Compositions comprising (z)-endoxifen and a CDK4 / 6 inhibitor and methods of use thereof

Abstract

The present disclosure relates to compositions and methods for treating hormone receptor positive (HR+) cancer with (Z)-endoxifen and a CDK4 / 6 inhibitor, such as abemaciclib. The disclosure is based on the discovery that (Z)-endoxifen and abemaciclib have synergistic effects on reducing tumor growth and proliferation in breast cancer models. The disclosure also provides fixed dose combinations of (Z)-endoxifen and abemaciclib, which offers advantages in terms of convenience and compliance. The compositions and methods are suitable for treating subjects with hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer, especially those who are contraindicated for aromatase inhibitor therapy and / or ovarian suppression therapy.

Description

COMPOSITIONS COMPRISING (Z)-ENDOXIFEN AND A CDK4 / 6 INHIBITOR AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority under 35 U. S. C. § 119(e) of U. S.Provisional Patent Application No. 63 / 716,038 filed on November 4, 2024. The disclosure of the prior applications is considered part of and is herein incorporated by reference in the disclosure of this application in its entirety.BACKGROUND

[0002] Breast cancer stands as the most common cancer globally and ranks as the second most lethal cancer in humans. The incidence of breast cancer has been on an upward trajectory, increasing approximately 1% annually since the 1940s. In North America, women face the highest risk of developing breast cancer, with a one in eight chance over their lifetime. Other breast-related conditions, which are non-malignant yet frequently a precursor to cancer, are also prevalent. These include various forms of hyperplasia, such as ductal and lobular hyperplasia, along with their atypical counterparts.

[0003] The gold standard for breast cancer management involves early detection through mammography, followed by a combination of surgical intervention, radiation, and chemotherapy. Enhanced breast cancer detection has been a significant benefit of widespread mammography. Although significantly rarer in men, with a lifetime risk of 1 in 1,000, it is estimated that 2,470 men will be diagnosed with invasive breast cancer, and approximately 460 will succumb to the disease. The American Cancer Society projected that in 2017, there would be 255,180 new diagnoses of breast cancer across all genders, with 41,070 fatalities. Despite these numbers, the mortality' rate from breast cancer has remained relatively stable, with about 21 deaths per 100,000 individuals. Breast cancer is often detected at an advanced stage, limiting the effectiveness of treatment and reducing survival prospects.

[0004] Breast cancers encompass a range of malignant growths originating from breast tissue. The spectrum of breast cancer ty pes is broad, including but not limited to ductal carcinoma in situ, lobular carcinoma in situ, various invasive carcinomas, inflammatory' breast cancer, and several other subtypes. In some aspects, the tumor presents as a single type or as a combination thereof and also displays a mix of invasive and non-invasive characteristics. There remains unmet medical need for new compositions and methods for the treatment and / or prevention of breast cancer.SUMMARY

[0005] In some aspects, the techniques described herein relate to a method of treating a subject having a hormone receptor positive (HR+) cancer, the method including administering to the subject a pharmaceutical composition including a therapeutically effective amount of endoxifen which is a compound of Formula (I):or a pharmaceutically acceptable salt, tautomer, or solvate thereof, and a therapeutically effective amount of a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof.

[0006] In some aspects, the endoxifen is >90% (Z)-endoxifen. In some aspects, the endoxifen is >95%, >96%, >97%, >98%, >99%, or >99.5% (Z)-endoxifen. In some aspects, the endoxifen is in a free base form. In some aspects, the pharmaceutically acceptable salt of the (Z)-endoxifen is selected from the group consisting of an: arecoline, besylate, bicarbonate, bitartrate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / di phosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc salt. In some aspects, the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen gluconate. In some aspects, the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen citrate. In some aspects, the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen hydrochloride.

[0007] In some aspects, the CDK4 / 6 inhibitor is palbociclib, abemaciclib, ribociclib, trilaciclib, SHR-6390, FCN-437c, lerociclib, milciclib, PF-06873600, XZP-3287, zotiraciclib, BEBT-209. BPI-16350, CS-3002, fadraciclib, HS-10342, ON-123300, PF-06842874, TQ-05510, BPI-1178, JS-101, NUV-422, AU-294, CCT-68127. ETH-155008, HEC-80797, JRP-890, JS-104, NEOS-518, PF-07104091, PF-07220060, RMC-4550, SRX-3177, VS-2370, and VS- 2370. In some aspects, the CDK4 / 6 inhibitor is abemaciclib which is a compound of Formula (II):Formula (II),or a pharmaceutically acceptable salt or tautomer thereof.

[0008] In some aspects, the pharmaceutically acceptable salt of the CDK4 / 6 inhibitor is selected from the group consisting of an: arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / di phosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc salt. In some aspects the pharmaceutically acceptable salt of the CDK4 / 6 inhibitor is the hydrochloride salt. In some aspects, the pharmaceutically acceptable salt of the CDK4 / 6 inhibitor is the mesylate salt.

[0009] In some aspects, the (Z)-endoxifen is administered in a first dosage form and the CDK4 / 6 inhibitor is administered in a second dosage form. In some aspects, the techniques described herein relate to a method wherein the first dosage form is administered orally. In some aspects, the first dosage form is formulated as an enteric formulation. In some aspects, the first dosage form is formulated as an enteric caplet, an enteric capsule, a delay ed-release tablet, a delayed-release caplet, or a del ay ed-release capsule. In some aspects, the first dosage form comprises hydroxypropyl methyl cellulose. In some aspects, the first dosage form is formulated as a delayed release composition. In some aspects, the first dosage form comprises from 0.01 to 360 mg of the (Z)-endoxifen. In some aspects, the first dosage form includes from 0.01 mg to 200 mg, from 0.1 mg to 100 mg, from 0.1 mg to 50 mg, from 0.1 mg to 20 mg, from 1 mg to 20 mg, from 20 mg to 50 mg, from 50 mg to 100 mg, from 100 mg to 200 mg, or from 200 mg to 360 mg of the (Z)-endoxifen. In some aspects, the therapeutically effective amount of (Z)-endoxifen is between about 1 and 80 mg. In some aspects, the first dosage form comprises a 0.05 mg / kg unit dose, a 0.1 mg / kg unit dose, a 0.5 mg / kg unit dose, a 1 mg / kg unit dose, a 1.5 mg / kg unit dose of the (Z)-endoxifen, or a 2.0 mg / kg unit dose ofthe (Z)-endoxifen. In some aspects, the (Z)-endoxifen is administered at a dosage of about 0.05 to 0.5 mg / kg, about 0.5 to 1 mg / kg, about 1 to 1.5 mg / kg, about 1.5 to 2 mg / kg, about 2 to 5 mg / kg, or about 5 to 10 mg / kg. In some aspects, the (Z)-endoxifen is administered at a dosage of 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2.0 mg / kg.

[0010] In some aspects, the (Z)-endoxifen is administered once a day, twice a day, three times a day, four times a day, every other day, once every three days, or once every four days. In some aspects, the (Z)-endoxifen is administered for at least 1 month to 5 years.

[0011] In some aspects, the second dosage form comprises about 0.1 to 600 mg of the CDK4 / 6 inhibitor, the CDK4 / 6 inhibitor being abemaciclib. In some aspects, the therapeutically effective amount of abemaciclib is between about 0.1 mg to 600 mg. In some aspects, the second dosage form comprises 25 mg, 50 mg. 100 mg, 150 mg, or 200 mg of abemaciclib. In some aspects, the abemaciclib is administered at a dose of 25 to 600 mg daily. In some aspects, the abemaciclib is administered at 0.1 to 5 mg / kg, 5 to 10 mg / kg, 10 to 20 mg / kg, 20 to 30 mg / kg, 30 to 40 mg / kg, 40 to 50 mg / kg, 50 to 60 mg / kg, 60 to 70 mg / kg, 70 to 80 mg / kg, 80 to 90 mg / kg, or 90 to 100 mg / kg. In some aspects, the abemaciclib is administered at a dosage or 25 mg / kg, 50 mg / kg, 50 mg / kg, or 100 mg / kg. In some aspects, the abemaciclib is administered once a day, twice a day, three times a day, four times a day, every' other day, once every three days, or once every' four days. In some aspects, the abemaciclib is administered in an amount of 50 mg twice daily, 100 mg twice daily, 150 mg twice daily, or 200 mg twice daily. In some aspects, the abemaciclib is administered in an amount of 150 mg or 200 mg twice daily.

[0012] In some aspects, the (Z)-endoxifen and the abemaciclib are administered in a single dosage form. In some aspects, the single dosage form is formulated as a suspension, a tablet, a capsule, a caplet, a liquid, or a gel. In some aspects, the single dosage form is formulated as an enteric formulation. In some aspects, the single dosage form is formulated as an enteric caplet, an enteric capsule, a delay ed-release tablet, a delay ed-release caplet, or a delay ed-release capsule. In some aspects, the single dosage form includes hydroxypropyl methyl cellulose. In some aspects, the single dosage form is administered orally. In some aspects, the (Z)-endoxifen is administered at an amount of 0.01 mg to 200 mg. In some aspects, the single dosage form includes from about 0.01 mg to 200 mg, about 0.1 mg to 100 mg, about 0.1 mg to 50 mg, about 0.1 mg to 20 mg, or about 1 mg to 20 mg of the (Z)-endoxifen. In some aspects, the (Z)-endoxifen is administered at a dosage of 0.05 to 0.5 mg / kg, 0.5 to 1 mg / kg, 1 to 1.5 mg / kg. 1.5 to 2 mg / kg, 2 to 5 mg / kg, 5 to 10 mg / kg, or 10 to 20 mg / kg. In someaspects, the (Z)-endoxifen is administered at a dosage of 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2.0 mg / kg In some aspects, the therapeutically effective amount of abemaciclib is 50 mg, 100 mg, 150 mg, or 200 mg. In some aspects, the single dosage form includes about 0.1 to 400 mg of the abemaciclib. In some aspects, the single dosage form includes 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg of the abemaciclib. In some aspects, the abemaciclib is administered at a dose of 25 to 800 mg daily. In some aspects, the abemaciclib is administered at a dosage of 0.1 to 5 mg / kg, 5 to 10 mg / kg, 10 to 20 mg / kg, 20 to 30 mg / kg, 30 to 40 mg / kg, 40 to 50 mg / kg, 50 to 60 mg / kg, 60 to 70 mg / kg, 70 to 80 mg / kg, 80 to 90 mg / kg, or 90 to 100 mg / kg. In some aspects, the abemaciclib is administered at a dosage of 25 mg / kg, 50 mg / kg, 50 mg / kg, or 100 mg / kg.

[0013] In some aspects, the techniques described herein relate to a method, wherein the single dosage form is administered once a day, twice a day, three times a day, four times a day, every other day, every two days, every' three days, or every four days. In some aspects, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released in the intestines.

[0014] In some aspects, administration of the composition achieves a mean area under the curve extrapolated to time infinity (AUCO-inf) of (Z)-endoxifen of 200 hr*ng / mL to 10000 hr*ng / mL, of 300 hr*ng / mL to 8000 hr*ng / mL, of 400 hr*ng / mL to 6000 hr*ng / mL or of 700 hr*ng / mL to 6000 hr*ng / mL. In some aspects, a steady state plasma level of endoxifen in the subject is greater than 30 nM. In some aspects, a steady state plasma level of endoxifen is achieved within 7 to 21 days of a first administration of the composition. In some aspects, time to maximum plasma levels of endoxifen ranges from 2 hours to 10 hours or from 4 hours to 8 hours after administering the composition.

[0015] In some aspects, prior to administering the composition, a biomarker measurement of the subject is at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% higher than a baseline biomarker measurement of a subject without breast cancer. In some aspects, after at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 3 months, at least 4 months, at least 5 months, or at least 6 months of administering the composition, a biomarker measurement of the subject is at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% low er than an initial biomarker measurement of a subject without breast cancer.

[0016] In some aspects, the biomarker is PKCβ1, Ki-67, ER, PgR, cyclin DI, E2F1, pAKT, total AKT, c-PARP, BCL2, or serum TK1. In some aspects, the biomarker is Ki-67. In some aspects, the subject has a Ki-67 level of at most 10% at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks prior to surgery. In some aspects, the method further includes administering the composition at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks prior to surgery. In some aspects, administering the composition continues after surgery.

[0017] In some aspects, the HR+ cancer is estrogen receptor positive (ER+) cancer. In some aspects, the ER+ cancer is breast cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, lung cancer or ovarian cancer. In some aspects, the ER+ cancer is low grade endometrial or low grade serous ovarian carcinoma. In some aspects, the cancer is human epidermal growth factor receptor 2 negative (HER2-) breast cancer. In some aspects, the subject has metastatic breast cancer. In some aspects, the subject has or is at risk for developing a breast cancer-associated co-morbidity.

[0018] In some aspects, the subject is tamoxifen-refractory or tamoxifen-resistant. In some aspects, the subject is contraindicated for aromatase inhibitor therapy. In some aspects, an additional aromatase inhibitor is not administered. In some aspects, the subject is contraindicated for ovarian suppression therapy. In some aspects, ovarian suppression therapy is not administered. In some aspects, the subject is premenopausal. In some aspects, the subject is postmenopausal. In some aspects, administering the composition continues after surgery.

[0019] In some aspects, the techniques described herein relate to a method, resulting in rates of disease-free survival (DFS) at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% higher compared to treatment with letrozole, with (Z)-endoxifen and letrozole, or with (Z)-endoxifen alone. In some aspects, the techniques described herein relate to a method, resulting in rates of partial mastectomy at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% higher compared to treatment with letrozole, with (Z)-endoxifen and letrozole, or with (Z)-endoxifen alone. In some aspects, the techniques described herein relate to a method, resulting in rates of full mastectomy at least 80%, at least 85%, at least 90%, atleast 95%, or at least 98% lower compared to treatment with letrozole, with (Z)-endoxifen and letrozole. or with (Z)-endoxifen alone.

[0020] In some aspects, administration of composition results in increased treatment of the cancer compared to treatment with letrozole, with (Z)-endoxifen and letrozole, or with (Z)-endoxifen alone. In some aspects, the techniques described herein relate to a method, further including administration of a chemotherapy. In some aspects, administration of the composition results in synergistic treatment of the cancer. In some aspects, administration of the composition results in an increase in effectiveness compared to treatment with letrozole, with (Z)-endoxifen and letrozole, or with (Z)-endoxifen alone.

[0021] In some aspects, the techniques described herein relate to a method, wherein the subject is disease-free for 6 months, 7 months. 8 months, 9 months. 10 months. 11 months. 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 36 months, 37 months, 38 months, 39 months, 40 months, 41 months, 42 months, 43 months, 44 months, 45 months, 46 months, 47 months, 48 months, 49 months, 50 months, 51 months, 52 months, 53 months, 54 months, 55 months, 56 months, 57 months, 58 months, 59 months, 60 months, 61 months, 62 months, 63 months, 64 months, 65 months, 66 months, 67 months, 68 months, 69 months, 70 months, 71 months, 72 months, or greater. In some aspects, the subject has an objective response rate of at least 10%.

[0022] In some aspects, the techniques described herein relate to a method of treating a subject having or at risk of having an HR+ HER2- breast cancer, the method including administering an oral composition including a combination of a therapeutically effective amount of (Z)-endoxifen or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of abemaciclib or a pharmaceutically acceptable salt thereof, wherein administration of the composition achieves: a mean half-life of endoxifen in the subject ranging from 30 hours to 60 hours after administration; a time to maximum plasma levels of endoxifen ranging from 4 hours to 8 hours after administration; a steady state plasma level of endoxifen greater than 30 nM; a mean half-life of abemaciclib in the subject ranging from 8 to 65 hours after administration; and a time to maximum plasma levels of abemaciclib ranging from 0-11 hours after administration.

[0023] In some aspects, the techniques described herein relate to a method of treating a subject having or at risk of having an HR+ endometrial or ovarian cancer, the methodincluding administering an oral composition including a combination of a therapeutically effective amount of (Z)-endoxifen or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of abemaciclib or a pharmaceutically acceptable salt thereof.

[0024] In some aspects, the techniques described herein relate to a method of treating a subject having or at risk of having an HR+ cancer, the method including administering an oral composition including a combination of a therapeutically effective amount of (Z)-endoxifen or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of abemaciclib or a pharmaceutically acceptable salt thereof, wherein the cancer is HR+, and has failed previous CDK4 / 6 inhibitor therapy.

[0025] In some aspects, the techniques described herein relate to a method for treating an HR+ cancer in a subject in need thereof, including: determining that a biopsy or tissue sample from the subject has a positive or high score for a biomarker including PKC[ 1, Ki-67, ER, PgR, cyclin DI, E2F1, pAKT, total AKT, c-PARP, BCL2, or serum TK1; administering a therapeutically effective amount of (Z)-endoxifen or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of abemaciclib or a pharmaceutically acceptable salt thereof.

[0026] In some aspects, a Ki-67 score is 20% or higher. In some aspects, the Ki-67 score is a number of Ki-67 staining viable cancer cells in the biopsy or tissue sample divided by a total number of cancer cells in the biopsy or tissue sample, multiplied by 100. In some aspects, the techniques described herein relate to a method, including administering the (Z)-endoxifen or a pharmaceutically acceptable salt thereof concurrently, at separate times, or in sequential times with the abemaciclib or pharmaceutically acceptable salt thereof. In some aspects, the techniques described herein relate to a method, including administering the (Z)-endoxifen or a pharmaceutically acceptable salt thereof sequentially with the abemaciclib or pharmaceutically acceptable salt thereof. In some aspects, the techniques described herein relate to a method, including administering the (Z)-endoxifen or a pharmaceutically acceptable salt thereof and the abemaciclib or pharmaceutically acceptable salt thereof for a length of time, wherein progression-free survival of the subject is improved over a previous treatment.

