How to treat cancer using a combination of SERD drug regimens

Abstract

To provide potent anti-estrogen treatment that antagonizes and degrades the estrogen receptor for cancer treatment.SOLUTION: Provided herein are dosing regimens for the administration of a compound represented by the formula in the figure or a pharmaceutically acceptable salt thereof to patients in need of cancer treatment. The dosing regimens include adjuvant therapy.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross-reference This application incorporates by reference in its entirety U.S. Provisional Application No. 63 / 158,688, filed on March 9, 2021, for all purposes.

[0002] This disclosure relates to the field of cancer treatment.

Background Art

[0003] Selective estrogen receptor degraders (SERDs) bind to estrogen receptors (ERs) and downregulate ER-mediated transcriptional activity. This degradation and downregulation induced by SERDs may be useful in the treatment of cell proliferation disorders such as cancer.

[0004] Drug development is unpredictable. Often, for largely unknown reasons, it is common for new molecules to fail at the preclinical and / or clinical stages. Added complexity is introduced by dosing, which results in further unpredictability. Not all drug dosing regimens are necessarily equally effective in all patient populations due to various factors including, but not limited to, body weight, performance status, number of previous systemic therapies, genetics, and histological tumor type. Toxicity issues add further complexity. A balance between efficacy and toxicity needs to be achieved. In addition, it is not always possible to predict which patients will achieve therapeutic serum levels quickly enough to benefit before disease progression. Administration of a loading dose seeks to provide an improvement in the likelihood of early progression in subsets of patients who previously did not respond, without presenting a toxicological barrier to that subset or to previously responsive populations.

[0005] Providing alternative treatments for cancer patients remains necessary. In addition, there is still a need for alternative treatments with a better tolerability profile, or alternative treatments that enable maximum activity with limited adverse events and fewer interruptions or discontinuations. There is still a need for potent anti-estrogen therapies that antagonistize and degrade the ER with clinically relevant activity and bioavailability. (Shagufta, et al., Recent progress in selective estrogen receptor down regulators (SERDs) for the treatment of breast cancer, RSC Med.Chem., 2020, 11, 438-454). [Overview of the project]

[0006] This disclosure relates to a novel drug delivery protocol for using (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol, represented by formula I below, or a pharmaceutically acceptable salt thereof, as part of adjuvant therapy for the treatment of cancer.

[0007] The compound of formula I has the following structure:

[0008] [ka] or a pharmaceutically acceptable salt thereof.

[0009] This compound can be prepared as a free base or a pharmaceutically acceptable salt thereof using the synthesis steps described in International Publication No. 20 / 014435 or U.S. Patent No. 10,654,866. This compound is known by the trade name "Imulnestrant".

[0010] The compound of formula I is an orally bioavailable selective SERD. It is a potent degrader and selective antagonist of wild-type and mutant estrogen receptor α (ERα or ESR1). It would be useful to develop novel treatment regimens and dosing protocols for the treatment of cancer, using the compound of formula I as part of adjuvant therapy, in combination with one or more other therapeutic agents, in conjunction with surgery, or in combination with one or more other therapeutic agents and in conjunction with surgery.

[0011] A drug administration protocol using a compound of formula I for the treatment of cancer is disclosed herein. The protocol may be monotherapy or adjuvant therapy.

[0012] In one embodiment, the drug protocol is a method for treating cancer, Formula I for doses of approximately 200 mg to 800 mg

[0013] [ka] A method comprising administering a compound or a pharmaceutically acceptable salt thereof to a patient in need of such treatment at least once daily.

[0014] In another embodiment, the drug protocol is a method for treating cancer, Compounds of formula I in doses of approximately 200 mg to approximately 400 mg, Or a method comprising administering a pharmaceutically acceptable salt thereof to a patient in need of such treatment at least once daily for at least one week.

[0015] In one embodiment, the drug protocol is a method for treating cancer, A method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of approximately 200 mg to a patient in need of such treatment at least once daily for at least one week, and then increasing the dose to approximately 300 mg or approximately 400 mg at least once daily.

[0016] In one embodiment, the drug protocol is a method for treating cancer, Approximately 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, The method includes administering the drug to patients requiring such treatment at least once a day for about two weeks to about six months, and then increasing the dose to about 300 mg at least once a day for at least 21 days.

[0017] In one embodiment, the drug protocol is a method for treating cancer, The method includes administering a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of approximately 200 mg to a patient requiring such treatment at least once daily for approximately 2 weeks to approximately 6 months, and then increasing the dose to approximately 400 mg at least once daily for at least 21 days.

[0018] In another embodiment, the drug protocol is a method for treating cancer, comprising a compound of formula I in a dose of about 400 mg. Or a method comprising administering a pharmaceutically acceptable salt thereof to a patient requiring such treatment at least once daily.

[0019] In one embodiment, the drug protocol includes a method for treating breast cancer, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 400 mg to a patient in need of such treatment at least once daily.

[0020] In one embodiment, the drug protocol is a method for treating breast cancer, comprising a dose of approximately 400 mg of the compound of formula I or a pharmaceutically acceptable salt thereof. The method includes administering the drug to patients requiring such treatment at least once a day for at least about one week to about six months, and then reducing the dose to at least 200 mg once a day.

[0021] In one aspect, a dosing protocol is a method of treating cancer, comprising administering to a patient who needs such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 400 mg once a day for at least about two weeks to about six months, and then reducing the dose to about 200 mg once a day for at least at least 21 days.

[0022] In one aspect, a dosing protocol is a method of treating cancer, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent for the treatment of cancer in a patient, wherein the cancer is selected from the group consisting of metastatic breast cancer (mBC), breast cancer including advanced breast cancer, ovarian cancer, endometrial cancer including endometrioid endometrial cancer (EEC), prostate cancer, uterine cancer, gastric cancer, and lung cancer, and the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg to about 400 mg.

[0023] In one aspect, a dosing protocol is a method of treating cancer, comprising administering to a patient who needs such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 400 mg once a day.

[0024] In one aspect, a method of treating cancer, comprising administering to a patient who needs such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 200 mg to about 400 mg, a second therapeutic agent, and a third therapeutic agent once a day for at least one week, wherein the second therapeutic agent and the third therapeutic agent are different, is disclosed herein.

[0025] In one aspect, a method of treating breast cancer, comprising administering to a patient who needs such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 400 mg once a day, is disclosed herein.

[0026] In one embodiment, the drug protocol is a method for treating ER+, HER2-negative breast cancer, comprising administering (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-clomeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1), pertuzumab, and trastuzumab.

[0027] In another embodiment, the drug protocol comprises a method for treating ER+, HER2-positive breast cancer, comprising administering (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-clomeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1), pertuzumab, and trastuzumab.

[0028] In one embodiment, the drug protocol is a method for treating ER+, HER2-negative breast cancer, comprising administering 400 mg of (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-clomeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1), 6 mg / kg of pertuzumab (Q21D), and 420 mg of trastuzumab (Q21D), where Q21D means every 21 days.

[0029] In another embodiment, the drug protocol includes a method for treating ER+, HER2-positive breast cancer, comprising administering (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-clomeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1), 6 mg / kg of pertuzumab (Q21D), and 420 mg of trastuzumab (Q21D).

[0030] In one embodiment, the drug protocol is a method for treating ER+, HER2-negative breast cancer, comprising administering at least once daily about 400 mg of (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-clomeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1) and abemaciclib.

[0031] In one embodiment, the drug protocol comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer, to be administered to a patient at a dose of about 200 mg to about 800 mg, at least once daily for at least one week.

[0032] In another embodiment, the drug protocol comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer, to be administered to a patient at a dose of about 200 mg at least once daily for about 2 weeks to about 6 months, and then the dose is increased to about 300 mg at least once daily for at least 21 days.

[0033] In one embodiment, a drug protocol comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a patient at a dose of about 200 mg at least once daily for about 2 weeks to about 6 months, and then the dose is increased to about 400 mg at least once daily for at least 21 days. In one embodiment, the drug protocol comprises the compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer, wherein the compound or a pharmaceutically acceptable compound is administered to a patient at a dose of about 200 mg at least once daily for about 2 weeks to about 6 months, and then the dose is increased to about 400 mg at least once daily for at least 21 days.

[0034] In one embodiment, the drug protocol comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer, wherein the compound or pharmaceutically acceptable compound is administered to the patient at a dose of about 400 mg at least once daily.

[0035] In one embodiment, the drug protocol comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer, wherein the compound or the pharmaceutically acceptable compound is administered to the patient at a dose of about 400 mg at least once daily for about 2 weeks to about 6 months, and then the dose is reduced to about 200 mg at least once daily for at least 21 days.

[0036] In one embodiment, the drug protocol includes a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in combination with a second therapeutic agent in the treatment of cancer in a patient, either concurrently, separately, or in a sequence, administered at a dose of about 200 mg to about 400 mg at least once daily for at least one week.

[0037] In one embodiment, the drug protocol comprises a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in combination with a second and a third therapeutic agent in the treatment of cancer in a patient, either concurrently, separately, or in a sequence, wherein the second and third therapeutic agents are different, and the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg to about 400 mg at least once daily for at least one week.

