen receptor downregulator—that acts as an anti-breast cancer drug. It binds to estrogen receptors at the cellular level, blocking and degrading estrogen receptors, thereby inhibiting the growth of tumor cells under the influence of estrogen.

[0008] According to the World Cancer Report, in 2012, there were approximately 1.7 million new cases of breast cancer globally, and about 500,000 deaths, accounting for 25% of all new cancer cases in women and 15% of all cancer deaths, ranking first in both categories. Of the new breast cancer cases each year, 3%-10% of women already have distant metastases at the time of diagnosis. Among early-stage patients, 30%-40% may progress to advanced breast cancer, with a 5-year survival rate of approximately 20%.

[0009] Advanced breast cancer (ABC) presents unique challenges in terms of treatment options and efficacy, and currently lacks a universally accepted standard treatment regimen. The overall median survival for advanced breast cancer is 2-3 years, varying depending on the molecular subtype. For HER2-positive ABC patients, anti-HER2 therapy can alter the natural course of the disease and significantly prolong survival; however, for triple-negative ABC patients, the overall prognosis has not yet shown significant improvement. Hormone receptor-positive (HR+) breast cancer accounts for approximately 65%-75% of breast cancers. Endocrine therapy, with its comparable efficacy to chemotherapy and fewer toxic side effects, has become the preferred treatment for hormone receptor-positive (HR+) metastatic breast cancer.

[0010] Although endocrine therapy is the main treatment option for hormone receptor-positive breast cancer, about 30% of hormone receptor-positive breast cancers are resistant to endocrine therapy, and almost all patients develop secondary resistance during subsequent treatment. Therefore, overcoming endocrine therapy resistance has become an urgent problem to be solved in the field of breast cancer treatment. Summary of the Invention

[0011] On the one hand, this disclosure provides a combination pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant.

[0012]

[0013] On the other hand, this disclosure provides a combination pharmaceutical composition for the treatment or prevention of breast cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant.

[0014] In some embodiments of this disclosure, the combination drug composition is packaged in the same kit, which also includes instructions for using a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with fulvestrant to treat or prevent breast cancer.

[0015] In some embodiments of this disclosure, the combination drug composition comprises: a drug composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a drug composition of fulvestrant.

[0016] In some embodiments of this disclosure, the combination pharmaceutical compositions are packaged in the same kit, which also includes instructions for using a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutical composition of fulvestrant to treat or prevent breast cancer.

[0017] In some embodiments of this disclosure, in the combined pharmaceutical composition, a pharmaceutically acceptable salt of the compound of formula (I) is a maleate, such as a monomaleate of the compound of formula (I).

[0018] In some embodiments of this disclosure, the combination pharmaceutical composition contains 20-240 mg, 40-180 mg, 60-180 mg, 80-180 mg, 100-180 mg, 120-180 mg, 150-180 mg, or 150-240 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0019] In some embodiments of this disclosure, the combination drug composition contains 20-240 mg, 40-180 mg, 60-180 mg, 80-180 mg, 100-180 mg, 120-180 mg, or 150-180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a drug composition thereof, calculated as a compound of formula (I).

[0020] In some embodiments of this disclosure, the combination drug composition contains 150 to 240 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a drug composition thereof, calculated as a compound of formula (I).

[0021] In some embodiments of this disclosure, the combination drug composition contains 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 180 mg or 240 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a drug composition thereof.

[0022] In some embodiments of this disclosure, the combination drug composition contains 60 mg, 120 mg, or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a drug composition thereof, calculated as a compound of formula (I).

[0023] In some embodiments of this disclosure, the combination drug composition contains 150 mg or 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a drug composition thereof, calculated as a compound of formula (I).

[0024] In some embodiments of this disclosure, the combination pharmaceutical composition contains 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as a compound of formula (I).

[0025] In some embodiments of this disclosure, the pharmaceutical composition of formula (I) or a pharmaceutically acceptable salt thereof is in a single-dose or multiple-dose form. In some embodiments of this disclosure, the pharmaceutical composition of formula (I) or a pharmaceutically acceptable salt thereof is in a multiple-dose form.

[0026] In some embodiments of this disclosure, the combination drug composition contains a daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments of this disclosure, the combination drug composition contains a compound of formula (I) or a pharmaceutically acceptable salt thereof in a once-daily dose.

[0028] In some embodiments of this disclosure, the combination drug composition contains a compound of formula (I) or a pharmaceutically acceptable salt thereof in a once-daily dose, and each dose is a single dose or multiple doses, usually multiple doses.

[0029] In some embodiments of this disclosure, the combination drug composition comprises a single dose of 5 mg, 50 mg, or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, the combination drug composition is in the form of a single-dose formulation containing 5 mg, 50 mg, or 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof thereof.

[0030] In some embodiments of this disclosure, the combination drug composition comprises a single dose of 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, the combination drug composition is in the form of a single-dose formulation containing 60 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof thereof.

[0031] In some embodiments of this disclosure, the combination pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit containing instructions for the treatment or prevention of breast cancer of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments of this disclosure, the combination drug composition contains 125 mg to 1000 mg, 125 mg to 750 mg, 250 mg to 750 mg, or 250 mg to 500 mg of fulvestrant, or a drug composition thereof.

