Combined pharmaceutical composition of CDK4 / 6 inhibitor and application thereof

Abstract

The invention relates to a combined pharmaceutical composition of a CDK4 / 6 inhibitor and application of the combined pharmaceutical composition, in particular to a combined pharmaceutical composition containing a compound shown in a formula (I) or pharmaceutically acceptable salt of the compound and fulvestrant. The invention further relates to application of the combined pharmaceutical composition to treatment of breast cancer. The combined pharmaceutical composition disclosed by the invention has a better curative effect in the aspect of reducing the growth of tumors or even eliminating tumors. # imgabs0 #

Description

[0001] This application is a divisional application based on an application with an application date of March 3, 2022, application number 202280017434.5, and invention name “Combination pharmaceutical composition of CDK4 / 6 inhibitors and use thereof”

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This disclosure claims the benefits and priority of Chinese invention 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 by reference in their entirety. Technical Field

[0004] The present disclosure belongs to the field of medical technology and relates to a combination pharmaceutical composition of CDK4 / 6 inhibitors and use thereof in treating breast cancer. Background Art

[0005] Cyclin-dependent kinase (CDK) 4 / 6 is a key regulator of the cell cycle, which can trigger the cell cycle to enter the DNA replication phase (S1 phase) from the growth phase (G1 phase). During cell proliferation, the complex formed by CDK4 / 6 and cyclin D (CyclinD) can phosphorylate the retinoblastoma protein (Rb). Once the tumor suppressor protein Rb is phosphorylated, it can release the transcription factor E2F that it tightly binds to in the unphosphorylated state. E2F activates further transcription and promotes the cell cycle through the restriction point (R point) and progresses from the G1 phase to the S phase. Therefore, inhibiting CDK4 / 6 so that it cannot form a CyclinD-CDK4 / 6 complex can block the progression of the cell cycle from the G1 phase to the S phase, thereby achieving the purpose of inhibiting tumor proliferation. WO2016141881 discloses substituted 2-hydrogen-pyrazole derivatives as selective CDK4 / 6 inhibitors, and specifically discloses the following structure of the compound of formula (I),

[0006]

[0007] Fulvestrant, chemical name: 7-α-[9-(4,4,5,5,5-pentafluoropentanesulfinyl)nonyl]estra-1,3,5-(10)-triene-3,17-β-diol. Fulvestrant has a relative molecular mass of 606.77, is a white or off-white powder, and is insoluble in water. Fulvestrant is a new class of estrogen receptor antagonists - estrogen receptor downregulators for breast cancer treatment, which can bind to estrogen receptors at the cellular level, block and degrade estrogen receptors, thereby blocking the growth of tumor cells under the action of estrogen.

[0008] Data from the World Cancer Report show that in 2012, there were approximately 1.7 million new cases of breast cancer and approximately 500,000 deaths worldwide, accounting for 25% of all new cancers in women and 15% of all cancer deaths, both ranking first. Among new breast cancer cases each year, 3%-10% of women have distant metastasis at the time of diagnosis. Among early-stage patients, 30%-40% may develop into advanced breast cancer, with a 5-year survival rate of approximately 20%.

[0009] Advanced breast cancer (ABC) patients have their own particularities in terms of treatment options and efficacy, and there is currently a lack of recognized standard treatment options. The overall median survival of advanced breast cancer is 2-3 years, and the situation varies for different molecular subtypes. For ABC patients who are positive for human epidermal growth factor receptor 2 (HER2), anti-HER2 therapy can change the natural course of HER2-positive ABC patients and significantly prolong survival time; however, for triple-negative ABC patients, their overall prognosis has not been significantly improved. Hormone receptor-positive (HR+) breast cancer accounts for approximately 65%-75% of breast cancer. Endocrine therapy has become the preferred treatment option for hormone receptor-positive (HR+) metastatic breast cancer with its comparable therapeutic efficacy to chemotherapy and less toxic side effects.