[0038] In one embodiment, the drug protocol includes a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in concurrent, separate, or sequential combination with a second therapeutic agent in the treatment of cancer in a patient, wherein the cancer is selected from the group consisting of breast cancer, including metastatic breast cancer (mBC) and advanced breast cancer, ovarian cancer, endometrial cancer, including endometrioid endometrial cancer (EEC), prostate cancer, uterine cancer, gastric cancer, and lung cancer, and the compound or a pharmaceutically acceptable salt thereof is administered in doses of approximately 200 mg to approximately 400 mg.

[0039] In one embodiment, a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a patient, is disclosed herein, administered at a dose of about 400 mg at least once daily. In one embodiment, the breast cancer is ER+, HER2-, metastatic breast cancer. In another embodiment, the breast cancer is ER+, HER2-, advanced breast cancer.

[0040] In one embodiment, the drug protocol comprises a compound, (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1), for use concurrently, separately, or in sequential combination with pertuzumab and trastuzumab to treat ER+, HER2-negative breast cancer.

[0041] In one embodiment, the drug protocol comprises a compound, (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1), for use concurrently, separately, or in sequential combination with pertuzumab and trastuzumab to treat ER+, HER2-positive breast cancer.

[0042] In one embodiment, the drug protocol contains the compound (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1), administered in a dose of approximately 400 mg, for use concurrently, separately, or in sequential combination with abemaciclib to treat ER+, HER2-negative breast cancer. In one embodiment, the compound is administered in a dose of approximately 200 mg. In another embodiment, the compound is administered in a dose of approximately 300 mg.

[0043] The protocol involves the use of the compound of formula I or a pharmaceutically acceptable salt thereof in adjuvant therapy, either in combination with one or more other therapeutic agents in conjunction with surgery, or in combination with one or more other therapeutic agents and in conjunction with surgery. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered for at least one week prior to surgery. In an alternative embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered for at least one week after surgery. In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered for at least one week prior to surgery and at least one week after surgery. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1).

[0044] In one embodiment, a method for treating cancer, A method is disclosed herein, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of approximately 200 mg to approximately 400 mg to a patient requiring such treatment, at least once daily for at least one week.

[0045] Preferably, the pharmaceutically acceptable salt of the compound of formula I is (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1).

[0046] In another embodiment, a method for treating cancer is disclosed herein, comprising administering a dose of about 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment at least once daily for about two weeks to about six months, and then increasing the dose to about 300 mg at least once daily for at least 14 days, or at least 21 days, or at least 28 days. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1).

[0047] In another embodiment, a method for treating cancer is disclosed herein, comprising administering a dose of about 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment at least once daily for about two weeks to about six months, and then increasing the dose to about 400 mg at least once daily for at least 14 days, or at least 21 days, or at least 28 days. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1).

[0048] In yet another embodiment, a method for treating cancer is disclosed herein, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 400 mg to a patient in need of such treatment at least once daily for about two weeks to about six months, and then reducing the dose to about 200 mg at least once daily for at least 14 days, or at least 21 days, or at least 28 days. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1).

[0049] In a further embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of cancer is disclosed herein, comprising administering a dose of about 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment at least once daily for about two weeks to about six months, and then increasing the dose to about 400 mg at least once daily for at least 14 days, or at least 21 days, or at least 28 days. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1).

[0050] In a further embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of cancer is disclosed herein, comprising administering a dose of about 400 mg of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment at least once daily for about two weeks to about six months, and then reducing the dose to about 200 mg at least once daily for at least 14 days, or at least 21 days, or at least 28 days. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1).

[0051] In yet another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer is disclosed herein, wherein the medicament comprises about 200 mg to about 400 mg of the compound or a salt thereof, and the medicament is administered at least once daily for at least one week. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1).

[0052] In one embodiment, the drug protocol comprises 400 mg of (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1) for use in combination, separately or sequentially, with 6 mg / kg of pertuzumab (Q21D) and 420 mg of trastuzumab (Q21D) to treat ER+, HER2-negative breast cancer, where Q21D means every 21 days.

[0053] In one embodiment, the drug protocol comprises 400 mg of (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1) for use in combination, separately or sequentially, with 6 mg / kg of pertuzumab (Q21D) and 420 mg of trastuzumab (Q21D) to treat ER+, HER2-positive breast cancer, where Q21D means every 21 days.

[0054] In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to patients with ER-positive, human epidermal growth factor receptor 2-negative (HER2-negative) early-stage (stages I-III) breast cancer for approximately two weeks. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1).

[0055] In one embodiment, a method for treating cancer, A method is disclosed herein that comprises administering a compound of formula I or a pharmaceutically acceptable salt thereof, a second therapeutic agent, and a third therapeutic agent in doses of approximately 200 mg to approximately 400 mg to a patient requiring such treatment, at least once daily for at least one week, wherein the second therapeutic agent and the third therapeutic agent differ. In all embodiments, the preferred pharmaceutically acceptable salt of the compound of formula I is a tosylate salt, i.e., 4-methylbenzenesulfonate. [Brief explanation of the drawing]

[0056] [Figure 1]This figure shows the mean (± standard deviation) total plasma concentration-time profile on day 15 of a clinical trial dose escalation study after multiple oral doses of (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1) in the range of 200 mg to 1200 mg in QD. [Figure 2] This figure shows the mean (± standard deviation) unbound plasma concentration-time profile on day 15 of a clinical trial dose escalation study after multiple oral doses of (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1) in the range of 200 mg to 1200 mg in QD. [Modes for carrying out the invention]

[0057] Pharmaceutically acceptable salts The compound of formula I is preferably used as a tosylate salt, which is also known in the art as 4-methylbenzenesulfonate or p-toluenesulfonate. However, other pharmaceutically acceptable acid addition salts may be used. Such pharmaceutically acceptable acid addition salts and methods for preparing them are known. For example, see P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA / Wiley-VCH, 2002), LDBighley, SMBerge, DC Monkhouse, in "Encyclopedia of Pharmaceutical Technology," Eds. J. Swarbrick and JCBoylan, Vol. 13, Marcel Dekker, Inc., New York, Basel, Hong Kong 1995, pp. 453-499, and SMBerge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977. Specific examples of acids that can be used to prepare these other salts include methanesulfonic acid (which forms mesylates), benzenesulfonic acid (which forms besylates), trifluoromethanesulfonic acid (which forms triflates), HCl, H2SO4, HNO3, and H3PO4.

[0058] cancer In one embodiment, cancer is selected from the group consisting of breast cancer including advanced breast cancer and metastatic breast cancer (mBC), ovarian cancer, endometrial cancer including endometrioid endometrial cancer (EEC), prostate cancer, uterine cancer, gastric cancer, and lung cancer. In another embodiment, cancer is breast cancer and / or endometrial cancer.

[0059] In one embodiment, cancer is hormone receptor-positive (HR-positive), meaning that cancer cells express hormone receptors. Hormone receptors include both estrogen receptors and progesterone receptors. In one embodiment, cancer is estrogen receptor-positive (ER-positive). In one embodiment, cancer expresses tyrosine kinase receptors such as HER2. Cancer can be HER2-positive or HER2-negative.

[0060] In one embodiment, cancers that can be treated with a compound of formula I or a pharmaceutically acceptable salt thereof are HR-positive, e.g., ER-positive, and tyrosine kinase receptor-positive, e.g., HER2-positive or HER2-negative.

[0061] In one embodiment, the cancer is ER+, HER2- breast cancer. The breast cancer may be progressive or metastatic.

[0062] Medication regimen In one embodiment, the compound of formula I or a pharmaceutically acceptable salt is administered to a patient requiring such treatment in doses ranging from approximately 200 mg to approximately 1200 mg. Doses of approximately 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 150 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or approximately 1200 mg may be administered. The maximum daily dose, i.e., the maximum 24-hour dose, is not more than approximately 1200 mg. In some embodiments, the dose is about 200 to about 1000 mg, or about 200 to about 800 mg, or about 200 to about 600 mg, or about 200 to about 400 mg. Preferably, the dose is about 200 mg to about 400 mg. In preferred embodiments, the dose is 400 mg. Preferably, the compound of formula I is (5R)-5-[4-[2-[3-(fluoromethyl)azetidine-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinoline-2-ol,4-methylbenzenesulfonic acid (1 / 1). Preferably, the dose is administered at least once a day for at least one week. The dose may be administered twice a day or more.

[0063] Preceding treatment In one embodiment, the patient requiring treatment has previously received endocrine therapy, which is a hormone therapy used to treat cancer. In some embodiments, the patient has been diagnosed as sensitive to endocrine therapy. In some embodiments, the patient has not received cyclin-dependent kinase (CDK4 / 6) inhibitor-containing therapy.

[0064] In another embodiment, a method is disclosed herein in which a patient requiring treatment has received one or fewer prior therapies. In yet another embodiment, a method is disclosed herein in which a patient has received two or fewer prior therapies. In yet another embodiment, a method is disclosed herein in which a patient has received three or fewer prior therapies. In yet another embodiment, a method is disclosed herein in which a patient has received four or fewer prior therapies. In some embodiments, the patient has received eight or more prior therapies.