[0033] In some embodiments of this disclosure, the combination drug composition contains 125 mg, 250 mg, 500 mg, 750 mg or 1000 mg of fulvestrant, or a drug composition thereof.

[0034] In some embodiments of this disclosure, the combination drug composition contains 250 mg or 500 mg of fulvestrant, or a drug composition thereof.

[0035] In some embodiments of this disclosure, the combination drug composition contains 500 mg of fulvestrant, or a drug composition thereof.

[0036] In some embodiments of this disclosure, the fulvestrant drug composition in the combination drug composition is in single-dose or multi-dose form.

[0037] In some embodiments of this disclosure, the combination drug composition of fulvestrant is in a multi-dose form.

[0038] In some embodiments of this disclosure, the content of fulvestrant in the combination drug composition is a dose for each treatment cycle.

[0039] In some embodiments of this disclosure, the fulvestrant content in the combination drug composition is a once-dose dose per treatment cycle.

[0040] In some embodiments of this disclosure, the combination drug composition contains a single dose of 250 mg of fulvestrant. Alternatively, the combination drug composition is in the form of a single-dose formulation containing 250 mg of fulvestrant or a drug composition thereof.

[0041] In some embodiments of this disclosure, the combination drug composition contains a fulvestrant drug composition packaged in a kit that also contains instructions for the use of fulvestrant in the treatment or prevention of breast cancer.

[0042] In some embodiments of this disclosure, the combination drug composition containing fulvestrant is packaged in a kit, the kit also containing instructions for the use of fulvestrant for the treatment or prevention of breast cancer, which may be the instructions in the package insert of a commercially available fulvestrant injection kit. In some embodiments of this disclosure, the instructions are for fulvestrant injection manufactured by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. (e.g., fulvestrant injection). The instructions are as described in the manual.

[0043] In some embodiments of this disclosure, the combination drug composition contains 20 to 240 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 125 mg to 1000 mg of fulvestrant.

[0044] In some embodiments of this disclosure, the combination drug composition contains 120 to 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 250 to 500 mg of fulvestrant.

[0045] In some embodiments of this disclosure, the combination drug composition comprises: a daily dose of a compound of formula (I) at a dose of 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 180 mg, or 240 mg, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and fulvestrant at a dose of 250 mg or 500 mg per treatment cycle.

[0046] In some embodiments of this disclosure, the combination drug composition comprises: a daily dose of a compound of formula (I) at a dose of 60 mg, 120 mg, 180 mg or 240 mg, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and a dose of fulvestrant at a dose of 250 mg or 500 mg per treatment cycle.

[0047] In some embodiments of this disclosure, the combination drug composition comprises: a daily dose of a compound of formula (I) at a dose of 150 mg or 180 mg, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and 500 mg of fulvestrant per treatment cycle.

[0048] In some embodiments of this disclosure, the combination drug composition comprises: a daily dose of a compound of formula (I) at a dose of 150 mg or 180 mg, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and 1000 mg of fulvestrant for the first treatment cycle.

[0049] In some embodiments of this disclosure, the combination drug composition comprises: a daily dose of a compound of formula (I) at a dose of 150 mg or 180 mg, or a pharmaceutically acceptable salt thereof, calculated as a compound of formula (I); and fulvestrant at a dose of 1000 mg for the first treatment cycle and 500 mg for each subsequent treatment cycle.

[0050] In some embodiments of this disclosure, the combination drug composition comprises: a daily dose of a compound of formula (I) at a dose of 180 mg, or a pharmaceutically acceptable salt thereof; and 500 mg of fulvestrant per treatment cycle.

[0051] In some embodiments of this disclosure, the combination drug composition comprises: a daily dose of a compound of formula (I) at a dose of 180 mg, or a pharmaceutically acceptable salt thereof; and fulvestrant at a dose of 1000 mg for the first treatment cycle and 500 mg for each subsequent treatment cycle.

[0052] In some embodiments of this disclosure, each treatment cycle is 28 days.

[0053] In some embodiments of this disclosure, the combination drug composition comprises: a pharmaceutical composition of a compound of formula (I) in a single dose of 50 mg, calculated as a compound of formula (I), or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition of fulvestrant in a single dose of 250 mg, calculated as fulvestrant. Alternatively, the combination drug composition is in the form of a single-dose formulation comprising: a compound of formula (I) in a single dose of 50 mg, calculated as a compound of formula (I), or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition of fulvestrant in a single dose of 250 mg, calculated as fulvestrant.

[0054] In some embodiments of this disclosure, the combination drug composition comprises: a pharmaceutical composition of a compound of formula (I) in a single dose of 60 mg, calculated as a compound of formula (I), or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition comprising a single dose of fulvestrant in a single dose of 250 mg, calculated as fulvestrant. Alternatively, the combination drug composition is in the form of a single-dose formulation comprising: a compound of formula (I) in a single dose of 60 mg, calculated as a compound of formula (I), or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition thereof comprising fulvestrant in a single dose of 250 mg, calculated as fulvestrant.

[0055] In some embodiments of this disclosure, the combination pharmaceutical composition is a formulation suitable for administration over a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a total dose of 1680–5040 mg (e.g., 3360 mg, 4200 mg, or 5040 mg) based on a compound of formula (I); and a pharmaceutical composition containing fulvestrant, in a total dose of 500–1000 mg based on fulvestrant.

