Methods of treating cancer using combination of serd dosing regimens

Abstract

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

Description

[Technical Field]

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

[0002] The present disclosure relates to the field of cancer treatment. [Background technology]

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

[0004] Drug development is unpredictable. It is common for new molecules to fail in the preclinical and / or clinical stages, often for largely unknown reasons. Dosing adds complexity and further unpredictability. Not all drug dosing regimens are equally effective in all patient populations due to a variety of factors, including, but not limited to, body weight, performance status, number of prior systemic therapies, genetics, and histological tumor type. Toxicity issues add further complexity. Efficacy and toxicity must be balanced. Additionally, it is not always possible to predict which patients will achieve therapeutic serum levels quickly enough to benefit before disease progression. Loading dose administration seeks to provide improvement in previously non-responding subpopulations, potentially leading to early progression, without posing toxicological barriers to either that population or previously responding populations.

[0005] There remains a need to provide alternative therapies for patients with cancer. Additionally, there remains a need to provide alternative therapies with better tolerability profiles or that enable maximal activity with limited adverse events and fewer dose interruptions or discontinuations. There remains a need for potent anti-estrogen therapies that antagonize and degrade ER with clinically relevant activity and bioavailability. (Shagufta, et al., Recent progress in selective estrogen receptor down regulators (SERDs) for the treatment of breast cancer, RSC Med. Chem., 2020, 11, 438-454). Summary of the Invention

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

[0007] Compounds of formula I have the following structure:

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

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

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

[0011] Disclosed herein are dosing protocols using compounds of Formula I to treat cancer. The protocols can be monotherapy or adjuvant therapy.

[0012] In one embodiment, the dosing protocol is a method of treating cancer, comprising: Formula I in a dose of about 200 mg to about 800 mg

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

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

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

[0016] In one embodiment, the dosing protocol is a method of treating cancer, comprising: A dose of about 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof The method includes administering to a patient in need of such treatment at least once daily for about 2 weeks to about 6 months, and then increasing the dose to about 300 mg at least once daily for at least 21 days.

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

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

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

[0020] In one embodiment, the dosing protocol is a method of treating breast cancer comprising administering a dose of about 400 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof to: to a patient in need of such treatment at least once daily for at least about 1 week to about 6 months, and then reducing the dose to about 200 mg at least once daily.

[0021] In one embodiment, the dosing protocol comprises a method of treating cancer comprising administering to a patient in need of such treatment a dose of about 400 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof at least once daily for about 2 weeks to about 6 months, and then reducing the dose to about 200 mg at least once daily for at least 21 days.

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

[0024] In one embodiment, there is provided a method of treating cancer, comprising: Disclosed herein are methods comprising administering to a patient in need of such treatment at least once daily for at least one week a dose of 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 therapeutic agent and the third therapeutic agent are different.

[0025] In one aspect, disclosed herein is a method of treating breast cancer, comprising administering a dose of about 400 mg of the compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment at least once daily.

[0026] In one embodiment, the dosing protocol comprises 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 embodiment, the dosing protocol comprises 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, the dosing protocol includes 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 pertuzumab (Q21D), and 420 mg trastuzumab (Q21D), where Q21D means every 21 days.

[0029] In another embodiment, the dosing protocol comprises 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 pertuzumab (Q21D), and 420 mg trastuzumab (Q21D).

[0030] In one embodiment, the dosing protocol comprises a method of treating ER+, HER2-negative breast cancer comprising administering at least once daily 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 embodiment, the dosing protocol comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in treating cancer, wherein the compound or pharmaceutically acceptable salt thereof is administered to a patient at a dose of about 200 mg to about 800 mg at least once daily for at least one week.

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

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

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

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

[0036] In one aspect, the dosing protocol comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a second therapeutic agent in the treatment of cancer in a patient, wherein the compound or pharmaceutically acceptable salt thereof is administered at least once daily for at least one week at a dose of about 200 mg to about 400 mg.

[0037] In one aspect, a dosing protocol comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a second therapeutic agent and a third therapeutic agent 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 salt thereof is administered at a dose of about 200 mg to about 400 mg at least once daily for at least one week.

[0038] In one aspect, the dosing protocol comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a second therapeutic agent in the treatment of cancer in a patient, wherein the cancer is selected from the group consisting of breast cancer, including metastatic breast cancer (mBC) and advanced breast cancer, ovarian cancer, endometrial cancer, including endometrioid endometrial cancer (EEC), prostate cancer, uterine cancer, gastric cancer, and lung cancer, and wherein the compound or pharmaceutically acceptable salt thereof is administered at a dose of from about 200 mg to about 400 mg.

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

[0040] In one embodiment, the dosing protocol comprises 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 simultaneous, separate, or sequential combination with pertuzumab and trastuzumab to treat ER+, HER2-negative breast cancer.

[0041] In one embodiment, the dosing protocol comprises 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 simultaneous, separate, or sequential combination with pertuzumab and trastuzumab to treat ER+, HER2-positive breast cancer.

[0042] 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), administered at a dose of about 400 mg, for use in simultaneous, separate, or sequential combination with abemaciclib to treat ER+, HER2-negative breast cancer. 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 utilizes a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents in conjunction with surgery, or in combination with one or more other therapeutic agents and in conjunction with surgery, in adjuvant therapy. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at least one week before surgery. In an alternative embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at least one week after surgery. In another embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at least one week before surgery and 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 embodiment, there is provided a method of treating cancer, comprising: Disclosed herein are methods that include administering a dose of about 200 mg to about 400 mg of a compound of formula I, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment at least once daily for at least one week.