[0065] As used herein, “prior treatment” refers to any treatment previously administered or used to treat cancer. Administering a single drug, or two or more drugs as part of adjuvant therapy, are examples of prior treatment. Surgical intervention is also an example of prior treatment. Endocrine therapy and aromatase inhibitor therapy are examples of prior treatment, as are treatment with platinum-based chemotherapy agents, CDK4 / 6 inhibitors, or fulvestrant. Treating a patient with a drug followed by surgery is two examples of prior treatment.

[0066] The compound of formula I and its pharmaceutically acceptable salts are administered to patients who are experiencing or exhibiting at least one symptom of the cancer to be treated. In some embodiments, the patient has not received CDK4 / 6 inhibitor-containing therapy. In other embodiments, the patient has previously received endocrine therapy.

[0067] In yet another embodiment, a method is disclosed herein in which the patient has previously received endocrine therapy.

[0068] In another embodiment, a method is disclosed herein in which a patient requiring treatment has been identified or diagnosed with EEC. In another embodiment, a method is disclosed herein in which EEC is ER-positive. In another embodiment, EEC has not been treated with platinum therapy. In another embodiment, EEC has been treated with platinum therapy. In another embodiment, a method is disclosed herein in which EEC is progressing after treatment with platinum therapy. In another embodiment, a method is disclosed herein in which EEC has not been treated with fulvestrant or aromatase inhibitor therapy.

[0069] Monotherapy In another embodiment, a method for treating cancer is disclosed herein, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 200 mg to about 800 mg or about 200 mg to about 400 mg to a patient in need. In yet another embodiment, a method for treating cancer is disclosed herein, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 200 mg to about 800 mg or about 200 mg to about 400 mg to a patient in need, at least once daily for at least one week.

[0070] In another embodiment, a method is disclosed herein that includes administering a compound of formula I or a pharmaceutically acceptable salt thereof in doses of about 200 mg, about 300 mg, about 400 mg, or about 800 mg to a patient in need. In one embodiment, the method includes administering a dose of about 200 mg. In an alternative embodiment, the method includes administering a dose of about 400 mg.

[0071] In another embodiment, a method is disclosed herein in which the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 200 mg to a patient in need. In another embodiment, a method is disclosed herein further comprising the steps of administering to a patient at least once daily a dose of about 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, followed by administering to the patient at least once daily an increased dose of about 300 mg to about 400 mg. In another embodiment, a method is disclosed herein in which the step of administering a dose of about 200 mg is performed before surgery. In another embodiment, a method is disclosed herein in which the step of administering an increased dose is performed after surgery. In another embodiment, the disclosure provides a method in which the step of administering an increased dose is performed daily for at least three months up to the patient's lifespan.

[0072] In another embodiment, a method is disclosed herein in which the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 400 mg to a patient in need. In another embodiment, a method is disclosed herein further comprising the steps of administering a dose of about 400 mg to the patient at least once daily, followed by administering a reduced dose of about 200 mg to about 300 mg to the patient at least once daily. In another embodiment, a method is disclosed herein in which the step of administering a dose of about 400 mg is performed before surgery. In one embodiment, the patient is scheduled to undergo surgery to treat EEC, and the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 400 mg, and the dose is administered at least once daily for at least one week prior to surgery. In a further embodiment, the 400 mg dose is administered at least once daily for about two weeks prior to surgery. In another embodiment, a method is disclosed herein in which the step of administering the reduced dose is performed after surgery. In one embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is reduced to about 200 mg at least once daily after surgery. In another embodiment, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is reduced to about 300 mg at least once daily after surgery. In yet another embodiment, a method is disclosed herein in which the step of administering the reduced dose is performed daily for at least one day, at least one week, at least two weeks, at least four weeks, at least two months, or at least three months, or up to the end of the patient's life.

[0073] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to the patient at a dose of about 200 mg at least once daily for at least one week, followed by an increased dose of about 300 mg to about 400 mg, administered to the patient at least once daily for at least one week. If the patient is scheduled to undergo surgery to treat EEC, a dose of about 200 mg is administered at least once daily for at least one week prior to the surgery. In some embodiments, a dose of 200 mg is administered at least once daily for about two weeks prior to the surgery. In further embodiments, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is increased to about 300 mg at least once daily after surgery, or alternatively, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is increased to about 400 mg at least once daily after surgery. If desired, the step of administering the increased dose is performed daily for at least one week.

[0074] In one embodiment, a patient in need of treatment is scheduled to undergo surgery to treat cancer, and a method is disclosed herein in which a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 400 mg is administered at least once daily for at least one week prior to the surgery. In a further embodiment, the cancer is metastatic breast cancer. In another embodiment, the cancer is advanced breast cancer. In yet another embodiment, a patient in need of treatment is scheduled to undergo surgery to treat EEC, and a method is disclosed herein in which a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 400 mg is administered at least once daily for at least one week prior to the surgery.

[0075] In another embodiment, a method is disclosed herein in which a patient in need of treatment has been identified or diagnosed with a cancer selected from the group consisting of mBC, breast cancer including advanced breast cancer, ovarian cancer, endometrial cancer including EEC, prostate cancer, uterine cancer, gastric cancer, and lung cancer. In another embodiment, a method is disclosed herein in which the breast cancer is ER-positive. In another embodiment, a method is disclosed herein in which the breast cancer is HER2-negative. In another embodiment, a method is disclosed herein in which the breast cancer is HER2-positive. In a preferred embodiment, the cancer is ER+ and HER2-. More preferably, in one embodiment, the cancer is ER+ and HER2- breast cancer.

[0076] In another embodiment, a method is disclosed herein in which a patient requiring treatment has been identified or diagnosed with mBC. In another embodiment, a method is disclosed herein in which the mBC is HER2-negative. In another embodiment, a method is disclosed herein in which the mBC is HER2-positive. In another embodiment, a method is disclosed herein in which the mBC is untreated or de novo, and de novo means starting from scratch or starting anew.

[0077] In another embodiment, a method is disclosed herein in which a patient requiring treatment has been identified or diagnosed with advanced breast cancer. In another embodiment, a method is disclosed herein in which the advanced breast cancer is HER2-negative. In another embodiment, a method is disclosed herein in which the advanced breast cancer is HER2-positive. In another embodiment, a method is disclosed herein in which the advanced breast cancer is untreated or de novo, and de novo means starting from scratch or starting anew.

[0078] In another embodiment, a method is disclosed herein for a patient requiring treatment who has ER-positive (ER+) and HER2-positive (HER2+) breast cancer. In yet another embodiment, a method is disclosed herein for a patient requiring treatment who has breast cancer that is locally advanced, unresectable, or metastatic.

[0079] In another embodiment, a method is disclosed herein for a patient requiring treatment who has ER-positive (ER+) and HER2-negative (HER2-) breast cancer. In yet another embodiment, a method is disclosed herein for a patient requiring treatment who has breast cancer that is locally advanced, unresectable, or metastatic.

[0080] In another embodiment, the patient is receiving induction taxane chemotherapy in combination with trastuzumab and pertuzumab as the first-line treatment regimen. In another embodiment, the patient is considered suitable for continued treatment with trastuzumab and pertuzumab. In another embodiment, the patient has not progressed with the first-line treatment regimen. In another embodiment, the patient has progressed with the first-line treatment regimen. In another embodiment, the patient has not received more than one HER2-targeted regimen for progressive disease, any endocrine therapy, or any prior CDK4 / 6 inhibitor therapy.

[0081] In another embodiment, the patient has a left ventricular ejection fraction (LVEF) of 50% or higher at baseline, as determined by echocardiography or multigated acquisition scanning. In another embodiment, the patient does not have a left ventricular ejection fraction (LVEF) of 50% or higher at baseline, as determined by echocardiography or multigated acquisition scanning.

[0082] Adjuvant therapy A method for treating cancer is disclosed herein, further comprising administering a second therapeutic agent. In one embodiment, the method for treating cancer comprises administering to a patient in need of treatment a dose of the compound of formula I or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent at least once daily, in a dose of about 200 mg to about 400 mg. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered for at least one week. In another embodiment, a method is disclosed herein in which the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 200 mg, about 300 mg, or about 400 mg. In another embodiment, a method is disclosed herein in which the dose is about 200 mg. In another embodiment, a method is disclosed herein in which the dose is about 300 mg. In another embodiment, a method is disclosed herein in which the dose is about 400 mg.

[0083] In another embodiment, a method for treating cancer is disclosed, comprising administering to a patient in need a dose of about 200 mg to about 400 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, in combination with a second and a third therapeutic agent, at least once daily for at least one week. In another embodiment, a method is disclosed herein in which the dose is about 200 mg, about 300 mg, or about 400 mg. In one embodiment, the dose of the compound of formula I is about 400 mg.

[0084] In all aspects and embodiments disclosed herein, the second therapeutic agent is administered simultaneously, separately, or sequentially with the compound of formula I or a pharmaceutically acceptable salt thereof. The third therapeutic agent is administered simultaneously, separately, or sequentially with the second therapeutic agent and / or the compound of formula I or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the second therapeutic agent is selected from the group consisting of abemaciclib, aromatase inhibitors, everolimus, alpelisib, trastuzumab, and pertuzumab. In some embodiments, the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, and letrozole. In some embodiments, the second therapeutic agent is abemaciclib. In alternative embodiments, the second therapeutic agent is trastuzumab. In preferred embodiments, the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is 400 mg, and the second therapeutic agent is abemaciclib.