[0027] In some aspects, the subject has previously undergone treatment with a CDK4 / 6 inhibitor. In some aspects, the cancer increased in size or metastasized upon previous treatment with a CDK4 / 6 inhibitor. In some aspects, the breast cancer includes an ESRImutation. In some aspects, the (Z)-endoxifen inhibits transcriptional activity of the ESRI mutation in the breast cancer.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] The features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0029] FIG. 1 is a schematic diagram of a screening method to determine tumor eligibility and randomization for the clinical trials;

[0030] FIG. 2 is a schematic diagram of the study therapy timeline;

[0031] FIG. 3 is a schematic diagram of the dosing regimen of abemaciclib;

[0032] FIG. 4 is a schematic diagram of the study schema of the clinical trial for treating subjects with endometrial cancer;

[0033] FIG. 5 shows cell viability of Ishikawa cells treated with estradiol;

[0034] FIG. 6 shows cell viability HCL-EC23 cells treated with estradiol;

[0035] FIG. 7 shows cell viability ARK-1 cells treated with estradiol;

[0036] FIG. 8 shows cell viability ARK-2 cells treated with estradiol;

[0037] FIG. 9 shows cell viability Ishikawa cells treated with estradiol and fulvestrant;

[0038] FIG. 10 shows cell viability HCL-EC23 cells treated with estradiol and fulvestrant;

[0039] FIG. 11 shows cell viability ARK-2 cells treated with estradiol and fulvestrant;

[0040] FIG. 12 shows cell viability Ishikawa cells treated with estradiol and either (Z)-endoxifen, abemaciclib, or a combination of (Z)-endoxifen and abemaciclib;

[0041] FIG. 13 shows cell viability HCL-EC23 cells treated with estradiol and either (Z)-endoxifen, abemaciclib, or a combination of (Z)-endoxifen and abemaciclib;

[0042] FIG. 14 shows cell viability ARK-2 cells treated with estradiol and either (Z)-endoxifen, abemaciclib, or a combination of (Z)-endoxifen and abemaciclib;

[0043] FIG. 15 shows immunohistochemistry demonstrating estrogen receptor (ER) and progesterone receptor (PR) [[Atossa: please confirm]] expression on 3D organoid cultures;

[0044] FIG. 16A shows cell viability of 3D organoid cultures treated with either endoxifen, abemaciclib, or a combination of both;

[0045] FIG. 16B shows cell viability of 3D organoid cultures treated with either endoxifen. fulvestrant, or a combination of both; and

[0046] FIG. 17 is a schematic of a phase II study to evaluate efficacy of (Z)-endoxifen and abemaciclib in ER positive Low Grade Endometrial Carcinoma (LGEC).INCORPORATION BY REFERENCE

[0047] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION

[0048] The present disclosure relates to methods of treating gynecologic malignancies using (Z)-endoxifen in combination with a CDK4 / 6 inhibitor, a class of drugs that inhibit the cell cycle and enhance the efficacy of hormone therapy. The present disclosure provides a combination of endoxifen and a CDK4 / 6 inhibitor, such as abemaciclib, and its synergistic effects on reducing tumor growth and proliferation in cancer models. The disclosure also provides fixed dose combinations of endoxifen and a CDK4 / 6 inhibitor, which offers advantages in terms of convenience, compliance, and patent protection.

[0049] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below:

[0050] As used herein and in the appended claims, the singular forms “a", “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality’ of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included.

[0051] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary up to 10% of the stated number or numerical range. For example, anXRPD peak (e.g., about 5.00° 2-Theta, about 10.00° 2-Theta, about 15.00° 2-Theta) can vary within a range of ±0.1 °2-Theta, ±0.2° 2-Theta, ±0.3 °2-Theta, ±0.4° 2-Theta, or ±0.5° 2-Theta. In some embodiments of XRPD peaks, about means ± 0.502-Theta. For example, a temperature (e.g., about 80.0 °C, about 100.0 °C, about 120.0 °C) associated with a feature in a TGA pattern or a DCS thermogram can vary within a range of ±1.0 °C, ±2.0 °C, ±3.0 °C, ±4.0 °C, or ±5.0 °C.

[0052] The term "substantially as shown in” or ‘"substantially the same” when referring, for example, to an XRPD pattern, DSC thermogram, or TGA thermogram, resembles the reference spectrum to a great degree in both the peak locations and peak intensity but is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art. The relative intensities of XRPD peaks can vary, depending upon the particle size, the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-Theta (20) values. Accordingly, when a specified 2-Theta angle is provided, it is to be understood that the specified two theta angle can vary by the specified value ± 0.5° 2-Theta, such as ± 0.4° 2-Theta, ± 0.3° 2-Theta, ± 0.2° 2-Theta, or ± 0.1° 2-Theta. As used herein, “major peak” can refer to an XRPD peak with a relative intensity greater than 30%, such as greater than 35%. Alternatively, or in addition thereto, “major peak” can refer to an XRPD peak which is among the ten most intense XRPD peaks within an XRPD pattern. Relative intensity is calculated as a ratio of the peak intensity of the peak of interest versus the peak intensity of the largest peak in the XRPD pattern.

[0053] It is specifically understood that any numerical value cited herein includes all values from the lower value to the upper value, i.e., all possible combination of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application and the endpoint of all ranges are included within the range and independently combinable. For example, if a concentration range or beneficial range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3% etc., are expressly enumerated in this specification. It is also to be understood that if a concentration or dose is stated as a specific value such as 1 mg or 10 mg, it is intended that it is intended to include 10% variation. As another example, a stated concentration of 20% is intended to include values ± 10%. Y et another example, if a ratio of 1: 10 to 10: 1 is stated, then it is intended that ratios such as 1:9 to 9:1, from 1:8 to 8:1, from 1:7 to 7:1, from 1:6 to 6:1, from 1:5 to 5:1, from 1:4 to 4:1, from 1:3 to 3:1, from 1:2 to 2:1. from 1: 1 to 2:1 orfrom 2:5 to 3:5 etc. are specifically intended. There are only some examples of what is specifically intended. Unless specified otherwise, the values of the constituents or components of the compositions are expressed in weight percent of each ingredient in the component.

[0054] All methods described herein can be performed in a suitable order unless otherwise indicated or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., ‘"such as” and "the like”) is intended merely to illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as any indicating any nonclaimed element as essential to practice of the invention as used herein.

[0055] As used herein and in the claims, the terms "comprising." “containing,” “having”, and “including” are inclusive, open-ended and do not exclude additional unrecited elements, compositional components or method steps. Accordingly, the terms “comprising” and “including” encompass the more restrictive terms “consisting of’ and “consisting essentially of’.

[0056] The term “modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, inverse agonists, antagonists, and allosteric modulators of a G protein-coupled receptor are modulators of the G protein-coupled receptor.

[0057] The term “selective inhibition” or “selectively inhibit” as referred to a biologically active agent refers to the agent’s ability to preferentially reduce the target signaling activity’ as compared to off-target signaling activity, via direct or interact interaction with the target.

[0058] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0059] The phrase “pharmaceutically acceptable” is employ ed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. In some embodiments, the phrase “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relativelynontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0060] The phrase '‘pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0061] In some embodiments, the composition described herein is a “pharmaceutical composition” including a combination of at least one active agent (e.g., at least one active pharmaceutical compound or ingredient, API) with a carrier, inert or active (e.g., a phospholipid), making the compositions suitable for diagnostic or therapeutic uses in vitro, in vivo, or ex vivo.

[0062] The term “salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art, such as organic and inorganic counter ions derived from inorganic or organic acids and bases. The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation that is physiologically tolerated in a subject (e.g., a mammal, and / or in vivo, ex vivo, in vitro cells, tissues, or organs). Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. Typically, pharmaceutical salts are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this cap ability7can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0063] For the purposes of this application, the salts of the compounds of the present disclosure are pharmaceutically acceptable for therapeutic uses. However, salts of acids and bases that are non-pharmaceutically acceptable are also useful; for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0064] Examples of anion salts of endoxifen include arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / di phosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, Teoclate, and triethiodide. Examples of cation salts of (Z)-endoxifen selected from the group consisting of benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium.magnesium, potassium, and zinc, and the like. In some embodiments, the present disclosure provides that embodiments include salts made with acids that are not pharmaceutically acceptable.

[0065] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays theonset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0066] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0067] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary' depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the w eight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by' one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination w ith other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0068] The terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, preventing, abating, or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, preventing the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically. In someembodiments, the terms “treat,” “treating” or “treatment,” may refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may include the eradication, prevention, or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying, preventing, or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment, prevention, or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0069] A “therapeutic effect”, as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic benefit includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0070] The term “co-administered” or “co-administration” refers to concomitant administration of two or more active agents such that one active agent is given in the presence of another active agent. The active agents may be, but need not be, administered in a substantially simultaneous manner (e.g., within about 5 min of each other), in a sequential manner, or both. It is contemplated, for example, that co-administration may include administering one active agent multiple times between the administrations of the other. The time penod between the administration of each agent may range from a few seconds (or less) to several hours or days, and will depend on, for example, the properties of each composition and active ingredient (e.g., potency, solubility, bioavailability, half-life, and kinetic profile), as w ell as the condition of the patient.

[0071] As used herein, the terms “active pharmaceutical ingredient'’ (API), “active ingredient”, “API,” “drug,” “active,” “actives” or “therapeutic agent” are used interchangeably to refer to the pharmaceutically active compound(s) in a pharmaceutical composition. This is in contrast to other ingredients in the compositions, such as excipients, which are substantially or completely pharmaceutically inert. A suitable API in accordance with the present disclosure is one where there are or likely are subject compliance issues for treating a certain disease, condition, or disorder. The therapeutic agent as used herein includes the active compounds and their salts, prodrugs, and metabolites. As used herein the term “drug” means a compound intended for use in diagnosis, cure, mitigation, treatment, and / or prevention of disease in man or other animals.

[0072] As used herein, the terms “unit dose” or “unit dosage” refers to is discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient calculated to produce the desired therapeutic effect. In some embodiments, the unit dose comprises one or more suitable pharmaceutically acceptable excipients. A unit dose a single dose that is capable of being administered to a subject and which can be readily handled and packaged.

[0073] As used herein, the terms “dose form” or “dosage form” refers to physically discrete unit suitable for unitary' dosages for a subject, each unit containing a predetermined quantity' of active material calculated to produce the desired therapeutic effect. In some embodiments, the dosage form comprises one or more suitable pharmaceutical excipients. Pharmaceutical compositions may be prepared in a variety of dosage forms suitable for a variety of routes and methods of administration. By way of example only, a pharmaceutical composition may be prepared in a liquid dosage form selected from emulsions, microemulsions, nanoemulsions, solutions, suspensions, syrups, and elixirs; an injectable dosage form; a solid dosage form selected from capsules, tablets, pills, powders, and granules; and a dosage form for topical and / or transdermal administration selected from ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and patches.

[0074] As used herein, the phrase "a subject in need thereof' refers to a subject that suffers from a disease or disorder, has previously suffered from a disease or disorder, experiences a disease or disorder, has previously experienced a disease or disorder, or is at risk of developing a disease or disorder.

[0075] As used herein, the term “abemaciclib” refers to [5-(4-Ethyl-piperazin-l-ylmethyl)-pyri din-2 -yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyri midin-2-yl]-amine. [5-(4-Ethyl-piperazin-l-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl] -amine or a pharmaceutically acceptable salt thereof, may be prepared by a variety of procedures known in the art.

[0076] As used herein, the term “tamoxifen” refers to 2-[4-(l,2-diphenyl-l-butenyl)phenoxy]-N, N-dimethylethanamine, which has two isomeric forms: (Z)-tamoxifen ((Z)-2- [4-( 1,2-dipheny 1- 1 -butenyl)phenoxy ] -N, N-dimethy lethanamine) and (E)-tamoxifen ((E)-2-[4-(l,2-diphenyl-l -butenyl)phenoxy]-N, N-dimethylethanamine). Unless otherwise specified, “tamoxifen” refers to a mixture of (E)-tamoxifen and (Z)-tamoxifen. Furthermore, unless otherwise specified, “tamoxifen” refers to the free base (i.e., not a salt) of tamoxifen. Therefore, “tamoxifen” and “tamoxifen free base” are equivalent terms.

[0077] As used herein, the terms “4-hydroxy tamoxifen”, “afimoxifene”, and “4-OHT” used interchangeably refer to 4-l-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-l-enyl]phenol, and constitutes an active metabolite of tamoxifen. 4-OHT has two isomeric forms: (Z)-4-OHT and (E)-4-OHT. Unless specified, “4-OHT” refers to a mixture of (E)-4-OHT and (Z)-4-OHT. Furthermore, unless otherwise specified, “4-OHT” refers to the free base (i.e., not a salt) of tamoxifen. Therefore, “4-OHT” and “4-OHT free base” are equivalent terms.

[0078] As used herein, the term “endoxifen” refers to 4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol) (also known as 4-hydroxy-N-desmethyl-tamoxifen or desmethylhydroxytamoxifen). Endoxifen has two isomeric forms: (E)-endoxifen ( (E)-4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol ) and (Z)-endoxifen ( (Z)-4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol). Unless otherwise specified, “endoxifen”, also referred to as “(Z / E)-endoxifen”, is a mixture of (Z)-endoxifen and (E)-endoxifen with a Z: E ratio of 1: 1. By way of example only:“(95:5) endoxifen”, “endoxifen (95:5)”, “endoxifen (Z: E = 95:5)”, “(Z: E = 95:5)”, “endoxifen (Z / E = 95:5)”, and “(Z / E = 95:5)”, are all equivalent terms to denote the endoxifen mixture has a Z: E ratio of 95:5;“(95>5) endoxifen”, “endoxifen (95>5)”, “endoxifen (Z: E = 95>5)”, “(Z: E = 95>5)”, “endoxifen (Z / E = 95>5)”, and “(Z / E = 95>5)”, are all equivalent terms to denote the endoxifen mixture has a Z: E ratio greater than 95:5;“(95>5) endoxifen'’, ‘‘endoxifen (95>5)”, “endoxifen (Z: E = 95>5)”, “(Z: E = 95>5)”, “endoxifen (Z / E = 95>5)”, and “(Z / E = 95>5)”, are all equivalent terms to denote the endoxifen mixture has a Z: E ratio greater than or equal to 95:5;“(95<5) endoxifen”, “endoxifen (95<5)”, “endoxifen (Z: E = 95<5)”, “(Z: E = 95<5)”, “endoxifen (Z< E = 95:5)”, and “(Z / E = 95<5)”, are all equivalent terms to denote the endoxifen mixture has aZ: E ratio less than 95:5; and“(95<5) endoxifen”, “endoxifen (95<5)”, “endoxifen (Z: E = 95<5)”, “(Z: E = 95<5)”, “endoxifen (Z< E = 95:5)”, and “(Z / E = 95<5)”, are all equivalent terms to denote the endoxifen mixture has a Z: E ratio less than or equal to 95:5.

[0079] As used herein, unless otherwise specified, “endoxifen” refers to the free base (i.e., not a salt) of endoxifen. Therefore, “endoxifen”. “endoxifen free base”. “(Z / E)-endoxifen”, and “(ZZE)-endoxifen free base” are all equivalent terms. By way of example only:p andrepresent endoxifen ((Z / E)-endoxifen).

[0080] As used herein, the term “(Z)-endoxifen” is isomeric pure (100% of one alkene isomer) (Z)-endoxifen. (Z)-endoxifen is represented by the structure

[0081] As used herein, the term "(E)-endo.xifen" is isomeric pure (100% of one alkene isomer) (E)-endoxifen. (E)-endoxifen is represented by the structure

[0082] As used throughout the present disclosure, the wiggly line (^j attached to the tetrasubstituted alkene bond of endoxifen or thewritten adjacent to the tetrasubstituted alkene bond of endoxifen denotes a mixture of (E)-endoxifen and (Z)-endoxifen:

[0083] Furthermore, salts of endoxifen, (Z)-endoxifen, and / or (E)-endoxifen are disclosed herein. By way of example only, below are representations of salts of (Z)-endoxifen:the following structures are equivalent representations of (Z)-endoxifen citrate (as referred tothe following structures are equivalent representations of (Z)-endoxifen hydrochloride (also referred to as (Z)-endoxifen hydrochloride):embodiments, the salt is a pharmaceutically acceptable salt.

[0084] The term ”Cx-y" orwhen used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbon atoms in the moiety. For example, the term “Ci-6 alkyl” or “Ci-Ce alky l” refers to saturated hydrocarbon groups, including straight-chain alky l and branched-chain alkyl groups, that contain from 1 to 6 carbon atoms. The termL‘Cx-yalkylene” or "Cx-C alkylene” refers to an alkyd ene chain with from x to y carbon atoms in the alkylene chain. For example, Ci-6 alkydene may7be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which may be optionally substituted. Thus, by way of example only, “Ci-4 alkyd” or “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, zso-propyl, n-butyd. zso-butyl, sec-butyl, and / -butyl. any one of which is optionally substituted. The terms ‘ Cx-y alkenyl” (or “Cx-Cyalkenyl”) and “Cx-y alkynyl” (or “Cx-Cyalkynyl”) refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0085] "Alkyl” refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond. An alkyl chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-12 alkyl). Tn certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-8 alky 1). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., Ci-4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-8 alkyl). In other embodiments, an alkylcomprises two to five carbon atoms (i.e., C2-5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-5 alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bond, such as, methyl, ethyl, 1 -propyl (n-propyl), 1 -methylethyl (iso-propyl), I-butyl (n-butyl), 1 -methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1, 1 -dimethylethyl (tert-butyl), 1 -penty l (n-pentyl), and the like.

[0086] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3- to 10-membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings.Polycyclic carbocycles may be fused, bridged or spiro-ring systems. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkeny l. In an exemplary embodiment, an aromatic ring, e.g.. phenyl, may be fused to a saturated or unsaturated ring, e g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyd, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein. By way of example only, C6-12 carbocycle includes 3- to 12-membered monocyclic rings and polycyclic rings.

[0087] ;‘Cycloalkyl” refers to a stable, fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, bridged, or spiro-ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkyl). The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2. l]heptanyl), norbomenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.

[0088] A “Cx-y carbocycle'’ is meant to include groups that contain from x to y carbons in a ring. For example, the term “C3-6 carbocycle” can be a saturated, unsaturated, or aromatic ring system that contains from 3 to 6 carbon atom, any one of which may be optionally substituted one or more substituents such as provided herein.

[0089] “Halo” or “halogen” refers to halogen substituents such as fluoro (F), chloro (Cl), bromo (Br), and iodo (I) substituents.

[0090] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0091] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0092] The term “substituted” or “optionally substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or a hydrogen on one or more substitutable heteroatoms, e.g., an NH or NH2 of a compound. Unless specified otherwise (e.g., by using the terms “substituted” or “optionally substituted,” or by the inclusion of an “-R” group), chemical groups described herein are unsubstituted. It will be understood that “substitution”, “substituted with”, and “optional substitution” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, “substituted” or “optionally substituted” refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. The permissible substituent can be one or more and the same or different for appropriate organic compounds.

[0093] In some embodiments, substituents may include any substituents described herein. In some embodiments, the referenced moiety is optionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H. -CO2(CI-4 alkyl). -C(=O)NH2, -C(=0)NH(CI-4 alkyl), -C(=O)N(CI-4alkyl)2, -S(=O)2NH2. -S(=O)2NH(CI-4alkyl), -S(=O)2N(CI-4 alkyl)2. Ci-4 alkyl, C3-6 cycloalkyl, Ci-4fluoroalkyl, C1-4 heteroalkyl, C1-4 alkoxy, C1-4 fluoroalkoxy, -S-C1-4 alkyl, -S(=O)Ci-4 alkyl, and -S(=O)2Ci-4 alky l. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3. -OCH3, -OCHF2, and -OCF3. In some embodiments, optional substituents are independently selected from -F, -Cl, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CFS, -OCHS, -OCHF2, and -OCF3. In some embodiments, optional substituents are independently selected from F, Cl, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, and -OCH3. In some embodiments, optional substituents are independently selected from -F, -CL -CN, -OH, -CH3, -CH2CH3, -CHF2, -CF3, and -OCH3. In some embodiments, optional substituents are independently selected from F, Cl, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, and -OCH3. In some embodiments, substituted moieties / groups are substituted with one or two of the preceding moieties / groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).

[0094] The term “optional1’ or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted C1-6 alkyl” means either “C1-6 alkyl” or “substituted C1-6 alkyl” as defined above. Further, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyd includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alky l groups, potentially ad infinitum) that are sterically impractical and / or synthetically non-feasible.Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1.000 daltons, and more typically, up to about 500 daltons.