[0056] In some embodiments of this disclosure, the combination drug composition is a formulation suitable for administration over a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a drug composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a total dose of 5040 mg based on the compound of formula (I); and a drug composition containing fulvestrant, in a total dose of 500–1000 mg based on fulvestrant.

[0057] In some embodiments of this disclosure, the combination drug composition is a formulation suitable for administration during a first treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a drug composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a total dose of 5040 mg based on the compound of formula (I); and a drug composition containing fulvestrant, in a total dose of 1000 mg based on fulvestrant.

[0058] In some embodiments of this disclosure, the combination drug composition is a formulation suitable for administration in a single treatment cycle (e.g., a 28-day treatment cycle) following a second treatment cycle, the formulation comprising: a drug composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a total dose of 5040 mg based on the compound of formula (I); and a drug composition containing fulvestrant, in a total dose of 500 mg based on fulvestrant.

[0059] In some embodiments of this disclosure, the combination pharmaceutical composition is a formulation suitable for administration over a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose ratio of (1-30):1, for example (1-25):1, (1.5-25):1, (1.5-20):1, (1.5-15):1, or (1.5-12):1, or any ratio within the foregoing range, and a pharmaceutical composition containing fulvestrant, wherein the dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is based on the compound of formula (I), and the dose of the pharmaceutical composition containing fulvestrant is based on fulvestrant.

[0060] In some embodiments of this disclosure, the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant may be in the form of a pharmaceutical composition, either individually or together.

[0061] On the other hand, this disclosure also provides a kit comprising (a) a first pharmaceutical composition comprising a compound of formula (I) as described in this disclosure or a pharmaceutically acceptable salt thereof; and (b) a second pharmaceutical composition comprising fulvestrant.

[0062] On the other hand, this disclosure also provides a kit for a pharmaceutical composition for treating or preventing breast cancer, comprising (a) a first pharmaceutical composition comprising a compound of formula (I) as described in this disclosure or a pharmaceutically acceptable salt thereof; and (b) a second pharmaceutical composition comprising fulvestrant. Alternatively, this disclosure also provides a combination pharmaceutical composition for treating or preventing breast cancer comprising: a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition of fulvestrant.

[0063] In some embodiments of this disclosure, in the combination drug composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared in a unit dosage form containing 5 mg, 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the fulvestrant is prepared in a unit dosage form containing 250 mg of fulvestrant.

[0064] In some embodiments of this disclosure, in the combination drug composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared in a unit dosage form containing 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the fulvestrant is prepared in a unit dosage form containing 250 mg of fulvestrant.

[0065] On the other hand, this disclosure also provides methods for treating or preventing breast cancer, comprising administering to an individual in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant, such as administering to an individual in need a therapeutically effective amount of the combination pharmaceutical composition described above in this disclosure.

[0066] On the other hand, this disclosure also provides a combination therapy for treating an individual with breast cancer, the method comprising administering to the individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of fulvestrant, administered alone.

[0067] On the other hand, this disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with fulvestrant in the preparation of a medicament for the treatment or prevention of breast cancer, such as the use of the above-described combination pharmaceutical compositions in the preparation of a medicament for the treatment or prevention of breast cancer. In some embodiments of this disclosure, the combination pharmaceutical composition is any of the combination pharmaceutical compositions described above in this disclosure.

[0068] On the other hand, this disclosure also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with fulvestrant for the treatment or prevention of breast cancer, such as the use of the combination pharmaceutical composition described above in this disclosure for the treatment or prevention of breast cancer.

[0069] In some embodiments of this disclosure, in the kits, methods, combination therapies, or uses, the definitions of the compound of formula (I) or its pharmaceutically acceptable salts and fulvestrant are the same as those defined for the compound of formula (I) or its pharmaceutically acceptable salts and fulvestrant in the combination drug compositions described above, such as content, dosage, form of presence, packaging form, etc.

[0070] In some embodiments of this disclosure, in the methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant are each in the form of a pharmaceutical composition and may be administered simultaneously, separately, in parallel, sequentially or at intervals.

[0071] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant have the same or different treatment cycles. In some specific embodiments of this disclosure, in the methods, combination therapies, or uses, the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.

[0072] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is a daily dose, which is administered by administering the compound of formula (I) or a pharmaceutically acceptable salt thereof once daily.

[0073] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is a daily dose, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a single-dose or multiple-dose manner, usually in a multiple-dose manner; further, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0074] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 60 mg; or, a daily dose of 120 mg; or, a daily dose of 180 mg; or, a daily dose of 240 mg.

[0075] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 150 mg; or a daily dose of 180 mg.

[0076] In some embodiments of this disclosure, in the methods, combination therapies or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of 180 mg.

[0077] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is administered in a multiple-dose manner, said multiple doses consisting of a pharmaceutical composition of a single 50 mg dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of this disclosure, in the methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily manner.

[0078] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is administered in a multiple-dose manner, said multiple doses consisting of a pharmaceutical composition of a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of this disclosure, in the methods, combination therapies, or uses, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily manner.