[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, disclosed herein is a method of treating cancer, comprising administering to a patient in need of such treatment a dose of about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof at least once daily for about two weeks to about six months, and then increasing the dose to about 300 mg at least once daily for at least 14 days, or at least 21 days, or at least 28 days. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)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, disclosed herein is a method of treating cancer, comprising administering to a patient in need of such treatment a dose of about 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof at least once daily for about two weeks to about six months, and then increasing the dose to about 400 mg at least once daily for at least 14 days, or at least 21 days, or at least 28 days. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)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, disclosed herein is a method of treating cancer, comprising administering to a patient in need of such treatment a dose of about 400 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof at least once daily for about two weeks to about six months, and then reducing the dose to about 200 mg at least once daily for at least 14 days, or at least 21 days, or at least 28 days. Preferably, the compound is (5R)-5-[4-[2-[3-(fluoromethyl)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, disclosed herein is a 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 dose of about 200 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof at least once daily for 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, disclosed herein is a 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 dose of about 400 mg of the compound of Formula I or a pharmaceutically acceptable salt thereof at least once daily for 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).

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

[0052] In one embodiment, the dosing protocol comprises 400 mg of 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 simultaneous, separate, or sequential combination with 6 mg / kg pertuzumab (Q21D) and 420 mg trastuzumab (Q21D) to treat ER+, HER2-negative breast cancer, where Q21D means every 21 days.

[0053] In one embodiment, the dosing protocol comprises 400 mg of 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 simultaneous, separate, or sequential combination with 6 mg / kg pertuzumab (Q21D) and 420 mg trastuzumab (Q21D) to treat ER+, HER2-positive breast cancer, where Q21D means every 21 days.

[0054] In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered for about two weeks to patients with ER-positive, human epidermal growth factor receptor 2-negative (HER2-negative) early stage (stage I-III) breast cancer. 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 embodiment, there is provided a method of treating cancer, comprising: Disclosed herein are methods comprising administering to a patient in need of such treatment at least once daily for at least one week a dose of 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 therapeutic agent and the third therapeutic agent are different. In all embodiments, a preferred pharmaceutically acceptable salt of the compound of Formula I is the tosylate salt, i.e., 4-methylbenzenesulfonate salt. [Brief explanation of the drawings]

[0056] [Figure 1]Figure 1 shows the mean (± standard deviation) total plasma concentration time profiles on day 15 of a clinical trial dose escalation study after multiple oral dosing 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) ranging from 200 mg to 1200 mg QD. [Figure 2] Figure 1 shows the mean (± standard deviation) unbound plasma concentration time profiles on day 15 of a clinical trial dose escalation study after multiple oral dosing 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) ranging from 200 mg to 1200 mg QD. DETAILED DESCRIPTION OF THE INVENTION

[0057] pharmaceutically acceptable salts The compounds of Formula I are 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. See, for example, 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, and 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 (to form the mesylate salt), benzenesulfonic acid (to form the besylate salt), trifluoromethanesulfonic acid (to form the triflate salt), HCl, H2SO4, HNO3, and H3PO4.

[0058] cancer In one embodiment, the cancer is selected from the group consisting of breast cancer, including advanced breast cancer, 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 hormone receptor positive (HR positive), such that the cancer cells express hormone receptors. Hormone receptors include both estrogen receptors and progesterone receptors. 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 a compound of formula I or a pharmaceutically acceptable salt thereof is one that is HR positive, e.g., ER positive, and tyrosine kinase receptor, e.g., HER2 positive or HER2 negative.

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

[0062] Medication regimen In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt 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 may be administered. The maximum daily dose, i.e., the maximum dose in a 24-hour period, 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 to about 600 mg, or about 200 to about 400 mg. Preferably, the dose is about 200 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 daily for at least one week. The dose can be administered more than once daily.

[0063] Upfront therapy In one embodiment, the patient in need of treatment has previously undergone endocrine therapy, which is a hormone 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 undergone cyclin-dependent kinase (CDK4 / 6) inhibitor-containing therapy.

[0064] In another embodiment, a method is disclosed herein wherein the patient in need of treatment has received no more than one prior therapy. In yet another embodiment, a method is disclosed herein wherein the patient has received no more than two prior therapies. In yet another embodiment, a method is disclosed herein wherein the patient has received no more than three prior therapies. In yet another embodiment, a method is disclosed herein wherein the patient has received no more than four prior therapies. In some embodiments, the patient has received eight or more prior therapies.

[0065] As used herein, "prior therapy" refers to a therapy previously administered or used to treat cancer. Administering a single medication or administering two or more medications as part of 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 platinum-based chemotherapy drugs, treatment with CDK4 / 6 inhibitors, or treatment with fulvestrant. Treating a patient with a medication followed by surgery are two examples of prior therapy.

[0066] The compound of Formula I and its pharmaceutically acceptable salts are administered to a patient experiencing or exhibiting 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 other embodiments, the patient has previously received endocrine therapy.

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

[0068] In another embodiment, a method is disclosed herein, wherein the patient in need of treatment has been identified or diagnosed with 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, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at a dose of about 200 mg to about 800 mg, or about 200 mg to about 400 mg. In yet another embodiment, disclosed herein is a method of treating cancer, comprising administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof at least once daily for at least one week at least once daily for at least one week.

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

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

[0072] In another embodiment, a method is disclosed herein, wherein the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 400 mg to a patient in need thereof. In another embodiment, a method is disclosed herein, further comprising the step of administering a dose of about 400 mg to the patient at least once daily, followed by the step of administering a reduced dose of about 200 mg to about 300 mg to the patient at least once daily. In another embodiment, a method is disclosed herein, wherein the step of administering a dose of about 400 mg occurs before surgery. In one embodiment, the patient is scheduled to undergo surgery to treat EEC, and the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 400 mg, and the dose is administered at least once daily for at least one week before surgery. In a further embodiment, the 400 mg dose is administered at least once daily for about two weeks before surgery. In another embodiment, a method is disclosed herein, wherein the step of administering a reduced dose occurs after surgery. In one embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is reduced to about 200 mg at least once daily after surgery. In another embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is reduced to about 300 mg at least once daily after surgery. In another embodiment, methods are disclosed herein wherein administering the reduced dose occurs 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 daily for at least one week, followed by an increased dose of about 300 mg to about 400 mg administered to the patient at least once daily for at least one week. If the patient is scheduled to undergo surgery to treat EEC, the dose of about 200 mg is administered at least once daily for at least one week prior to the surgery. In some embodiments, the 200 mg dose is administered at least once daily for about two weeks prior to the surgery. In a further embodiment, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is increased to about 300 mg at least once daily after the surgery, or alternatively, the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is increased to about 400 mg at least once daily after the 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 where 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 daily for at least one week prior to the surgery. In a further embodiment, the cancer is metastatic breast cancer. In another embodiment, the cancer is advanced breast cancer. In another embodiment, a method is disclosed herein where 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 daily for at least one week prior to the surgery.