[0095] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0096] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.Breast Cancer

[0097] Subjects with estrogen receptor-positive (ER+) invasive breast cancer whose tumors are predicted to be sensitive to endocrine therapy but for whom chemotherapy is expected to provide little or no benefit have substantial risk for recurrence, often after five years.Treatment of such breast cancer benefits from novel agents that are more tolerable to the subject, and more effective than the current standard of care. Desirable treatments also address the risk of recurrence.

[0098] Hormone positive breast cancers that are slow growing have increased risk of recurring for up to 15 years or more, and predictors of response are needed to prevent late recurrence. Also, many breast cancer subjects suffer from the side effects of years of extended endocrine therapy, especially when they have larger tumors. More effective and tolerable treatments are needed so that people at risk of breast cancer, or diagnosed with breast cancer, will live longer with better quality of life.

[0099] There remains a need for improvement in the endocrine treatment of breast cancer subjects who are premenopausal with estrogen receptor positive / human epidermal grow th factor receptor 2 negative (ER+ / HER2-) breast cancer. In some aspects, the present disclosure describes co-administration of an ovarian suppression agent with an additional therapeutic agent. In other aspects, the present disclosure provides for treatment of a subject in the absence of ovarian suppression. Ovarian suppression is a treatment that stops or lowers the amount of estrogen produced by the ovaries and is used in premenopausal subjects with ER+ breast cancer. In some cases, reduction of the amount of estrogen available decreases or stops the rate of growth of an ER+ tumor and also preserves ovarian function during chemotherapy; ovarian suppression includes use of a gonadotropin-releasing hormone agonist (GnRHa) or a bilateral oophorectomy. In certain instances, ovarian suppression therapy leads to unwanted effects, such as decreased bone density, fluctuations in mood, diminished sexual desire, cognitive decline, and increased body weight. Patients who are unable or unwilling to undergo suppression of ovarian function have limited treatment alternatives, as tamoxifenmonotherapy is the only present FDA approved alternative. This approach is considered less effective compared to two other strategies: combining tamoxifen with ovarian function suppression or using an aromatase inhibitor with ovarian function suppression. Both of these strategies aim to lower estrogen levels in the body, though they do so through different biological pathways. For instance, one study revealed that only 41% of premenopausal patients receiving only tamoxifen showed a positive response to endocrine therapy (defined as a Ki-67 level of 10% or lower) after a period of 4 weeks.

[0100] Tamoxifen, a selective estrogen receptor modulator (SERM), is commonly prescribed for treating hormone-responsive breast cancer. While tamoxifen is a cornerstone of endocrine therapy, its administration, typically oral, is associated with significant adverse effects such as vasomotor symptoms and an increased risk of gynecologic cancers. These side effects contribute to issues with subject adherence to tamoxifen therapy. Moreover, a substantial proportion of subjects do not benefit from tamoxifen, with 30-50% eventually succumbing to their disease despite treatment.

[0101] Variations in the cytochrome P450 (CYP) enzyme, such as CYP2D6, have been implicated in the reduced efficacy of tamoxifen due to poor conversion to its active form, endoxifen, leading to drug resistance. Over 140 allelic variants of CYP2D6 have been identified, many of which result in diminished or absent enzy me activity7. Individuals are categorized into one of four phenotypic groups based on their specific allele combinations, ranging from poor metabolizers with low endoxifen levels to ultra-rapid metabolizers with high levels. However, these genetic variations alone do not fully account for the observed resistance to tamoxifen and the decreased levels of endoxifen in certain subjects.

[0102] Endoxifen is one of the metabolites of tamoxifen and can exist as the (E)- or (Z)-isomer, or mixtures thereof, with (Z)-endoxifen being the active isomer. (Z)-endoxifen is a more potent ER-a-targeting drug than tamoxifen and has greater in vivo activity versus letrozole in an aromatase expression model. Notably, and by contrast to tamoxifen, the greater potency of (Z)-endoxifen renders it suitable for treating premenopausal subjects without the need for ovarian function suppression. (Z)-endoxifen's potent and selective targeting of ERa, without systemic estrogen deprivation, presents a major advance for premenopausal subjects with ER+ / HER2- breast cancers. Advantageously, the present disclosure provides compositions and methods suitable for treating subjects with endocrine sensitive breast cancer, which avoid the short- and long-term side effects of both ovarian function suppression and chemotherapy.

[0103] Given that many tamoxifen-treated premenopausal subjects do not obtain sufficient blockade of the estrogen receptor to achieve endocrine therapy response, there is a need to develop a more potent ER inhibitor that does not require ovarian function suppression. This allows treatment for those premenopausal subjects who do not tolerate ovarian function suppression and for whom tamoxifen is the treatment used. As set forth in the present disclosure, (Z)-endoxifen is advantageously used for subjects who are unable to tolerate ovarian function suppression and as an alternative to tamoxifen monotherapy.

[0104] In ER+ / HER2- breast cancer current endocrine therapy combinations include tamoxifen, aromatase inhibitors, and fulvestrant, as well as several oral selective estrogen receptor degraders (SERDS), in combination with CDK4 / 6 inhibitors such as abemaciclib. Endocrine therapy as administered using (Z)-endoxifen targets protein kinase C beta 1 (PKCβ1), resulting in suppression of the protein kinase B alpha (AKT) signaling pathway, which is instrumental in cell survival and growth. The suppression of the AKT pathway induces apoptosis in breast cancer. Additionally, in estrogen ER+ breast cancer cell lines, the combination of abemaciclib and (Z)-endoxifen compared to other estrogen therapies (e.g. tamoxifen, Al, fulvestrant) induced an increased immune mediate response with increased tumor-related apoptosis.Endometrial Cancer and Ovarian Cancer

[0105] Endometrial cancer and ovarian cancer are the most common gynecologic malignancies, with high mortality rates for those with platinum resistant or advanced cancers. As a result, there is an urgent need to develop novel therapeutic strategies.

[0106] Estrogen receptor alpha (ERa) is an established oncogenic driver for ER+ endometrial cancer and low-grade serous ovarian carcinoma. Endocrine therapy, including tamoxifen alternating with progesterone, aromatase inhibitors and selective estrogen degraders (fulvestrant) are all recommended by the National Comprehensive Cancer Network® for low-grade endometrial cancer and low-grade serous ovarian carcinoma, but objective response rates are low. ranging from 10-30% in low-grade endometrial cancer and 9-10% in low-grade serous ovarian carcinoma. Development of better endocnne-targeting strategies as well as identification of biomarkers of response is warranted due to the favorable toxicity profile of these treatments and potential for greater efficacy compared to single-agent chemotherapy.

[0107] Combination strategies with endocrine therapy have been developed and demonstrated to be efficacious in multiple clinical trials. In particular, there is great interest in the combination of CDK 4 / 6 inhibitors in endometrial cancer and ovarian cancer patients, severalPhase II clinical trials have been reported with ORR ranging from 20-30% in low-grade serous ovarian carcinoma and endometrial cancer. Abemaciclib has demonstrated antitumor activity when combined with letrozole in recurrent ER+ endometrial cancer and as neoadjuvant therapy for low-grade endometrial cancer when combined with fulvestrant.

[0108] (Z)-endoxifen has efficacy in patients with ER-resistant breast cancer. (Z)-endoxifen exhibits a 100-fold greater affinity for the ER in comparison to its parent compound, tamoxifen and in vivo studies demonstrated that (Z)-endoxifen was superior not only to tamoxifen but additionally to the aromatase inhibitor, letrozole. In the NCI phase I study evaluating (Z)-endoxifen in multiple tumors, including ovarian cancer and endometrial cancer, (Z)-endoxifen demonstrated stable disease as best response, though confirmation for ER-positivity was not required for enrollment.

[0109] First-in-human studies of (Z)-endoxifen in postmenopausal women (at doses of 20 to 360 mg) were conducted, and (Z)-endoxifen was tolerable with anti-tumor efficacy in endocrine-resistant ER+ breast cancer. Further, in a randomized phase II trial comparing (Z)-endoxifen with tamoxifen in subjects with endocrine resistant ER+ / HER2- breast cancer (A011203), (Z)-endoxifen improved progression free survival compared to tamoxifen (4.1 vs 1.8 months), most notably in patients without prior exposure to CDK 4 / 6 inhibitors (2.2 vs 7.7 months).

[0110] There is controversy regarding the optimal endocrine therapy backbone in combination with CDK4 / 6 inhibitors. In ER+ / HER2- breast cancer treated with abemaciclib. current endocrine therapy combinations include tamoxifen, aromatase inhibitors, fulvestrant as well as several SERDS. Recently, PKC0I is a target of (Z)-endoxifen, resulting in suppression of AKT signaling and inducing apoptosis in breast cancer. Additionally, data has demonstrated that in ER+ breast cancer cell lines, the combination of abemaciclib and (Z)-endoxifen compared to other endocrine therapy partners (e.g. tamoxifen, aromatase inhibitors, fulvestrant) induces an increased immune mediate response with increased tumor-related apoptosis.[OHl] The present disclosure provides methods and compositions for treatment of subjects with ER+ endometrial cancer and low-grade serous ovarian carcinoma. Treatment results in superior response rates to (Z)-endoxifen compared to historical controls (ORR>10%) and the combination of (Z)-endoxifen and abemaciclib results in synergistic anti-tumor effects, which result in significantly improved response rates compared to treatment with single agent (Z)-endoxifen. Compounds are described using standard nomenclature. Unless otherwise defined,all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.Biomarkers for Determining Treatment Methods and Compositions

[0112] Tumor ER and progesterone receptor (PgR) status and HER2 status is determined by immunohistochemistry and / or fluorescence in situ hybridization. A tumor is considered HER2+ if any one of the assays (immunohistochemistry, fluorescence in situ hybridization, or alternative probe fluorescence in situ hybridization) is positive. In some embodiments, a core biopsy of a tumor is performed, and sections are sent for MammaPrint® score gene expression assays using the Agendia 44K full genome microarray (MammaPrint 44K Array Low and High scores). In some embodiments, a pretreatment MRI is taken for determination of maximum tumor dimension. In some embodiments, a MammaPrint 44K Array score is determined through MammaPrint® analysis, which generates a gene expression profile of a tumor sample, which is compared to the mean expression profile of 44 tumors with a known good clinical outcome, available from the manufacturer. A Low / High score is adjusted to either the MammaPrint Low, MammaPrint Highl (MP1) or MammaPrint High2 (MP2) class. In some embodiments, subjects with a MPlow or MPhigh score are treated with the methods and compositions described herein. In other aspects, the ER and PgR status of a subject’s tumor are used to determine their HR status. A subject whose tumor scores ER+ and / or PgR+ is defined as HR+. HR- is defined as ER- and PgR-. In some embodiments, the subject having breast cancer has a tumor that is HR+ and HER2-.

[0113] In some embodiments, the term “biomarker’' refers to a molecule that indicates the disease status or potential appropriate treatment methods for a subject. In some aspects, a biopsy or other tissue sample of a subject is tested and has a biomarker profile that is indicative of HR+ breast cancer. Such biomarkers are known in the art and include, by way of non-limiting examples, CYP2D6, Ki-67, BRCA-1, BRCA-2, PKCpi, PgR, cyclin DI, E2F1, pAKT, total AKT, PARP, ER, PR. HER2, uPA, PAI, Tf, p53. MRI, cytokeratins, cancer tumor antigens, and other biomarkers measured by Mammaprint, OncotypeDx, PAM50, EndoxPredict, MammoStrat, or other diagnostic or predictive tests. In some aspects, a subject with a biomarker profile indicating that the subject has or is at risk of having HR+ breast cancer is administered a composition as disclosed herein.

[0114] In some embodiments, the biomarkers measured by Mammaprint. OncotypeDx, PAM50, EndoxPredict, MammoStrat, and other diagnostic or predictive tests indicate that thecancer is a less proliferative tumor, or molecularly of low risk, or indicates that the cancer has a high risk of recurrence compared to a cancer with biomarkers that do not indicate that the cancer is a less proliferative tumor, or if the biomarkers indicate that the cancer is molecularly high risk.

[0115] Several cytochrome P450 (CYP) mutations have been proposed to cause reduced conversion of tamoxifen to its active metabolite, endoxifen, and to reduce tamoxifen efficacy and to increase resistance to the drug. So far, over 140 allelic variants of CYP2D6 have been described, and a substantial part of these are associated with reduced or absent activity of the encoded enzy me. Based on the combination of the detected genetic alleles, each individual subject is classified into one of four phenotypic groups: (a) poor metabolizer (PM) with plasma endoxifen levels less than 30 nM, (b) intermediate metabolizer (IM), (c) extensive metabolizer (EM), and (d) ultra-rapid metabolizer (UM), reflecting variations in levels of serum endoxifen. However, variations in CYP genotypes do not fully explain the tamoxifen resistance and reduced endoxifen levels observed in some subjects. In some aspects, tamoxifen resistance is determined experimentally as described herein.

[0116] In some aspects, subjects are dosed daily with tamoxifen for at least 2 days and have a level of plasma endoxifen of less than 30 nM (e.g., less than 20 nM, less than 25 nM, or less than 30 nM), and these subjects are identified as “tamoxifen refractory". As used herein, the term “tamoxifen resistance” refers to two classes of resistance: (a) de novo resistance, i.e., non-responsiveness to tamoxifen therapy from the beginning of the treatment, and (b) acquired resistance, i.e., non-responsiveness to tamoxifen therapy after initial responsiveness or tamoxifen-dependent grow th / stimulated grow th while continuing to express estrogen receptors. In various aspects, the acquired resistance to tamoxifen develops as early as 3 m to 1 year, to as late as 5 to 10 years. As used herein, the term “reference plasma endoxifen level” refers to a value of 30 nM.

[0117] In some aspects, the present disclosure provides a method of treating a subject having or at risk of having HR+ breast cancer including determining a subject’s tamoxifen-refractory or tamoxifen-resistant status and administering to the subject a composition described herein. In some aspects, the biomarkers are assessed through genetic testing such as single-strand conformation polymorphism, restriction endonuclease fingerprinting, conformation-sensitive gene electrophoresis, fluorescence-based conformation sensitive gel electrophoresis (CSGE), tw o-dimensional gene scanning, protein truncation tests, next-generation sequencing, denaturing high-performance liquid chromatography, or combinations thereof.

[0118] The Ki-67 protein, or marker of proliferation Kiel 67 (MKI67), is associated with ribosomal RNA transcription and is found in the nucleus of actively growing cancer cells. Ki-67 is not found in non-dividing cells. In some aspects, Ki-67 levels > 10% are indicative of a more actively growing cancer, while Ki-67 levels < 10% are used to determine an endocrine sensitive disease (ESD) rate. Subjects with levels of Ki-67 index at most 10% after 4 weeks of neoadjuvant therapy have improved outcomes such as disease-free survival (DFS), objective response rate (ORR), progression-free survival (PFS), or overall survival (OS).

[0119] In some embodiments presented herein, the breast cancer is endocrine sensitive (ESD), which responds well to hormonal therapies such as tamoxifen, endoxifen, or aromatase inhibitors. In several aspects, subjects with a low Ki-67 have better endocrine-sensitive disease rates (ESDR), though Ki-67 values vary in prediction of ESD. After neoadjuvant endocrine therapy, subjects with a low Ki-67 have higher rates of ESD and a higher chance of breast-conserving surgery. In some aspects, treatment with the described methods and compositions results in a biopsy of a tumor of a subject with a Ki-67 index of no more than 10%. In some aspects, the methods and compositions described herein result in a subject having a Ki-67 index of no more than 10%, no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, or any value contained within a range formed by any two of the preceding values. In some aspects, a subject with a Ki-67 index of no more than 10% has improved outcomes, as described further below.

[0120] Serum thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression during the S phase of DNA synthesis. It serves as a useful biomarker of cell proliferation, as elevated levels indicate the presence of rapidly dividing cells. In subjects with early-stage breast cancer, serum TK1 activity is often elevated. In some embodiments, TK1 is assayed through measurement of [3H] deoxythymidine phosphorylation levels. In some aspects, when [3H] deoxythymidine phosphorylation levels are 0.9-48 pmol / min / mL, a subject is administered the claimed compositions. In some embodiments, TK1 levels are assayed through measurement of TK-radio enzymatic assay (TKREA). In some aspects, when the TKREA levels are low-grade, or 4.6 U / L, a subject is administered the claimed compositions. In some aspects, when the TKREA levels are intermediate grade (28.8 U / L), a subject is administered the claimed compositions. In some aspects, when the TKREA levels are high grade (45 U / L), a subject is administered the claimed compositions.

[0121] In some aspects, subjects testing positive for serum thymidine kinase 1 are administered the compositions described herein. In some embodiments. TK1 levels are assayed using TK1 -Liaison values. In some aspects, when the TKl-Liaison levels are 4.0-8.2 U / L, a subject is administered the claimed compositions. In some embodiments, TK1 levels are assayed using DiviTum™, and when the values are 20-92 Du / L, the subject is administered the claimed compositions. In some aspects, TK1 levels are assayed using a chemiluminescent dot blot (IgY), and when levels are > 2.0 pM, the subject is treated. In some embodiments, TK1 levels are assayed using TK1-210 values, and when TK1-210 values are between about 0.17-9.9 ng / mL, the subject is administered the claimed compositions.

[0122] In some embodiments, the methods described herein include detection of tumor suppressor gene varieties, and appropriate treatments for a breast cancer subject are administered. BRCA-1 and BRCA-2 are genes that produce tumor suppressor proteins, which help repair damaged DNA, ensuring the stability of the cell’s genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, many times the DNA damage is not repaired properly. As a result, cells more often develop additional genetic alterations that lead to cancer. In some embodiments, a biopsy of a tumor indicates mutations in BRCA1 and BRCA2 that are associated with an increased risk of female breast and ovarian cancers. In some aspects, the breast cancer is also HR+, and the subject is treated according to methods and compositions disclosed herein.

[0123] Protein kinase C beta 1 (PKCβ1) is an isoform of protein kinase C, which is a family of protein kinases involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKCpi has been implicated in various cellular processes, including roles in growth, differentiation, and apoptosis. In some aspects, a biopsy of a tumor of a subject tests positive for protein kinase C beta 1, and the subject is treated according to the claimed methods and compositions.

[0124] The progesterone receptor (PgR) is a protein found inside cells that binds to the hormone progesterone. When bound to progesterone, the receptor stimulates or inhibits the transcription of genes that regulate cell growth. In some aspects, the methods described herein include detecting a positive level of PgR, determining that the cancer is HR+ and treating the subject with the methods and compounds described herein.

[0125] Cyclin DI is a protein that is involved in cell cycle regulation. It helps control the transition from the G1 phase to the S phase of the cell cycle. In some aspects, overexpressionof cyclin DI leads to uncontrolled cell proliferation and is observed in various types of cancer. It is often considered an oncogene. When overexpression of cyclin DI is detected in a cancer, the subject is treated with the methods and compounds described herein.

[0126] E2 promoter binding factor 1 (E2F 1) is a transcription factor that plays a role in the control of the cell cycle and action of tumor suppressor proteins. It is also involved in the process of DNA repair and apoptosis. Dysregulation of E2F1 has been implicated in the development of cancer. In some aspects, when E2F1 levels are high, the cancer is treated with the methods and compounds herein.