[0079] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is a dose for each treatment cycle, administered by daily application of the compound of formula (I) or a pharmaceutically acceptable salt thereof. The compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in single or multiple portions (e.g., 2 portions, 4 portions, 7 portions, 14 portions, 28 portions, or more portions).

[0080] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the content of fulvestrant in the combination drug composition is a dose for each treatment cycle, administered as follows: fulvestrant is administered on days 1 and 15 of the first treatment cycle, followed by administration on day 1 of each subsequent treatment cycle. Wherein, fulvestrant is packaged in single or multiple portions (e.g., 2 portions, 4 portions, or more portions). In some embodiments of this disclosure, fulvestrant is administered on days 1 and 15 of the first treatment cycle at the same dose each time; subsequently, it is administered on day 1 of each subsequent treatment cycle at the same dose as on day 1 of the first treatment cycle. In some embodiments of this disclosure, the dose administered each time during a treatment cycle of fulvestrant is the same.

[0081] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the content of fulvestrant in the combination drug composition is a dose for each treatment cycle, wherein fulvestrant is administered in a single-dose or multiple-dose manner. In some embodiments of this disclosure, fulvestrant is administered in a multiple-dose manner.

[0082] In some embodiments of this disclosure, in the methods, combination therapies, or uses, the content of fulvestrant in the combination pharmaceutical composition is a dose for each treatment cycle, wherein fulvestrant is administered in a multi-dose manner, the multi-dose consisting of a pharmaceutical composition of fulvestrant in a single dose of 250 mg.

[0083] In some embodiments of this disclosure, in the methods, combination therapies or uses, a treatment cycle is 28 days, with fulvestrant administered on days 1 and 15 of the first cycle, followed by fulvestrant administered on day 1 of each subsequent treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof administered daily from day 1 to day 28 of each treatment cycle.

[0084] In some specific embodiments of this disclosure, in the methods, combination therapies or uses, a treatment cycle is 28 days, with fulvestrant administered once on day 1 and day 15 of the first cycle, followed by fulvestrant administered once on day 1 of each subsequent treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof administered once daily from day 1 to day 28 of each treatment cycle.

[0085] In some embodiments of this disclosure, in the methods, combination therapies, or uses, a treatment cycle is 28 days, with administration once daily for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 1680 to 5040 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from a range of 1680 mg, 3360 mg, 4200 mg, 5040 mg, or any two of the above values. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 4200 mg or 5040 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably 5040 mg.

[0086] In some embodiments of this disclosure, in the methods, combination therapies or uses, a treatment cycle is 28 days, with 500 mg of fulvestrant administered once on day 1 and day 15 of the first treatment cycle, and 500 mg of fulvestrant administered once on day 1 of each subsequent treatment cycle.

[0087] In some embodiments of this disclosure, in the methods, combination therapies, or uses, a treatment cycle is 28 days; a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily for 28 consecutive days, with a total dose of 5040 mg administered per treatment cycle; 500 mg of fulvestrant is administered once on day 1 and day 15 of the first treatment cycle, and 500 mg of fulvestrant is administered once on day 1 of each subsequent treatment cycle.

[0088] In the embodiments of this disclosure, the above treatment cycle is repeated as long as the disease remains under control and the dosing regimen is clinically tolerable.

[0089] In some embodiments of this disclosure, the fulvestrant is prepared to be suitable for administering a single or multiple dose of 250 mg to 750 mg or 250 mg to 500 mg of fulvestrant to a patient per treatment cycle; pharmaceutical compositions containing the compound of formula (I) or a pharmaceutically acceptable salt thereof are prepared to be suitable for administering a single or multiple dose of 60 mg, 120 mg, 180 mg and / or 240 mg of the compound of formula (I) itself to a patient continuously daily.

[0090] In some embodiments of this disclosure, the fulvestrant is prepared to be administered to a patient in single or multiple doses of 250 mg to 750 mg or 250 mg to 500 mg per treatment cycle; pharmaceutical compositions containing the compound of formula (I) or a pharmaceutically acceptable salt thereof are prepared to be administered to a patient in single or multiple doses of 150 mg and / or 180 mg per day, based on the compound of formula (I) itself.

[0091] In some embodiments of this disclosure, in the methods, combination therapies or uses, the patient is given 125 mg, 250 mg, 500 mg, 750 mg or 1000 mg of fulvestrant per treatment cycle; or 250 mg or 500 mg of fulvestrant per treatment cycle.

[0092] In embodiments of this disclosure, in the methods, combination therapies, or uses, administration of fulvestrant on day 1 and day 15 of the first 28-day treatment cycle is each counted as one treatment cycle.

[0093] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for continuous daily administration to a patient in single or multiple doses of 60 mg, 120 mg, 180 mg and / or 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; or, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for continuous daily administration to a patient in single or multiple doses of 120 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for continuous daily administration to a patient in single or multiple doses of 60 mg, 120 mg, 180 mg and / or 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; or, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for continuous daily administration to a patient in single or multiple doses of 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative breast cancer.

[0096] In some embodiments of this disclosure, the breast cancer is selected from locally advanced and / or metastatic breast cancer.

[0097] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer.

[0098] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that is not eligible for radical surgery or radiotherapy.

[0099] In some embodiments of this disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopause breast cancer.

[0100] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer in postmenopausal or premenopausal / perimenopause patients.