[0075] In another embodiment, a method is disclosed herein wherein the patient in need of treatment has been identified or diagnosed with a cancer selected from the group consisting of mBC, breast cancer including advanced breast cancer, ovarian cancer, endometrial cancer including EEC, prostate cancer, uterine cancer, gastric cancer, and lung cancer. In another embodiment, a method is disclosed herein 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 the patient in need of treatment has been 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 scratch or starting anew.

[0077] In another embodiment, a method is disclosed herein wherein the patient in need of treatment has been identified or diagnosed with 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 scratch or starting anew.

[0078] In another embodiment, a method is disclosed herein, wherein a 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 a patient in need of treatment has breast cancer, and the breast cancer is locally advanced, unresectable, or metastatic.

[0079] In another embodiment, a method is disclosed herein, wherein a 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 a patient in need of treatment has breast cancer, and the breast cancer is locally advanced, unresectable, 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 has not progressed on a first-line treatment regimen. In another embodiment, the patient has progressed on a first-line treatment regimen. In another embodiment, the patient has not received more than one HER2-directed regimen for progressive disease, or any endocrine therapy, or any prior CDK4 / 6 inhibitor therapy.

[0081] In another embodiment, the patient has a Left Ventricular Ejection Fraction (LVEF) of 50% or greater at baseline as determined by echocardiography or multigated acquisition scanning. In another embodiment, the patient does not have a Left Ventricular Ejection Fraction (LVEF) of 50% or greater at baseline as determined by echocardiography or multigated acquisition scanning.

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

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

[0085] In some embodiments, the second therapeutic agent is selected from the group consisting of abemaciclib, 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 dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is 400 mg, and the second therapeutic agent is abemaciclib.

[0086] In some embodiments, the 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 another embodiment, the 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 / difenoxin, 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, a method is disclosed herein wherein the dose of the compound of Formula I or a pharmaceutically acceptable salt thereof is about 200 mg. In another embodiment, a method is disclosed herein further comprising administering to the patient a dose of about 200 mg at least once daily, followed by administering to the patient an increased dose of about 300 mg to about 400 mg at least once daily. In another embodiment, a method is disclosed herein wherein the step of administering the dose of about 200 mg occurs before surgery. In another embodiment, a method is disclosed herein wherein the step of administering the increased dose occurs after surgery. In another embodiment, a method is disclosed herein wherein the step of administering the increased dose occurs daily for at least three months up to the lifespan of the patient.

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

[0092] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof described herein may be used in combination with one or more other therapies to treat related diseases, disorders, or conditions. In some embodiments, the dosing of the compound of Formula I or a pharmaceutically acceptable salt thereof is altered when used in adjuvant therapy compared to when administered as monotherapy. Alternatively, or additionally, in some embodiments, a therapy administered in combination with the compound of Formula I or a pharmaceutically acceptable salt thereof described herein is administered according to a different regimen or protocol than when administered alone or in combination with one or more therapies other than the compound of Formula I. In some embodiments, a composition comprising an additional therapeutic agent, the additional therapeutic agent, and the provided compound may act synergistically. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof may act synergistically in combination with a second therapeutic agent or a pharmaceutically acceptable salt thereof. In some embodiments, one or both therapies utilized in a combination regimen are administered at a lower level or less frequently than when 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 in combination with a second therapeutic agent or a pharmaceutically acceptable salt thereof, at a dose of about 200 mg to about 400 mg. In some embodiments, the dose is about 200 mg or about 400 mg. In some embodiments, the dose is 200 mg. In some embodiments, an additional step comprises administering a dose of about 200 mg to the patient at least once daily, followed by administering an increased dose of about 300 mg to about 400 mg to the patient at least once daily. In some embodiments, the dose is 400 mg. In some embodiments, an additional step comprises administering a dose of about 400 mg to the patient at least once daily, followed by administering a decreased dose of about 200 mg to about 300 mg to the patient at least once daily.

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

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

[0096] BRAF kinase inhibitors such as trametinib, vemurafenib, dabrafenib, sorafenib, or regorafenib, PARP inhibitors such as olaparib, rucaparib, or niraparib, and monoclonal antibodies such as (cetuximab) Erbitux.In some embodiments, the additional anticancer drug includes a polyfunctional alkylating agent, such as a nitrosourea, mustard (nitrogen mustard), methanesulfonate (busulfan), or ethyleneimine; a non-polyfunctional alkylating agent, such as procarbazine (Matulane), dacarbazine (DTIC), altretamine (Hexalen), or cisplatin (Platinol); an antimetabolite, such as an antifolate compound (methotrexate) or an amino acid antagonist (azaserine); a purine antagonist anti-inflammatory drugs, 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 (Hycamti), n), 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 anticancer 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 / difenoxin), Acidophilus (Lactobacillus acidophilus), Florajen (Lactobacillus acidophilus), Imodium AD (loperamide), Kaopectate (bismuth subsalicylate), Imotil (loperamide), Pink Bismuth (bismuth subsalicylate), Pepto-Bismol (bismuth subsalicylate), Lomotil(Pro) (atropine / diphenoxylate), Diamode (loperamide), Imodium(Pro) (loperamide), Florastor (Saccharomyces boulardii lyo), Kapectolin (New Formula) (bismuth subsalicylate), Florastor Kids (Saccharomyces boulardii lyo), 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), PercyIn some embodiments, the use comprises administering an antidiarrheal agent, but is not limited to, Risa-Bid (Lactobacillus acidophilus), RisaQuad (Lactobacillus acidophilus), Soothe Caplets (Bismuth subsalicylate), or Superdophilus (Lactobacillus acidophilus).