[0010] Although endocrine therapy is the main treatment option for hormone receptor-positive breast cancer, approximately 30% of hormone receptor-positive breast cancers are primarily resistant to endocrine therapy, and almost all patients develop secondary resistance in subsequent treatments. Therefore, how to overcome endocrine therapy resistance has become a difficult problem that needs to be urgently solved in the field of breast cancer treatment. Summary of the invention

[0011] In one aspect, the present disclosure provides a combination pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant

[0012]

[0013] In another aspect, the present disclosure provides a combination pharmaceutical composition for treating or preventing breast cancer, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant.

[0014] In some embodiments of the present disclosure, the combination pharmaceutical composition is packaged in the same kit, which further comprises instructions for using the compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant in combination to treat or prevent breast cancer.

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

[0016] In some embodiments of the present disclosure, the combination pharmaceutical composition is packaged in the same kit, which further comprises 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 the present disclosure, in the combination pharmaceutical composition, the pharmaceutically acceptable salt of the compound of formula (I) is a maleate, such as a monomaleate salt of the compound of formula (I).

[0018] In some embodiments of the present 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 the present disclosure, the combination pharmaceutical 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 pharmaceutical composition thereof, calculated as the compound of formula (I).

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

[0021] In some embodiments of the present disclosure, the combination pharmaceutical 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 pharmaceutical composition thereof, calculated as the compound of formula (I).

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

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

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

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

[0026] In some embodiments of the present disclosure, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is a daily dose.

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

[0028] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a dose once a day, and each dose is a single dose or multiple doses, usually multiple doses.

[0029] In some embodiments of the present disclosure, the combination pharmaceutical composition contains a single dose of 5 mg, 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the combination pharmaceutical composition is in the form of a single administration preparation, and the combination pharmaceutical composition contains 5 mg, 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula (I).

[0030] In some embodiments of the present disclosure, the combination pharmaceutical composition contains a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I). Alternatively, the combination pharmaceutical composition is in the form of a single administration preparation, and the combination pharmaceutical composition contains 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I).

[0031] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is packaged in a kit, and the kit also contains instructions for using the compound of formula (I) or a pharmaceutically acceptable salt thereof to treat or prevent breast cancer.

[0032] In some embodiments of the present disclosure, the combination pharmaceutical 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 pharmaceutical composition thereof.

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

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

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

[0036] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the pharmaceutical composition of fulvestrant is in the form of a single dose or multiple doses.

[0037] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the pharmaceutical composition of fulvestrant is in a multiple-dose form.

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

[0039] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the content of fulvestrant is a single dosage per treatment cycle.

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

[0041] In some embodiments of the present disclosure, the pharmaceutical composition of fulvestrant contained in the combination pharmaceutical composition is packaged in a kit, and the kit also contains instructions for using fulvestrant to treat or prevent breast cancer.

[0042] In some embodiments of the present disclosure, the pharmaceutical composition of fulvestrant contained in the combination pharmaceutical composition is packaged in a kit, and the kit also contains instructions for using fulvestrant to treat or prevent breast cancer, and the instructions can be instructions in the instructions of a commercially available fulvestrant injection kit. In some embodiments of the present disclosure, the instructions are instructions for fulvestrant injection (e.g., ) instructions in the instruction manual.

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

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

[0045] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 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; and a dose of 250 mg or 500 mg of fulvestrant per treatment cycle.

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

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

[0048] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; and a first treatment cycle dose of 1000 mg of fulvestrant.

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

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

[0051] In some embodiments of the present disclosure, the combination pharmaceutical composition contains: a daily dose of 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I); and a first treatment cycle dose of 1000 mg and a subsequent dose of 500 mg per treatment cycle of fulvestrant.

[0052] In some embodiments of the present disclosure, every 28 days is one treatment cycle.

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

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

[0055] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof at a total dose of 1680 to 5040 mg (e.g., 3360 mg, 4200 mg, or 5040 mg) calculated as the compound of formula (I); and a pharmaceutical composition containing fulvestrant at a total dose of 500 to 1000 mg calculated as fulvestrant.