[0086] In some embodiments, ER+, HER2- advanced breast cancer is treated with approximately 400 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is abemaciclib.

[0087] In other embodiments, ER+, HER2- metastatic breast cancer is treated with approximately 400 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, the second therapeutic agent being abemaciclib.

[0088] In some embodiments, the third therapeutic agent is selected from the group consisting of aromatase inhibitors, everolimus, alpelisib, trastuzumab, and pertuzumab. The third therapeutic agent is different from the second therapeutic agent. In some embodiments, the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, and letrozole. In some embodiments, the third therapeutic agent is selected from the group consisting of aromatase inhibitors and trastuzumab. In some embodiments, the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, and letrozole. In one embodiment, the third therapeutic agent is an antidiarrheal agent. In one embodiment, the third therapeutic agent is pertuzumab. In other embodiments, the second therapeutic agent is trastuzumab, and the third therapeutic agent is pertuzumab.

[0089] Examples of antidiarrheal agents include, but are not limited to, those selected from the group consisting of Lactobacillus acidophilus, atropine / diphenoxylate, atropine / diphenoxine, loperamide, bismuth subsalicylate, loperamide, Saccharomyces boulardii, lyoactobacillus acidophilus / lactobacillus bulgaricus, Lactobacillus rhamnosus, and cloferemer. In one embodiment, the antidiarrheal agent is loperamide.

[0090] In another embodiment, a method is disclosed herein in which the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 200 mg. In another embodiment, a method is disclosed herein further comprising the steps of administering a dose of about 200 mg to a patient at least once daily, followed by administering an increased dose of about 300 mg to about 400 mg to the patient at least once daily. In another embodiment, a method is disclosed herein in which the step of administering a dose of about 200 mg is performed before surgery. In another embodiment, a method is disclosed herein in which the step of administering an increased dose is performed after surgery. In another embodiment, a method is disclosed herein in which the step of administering an increased dose is performed daily for at least three months up to the patient's lifespan.

[0091] In another embodiment, a method is disclosed herein in which the dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 400 mg. In another embodiment, a method is disclosed herein further comprising the steps of administering to a patient at least once daily a dose of the compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 400 mg, followed by administering to the patient at least once daily a reduced dose of about 200 mg to about 300 mg. In another embodiment, a method is disclosed herein in which the step of administering the dose of about 400 mg is performed before surgery. In another embodiment, a method is disclosed herein in which the step of administering the reduced dose is performed after surgery. In another embodiment, a method is provided herein in which the step of administering the reduced dose is performed daily for at least 3 months up to the patient's lifespan.

[0092] In some embodiments, the compounds of formula I described herein or their pharmaceutically acceptable salts may be used in combination with one or more other therapies to treat a related disease, disorder, or condition. In some embodiments, the administration of the compounds of formula I or their pharmaceutically acceptable salts is modified when used in adjuvant therapy compared to when administered as monotherapy. Alternatively or additionally, in some embodiments, therapies administered in combination with the compounds of formula I described herein or their pharmaceutically acceptable salts are administered according to a different regimen or protocol than when administered alone or in combination with one or more other therapies other than the compounds of formula I. In some embodiments, a composition containing an additional therapeutic agent, the additional therapeutic agent, and the compound provided may act synergistically. In some embodiments, the compounds of formula I or their pharmaceutically acceptable salts may act synergistically when combined with a second therapeutic agent or its pharmaceutically acceptable salt. In some embodiments, one or both therapies used in a combination regimen are administered at lower levels or less frequently than when used as monotherapy.

[0093] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof may be administered to a patient in need of treatment in a dose of about 200 mg to about 400 mg in combination with one or more other therapeutic agents, including a combination with a second therapeutic agent or a pharmaceutically acceptable salt thereof. In some embodiments, the dose is about 200 mg or about 400 mg. In some embodiments, the dose is 200 mg. In some embodiments, an additional step includes administering a dose of about 200 mg to the patient at least once daily, followed by an increased dose of about 300 mg to about 400 mg, administered to the patient at least once daily. In some embodiments, the dose is 400 mg. In some embodiments, an additional step includes administering a dose of about 400 mg to the patient at least once daily, followed by a decreased dose of about 200 mg to about 300 mg, administered to the patient at least once daily.

[0094] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof may be administered in combination with one or more other therapeutic agents, including a combination of a second therapeutic agent or a pharmaceutically acceptable salt thereof and a third therapeutic agent or a pharmaceutically acceptable salt thereof, in doses of about 200 mg to about 400 mg.

[0095] In another embodiment, different or additional compounds may also be administered. Examples of different or additional compounds include, but are not limited to, additional anticancer drugs, other inhibitors along the MAPK pathway, including inhibitors along the RAS / RAF pathway, e.g., tyrosine kinase inhibitors, e.g., ruxolitinib, ponatinib, erlotinib, alectinib, osimertinib, afatinib, bosutinib, axitinib, ceritinib, acalabrutinib, sunitinib, lenvatinib, brigatinib, imatinib, neratinib, lapatinib, crizotinib, cabozantinib, ibrutinib, dasatinib, gefitinib, or binimetinib, and inhibitors along the MEK1 / 2 cascade, including inhibitors along the ERK pathway, e.g., urixertinib, MK-8353, LTT-462, ASTX029, and JSI-1187.

[0096] BRAF kinase inhibitors, such as trametinib, vemurafenib, dabrafenib, sorafenib, or regorafenib; PARP inhibitors, such as olaparib, lucaparib, or niraparib; and monoclonal antibodies, such as (cetuximab) erbitux.In some embodiments, additional anticancer agents include: polyfunctional alkylating agents, e.g., nitrosourea, mustard (nitrogen mustard), methanesulfonate (busulfan), or ethyleneimine; non-polyfunctional alkylating agents, e.g., procarbazine (Matulane), dacarbazine (DTIC), altretamine (Hexalen), or cisplatin (Platinol); antimetabolites, e.g., antifolate compounds (methotrexate) or amino acid antagonists (azaserine); and purine antagonists. For example, mercaptopurine (6-MP), thioguanine (6-TG), fludarabine phosphate, cladribine (Leustatin), or pentostatin (Nipent); pyrimidine antagonists, for example, fluorouracil (5-FU), cytarabine (ARA-C), or azacitidine; plant alkaloids, for example, vinblastine (Velban), vincristine (Oncovin), etoposide (VP-16, VePe-sid), teniposide (Vumon), topotecan (Hycamti); n) Irinotecan (Camptosar), paclitaxel (Taxol), or docetaxel (Taxotere); antibiotics, e.g., anthracyclines, doxorubicin (Adriamycin, Rubex, Doxil), daunorubicin (DaunoXome), dactinomycin (Cosmegen), idarubicin (Idamycin), plicamycin (Mithramycin), mitomycin (Mutamycin), or bleomycin (Blenoxane); hormones, e.g., Examples include tamoxifen (Nolvadex), flutamide (Eulexin), gonadotropin-releasing hormone agonists (leuprolide and goserelin (Zoladex)), aromatase inhibitors, aminoglutethimide, or anastrozole (Arimidex); or other anticancer drugs, such as amsacrin, hydroxyurea (Hydrea), asparaginase (El-spar), mitoxantrone (Novantrone), mitotane, retinoic acid derivatives, myeloproliferative factors, or amiphostin.

[0097] Examples of different or additional compounds include antidiarrheal drugs such as Intestinex (Lactobacillus acidophilus), Lonox (atropine / diphenoxylate), Motofen(Pro) (atropine / diphenoxine), Acidophilus (Lactobacillus acidophilus), Florajen (Lactobacillus acidophilus), Imodium AD (loperamide), Kaopectate (bismuth subsalicylate), Imotil (loperamide), Pink Bismuth (bismuth subsalicylate), Pepto-Bismol (bismuth subsalicylate), Lomotil(Pro) (atropine / diphenoxylate), Diamode (loperamide), Imodium(Pro) (loperamide), Florastor (Saccharomyces boudiciformis), Kapectolin (New Formula) (Bismuth subsalicylate), Florastor Kids (Saccharomyces blaudilyo), Bacid (LAC) (Lactobacillus acidophilus), BD Lactinex (Lactobacillus acidophilus / Lactobacillus bulgaricus), Bismarex (Bismuth subsalicylate), Bismatrol (Bismuth subsalicylate), Bismatrol Maximum Strength (Bismuth subsalicylate), Culturelle Digestive Health (Lactobacillus rhamnosus gg), Culturelle Health and Wellness (Lactobacillus rhamnosus gg), Dofus (Lactobacillus acidophilus), Flora-Q (Lactobacillus acidophilus), Floranex (Lactobacillus acidophilus / Lactobacillus bulgaricus), Fulyzaq (Pro) (Clofelemer), Kao-Paverin (Loperamide), Kola-Pectin DS (Bismuth subsalicylate), Lomocot (Atropine / Diphenoxylate), Mytesi (Pro) (Clofelemer), Novaflor (Lactobacillus acidophilus), Peptic Relief (Bismuth subsalicylate), PercyExamples include, but are not limited to, Medicine (bismuth subsalicylate), Risa-Bid (Lactobacillus acidophilus), RisaQuad (Lactobacillus acidophilus), Soothe Caplets (bismuth subsalicylate), or Superdophilus (Lactobacillus acidophilus). In some embodiments, use involves the administration of an antidiarrheal agent.