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

[0099] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally, with or without a second therapeutic agent or a pharmaceutically acceptable salt thereof, or a second therapeutic agent and a third therapeutic agent or a pharmaceutically acceptable salt thereof. Alternatively, the compound of Formula I or a pharmaceutically acceptable salt thereof is formulated for parenteral administration, e.g., 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, the compound of Formula I, the second therapeutic agent, the third therapeutic agent, or one of their pharmaceutically acceptable salts is formulated for oral administration. In some embodiments, the compound of Formula I, the second therapeutic agent, the third therapeutic agent, or one of their pharmaceutically acceptable salts is formulated for parenteral administration, e.g., intravenous administration. In some embodiments, the compound of Formula I, the second therapeutic agent, the third therapeutic agent, or one of their pharmaceutically acceptable salts 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 Edition, Pharmaceutical Press, 2012).

[0100] In some aspects, the disclosure relates to a compound of Formula I or a pharmaceutically acceptable salt thereof, together 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 simultaneous, separate, or sequential combination in the treatment of breast cancer, including mBC, ovarian cancer, endometrial cancer, including EEC, prostate cancer, uterine cancer, gastric cancer, and lung cancer.

[0101] In one embodiment, there is provided a method of treating cancer, comprising: Formula I in a dose of about 200 mg to about 400 mg

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

[0103] In one preferred embodiment, the second therapeutic agent is trastuzumab. Trastuzumab can be administered at a dose of about 8 mg / kg at least once a day. Alternatively, trastuzumab can be administered at a dose of about 6 mg / kg at least once a day. Alternatively, trastuzumab can be administered at a dose of about 4 mg / kg at least once a day. 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 dose of about 840 mg.Alternatively, pertuzumab can be administered at a dose 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, and the breast cancer is advanced or metastatic breast cancer (mBC), and the endometrial cancer is endometrioid endometrial cancer (EEC). In certain embodiments, the cancer is HR-positive. HR-positive cancers can be ER-positive and HER2-negative. Alternatively, HR-positive cancers can be ER-positive and HER2-positive.

[0106] When the cancer is breast cancer, the breast cancer may be locally advanced, unresectable, or metastatic. In one embodiment, the breast cancer is metastatic breast cancer (mBC). In one embodiment, the breast cancer is advanced breast cancer. In some embodiments, the methods disclosed herein are used to treat previously untreated metastatic breast cancer. In one embodiment, the advanced breast cancer 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 for advanced disease, or any prior CDK4 / 6 inhibitor therapy.

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

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

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

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

[0114] As used herein, the term "primary tumor" or "primary cancer" refers to the cancer where it first began, and not to a metastatic lesion located in another tissue, organ, or location in a subject.

[0115] As used herein, the term "polymorph" refers to crystals of the same compound that have different physical properties as a result of molecular ordering within the crystal lattice. Different polymorphs of a single compound have one or more different chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties. 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 (a key factor in determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, moisture sorption, compaction, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such as a dosage form discoloring more rapidly when composed of one polymorph than when composed of another) or mechanical changes (e.g., crystalline changes upon storage when a kinetically favored polymorph transforms to a thermodynamically more stable polymorph), or both (e.g., one polymorph is more hygroscopic than another). As a result of differences in solubility / dissolution, some transitions affect efficacy and / or toxicity. In addition, the physical properties of the crystals may be important in processing; for example, a polymorph may be more likely to form solvates or may be difficult to filter and wash free of impurities (i.e., the particle shape and size distribution may be different between one polymorph and another). As used herein, "polymorph" does not include amorphous forms of the compound of Formula I. As used herein, "amorphous" refers to a non-crystalline form of a compound, which may be a solid form of the compound of Formula I or a pharmaceutically acceptable salt thereof, or a solubilized form of the compound of Formula I. For example, "amorphous" refers to a compound that does not have a regular repeating arrangement of molecules or external planes, e.g., a solid form of a compound.

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

[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 solvents of crystallization.

[0118] "Purity," when used in reference to a composition comprising a polymorph of the compound of Formula I, refers to the percentage of one particular polymorphic form relative to another polymorphic form or amorphous form of the compound of Formula I or a pharmaceutically acceptable salt thereof in the referenced composition. For example, a composition comprising polymorphic Form 1 having a purity of 90% would contain 90 parts by weight of Form 1 and 10 parts by weight of other polymorphic forms and / or amorphous forms of the compound of Formula I.

[0119] As used herein, a compound of Formula I or a pharmaceutically acceptable salt thereof, or a composition is "substantially free" of one or more other components. A compound of Formula I or a pharmaceutically acceptable salt thereof, or a composition does not contain significant amounts 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 may include starting materials, residual solvents, or other impurities that may result from the preparation and / or isolation of the compounds of Formula I and compositions provided herein. In some embodiments, the polymorphic forms provided herein are substantially free of other polymorphic forms. In some embodiments, a particular polymorph of a compound of Formula I or a pharmaceutically acceptable salt thereof is "substantially free" of other polymorphs if the particular polymorph constitutes at least about 95% by weight of the compound of Formula I or a pharmaceutically acceptable salt thereof present. In some embodiments, a particular polymorph of the compound of Formula I or a pharmaceutically acceptable salt thereof is "substantially free" of other polymorphs if the particular polymorph constitutes at least about 97%, about 98%, about 99%, or about 99.5% by weight of the compound of Formula I or a pharmaceutically acceptable salt thereof present. In certain embodiments, a particular polymorph of the compound of Formula I or a pharmaceutically acceptable salt thereof is "substantially free" of water if the amount of water constitutes no more than about 2%, no more than about 1%, or no more than about 0.5% by weight of the polymorph.