[0056] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 5040 mg calculated as the compound of formula (I); and a pharmaceutical composition containing fulvestrant in a total dose of 500-1000 mg calculated as fulvestrant.

[0057] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within the first treatment cycle (e.g., a treatment cycle of 28 days), the preparation comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof with a total dose of 5040 mg calculated as the compound of formula (I); and a pharmaceutical composition containing fulvestrant with a total dose of 1000 mg calculated as fulvestrant.

[0058] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration in a single treatment cycle (e.g., a treatment cycle of 28 days) after the second treatment cycle, the preparation comprising: a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a total dose of 5040 mg calculated as the compound of formula (I); and a pharmaceutical composition containing fulvestrant in a total dose of 500 mg calculated as fulvestrant.

[0059] In some embodiments of the present disclosure, the combination pharmaceutical composition is a preparation suitable for administration within a single treatment cycle (e.g., a treatment cycle of 28 days), comprising a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing fulvestrant at 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 above range, wherein the dose of the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is calculated based on the compound of formula (I), and the dose of the pharmaceutical composition containing fulvestrant is calculated based on fulvestrant.

[0060] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant may be in the form of a pharmaceutical composition separately or together.

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

[0062] On the other hand, the present disclosure also provides a kit of pharmaceutical compositions for treating or preventing breast cancer, which contains (a) a first pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in the present disclosure; and (b) a second pharmaceutical composition containing fulvestrant. Alternatively, the present disclosure also provides a combination pharmaceutical composition for treating or preventing breast cancer, which contains: 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 the present disclosure, in the combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 5 mg, 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and the fulvestrant is prepared into a unit preparation containing 250 mg of fulvestrant.

[0064] In some embodiments of the present disclosure, in the combination pharmaceutical composition, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 50 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof, calculated as the compound of formula (I), and the fulvestrant is prepared into a unit preparation containing 250 mg of fulvestrant.

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

[0066] In another aspect, the present 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 alone.

[0067] On the other hand, the present 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 drug for treating or preventing breast cancer, for example, the use of the above-mentioned combination pharmaceutical composition of the present disclosure in the preparation of a drug for treating or preventing breast cancer. In some embodiments of the present disclosure, the combination pharmaceutical composition is any combination pharmaceutical composition described above in the present disclosure.

[0068] On the other hand, the present disclosure also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with fulvestrant for treating or preventing breast cancer, for example, the use of the above-mentioned combination pharmaceutical composition of the present disclosure for treating or preventing breast cancer.

[0069] In some embodiments of the present disclosure, in the kit, method, combination therapy or use, the definitions of the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant are the same as those of the compound of formula (I) or its pharmaceutically acceptable salt and fulvestrant in the combination pharmaceutical composition described above, such as content, dosage, form of existence, packaging form, etc.

[0070] In some embodiments of the present disclosure, in the method, combination therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant are each in the form of a pharmaceutical composition and can be administered simultaneously, separately, concurrently, sequentially or intermittently.

[0071] In some embodiments of the present disclosure, in the method, combination therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant have the same or different treatment cycles, respectively. In some specific embodiments of the present disclosure, in the method, combination therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant have the same treatment cycle, for example, one treatment cycle is one week, ...

[0072] In some embodiments of the present disclosure, in the method, combination therapy or use, 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 in the following manner: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day.

[0073] In some embodiments of the present disclosure, in the method, combination therapy or use, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the combination pharmaceutical composition is a daily dose, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered in a single dose or multiple doses, usually in multiple doses; further, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day.

[0074] In some embodiments of the present disclosure, in the method, combination therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: 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 the present disclosure, in the method, combination therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 150 mg; or, a daily dose of 180 mg.

[0076] In some embodiments of the present disclosure, in the method, combination therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as follows: a daily dose of 180 mg.

[0077] In some embodiments of the present disclosure, in the method, combination therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is administered in multiple doses, and the multiple doses are composed of a pharmaceutical composition with a single dose of 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the method, combination therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily administration manner.

