Methods of treating cancer using combinations of SERD dosing regimens

Abstract

Formula I [Chemical 1] A dosing regimen for administering a compound of JPEG0007703124000008.jpg29128, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment is disclosed herein. The dosing regimen includes adjuvant therapy.

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 for the treatment of cell proliferation disorders such as cancer.

[0004] Drug development is unpredictable. Often, for mostly unknown reasons, it is common for new molecules to fail at the preclinical and / or clinical stages. Complexity is added by dosing, thereby creating further unpredictability. Due to various factors including but not limited to body weight, performance status, number of previous systemic therapies, genetics, and histological tumor type, not all drug dosing regimens are necessarily equally effective in all patient populations. Toxicity issues add further complexity. A balance between efficacy and toxicity needs to be achieved. Additionally, 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 a subset of patients who previously did not respond, without creating a toxicological barrier for that subset or for the previously responsive population.

[0005] There is still a need to provide alternative therapies for patients suffering from cancer. In addition, there is still a need to provide alternative therapies with a better tolerance profile, or alternative therapies that allow for maximum activity with limited adverse events and fewer dosing interruptions or discontinuation. There is still a need for a potent anti-estrogen therapy that antagonizes and degrades the ER and has 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).

Summary of the Invention

[0006] The present disclosure relates to a new dosing protocol for using (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, or a pharmaceutically acceptable salt thereof, as part of an adjuvant therapy for treating cancer.

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

[0008]

Chemical formula

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

[0010] The compounds of formula I are orally bioavailable selective SERDs. They are potent degraders and selective antagonists of wild-type and mutant estrogen receptor α (ERα or ESR1). It would be useful to develop new treatment regimens and dosing protocols for using the compounds of formula I in cancer treatment, either as part of an 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] Dosing protocols for using the compounds of formula I in treating cancer are disclosed herein. The protocol can be a monotherapy or an adjuvant therapy.

[0012] In one aspect, the dosing protocol is a method of treating cancer comprising administering to a patient in need of such treatment at least once a day a dose of from about 200 mg to about 800 mg of a compound of formula I

[0013]

Chemical formula

[0014] In another aspect, the dosing protocol is a method of treating cancer comprising administering to a patient in need of such treatment at least once a day for at least one week a dose of from about 200 mg to about 400 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

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

[0016] In one aspect, the dosing protocol is a method of treating cancer, administering to a patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 200 mg, 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 aspect, the dosing protocol is a method of treating cancer, administering to a patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 200 mg, at least once a day for about two weeks to about six months, and then increasing the dose to about 400 mg at least once a day for at least 21 days.

[0018] In another aspect, the dosing protocol is a method of treating cancer, comprising administering to a patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt thereof at least once a day.

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

[0020] In one aspect, the dosing protocol is a method of treating breast cancer, administering to a patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 400 mg at least once a day for at least about one week to about six months, and then reducing the dose to about 200 mg at least once a day.

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

[0022] In one aspect, a dosing protocol is a method of treating cancer, comprising administering in combination with a second therapeutic agent for the treatment of cancer in a patient a compound of Formula I or a pharmaceutically acceptable salt thereof, 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 in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 400 mg, at least once daily.

[0024] In one aspect, a method of treating cancer, comprising administering to a patient in need of 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, at least once daily 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 in need of such treatment a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 400 mg, at least once daily, is disclosed herein.

[0026] In one aspect, a dosing protocol is a method of treating ER+, HER2-negative breast cancer, comprising administering (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1), pertuzumab, and trastuzumab.

[0027] In another aspect, a dosing protocol is a method of treating ER+, HER2-positive breast cancer, comprising administering (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1), pertuzumab, and trastuzumab.

[0028] In one aspect, a dosing protocol is a method of treating ER+, HER2-negative breast cancer, comprising administering 400 mg of (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1), 6 mg / kg of pertuzumab (Q21D), and 420 mg of trastuzumab (Q21D), wherein Q21D means every 21 days.

[0029] In another aspect, a dosing protocol is a method of treating ER+, HER2-positive breast cancer, comprising administering (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1), 6 mg / kg of pertuzumab (Q21D), and 420 mg of trastuzumab (Q21D).

[0030] In one aspect, the dosing protocol is a method of treating ER+, HER2-negative breast cancer, comprising administering at least once a day about 400 mg of (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1), and abemaciclib.

[0031] In one aspect, the dosing protocol is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer, comprising administering to a patient at a dose of about 200 mg to about 800 mg, at least once a day, for at least one week.

[0032] In another aspect, the dosing protocol is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer, comprising administering to a patient at a dose of about 200 mg, for about two weeks to about six months, at least once a day, and then the dose is increased to about 300 mg, at least once a day, for at least 21 days.

[0033] In one aspect, a dosing protocol comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer, comprising administering to a patient at a dose of about 200 mg, for about two weeks to about six months, at least once a day, and then the dose is increased to about 400 mg, at least once a day, for at least 21 days. In one aspect, the dosing protocol is 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 a patient at a dose of about 200 mg, for about two weeks to about six months, at least once a day, and then the dose is increased to about 400 mg, at least once a day, for at least 21 days.

[0034] In one aspect, the dosing protocol is 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 a patient at a dose of about 400 mg at least once a day.

[0035] In one aspect, the dosing protocol is 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 a patient at a dose of about 400 mg at least once a day for about 2 weeks to about 6 months, and then the dose is reduced to about 200 mg at least once a day for at least 21 days.

[0036] In one aspect, the dosing protocol is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in combination with a second therapeutic agent simultaneously, separately, or sequentially in the treatment of cancer in a patient, wherein the compound or pharmaceutically acceptable compound is administered at a dose of about 200 mg to about 400 mg at least once a day for at least 1 week.

[0037] In one aspect, the dosing protocol is a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in combination with a second therapeutic agent and a third therapeutic agent simultaneously, separately, or sequentially in the treatment of cancer in a patient, wherein the second therapeutic agent and the third therapeutic agent are different, and the compound or pharmaceutically acceptable compound is administered at a dose of about 200 mg to about 400 mg at least once a day for at least 1 week.