[0120] As used herein, "substantially pure," when used in reference to a polymorphic form of the compound of Formula I, means a sample of a polymorphic form of the 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%, of the compound of Formula I, based on the weight of the compound of Formula I. The remaining material comprises other forms of the compound and / or reaction and / or processing impurities resulting from its preparation. For example, a polymorphic form of the compound of Formula I or a pharmaceutically acceptable salt thereof may be considered substantially pure in that the purity of the polymorphic form of the compound of Formula I is greater than 90%, and the remaining less than 10% of the material comprises other forms of the compound of Formula I or a pharmaceutically acceptable salt thereof and / or reaction and / or processing impurities, as measured by means currently known and generally accepted in the art. The presence of reaction and / or processing impurities may be determined by analytical techniques known in the art, such as, for example, chromatography, nuclear magnetic resonance spectroscopy, mass spectroscopy, or infrared spectroscopy.

[0121] For ease of explanation, some of the quantitative expressions herein are recited as ranges from about X to about Y. When a range is recited, it is understood that the range is not limited to the recited upper and lower limits, but rather includes the entire range from about X to about Y, or any range therein.

[0122] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, cosolvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, 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 insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions provided herein is contemplated. Supplementary active ingredients can also be incorporated into the compositions. Additionally, various excipients commonly used in the art may be included. These and other such compounds are described in the literature, for example, in The Merck Index, Merck & Company, Rahway, NJ. Considerations for including various ingredients 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 a mammal, e.g., a human. In some embodiments, the patient is a human.

[0124] In some embodiments, the patient is experiencing and / or exhibiting at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the patient has been identified or diagnosed with cancer, for example, 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 no more than one prior therapy. In some embodiments, the patient has received no more than two prior therapies.

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

[0127] In some embodiments, the patient is naive to a CDK4 / 6 inhibitor-containing therapy.

[0128] In some embodiments, the patient is receiving, will receive, or has not yet received neoadjuvant therapy concomitant with any other non-protocol anticancer therapy. In some embodiments, the patient is receiving, will receive, or has not yet received radiation therapy to the ipsilateral chest wall for any malignancy. In some embodiments, the patient is receiving, will receive, or has not yet received anti-estrogen therapy with raloxifene, tamoxifen, aromatase inhibitors, or other SERMs for either osteoporosis or breast cancer prevention. In some embodiments, the patient is receiving, will receive, or has not yet received hormone replacement therapy within 4 weeks of the start of study treatment. In some embodiments, the patient has undergone major surgery within about 28 days prior to randomization to allow for post-operative healing of surgical wounds and sites. In some embodiments, the patient is pregnant or breastfeeding. In some embodiments, the patient has certain infections, such as uncontrolled 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 curative or palliative measures. Beneficial or desired clinical results include, but are not limited to, cure, total or partial alleviation of symptoms associated with a disease or disorder or condition, whether detectable or undetectable, diminishment or reduction in the extent of the disease, reversal of the progression or severity of an existing symptom, disorder, condition, or disease, halting disease progression, a stable (i.e., not worsening) state of disease, delay, inhibition, or slowing of disease progression, improvement or palliation of the disease state (e.g., one or more symptoms of a disease), and regression or remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

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

[0131] In one aspect, the term "preventing" as used herein refers to the prevention of 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 bone fractures), or symptoms thereof, in whole or in part.

[0132] The term "progression," as defined by the National Cancer Institute (NCI) Cancer Dictionary, refers to cancer that worsens or spreads within 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, a total or partial worsening of symptoms associated with cancer, an increase in the extent of disease, and / or an accelerated progression of disease. "Progression" can also mean a shortened survival compared to the expected survival in the absence of treatment. In some embodiments, progression can include detecting one or more of the following: an increase in the percentage of blasts, an increase in the myeloid-to-erythroblast ratio, an increase in dysplasia (e.g., leukodysplasia), an increase in the percentage of bone marrow plasma cells, and an increase in the percentage of bone marrow lymphocytes (see, e.g., Sever, et al., Arch Pathol Lab Med. 2016 Sep;140(9):932-49, which is incorporated herein by reference in its entirety). In some embodiments, progression may include detecting one or more of 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 may be assessed 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 incorporated herein by reference in its entirety. In some embodiments, tumor burden may be assessed using PERCIST. See, e.g., Wahl, et al. J. nucl. med. 2009, 50:122S-150S, which is incorporated herein by reference in its entirety.

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

[0134] "Relapse" can also include "recurrence," which the National Cancer Institute defines as cancer that has returned, usually after a period of time during which it was undetectable. Cancer may return in the same location in the body as the original (primary) tumor or in another location in the body (NCI Cancer Dictionary). In some embodiments, failure to detect cancer can include failure to detect cancer cells in a patient, failure to detect a tumor in a patient, and / or the absence of symptoms related to cancer, in whole or in part.

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

[0136] The term "administration" or "administering" refers to a method of providing a dosage of a compound or pharmaceutical composition to a patient. The preferred method of administration can 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, spray-dried dispersion thereof, or pharmaceutical composition thereof, can vary over a wide range, from 1.0 to 10,000 mg per adult, or more, or any range therein, administered at least once daily. An effective amount of drug is typically supplied at a dosage level of from about 0.1 mg / kg body weight / day to about 1,000 mg / kg body weight, or any range therein, administered at least once daily. The range can be from about 0.5 to about 500 mg / kg body weight, administered at least once daily, or any range therein. The range can be from about 1.0 to about 250 mg / kg body weight, administered at least once daily, or any range therein. The range can be from about 0.1 to about 100 mg / kg body weight, administered at least once daily, or any range therein. By way of example, the range can be from about 0.1 to about 50.0 mg / kg body weight, at least once daily, or any amount or range therein. As another example, the range can be from about 0.1 to about 15.0 mg / kg body weight, at least once daily, or any range therein. As yet another example, the range can be from about 0.5 to about 7.5 mg / kg body weight, at least once daily, or any amount or range therein. The pharmaceutical compositions provided herein can be administered on a regimen of at least once daily, 1 to 4 times daily, or in a single daily dose.