[0127] Phosphorylated AKT (pAKT) is a serine / threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. The phosphorylated form of AKT (pAKT) is the active form that promotes cell survival and growth. Abnormal activation of AKT signaling is a common feature in many cancers. In some aspects, when pAKT levels are high, the cancer is treated with the methods and compounds herein.

[0128] Total AKT refers to the total amount of AKT protein in a cell, regardless of its phosphorylation status. Measuring both total AKT and pAKT provides insights into the activation state of the AKT pathway. In some aspects, when pAKT levels, total AKT levels, or both are high, the cancer is treated with the methods and compounds herein.

[0129] Poly ADP-ribose polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death. PARP inhibitors are a class of drugs that are used in cancer treatment, particularly in cancers with BRCA mutations, as they exploit the defective DNA repair mechanism in these cells. In some aspects, when PARP levels are high, the cancer is treated with the methods and compounds herein.

[0130] Estrogen receptor (ER) is a protein that is activated by the hormone estrogen. Similar to the progesterone receptor, it is involved in the transcription of genes that regulate cell growth and differentiation. In breast cancer, the presence of ER is an important biomarker for prognosis and treatment, as estrogen receptor positive (ER+) cancers are often treated with hormone therapy. In some aspects, ER degradation is measured. In additional aspects, ER signaling activity is measured through genetic profiling. In some aspects of the present disclosure, the cancer is an ER+ breast cancer.

[0131] Human epidermal growth factor receptor 2 (HER2) is a protein that helps control cell growth, division, and repair. When the HER2 gene is amplified or overexpressed, it leads tothe overproduction of the receptor protein, which causes cells to divide and grow more rapidly. HER2 overexpression is found in some types of breast cancer and is an important factor in treatment decisions. In some aspects of the present disclosure, the cancer is a HER2-breast cancer. In some aspects, the cancer is a node-positive cancer. The cancer can also be an HR+ HER2- node-positive, early breast cancer at high risk of recurrence. In some aspects, the cancer is an HR+ HER2- advanced or metastatic breast cancer. In some aspects, the cancer is an HR+ HER2- advanced or metastatic breast cancer with disease progression following prior endocrine therapy and / or prior chemotherapy. In additional aspects, the cancer is an HR+ HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

[0132] Urokinase plasminogen activator (uPA) is a serine protease involved in the degradation of the extracellular matrix and is important for cell migration and tissue remodeling. High levels of uPA have been associated with increased tumor aggressiveness and metastasis in various cancers. In some aspects, when uPA levels are high, the cancer is treated with the methods and compounds herein.

[0133] Plasminogen activator inhibitor (PAI) is a protein that inhibits uPA and thus regulates the balance of tissue breakdown and remodeling. It is involved in various physiological processes, including fibrinolysis and tissue repair. In cancer, PAI-1 has been studied for its role in tumor progression and as a potential prognostic marker. In some aspects, when PAI-1 levels are high, the cancer is treated with the methods and compounds herein.

[0134] Transferrin (Tf) is a blood plasma protein that transports iron throughout the body. Iron is essential for cell proliferation, and transferrin levels are altered in various diseases, including cancer. Transferrin receptors are often overexpressed in malignant cells due to their increased iron requirements. In some aspects, when Tf levels are high, the cancer is treated with the methods and compounds herein.

[0135] The protein that is detected as the biomarker called p53 is a tumor suppressor protein that plays a role in preventing cancer formation. It does this by inducing cell cycle arrest, apoptosis, or senescence in response to genomic damage or stress. Mutations in the p53 gene are often seen in human cancers. In some aspects, a p53 mutant is detected, and the cancer is treated with the methods and compounds herein.

[0136] Major histocompatibility complex, class I-related (MR1) is a protein that presents metabolite antigens to mucosal-associated invariant T cells. The role of MR1 in the immuneresponse to cancer is an area of ongoing research. In some aspects, when MR1 levels are high, the cancer is treated with the methods and compounds herein.

[0137] Cytokeratins are a family of intermediate filament proteins found in the cytoskeleton of epithelial cells. Cytokeratins are used as biomarkers to help in the diagnosis and classification of breast cancer. In breast cancer, certain cytokeratins such as CK7 and CK20 are informative. In some embodiments, the breast cancer described herein is CK7 positive and CK20 negative. Among other tests, this pattern confirms a diagnosis of primary breast cancer rather than a breast cancer that originated in another tissue. Additionally, other cytokeratins, like CK5 / 6 and CK17, are often used to identify specific subtypes of breast cancer, such as basal -like breast cancers. In some embodiments, expression of CK8 / 18 in the tumor leads to identification of luminal -type breast cancers, which generally have a better prognosis and respond well to hormonal therapies. In further embodiments, the presence of CK5 / 6 along with epidermal growth factor receptor (EGFR) indicates a basal-like phenotype, which in some aspects has a poorer prognosis and does not respond to hormonal therapies but is more responsive to chemotherapy. In some embodiments, a tumor lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), and cytokeratins such as CK5 / 6 and EGFR are used to identify’ the basal-like subfype that is referred to as tumor triple-negative breast cancer (TNBC). In some embodiments, the methods and treatments herein refer to treatment of a subject with a tumor that is tumor triple negative.

[0138] In some embodiments, the biomarkers indicate that the cancer is ER+ and HER2-, is MPIow or MPhigh. In some aspects, a sensitive to endocrine therapy index (SET2,3) is measured. SET2,3 is an RNA-based measure of sensitivity' to endocrine therapy, and measures gene expression related to nonproliferation related to estrogen and progesterone receptors. In some aspects, a cancer biopsy has a high SET2,3 value, and the cancer is treated with the methods described herein.Compounds for Treating Breast Cancer(Z)-Endoxifen, a Potent Selective Estrogen Receptor Modulator

[0139] Endoxifen is an active metabolite of tamoxifen that is broken down in the liver into active compounds, or metabolites. One of the active tamoxifen metabolites is endoxifen, also referred to as 4-hydroxy-N-desmethyltamoxifen. Endoxifen, particularly the active isomer (Z)-endoxifen, is a selective estrogen receptor modulator (SERM) that functions as acompetitive partial agonist of estrogen receptor in a tissue-specific manner. (Z)-endoxifen has robust antitumor and anti-estrogenic activity compared to tamoxifen therapy and aromatase inhibitor therapy. (Z)-endoxifen is beneficial in treating cancers in patients that are resistant to other hormone therapies, such as tamoxifen, aromatase inhibitors, or fulvestrant, in part because endoxifen functions independently of metabolic enzy mes such as CYP2D6.

[0140] In some embodiments, the compositions described herein include endoxifen, which may comprise (Z)-endoxifen, (E)-endoxifen, or a combination thereof. In some embodiments, the composition includes endoxifen which is represented by the compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof.

[0141] In another aspect, the present disclosure provides a compound of Formula (I-Z):or a pharmaceutically acceptable salt thereof.

[0142] In another aspect, the present disclosure provides a compound of Formula (I-E):or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, for a compound of Formula (I), Formula (I) is represented by Formula (I-Z). In some embodiments, Formula (I) is represented by Formula (I-E).

[0144] In some embodiments, at least 90% by weight of the compound of Formula (I) in the composition is (Z)-endoxifen. In some embodiments, the endoxifen is in a crystalline form which is Form I. In some aspects, Form I is characterized by an x-ray powder diffraction (XRPD) pattern which includes major peaks at 16.8 ± 0.3°, 17.1 ± 0.3° and 21.8 ± 0.3° two theta. In some embodiments, the XRPD pattern of Form I further includes at least one peakselected from 16.0 ± 0.3°, 18.8 ± 0.3° and 26.5 ± 0.3° two theta. In some embodiments, the x-ray powder diffraction pattern further includes at least one peak selected from 12.3 ± 0.3°, 28.0 ±0.3°, and 29.0 ± 0.3° two theta. In further aspects, the x-ray powder diffraction pattern further includes peaks at 12.3 ± 0.3°, 16.0 ± 0.3°, 18.8 ± 0.3°, 26.5 ± 0.3°, 28.0 ± 0.3°, and 29.0 ± 0.3° two theta. In some aspects, greater than 90%, 95%, 99%, or any value contained within a range formed by any two of the preceding values, by weight of the compound of Formula (I) in the composition is crystalline Form I. In some aspects, the composition includes 0.01 mg to 200 mg of crystalline Form I, such as about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, or any value contained within a range formed by any two of the preceding values of crystalline Form I.

[0145] In some embodiments, the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (I) in an E / Z ratio between 0.9 and 1.3, such as about 1.1. In some embodiments, the endoxifen is in a crystalline form which is Form II. In some aspects, Form II is characterized by an x-ray powder diffraction pattern including major peaks at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3° and 18.4 ± 0.3° two theta, and optionally further including a peak at 22.0 ± 0.3° two theta. In some embodiments, the x-ray powder diffraction pattern further includes at least one peak selected from 6.6 ± 0.3°, 13.3 ± 0.3° and 20.0 ± 0.3° two theta. In various aspects, the x-ray powder diffraction pattern further including peaks at 6.6 ± 0.3°, 13.3 ± 0.3°, 20.0 ± 0.3° and 22.0 ± 0.3° two theta. In some aspects, greater than 90%, 95%, 99%, or any value contained within a range formed by any two of the preceding values, by weight of the compound of Formula (I) in the composition is crystalline Form II. In some aspects, the composition includes 0.01 mg to 200 mg of crystalline Form II, such as about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, or any value contained within a range formed by any two of the preceding values, of crystalline Form II.

[0146] In some embodiments, the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (I) in an E / Z ratio between 0.9 and 1.3, such as about 1.1. In some aspects, the ratio of (E)-isomer to (Z)-isomer is between 1:99 to 99:1. In some aspects, the ratio of (E)-isomer to (Z)-isomer is about 1:1. In some aspects, the ratio of (E)-isomer to (Z)-isomer is between 1:1 to 1:10, 1:10-1:20, 1:20-1:30. 1:30-1:40, 1:40-1:50, 1:50-1:60. 1:60-1:70, 1:70-1:80, 1:80-1:90, or 1:90-1:99. In some aspects, the ratio of (Z)-isomer to (E)-isomer is between 1:1 to 1:10, 1:10-1:20, 1:20-1:30, 1:30-1:40, 1:40-1:50, 1:50-1:60, 1:60-1:70, 1:70-1:80, 1:80-1:90, or 1:90-1:99.

[0147] In some embodiments, the endoxifen is in a crystalline form which is Form III. In some aspects, crystalline Form III is characterized by an x-ray powder diffraction pattern including major peaks at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3° and 17.7 ± 0.3° two theta, and optionally further including a peak at 25.3 ± 0.3° two theta. In some embodiments, the x-ray powder diffraction pattern further includes at least one peak selected from 18.2 ± 0.3°, 22.5 ± 0.3° and 26.8 ± 0.3° two theta. In some aspects, the x-ray powder diffraction pattern further includes peaks at 18.2 ± 0.3°, 22.5 ± 0.3°, 25.3 ± 0.3° and 26.8 ± 0.3° two theta. Greater than 90%, 95%, 99%, or any value contained within a range formed by any two of the preceding values, by weight of the compound of Formula (I) in the composition is crystalline Form III. In some aspects, the composition includes 0.01 mg to 200 mg of crystalline Form III, such as about 1 mg, 2 mg, 4 mg, 6 mg. 10 mg. 20 mg, 50 mg, 100 mg, 200 mg, or any value contained within a range formed by any two of the preceding values, of crystalline Form III.

[0148] A “pharmaceutically acceptable salt” is any salt (e.g., obtained by reaction with an acid or a base) of a compound of the present disclosure that is physiologically tolerated in a subject (e.g., a mammal, and / or in vivo, ex-vivo, in vitro cells, tissues, or organs). In some embodiments, a “salt” of a compound of the present disclosure is derived from inorganic or organic acids and bases. In some aspects, a “salt” of a compound described herein is derived from inorganic or organic acids and bases. Suitable counter-anions include, arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate. gluconate, glutamate, glycollylarsanilate. hexylresorcinate. hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, fattyacid anions, and triethiodide. Suitable counter-cations include benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some embodiments, a (Z)-endoxifen salt includes arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide. benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine,meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, or a zinc salt.

[0149] In some embodiments, the compositions comprises (Z)-endoxifen or a (Z)-endoxifen salt or polymorph are administered to the subject at a dose of 0.01 mg to 200.0 mg of (Z)-endoxifen per unit dose. In other embodiments, the oral compositions including (Z)-endoxifen or a (Z)-endoxifen salt or polymorph are administered to the subject at a dose of 1 mg to 200.0 mg of (Z)-endoxifen. In some embodiments, the oral compositions including (Z)-endoxifen or a (Z)-endoxifen salt or polymorph are administered to the subject at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg or 200 mg of (Z)-endoxifen per unit dose. In certain embodiments, the oral compositions include at least 90% (Z)-endoxifen (wt / wt) of (Z)-endoxifen and are administered at a dose of 1 mg, 2.0 mg, 4.0 mg 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50, 100 mg or 200 mg of (Z)-endoxifen per unit dose. In some embodiments, the compositions include (Z)-endoxifen gluconate and are administered at a dose ranging from 0.01 to 20 mg of (Z)-endoxifen per unit dose. In some embodiments, a composition including (Z)-endoxifen D-gluconate is administered at 0.5 mg, 1 mg, 2 mg 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, and 200 mg of (Z)-endoxifen per unit dose. In some embodiments, a composition including 1 mg of (Z)-endoxifen D-gluconate is administered. In other embodiments, a composition including 1 mg of (Z)-endoxifen L-gluconate is administered. In yet other embodiments, a composition including 2 mg of (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate is administered. In certain embodiments, an oral composition including at least 90% of a polymorph of endoxifen (wt / wt) is administered at a dose of 1 mg, 2 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg or 200 mg per unit dose. In some embodiments, a composition including a polymorphic form of (Z)-endoxifen is administered at a dose ranging from 0.01 mg to 20 mg per unit dose.

[0150] In some embodiments, for a compound or salt of Formula (I), Formula (I-Z), or Formula (I-E), the salt is selected from the acetate, arecoline, benzathine, benzoic, besylate, benzosulfonate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glucolate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate. napsylate, nitric, nitrate, oxalate, pamaoate (Embonate).pantothenate, perchloric, phosphate, diphosphate, piperazine, procaine, polygalacuronate, p-toluenesulfonate. salicylate, stearate, succinate, sulfate, sulfonate, sulfuric, tannate, tartarate, teoclate, triethiodide, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc, or any combination thereof. In some embodiments, the salt is selected from the group consisting of arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, Teoclate, triethiodide. benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some embodiments, the salt is D-gluconate, L-gluconate, or a combination thereof. In some embodiments, the salt is hydrochloride. In some embodiments, the salt is citrate. In some embodiments, the salt is (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, or a combination thereof. In some embodiments, the salt is selected from (Z)-endoxifen hydrochloride and (Z)-endoxifen citrate. In some embodiments, the salt is (Z)-endoxifen D-gluconate. In some embodiments, the salt is (Z)-endoxifen L-gluconate. In some embodiments, the salt is (Z)-endoxifen hydrochloride. In some embodiments, the salt is (Z)-endoxifen citrate. In some embodiments, the salt is (E)-endoxifen D-gluconate, (E)-endoxifen L-gluconate, or a combination thereof. In some embodiments, the salt is (E)-endoxifen D-gluconate. In some embodiments, the salt is (E)-endoxifen L-gluconate. In some embodiments, the salt is (E)-endoxifen hydrochloride. In some embodiments, the salt is (E)-endoxifen citrate. In some embodiments, the salt is endoxifen D-gluconate. In some embodiments, the salt is endoxifen L-gluconate. In some embodiments, the salt is endoxifen hydrochloride. In some embodiments, the salt is endoxifen citrate.

[0151] In some embodiments, the compound or salt of Formula (I) is (Z)-endoxifen, (E)-endoxifen, (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, (Z)-endoxifen citrate, (E)-endoxifen citrate, or any combination thereof. In some embodiments, the compound of Formula (I) is (Z)-endoxifen, (E)-endoxifen, (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, (Z)-endoxifen citrate, (E)-endoxifen citrate, or a combination thereof. In some embodiments, the compound of Formula (I) is (Z)-endoxifen, (E)-endoxifen, or a combinationthereof. In some embodiments, the compound of Formula (I) is (Z)-endoxifen, (E)-endoxifen, (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, or any combinations thereof. In some embodiments, the compound of Formula (I) is (Z)-endoxifen, (E)-endoxifen, (Z)-endoxifen citrate, (E)-endoxifen citrate, or any combinations thereof. In some embodiments, the compound of Formula (I) is (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, or a combination thereof. In some embodiments, the compound or salt of Formula (I) is (Z)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I) is (E)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I) is (Z)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (I) is (E)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (I) is (Z)-endoxifen. In some embodiments, the compound or salt of Formula (I) is (E)-endoxifen.

[0152] In some embodiments, the compound or salt of Formula (I-Z) is (Z)-endoxifen, (Z)-endoxifen hydrochloride or (Z)-endoxifen citrate. In some embodiments, the compound of Formula (I-Z) is (Z)-endoxifen. In some embodiments, the compound of Formula (I-Z) is (Z)-endoxifen hydrochloride or (Z)-endoxifen citrate. In some embodiments, the compound of Formula (I-Z) is (Z)-endoxifen hydrochloride. In some embodiments, the compound of Formula (I-Z) is (Z)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I-Z) is (Z)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I-Z) is (Z)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (I-Z) is (Z)-endoxifen.

[0153] In some embodiments, the compound or salt of Formula (I-E) is (E)-endoxifen, (E)-endoxifen hydrochloride, (E)-endoxifen hydrochloride or (E)-endoxifen citrate. In some embodiments, the compound of Formula (I-E) is (E)-endoxifen. In some embodiments, the compound of Formula (I-E) is (E)-endoxifen hydrochloride or (E)-endoxifen citrate. In some embodiments, the compound of Formula (I-E) is (E)-endoxifen hydrochloride. In some embodiments, the compound of Formula (I-E) is (E)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I-E) is (E)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I-E) is (E)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (I-E) is (E)-endoxifen.

[0154] In some embodiments, for a compound or salt of Formula (I), Formula (I-Z), or Formula (I-E), the compound or salt of Formula (I), Formula (I-Z), or Formula (I-E) is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, thecompound or salt is a crystalline form. In some embodiments, the compound or salt is a solvate form. In some embodiments, the compound or salt is a polymorph form. In some embodiments, the compound or salt is an amorphous form. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the crystalline form is hydrated. In some embodiments, the crystalline form is anhydrous. In some embodiments, the crystalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, the solvate form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvate form is an ethanol solvate form. In some embodiments, the solvate form is a methanol solvate form. In some embodiments, the solvate form is an isopropanol solvate form. In some embodiments, the solvate form is a hydrate.

[0155] In some embodiments, endoxifen or salt thereof is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the cry stal I i ne form is hydrated. In some embodiments, the cry stalline form is anhydrous. In some embodiments, the crystalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, the solvate form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvate form is an ethanol solvate form. In some embodiments, the solvate form is a methanol solvate form. In some embodiments, the solvate form is an isopropanol solvate form. In some embodiments, the solvate form is a hydrate.