[0038] In one aspect, the dosing protocol is for use in combination with a second therapeutic agent simultaneously, separately, or sequentially in the treatment of cancer in a patient, and is a compound of Formula I, or a pharmaceutically acceptable salt thereof, 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 its pharmaceutically acceptable salt is administered at a dose of about 200 mg to about 400 mg, and includes the compound or its pharmaceutically acceptable salt.

[0039] In one aspect, a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a patient, and administered at a dose of about 400 mg at least once a day, is disclosed herein. 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 aspect, the dosing protocol includes the compound (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1) for use in combination with pertuzumab and trastuzumab simultaneously, separately, or sequentially in the treatment of ER+, HER2-negative breast cancer.

[0041] In one aspect, the dosing protocol comprises a compound that is (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1) for use in combination with, separately from, or sequentially to pertuzumab and trastuzumab for treating ER+, HER2-positive breast cancer.

[0042] In one aspect, the dosing protocol comprises a compound that is (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1) for use in combination with, separately from, or sequentially to abemaciclib for treating ER+, HER2-negative breast cancer, and is administered at a dose of about 400 mg. In one embodiment, the compound is administered at a dose of about 200 mg. In another embodiment, the compound is administered at a dose of about 300 mg.

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

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

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

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

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

[0048] In yet another aspect, there is disclosed herein a method of treating cancer, comprising administering to a patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 400 mg, at least once daily, for from about 2 weeks to about 6 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)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1).

[0049] In a further aspect, there is disclosed herein the use of a compound of formula I or a pharmaceutically acceptable salt thereof for treating cancer, comprising administering to a patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of about 200 mg, at least once daily, for from about 2 weeks to about 6 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)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1).

[0050] In yet a further aspect, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof for treating cancer, the use comprising administering to a patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt thereof at a dose of about 400 mg once daily for from about 2 weeks to about 6 months and then reducing the dose to about 200 mg 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)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1).

[0051] In still yet a further aspect, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer, the medicament comprising from about 200 mg to about 400 mg of the compound or a salt thereof and being administered once daily for at least 1 week. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1).

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

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

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

[0055] In one aspect, a method of treating cancer, comprising administering to a patient in need of such treatment at least once a day for at least 1 week a dose of from about 200 mg to about 400 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, a second therapeutic agent, and a third therapeutic agent, wherein the second and third therapeutic agents are different, is disclosed herein. In all aspects, the preferred pharmaceutically acceptable salt of the compound of formula I is the tosylate salt, i.e., the 4-methylbenzenesulfonate salt. BRIEF DESCRIPTION OF THE DRAWINGS

[0056]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0057] Pharmaceutically acceptable salts The compound of formula I is preferably used as the tosylate salt, which is also known in the art as 4-methylbenzenesulfonate or p-toluenesulfonate. However, other pharmaceutically acceptable acid addition salts may also be utilized. Such pharmaceutically acceptable acid addition salts and methods for their preparation are known. For example, by way of example, see P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA / Wiley-VCH, 2002), L.D. Bighley, S.M. Berge, D.C. Monkhouse, in "Encyclopedia of Pharmaceutical Technology". Eds. J. Swarbrick and J.C. Boylan, Vol. 13, Marcel Dekker, Inc., New York, Basel, Hong Kong 1995, pp. 453-499, S.M. Berge, 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 mesylate salts), benzenesulfonic acid (which forms besylate salts), trifluoromethanesulfonic acid (which forms triflate salts), HCl, H2SO4, HNO3, and H3PO4.

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

[0059] In one embodiment, the cancer is a hormone receptor positive (HR positive) cancer in which cancer cells express a hormone receptor. The hormone receptor includes both an estrogen receptor and a progesterone receptor. In one embodiment, the cancer is estrogen receptor positive (ER positive). In one embodiment, the cancer expresses a tyrosine kinase receptor such as HER2. The cancer can be HER2 positive or HER2 negative.

[0060] In one embodiment, the cancer that can be treated using the compound of Formula I or a pharmaceutically acceptable salt thereof is one that is HR positive, for example, ER positive, and a tyrosine kinase receptor, for example, HER2 positive or HER2 negative.

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

[0062] Dosage regimen In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient in need of such treatment at a dose of about 200 mg to about 1200 mg. Doses of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 150 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg can be administered. The maximum daily dose, i.e., the maximum dose in 24 hours, is about 1200 mg or less. In some embodiments, the dose is about 200 to about 1000 mg, or about 200 to about 800 mg, or about 200 mg to about 600 mg, or about 200 mg to about 400 mg. Preferably, the dose is about 200 mg to about 400 mg. In a preferred embodiment, the dose is 400 mg. Preferably, the compound of formula I is (5R)-5-[4-[2-[3-(fluoromethyl)azetidin-1-yl]ethoxy]phenyl]-8-(trifluoromethyl)-5H-chromeno[4,3-c]quinolin-2-ol, 4-methylbenzenesulfonic acid (1 / 1). Preferably, the dose is administered at least once a day for at least one week. The dose can be administered more than once a day.

[0063] Prior therapy In one embodiment, a patient in need of treatment has previously received endocrine therapy, which is a hormonal therapy used to treat cancer. In some embodiments, the patient has been diagnosed as having sensitivity to endocrine therapy. In some embodiments, the patient has not received a cyclin-dependent kinase (CDK4 / 6) inhibitor-containing therapy.

[0064] In another embodiment, methods are disclosed herein where the patient in need of treatment has received 1 or fewer prior therapies. In yet another embodiment, methods are disclosed herein where the patient has received 2 or fewer prior therapies. In yet another embodiment, methods are disclosed herein where the patient has received 3 or fewer prior therapies. In yet another embodiment, methods are disclosed herein where the patient has received 4 or fewer prior therapies. In some embodiments, the patient has received 8 or more prior therapies.

[0065] As used herein, "prior therapy" refers to a treatment that has been previously administered or used to treat cancer. Administering a single pharmaceutical, or administering two or more pharmaceuticals as part of an adjuvant therapy, are examples of prior therapy. Surgery is also an example of prior therapy. Endocrine therapy and aromatase inhibitor therapy are examples of prior therapy, as are treatment with a platinum-based chemotherapeutic agent, treatment with a CDK4 / 6 inhibitor, or treatment with fulvestrant. Treating a patient with a pharmaceutical and subsequently performing surgery are examples of two prior therapies.