[0138] Optimal dosages to be administered may be readily determined by those skilled in the art and will vary with the mode of administration, the strength of the formulation, the mode of administration, and the advancement of the disease state. Further, it will be necessary to adjust the dosage depending on factors related to the particular subject being treated, including the subject's age, weight, diet, and time of administration.

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

[0140] The compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose 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 dose 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 yet another embodiment, the dosage is 400 mg.

[0141] Those skilled in the art will further recognize that human clinical trials, including initial human administration, dose ranging studies, and efficacy studies 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] An effective amount can be determined by the attending diagnostician, such as one skilled in the art, by the use of known techniques and by observing results obtained under similar circumstances. In determining an effective amount for a patient, numerous factors will be considered by the attending diagnostician, including, but not limited to, the patient's species, its size, age, and general health, the particular disease or disorder involved, the extent or involvement or severity of the disease or disorder, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the administered formulation, the selected dosing regimen, the use of concomitant medications, and other relevant circumstances.

[0143] The compound of formula I or a pharmaceutically acceptable salt thereof may be administered orally 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, at specific frequencies and doses determined separately.

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

[0145] A "first-line treatment" is the initial treatment given for a disease.

[0146] A "therapeutically effective amount" or "pharmaceutically effective amount" or "effective amount" of a compound provided herein is an amount sufficient to achieve a desired effect, which may vary depending on the nature and severity of the disease state and the efficacy of the compound of Formula I. A therapeutic effect is some relief of one or more symptoms of the disease and may include curing the disease.

[0147] As used herein, the phrase "in combination with" refers to either the administration of a compound or a pharmaceutically acceptable salt thereof with a second therapeutic agent or a pharmaceutically acceptable salt thereof, or with a second therapeutic agent and a third therapeutic agent or a pharmaceutically acceptable salt thereof, either simultaneously or sequentially in any order, for example, at repeated intervals such as, for example, during a standard course of therapy for a single cycle or more than one cycle, where one agent may be administered before, simultaneously with, or following the administration of the other agent, or any combination thereof; or the administration of a compound of Formula I or a pharmaceutically acceptable salt thereof with a second therapeutic agent or a pharmaceutically acceptable salt thereof, or with a second therapeutic agent and a third therapeutic agent or a pharmaceutically acceptable salt thereof, either simultaneously or sequentially in any order, for example, at repeated intervals such as, for example, during a standard course of therapy for a single cycle or more than one cycle, where one agent may be administered before, simultaneously with, or following the administration of either one, both, or all of the other agents, or any combination thereof.

[0148] It is also understood that adjuvant therapy may be performed 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, thereby providing in the body effective levels 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 a third therapeutic agent or a pharmaceutically acceptable salt thereof.

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

[0150] The phrase "risk of developing metastases" refers to the risk that a patient or patient with 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, wherein the additional tumors contain the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing metastases in a patient or patient with cancer are described herein.

[0151] The phrase "risk of developing additional metastases" refers to the risk that a patient who has a primary tumor and one or more additional tumors at sites distant from the primary tumor, where the one or more additional tumors contain the same or similar cancer cells as the primary tumor, will develop one or more additional tumors distant from the primary tumor, where the additional tumors contain the same or similar cancer cells as the primary tumor. Methods for reducing the risk of developing additional metastases are described herein.

[0152] The following examples serve only to illustrate various aspects and embodiments of the present disclosure and should not be construed as limiting the scope of the present disclosure.

[0153] Example 1: Phase 3 study of imrunestrant versus investigator's choice of endocrine therapy in patients with estrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer previously treated with endocrine therapy. This is a two-arm, randomized, active treatment trial 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 = oral; QD = once daily.

[0156] [Table 2]

[0157] Patient inclusion criteria: Participants are eligible for inclusion in the study only if all of the following criteria apply: 1. Participants must be at least 18 years of age. 2. Have a diagnosis of ER+, HER2- breast cancer To qualify as ER+ disease, breast cancer must express ER by immunohistochemistry as defined in the relevant ASCO / CAP guidelines (Allison et al. 2020). To qualify for HER2- disease, the breast cancer must not demonstrate HER2 overexpression by immunohistochemistry (IHC) or in situ hybridization at the time of initial diagnosis or subsequent biopsy, as defined in the relevant ASCO / CAP guidelines (Wolff et al. 2018). Although not required as a protocol step, patients with new metastatic disease should be considered for biopsy whenever possible to reassess their HER2 status prior to study enrollment, if clinically indicated. 3. Have locally advanced (not amenable to curative surgical treatment) or metastatic disease and meet one of the following criteria: a. Relapse 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 for progressive disease b. Relapsed with evidence of progression more than 12 months after completion of (neo)adjuvant ET followed by progression during or after only 1 line of treatment with an AI alone or in combination with a CDK4 / 6 inhibitor. Patients may not have received any other prior therapy (other than those mentioned above: an AI alone or in combination with a CDK4 / 6 inhibitor) in the advanced / metastatic setting. c. Newly presented metastatic disease that subsequently progressed during or after only one line of treatment with an AI alone or in combination with a CDK4 / 6 inhibitor. Patients may not have received any other prior therapy (other than those mentioned above: an 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. If female, must be postmenopausal due to either surgical / natural menopause or ovarian suppression with gonadotropin-releasing hormone agonists such as goserelin or leuprolide (administered monthly, starting at least 28 days prior to Day 1 of Cycle 1). Postmenopausal due to surgical / natural menopause requires at least one of the following: a. Previous bilateral oophorectomy b. Age 60 or older c. Age < 60 years, amenorrhea for at least 12 months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression), and FSH and estradiol levels in the postmenopausal range 6. For women whose postmenopausal status is due to ovarian suppression, participants must have a negative serum pregnancy test at baseline (within 14 days prior to enrollment) and agree to use highly effective medically approved precautions (see Appendix 7, Section 10.7) to prevent pregnancy during the study and for 6 months after the last dose of study treatment. 7. If you are a male, you must agree to the following: a. Hormonal suppression with gonadotropin-releasing hormone agonists such as goserelin or leuprolide (administered monthly and initiated at least 28 days before Day 1 of Cycle 1) b. Use highly effective contraception and refrain from donating sperm during the study and for at least 6 months after the last dose of study drug(s), or for the period specified by national requirements, whichever is longer. 8. Have one of the following as defined by RECIST v1.1 (Eisenhauer et al. 2009, Appendix 3, section 10.3): Measurable disease Non-measurable bone-only disease. Non-measurable bone-only disease can include any of the following: i.blastic bone lesion ii. Lytic bone lesions without measurable soft tissue components 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. Adequate organ function as defined in the table below