[0098] In some embodiments, the compounds of formula I or pharmaceutically acceptable salts thereof are formulated as pharmaceutical compositions administered by any route that makes each of these compounds bioavailable, with or without a second therapeutic agent or a pharmaceutically acceptable salt thereof, or with or without the second and third therapeutic agents or pharmaceutically acceptable salts thereof. The route of administration may vary in any way and may be limited by the physical properties of the drug and the convenience of the patient and caregiver.

[0099] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered orally with or without a second therapeutic agent or a pharmaceutically acceptable salt thereof, or with or without a second therapeutic agent and a third therapeutic agent or a pharmaceutically acceptable salt thereof. Alternatively, the compound of formula I or a pharmaceutically acceptable salt thereof is formulated for parenteral administration, for example, intravenous (IV) or subcutaneous administration, with or without a second therapeutic agent or a pharmaceutically acceptable salt thereof, or with or without a second therapeutic agent and a third therapeutic agent or a pharmaceutically acceptable salt thereof. In some embodiments, one of the compounds of formula I, the second therapeutic agent, the third therapeutic agent, or a pharmaceutically acceptable salt thereof is formulated for oral administration. In some embodiments, one of the compounds of formula I, the second therapeutic agent, the third therapeutic agent, or a pharmaceutically acceptable salt thereof is formulated for parenteral administration, for example, intravenous administration. In some embodiments, one of the compounds of formula I, the second therapeutic agent, the third therapeutic agent, or pharmaceutically acceptable salts thereof is formulated for intravenous administration. Such pharmaceutical compositions and processes for preparing them are well known in the art. (e.g., Remington: The Science and Practice of Pharmacy, LV Allen, Editor, 22) nd (See Edition, Pharmaceutical Press, 2012.)

[0100] In certain embodiments, the Disclosure relates to a second therapeutic agent or a pharmaceutically acceptable salt thereof, or a compound of formula I or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination in the treatment of breast cancer including mBC, ovarian cancer, endometrial cancer including EEC, prostate cancer, uterine cancer, gastric cancer, and lung cancer.

[0101] In one embodiment, a method for treating cancer, Formula I for doses of approximately 200 mg to 400 mg

[0102] [ka] A method is disclosed herein comprising administering a compound of formula I, or a pharmaceutically acceptable salt thereof, a second therapeutic agent, and a third therapeutic agent to a patient in need of such treatment, at least once daily for at least one week, wherein the second and third therapeutic agents are different. In some embodiments, the dose of the compound of formula I is about 400 mg at least once daily. In other embodiments, the dose of the compound of formula I is about 300 mg at least once daily. In yet another embodiment, the dose of the compound of formula I is about 200 mg at least once daily. Many different pharmaceutically acceptable salts of the compound of formula I may be used. A preferred pharmaceutically acceptable salt is 4-methylbenzenesulfonate.

[0103] In one preferred embodiment, the second therapeutic agent is trastuzumab. Trastuzumab may be administered at a dose of about 8 mg / kg at least once daily. Alternatively, trastuzumab may be administered at a dose of about 6 mg / kg at least once daily. Alternatively, trastuzumab may be administered at a dose of about 4 mg / kg at least once daily. In one embodiment, an initial dose of about 8 mg / kg is administered, followed by a dose of about 4 mg / kg about 24 hours later.

[0104] In one preferred embodiment, the third therapeutic agent is pertuzumab. Pertuzumab may be administered in a dose of about 840 mg. Alternatively, pertuzumab may be administered in a dose of about 420 mg. In one embodiment, an initial dose of about 840 mg of pertuzumab is administered, followed by a dose of about 420 mg about 24 hours later.

[0105] In one embodiment, the cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer. In some embodiments, the cancer is breast cancer, and the breast cancer is advanced breast cancer or metastatic breast cancer (mBC), and the endometrial cancer is endometrioid endometrial carcinoma (EEC). In certain embodiments, the cancer is HR-positive. An HR-positive cancer may be ER-positive and HER2-negative. Alternatively, an HR-positive cancer may be ER-positive and HER2-positive.

[0106] If the cancer is breast cancer, it may be locally advanced, unresectable, or metastatic. In one embodiment, the breast cancer is metastatic breast cancer (mBC). In one embodiment, the breast cancer is advanced breast cancer. In some embodiments, the methods disclosed herein are used to treat previously untreated metastatic breast cancer. In one embodiment, the advanced breast cancer is previously untreated.

[0107] In some embodiments, the methods disclosed herein are used to treat patients who have received induction taxane chemotherapy in combination with trastuzumab and pertuzumab as a first-line treatment regimen.

[0108] In some embodiments, the methods disclosed herein are used to treat patients who have not received one or more HER2-targeted regimens for progressive disease, any endocrine therapy, or any prior CDK4 / 6 inhibitor therapy.

[0109] In some embodiments, the methods disclosed herein are used to treat patients who, as determined by echocardiography or multi-gate acquisition scans, have a baseline left ventricular ejection fraction (LVEF) of 50% or greater.

[0110] In some embodiments, the methods disclosed herein are used to treat patients who, as determined by echocardiography or multi-gate acquisition scans, do not have a left ventricular ejection fraction (LVEF) of 50% or greater at baseline.

[0111] In another embodiment, the treatment method comprises a compound of formula I or a pharmaceutically acceptable salt thereof, trastuzumab, and pertuzumab, wherein if trastuzumab is interrupted or discontinued, pertuzumab is also interrupted or discontinued.

[0112] The SERDs disclosed herein provide inhibition of ER-mediated transcription, which may be useful in treating cancers such as breast cancer including mBCs, ovarian cancer, endometrial cancer including EECs, prostate cancer, uterine cancer, gastric cancer, and lung cancer, as well as mutations due to new resistance. These SERDs can be used as monotherapy or in combination with other classes of drugs, including selective estrogen receptor modulators (SERMs), aromatase inhibitors, CDK4 inhibitors, CDK6 inhibitors, PI3K inhibitors, and mammalian target of rapamycin (mTOR) inhibitors, to treat HR-positive cancers such as advanced breast cancer, breast cancer including mBCs, ovarian cancer, endometrial cancer including EECs, prostate cancer, uterine cancer, gastric cancer, and lung cancer.

[0113] definition As used herein, the term “cancer” refers to or describes a physiological condition in a patient that is typically characterized by uncontrolled cell proliferation. This definition includes benign and malignant cancers.

[0114] As used herein, the terms “primary tumor” or “primary cancer” refer to the cancer that first developed and do not refer to metastatic lesions located in other tissues, organs, or sites in the subject.

[0115] As used herein, the term “polymorph” refers to crystals of the same compound that have different physical properties as a result of the order of molecules within the crystal lattice. Different polymorphs of a single compound have one or more different chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties from one another. Differences in physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in the manufacture of compositions and products), dissolution rate (an important factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, moisture adsorption, compressibility, and particle morphology. Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, where the dosage form changes color more rapidly when composed of one polymorph than when composed of another) or mechanical changes (e.g., crystalline changes during storage when a kinetically preferred polymorph is converted to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). As a result of differences in solubility / dissolution, several transitions affect potency and / or toxicity. In addition, the physical properties of the crystals may be important in processing; for example, one polymorph may be more likely to form a solvate, or it may be more difficult to remove impurities by filtering and washing (i.e., the shape and size distribution of particles may differ between one polymorph and another). As used herein, “polymorph” does not include the amorphous form of the compound of formula I. As used herein, “amorphous” refers to the non-crystalline form of a compound, which may be the solid form of the compound of formula I or a pharmaceutically acceptable salt thereof, or the solubilized form of the compound of formula I. For example, “amorphous” refers to a compound that does not have a regular repeating arrangement of molecules or outer planes, e.g., the solid form of the compound.

[0116] As used herein, the term “anhydrous” refers to a crystalline form of the compound of formula I or a pharmaceutically acceptable salt thereof having 1% by weight or less of water. For example, having 0.5% by weight or less, 0.25% by weight or less, or 0.1% by weight or less of water.

[0117] As used herein, the term “solvate” refers to a crystalline form of a compound of formula I, such as a polymorph of the compound of formula I, in which the crystal lattice contains one or more crystallizing solvents.

[0118] When used in reference to a composition containing polymorphs of a compound of formula I, "purity" refers to the percentage of one particular polymorph in the composition referred to, relative to other polymorphs or amorphous forms of the compound of formula I or a pharmaceutically acceptable salt thereof. For example, a composition containing polymorph 1 having a purity of 90% contains 90 parts by weight of form 1 and 10 parts by weight of other polymorphs and / or amorphous forms of the compound of formula I.