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

[0067] In yet another embodiment, methods are disclosed herein where the patient has previously received endocrine therapy.

[0068] In another embodiment, a method is disclosed herein, wherein a patient in need of treatment has been identified or diagnosed as having an EEC. In another embodiment, a method is disclosed herein, wherein the EEC is ER positive. In another embodiment, the EEC has not been treated with platinum therapy. In another embodiment, the EEC has been treated with platinum therapy. In another embodiment, a method is disclosed herein, wherein the EEC has progressed after treatment with platinum therapy. In another embodiment, a method is disclosed herein, wherein the 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 to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of from about 200 mg to about 800 mg or from about 200 mg to about 400 mg. In yet another embodiment, a method for treating cancer is disclosed herein, comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof in a dose of from about 200 mg to about 800 mg or from about 200 mg to about 400 mg, once daily for at least 1 week.

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

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

[0072] In another embodiment, a method is disclosed herein wherein the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 400 mg for a patient in need thereof. In another embodiment, a method is disclosed herein that further comprises the steps of administering a dosage of about 400 mg to the patient at least once a day, followed by administering a reduced dosage of about 200 mg to about 300 mg to the patient at least once a day. In another embodiment, a method is disclosed herein wherein the step of administering a dosage of about 400 mg is performed prior to surgery. In one embodiment, the patient is scheduled to undergo surgery for the treatment of EEC, the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 400 mg, and the dosage is administered at least once a day for at least one week prior to surgery. In a further embodiment, the 400 mg dosage is administered at least once a day for about two weeks prior to surgery. In another embodiment, a method is disclosed herein wherein the step of administering the reduced dosage is performed after surgery. In one embodiment, the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof is reduced to about 200 mg at least once a day after surgery. In another embodiment, the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof is reduced to about 300 mg at least once a day after surgery. In another embodiment, a method is disclosed herein wherein the step of administering the reduced dosage 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 a patient at a dose of about 200 mg at least once a day for at least one week, followed by an increased dose of about 300 mg to about 400 mg being administered to the patient at least once a day 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 a day for at least one week prior to surgery. In some embodiments, the 200 mg dose is administered at least once a day for about two weeks prior to surgery. In a further embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is increased to at least once a day to about 300 mg after surgery, or alternatively, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is increased to at least once a day to about 400 mg after surgery. If desired, the step of administering the increased dose is performed daily for at least one week.

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

[0075] In another embodiment, a method is disclosed herein, wherein a patient in need of treatment is identified or diagnosed as having 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, wherein the breast cancer is ER positive. In another embodiment, a method is disclosed herein, wherein the breast cancer is HER2 negative. In another embodiment, a method is disclosed herein, wherein the breast cancer is HER2 positive. In a preferred embodiment, the cancer is ER+ and HER2-. Even more preferably, in one embodiment, the cancer is ER+ and HER2- breast cancer.

[0076] In another embodiment, a method is disclosed herein, wherein a patient in need of treatment is identified or diagnosed as having mBC. In another embodiment, a method is disclosed herein, wherein the mBC is HER2 negative. In another embodiment, a method is disclosed herein, wherein the mBC is HER2 positive. In another embodiment, a method is disclosed herein, wherein the mBC is untreated or de novo, where de novo means starting from the beginning or newly initiated.

[0077] In another embodiment, a method is disclosed herein, wherein a patient in need of treatment is identified or diagnosed as having advanced breast cancer. In another embodiment, a method is disclosed herein, wherein the advanced breast cancer is HER2 negative. In another embodiment, a method is disclosed herein, wherein the advanced breast cancer is HER2 positive. In another embodiment, a method is disclosed herein, wherein the advanced breast cancer is untreated or de novo, where de novo means starting from the beginning or newly initiated.

[0078] In another embodiment, a method is disclosed herein, wherein the patient in need of treatment has breast cancer that is ER positive (ER+) and HER2 positive (HER2+). In another embodiment, a method is disclosed herein, wherein the patient in need of treatment has breast cancer, and the breast cancer is locally advanced, inoperable, or metastatic.

[0079] In another embodiment, a method is disclosed herein, wherein the patient in need of treatment has breast cancer that is ER positive (ER+) and HER2 negative (HER2-). In another embodiment, a method is disclosed herein, wherein the patient in need of treatment has breast cancer, and the breast cancer is locally advanced, inoperable, or metastatic.

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

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

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

[0083] In another embodiment, methods of treating cancer are disclosed that comprise administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof in a dose of from about 200 mg to about 400 mg, in combination with a second therapeutic agent and a third therapeutic agent, at least once daily for at least one week. In another embodiment, methods are disclosed herein wherein 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 with, separately from, or sequentially to the compound of Formula I or a pharmaceutically acceptable salt thereof. The third therapeutic agent is administered simultaneously with, separately from, or sequentially to 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, an aromatase inhibitor, 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 a preferred embodiment, the dosage 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 about 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 about 400 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof, and the second therapeutic agent is abemaciclib.

[0088] In some embodiments, the third therapeutic agent is selected from the group consisting of an aromatase inhibitor, 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 an aromatase inhibitor 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, antidiarrheal agents selected from the group consisting of Lactobacillus acidophilus, atropine / diphenoxylate, atropine / diphenoxin, loperamide, bismuth subsalicylate, loperamide, Saccharomyces boulardii, Lyoactobacillus acidophilus / Lactobacillus bulgaricus, Lactobacillus rhamnosus gg, and crofelemer. In one embodiment, the antidiarrheal agent is loperamide.

[0090] In another embodiment, methods are disclosed herein where the dosage of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 200 mg. In another embodiment, methods are disclosed herein further comprising administering to a patient a dosage of about 200 mg at least once a day, followed by administering to the patient an increased dosage of about 300 mg to about 400 mg at least once a day. In another embodiment, methods are disclosed herein where the step of administering a dosage of about 200 mg is performed prior to surgery. In another embodiment, methods are disclosed herein where the step of administering the increased dosage is performed after surgery. In another embodiment, methods are disclosed herein where the step of administering the increased dosage is performed daily for at least three months up to the lifespan of the patient.