[0101] In some embodiments of this disclosure, the breast cancer is selected from breast cancers from patients who have previously undergone bilateral oophorectomy.

[0102] In some embodiments of this disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopause breast cancer in patients who have previously undergone bilateral oophorectomy.

[0103] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer in postmenopausal or premenopausal / perimenopause patients who have previously undergone bilateral oophorectomy.

[0104] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that is not eligible for radical surgery or radiotherapy in postmenopausal or premenopausal / perimenopause patients.

[0105] In some embodiments of this disclosure, HR positivity includes estrogen receptor (ER) positivity and / or progesterone receptor (PR) positivity, defined as: the proportion of positively stained tumor cells ≥1% of all tumor cells.

[0106] In some embodiments of this disclosure, HER2 negative is defined as: immunohistochemical staining (IHC) showing HER2 as 0 / 1+; if the test shows 2+, fluorescence in situ hybridization (FISH) must be performed to confirm that it is negative or FISH test alone is negative.

[0107] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that has previously received no more than one line of chemotherapy.

[0108] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative breast cancer that has recurred or progressed during or within one year after adjuvant endocrine therapy and has not subsequently received endocrine therapy.

[0109] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative breast cancer that has relapsed or progressed more than 1 year after adjuvant endocrine therapy and subsequently progressed again after receiving advanced endocrine therapy; the advanced endocrine therapy is no more than one line of treatment.

[0110] In some embodiments of this disclosure, the breast cancer is selected from breast cancer that has progressed after primary metastatic disease received advanced endocrine therapy; the advanced endocrine therapy is no more than one line of treatment.

[0111] In some embodiments of this disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that has not previously received any systemic antitumor therapy for localized recurrence or metastatic disease.

[0112] In some embodiments of this disclosure, the endocrine therapy refers to treatment with tamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestane, goserelin, and leuprorelin.

[0113] In some embodiments of this disclosure, the endocrine therapy refers to treatment with tamoxifen, letrozole, exemestane, and goserelin.

[0114] In some embodiments of this disclosure, the endocrine therapy refers to tamoxifen and goserelin treatment.

[0115] The active components in the pharmaceutical combinations disclosed herein may be formulated independently, or in combination, with a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical combinations of this disclosure may also include additional therapeutic agents. In some embodiments of this disclosure, the additional therapeutic agents may be therapeutic agents known in the art for cancer, preferably therapeutic agents for breast cancer.

[0116] In some embodiments of this disclosure, the period is 28 days.

[0117] The amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof administered may be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the patient’s age, and health status.

[0118] Compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered via a variety of routes, including but not limited to: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, local, subcutaneous, intra-fat, intra-articular, intraperitoneal, and intrathecal. In one specific embodiment, compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[0119] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally on a continuous daily basis.

[0120] Compound (I) or a pharmaceutically acceptable salt thereof may be administered once or more daily. In some embodiments of this disclosure, compound (I) or a pharmaceutically acceptable salt thereof is administered once daily. Compound (I) or a pharmaceutically acceptable salt thereof may also be administered in single or multiple doses. In one embodiment, compound (I) or a pharmaceutically acceptable salt thereof is administered in multiple doses once daily.

[0121] In some embodiments of this disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily in multiple doses as an oral solid dosage form. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily in multiple doses.

[0122] The method of administration can be determined comprehensively based on factors such as the drug's activity, toxicity, and the patient's tolerance.

[0123] Compound of formula (I) or a pharmaceutically acceptable salt thereof

[0124] The compound of formula (I) disclosed herein can be administered in its free base form, or in the form of a pharmaceutically acceptable salt, hydrate, or prodrug, which is converted in vivo into the form of compound (I). For example, a pharmaceutically acceptable salt of compound (I) within the scope of this disclosure can be generated from various organic and inorganic acids according to methods known in the art.

[0125] Regarding pharmaceutically acceptable salts of the compounds of formula (I) described in this disclosure, the molar ratio of the compound of formula (I) to the anion forming the pharmaceutically acceptable salt may be 1:1.

[0126] Pharmaceutically acceptable salts of compounds of formula (I) may be maleates of compounds of formula (I) (e.g., monomaleates of compounds of formula (I)).

[0127] Unless otherwise stated, the dosage of compounds of formula (I) or pharmaceutically acceptable salts thereof mentioned in this disclosure is based on the amount of compound of formula (I).

[0128] In some embodiments of this disclosure, a pharmaceutically acceptable salt of the compound of formula (I) is present in the form of a salt of the compound of formula (I).

[0129] The compounds of formula (I) used in this disclosure or their pharmaceutically acceptable salts can be prepared by methods in the prior art, for example, by referring to the method in WO2016141881.

[0130] Pharmaceutical compositions of compounds of formula (I) or pharmaceutically acceptable salts thereof

[0131] In some embodiments of this disclosure, a single dose of a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg or 60 mg, calculated as the compound of formula (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared such that a unit dosage form contains 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0132] In some embodiments of this disclosure, a single dose of a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 60 mg, calculated as compound (I). Alternatively, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared such that a unit dosage form contains 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as compound (I).

[0133] The method of administration can be determined comprehensively based on factors such as the drug's activity, toxicity, and the patient's tolerance.