[0078] In some embodiments of the present disclosure, in the method, combination therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof in the combination pharmaceutical composition is administered in multiple doses, and the multiple doses consist of a pharmaceutical composition with a single dose of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments of the present disclosure, in the method, combination therapy or use, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily administration manner.

[0079] In some embodiments of the present disclosure, in the method, combination therapy or use, the content of the compound of formula (I) or its pharmaceutically acceptable salt in the combination pharmaceutical composition is the dosage per treatment cycle, which is administered in the following manner: daily administration of the compound of formula (I) or its pharmaceutically acceptable salt. Wherein, the compound of formula (I) or its pharmaceutically acceptable salt is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more aliquots).

[0080] In some embodiments of the present disclosure, in the method, combination therapy or use, the content of Fulvestrant in the combination pharmaceutical composition is a dose for each treatment cycle, which is administered in the following manner: Fulvestrant is administered on the 1st and 15th day of the first treatment cycle, and then on the first day of each treatment cycle. Wherein, Fulvestrant is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots or more aliquots). In some embodiments of the present disclosure, Fulvestrant is administered on the 1st and 15th day of the first treatment cycle, with the same dose each time; and then administered on the 1st day of each treatment cycle, and the dose administered on the 1st day of each treatment cycle is the same as the dose on the 1st day of the first treatment cycle. In some embodiments of the present disclosure, in the treatment cycle of Fulvestrant, the dose administered each time is the same.

[0081] In some embodiments of the present disclosure, in the method, combination therapy or use, the content of fulvestrant in the combination pharmaceutical composition is a dose per treatment cycle, wherein fulvestrant is administered in a single dose or multiple doses. In some embodiments of the present disclosure, wherein fulvestrant is administered in multiple doses.

[0082] In some embodiments of the present disclosure, in the method, combination therapy or use, the content of fulvestrant in the combination pharmaceutical composition is a dose per treatment cycle, wherein fulvestrant is administered in multiple doses, and the multiple doses consist of a single dose of 250 mg of the pharmaceutical composition of fulvestrant.

[0083] In some embodiments of the present disclosure, in the method, combination therapy or use, 28 days is a treatment cycle, fulvestrant is administered on day 1 and day 15 of the first cycle, fulvestrant is subsequently administered on day 1 of each treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 28 of each treatment cycle.

[0084] In some specific embodiments of the present disclosure, in the method, combination therapy or use, 28 days is a treatment cycle, and fulvestrant is administered once on day 1 and day 15 of the first cycle, and then fulvestrant is administered once on day 1 of each treatment cycle, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day on days 1 to 28 of each treatment cycle.

[0085] In some embodiments of the present disclosure, in the method, combination therapy or use, 28 days is a treatment cycle, the drug is administered once a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is 1680-5040 mg per treatment cycle. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is selected from 1680 mg, 3360 mg, 4200 mg, 5040 mg or the range formed by any two of the above values. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 4200 mg, 5040 mg. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula (I) or its pharmaceutically acceptable salt is preferably 5040 mg.

[0086] In some embodiments of the present disclosure, in the method, combination therapy or use, 28 days is a treatment cycle, and 500 mg of fulvestrant is administered once on day 1 and day 15 of the first treatment cycle, respectively, and 500 mg of fulvestrant is administered once on day 1 of each subsequent treatment cycle.

[0087] In some embodiments of the present disclosure, in the method, combination therapy or use, 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day 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 5040 mg; 500 mg of fulvestrant is administered once on the 1st day and the 15th day of the first treatment cycle, respectively, and 500 mg of fulvestrant is administered once on the 1st day of each subsequent treatment cycle.

[0088] In embodiments of the present disclosure, the above treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

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

[0090] In some embodiments of the present disclosure, the fulvestrant is prepared as a single dose or multiple doses suitable for administering 250 mg-750 mg or 250 mg to 500 mg of fulvestrant to the patient per treatment cycle; the pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for continuously administering 150 mg and / or 180 mg of the compound of formula (I) itself to the patient every day.