[0091] In another embodiment, methods are disclosed herein where the dosage of a compound of formula I or a pharmaceutically acceptable salt thereof is about 400 mg. In another embodiment, methods are disclosed herein that further comprise the step of administering to a patient a dosage of about 400 mg of a compound of formula I or a pharmaceutically acceptable salt thereof at least once a day, followed by the step of administering to the patient a reduced dosage of about 200 mg to about 300 mg at least once a day. In another embodiment, methods are disclosed herein where the step of administering the about 400 mg dosage is performed prior to surgery. In another embodiment, methods are disclosed herein where the step of administering the reduced dosage is performed after surgery. In another embodiment, methods are provided herein where the step of administering the reduced dosage is performed daily for at least 3 months up to the lifespan of the patient at most.

[0092] In some embodiments, the compounds of formula I or pharmaceutically acceptable salts thereof described herein can be utilized in combination with one or more other therapies to treat the relevant disease, disorder, or condition. In some embodiments, the dosing of the compounds of formula I or pharmaceutically acceptable salts thereof is altered when utilized in adjuvant therapy as compared to when administered as monotherapy. Alternatively, or in addition, in some embodiments, the therapy administered in combination with the compounds of formula I or pharmaceutically acceptable salts thereof described herein is administered according to a regimen or protocol different from that when administered alone or in combination with one or more therapies other than the compounds of formula I. In some embodiments, the compositions containing additional therapeutic agents, the additional therapeutic agents, and the compounds provided can act synergistically. In some embodiments, the compounds of formula I or pharmaceutically acceptable salts thereof can act synergistically in combination with a second therapeutic agent or a pharmaceutically acceptable salt thereof. In some embodiments, one or both of the therapies utilized in a combination regimen are administered at a lower level or less frequently than when it is utilized as monotherapy.

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

[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 second therapeutic agent or a pharmaceutically acceptable salt thereof and a third therapeutic agent or a pharmaceutically acceptable salt thereof, in a dosage of about 200 mg to about 400 mg.

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

[0096] BRAF kinase inhibitors, such as trametinib, vemurafenib, dabrafenib, sorafenib, or regorafenib, PARP inhibitors, such as olaparib, rucaparib, or niraparib, and monoclonal antibodies, such as (cetuximab) Erbitux.In some embodiments, additional anti-cancer drugs include polyfunctional alkylating agents such as nitrosoureas, mustards (nitrogen mustards), methanesulfonates (busulfan), or ethyleneimines; non-polyfunctional alkylating agents such as procarbazine (Matulane), dacarbazine (DTIC), altretamine (Hexalen), or cisplatin (Platinol); antimetabolites such as antifolate compounds (methotrexate) or amino acid antagonists (azaserine); purine antagonists such as mercaptopurine (6-MP), thioguanine (6-TG), fludarabine phosphate, cladribine (Leustatin), or pentostatin (Nipent); pyrimidine antagonists such as fluorouracil (5-FU), cytarabine (ARA-C), or azacitidine; plant alkaloids such as vinblastine (Velban), vincristine (Oncovin), etoposide (VP-16, VePe-sid), teniposide (Vumon), topotecan (Hycamtin), irinotecan (Camptosar), paclitaxel (Taxol), or docetaxel (Taxotere); antibiotics such as anthracyclines, doxorubicin (Adriamycin, Rubex, Doxil), daunorubicin (DaunoXome), dactinomycin (Cosmegen), idarubicin (Idamycin), plicamycin (Mithramycin), mitomycin (Mutamycin), or bleomycin (Blenoxane); hormonal agents such as tamoxifen (Nolvadex), flutamide (Eulexin), gonadotropin-releasing hormone agonists (leuprolide and goserelin (Zoladex)), aromatase inhibitors, aminoglutethimide, or anastrozole (Arimidex); or other anti-cancer drugs such as amsacrine, hydroxyurea (Hydrea), asparaginase (El-spar), mitoxantrone (Novantrone), mitotane, retinoic acid derivatives, myeloid growth factors, or amifostine.

[0097] Examples of different or additional compounds include antidiarrheal agents such as Intestinex (Lactobacillus acidophilus), Lonox (atropine / diphenoxylate), Motofen (Pro) (atropine / diphenoxin), Acidophilus (Lactobacillus acidophilus), Florajen (Lactobacillus acidophilus), Imodium A-D (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 boulardii), Kapectolin (New Formula) (bismuth subsalicylate), Florastor Kids (Saccharomyces boulardii), 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) (crofelemer), Kao-Paverin (loperamide), Kola-Pectin DS (bismuth subsalicylate), Lomocot (atropine / diphenoxylate), Mytesi (Pro) (crofelemer), 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, the use includes administration of an antidiarrheal agent.

[0098] In some aspects, a compound of formula I or a pharmaceutically acceptable salt thereof is formulated as a pharmaceutical composition administered by any route that bio - availabilizes each of these compounds, with or without a second therapeutic agent or a pharmaceutically acceptable salt thereof, or a second therapeutic agent and a third therapeutic agent or a pharmaceutically acceptable salt thereof. The route of administration can vary in any form and can be limited by the physical properties of the drug as well as the convenience of the patient and caregiver.

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

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

[0101] In one aspect, a method of treating cancer, comprising a dose of from about 200 mg to about 400 mg of formula I

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

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

[0104] In one preferred embodiment, the third therapeutic agent is pertuzumab. Pertuzumab can be administered at a dosage of about 840 mg. Alternatively, pertuzumab can be administered at a dosage of about 420 mg. In one embodiment, an initial dose of about 840 mg of pertuzumab is administered and about 24 hours later, a dose of about 420 mg is administered.

[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, the breast cancer is advanced breast cancer or metastatic breast cancer (mBC), and the endometrial cancer is endometrioid endometrial cancer (EEC). In certain embodiments, the cancer is HR-positive. The HR-positive cancer can be ER-positive and HER2-negative. Alternatively, the HR-positive cancer can be ER-positive and HER2-positive.