[0134] In some embodiments of this disclosure, the pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof further contains pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, etc. In some embodiments of this disclosure, the pharmaceutical composition includes, but is not limited to, formulations suitable for oral, parenteral, or topical administration. In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration. In some embodiments, the pharmaceutical composition is a solid dosage form suitable for oral administration. In some embodiments, the pharmaceutical composition includes, but is not limited to, tablets and capsules.

[0135] In some embodiments of this disclosure, the pharmaceutical composition is a solid pharmaceutical composition.

[0136] In some embodiments of this disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments of this disclosure, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0138] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0139] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0140] Fulvestrant

[0141] As used in this disclosure, fulvestrant is chemically named 7-α-[9-(4,4,5,5,5-pentafluoropentanesulfinyl)nonyl]estrog-1,3,5-(10)-trien-3,17-β-diol, and has the structural formula shown in compound (II) below:

[0142]

[0143] fulvestrant pharmaceutical compositions

[0144] In some embodiments of this disclosure, the fulvestrant pharmaceutical composition further comprises pharmaceutically acceptable excipients. Preferably, the pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, water for injection, etc.

[0145] In some embodiments of this disclosure, the pharmaceutical composition is an injection solution.

[0146] In some embodiments of this disclosure, the pharmaceutical composition is a water-soluble injection, which includes, but is not limited to, water-soluble formulations that have not been lyophilized or water-soluble formulations reconstituted from lyophilized powder.

[0147] In some embodiments of this disclosure, a single dose of a pharmaceutical composition of the compound of formula (II) or a pharmaceutically acceptable salt thereof is 250 mg.

[0148] In some embodiments of this disclosure, the amount of fulvestrant in the pharmaceutical composition is 250 mg or 500 mg.

[0149] The fulvestrant injection used in this disclosure is commercially available.

[0150] Application method

[0151] The following content is not intended to limit the administration of the combination drug compositions disclosed herein.

[0152] The active ingredients in the combination pharmaceutical compositions of this disclosure may be administered individually, or in combination, via suitable routes, including but not limited to, oral or parenteral (via intravenous, intramuscular, local, or subcutaneous routes). In some embodiments of this disclosure, the active ingredients in the combination pharmaceutical compositions of this disclosure may be administered orally individually, or in combination, via suitable routes, including but not limited to, oral or parenteral (via intravenous, intramuscular, local, or subcutaneous routes).

[0153] The active ingredients in the combination pharmaceutical compositions disclosed herein may be individually, or together in part or in whole, suitable dosage forms, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersants, and sustained-release formulations for oral or non-oral administration.

[0154] Technical effect

[0155] Generally, using the combination pharmaceutical compositions of this disclosure described above will help:

[0156] (1) Compared with any one of the drugs in the combination alone, it produces better efficacy in reducing tumor growth or even eliminating tumors;

[0157] (2) Provides a smaller dosage compared to any one of the drugs in the combination when administered alone;

[0158] (3) Provide treatment that is well tolerated in patients and has fewer adverse reactions and / or complications compared to either drug administered alone;

[0159] (4) Provides better disease control rates among the patients treated;

[0160] (5) Provides longer survival (e.g., median survival, progression-free survival, or overall survival) in the patients treated;

[0161] (6) Provides patients with longer survival (e.g., median survival, progression-free survival, or overall survival) compared to standard chemotherapy;

[0162] (7) Provide a longer duration of disease remission (DOR); and / or

[0163] (8) Compared with any one of the drugs in the combination alone, it has good activity in treating tumors or proliferative diseases and shows a better anti-tumor synergistic effect.

[0164] The combination drug compositions disclosed herein are "clinically beneficial" in the following ways, including but not limited to: prolonged progression-free survival (PFS), prolonged overall survival (OS), improved objective response rate (ORR), improved disease control rate (DCR), reduced number and / or severity of adverse reactions, and decreased distant metastasis rate and local control rate.

[0165] Definitions and Explanations

[0166] As used herein, the term "combination drug composition" refers to a combination of two or more active ingredients administered simultaneously or sequentially (in the form of their respective active ingredients as they are, or in the form of their respective pharmaceutically acceptable salts or esters, prodrugs, or compositions). In this document, the terms "combination drug composition" and "drug combination" are used interchangeably.

[0167] The word “comprise” or “comprise” and its English variants such as comprises or comprising, and their equivalents, should be understood in an open, non-exclusive sense, meaning “including but not limited to”, implying that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included.

[0168] The term "patient" or "individual / subject" refers to mammals, such as primates (humans, macaques, chimpanzees, etc.), rodents (mice, rats, rabbits, etc.), felines, canines, etc., preferably humans. In some embodiments of this disclosure, the patient and the individual are patients who have failed standard treatment or lack standard treatment.

[0169] The terms “pharmaceutical acceptable” or “medicinal” refer to a carrier, excipient, or excipient used in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and whose use in a human medicine is acceptable.

[0170] The term "therapeutic effective amount" refers to the amount of a compound that, when administered to a person to treat a disease, is sufficient to achieve therapeutic effect on that disease.

[0171] The term “treatment” means administering the compounds or preparations described in this disclosure to improve, alleviate or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) suppressing the disease or disease state, i.e., halting or delaying its development; (ii) alleviating the disease or disease state, even if the disease or disease state subsides.