[0158] [Table 3] Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; G-CSF = granulocyte colony-stimulating factor; ULN = upper limit of normal. 11. Have discontinued prior cancer therapy prior to receiving study drug, have recovered from the effects of treatment to at least Grade 1, excluding residual alopecia and peripheral neuropathy, and have undergone the required treatment washout period before receiving any clinical trial drug, as follows: a. For myelosuppressive drugs (e.g., CDK4 / 6 inhibitors), for at least 21 days b. For non-myelosuppressive agents (e.g., endocrine therapy), 7 days or 5 half-lives, whichever is shorter c. For test agents, 28 days or 5 half-lives, whichever is shorter. 12. Patient must be able to swallow capsules / tablets 13. Willingness to participate for the duration of the study and comply with study procedures. 14. Be able to sign the informed consent form (ICF) as set forth in Appendix 1, including compliance with the requirements and limitations listed in this protocol.

[0159] Patient exclusion criteria Participants will be excluded from the study if they meet any of the following criteria: 1. Previously treated with chemotherapy (excluding neoadjuvant / adjuvant chemotherapy), fulvestrant, any clinical trial ER-directed therapy (including SERD and non-SERD), any PI3K inhibitor, mTOR inhibitor, or AKT inhibitor 2. Currently receiving an investigational drug in a clinical trial or participating in any other type of medical research that is deemed scientifically or medically incompatible with this study 3.Having inflammatory breast cancer 4. Patients with known pathogenic germline mutations suitable for treatment with PARP inhibitors are not eligible for this study in regions where these treatments are approved and available. 5. Visceral crisis, lymphangitic spread within the lungs, or any evidence of leptomeningeal disease. Visceral crisis refers to severe organ dysfunction as assessed by symptoms and signs, laboratory findings, and rapid disease progression, rather than the mere presence of visceral metastases. 6. Symptomatic or untreated brain metastases. Patients with treated brain metastases are eligible for the study if they have completed prior therapy (including radiation and / or surgery) ≥28 days prior to the first dose of study treatment, have not received corticosteroids and / or anticonvulsants for at least 14 days prior to the first dose of study treatment, and have disease that is asymptomatic and radiographically stable with repeat imaging for at least 28 days prior to consent (repeat imaging should be performed during study screening). 7. Had undergone major surgery within 14 days prior to randomization 8. Received wide-field radiotherapy (defined as involvement of ≥25% of the bone marrow) within 4 weeks prior to randomization or palliative limited-field radiation within 1 week. Patients must also have recovered from grade 1 or better related side effects of such therapy (excluding alopecia). 9. Have a serious cardiac condition such as: Congestive heart failure b. New York Heart Association Class III / IV heart disease C. Unstable angina d. Myocardial infarction within the past 3 months e. Valvular disease that is severe, moderate, or considered clinically significant f. Symptomatic or treatment-requiring arrhythmias (excluding patients with rate-controlled atrial fibrillation) g. Cerebrovascular accident (stroke) within the past 3 months h. A mean QT interval of 470 milliseconds or greater, corrected for heart rate, on the screening ECG when calculated using the Fridericia formula on consecutive days of evaluation. i. Baseline bradycardia with a resting heart rate below 60 beats per minute 10. Have a serious pre-existing medical condition that, in the opinion of the investigator, prevents participation in this study 11. History of other cancers (excluding non-melanoma skin cancer or cervical intraepithelial neoplasia) unless in complete remission without treatment for at least 3 years 12.Receiving autologous or allogeneic stem cell transplantation 13. Have 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 enrollment. 14. Pregnant, breastfeeding, or planning to become pregnant or have a child within the study planning period starting from the screening visit and ending 180 days after the last dose of the study intervention. 15. Started a bisphosphonate or approved RANK ligand (RANK-L)-targeted agent (e.g., denosumab) within 7 days prior to randomization 16. Known allergic reaction to any of the components of the study treatment.

Claims

1. 1. A method of treating cancer, comprising: Formula I at a dose of about 200 mg to about 400 mg 【Chemical 1】 or a pharmaceutically acceptable salt thereof to a patient in need of such treatment at least once daily for at least one week.

2. The method of claim 1 , wherein the pharmaceutically acceptable salt is a tosylate salt.

3. 3. The method of claim 1 or 2, wherein the dose is about 200 mg, about 300 mg, or about 400 mg.

4. 10. The method of claim 1, wherein the dose is about 400 mg.

5. 5. The method of any one of claims 1 to 4, wherein the patient has been identified or diagnosed with a cancer selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer.

6. The method of any one of claims 1 to 5, wherein the cancer is HR positive.

7. 7. The method of claim 6, wherein the HR-positive cancer is ER-positive and HER2-negative.

8. 7. The method of claim 6, wherein the HR-positive cancer is ER-positive and HER2-positive.