[0106] When the cancer is breast cancer, the breast cancer can be locally advanced, inoperable, 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 has not been previously treated.

[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 more than one HER2-directed regimen or any endocrine therapy or any prior CDK4 / 6 inhibitor therapy for advanced disease.

[0109] In some embodiments, the methods disclosed herein are used to treat patients who have a left ventricular ejection fraction (LVEF) of 50% or more at baseline as determined by echocardiogram or multigated acquisition scan.

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

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

[0112] The disclosed SERDs described herein provide inhibition of ER-mediated transcription, which would be useful for the treatment of cancers such as breast cancer, including mBC, ovarian cancer, endometrial cancer including EEC, prostate cancer, uterine cancer, gastric cancer, and lung cancer, as well as treatment of mutations due to new resistance. These SERDs can be used as a single agent 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 for the treatment of HR-positive cancers such as advanced breast cancer, breast cancer including mBC, ovarian cancer, endometrial cancer including EEC, prostate cancer, uterine cancer, gastric cancer, and lung cancer.

[0113] Definitions As used herein, the term "cancer" typically refers to or describes a physiological state in a patient characterized by unregulated cell growth. This definition includes both benign and malignant cancers.

[0114] As used herein, the term "primary tumor" or "primary cancer" refers to the cancer that first occurred and does not refer to metastatic lesions located in another tissue, organ, or location 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 each other. The 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, compression, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation such that a dosage form discolors more rapidly when composed of one polymorph than another) or mechanical changes (e.g., crystalline changes during storage when a kinetically preferred polymorph converts to a more thermodynamically stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). As a result of differences in solubility / dissolution, some transitions affect efficacy and / or toxicity. In addition, the physical properties of the crystals can be important in processing, for example, one polymorph may be more likely to form solvates or it may be difficult to filter and wash out impurities (i.e., the shape and size distribution of the particles may differ between one polymorph and another). As used herein, "polymorph" does not include amorphous forms of the compounds of Formula I. As used herein, "amorphous" refers to a non-crystalline form of a compound that can be a solid form of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a solubilized form of a compound of Formula I. For example, "amorphous" refers to a compound that does not have a regular repeating arrangement of molecules or outer plane, e.g., a solid form of a compound.

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

[0117] As used herein, the term "solvate" refers to a crystalline form of a compound of Formula I, such as a polymorphic form of a compound of Formula I, in which the crystal lattice contains one or more crystallization solvents.

[0118] "Purity", when used with respect to a composition containing a polymorph of a compound of Formula I, refers to the percentage of one particular polymorph with respect to another polymorphic or amorphous form of the compound of Formula I or a pharmaceutically acceptable salt thereof in the composition being referred to. For example, a composition containing polymorph form 1 with 90% purity contains 90 parts by weight of form 1 and 10 parts by weight of other polymorphic and / or amorphous forms of the compound of Formula I.

[0119] As used herein, a compound of Formula I or a pharmaceutically acceptable salt or composition thereof that "substantially does not contain" one or more other components does not contain a significant amount of such other components. For example, the 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 can include starting materials, residual solvents, or other impurities that may arise from the preparation and / or isolation of the Formulas I s and compositions provided herein. In some embodiments, the polymorphs provided herein substantially do not contain other polymorphs. In some embodiments, a particular polymorph of a compound of Formula I or a pharmaceutically acceptable salt thereof "substantially does not contain" other polymorphs when 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 some embodiments, a particular polymorph of a compound of Formula I or a pharmaceutically acceptable salt thereof "substantially does not contain" other polymorphs when 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 "substantially does not contain" water when 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", when used with respect to a polymorphic form of a compound of Formula I, means a sample of a polymorphic form of a compound of Formula I or a pharmaceutically acceptable salt thereof having a purity of greater than 90%, including greater than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% and including about 100%, based on the weight of the compound of Formula I. The remaining material includes other forms of the compound, as well as reaction impurities and / or processing impurities resulting from its preparation. For example, a polymorphic form of a compound of Formula I or a pharmaceutically acceptable salt thereof can be considered to be substantially pure in that, when measured by means known and generally accepted in the art at the present time, the purity of the polymorphic form of the compound of Formula I exceeds 90% and the remaining less than 10% 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 processing 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 of description, some of the quantitative expressions in this specification are listed as ranging from about amount X to about amount Y. When a range is listed, the range is not limited to its recited upper and lower limits, but rather is understood to include the entire range from about amount X to about amount Y, or any range therein.

[0122] As used herein, the terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except where any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions provided herein is intended. Auxiliary active ingredients can also be incorporated into the compositions. Further, various excipients as are commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, NJ. Considerations for including various components in pharmaceutical compositions are described, for example, in 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 is experiencing and / or presenting at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the patient is identified or diagnosed as having cancer, such as breast cancer including mBC, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric 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 1 or fewer prior therapies. In some embodiments, the patient has received 2 or fewer prior therapies.

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

[0127] In some embodiments, the patient has not received a 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 non-protocol anti-cancer therapy. In some embodiments, the patient is receiving, scheduled to receive, or has not yet received radiation therapy 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, an aromatase inhibitor, or another SERM for either prevention of osteoporosis or breast cancer. In some embodiments, the patient is receiving, scheduled to receive, or has not yet received hormone replacement therapy within 4 weeks of the start of the investigational treatment. In some embodiments, the patient has undergone major surgery within about 28 days prior to randomization to enable surgical wound and site postoperative healing. In some embodiments, the patient is pregnant or lactating. In some embodiments, the patient has a certain infectious disease such as poorly controlled hepatitis, 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 desired clinical results include, but are not limited to, cure, complete or partial alleviation of symptoms associated with a disease, disorder or condition, whether detectable or not, diminution or reduction of the degree of the disease, reversal of the progression or severity of an existing symptom, disorder, condition or disease, arrest of disease progression, a stable (i.e., non-worsening) state of the disease, delay, suppression or slowing of disease progression, improvement or alleviation of a disease state (e.g., one or more symptoms of a disease), and regression or remission, whether partial or complete. "Treatment" can also mean prolonging the survival period as compared to the expected survival period without receiving treatment.