[0156] In some embodiments, (Z)-endoxifen or salt thereof is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the crystalline form is hydrated. In some embodiments, the cry stalline form is anhydrous. In some embodiments, the cry stalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In someembodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, (Z)-endoxifen or a salt thereof exists as one or more polymorphs. In some embodiments, the solvate form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvate form is an ethanol solvate form. In some embodiments, the solvate form is a methanol solvate form. In some embodiments, the solvate form is an isopropanol solvate form. In some embodiments, the solvate form is a hydrate.

[0157] In some embodiments, (E)-endoxifen or salt thereof is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the crystalline form is hydrated. In some embodiments, the crystalline form is anhydrous. In some embodiments, the cry stalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, (E)-endoxifen or a salt thereof exists as one or more polymorphs. In some embodiments, endoxifen is a solvated form. In some embodiments, the solvated form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvated form is an ethanol solvate form. In some embodiments, the solvated form is a methanol solvate form. In some embodiments, the solvated form is an isopropanol solvate form. In some embodiments, the solvated form is a hydrate.

[0158] In some embodiments, for a compound or salt of Formula (I) or Formula (I-Z), the compound is crystalline Form I of (Z)-endoxifen. In some embodiments, crystalline Form I is characterized by an x-ray powder diffraction (XRPD) pattern which includes major peaks at 16.8 ± 0.3° 2-Theta, 17.1 ± 0.3° 2-Theta and 21.8 ± 0.3° 2-Theta. In some embodiments, the XRPD pattern of crystalline Form I further includes at least one peak selected from 16.0 ± 0.3° 2-Theta, 18.8 ± 0.3° 2-Theta, and 26.5 ± 0.3° 2-Theta. In some embodiments, the XRPD pattern of crystalline Form I further includes at least one peak selected from 12.3 ± 0.3° 2-Theta, 28.0 ±0.3° 2-Theta, and 29.0 ± 0.3° 2-Theta. In some embodiments, the XRPD pattern of cry stalline Form I further includes peaks at 12.3 ± 0.3° 2-Theta, 16.0 ± 0.3° 2-Theta, 18.8 ± 0.3°, 26.5 ± 0.3° 2-Theta, 28.0 ± 0.3° 2-Theta, and 29.0 ± 0.3° 2-Theta.CDK4 / 6 Inhibitors for Combination Treatment of Breast Cancer

[0159] Uncontrolled cell proliferation is curbed by targeting enzymes that regulate the cell cycle. D-type cyclins are associated with cyclin-dependent kinases to form a cychn D / CDK dimer complex that responds to signals from cytokines to drive cell division. There at least 20 members of the cyclin-dependent kinase (CDK) family, and they are involved in cell cycle regulation, transcription, cell-to-cell communication, metabolism regulation, and apoptosis. CDK 4 and CDK 6 complex with cyclin D to form dimers that prevent the cell cycle from advancing from the G1 (growth) to the S (DNA replication) phase. This is accomplished through phosphorylation of the retinoblastoma (RB) protein, leading to gene expression that regulates cell transition from G1 to the S phase. Many breast cancers demonstrate traits consistent with hyperactivity of the cyclin D-CDK4 / 6 pathway. CDK4 / 6 inhibitors act in part by blocking phosphorylation of RB, which prevents the cell cycle from advancing from the G1 to S phase. CDK4 / 6 inhibitors are effective in hormone receptor (HR)-positive breast cancers, which often retain retinoblastoma (RB) function and / or express high levels of cychn DI, a gene that promotes CDK4 / 6 activity. CDK4 / 6 inhibitors have other functions beyond cell cycle regulation, such as modulating the immune system, the tumor microenvironment, and DNA damage response.

[0160] In some embodiments, a combination of (Z)-endoxifen and a CDK4 / 6 inhibitor is administered according to the methods and compositions disclosed herein. As used herein, the term “CDK4 / 6 inhibitor” is used to refer to a compound that inhibits cyclin-dependent kinase CDK4 and / or cyclin-dependent kinase CDK6. In some embodiments, CDK4 / 6 inhibitors also inhibit cyclin-dependent kinase CDK2. Non-limiting examples of CDK4 / 6 inhibitors include but are not limited to, palbociclib, abemaciclib, ribociclib, trilaciclib, SHR-6390, FCN-437c, lerociclib, milciclib, PF-06873600, XZP-3287, zotiraciclib, BEBT-209. BPI-16350, CS-3002, fadraciclib, HS-10342, ON-123300, PF-06842874, TQ-05510, BPI-1178, JS-101, NUV-422, AU-294, CCT-68127, ETH-155008, HEC-80797, JRP- 890, JS-104, NEOS-518, PF-07104091, PF-07220060, RMC-4550, SRX-3177, VS-2370, and VS- 2370. In some aspects, a CDK4 / 6 inhibitor is selected from any of the pharmaceutically acceptable salts of the aforementioned compounds. In some aspects, the CDK4 / 6 inhibitor is abemaciclib.CDK4 / 6 Inhibitors

[0161] In some embodiments, the CDK / 4 inhibitor is a compound of Formula (II-A):Formula (II -A)or a pharmaceutically acceptable salt thereof, wherein:R1is selected from C3-5 alkyl, C3-5 cycloalkyl, and -CH2-C3-5 cycloalkyl;R2and R3are each independently selected from H and F;R4is selected from H and -CHs;R5is selected from C1-6 alkyl and -NR6R7;R6is selected from C1-3 alkyl;R7is selected from C1-3 alkyl;Q is selected from CH2, O, and S or a direct bond; andW and Y are each independently selected from -CH and N,wherein:at least one of R2or R3is F;at least one of W or Y is N.wherein when Q is O or S, W is CH.

[0162] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (Il-a), R1is selected from C3-5 alkyl, C3-5 cycloalkyl, and -CH2-C3-5 cycloalkyl.

[0163] In some embodiments, R1is selected from -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, C3-5 cycloalkyl, and -CH2-C3-5 cycloalkyl. In some embodiments, R1is selected from -CH(CH3)2, -CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, and -Qb-cyclopentyl. In some embodiments, R1is selected from -CH(CH3)2, -CH2CH2CH3, cyclopropyl, cyclopentyl, -CH2-cyclopropyl, and -CH2-cyclopentyl. In some embodiments, R1is selected from -CH(CH3)2. cyclopropyl, cyclopentyl, and -CH2-cyclopropyl. In some embodiments, R1is -CH(CH?)2.

[0164] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (Il-a), are each independently selected from H and F. In some embodiments, R2is F and R3is H. In some embodiments, R2is H and R3is F. In some embodiments, R2is F and R3is F.

[0165]

[0166] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (Il-a), R4is selected from H and -CH3. In some embodiments, R4is H. R4is -CH3.

[0167] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (Il-a), R5is selected from C1-6 alkyl and -NR6R7. In some embodiments, R5is selected from -CH3, -CH2CH3. -CH(CH3)2, -CH2CH2CH3. -CH2CH(CH3)2, -CH2CH2CH2CH3, -CH(CH2CH3)2, and -CH2CH(CH2CH3)2. In some embodiments, R5is selected from -CH3, -CH2CH3, -CH(CHS)2, and -CH2CH(CH3)2, and -NR6R7. In some embodiments, R3is selected from -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CH2CH2CH3, -CH(CH2CH3)2, -CH2CH(CH2CH3)2, and -NR6R7. In some embodiments, R5is selected from -CH3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, and -NR6R7. In some embodiments, R5is -NR6R7.

[0168] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (Il-a), R6is selected from C1-3 alkyl. In some embodiments, R6is selected from -CH3, -CH2CH3. -CH(CH3)2, and -CH2CH2CH3. In some embodiments, R6is selected from -CH3, and -CH2CH3. In some embodiments, R6is -CH2CH3.

[0169] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (Il-a), R7is selected from C1-3 alkyl. In some embodiments, R7is selected from -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH2CH3. In some embodiments, R7is selected from -CH3, and -CH2CH3. In some embodiments, R7is -CH2CH3.

[0170] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (Il-a), Q is selected from CH2, O, and S or a direct bond. In some embodiments, Q is CH2 or a direct bond. In some embodiments, Q is CH2 or S. In some embodiments. Q isS or a direct bond. In some embodiments, Q is CH2 or S. In some embodiments, Q is a direct bond. In some embodiments, Q is selected from CH2 and a direct bond. In some embodiments, Q is CH2. In some embodiments, Q is O.

[0171] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (Il-a), W and Y are each independently selected from -CH and N. In some embodiments. Y is N and W is -CH. In some embodiments, Y is -CH and W is N. In some embodiments, Y is N and W is N.

[0172] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (Il-a), the compound is a CDK.4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor issome embodiments, for a compound or pharmaceutically acceptable salt of Formula (Il-a), the compound is a CDK.4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected frominhibitor isome embodiments, the CDK4 / 6 inhibitorsome embodiments, the CDK4 / 6 inhibitorsome embodiments,the CDK4 / 6 inhibitorsome embodiments, the CDK4 / 6 inhibitor,some embodiments, the CDK4 / 6 inhibitorsome embodiments, the CDK4 / 6 inhibitor iIn some embodiments, the CDK4 / 6 inhibitor isinhibitor isome embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, abemaciclib is represented by thestructuresome embodiments, abemaciclibis represented by a compound of FormulaFormula (II). In some embodiments, Formula (II- A) is represented by Formula (II).

[0173] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (11-A) or Formula (II), the pharmaceutically acceptable salt is selected from arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / di phosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some embodiments, the pharmaceutically acceptable salt is selected from hydrochloride and methanesulfonate. In some embodiments, the pharmaceutically acceptable salt is methanesulfonate. In some embodiments, the pharmaceutically acceptable salt is hydrochloride.

[0174] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (II), the compound is a crystalline form. In some embodiments, the crystalline form iscrystalline Form I that is characterized as having a X-Ray Powder Diffraction (XRPD) pattern with peaks at about 4.51±0.1 °2-Theta 13.09±0.1 °2-Theta, 16.31±0.1 °2-Theta, and 18.82±0.1 °2-Theta as measured using Cu Ka radiation. In some embodiments, the crystalline form is crystalline Form III that is characterized as having a X-Ray Powder Diffraction (XRPD) pattern with peaks at about 21.29±0.1 °2-Theta 11.54±0.1 °2-Theta, 10.91±0.1 °2-Theta, and 12.13±0.1 °2-Theta as measured using Cu Ka radiation. In some embodiments, the crystalline form is an amorphous form that is characterized as having a XRPD pattern showing a lack of crystallinitye.

[0175] In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. Abemaciclib is an antitumor agent and dual inhibitor of cyclin-dependent kinases 4 (CDK4) and 6 (CDK6). CDK4 and CDK6 are involved in the cell cycle and promotion of cancer cell growth in case of unregulated activity. Abemaciclib is also an ATP competitive inhibitor of cyclin-dependent kinases 4 and 6. As used herein, the abemaciclib is a compound of Formula (II):Formula (II).

[0176] In some embodiments, compositions described herein include the compound of Formula (II) and a pharmaceutically acceptable carrier, diluent or excipient.

[0177] As used herein, abemaciclib is [5-(4-Ethyl-piperazin-l-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine crystalline form III, 2-Pyrimidinamine, N-[5-[(4-ethyl-l-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4-fluoro-2 -methyl- 1 -(1 -methylethyl)-lH-benzimidazol-6-yl], or [5-(4-Ethyl-piperazin-1 -ylmethyl)-pyri din-2 -yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine methanesulfonate. In some aspects, abemaciclib is [5-(4-Ethyl-piperazin-l-ylmethyl)-pyridin-2-yl]-[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl] -amine crystalline form III, characterized by an X-ray powder diffraction pattern (CuKa radiation, =l.54056 A) including a peak at 21.29 (2G±0.1°) and optionally one or more peaks selected from the group including 11.54, 10.91, and 12.13 (20±O.1°). In some aspects, abemaciclib is [5-(4-Ethyl-piperazin-l-ylmethyl)-pyri din-2 -yl]-[5-fIuoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyri midin2-yl]-amine crystalline form III as claimed in claim 14 which is further characterized by a 13C NMR spectrum including chemical shift peaks v(Fl) [ppm] at 112.7. 127.3 and 129.4.

[0178] In some embodiments, the abemaciclib is taken orally with or without food. In some embodiments, the abemaciclib is administered in combination with fulvestrant, (Z)-endoxifen, or an aromatase inhibitor. In some aspects, the abemaciclib is administered in an amount of 50 mg twice daily, 100 mg twice daily, 150 mg twice daily, or 200 mg twice daily. In various aspects, the abemaciclib is administered in an amount of 150 mg twice daily. In some aspects, the abemaciclib is administered in an amount of 200 mg twice daily. In some aspects, when the abemaciclib is administered in combination with (Z)-endoxifen at a dosage of 150 mg twice daily. In some embodiments, the dosage of the abemaciclib is reduced based on individual safety and tolerability.

[0179] In some embodiments, the mean half-life of abemaciclib in the subject ranges from 8 to 65 hours after administration with an average of 22.8 hours. In some aspects, the time to maximum plasma levels of abemaciclib ranges from 0-11 hours after administration, with an average of 4 hours. Sampling for Abemaciclib pharmacokinetic parameters is taken at DI and D2 of the run-in single dose period, and then at D15, D16, D17 and D18 of cycle 1 of treatment, as indicated in FIG. 3.

[0180] In some embodiments, the mean half-life of the CDK4 / 6 inhibitor in the subject ranges from 8 to 65 hours after administration with an average of 22.8 hours. In some aspects, the time to maximum plasma levels of the CDK4 / 6 inhibitor ranges from 0-11 hours after administration, with an average of 4 hours. Sampling for the CDK4 / 6 inhibitor pharmacokinetic parameters is taken at DI and D2 of the run-in single dose period, and then at D15, D16, D17 and D18 of cycle 1 of treatment, as indicated in FIG. 3.Aromatase Inhibitor Therapeutic Treatment

[0181] Though the embodiments described herein relate to methods of treatment for subjects contraindicated for aromatase inhibitors; optional embodiments include administration of an aromatase inhibitor according to the methods disclosed herein. Aromatase inhibitors work byinhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is used as a way of suppressing recurrence of the breast tumor tissue. The main source of estrogen is the ovaries in premenopausal subjects, while in postmenopausal subjects most of the body's estrogen is produced in peripheral tissues, such as outside the central nervous system (CNS), and also in a few CNS sites in various regions within the brain. Insome embodiments, the subj ect is postmenopausal, and the method includes administration of an aromatase inhibitor. In some aspects, the ovaries in a premenopausal subject produce too much aromatase for the inhibitors to block effectively. In other aspects, a premenopausal subject is contraindicated for aromatase inhibitor therapy because upon administration of an aromatase inhibitor, the body’s feedback mechanism increases the production of estrogen by the ovaries when estrogen levels drop, dramatically decreasing any benefit of the aromatase inhibitor. In some embodiments, to increase effectiveness of aromatase inhibitors in premenopausal subjects, the aromatase inhibitor is combined with ovarian suppression therapy, which is described below. Though in some aspects of the present disclosure, aromatase inhibitors are used in combination with (Z)-endoxifen, one of the advantages of the present disclosure is that administration of a combination of (Z)-endoxifen with a CDK4 / 6 inhibitor treats the cancer without also requiring administration of additional aromatase inhibitors. In some aspects, the (Z)-endoxifen is an aromatase inhibitor.

[0182] In some embodiments, the aromatase inhibitor is a steroidal aromatase inhibitor. As a non-limiting example, the steroidal aromatase inhibitor is exemestane (Aromasin®). In some embodiments, the aromatase inhibitor is a non-steroidal aromatase inhibitor such as, but not limited to, anastrozole (Arimide76®) or letrozole (FemarTa®) which inhibit the synthesis of estrogen via reversible competition for the aromatase enzyme.Ovarian Suppression Therapeutic Treatment

[0183] Though the embodiments described herein relate to methods of treatment for subjects contraindicated for ovarian suppression therapeutic agents, in some embodiments, the present disclosure provides a method of treatment using one or more ovarian suppression therapeutic agents. As used herein, the term “ovarian suppression therapeutic agents” refers to any therapeutic agent such as a small molecule or a biologic, that slows down, deters, or stops the function of an ovary, either permanently or temporarily.

[0184] In various aspects, side effects of ovarian suppression therapy are similar to those experienced during menopause. The effects are more pronounced during ovarian suppression therapy than menopause due to an abrupt drop in estrogen levels. Undesirable side effects of ovarian suppression therapy include musculoskeletal pain, bone loss, vaginal dryness and atrophy, cardiovascular risks, mood swings, loss of libido, cognitive impairment, and weight gain. Rare but potentially serious side effects include hepatitis and an increase in cholesterol levels. For subjects who cannot tolerate or do not wish to endure ovarian function suppression, the only currently approved treatment option is tamoxifen monotherapy, whichis therapeutically inferior to either (i) tamoxifen in combination with ovarian function suppression or (ii) an aromatase inhibitor in combination with ovarian function suppression. Though in some aspects, ovarian suppression agents are used in combination with (Z)-endoxifen, one of the advantages of the present disclosure is that administration of a combination of (Z)-endoxifen with a CDK4 / 6 inhibitor treats the cancer while not also requiring ovarian suppression therapy or aromatase inhibitor therapy.

[0185] In some embodiments, the ovarian suppression therapeutic agent includes a hormone or an agonist thereof. In some embodiments, the ovarian suppression therapeutic agent is a gonadotropin releasing hormone (GnRH) agonist. Infusions of GnRH agonists produce an initial transient increase in sex hormones, but with continued non-pulsatile stimulation, luteinizing hormone (LH) and follicle stimulating hormone (FSH) synthesis are inhibited and estrogen levels decline.

[0186] In some embodiments, the GnRH agonist is Goserelin, Triptorelin, Buserelin, or Leuprorelin. In some embodiments, the GnRH agonists include but are not limited to, leuprolide, also called leuprorelin (Lupron®), goserelin (Zoladex®), histrelin (Supprelin®), triptorelin (Trelstar®), degarelix (Firmagon®), and relugolix (Orgovyk®). In some embodiments, the GnRH agonists are long acting, and only require administration for example, at 1, 3, 6, and even 12-month intervals.Further Forms

[0187] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0188] "Isomers" are different compounds that have the same molecular formula.“Stereoisomers”' are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknowncan be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0189] When stereochemistry is not specified, molecules with stereocenters described herein include isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In certain embodiments, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers.Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0190] Methods of producing substantially pure enantiomers are known to those of skill in the art. For example, a single stereoisomer, e.g.. an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, NicGraw Hill; Lochmuller (1975) J. Chromatogr 113(3):283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0191] A “tautomer’" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0192] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C.13C and / or14C. Such deuterated forms can be made by the procedure described in U. S. Patent Nos. 5,846,514 and 6,334,997. As described in U. S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs

[0193] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogenby a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0194] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N.13N,15N,16N,160.17O,14F,15F.16F,17F,18F,33S.34S.35S,36S,35C1,37C1.79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0195] The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods

[0196] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Raj ender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem, 1981, 64(1-2), 9-32.