[0172] The term “prevention” means administering the compounds or preparations described in this disclosure to prevent a disease or one or more symptoms associated with the disease, including: preventing the occurrence of a disease or disease state in mammals, particularly when such mammals are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0173] The term "systemic therapy" refers to treatment in which drug substances are transported through the bloodstream to reach and affect cells throughout the body.

[0174] The term "systemic treatment" refers to systemic chemotherapy, whole-body or local radiation therapy.

[0175] The term "first-line treatment" refers to treatment with a drug that can be chosen first or as a standard choice based on the patient's condition. As used herein, "adverse event" (AE) is any unfavorable and usually unintentional or unwanted sign (including abnormal laboratory findings), symptom, or illness associated with the application of a medical treatment. For example, an adverse event may be associated with activation of the immune system in response to treatment or expansion of immune system cells (e.g., T cells). Medical treatment may have one or more associated AEs, and each AE may have the same or different levels of severity. References to methods capable of "modifying adverse events" refer to treatment regimens that reduce the incidence and / or severity of one or more AEs associated with the application of different treatment regimens.

[0176] The use of alternatives (e.g., "or") should be understood to mean any one, two, or any combination of the alternatives. The indefinite articles "a" or "an" as used herein should be understood to mean "one or more / a combination of" any enumerated or listed components.

[0177] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0178] The terms “application” and “administration” refer to the physical introduction of a composition containing a therapeutic agent into an individual using any of a variety of methods and delivery systems known to those skilled in the art. In some embodiments, application is oral administration.

[0179] The term "daily dose" refers to the dose administered to a patient each day.

[0180] The terms "single dose" or "unit dosage form" refer to the smallest packaged unit of a medicine containing a certain amount of active ingredient. For example, if a box of medicine contains seven capsules, then each capsule is a single dose or unit dosage form; if a box of medicine contains seven tablets, then each tablet is a single dose unit dosage form.

[0181] The term “multiple doses” consists of multiple single doses. As used herein, “combination” or “conjunctive use” means that two or more active substances may be administered to an individual simultaneously, in parallel, or in any order as single formulations.

[0182] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients or combinations thereof disclosed herein with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate individual administration of the compounds or combinations thereof disclosed herein.

[0183] When referring to dosing regimens, terms such as "day" or "daily" refer to the time within a calendar day, beginning at midnight and ending at the next midnight.

[0184] The term "recurrent" cancer refers to cancer that recurs at the initial site or a distant site after a response to initial treatment (such as surgery). "Locally recurrent" cancer refers to cancer that recurs at the same location as the previously treated cancer after treatment.

[0185] The term "unresectable" cancer refers to cancer that cannot be removed by surgery.

[0186] The term "metastatic" cancer refers to cancer that has spread from one part of the body (such as the lungs) to another part of the body.

[0187] As used herein, “combination” or “conjunctive use” means that two or more active substances may be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially as a single formulation in any order.

[0188] In this document, unless the context clearly indicates otherwise, singular terms encompass plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" is intended to include "and," and vice versa.

[0189] Unless otherwise stated, in this document, parameter values ​​representing the amount of an ingredient, its physicochemical properties, or reaction conditions, etc., should be understood to be modified by the term "about" in all cases. When the present disclosure is described using the term "about," the term "about" indicates an existing error value, such as a variation within ±5%, for example ±1%, or ±0.1% of a particular value.

[0190] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this disclosure. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art. Example

[0191] The specific embodiments described below are intended to enable those skilled in the art to better understand and implement this disclosure. They should not be considered as limiting the scope of this disclosure, but merely as exemplary illustrations and typical representatives of this disclosure.

[0192] Experimental Example 1: Clinical Trial

[0193] This study was divided into two cohorts, Cohort 1 and Cohort 2. The study drugs were both compounds of formula (I) combined with fulvestrant injection. The subjects were HR-positive, HER2-negative locally advanced and / or metastatic breast cancer, with 30-60 patients in each cohort. The preliminary efficacy and safety of compounds of formula (I) combined with fulvestrant injection were evaluated.

[0194] 1.1 Selection Criteria:

[0195] 1) Participants voluntarily joined this study, signed informed consent forms, and demonstrated good compliance;

[0196] 2) Age: 18-75 years old (at the time of signing the informed consent form); ECOGPS score: 0-1; expected survival period of more than 3 months;

[0197] 3) Subjects with locally advanced or metastatic breast cancer whose pathological examination confirms that the primary or metastatic tumor has a positive HR and a negative HER2.

[0198] 4) Subjects in the relapse / metastasis stage enrolled in Cohort 1 are permitted to receive no more than one line of treatment;

[0199] 5) Subjects enrolled in Cohort 2 had not previously received systemic anti-tumor therapy;

[0200] 6) Confirm at least one measurable lesion according to RECIST 1.1 criteria;

[0201] 7) Major organ functions are in good condition and meet the following standards:

[0202] Blood routine examination criteria (no blood transfusion or use of hematopoietic stimulating factor drugs within 7 days prior to screening):

[0203] a) Hemoglobin (HB) ≥ 100 g / L;

[0204] b) Absolute neutrophil count (NEUT) ≥ 1.5 × 10⁻⁶ 9 / L;

[0205] c) Platelet count (PLT) ≥ 90 × 10⁻⁶ 9 / L.