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

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

[0132] The term "progression", as defined by the National Cancer Institute (NCI Cancer Dictionary), refers to cancer that worsens or spreads in the body. For example, progression can 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 burden, an increase in the rate or extent of metastasis, an overall or partial worsening of cancer-related symptoms, an increase in the degree of the disease, and / or an acceleration of the progression of the disease. "Progression" can also mean a survival period that is shorter compared to the survival period expected if no treatment is received. In some embodiments, progression can include detecting one or more of an increase in the percentage of blast cells, an increase in the myeloid-to-erythroid ratio, an increase in dysplasia (e.g., leukocyte dysplasia), an increase in the percentage of myeloid plasma cells, and an increase in the percentage of myeloid lymphocytes (see, e.g., Sever, et al., Arch Pathol Lab Med. 2016 Sep;140(9):932-49, which is hereby incorporated by reference in its entirety). In some embodiments, progression can include detecting one or more of an increase in the percentage of white blood cells (e.g., polymorphonuclear leukocytes), a decrease in platelet count, and a decrease in hemoglobin in peripheral blood. In some embodiments, tumor burden can be evaluated using RECIST (e.g., RECIST version 1 or version 1.1). See, e.g., Eisenhauer et al., Eur. J. Cancer. 2009, 45(2):228-47, which is hereby incorporated by reference in its entirety. In some embodiments, tumor burden can be evaluated using PERCIST. See, e.g., Wahl, et al. J. nucl. med. 2009, 50:122S-150S, which is hereby incorporated by reference in its entirety).

[0133] The term "recurrence" refers to the return of a disease or signs and symptoms of a disease after a period of improvement, as defined by the National Cancer Institute (NCI Cancer 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, an overall or partial worsening of cancer-related symptoms, an increase in the extent of the disease, and / or an acceleration of the progression of the disease after a period of improvement. In some embodiments, recurrence may include progression of cancer 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, an overall or partial improvement of cancer-related symptoms, a decrease in the extent of the disease, and / or a slowing of the progression of the disease. In some embodiments, recurrence may include detecting one or more of an increase in the percentage of blast cells, an increase in the myeloid-to-erythroid ratio, an increase in dysplasia (e.g., leukocyte dysplasia), an increase in the percentage of myeloid plasma cells, and an increase in the percentage of myeloid lymphocytes after a period of improvement. In some embodiments, a period of improvement may include detecting one or more of a decrease in the percentage of blast cells, a decrease in the myeloid-to-erythroid ratio, a decrease in dysplasia (e.g., leukocyte dysplasia), a decrease in the percentage of myeloid plasma cells, and a decrease in the percentage of myeloid lymphocytes. In some embodiments, recurrence may include detecting one or more of an increase in the percentage of white blood cells (e.g., polymorphonuclear leukocytes), a decrease in platelet count, and a decrease in hemoglobin in peripheral blood after a period of improvement. In some embodiments, a period of improvement may include detecting one or more of a decrease in the percentage of white blood cells (e.g., polymorphonuclear leukocytes), an increase in platelet count, and an increase in hemoglobin in peripheral blood.

[0134] "Relapse" may also include "recurrence" as defined by the National Cancer Institute, which is generally cancer that recurs after a period during which the cancer could not be detected. The cancer may recur at the same location in the body as the original (primary) tumor or at a different location in the body (NCI Dictionary of Cancer Terms). In some embodiments, the failure to detect cancer may include the failure to detect cancer cells in the patient, the failure to detect a tumor in the patient, and / or the absence of symptoms, wholly or in part, associated with cancer.

[0135] As used herein, the terms "intolerant" and "is intolerant" can refer to the occurrence of severe, disabling, or life-threatening adverse events that result in unplanned hospitalization during therapy, discontinuation of therapy, and / or reduction of the therapy dose, functional decline due to the therapy, and / or decline in performance status. In some embodiments, the decline in performance status can be evaluated using the Eastern Cooperative Oncology Group (ECOG) scale for performance status (see, e.g., Oken et al., Am. J. Clin. Oncol. 5:649-655 (1982), which is hereby incorporated by reference in its entirety). In some embodiments, the decline in performance status can be evaluated using the Karnofsky performance status (see, e.g., Peus et al., BMC Med. Inform. Decis. Mak. 13:72 (2013), which is hereby incorporated by reference in its entirety). In some embodiments, the patient is a pediatric patient and the performance status is evaluated by the Lansky performance score (see, e.g., Lansky et al., Cancer. 60(7):1651-6 (1987), which is hereby incorporated by reference in its entirety).

[0136] The term "administer" or "administering" refers to a method of giving a dosage of a compound or pharmaceutical composition to a patient. Preferred methods 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 dosage of the compound of formula I described herein, or a pharmaceutically acceptable salt, amorphous, or polymorphic form thereof, their spray-dried dispersions, or their pharmaceutical compositions can vary over a wide range of at least once a day, from 1.0 to 10,000 mg or more per adult, or any range therein. An effective amount of the drug is usually supplied at a dosage level of at least once a day, from about 0.1 mg / kg body weight / day to about 1000 mg / kg body weight, or any range therein. The range can be at least once a day, from about 0.5 to about 500 mg / kg body weight, or any range therein. The range can be at least once a day, from about 1.0 to about 250 mg / kg body weight, or any range therein. The range can be at least once a day, from about 0.1 to about 100 mg / kg body weight, or any range therein. By way of example, the range can be at least once a day, from about 0.1 to about 50.0 mg / kg body weight, or any amount or range therein. As another example, the range can be at least once a day, from about 0.1 to about 15.0 mg / kg body weight, or any range therein. As yet another example, the range can be at least once a day, from about 0.5 to about 7.5 mg / kg body weight, or any amount or range therein. The pharmaceutical compositions provided herein can be administered at least once a day, in a regimen of 1 to 4 times, or as a single daily dose.

[0138] The optimal dosage to be administered can be readily determined by one of ordinary skill 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 state. Further, it may be necessary to adjust the dosage due to factors related to the particular subject being treated, including the subject's age, weight, diet, and time of administration.