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

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

[0093] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for continuous daily administration to a patient 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 as a single dose or multiple doses suitable for continuous daily administration to a patient of 120 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is prepared as a single dose or multiple doses suitable for continuous daily administration to a patient 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 as a single dose or multiple doses suitable for continuous daily administration to a patient of 150 mg or 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

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

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

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

[0098] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that cannot be treated with radical surgery or radiotherapy.

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

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

[0101] In some embodiments of the present disclosure, the breast cancer is selected from breast cancer that has been previously subjected to bilateral oophorectomy.

[0102] In some embodiments of the present disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopausal breast cancer that has undergone bilateral oophorectomy in the past.

[0103] In some embodiments of the present disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopausal HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that has undergone previous bilateral oophorectomy.

[0104] In some embodiments of the present disclosure, the breast cancer is selected from postmenopausal or premenopausal / perimenopausal HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that is not amenable to radical surgery or radiotherapy.

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

[0106] In some embodiments of the present disclosure, HER2 negativity is defined as: immunohistochemistry (IHC) detection shows HER2 as 0 / 1+; if the detection shows 2+, fluorescent in situ hybridization (FISH) must be performed to confirm that it is negative, or only FISH detection is negative.

[0107] In some embodiments of the present 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 1 line of chemotherapy.

[0108] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative breast cancer that relapses or progresses during adjuvant endocrine therapy or within 1 year after completion of adjuvant endocrine therapy and has not subsequently received endocrine therapy.

[0109] In some embodiments of the present disclosure, the breast cancer is selected from HR-positive, HER2-negative breast cancer that relapses or progresses more than 1 year after completion of adjuvant endocrine therapy and progresses again after subsequent advanced endocrine therapy; the advanced endocrine therapy is no more than 1 line of treatment.

[0110] In some embodiments of the present disclosure, the breast cancer is selected from breast cancer with disease progression after primary metastatic disease has been treated with advanced endocrine therapy; the advanced endocrine therapy is no more than 1 line of treatment.

[0111] In some embodiments of the present 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 anti-tumor treatment for local lesion recurrence or metastatic disease.

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

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

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

[0115] The active ingredients in the drug combination of the present disclosure can be formulated with a pharmaceutically acceptable carrier and / or excipient independently of each other, or part or all of them together. The drug combination of the present disclosure can also include another therapeutic agent. In some embodiments of the present disclosure, the other therapeutic agent can be a therapeutic agent for cancer known in the art, preferably a therapeutic agent for breast cancer.

[0116] In some embodiments of the present disclosure, the cycle is 28 days.

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

[0118] The compound of formula (I) or its pharmaceutically acceptable salt can be administered by a variety of routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, by inhalation, vaginal, intraocular, by topical administration, subcutaneous, intrafatty, intraarticular, intraperitoneal and intrathecal. In a specific embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered orally.

[0119] In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a continuous daily oral administration manner.

[0120] The compound of formula (I) or its pharmaceutically acceptable salt can be administered once or more daily. In some embodiments of the present disclosure, the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day. The compound of formula (I) or its pharmaceutically acceptable salt can also be administered in a single dose or multiple doses. In one embodiment, the compound of formula (I) or its pharmaceutically acceptable salt is administered once a day in multiple doses.

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

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

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

[0124] The compounds of formula (I) disclosed herein can be administered in the form of their free base, or in the form of their pharmaceutically acceptable salts, hydrates, and prodrugs, which are converted into the form of the compounds of formula (I) in vivo. For example, pharmaceutically acceptable salts of the compounds of formula (I) are within the scope of the present disclosure, and the salts can be produced from various organic acids and inorganic acids according to methods known in the art.

[0125] Regarding the pharmaceutically acceptable salts of the compounds of formula (I) described in the present disclosure, the molar ratio of the compounds of formula (I) to the acid ions forming the pharmaceutically acceptable salts may be 1:1.

[0126] The pharmaceutically acceptable salt of the compound of formula (I) may be a maleate salt of the compound of formula (I) (eg a monomaleate salt of the compound of formula (I)).