[0197] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0198] The compounds, compositions, and methods described herein include amorphous forms as well as crystalline forms, including crystalline polymorph forms where applicable. The compounds described herein may be in the form of a pharmaceutically acceptable salt, salt, free base, or free acid. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in an unsolvate form as well as a solvate form. In some embodiments, the solvate form comprises a pharmaceutically acceptable solvent such as water, ethanol, and the like. In some embodiments, the unsolvate form is referred to as an anhydrous form or anhydrate form. In some embodiments, the solvate form comprises water and is referred to as a hydrate form. In some embodiments, the solvate form is referred to as a pseudopolymorph. In some embodiments, the hydrate form isreferred to as a pseudopolymorph. Both unsolvate and solvate forms of the compounds presented herein are also considered to be disclosed herein.

[0199] The term “form” refers to a solid-state form of a particular compound (e.g., the free base, the free acid, a salt or a pharmaceutically acceptable salt). The term “form” includes crystalline polymorphs, hydrates and solvates (pseudopolymorphs), amorphous forms, and mixtures thereof, unless a particular crystalline, polymorph, pseudopolymorph, or amorphous form is expressly referred to. The term “polymorph” refers to a crystalline form of a given chemical species that differs from another crystalline form of that same molecular formula solely in crystal packing and / or molecular conformation within the lattice and, unless otherwise specified, excludes hydrates and solvates. If more than one polymorph, hydrate, or solvate exists, they will be designated for clarity (e.g.. Form I, Form II; monohydrate, dihydrate; ethanol solvate, methanol solvate).

[0200] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).Pharmaceutical Compositions / F ormulations

[0201] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (I-E), Formula (II-A), Formula (II), or any combinations thereof. In some embodiments, the compositions are pharmaceutical compositions. In some embodiments, the pharmaceutical composition comprises a first dosage form and a second dosage form. In some embodiments, the pharmaceutical composition comprises a single dosage form. In some embodiments, the first dosage form comprises a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z). In some embodiments, the second dosage form comprises a compound or pharmaceutically acceptable salt of Formula (II-A) or Formula (II). In some embodiments, the second dosage form comprises a compound or pharmaceutically acceptable salt of Formula (II). In some embodiments, the single dosage form comprises a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z) and a compound or pharmaceutically acceptable salt of Formula (II-A) orFormula (II). Insome embodiments, the single dosage form comprises a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z) and a compound or pharmaceutically acceptable salt of Formula (II).

[0202] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman. L., Eds., Pharmaceutical Dosage Forms. Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0203] The compounds and pharmaceutically acceptable salts thereof, compositions, and methods of the present disclosure may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human, or a non-human mammal. When administered to an mammal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient.Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.

[0204] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including aphysiologically acceptable agent, depends, for example, on the route of administration of the composition.

[0205] An ‘'effective amount” or “therapeutically effective” amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect benefit and / or a prophylactic benefit.

[0206] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0207] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration.

[0208] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co.. Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s).

[0209] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivers’ with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.

[0210] Preservatives can be used to prevent the grow th of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and any combinations thereof.

[0211] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound of Formula (I), Formula (I-Z), Formula (I-E), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen, (E)-endoxifen, or a combination thereof. In some embodiments, the pharmaceutical composition comprises at least 50%, at least 60%, at least 70%. at least 80%, at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 80%, at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 80% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 90%, (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 95% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition is a therapeutic composition.

[0212] In some embodiments, an endoxifen pharmaceutical composition comprises (Z)-endoxifen, (E)-endoxifen, or a combination thereof. In some embodiments, the endoxifenpharmaceutical composition comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 80%, at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 80% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 90%, (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 95% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0213] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A). or Formula (II). In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%. less than 2%. less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, or less than 9% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, or less than 8% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, or less than 7% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, or less than 6% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%,less than 2%, less than 3%. less than 4%, or less than 5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 2% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 3% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 4% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 0.5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0214] In some embodiments, an endoxifen pharmaceutical composition comprises (Z)-endoxifen, (E)-endoxifen, or a combination thereof. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, or less than 9% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, or less than 8% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, or less than 7% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, or less than 6% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, or less than 5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 2% (E)-endoxifen by weight of total endoxifen. In some embodiments, theendoxifen pharmaceutical composition comprises less than 3% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 4% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 0.5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0215] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A). or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 50:50, at least 60:40, at least 64:36, at least 70:30, at least 80:30, at least 82:18, at least 85:15, at least 90:10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 85: 15, at least 90: 10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 90:10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 90:10. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 94:6. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 95:5. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 96:4, at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 95:5. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 96:4. In some embodiments, thepharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 97:3. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 98:2, at least 99: 1. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is 100:0. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0216] In some embodiments, an endoxifen pharmaceutical composition comprises (Z)-endoxifen or a pharmaceutically acceptable salt thereof and (E)-endoxifen or a pharmaceutically acceptable salt thereof in a Z: E ratio that is at least 50:50. at least 60:40, at least 64:36, at least 70:30, at least 80:30, at least 82:18, at least 85:15, at least 90:10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 85:15, at least 90: 10. at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 90:10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 90:10. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 94:6. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 95:5. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 96:4, at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 97:3, at least 98:2, at least 99:1, or at least 100:0. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 95:5. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 96:4. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is at least 97:3. In some embodiments, the endoxifen pharmaceutical compositioncomprises (Z)-endoxifen and (E)-endoxifen in aZ: E ratio that is at least 98:2. at least 99:1. In some embodiments, the endoxifen composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: E ratio that is 100:0. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0217] In certain aspects, the present disclosure further provides pharmaceutical compositions comprising the crystalline forms, solvate forms, polymorph forms, or amorphous forms described herein. A cry stalline form, a solvate form, a polymorph form, or an amorphous form of a compound or salt disclosed herein may provide the advantage of bioavailability and stability’, suitable for use as an active ingredient in a pharmaceutical composition. Variations in the crystal structure of a pharmaceutical drug substance or active ingredient may affect the dissolution rate (which may affect bioavailability, etc.), manufacturability (such as ease of handling, ability7to consistently prepare doses of known strength) and stability7(such as thermal stability, shelflife, etc.) of a pharmaceutical drug product or active ingredient.

[0218] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition may comprise one or more crystalline forms of a compound or salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). A crystalline form may be distinguished by its x-ray powder diffraction pattern. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%. or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single cry stalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%. greater than or equal to 98%, or greater than or equal to 99% ofa single crystalline form of the compound. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0219] In some embodiments, for endoxifen, a pharmaceutical composition is provided comprising endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may comprise one or more crystalline forms of endoxifen or a pharmaceutically acceptable salt thereof. A crystal line form may be distinguished by its x-ray powder diffraction pattern. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%. or greater than or equal to 99.5% of a single crystalline form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96% of a single crystalline form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 98% of a single crystalline form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 99% of a single crystalline form of endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0220] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable of Formula (I), Formula (I-Z), or Formula (II). In some embodiments, the pharmaceutical composition may comprise one or more polymorphic forms of a compound or salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). A polymorphic form may be distinguished by its x-ray powder diffraction pattern. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%. or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 98%, greater than or equal to 99%. or greater than or equal to 99.5% of a single polymorphic form of the compound. Insome embodiments, the pharmaceutical composition comprises greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, or greater than or equal to 99% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0221] In some embodiments, for endoxifen or a pharmaceutically acceptable salt thereof, a pharmaceutical composition is provided comprising endoxifen or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may comprise one or more polymorphic forms of endoxifen or salt thereof. A polymorphic form may be distinguished by its x-ray powder diffraction pattern. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%. greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96% of a single polymorphic form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 98% of a single polymorphic form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 99% of a single polymorphic form of endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0222] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A). or Formula (II). In some embodiments, the pharmaceutical composition comprises crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% cry stal I ine Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 80%, at least 90%, at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weightof total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 90%, at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 80% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 90%, crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 95% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0223] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition comprises from 0.01 mg to 200 mg of cry stalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 1 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 2 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 3 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 4 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 6 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 10 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 20 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 30 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 40 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 50 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 100 mg crystalline Form I of(Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 200 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 10 mg to 50 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 20 mg to 40 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 100 mg to 200 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 40 mg to 80 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 60 mg to 80 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0224] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition comprises from 0.01 mg to 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 1 mg (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 2 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 3 mg (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 4 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 6 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 10 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 20 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 30 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 40 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 50 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 60 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 100 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 10 mg to 50 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 20 mg to40 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 100 mg to 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 40 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0225] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I). Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen D-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen L-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen D-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen L-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 30% to 60% of (Z)-endoxifen D-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 30% to 60% of (Z)-endoxifen L-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 60% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 40% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 20% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to30% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen citrate in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 60% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 40% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 20% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 30% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0226] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A). or Formula (II). In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is an oral formulation. In some embodiments, the pharmaceutical composition comprises a tablet, a caplet, or a capsule. In some embodiments, the tablet is coated with one or more of an enteric coating agent, a control release agent or a film forming agent. The enteric coating agent, the control release agent and / or the film forming agent control or delaydisintegration and absorption of the compositions including (Z)-endoxifen or salts thereof and elagolix or salts thereof in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. In some embodiments, the caplet is coated with one or more of an enteric coating agent, a control release agent or a film forming agent. In some embodiments, the capsule is coated with one or more of an enteric coating agent, a control release agent or a film forming. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the tablet is an enteric tablet. In some embodiments, the caplet is an enteric coated caplet. In some embodiments, the caplet is an enteric caplet. In someembodiments, the capsule is an enteric capsule. In some embodiments, the capsule is an enteric coated capsule. The enteric tablets, enteric caplets, or enteric capsules of the present disclosure are prepared by techniques known in the art. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0227] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition comprises at least one pharmaceutical acceptable excipient and at least one pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical composition comprises at least one pharmaceutical acceptable excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutical acceptable excipient and a pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutical acceptable excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical acceptable excipients are selected from pharmaceutical acceptable disintegrants, pharmaceutical acceptable fillers, pharmaceutical acceptable lubricants, and pharmaceutical acceptable binders. In some embodiments, the pharmaceutical composition further comprises an enteric coating, an enteric capsule, an enteric caplet, an enteric tablet, or any combinations thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, an enteric capsule, an enteric caplet, an enteric tablet, or a combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric capsule. In some embodiments, the pharmaceutical composition further comprises an enteric caplet. In some embodiments, the pharmaceutical composition further comprises an enteric tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a capsule, a caplet, or a tablet, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a capsule, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a caplet, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a tablet, or any combination thereof. In some embodiments, the pharmaceutical composition furthercomprises a capsule, a caplet, or a tablet. In some embodiments, the pharmaceutical composition further comprises a capsule. In some embodiments, the pharmaceutical composition further comprises a caplet. In some embodiments, the pharmaceutical composition further comprises a tablet. In some embodiments, the pharmaceutical composition further comprises a tablet-in-tablet, a tablet-in-capsules, a beads-in-capsule, or a spheres-in capsule. In some embodiments, the pharmaceutical composition further comprises a tablet-in-tablet. In some embodiments, the pharmaceutical composition further comprises a tablet-in-capsule. In some embodiments, the pharmaceutical composition further comprises a beads-in-capsule. In some embodiments, the pharmaceutical composition further comprises a spheres-in capsule. In some embodiments, the tablet is an enteric tablet. In some embodiments, the caplet is an enteric caplet. In some embodiments, the capsule is an enteric capsule. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the caplet is an enteric coated caplet. In some embodiments, the capsule is an enteric coated capsule. In some embodiments, the tablet is a delayed-release tablet. In some embodiments, the caplet is a delayed-release caplet. In some embodiments, the capsule is a delayed-release capsule. In some embodiments, the tablet is an enteric coated delayed-release tablet. In some embodiments, the caplet is an enteric coated delayed-release caplet. In some embodiments, the capsule is an enteric coated delayed-release capsule. In some embodiments, the tablet of the tablet-in-capsule is a delayed-release tablet. In some embodiments, the capsule of the tablet-in-capsule is a delayed-release capsule. In some embodiments, one of the tablets of the tablet-in-tablet is a delayed-release tablet. In some embodiments, both of the tablets of the tablet-in-tablet are a delayed-release tablet. In some embodiments, the capsule of the beads-in-capsule is a delayed-release capsule. In some embodiments, the capsule of the spheres-in-capsule is a delayed-release capsule. In some embodiments, the tablet of the tablet-in-capsule is an enteric coated tablet. In some embodiments, the capsule of the tablet-in-capsule is an enteric coated capsule. In some embodiments, one of the tablets of the tablet-in-tablet is an enteric coated tablet. In some embodiments, both of the tablets of the tablet-in-tablet are an enteric coated tablet. In some embodiments, the capsule of the beads-in-capsule is an enteric coated capsule. In some embodiments, the capsule of the spheres-in-capsule is an enteric coated capsule. In some embodiments, the tablet of the tablet-in-capsule is an enteric tablet. In some embodiments, the capsule of the tablet-in-capsule is an enteric capsule. In some embodiments, one of the tablets of the tablet-in-tablet is an enteric tablet. In some embodiments, both of the tablets of the tablet-in-tablet are an enteric tablet. In someembodiments, the capsule of the beads-in-capsule is an enteric capsule. In some embodiments, the capsule of the spheres-in-capsule is an enteric capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated caplet. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coated delayed release capsule, an enteric coated delayed release tablet, an enteric coated delayed release tablet-in-tablet, an enteric coated delayed release tablet-in-capsule, an enteric coated delayed release beads-in-capsule, or an enteric coated delayed release spheres-in capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated capsule, an enteric coated tablet, an enteric coated tablet-in-tablet, an enteric coated tablet-in-capsule, an enteric coated beads-in-capsule, or an enteric coated spheres-in capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet. In some embodiments, the pharmaceutical composition further compnses an enteric coated tablet-in-tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet-in-capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated beads-in-capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated spheres-in capsule. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for oral administration in a subject in need thereof.

[0228] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), the enteric tablet is a hard tablet comprising the compound or the pharmaceutically acceptable salt of Formula (I) Formula (I-Z), Formula (II-A). or Formula (II), or a pharmaceutical composition thereof. In some embodiments, the pharmaceutical composition is formulated as an enteric tablet. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0229] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). the enteric capsule is a capsule comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), or a pharmaceutical composition thereof. In some embodiments, the pharmaceutical composition is formulated as an enteric capsule. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0230] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), the enteric coated tablet is a hard tablet comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), or a pharmaceutical composition thereof. In some embodiments, the pharmaceutical composition is formulated as an enteric coated tablet. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0231] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). the enteric coated capsule is a capsule comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), or a pharmaceutical composition thereof. In some embodiments, the pharmaceutical composition is formulated as an enteric coated capsule. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0232] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition is formulated as an enteric tablet. In some embodiments, the pharmaceutical composition is formulated as an enteric capsule. In some embodiments, the pharmaceuticalcomposition is formulated as an enteric coated tablet. In some embodiments, the pharmaceutical composition is formulated as an enteric coated capsule. In some embodiments, the pharmaceutical composition is formulated as a capsule. In some embodiments, the pharmaceutical composition is formulated as a tablet. In some embodiments, the pharmaceutical composition is formulated as a delayed-release capsule. In some embodiments, the pharmaceutical composition is formulated as a delayed-release tablet. In some embodiments, the enteric capsule or the enteric tablet is further coated with an enteric coating. In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0233] In some embodiments, for a pharmaceutical composition disclosed herein, the enteric capsule is selected from a non-animal-based capsule, such as a hypromellose capsule (for example, commercially available self-gelling Vcaps, VCaps Plus, VCaps enteric, other enteric capsules made using Xcellodose, ENCODE colonic delivery technology, and EnTrinsic™ drug delivery technology from Capsugel). Other technologies known in the art and available commercially (for example, Qualicaps, USA, Nutrascience, USA. etc.) can also be utilized for formulating enteric forms of oral solid dosage forms. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen or pharmaceutical composition thereof or elagolix or pharmaceutical composition thereof is filled neat into the capsule. In such API-in-capsule oral dosage forms, the active ingredient, (Z)-endoxifen or elagolix or pharmaceutical compositions thereof are free flowing powders or micronized powders. In some embodiments, the dosage form is a capsule. In some embodiments, the dosage form is an enteric capsule. In some embodiments, the dosage form is an enteric coated capsule. In some embodiments, the capsule is a seamless capsule. In some embodiments, the capsule is a banded capsule. In some embodiments, the capsule is a enteric, seamless capsule. In some embodiments, the capsule is a enteric, banded capsule. In some embodiments, the capsule is a enteric coated, seamless capsule. In some embodiments, the capsule is a enteric coated, banded capsule.

[0234] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical compositions (preparations) compnses a control release agent. Examples of control release agent suitable for use include, without limitation, pH-dependent polymers, acid-insoluble polymers, methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinylacetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, waxes, including synthetic waxes, microcrystalline waxes, paraffin wax, carnauba wax, and beeswax; polyethoxylated castor oil derivatives, hydrogenated oils, glycery l mono-, di-tribenates, glyceryl monostearate, glyceryl distearate, long chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol, and any combinations thereof. In some embodiments, a time delay material such as glycery l monostearate or glyceryl distearate may be used. In some embodiments, the controlled release reagent is a digestible waxy substance such as hard paraffin wax. In some embodiments, the control release agent is selected from methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, glyceryl mono-, di-tribenates, glyceryl monostearate, glyceryl distearate, long chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol, and any combinations thereof. In some embodiments, the control release agent is selected from methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate, and any combinations thereof. In some embodiments, the control release agent is selected from methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, and cellulose acetate.