[0206] Biochemical tests must meet the following standards:

[0207] a) Total bilirubin (TBIL) ≤ 2.5 times the upper limit of normal (ULN);

[0208] b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If liver metastasis is present, ALT and AST...

[0209] ≤5×ULN;

[0210] c) Serum creatinine (CR) ≤ 1.5 × ULN, or creatinine clearance (CCR) ≥ 60 ml / min.

[0211] Coagulation function tests must meet the following standards:

[0212] Prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ≤ 1.5 × ULN (who have not received anticoagulation therapy);

[0213] Echocardiography assessment: Left ventricular ejection fraction (LVEF) ≥ 50%.

[0214] 1.2 Test Drug

[0215] Capsules of compound (I): 50 mg or 60 mg, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0216] Fulvestrant Injection: 250mg, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0217] 1.3 Dosing regimen

[0218] Capsules of compound (I): 180 mg / dose (calculated as compound (I)), taken orally on an empty stomach, once daily, for 28 consecutive days as one treatment cycle.

[0219] Fulvestrant injection: 500 mg / time intramuscular injection, with each treatment cycle lasting 28 days. In the first treatment cycle, the medication is administered on day 1 and day 15, and in subsequent treatment cycles, the medication is administered on day 1.

[0220] 1.4 Evaluation Criteria

[0221] Efficacy evaluation criteria: The RECIST 1.1 criteria were used to determine the disease status.

[0222] Safety evaluation criteria: The severity of adverse events was assessed using the NCI-CTC AE 5.0 standard. Adverse event record forms should be completed accurately during the trial, including the time of occurrence, severity, relevance to the study treatment, duration, interventions taken, and outcome of each adverse event.

[0223] 1.5 Test Results

[0224] 1.5.1 Security

[0225] Gastrointestinal reactions (diarrhea, vomiting, etc.) were mainly grade 1-2 and could be controlled with symptomatic treatment. The overall incidence of grade 3 and above TEAEs was 39.2%, the incidence of grade 3 hematologic toxicity was 9.6%, and the incidence of grade 3 diarrhea was 7.8%, indicating good overall safety.

[0226] 1.5.2 Validity

[0227] A total of 110 patients were enrolled, with a median treatment duration of 6.6 months. The objective response rate (ORR) was 58.2% (64 / 110), including 2 patients with complete remission (CR), 62 patients with partial remission (PR), and 38 patients with stable disease (SD). The disease control rate (DCR) was 92.7% (102 / 110). These results demonstrate the clinical benefit of the combination drug composition disclosed herein.

[0228] The following are representative cases:

[0229]

[0230] Note: "--" indicates that the data has not yet been obtained.

[0231] Those skilled in the art will recognize that the scope of this disclosure is not limited to the various specific implementations and embodiments described above, but rather that various modifications, substitutions, or recombinations can be made without departing from the spirit and concept of this disclosure, all of which fall within the protection scope of this disclosure.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a combination thereof with fulvestrant in the preparation of a medicament for the treatment of HR-positive, HER2-negative locally advanced and / or metastatic breast cancer, 。 2. The use according to claim 1, wherein the breast cancer is breast cancer that has progressed after receiving endocrine therapy.

3. The use according to claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for single or multiple doses of 60 mg, 120 mg, 180 mg or 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered to a patient continuously daily.

4. According to claim 3, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for single or multiple doses of 120 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered to a patient continuously daily.

5. The use according to claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be suitable for single or multiple doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered to a patient continuously daily at a dose of 150 mg or 180 mg.

6. In accordance with the use according to claim 1 or 2, the fulvestrant is prepared to be administered to a patient in single or multiple doses of 250 mg to 750 mg of fulvestrant per treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be administered to a patient in single or multiple doses of 60 mg, 120 mg, 180 mg or 240 mg of the compound of formula (I) itself per day.

7. The use according to claim 1 or 2, wherein the fulvestrant is prepared to be administered to a patient in single or multiple doses of 250 mg to 500 mg per treatment cycle; and the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared to be administered to a patient in single or multiple doses of 150 mg or 180 mg of the compound of formula (I) itself per day.

8. The use according to claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a multiple-dose manner, the multiple doses consisting of a pharmaceutical composition of a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

9. The use according to claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a multiple-dose manner, the multiple doses consisting of a pharmaceutical composition of a single dose of 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

10. The use according to claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant are each in the form of a pharmaceutical composition and may be administered simultaneously, separately, in parallel, sequentially or at intervals.

11. The use according to claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 60 mg; or, a daily dose of 120 mg; or, a daily dose of 180 mg; or, a daily dose of 240 mg.

12. The use according to claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the manner of: a daily dose of 150 mg; or, a daily dose of 180 mg.

13. The use according to claim 2, wherein the endocrine therapy is selected from tamoxifen, toremifene, fulvestrant, letrozole, anastrozole, exemestane, goserelin, and leuprorelin.

14. The use according to claim 13, wherein the endocrine therapy is selected from tamoxifen, letrozole, exemestane, and goserelin.

15. The use according to claim 14, wherein the endocrine therapy is selected from tamoxifen and goserelin.

Images