[0127] The dosage of the compound of formula (I) or its pharmaceutically acceptable salt referred to in the present disclosure is based on the amount of the compound of formula (I) unless otherwise stated.

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

[0129] The compound of formula (I) or a pharmaceutically acceptable salt thereof used in the present disclosure can be prepared by methods of the prior art, for example, by referring to the method of WO2016141881.

[0130] Pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof

[0131] In some embodiments of the present disclosure, a single dose of the 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 into a unit preparation containing 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 the present disclosure, a single dose of the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 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 as a unit preparation containing 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof calculated as the compound of formula (I).

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

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

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

[0136] In some embodiments of the present 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 the present 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 composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0139] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or a dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0140] Fulvestrant

[0141] As used in the present disclosure, Fulvestrant is chemically named 7-α-[9-(4,4,5,5,5-pentafluoropentanesulfinyl)nonyl]estra-1,3,5-(10)-triene-3,17-β-diol, and has the structural formula shown in the following compound (II):

[0142]

[0143] Fulvestrant pharmaceutical composition

[0144] In some embodiments of the present disclosure, the pharmaceutical composition of fulvestrant further contains a pharmaceutically acceptable excipient. Preferably, the pharmaceutically acceptable excipient includes a filler, an absorbent, a wetting agent, a binder, a disintegrant, a lubricant, water for injection, and the like.

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

[0146] In some embodiments of the present disclosure, the pharmaceutical composition is a water-soluble injection, which includes but is not limited to a non-lyophilized water-soluble preparation or a water-soluble preparation reconstituted from a lyophilized powder.

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

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

[0149] The fulvestrant injection used in the present disclosure can be obtained commercially.

[0150] Mode of administration

[0151] The following contents do not limit the administration mode of the combined pharmaceutical composition of the present disclosure.

[0152] The active ingredients in the combined pharmaceutical composition of the present disclosure can be administered independently, or part or all of them can be administered together in various suitable routes, including but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments of the present disclosure, the active ingredients in the combined pharmaceutical composition of the present disclosure can be administered independently, or part or all of them can be administered together orally.

[0153] The active ingredients in the combination pharmaceutical composition of the present invention can be each independently, or some or all of them together can be in suitable dosage forms, including but not limited to, tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.

[0154] Technical Effects

[0155] Generally, use of the above-described combination pharmaceutical compositions of the present disclosure will help:

[0156] (1) Producing a better therapeutic effect in reducing tumor growth or even eliminating tumors compared to administering any of the drugs in the combination alone;

[0157] (2) provide for administration of a smaller amount of the drug in the combination than when either drug is administered alone;

[0158] (3) provide a treatment that is well tolerated in patients and has fewer adverse effects and / or complications than either drug given alone;

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

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

[0161] (6) Providing a longer survival (e.g., median survival, progression-free survival, or overall survival) for the treated patients compared to standard chemotherapy;

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

[0163] (8) Compared with the single administration of any drug in the combination, the combination has good activity in treating tumors or proliferative diseases and exhibits a more excellent anti-tumor synergistic effect.

[0164] The "clinical benefits" of the combination drug composition disclosed herein include, but are not limited to: prolonged progression-free survival (PFS) of clinical patients, prolonged overall survival (OS), improved objective response rate (ORR), improved disease control rate (DCR), reduced number and / or degree of adverse reactions, decreased distant metastasis rate and local control rate, etc.

[0165] Definition and Description

[0166] As used herein, the term "combination pharmaceutical composition" refers to a combination of two or more active ingredients (administered in the form of each active ingredient itself, or in the form of its own pharmaceutically acceptable salt or ester derivatives, prodrugs or compositions) administered simultaneously or sequentially. In this article, the terms "combination pharmaceutical composition" and "drug combination" are used interchangeably.

[0167] The word "comprise" or "comprises" and its English variations such as comprises or comprising and their equivalents should be understood as an open, non-exclusive meaning, that is, "including but not limited to", meaning 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.), cats, canines, etc., preferably humans. In some embodiments of the present disclosure, the patient and the individual are patients who have failed or lack standard treatment.