[0235] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition comprises is a sustained release agent. Sustained release agent present in a sustained release composition of the present disclosure may be any sustained release agent known in the art to slow the release of a hydrophobic drug such as (Z)-endoxifen or a salt thereof. In some embodiments, the pharmaceutical composition is a sustained releasepharmaceutical composition. In some embodiments, the sustained release agent is selected from cellulosic ethers, gums, acrylic resins such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methylacrylate, polyvinyl pyrrolidine, protein-derived compounds, and any combinations thereof. In some embodiments, the sustained release agent is selected from cellulosic ethers, gums, acrylic resins such as polymers and copolymers of acrylic acid, methacry lic acid, methyl acrylate, methyl methylacrylate, polyvinyl pyrrolidine, and any combinations thereof. Examples of cellulosic ethers include hydroxyalkyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses (HPMC or Hypromellose, for example Nos. 2208, 2906, 2910), hydroxypropyl methylcellulose phthalate (HPMCP or Hypromellose phthalate), carboxyalkyl celluloses, and carboxymethyl celluloses. In some embodiments, the sustained release agent is selected from hydroxyalkyl celluloses, hydroxy ethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses (HPMC or Hypromellose, for example Nos. 2208, 2906, 2910), hy droxy propyl methy lcellulose phthalate (HPMCP or Hypromellose phthalate), carboxyalkyl celluloses, and carboxymethyl celluloses. In some embodiments, the sustained release agent is selected from hydroxyalkyl celluloses, hydroxy ethyl celluloses, hydroxypropyl celluloses, and hydroxypropyl methylcelluloses (HPMC or Hypromellose, for example Nos. 2208, 2906, 2910). In some embodiments, the sustained release agent is selected from HPMC. In some embodiments, the sustained release agent is a pH sustained release agent. Examples of pH sustained release agents include, but are not limited to, acid insoluble polymers which become increasingly soluble and permeable above pH 5.0 but remaining impermeable below pH 5.0. Such controlled release polymers target upper small intestines and / or colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers, including those available commercially from EVON IK" or ROHM® (e g., EUDRAGIT* sustained release polymers EUDRAGIT® RL (high permeability), EUDRAGIT® RS (low permeability) and EUDRAGIT® NM 30D (low permeability)), and any combinations thereof. In some embodiments, the pH sustained release agent is selected from cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, and acry lic acid-methy lacr lic acid copolymers such as EUDRAGIT® sustained release poly mers EUDRAGIT® RL, EUDRAGIT® RS, and EUDRAGIT® NM 30D. In someembodiments, the acid-insoluble polymers are selected from cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers (commercially available under the tradename EUDRAGIT® L and EUDRAGIT® S from Rohm America Inc., Piscataway, NJ as a powder or a 30% aqueous dispersion; or under the tradename EASTACRYL®, from Eastman Chemical Co., Kingsport, TN, as a 30% dispersion). In some embodiments, the acid-insoluble polymers are selected from EUDRAGIT® LI 00-55, EUDRAGIT* L30D-55, EUDRAGIT* L100, EUDRAGIT* L100 12,5, EUDRAGIT® S100, EUDRAGIT® S125, EUDRAGIT® FS 30D, EUDRAGIT® E100, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In some embodiments, the acid-insoluble polymers are selected from EUDRAGIT® LI 00-55, EUDRAGIT® RS, EUDRAGIT® RL, EUDRAGIT® NE, EUDRAGIT® NM 30D, EUDRAGIT® S, EUDRAGIT® L and any combinations thereof. In some embodiments, the acid-insoluble polymers is selected from EUDRAGIT® S, EUDRAGIT® L, and a combination thereof. In some embodiments, the pH sustained release agent is selected from EUDRAGIT® L100-55. EUDRAGIT® RS, EUDRAGIT® RL, EUDRAGIT® NE, and EUDRAGIT® NM, and any combinations thereof. In some embodiments, the pH sustained release agent is selected from EUDRAGIT® LI 00-55, EUDRAGIT® RS, EUDRAGIT® RL, EUDRAGIT® NE, and EUDRAGIT® NM, and any combination thereof. In some embodiments, the pH sustained release agent is EUDRAGIT® L30D 55. One of skill in the art will recognize that at least some acid insoluble polymers listed herein will also be biodegradable.

[0236] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (ILA), or Formula (II). In some embodiments, the pharmaceutical composition further comprises a delay or delay ed-release agent. Examples of delay or delay ed-release agents glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, for example polymethacrylate pH-sensitive polymer-based coatings, are used, (e.g., as coating material, i.e., enteric coating agents, for enteric coating of capsules, caplets, and tablets). Commercial sources for delayed-release oral dosage forms are available, for example DRCaps made of hypromellose (HPMC) from Capsugel, USA. Such delayed-release oral dosage forms are acid-resistant and resist acidity as seen in stomach for at least 30 min, such as for at least 1 hour, for at least 1.5 hour, or for at least 2 hours. Such delayed release oraldosage forms release at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the (Z)-endoxifen or salts thereof or elagolix or salts thereof in the intestines (small intestines, large intestin e / col on etc.).

[0237] Commercially available delayed release capsules such as those available from Capsugel (e.g., VCAPS® Plus enteric capsules), can be used to prepared delayed release capsules and are encompassed in the present disclosure. In some embodiments, the enteric delayed release capsules can be non-animal-based capsules, such as a Hypromellose capsule (for example, commercially available self-gelling VCAPS®, VCAPS® Plus, VCAPS® Enteric, other enteric capsules made using XCELLODOSE®, DRCAPS®, Encap Colonic Delivery' (ENCODE), and ENTRINSIC™ drug delivery' technology from CAPSUGEL®). Other technologies known in the art and available commercially (for example, QUALICAPS®, USA, NutraScience, USA, etc.) for the formulating enteric forms of oral solid dosage forms can also be utilized. In some embodiments, the pharmaceutical compositions of the present disclosure may be encapsulated in a DRCAPS® enteric-resistant delayed release capsule. In some embodiments, the pharmaceutical compositions of the present disclosure may be encapsulated in a EurdaCap® capsule. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen free base or salts thereof is filled neat into the capsule. In such API-in-capsule oral dosage forms, the active ingredient, (Z)-endoxifen or salts thereof can be free flowing powders or micronized powders. When the dosage form is a capsule, in at least one embodiment, the capsule can be a seamless capsule or a banded capsule.

[0238] In some embodiments, for a pharmaceutical composition disclosed herein, an oral dosage form can be of any shape suitable for oral administration, such as spherical (0.05 - 5 mL), oval (0.05 - 7 mL), ellipsoidal, pear (0.3 - 5 mL), cylindrical, cubic, regular and / or irregular shaped. An oral dosage form may be of any size suitable for oral administration, for example, size 0, size 2, and the like.

[0239] In some embodiments, for a pharmaceutical composition disclosed herein, an entericresistant delayed release pharmaceutical composition may comprise an enteric coated delayed release capsule comprising from about from 65% to 95% hydroxypropyl methylcellulose by weight and from 3% to 10% gellan gum by weight, relative to total unfilled capsule weight, endoxifen or a pharmaceutical composition thereof comprising from 10% to 30% (Z)-endoxifen by weight, from 1% to 5% croscarmellose sodium by w eight, from 60% to 95% microcrystalline cellulose by weight, and from 0.5% to 3% magnesium stearate by weight.relative to total fill weight of the composition. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising from 10 mg to 80 mg (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 10 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 20 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 30 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 40 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 50 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 60 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 70 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 80 mg of (Z)-endoxifen per capsule.

[0240] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition further comprises one or more excipients from 1% to 99%, 5% to 95%, from 5% to 90%, from 10% to 80%, from 15% to 70%, from 20% to 60%, from 30% to 95%, from 50% to 90%, from 60% to 90%, from 60% to 80%, or from 70% to 80% by weight of the total composition. In some embodiments, the composition comprises one or more excipients from 50% to 60%, from 60% to 70%, from 70% to 80%, or from 80% to 90% by weight of the total composition. In some embodiments, the composition comprises one or more excipients from 5% to 10%, from 10% to 20%, from 20% to 30%, or from 30% to 40% by weight of the total composition. In some embodiments, the composition comprises one or more excipients from 70% to 80%, or from 80% to 90% by weight of the total composition. In some embodiments, the composition comprises one or more excipient from 40% to 60% orfrom 60% to 80% by weight of the total composition. In some embodiments, the excipients are selected from bulking agents, binders, fillers, disintegrating agents, lubricants, glidants. control release agents, enteric coatings, film-forming agents, plasticizers, colorants, sweeteners, flavoring agents, or any combination thereof.

[0241] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a binder. Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, sucrose, starches such as com starch, potato starch, or starches such as starch paste, pregelatinized starch, and starch 1500, PEG 6000, methocel, WALOCEL* HM, LUVITEC®, caparolactam, AVICEL®, SMCC, UNI -PURE®, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL® PH 101, AVICEL® PH 103 AVICEL® RC 581, AVICEL® PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. In some embodiments, pharmaceutical composition further comprises a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose.Suitable anhydrous or low moisture excipients or additives include AVICEL* PH 103 and Starch 1500 LM.

[0242] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a filler. In some embodiments, the filler is selected from microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), sugars such as dextrose, sucrose, lactose, a salt such as calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starches, powdered cellulose, cellulosic bases such as methyl cellulose, carboxymethyl cellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and any combinations thereof.

[0243] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition comprises one or more fillers from 1% to 99%, 5% to 95%, from 5% to 90%,from 10% to 80%, from 15% to 70%, from 20% to 60%, from 30% to 95%, from 50% to 90%, from 60% to 90%, from 60% to 80%, or from 70% to 80% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 50% to 60%, from 60% to 70%, from 70% to 80%, or from 80% to 90% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 5% to 10%, from 10% to 20%, from 20% to 30%, or from 30% to 40% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 70% to 80%, or from 80% to 90% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 40% to 60% or from 60% to 80% by weight of the total composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 5% to 10% or from 10% to 20% by weight of the total pharmaceutical composition. In some embodiments, the fillers are selected from dextrose, sucrose, lactose, calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starches, powdered cellulose, cellulosic bases such as methyl cellulose, carboxymethyl cellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and any combination thereof. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0244] In some embodiments, for a pharmaceutical composition disclosed herein, one or more of a binder or a filler is present from 10% to 99% wt / wt of the pharmaceutical composition or the dosage form. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 15% to 99%, from 20% to 60%, from 25% to 55%, from 30% to 50%, from 35% to 60%, from 50% to 99% wt / wt of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 15% to 30% wt / wt of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 5% to 10% wt / wt of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 30% to 60% wt / wt of the total pharmaceutical composition.

[0245] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a disintegrant. Disintegrants are used in the pharmaceutical composition to provide tablets that disintegrate when exposed to an aqueous environment. In some embodiments, disintegrants are selected from starches, modified starches, sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, alginates, guar gum. xanthan gum, and resins. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. In some embodiments, the disintegrant is deep in the oral solid dosage form to delay disintegration. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

[0246] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition comprises a disintegrant from 0.1% to 10%, from 1.0% to 10%, from 1.5% to 10%, from 2.0% to 10%, from 2.5% to 10%, from 2.6% to 10%, from 2.8% to 10%, or from 2.9% to 10% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the formulation comprises a disintegrant from 0.1 % to 8.0%, from 1.0% to 8.0%, from 1.5% to 8.0%, from 2.0% to 8.0%, from 2.5% to 8.0%, from 2.6% to 8.0%, from 2.8% to 8.0%, from 2.9% to 8.0% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 0.1% to 1.0% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 8% by weight of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 2% to 8% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 2% to 4% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 4% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical compositioncomprises a disintegrant from 4% to 8% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 0.5% to 15% wt / wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 3% wt / wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 5% wt / wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 5% to 10% wt / wt of the pharmaceutical composition. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is selected from starches, modified starches, sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, alginates, guar gum, and xanthan gum. and any combination thereof. In some embodiments, the disintegrant is selected from sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, and any combinations thereof. In some embodiments, the disintegrant is selected from sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, and any combination thereof. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is selected from agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and any combinations thereof.

[0247] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a lubricant. Lubricant that are used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, magnesium stearate or potassium stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a SYLOID silica gel (AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CABOSIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), silicon dioxide, Q7-9120 (Dow Coming), and any combination thereof. If used at all, lubricants are typically used in an amount of less than 1% wt / wt of the formulation, composition, or dosage forms into which they are incorporated.In some embodiments, the lubricant is from 0.1% to 1% of the pharmaceutical composition or dosage form. In some embodiments, the lubricant is from 0.5% to 2% of the pharmaceutical composition or dosage form. In some embodiments, the lubricant is from 1% to 3% of the pharmaceutical composition or dosage form. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is selected from zinc stearate, magnesium stearate, potassium stearate, and any combination thereof.

[0248] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a plasticizer. Plasticizers may be added to control the softness or pl i abi 1 i ty of oral dosage forms such as shell of a capsule, caplet, or a tablet and thus, may improve the mechanical properties of the pH-sensitive materials of the capsules or coatings on the oral dosage forms. Suitable plasticizers, include, without limitation, petroleum oils (for e.g., a paraffinic process oil, a naphthenic process oil, and an aromatic process oil), squalene, squalane, plant oils, (e.g., olive oil, camelia oil, castor oil, tall oil, and a peanut oil), silicon oils, dibasic acid esters, (e.g., dibutyl phthalate, and dioctyl phthalate), liquid rubbers (e.g.. poly butene and a liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), hexyl laurate, diethyl sebacate, and diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycols, polypropylene glycol, phthalates, sorbitol, glycol salicylate, crotaminton, and glycerin or mixtures thereof. The amount of plasticizer may vary depending upon the chemical composition of the pharmaceutical preparation. In some embodiments, plasticizer is sorbitol, dimethyl isosorbide, or a glycerol. In some embodiments, the plasticizer is 1 % to 10%, such as 3% to 5% (wt / wt), of the pharmaceutical composition.

[0249] Examples of glidants include, but are not limited to, colloidal silicone dioxide, cellulose, calcium phosphate, di or tri-basic and the like. As an example, sweeteners or sweetening agents include sucrose, saccharin, dextrose, maltose, sugar substitutes, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, acesulfame K, and the like.Examples of flavoring agents include peppermint, methyl salicylate, peppermint, spearmint, methyl salicylate, raspberry’, red berry, strawberry, pineapple, orange, cherry and the like.

[0250] Rapid achievement of steady-state plasma levels of (Z)-endoxifen is also highly desirable. In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II -A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A). or Formula (II). In some embodiments, the pharmaceuticalcomposition provides a plasma level of (Z)-endoxifen in a subject administered the composition or formulation. In some embodiments, the (Z)-endoxifen is a crystalline form of (Z)-endoxifen, a polymorph of (Z)-endoxifen, a solvate of (Z)-endoxifen, or is amorphous (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is a crystalline form of (Z)-endoxifen or a polymorph of (Z)-endoxifen. In various aspects, steady state plasma levels are achieved from day 7 to day 21. In some aspects, the steady state plasma levels are achieved by day 7 upon daily administration of a composition disclosed herein.

[0251] In an aspect, the present disclosure provides that circulating (Z)-endoxifen released from a pharmaceutical composition disclosed herein is cleared faster than tamoxifen. In one aspect, terminal elimination half-life of tamoxifen is 5-7 days, and peak concentration time of tamoxifen is approximately 5 hours post-dose. (Z)-endoxifen released from a composition disclosed herein has a terminal elimination half-life ranging from 30 to 60 hours, significantly lower than tamoxifen. In some embodiments, the mean half-life ranges from 40 to 53 hours. The mean ratio of AUC24hr (Day 21) / AUCo-inf (Dayl) typically ranges from 0.7 to 1.2 for compositions including 1 mg to 4 mg (Z)-endoxifen, or a salt thereof. Thus, accumulation of (Z)-endoxifen released from a composition disclosed herein does not significantly vary over continued treatment.

[0252] Rapid absorption and bioavailability of the active agent are highly desirable. In an aspect, the present disclosure provides that the pharmaceutical compositions are formulated for certain pharmacokinetic (PK) properties. In some aspects, (Z)-endoxifen is released predominantly in the intestines (upper GI and colon) and is protected from the acidic environment in the stomach for at least 6 hours. Enteric coating of the capsule prevents the release of (Z)-endoxifen in the stomach for at least 6 hours as tested by a method of USP 711. In one aspect, rapid achievement of maximal and steady state plasma levels of (Z)-endoxifen is a particular aspect of the present disclosure. The present disclosure provides pharmaceutical compositions that achieve a maximal plasma level of (Z)-endoxifen ranging from 2 to 30 hours, from 3 to 20 hours, from 2 to 10 hours, or from 4 to 8 hours after administration of the compositions. Accordingly, in some embodiments, time to maximal (peak) plasma level of (Z)-endoxifen ranges from 2 to 10 hours after administration of the composition. In some embodiments, the time to maximal plasma level of (Z)-endoxifen ranges from 4 to 8 hours after administration of a composition disclosed herein. In some embodiments, the time to maximal plasma level of (Z)-endoxifen ranges from 6 to 8 hours after administration of a pharmaceutical composition disclosed herein.

[0253] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation. In some aspects, the pharmaceutical compositions intended for oral use are prepared in solid or fluid unit dosage forms. In at least some embodiments, the pharmaceutical compositions are formulated for oral delivery as tablets, caplets, capsules, pills, powders, troches, elixirs, suspensions, syrups, wafers, chewing gums, dragees, lozenges, and the like.

[0254] One of skill in the art will further recognize that pharmaceutical compositions disclosed herein may include one or more of the excipients known in the art and disclosed herein in any combination appropriate for a desired formulation or preparation. Additional excipients may generally be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia / National Formulary. One of skill in the art will be able to select suitable excipients necessary7for the preparation of the formulations and appropriate dosage forms compatible with the route of administration based on his or her skill and knowledge in the art and the disclosures made herein. In all cases, the ultimate dosage form should be sterile and stable under the conditions of manufacture and storage.

[0255] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition comprises a water activity (Aw) from 0.5 to 0.9. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.5 to 0.8. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.5 to 0.75. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.4 to 0.6. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.2 to 0.4. In some embodiments, the pharmaceutical composition comprises a water activity' (Aw) from 0.25 to 0.5. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.1 to 0.25. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.05 to 0.1. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.1 to 0.25. When the water activity (Aw) is less than 0.75, testing Total Aerobic Plate Count (TAC) and USP indicator organism is typically not necessary7. The publication, “Microbial Bioburden on Oral Solid Dosage Form,” by Jose E. Martinez, Pharmaceutical Technology7, February 2002, pages 58 to 70, is hereby incorporated by reference in its entirety. In some embodiments, pharmaceutical composition is formulated as a solid dosage.In some embodiments, the solid dosage is an oral solid dosage. In some embodiments, the solid dosage is a tablet or a capsule. In some embodiments, the solid dosage is a tablet.

[0256] In some embodiments, for a pharmaceutical composition disclosed herein, the solid dosage form is a solid oral dosage form. In some embodiments, the solid oral dosage is selected from a tablet, a caplet, a capsule, and any combination thereof. In some embodiments, the capsule is a hard capsule or a soft capsule. In other embodiments, the capsule is a gelatin capsule, gelatin-free capsule, a “cap-in-cap” capsule, an alginate capsule, a hydroxypropylmethyl cellulose (HPMC) capsule, a polyvinyl alcohol (PVA) capsule, a hypromellose capsule, or a starch capsule.

[0257] Dosage to be administered to a subject will be usually in a unit dosage form.

[0258] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (II-A), or Formula (II), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z) Formula (II-A), or Formula (II). In some embodiments, the pharmaceutical composition is administered at a dose of 0.01 mg to 10.0 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 0.1 mg to 10.0 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 1 mg to 10 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 1 mg to 5 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 5 mg to 10 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 10 mg to 20 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 20 mg to 40 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 40 mg to 60 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 80 mg to 100 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 120 mg to 140 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 140 mg to 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 40 mg, and 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 10 mg to 20 mg, 20 mg to 40 mg, and 60mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 20 mg to 40 mg and 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 20 mg to 40 mg, 60 mg to 80 mg, 80 mg to 100 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose about 20 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose about 30 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 40 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 50 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 60 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 70 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 90 mg of (Z)-endoxifen per unit dose to a subject in need thereof. In some embodiments, the pharmaceutical composition is administered at a dose of about 10 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 20 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 70 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 25 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 30 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 35 mg of (Z)-endoxifen per unit dose to a subject in need thereof. In some embodiments, the pharmaceutical composition is administered at a dose of about 45 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 55 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 65 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 75 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the (Z)-endoxifen is a pharmaceutically acceptable salt of (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is (Z)-endoxifen citrate. In some embodiments, the (Z)-endoxifen is (Z)-endoxifen hydrochloride. In some embodiments, the (Z)-endoxifen is a crystalline form of (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is a polymorph form of (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is a solvate form of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is orally administered. In some embodiments, the pharmaceutical composition is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is administered once every 1, 2, or 3 days. In some embodiments, the pharmaceutical composition is administered once every’ 5, 6, 7, or 8 days. In some embodiments, the pharmaceutical composition is administered once every 2 days. In some embodiments, the pharmaceutical composition is administered once every 3 days. In some embodiments, the pharmaceutical composition is administered twice every 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, the pharmaceutical composition is administered twice daily. In some embodiments, the pharmaceutical composition is administered twice every 1, 2, or 3 days. In some embodiments, the pharmaceutical composition is administered twice every75, 6, 7, or 8 days. In some embodiments, the pharmaceutical composition is administered twice every 2 days. In some embodiments, the pharmaceutical composition is administered twice every 3 days. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.Additional Dosage Forms for Administration of (Z)-Endoxifen

[0259] In certain aspects, the present disclosure provides a pharmaceutical composition including a pharmaceutically acceptable carrier or diluent and the composition comprises a crystalline form of a compound of Formula (I). In some embodiments, a composition of the present disclosure is formulated for oral, parenteral, topical, or intraductal delivery. In some embodiments, the composition is formulated for oral delivery' as an enteric tablet, an enteric caplet, an enteric capsule, a delay ed-release tablet, a delay ed-release caplet or a delay ed-release capsule. In some aspects, the enteric tablet, enteric caplet, enteric capsule, delayed-release tablet, delayed-release caplet or delayed-release capsule may be uncoated. In some aspects, hard uncoated capsules with enteric capability' using intrinsically enteric capsule technology (for example, EnTrinsic Drug Delivery' available from Capsugel) are used in the present disclosure. In related aspects, a mean half-life of endoxifen in a subject treated withthe methods and compositions described herein is between 30 hours to 60 hours. In some aspects, a composition including a crystalline form of a compound of Formula (I) is formulated for oral delivery as an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet or a delay ed-release capsule. In some embodiments, the composition is administered to a subject for the treatment or prevention of a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both in the subject.