[0119] When used herein, a compound of formula I or a pharmaceutically acceptable salt or composition thereof is "substantially free" of one or more other components. A compound of formula I or a pharmaceutically acceptable salt or composition thereof is not free of significant amounts of such other components. For example, a composition may contain less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, or less than 1% by weight of other components. Such components may include starting materials, residual solvents, or other impurities that may arise from the preparation and / or isolation of the formula I compounds and compositions provided herein. In some embodiments, the polymorphs provided herein are substantially free of other polymorphs. In some embodiments, a particular polymorph of a compound of formula I or a pharmaceutically acceptable salt thereof is "substantially free" of other polymorphs if the particular polymorph constitutes at least about 95% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof that is present. In certain embodiments, a particular polymorph of a compound of formula I or a pharmaceutically acceptable salt thereof is "substantially free" of other polymorphs if the particular polymorph constitutes at least about 97% by weight, about 98% by weight, about 99% by weight, or about 99.5% by weight of the compound of formula I or a pharmaceutically acceptable salt thereof that is present. In certain embodiments, a particular polymorph of a compound of formula I or a pharmaceutically acceptable salt thereof is "substantially free" of water if the amount of water constitutes about 2% by weight or less, about 1% by weight or less, or about 0.5% by weight or less of the polymorph.

[0120] As used herein, “substantially pure” means, when used in reference to polymorphs of the compound of formula I, a sample of polymorphs of the compound of formula I or a pharmaceutically acceptable salt thereof having a purity of more than 90%, including more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% of the compound of formula I, and also including about 100%. The remaining material includes other forms of the compound, and / or reaction impurities and / or processing impurities resulting from its preparation. For example, a polymorph of the compound of formula I or a pharmaceutically acceptable salt thereof may be considered substantially pure if measured by means currently known and generally accepted in the art, in that the purity of the polymorph of the compound of formula I exceeds 90%, and the remaining less than 10% of material includes other forms of the compound of formula I or a pharmaceutically acceptable salt thereof, and / or reaction impurities and / or processing impurities. The presence of reaction impurities and / or treatment impurities can be determined by analytical techniques known in the art, such as chromatography, nuclear magnetic resonance spectroscopy, mass spectrometry, or infrared spectroscopy.

[0121] For the sake of brevity, some of the quantitative expressions in this specification are enumerated as ranges of approximate quantities X to Y. Where ranges are enumerated, the range is understood not to be limited to the enumerated upper and lower limits, but rather to include the entire range of approximate quantities X to Y, or any range within that range.

[0122] The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” include all solvents, co-solvents, complexing agents, dispersions, coatings, antimicrobial and antifungal agents, isotonic agents and absorption retarders, etc., that are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions provided herein is intended. Auxiliary active ingredients may also be incorporated into the compositions. Furthermore, a variety of excipients, as commonly used in the art, may be included. These and other such compounds are described in the literature, e.g., Merck Index, Merck & Company, Rahway, NJ. Considerations for including various components in pharmaceutical compositions are described, e.g., Gilman et al. (Eds.). (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0123] As used herein, the term “patient” refers to any animal, including mammals, such as humans. In some embodiments, the patient is a human.

[0124] In some embodiments, the patient has experienced and / or exhibits at least one symptom of the disease or disorder being treated and / or prevented. In some embodiments, the patient is identified or diagnosed with cancer, such as breast cancer including mBC, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, stomach cancer, and lung cancer. In some embodiments, the patient does not have bilateral invasive breast cancer.

[0125] In some embodiments, the patient has received prior therapy for invasive or non-invasive breast cancer. In some embodiments, the patient has received one or fewer prior therapies. In some embodiments, the patient has received two or fewer prior therapies.

[0126] In some embodiments, the patient has previously received endocrine therapy. In some embodiments, the patient has been diagnosed as susceptible to endocrine therapy.

[0127] In some embodiments, the patient has not received CDK4 / 6 inhibitor-containing therapy.

[0128] In some embodiments, the patient is receiving, scheduled to receive, or has not yet received, neoadjuvant therapy concurrently with any other nonprotocol anticancer therapy. In some embodiments, the patient is receiving, scheduled to receive, or has not yet received, radiotherapy to the ipsilateral chest wall for any malignancy. In some embodiments, the patient is receiving, scheduled to receive, or has not yet received, anti-estrogen therapy with raloxifene, tamoxifen, aromatase inhibitors, or other SERMs for either osteoporosis or breast cancer prevention. In some embodiments, the patient is receiving, scheduled to receive, or has not yet received hormone replacement therapy within four weeks of the start of the study treatment. In some embodiments, the patient has undergone major surgery within approximately 28 days prior to randomization to allow for postoperative healing of surgical wounds and sites. In some embodiments, the patient is pregnant or lactating. In some embodiments, the patient has certain infections such as poorly controlled hepatitis or tuberculosis or HIV. In some embodiments, the patient has another serious medical condition.

[0129] As used herein, the terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desirable clinical outcomes include, but are not limited to, cure, whole or partial relief of symptoms associated with a disease or disorder or condition, reduction or mitigation of the degree of the disease, reversal of existing symptoms, disorders, conditions, or progression or severity of the disease, cessation of disease progression, a stable (i.e., non-worsening) state of the disease, delay, suppression, or slowing of disease progression, improvement or relief of a disease condition (e.g., one or more symptoms of the disease), and regression or remission (whether partial or whole), whether detectable or undetectable. “Treatment” may also mean extending survival compared to the expected survival time without treatment.

[0130] The term "therapy" refers to the administration of one or more doses of an active compound or drug to a patient as part of a treatment regimen.

[0131] In one embodiment, as used herein, the term “prevention” means the prevention of the onset, recurrence, or progression of all or part of a disease or condition described herein (e.g., inflammatory pain, neuropathic pain, and various types of pain, including pain associated with cancer, surgery, and fractures) or its symptoms.

[0132] The term “progression” refers to cancer that worsens or spreads throughout the body, as defined by the National Cancer Institute (NCI Cancer Terminology Dictionary). For example, progression may include an increase in the number of cancer cells in a patient, an increase in the size of one or more tumors in a patient, an increase in tumor volume, an increase in the rate or extent of metastasis, a general or partial worsening of cancer-related symptoms, an increase in the severity of the disease, and / or an acceleration of disease progression. “Progression” may also mean a shorter survival period compared to the survival period expected without treatment. In some embodiments, progression may include detecting one or more of the following: an increase in the percentage of blasts, an increase in the bone marrow-to-erythroblast ratio, an increase in dysplasia (e.g., leukocyte dysplasia), an increase in the percentage of bone marrow plasma cells, and an increase in the percentage of bone marrow lymphocytes (see, for example, Sever, et al., Arch Pathol Lab Med. 2016 Sep;140(9):932-49, which is incorporated herein by reference in its entirety). In some embodiments, progression may include detecting one or more of the following: an increase in the percentage of white blood cells (e.g., polymorphonuclear leukocytes), a decrease in platelet count, and a decrease in peripheral blood hemoglobin. In some embodiments, tumor volume can be assessed using RECIST (e.g., RECIST version 1 or version 1.1). See, for example, Eisenhauer et al., Eur. J. Cancer. 2009, 45(2):228-47, which is incorporated herein by reference in its entirety. In some embodiments, tumor volume can be assessed using PERCIST. See, for example, Wahl, et al. J. nucl. med. 2009, 50:122S-150S, which is incorporated herein by reference in its entirety.

[0133] The term “recurrence” refers to the return of disease or signs and symptoms of disease after a period of improvement, as defined by the National Cancer Institute (NCI Cancer Terminology Dictionary). For example, recurrence may include detecting an increase in the number of cancer cells in a patient, an increase in the size of one or more tumors in a patient, an increase in tumor burden, an increase in the rate or extent of metastasis, a general or partial worsening of cancer-related symptoms, an increase in the severity of the disease, and / or an acceleration of disease progression after a period of improvement. In some embodiments, recurrence may include cancer progression after a period of improvement. In some embodiments, a period of improvement may include detecting a decrease in the number of cancer cells in a patient, a decrease in the size of one or more tumors in a patient, a decrease in tumor burden, a decrease in the rate or extent of metastasis, a general or partial improvement in cancer-related symptoms, a decrease in the severity of the disease, and / or a slowing of disease progression. In some embodiments, relapse may include detecting one or more of the following after the improvement period: an increase in the percentage of blasts, an increase in the bone marrow-to-erythroblast ratio, an increase in dysplasia (e.g., leukocyte dysplasia), an increase in the percentage of bone marrow plasma cells, and an increase in the percentage of bone marrow lymphocytes. In some embodiments, the improvement period may include detecting one or more of the following: a decrease in the percentage of blasts, a decrease in the bone marrow-to-erythroblast ratio, a decrease in dysplasia (e.g., leukocyte dysplasia), a decrease in the percentage of bone marrow plasma cells, and a decrease in the percentage of bone marrow. In some embodiments, relapse may include detecting one or more of the following after the improvement period: an increase in the percentage of white blood cells (e.g., polymorphonuclear leukocytes), a decrease in platelet count, and a decrease in peripheral blood hemoglobin. In some embodiments, the improvement period may include detecting one or more of the following: a decrease in the percentage of white blood cells (e.g., polymorphonuclear leukocytes), an increase in platelet count, and an increase in peripheral blood hemoglobin.