[0169] The term "pharmaceutically acceptable" or "pharmaceutically usable" refers to a carrier, excipient or excipient used to prepare a pharmaceutical composition, which is generally safe, non-toxic and not biologically or otherwise undesirable, and includes those that are acceptable for use in human medicine.

[0170] The term "therapeutically effective amount" means the amount of a compound that, when administered to a human for treating a disease, is sufficient to effect treatment for the disease.

[0171] The term "treatment" means administering the compounds or formulations disclosed herein to improve, alleviate or eliminate a disease or one or more symptoms associated with the disease, and includes: (i) inhibiting a disease or disease state, i.e., curbing or delaying its development; (ii) alleviating a disease or disease state, i.e., causing the disease or disease state to regress.

[0172] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, including preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0173] The term "systemic therapy" refers to treatment in which a drug substance is delivered through the bloodstream to reach and affect cells throughout the body.

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

[0175] The term "first-line treatment" refers to the drug that can be first selected or selected by the standard according to the patient's condition for treatment. "Adverse event" (AE) used herein is any unfavorable and usually unintentional or undesirable sign (including abnormal laboratory findings), symptom or disease related to the application of medical treatment. For example, adverse events can be associated with the activation of the immune system in response to treatment or the amplification of immune system cells (e.g., T cells). Medical treatment can have one or more related AEs, and each AE can have the same or different levels of severity. Reference to the method that can "change adverse events" refers to the treatment regimen that reduces the incidence and / or severity of one or more AEs related to the application of different treatment regimens.

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

[0177] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance 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 "administering" and "administering" refer to the physical introduction of a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, administration is oral administration.

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

[0180] The term "single dose" or "unit preparation" refers to the smallest packaging unit of a drug containing a certain amount of active ingredient. For example, if a box of medicine contains seven capsules, each capsule is a single dose or unit preparation; for example, if a box of medicine contains seven tablets, each tablet is a single dose unit preparation.

[0181] The term "multiple doses" consists of a plurality of single doses. As used herein, "combination" or "combined use" means that two or more active substances can be administered to an individual simultaneously, concurrently, or sequentially in any order, each as a single formulation.

[0182] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure or a pharmaceutical combination thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure or a pharmaceutical combination thereof to an individual.

[0183] When referring to a dosing regimen, the terms "day," "daily," and the like refer to the times within a calendar day, beginning at midnight and ending at the following midnight.

[0184] The term "recurrent" cancer is a cancer that grows back in the original site or at a distant site after responding to initial treatment (eg, surgery). A "locally recurrent" cancer is a cancer that appears after treatment in the same location as a previously treated cancer.

[0185] The term "unresectable" means that the cancer 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 "combined 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 in any order as a single formulation.

[0188] In this document, unless the context clearly indicates otherwise, singular terms include 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 indicated, herein, parameter values ​​representing the amount of ingredients or physicochemical properties or reaction conditions, etc., should be understood to be modified by the term "about" in all cases. When the term "about" is used to describe the present disclosure, the term "about" indicates the error value that exists, for example, it indicates a change within the range of ±5%, such as ±1% or ±0.1% of a particular value.

[0190] For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present disclosure. All statements about the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission of the correctness of the dates of these documents or the contents of these documents. Moreover, any reference to these publications in this article does not constitute an admission that the publications become part of the common general knowledge in the art in any country. Example

[0191] The purpose of the following specific embodiments is to enable those skilled in the art to more clearly understand and implement the present disclosure. They should not be considered as limiting the scope of the present disclosure, but are merely exemplary descriptions and typical representatives of the present disclosure.

[0192] Experimental Example 1 Clinical Trial

[0193] This study was divided into 2 cohorts, Cohort 1 and Cohort 2. The study drugs were both a compound of formula (I) combined with fulvestrant injection. Subjects with HR-positive, HER2-negative locally advanced and / or metastatic breast cancer were enrolled, with 30-60 cases in each cohort, to evaluate the preliminary efficacy and safety of the compound of formula (I) combined with fulvestrant injection.