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

[0140] The compound of formula I or a pharmaceutically acceptable salt thereof is administered at a dosage of about 200 mg to about 1200 mg, or about 200 to about 1000 mg, or about 200 to about 800 mg, or about 200 mg to about 600 mg, or about 200 mg to about 400 mg. In some embodiments, the dosage is about 200 mg to about 400 mg. In other embodiments, the dosage is 200 mg. In other embodiments, the dosage is 300 mg. In still further other aspects, the dosage is 400 mg.

[0141] One of ordinary skill in the art will further recognize that human clinical trials, dosage range trials, and efficacy trials, including first-time administration to humans in healthy subjects and / or subjects suffering from a given disorder, can be accomplished by methods well known in the clinical and medical arts.

[0142] The effective amount can be determined by a responsible diagnostician such as one of ordinary skill in the art, using known techniques and by observing results obtained under similar circumstances. When determining the effective amount for a patient, a number of factors are considered by the responsible diagnostician, including the species of the patient, its size, age, and general health, the specific disease or disorder involved, the degree or involvement or severity of the disease or disorder, the response of the individual patient, the specific compound administered, the mode of administration, the bioavailability characteristics of the formulation administered, the dosage regimen selected, the use of concomitant medications, and other related circumstances, but are not limited thereto.

[0143] The compound of formula I or a pharmaceutically acceptable salt thereof can be administered orally at a particular frequency and dosage determined separately, with or without a second therapeutic agent or a pharmaceutically acceptable salt thereof, or a second therapeutic agent and a third therapeutic agent or pharmaceutically acceptable salts thereof.

[0144] "Adjuvant therapy" is understood to mean a therapy that is administered in addition to, or after, the first-choice therapy. The first-choice therapy includes the administration of one or more other therapeutic agents, radiotherapy, and / or surgery. The compound of formula I may be the first-choice therapy or may be used in adjuvant therapy.

[0145] "First-choice therapy" is the first therapy administered for a disease.

[0146] The "therapeutically effective amount" or "pharmaceutically 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 is a degree of alleviation of one or more symptoms of the disease and may include curing the disease.

[0147] As used herein, the phrase "in combination with" means that a compound or a pharmaceutically acceptable salt thereof is administered simultaneously with, or in any order sequentially with, a second therapeutic agent or a pharmaceutically acceptable salt thereof, or a second therapeutic agent and a third therapeutic agent or pharmaceutically acceptable salts thereof, for example, at repeated intervals such as during a standard course of treatment of a single cycle or more than one cycle, such that one agent can be administered before, simultaneously with, or following the administration of the other agent, or any combination thereof, or that a compound or a pharmaceutically acceptable salt thereof is administered simultaneously with, or in any order sequentially with, a second therapeutic agent or a pharmaceutically acceptable salt thereof, or a second therapeutic agent and a third therapeutic agent or pharmaceutically acceptable salts thereof, for example, at repeated intervals such as during a standard course of treatment of a single cycle or more than one cycle, such that one agent can be administered before, simultaneously with, or following the administration of any one or both or all of the other agents, or any combination thereof.

[0148] Adjuvant therapy can be carried out by administering to a patient an amount or dose of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with a second therapeutic agent or a pharmaceutically acceptable salt thereof, or a second therapeutic agent or a pharmaceutically acceptable salt thereof and a third therapeutic agent or a pharmaceutically acceptable salt thereof, whereby 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 the second therapeutic agent or a pharmaceutically acceptable salt thereof and the third therapeutic agent or a pharmaceutically acceptable salt thereof is provided in the body, which is also understood.

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

[0150] The phrase "risk of developing metastases" means the risk that a patient or patient having a primary tumor will develop additional tumors (e.g., solid tumors) at sites distant from the primary tumor in the patient or patient over a period of time, and the additional tumors contain cancer cells that are the same as or similar to the primary tumor. Methods for reducing the risk of developing metastases in a patient or patient having cancer are described herein.

[0151] The phrase "risk of developing further metastases" means the risk that a patient or patient having a primary tumor and one or more additional tumors (the one or more additional tumors contain cancer cells that are the same as or similar to the primary tumor) at a site distant from the primary tumor will develop one or more additional tumors distant from the primary tumor, and the additional tumors contain cancer cells that are the same as or similar to the primary tumor. Methods for reducing the risk of developing further metastases are described herein.

[0152] The following examples are only useful for illustrating various aspects and embodiments of the present disclosure and should not be considered as limiting the scope of the present disclosure.

[0153] Example 1: A phase 3 trial comparing immunostrant with an investigator - selected endocrine therapy in patients with estrogen receptor - positive, HER2 - negative locally advanced or metastatic breast cancer previously treated with endocrine therapy. This is a randomized active - controlled trial with two arms in which patients and investigators are not blinded.

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

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

[0156] [Table 2]