9. The method of any one of claims 1 to 8, wherein the cancer is metastatic breast cancer (mBC).

10. The method of any one of claims 1 to 8, wherein the cancer is advanced breast cancer.

11. The method of any one of claims 1 to 8, wherein the cancer is endometrioid endometrial cancer (EEC).

12. The method of treating cancer according to any one of claims 1 to 11, further comprising administering a second therapeutic agent.

13. 13. The method of claim 12, wherein the second therapeutic agent is selected from the group consisting of abemaciclib, an aromatase inhibitor, everolimus, alpelisib, trastuzumab, and pertuzumab.

14. 14. The method of claim 13, wherein the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, and letrozole.

15. The method of any one of claims 12 to 13, wherein the second therapeutic agent is abemaciclib.

16. The method of any one of claims 12 to 13, wherein the second therapeutic agent is trastuzumab.

17. The method of any one of claims 12 to 16, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof and the second therapeutic agent are administered in conjunction with a third therapeutic agent.

18. 18. The method of claim 17, wherein a third therapeutic agent is selected from the group consisting of an aromatase inhibitor, everolimus, alpelisib, trastuzumab, and pertuzumab, and wherein the third therapeutic agent is different from the second therapeutic agent.

19. 19. The method of claim 18, wherein the third therapeutic agent is selected from the group consisting of an aromatase inhibitor and trastuzumab.

20. 19. The method of claim 18, wherein the aromatase inhibitor is selected from the group consisting of anastrozole, exemestane, and letrozole.

21. 18. The method of claim 17, wherein the third therapeutic agent is an antidiarrheal agent.

22. 19. The method of claim 17 or 18, wherein the third therapeutic agent is pertuzumab.

23. A compound of formula I for use in the treatment of cancer 【Chemistry 2】 or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a patient at least once daily for at least one week at a dose of about 200 mg to about 800 mg.

24. 24. The compound or a pharmaceutically acceptable salt thereof for use according to claim 23, wherein the dose is about 400 mg.

25. 25. The compound or pharmaceutically acceptable salt thereof for use according to any one of claims 23 or 24, wherein the patient has been identified or diagnosed with a cancer selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer.

26. 26. The compound or a pharmaceutically acceptable salt thereof for use according to claim 25, wherein the cancer is an HR-positive cancer that is ER-positive and HER2-negative.

27. 26. The compound or a pharmaceutically acceptable salt thereof for use according to claim 25, wherein the HR positive cancer is ER positive and HER2 positive.

28. 28. The compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 23 to 27, wherein the breast cancer is metastatic breast cancer (mBC).

29. The compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 23 to 27, wherein the breast cancer is advanced breast cancer.

30. 28. The compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 23 to 27, wherein the cancer is endometrioid endometrial cancer (EEC).

31. 31. The compound or pharmaceutically acceptable salt thereof for use according to any one of claims 23 to 30, wherein said compound or pharmaceutically acceptable salt thereof is administered in simultaneous, separate or sequential combination with a second therapeutic agent.

32. 32. The compound or pharmaceutically acceptable salt thereof for use according to claim 31 , wherein the second therapeutic agent is selected from the group consisting of abemaciclib, an aromatase inhibitor, everolimus, alpelisib, trastuzumab, and pertuzumab.

33. 33. The compound or a pharmaceutically acceptable salt thereof for use according to claim 31 or 32, wherein the second therapeutic agent is abemaciclib.

34. 33. The compound or a pharmaceutically acceptable salt thereof for use according to claim 31 or 32, wherein the second therapeutic agent is trastuzumab.

35. 35. The compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 31 to 34, wherein the compound or a pharmaceutically acceptable salt thereof and the second therapeutic agent are administered in simultaneous, separate or sequential combination with a third therapeutic agent.

36. 36. The compound or pharmaceutically acceptable salt thereof for use according to claim 35, wherein the third therapeutic agent is selected from the group consisting of an aromatase inhibitor, everolimus, alpelisib, trastuzumab, and pertuzumab, and the third therapeutic agent is different from the second therapeutic agent.

37. 37. The compound or a pharmaceutically acceptable salt thereof for use according to claim 35 or 36, wherein the third therapeutic agent is selected from the group consisting of an aromatase inhibitor and trastuzumab.

38. 37. The compound or a pharmaceutically acceptable salt thereof for use according to claim 35 or 36, wherein the third therapeutic agent is pertuzumab.

39. 1. A compound of formula I for use in simultaneous, separate or sequential combination with a second and a third therapeutic agent in the treatment of cancer in a patient. 【Chemistry 3】 or a pharmaceutically acceptable salt thereof, wherein the second therapeutic agent and the third therapeutic agent are different, and the compound or pharmaceutically acceptable salt thereof is administered at a dose of about 200 mg to about 400 mg at least once daily for at least one week.

40. 40. The compound or a pharmaceutically acceptable salt thereof for use according to claim 39, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, and lung cancer.

41. 41. The compound or a pharmaceutically acceptable salt thereof for use according to claim 40, wherein the cancer is ER positive and HER2 negative.

42. 41. The compound or a pharmaceutically acceptable salt thereof for use according to claim 40, wherein the cancer is ER positive and HER2 positive.

43. 1. 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 simultaneous, separate, or sequential combination with pertuzumab and trastuzumab for the treatment of ER+, HER2-negative breast cancer.

44. 44. The compound for use according to claim 43, wherein the compound is administered at a dose of about 400 mg.

45. 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), administered at a dose of about 400 mg, for use in simultaneous, separate, or sequential combination with abemaciclib for the treatment of ER+, HER2-negative breast cancer.

46. 1. A method for treating ER+, HER2- 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.

47. 1. A method of treating HR+ and ER+ cancer, comprising administering 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, wherein the cancer is selected from the group consisting of HER2-positive breast cancer, HER2-negative breast cancer, and endometrioid endometrial cancer (EEC).

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