[0134] "Relapse" may also include "recurrence," as defined by the National Cancer Institute, as cancer that has returned after a period in which cancer was not detected. Cancer can recur in the same location in the body as the original (primary) tumor or in a different location in the body (NCI Cancer Terminology Dictionary). In some embodiments, failing to detect cancer may include failing to detect cancer cells in a patient, failing to detect a tumor in a patient, and / or the absence of symptoms associated with cancer as a whole or in part.

[0135] As used herein, the terms “intolerant” and “intolerant” may refer to the occurrence of a severe, disabling, or life-threatening adverse event resulting in unplanned hospitalization, discontinuation of therapy, and / or reduction of therapy dose, impairment of function due to therapy, and / or a decline in performance status. In some embodiments, a decline in performance status may be assessed using the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale (see, for example, Oken et al. Am.J.Clin.Oncol. 5:649-655 (1982), which is incorporated herein by reference in its entirety). In some embodiments, a decline in performance status may be assessed using the Karnovsky Performance Status (see, for example, Peus et al., BMC Med.Inform.Decis.Mak. 13:72 (2013), which is incorporated herein by reference in its entirety). In some embodiments, the patient is a pediatric patient, and performance status is assessed by the Lansky Performance Score (see, for example, Lansky et al., Cancer. 60(7):1651-6 (1987), which is incorporated herein by reference in its entirety).

[0136] The terms "administer" or "to administer" refer to the method of giving a patient a dosage of a compound or pharmaceutical composition. The preferred method of administration may vary depending on various factors, such as the components of the pharmaceutical composition, the site of the disease, and the severity of the disease.

[0137] The daily dose of any compound of Formula I described herein, or its pharmaceutically acceptable salts, amorphous or polymorphic forms, their spray-dried dispersions, or their pharmaceutical compositions, may vary over a wide range of 1.0 to 10,000 mg or more per adult, or any range within that range, at least once daily. An effective dose of the drug is usually supplied at least once daily at a dose level of about 0.1 mg / kg body weight / day to about 1,000 mg / kg body weight, or any range within that range. The range may be at least once daily at about 0.5 to about 500 mg / kg body weight, or any range within that range. The range may be at least once daily at about 1.0 to about 250 mg / kg body weight, or any range within that range. The range may be at least once daily at about 0.1 to about 100 mg / kg body weight, or any range within that range. For example, the range may be about 0.1 to about 50.0 mg / kg body weight, or any amount or range within that range, at least once daily. Another example is that the range may be about 0.1 to about 15.0 mg / kg body weight, or any range within that range, at least once daily. Yet another example is that the range may be about 0.5 to about 7.5 mg / kg body weight, or any amount or range within that range, at least once daily. The pharmaceutical compositions provided herein may be administered in regimens of 1 to 4 doses at least once daily, or as a single daily dose.

[0138] The optimal dosage can be easily determined by those skilled in the art and will vary depending on the mode of administration, the strength of the formulation, the mode of administration, and the progression of the disease. Furthermore, it may be necessary to adjust the dosage based on factors specific to the person being treated, including age, weight, diet, and time of administration.

[0139] For oral administration, the composition is provided in some embodiments in the form of tablets, pills, or capsules containing 200, 300, 400, 600, and 800 milligrams of the active ingredient, for symptomatic adjustment of the dosage for the target to be treated.

[0140] The compound of formula I or a pharmaceutically acceptable salt thereof is administered in doses of approximately 200 mg to approximately 1200 mg, or approximately 200 to approximately 1000 mg, or approximately 200 to approximately 800 mg, or approximately 200 mg to approximately 600 mg, or approximately 200 mg to approximately 400 mg. In some embodiments, the dose is approximately 200 mg to approximately 400 mg. In other embodiments, the dose is 200 mg. In other embodiments, the dose is 300 mg. In yet another embodiment, the dose is 400 mg.

[0141] Those skilled in the art will further recognize that human clinical trials, including initial dose studies, dose-range studies, and efficacy studies in healthy subjects and / or subjects with a given disorder can be carried out by methods well known in the clinical and medical fields.

[0142] The effective dose may be determined by a diagnostician skilled in the art, by the use of known techniques, and by observing results obtained under similar circumstances. Numerous factors are considered by the diagnostician when determining the effective dose for a patient, including, but not limited to, the patient's species, size, age, and overall health status; specific related diseases or disorders; the degree or involvement or severity of the disease or disorder; the individual patient's response; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the chosen drug regimen; the use of concomitant medications; and other relevant circumstances.

[0143] The compound of formula I or a pharmaceutically acceptable salt thereof may be administered orally at separately determined specific frequencies and doses, with or without the second therapeutic agent or a pharmaceutically acceptable salt thereof, or the second and third therapeutic agents or pharmaceutically acceptable salts thereof.

[0144] "Adjuvant therapy" is understood to mean a treatment administered in addition to, or after, a first-line treatment. First-line treatments include the administration of one or more other therapeutic agents, radiation therapy, and / or surgery. Compounds of formula I may be used in first-line treatments or in adjuvant therapy.

[0145] "First-line treatment" refers to the initial treatment given for a disease.

[0146] The “therapeutic effective amount,” “pharmaceutical effective amount,” or “effective amount” of the compounds provided herein is an amount sufficient to achieve the desired effect and may vary depending on the nature and severity of the disease state and the potency of the compound of formula I. The therapeutic effect may include some degree of relief of one or more symptoms of the disease and may include curing the disease.

[0147] As used herein, the phrase "in combination with" means an administration in which one agent may be administered simultaneously or sequentially in any order with a compound or a pharmaceutically acceptable salt thereof, with a second therapeutic agent or a pharmaceutically acceptable salt thereof, or with a second therapeutic agent and a third therapeutic agent or a pharmaceutically acceptable salt thereof, for example, at recurring intervals such as during a standard course of treatment consisting of a single cycle or more than one cycle, before, simultaneously with, or following, the administration of another agent, or an administration in which one agent may be administered simultaneously or sequentially in any order with a compound of formula I or a pharmaceutically acceptable salt thereof, with a second therapeutic agent or a pharmaceutically acceptable salt thereof, or with a second therapeutic agent and a third therapeutic agent or a pharmaceutically acceptable salt thereof, for example, at recurring intervals such as during a standard course of treatment consisting of a single cycle or more than one cycle, before, simultaneously with, or following, the administration of one agent, with one of the other agents, with one of the other agents, with one of the other agents, with one of the other agents, with one of the other agents, with one of the other agents, with one of the other agents, with one of the other agents, with one of the other agents, or all of the administration of one of the other agents, with

[0148] Adjuvant therapy may be administered to a patient in a certain amount or dose of the compound of formula I or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent or a pharmaceutically acceptable salt thereof, or with the second therapeutic agent or a pharmaceutically acceptable salt thereof and a third therapeutic agent or a pharmaceutically acceptable salt thereof, thereby providing the body with an effective level of the compound of formula I or a pharmaceutically acceptable salt thereof in combination with the second therapeutic agent or a pharmaceutically acceptable salt thereof, or with the second therapeutic agent or a pharmaceutically acceptable salt thereof and a third therapeutic agent or a pharmaceutically acceptable salt thereof.

[0149] The term "metastasis" is a term known in the art and means the formation of a further tumor (e.g., a solid tumor) in a patient or in a patient at a site distant from the primary tumor, and the further tumor contains cancer cells that are the same as or similar to those of the primary tumor.

[0150] The phrase "risk of developing metastasis" means the risk that a patient with a primary tumor or a patient will develop further tumors (e.g., solid tumors) in a site distant from the primary tumor over a period of time, and that these further tumors will contain cancer cells identical or similar to those of the primary tumor. Methods for reducing the risk of developing metastasis in a patient with cancer or a patient are described herein.

[0151] The phrase "risk of developing further metastases" means the risk that a patient or patient who has a primary tumor and one or more further tumors (each of which contains cancer cells identical or similar to those of the primary tumor) located at a site distant from the primary tumor will develop one or more further tumors at a site distant from the primary tumor, where each further tumor contains cancer cells identical or similar to those of the primary tumor. Methods for reducing the risk of developing further metastases are described herein.

[0152] The following examples are intended solely to illustrate various aspects and embodiments of the Disclosure and should not be considered to limit the scope of the Disclosure.

[0153] Example 1: A Phase 3 trial comparing imurunestrant with investigator-selected endocrine therapy in patients with locally advanced or metastatic estrogen receptor-positive, HER2-negative breast cancer who had previously been treated with endocrine therapy. This is a two-arm, randomized, active-treatment trial in which neither patients nor investigators are blinded.

[0154] Approximately 500 patients will be randomized in a 1:1 ratio to Arm A and Arm B.

[0155] [Table 1] Abbreviations: C = cycle; D = day; PO = oral; QD = once a day.