[0157] Inclusion criteria for patients: Participants are eligible for inclusion in the study only if all of the following criteria are met. 1. Participants must be at least 18 years of age. 2. Have a diagnosis of ER +, HER2 - breast cancer a. To meet the criteria for 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 criteria for HER2 - disease, breast cancer must not show overexpression of HER2 by immunohistochemistry (IHC) or in - situ hybridization as defined in the relevant ASCO / CAP guidelines (Wolff et al. 2018) at the time of initial diagnosis or subsequent biopsy. Although not required as part of the protocol procedure, patients with new metastatic lesions should be considered for biopsy at any time if clinically indicated to re - evaluate HER2 status prior to study enrollment. 3. Have locally advanced (not suitable for curative treatment by surgery) or metastatic disease and meet one of the following criteria. a. Recur with evidence of progression during or within 12 months after completion of (neo)adjuvant AI, alone or in combination with a CDK4 / 6 inhibitor, without treatment of progressive disease. b. Recur with evidence of progression more than 12 months after completion of (neo)adjuvant ET and subsequently progress during or after only one line of treatment with AI, alone or in combination with a CDK4 / 6 inhibitor. Patients may not have received any other prior therapy (other than those mentioned above: AI alone or in combination with a CDK4 / 6 inhibitor) in the progressive / metastatic setting. c. Present with newly metastatic disease and subsequently progress during or after only one line of treatment with AI, alone or in combination with a CDK4 / 6 inhibitor. Patients may not have received any other prior therapy (other than those mentioned above: AI alone or in combination with a CDK4 / 6 inhibitor) in the progressive / metastatic setting. 4. Must be considered suitable for treatment with ET 5. In the case of women, must have a postmenopausal state either by surgical / natural 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). For postmenopause due to surgical / natural menopause, at least one of the following is required. a. Previous bilateral oophorectomy b. Age 60 years or older c. Age less than 60 years and amenorrheic for at least 12 months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian function suppression), with FSH and estradiol levels in the postmenopausal range. 6. If the postmenopausal status in women is due to ovarian function suppression, the participant must have a negative serum pregnancy test at the baseline time point (within 14 days before registration) 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. In the case of men, the following must be agreed to: a. Hormonal suppression with a gonadotropin-releasing hormone agonist such as goserelin or leuprolide (administered monthly, starting at least 28 days before Day 1 of Cycle 1) b. Use of a highly effective contraceptive method and not donating sperm during the study and for at least 6 months after the last dose of the investigational medicinal product(s) or for the longer of either period as specified by national requirements. 8. Have one of the following as defined by RECIST v1.1 (Eisenhauer et al. 2009, Section 10.3 of Appendix 3): · Measurable disease · Disease of bone only that is not measurable. A disease of bone only that is not measurable may include any of the following: i. Blastic bone lesion ii. Lytic bone lesion without measurable soft tissue component iii. Mixed lytic-blastic bone lesion without measurable soft tissue component 9. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group scale (Oken et al. 1982) 10. Have appropriate organ function as defined in the following table

[0158]

Table 3

[0159] Patient Exclusion Criteria If a participant meets any of the following criteria, the participant will be excluded from this study. 1. Has previously been treated with chemotherapy (excluding neoadjuvant / adjuvant chemotherapy), fulvestrant, any ER-directed therapy (including SERD and non-SERD) in any clinical trial, any PI3K inhibitor, mTOR inhibitor, or AKT inhibitor 2. Is currently receiving an investigational drug in a clinical trial or is participating in any other type of medical research that is determined to be scientifically or medically incompatible with this study 3. Has inflammatory breast cancer 4. Patients with known pathogenic germline mutations eligible for treatment with PARP inhibitors are not eligible for this study in regions where these therapies are approved and available. 5. Has some basis for visceral crisis, lymphangitic spread in the lungs, or leptomeningeal disease. Visceral crisis means not just the presence of visceral metastases, but severe organ dysfunction evaluated by symptoms and signs, clinical findings, and rapid progression of the disease. 6. Has symptomatic or untreated brain metastases. Patients with treated brain metastases must have had prior therapy (including radiation and / or surgery) completed more than 28 days before the first dose of study treatment, and must not have received corticosteroids and / or anticonvulsants for at least 14 days before the first dose of study treatment. The disease is eligible for this study if it is asymptomatic and stable on repeated imaging (radiography) for at least 28 weeks before consent (repeated imaging should be performed during study screening). 7. Underwent major surgery within 14 days before randomization 8. Received wide-field radiotherapy (defined as involving more than 25% of the bone marrow) within 4 weeks before randomization, or limited field radiation for palliation within 1 week before randomization. The patient must also have recovered to Grade 1 or better from the side effects associated with such treatment (excluding alopecia). 9. Has severe cardiac conditions 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. Severe or moderate valvular disease or considered clinically significant f. Symptomatic or requiring treatment for arrhythmias (excluding patients with rate-controlled atrial fibrillation) g. Cerebrovascular attack (stroke) within the past 3 months h. An average QT interval of 470 milliseconds or more, corrected for heart rate on screening ECG, when calculated using Fridericia's formula, over a continuous period of several days of evaluation i. Baseline bradycardia with a resting heart rate below 60 beats per minute 10. Having a severe pre-existing medical condition that, in the judgment of the principal investigator of the clinical trial, precludes participation in this study 11. Having a history of other cancers (excluding non-melanoma skin cancer or cervical intraepithelial neoplasia), except when in complete remission without treatment for at least three years 12. Having received autologous or allogeneic stem cell transplantation 13. Having 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. Being pregnant, breastfeeding, or planning to become pregnant or have a child during the study planned period from the screening visit until 180 days after the last dose of the study intervention 15. Having initiated a bisphosphonate preparation or an approved RANK ligand (RANK-L) targeting agent (e.g., denosumab) less than 7 days before randomization 16. A known allergic reaction to any of the components of the study treatment.

Claims

1. An agent comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, for treating estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2−), and estrogen receptor 1 variant (ESR1m) breast cancer, wherein the compound or its pharmaceutically acceptable salt is used to be administered to a patient in need of such treatment at a dose of about 400 mg, at least once a day for at least one week, characterized in that the patient has previously received endocrine therapy. 【Chemical 1】

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

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

4. The agent according to claim 2, wherein the endocrine therapy comprises fulvestrant or exemestane.

5. The agent according to any one of claims 1 to 4, wherein the breast cancer is locally advanced, inoperable, or metastatic breast cancer.

6. The agent according to any one of claims 1 to 4, wherein the breast cancer is locally advanced breast cancer.

7. The agent according to any one of claims 1 to 4, wherein the breast cancer is metastatic breast cancer.

8. The agent according to any one of claims 1 to 4, wherein the breast cancer is inoperable breast cancer.

9. The agent according to claim 5, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is used to be administered simultaneously, separately, or sequentially with a second therapeutic agent that is a gonadotropin-releasing hormone agonist.

10. The agent according to claim 9, wherein the gonadotropin-releasing hormone agonist is selected from the group consisting of leuprorelin and goserelin.

11. The agent according to claim 5, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is used to be administered simultaneously, separately, or sequentially with a second therapeutic agent that is abemaciclib.

12. The agent according to claim 11, wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, is used to be administered simultaneously, separately, or sequentially with a third therapeutic agent that is a gonadotropin-releasing hormone agonist.

13. The agent according to claim 12, wherein the gonadotropin-releasing hormone agonist is selected from the group consisting of leuprorelin and goserelin. ​

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