[0194] 1.1 Selection criteria:

[0195] 1) The subjects voluntarily participated in this study, signed the informed consent form, and had good compliance;

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

[0197] 3) Subjects with locally advanced or metastatic breast cancer whose primary or metastatic tumors are confirmed to be HR-positive and HER2-negative by pathological testing.

[0198] 4) Subjects in the relapsed / metastatic stage enrolled in Cohort 1 were allowed to receive no more than one line of treatment;

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

[0200] 6) According to RECIST 1.1 criteria, at least one measurable lesion was confirmed;

[0201] 7) The main organs function well and meet the following criteria:

[0202] Routine blood test standards (no blood transfusion and no use of hematopoietic stimulating factor drugs for correction within 7 days before screening):

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

[0204] b) Neutrophil absolute count (NEUT) ≥ 1.5 × 10 9 / L;

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

[0206] Biochemical examinations must meet the following criteria:

[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 accompanied by liver metastasis, ALT and AST

[0209] ≤5×ULN;

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

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

[0212] Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (not receiving anticoagulant therapy);

[0213] Cardiac ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%.

[0214] 1.2 Experimental Drugs

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

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

[0217] 1.3 Dosage regimen

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

[0219] Fulvestrant injection: 500 mg / time intramuscular injection, each 28 days as a treatment cycle, with administration on the 1st and 15th days of the first treatment cycle, and on the 1st day of each subsequent treatment cycle.

[0220] 1.4 Evaluation Criteria

[0221] Effectiveness evaluation criteria: RECIST 1.1 standard was used to determine the disease status.

[0222] Safety evaluation criteria: The severity of adverse events was determined using the NCI-CTC AE 5.0 standard. During the trial, the adverse event record form should be filled in truthfully, including the time of occurrence, severity, relevance to the study treatment, duration, measures taken, and outcomes of the adverse event.

[0223] 1.5 Test results

[0224] 1.5.1 Security

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

[0226] 1.5.2 Validity

[0227] A total of 110 patients were enrolled, and the median treatment time for the evaluable patients was 6.6 months. The objective response rate (ORR) was 58.2% (64 / 110), of which 2 patients had complete remission (CR), 62 patients had partial remission (PR), 38 patients had stable disease (SD), and the disease control rate (DCR) was 92.7% (102 / 110). The results showed that the combined drug composition disclosed in the present invention has clinical benefits.

[0228] The following are representative cases:

[0229]

[0230] Note: “--” means the data is not available yet.

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

Claims

1. A combined pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and fulvestrant 2. The combination pharmaceutical composition according to claim 1, which contains 20-240 mg, 40-180 mg, 60-180 mg, 80-180 mg, 100-180 mg, 120-180 mg or 150-180 mg of the compound of formula (I) or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof, calculated as the compound of formula (I); or contains 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 180 mg or 240 mg of the compound of formula (I) or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

3. The combination pharmaceutical composition according to claim 1 or 2, comprising 125 mg-1000 mg, 125 mg-750 mg, 250 mg-750 mg or 250 mg-500 mg of fulvestrant, or a pharmaceutical composition thereof; or comprising 125 mg, 250 mg, 500 mg, 750 mg or 1000 mg of fulvestrant, or a pharmaceutical composition thereof.

4. The combination pharmaceutical composition according to any one of claims 1 to 3, comprising 120 to 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof and 250 mg to 500 mg of fulvestrant.

5. Use of the combined pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a medicament for treating or preventing breast cancer.

6. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating or preventing breast cancer 7. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing breast cancer in combination with fulvestrant.

8. The use according to any one of claims 5 to 7, wherein the breast cancer is selected from HR-positive and HER2-negative breast cancer.

9. The use according to claim 8, wherein the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer.

10. The use according to claim 9, wherein 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 treatment; or the breast cancer is selected from HR-positive, HER2-negative locally advanced and / or metastatic breast cancer that has not previously received systemic anti-tumor treatment.

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