[0156] [Table 2]

[0157] Patient inclusion criteria: Participants are eligible for inclusion in the study only if they meet all of the following criteria. 1. Participants must be at least 18 years old. 2. Having a diagnosis of ER-+, HER2- negative breast cancer. a. To meet the requirements for an ER+ disease, breast cancer must express ER by immunohistochemistry, as defined in the relevant ASCO / CAP guidelines (Allison et al. 2020). b. To meet the requirements for HER2-related disease, breast cancer must not show HER2 overexpression by immunohistochemistry (IHC) or in situ hybridization at the time of initial diagnosis or subsequent biopsy, as defined in the relevant ASCO / CAP guidelines (Wolff et al. 2018). Although not required by protocol, patients with new metastatic lesions should be considered for biopsy whenever possible to reassess their HER2 status before study enrollment, if clinically indicated. 3. Having a locally progressive (unsuitable for curative treatment by surgery) or metastatic disease and meeting one of the following criteria: a. Relapse with evidence of progression during or within 12 months after completion of (neo)adjuvant AI, either alone or in combination with a CDK4 / 6 inhibitor, without treatment for progressive disease. b. Relapse with evidence of progression more than 12 months after completion of (neo)adjuvant ET, followed by progression during or after single-line treatment with AI alone or in combination with a CDK4 / 6 inhibitor. Patients do not need to have received any other prior therapies (other than AI alone or in combination with a CDK4 / 6 inhibitor) in the progressive / metastatic stage. c. Patients who have newly presented with metastatic disease and subsequently progressed during or after single-line treatment with AI alone or in combination with a CDK4 / 6 inhibitor. Patients do not need to have received any other prior therapies (other than AI alone or in combination with a CDK4 / 6 inhibitor) in the progressive / metastatic stage. 4. Must be deemed suitable for treatment with ET. 5. In the case of women, they must be postmenopausal by either surgical / spontaneous menopause or ovarian suppression with a gonadotropin-releasing hormone agonist such as goserelin or leuprolide (administered monthly and started at least 28 days before day 1 of cycle 1). Postmenopausal by surgical / spontaneous menopause requires at least one of the following: a. Previous bilateral oophorectomy b. Being 60 years of age or older c. Age under 60, amenorrhea for at least 12 months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression), and FSH and estradiol levels within the postmenopausal range. 6. For women whose postmenopausal status is due to ovarian suppression, participants must have a negative serum pregnancy test at baseline (within 14 days prior to enrollment) and must agree to use highly effective medically approved preventive measures (see Section 10.7 of Appendix 7) to prevent pregnancy during the study and for 6 months after the last dose of study treatment. 7. If you are male, you must agree to the following uses: a. Hormone suppression with gonadotropin-releasing hormone agonists such as goserelin or leuprolide (administered monthly and started at least 28 days before day 1 of cycle 1) b. During the trial and for at least six months after the last dose of the investigational drug(s) or for the period specified by national requirements, whichever is longer, use a highly effective method of contraception and do not donate sperm. 8. Having one of the following as defined by RECIST v1.1 (Eisenhauer et al. 2009, Appendix 3, Section 10.3): • Measurable diseases • A disease consisting only of bone that cannot be measured. A disease consisting only of bone that cannot be measured may include any of the following: i. Blastic bone lesions ii. Resolving bone lesions that do not contain measurable soft tissue components iii. Mixed lytic-blastic bone lesions that do not contain measurable soft tissue components. 9. Having a performance status of 0 or 1 on the Eastern Cooperative Oncology Group scale (Oken et al. 1982). 10. Having appropriate organ function as defined in the table below.

[0158] [Table 3] Abbreviations: ALT = Alanine aminotransferase; ANC = Neutrophil absolute count; AST = Aspartate aminotransferase; G-CSF = Granulocyte colony-stimulating factor; ULN = Upper limit of normal. 11. Prior to receiving the study drug, the patient has discontinued prior cancer therapy, recovered to at least Grade 1 from the strong effects of treatment, except for residual alopecia and peripheral neuropathy, and has completed the following required treatment washout period before receiving the investigational drug. a. For bone marrow suppressants (e.g., CDK4 / 6 inhibitors), at least 21 days b. For non-myelosuppressants (e.g., endocrine therapy), the shorter of 7 days or 5 half-lives. c. For the test agent, whichever is shorter is 28 days or 5 half-lives. 12. The patient must be able to swallow capsules / tablets. 13. Willingness to participate during the examination period and follow the examination procedures. 14. The person is able to sign the informed consent described in Appendix 1, including compliance with the informed consent form (ICF) and the requirements and limitations listed in this protocol.

[0159] Patient exclusion criteria Participants will be excluded from this study if they meet any of the following criteria. 1. Previously treated with chemotherapy (excluding neoadjuvant / adjuvant chemotherapy), fulvestrant, any ER-directed therapy in clinical trials (including SERD and non-SERD), any PI3K inhibitor, mTOR inhibitor, or AKT inhibitor. 2. You are currently receiving an investigational drug in a clinical trial, or you are participating in any other type of medical research that is deemed scientifically or medically incompatible with this study. 3. Having inflammatory breast cancer 4. Patients with known pathogenic germline mutations that are suitable for treatment with PARP inhibitors are not eligible for this study in areas where these therapies are approved and available. 5. There is evidence of visceral crisis, lymphangitic spread in the lungs, or some indication of leptomeningeal disease. Visceral crisis means not merely the presence of visceral metastases, but severe organ dysfunction assessed by symptoms and signs, clinical laboratory findings, and rapid disease progression. 6. Patients with symptomatic or untreated brain metastases. Patients with treated brain metastases are eligible for this study if they have completed prior therapies (including radiation and / or surgery) at least 28 days prior to the first dose of the study treatment, have not received corticosteroids and / or anticonvulsants for at least 14 days prior to the first dose of the study treatment, and whose disease is asymptomatic and stable on repeated radiography for at least 28 days prior to consent (repeated radiography should be performed during study screening). 7. Had undergone major surgery within 14 days prior to randomization. 8. The patient had received wide-field radiotherapy (defined as involving 25% or more of the bone marrow) within four weeks prior to randomization, or palliative limited-field radiation within one week prior to randomization. The patient must also have recovered to grade 1 or better from any associated side effects (excluding alopecia) of such treatment. 9. Having a serious cardiac condition such as the following: a. Congestive heart failure b. New York Heart Association Class III / IV heart disease c. Unstable angina d. Myocardial infarction within the past 3 months e. Valvular heart disease that is severe, moderate, or considered clinically significant f. Symptomatic or treatment-requiring arrhythmias (excluding patients with rate-controlled atrial fibrillation) g. A stroke within the past three months. h. In evaluations over several consecutive days, the mean QT interval of 470 milliseconds or longer, corrected for heart rate in the screening ECG, when calculated using Fridericia's formula. i. Baseline bradycardia with a resting heart rate below 60 beats / min 10. The principal investigator has a serious pre-existing medical condition that would prevent participation in this study. 11. A history of other cancers (excluding non-melanoma skin cancer or cervical carcinoma in situ) unless the patient has been in complete remission without treatment for at least three years. 12. Have undergone autologous stem cell transplantation or allogeneic stem cell transplantation. 13. Has an active bacterial or fungal infection, or a detectable viral infection (e.g., human immunodeficiency virus [HIV] or viral hepatitis). Screening is not required for registration. 14. You are pregnant, breastfeeding, or planning to become pregnant or have a child within the study plan period, starting from your screening visit and up to 180 days after the last dose of the study intervention. 15. The patient initiated a bisphosphonate or an approved RANK ligand (RANK-L) targeted agent (e.g., denosumab) less than 7 days prior to randomization. 16. Known allergic reactions to any of the components of the research treatment.

Claims

1. Formula I for treating estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), and estrogen receptor 1 variant (ESR1m) breast cancers. 【Chemistry 1】 A drug comprising the compound or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a patient requiring such treatment at a dose of about 400 mg at least once daily for at least one week, and then the dose is reduced to a dose of about 200 mg at least once daily, wherein the patient has previously received endocrine therapy.

2. The drug according to claim 1, characterized in that the aforementioned dose of approximately 200 mg is administered at least once a day for at least 21 days.

3. The agent according to claim 1, wherein the dose is reduced to at least 200 mg once daily, starting after the patient has undergone surgery.

4. The agent according to claim 1, wherein the breast cancer is locally advanced, unresectable, or metastatic breast cancer.

5. The agent according to claim 1, wherein the pharmaceutically acceptable salt is a tosylate salt.

6. The agent according to claim 1, wherein the endocrine therapy comprises fulvestrant or exemestane.

7. Formula I for treating cancer 【Chemistry 2】 A drug comprising the compound or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a patient requiring such treatment at a dose of about 400 mg at least once daily for at least one week, and then the dose is reduced to a dose of about 200 mg at least once daily, wherein the patient has previously received endocrine therapy.

8. The drug according to claim 7, characterized in that the aforementioned dose of approximately 200 mg is administered at least once a day for at least 21 days.

9. The agent according to claim 7, wherein the dose is reduced to at least 200 mg once daily, starting after the patient has undergone surgery.

10. The agent according to claim 7, wherein the cancer is selected from breast cancer including advanced breast cancer and metastatic breast cancer (mBC), ovarian cancer, endometrial cancer including endometrioid endometrial cancer (EEC), prostate cancer, uterine cancer, gastric cancer, and lung cancer.

11. The drug according to claim 7, wherein the cancer is ER+, HER2- breast cancer.

12. The agent according to claim 7, wherein the pharmaceutically acceptable salt is a tosylate salt.

13. The agent according to claim 7, wherein the endocrine therapy comprises fulvestrant or exemestane.

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