[0260] In certain aspects, the present disclosure provides an oral composition including 1 mg to 200 mg per unit dose of the composition including a crystalline form of a compound of Formula (I) for administration to a subject in need thereof, wherein daily administration of the oral composition achieves in the subject at least one of the following: a steady state plasma level of endoxifen within 7 to 21 days; a steady state plasma level of endoxifen ranging from 25 nM to 300 nM; a steady state plasma level of endoxifen greater than 30 nM; maximal plasma levels of endoxifen within 2 to 10 hours after administering; or any combination thereof.

[0261] In some embodiments, a mean half-life of endoxifen in a subject treated with the composition including a crystalline form of a compound of Formula (I) is between 40 hours to 55 hours. In some embodiments, the composition is formulated as an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet or a delayed-release capsule. In some embodiments, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of endoxifen in the composition is released in the intestines. In some embodiments, the composition including a cry stalline form of a compound of Formula (I) exhibits a mean area under the curve extrapolated to time infinity' (AUCO-inf) of endoxifen of 200 hr*ng / mL to 10000 hr*ng / mL, of 300 hr*ng / mL to 8000 hr*ng / mL, of 400 hr*ng / mL to 6000 hr*ng / mL or of 700 hr*ng / mL to 6000 hr*ng / mL.

[0262] In another aspect, the present disclosure provides oral compositions including abemaciclib and 1 mg to 200 mg per unit dose of (Z)-endoxifen free base or a salt thereof, for administration to a subject in need thereof, wherein daily administration of the oral composition achieves in the subject: (i) a steady state plasma level of endoxifen within 7 to 21 days; or (ii) a steady state plasma level of endoxifen ranging from 25 nM to 300 nM; or (iii) a steady state plasma level of endoxifen greater than 30 nM; or (iv) maximal plasma levels of endoxifen within 2 to 10 hours after administering; or (v) any combination thereof. The present disclosure also provides that the compositions are administered to a subject in needthereof for the treatment and prevention of a hormone-dependent breast disorder, a hormonedependent reproductive tract disorder, or both in a subject.

[0263] In some embodiments, the endoxifen is administered topically. In some embodiments, the endoxifen is administered orally, topically, transdermally, rectally, intravenously, intraarterially, intra-ovarianly, vaginally, parenterally, or via inhalation. In some embodiments, the endoxifen is formulated as a sustained release composition. In some aspects, a composition including endoxifen is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day. In some embodiments, a composition including endoxifen is administered every day, every other day, every7two days, every three days, every four days, every' five days, every six days, or every' seven days. In some aspects, treatment is administered for at least 7, 14, 21, 28, 30, 35, 42, 49, 56, or 60 days. In some embodiments, treatment is administered until a cancer is treated (e.g., by eliminating or reducing the size of a tumor). In some embodiments, treatment is administered until unacceptable toxicity is observed in the subject. In some embodiments, endoxifen (e.g., (Z)-endoxifen) is administered to treat a cancer at a dose of from about 1 mg to about 160 mg, from about 1 mg to about 40 mg, from about 1 mg to about 10 mg, or from about 2 mg to about 5 mg per day.Abemctciclib and (Z)-Endoxifen Additional Dosage Forms

[0264] In one aspect, the present disclosure provides methods of treating a subject with abemaciclib and (Z)-endoxifen. Tamoxifen, a weak anti-estrogen compound, is metabolized into active metabolites, including 4-hydroxytamoxifen (4HT) and (Z)-endoxifen. In one embodiment, the present disclosure further relates to oral compositions including (Z)-endoxifen or salts thereof and abemaciclib or salts thereof, and methods of treating a subject in need thereof.

[0265] In some embodiments of the present disclosure, the (Z)-endoxifen is administered as an enteric table, enteric caplet, or enteric capsule. In some aspects, the enteric tablets, enteric caplets, and enteric capsules may be uncoated. Hard uncoated capsules with enteric capability' using intrinsically enteric capsule technology (for example, EnTrinsic Drug Delivery available from Capsugel) are suitable for the purpose of the present disclosure.

[0266] In some embodiments of the present disclosure, the abemaciclib is administered as an enteric table, enteric caplet, or enteric capsule. In some aspects, the enteric tablets, enteric caplets, and enteric capsules may be uncoated. Hard uncoated capsules with enteric capability using intrinsically enteric capsule technology (for example, EnTrinsic Drug Delivery available from Capsugel) are suitable for the purpose of the present disclosure.

[0267] In some embodiments of the present disclosure, the combination of abemaciclib and (Z)-endoxifen is administered as an enteric table, enteric caplet, or enteric capsule. In some aspects, the enteric tablets, enteric caplets, and enteric capsules may be uncoated. Hard uncoated capsules with enteric capability using intrinsically enteric capsule technology (for example, EnTrinsic Drug Delivery available from Capsugel) are suitable for the purpose of the present disclosure.

[0268] In various embodiments, the enteric tablet is a hard tablet made with free-flowing powder of endoxifen or a composition thereof. In various embodiments, the enteric capsule is a capsule made with free-flowing powder of (Z)-endoxifen or a composition thereof. In various embodiments, the enteric tablet is a hard tablet made with free-flowing powder of abemaciclib or a combination thereof. In various embodiments, the enteric capsule is a capsule made with free-flowing powder of (Z)-endoxifen or a composition thereof and abemaciclib or a composition thereof.

[0269] In some embodiments, the enteric capsule is a non-animal-based capsule, such as a hypromellose capsule (for example, commercially available self-gelling Vcaps. VCaps Plus, VCaps enteric, other enteric capsules made using Xcellodose, ENCODE colonic delivery technology, and EnTrinsicTM drug delivery technology from Capsugel). Other technologies known in the art and available commercially (for example, Qualicaps, USA, Nutrascience, USA, etc.) for the formulating enteric forms of oral solid dosage forms can also be utilized. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen or composition thereof or abemaciclib or composition thereof is filled neat into the capsule. In such API-in-capsule oral dosage forms, the active ingredient, (Z)-endoxifen or abemaciclib or compositions thereof are free flowing powders or micronized pow ders. When the dosage form is a capsule, in at least one embodiment, the capsule is a seamless capsule or a banded capsule.

[0270] In some embodiments, compositions formulated for oral delivery as disclosed herein, for example, tablets, caplets, and capsules, are coated with one or more enteric coating agent, control release agent or film forming agent to control or delay disintegration and absorption of the compositions including (Z)-endoxifen or salts thereof and abemaciclib or salts thereof in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. Accordingly, in some embodiments, the tablet is an enteric tablet, the caplet is an enteric caplet, or the capsule is an enteric capsule. The enteric tablets, enteric caplets, or enteric capsules of the present disclosure are prepared by techniques known in the art.

[0271] Pharmaceutical preparations disclosed herein may include a control release agent. Examples of control release agent suitable for use include, without limitation, pH-dependent polymers, acid-insoluble polymers, methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, waxes, including synthetic waxes, microcrystalline waxes, paraffin wax, carnauba wax, and beeswax; polyethoxylated castor oil derivatives, hydrogenated oils, glycery l mono-, di-tribenates, glyceryl monostearate, glycery l distearate, long chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol; and mixtures thereof. In some embodiments, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. In other embodiments, the controlled release reagent is a digestible waxy substance such as hard paraffin wax.

[0272] In some embodiments, compositions may include one or more of pH-dependent polymers such as acid insoluble polymers. The pH-dependent polymers become increasingly permeable above pH 5.0 but are impermeable at pH below 5.0 whereas acid insoluble polymers become soluble in neutral to weakly alkaline conditions. Such control release polymers target upper small intestines and colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers (commercially available under the tradename EUDRAGIT® L and EUDRAGIT® S from Rohm America Inc., Piscataway, NJ as a powder or a 30% aqueous dispersion; or under the tradename EASTACRYL®, from Eastman Chemical Co., Kingsport. TN, as a 30% dispersion). Additional examples include EUDRAGIT® L100-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S100, EUDRAGIT® S12,5, EUDRAGIT® FS 30D, EUDRAGIT® E100, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment, the composition includes EUDRAGIT® LI 00-55. EUDRAGIT® RS and RL and EUDRAGIT® NE and NM are also useful polymers for the purpose of this disclosure. In some embodiments, the composition includes EUDRAGIT® L30D 55. In another embodiment, the preparation includes EUDRAGIT® FS 30D. One of skill in the art will recognize that at least some acid insoluble polymers listed herein will also be biodegradable.

[0273] For time delay or delay ed-release pharmaceutical preparations of oral dosage forms, glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, for example polymethacrylate pH-sensitive polymer-based coatings, are used, (e.g., as coating material, i.e., enteric coating agents, for enteric coating of capsules, caplets, and tablets). Commercial sources for delay ed-release oral dosage forms are available, for example DRCaps made of hypromellose (HPMC) from Capsugel, USA. Such delayed-release oral dosage forms are acid-resistant and resist acidity as seen in stomach for at least 30 min, such as for at least 1 hour, for at least 1.5 hour, or for at least 2 hours. Such delayed release oral dosage forms release at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the (Z)-endoxifen or salts thereof or abemaciclib or salts thereof in the intestines (small intestines, large intestine / colon etc.).

[0274] In some embodiments, the enteric capsule is a non-animal based capsule, such as a hypromellose capsule (for example, commercially available self-gelling Vcaps, VCaps Plus, VCaps enteric, other enteric capsules made using Xcellodose, ENCODE colonic delivery technology, and EnTrinsicTM drug delivery technology from Capsugel). Other technologies known in the art and available commercially (for example, Qualicaps, USA, Nutrascience, USA, etc.) for the formulating enteric forms of oral solid dosage forms are also be utilized. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen free base or salts thereof is fdled neat into the capsule. In some embodiments, the abemaciclib or salts thereof is fdled neat into the capsule. In such API-in-capsule oral dosage forms, the active ingredient is a free flowing powder or micronized powder. When the dosage form is a capsule, in at least one embodiment, the capsule is a seamless capsule or a banded capsule.

[0275] Rapid absorption and bioavailability of the active agent that further reduces the cancer growth rate are highly desirable. In an aspect, the present disclosure provides that the compositions are formulated for certain pharmacokinetic (PK) properties. In some aspects, (Z)-endoxifen is released predominantly in the intestines (upper GI and colon) and is protected from the acidic environment in the stomach for at least 6 hours. Enteric coating of the capsule prevents the release of (Z)-endoxifen in the stomach for at least 6 hours as tested by a method of USP 711. In some aspects, abemaciclib is released predominantly in the intestines (upper GI and colon) and is protected from the acidic environment in the stomach for at least 6 hours. Enteric coating of the capsule prevents the release of abemaciclib in the stomach for at least 6 hours as tested by a method of USP 711. In some aspects, the (Z)-endoxifen and abemaciclib are released predominantly in the intestines (upper GI and colon)and are protected from the acidic environment in the stomach for at least 6 hours. Enteric coating of the capsule prevents the release of (Z)-endoxifen and abemaciclib in the stomach for at least 6 hours as tested by a method of USP 711.

[0276] In one aspect, rapid achievement of maximal and steady state plasma levels of (Z)-endoxifen is a particular aspect of the present disclosure. The present disclosure provides compositions that achieve a maximal plasma level of (Z)-endoxifen ranging within 2 to 30 hours, within 3 to 20 hours, within 2 to 10 hours or within 4 to 8 hours after administration of the compositions. Accordingly, in some embodiments, time to maximal (peak) plasma level of (Z)-endoxifen ranges from 2 to 10 hours after administration of the composition. In some embodiments, the time to maximal plasma level of (Z)-endoxifen ranges from 4 to 8 hours after administration of a composition disclosed herein.

[0277] In one aspect, rapid achievement of maximal and steady state plasma levels of abemaciclib is a particular aspect of the present disclosure. The present disclosure provides compositions that achieve a maximal plasma level of abemaciclib ranging within 2 to 30 hours, within 3 to 20 hours, within 2 to 10 hours or within 4 to 8 hours after administration of the compositions. Accordingly, in some embodiments, time to maximal (peak) plasma level of abemaciclib ranges from 2 to 10 hours after administration of the composition. In some embodiments, the time to maximal plasma level of abemaciclib ranges from 4 to 8 hours after administration of a composition disclosed herein.

[0278] Rapid achievement of steady-state plasma levels of (Z)-endoxifen is also highly desirable, and in some embodiments, a composition of the present disclosure provides a plasma level of (Z)-endoxifen in a subj ect administered the composition including a polymorphic form of endoxifen, (Z)-endoxifen or a salt thereof that rapidly achieves steady state. In various aspects, steady state plasma levels are achieved from day 7 to day 21. In some aspects, the steady state plasma levels are achieved by day 7 upon daily administration of a composition disclosed herein.

[0279] Rapid achievement of steady-state plasma levels of abemaciclib is also highly desirable, and in some embodiments, a composition of the present disclosure provides a plasma level of abemaciclib in a subject administered the composition including a polymorphic form of abemaciclib or a salt thereof that rapidly achieves steady state. In various aspects, steady state plasma levels are achieved from day 7 to day 21. In some aspects, the steady state plasma levels are achieved by day 7 upon daily administration of a composition disclosed herein.

[0280] In an aspect, the present disclosure provides that circulating (Z)-endoxifen released from a composition disclosed herein is cleared faster than tamoxifen. In one aspect, terminal elimination half-life of tamoxifen is 5-7 days, and peak concentration time of tamoxifen is approximately 5 hours post-dose. (Z)-endoxifen released from a composition disclosed herein has a terminal elimination half-life ranging from 30 to 60 hours, significantly lower than tamoxifen. In some embodiments, the mean half-life ranges from 40 to 53 hours. The mean ratio of AUC24hr (Day 21) / AUC0-inf (Day1) typically ranges from 0.7 to 1.2 for compositions including 1 mg to 4 mg (Z)-endoxifen, or a salt thereof. Thus, accumulation of (Z)-endoxifen released from a composition disclosed herein does not significantly vary' over continued treatment.

[0281] The formulations and compositions as described herein may be administered at a dosage proportional to a subject’s weight (e.g., a mg / kg unit dose). In some embodiments the compositions are administered at a unit dose between 0.1 mg / kg and 10 mg / kg. In some embodiments, the compositions may include a 0.05 mg / kg unit dose, a 0.1 mg / kg unit dose, a 0.5 mg / kg unit dose, a 1 mg / kg unit dose, or a 1.5 mg / kg unit dose of the (Z)-endoxifen. In some embodiments, a dose may be increased over time.

[0282] In some embodiments the (Z)-endoxifen is administered at a unit dose between 0.1 mg / kg and 10 mg / kg. In some embodiments, the composition including (Z)-endoxifen may include a 0.05 mg / kg unit dose, a 0.1 mg / kg unit dose, a 0.5 mg / kg unit dose, a 1 mg / kg unit dose, or a 1.5 mg / kg unit dose of the endoxifen. In some embodiments, a dose may be increased over time.

[0283] In some embodiments, the abemaciclib is administered in a single dosage form of 150 mg or 200 mg. In some aspects, the pharmaceutical composition comprises abemaciclib is a tablet. In some aspects, the pharmaceutical composition comprises abemaciclib further includes pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipient comprises microcrystalline cellulose 102, microcrystalline cellulose 101, lactose monohydrate, croscarmellose sodium, sodium stearyl fumarate, and silicon dioxide.

[0284] In some embodiments, the CDK4 / 6 inhibitor, e.g., palbociclib, abemaciclib, ribociclib, trilaciclib, SHR-6390, FCN-437c, lerociclib, milciclib, PF-06873600, XZP-3287, zotiraciclib, BEBT-209, BPI-16350, CS-3002, fadraciclib, HS-10342, ON-123300, PF-06842874, TQ-05510, BPI-1178, JS-101, NUV-422, AU-294, CCT-68127, ETH-155008, HEC-80797, JRP-890, JS-104, NEOS-518, PF-07104091, PF-07220060, RMC-4550, SRX-3177, VS-2370, or VS- 2370, is administered orally at a dose of 1-500 mg. For example, the dose is 50 mg,100mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg. In some embodiments, a combination dosage form including the CDK4 / 6 inhibitor is administered at a dose of 50 mg, 100 mg, 150 mg, or 200 mg of abemaciclib per unit dose. In some aspects, the dose is administered once, twice, three, or four times daily. As a non-limiting example, the daily dose is from about 50-100 mg, 100-200 mg, or 200-400 mg of the CDK4 / 6 inhibitor. As a non-limiting example, the daily dose of the CDK4 / 6 inhibitor is 300 mg or 400 mg.

[0285] In some aspects, the CDK4 / 6 inhibitor is administered at a dose of from about 50 mg-500 mg per dose. In related aspects, the dose of the CDK4 / 6 inhibitor is 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg. 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg. 210 mg, 215 mg. 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 300 mg, 400 mg, 500 mg, or more. The dose is administered once daily, twice daily, three time daily or more. The CDK4 / 6 inhibitor is administered every day, every two days, every three days, every' four days, every five days, every six days, every week, every two weeks, every three weeks, or more. In some embodiments, the CDK4 / 6 inhibitor is administered orally or parenterally. In some aspects, the CDK4 / 6 inhibitor is abemaciclib. In some aspects, the abemaciclib is administered at a dose of 150 mg twice daily. In other aspects, the abemaciclib is administered at a dose of 200 mg twice daily.

[0286] In some embodiments, the (Z)-endoxifen and the abemaciclib are administered at a fixed dosage ratio. In some aspects, the ratio of (Z)-endoxifen to the abemaciclib is between about 1:1 to 1:5. In some aspects, the ratio is between about 1:5 to 1:10. In some aspects, the ratio is about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. In some aspects, the ratio of the abemaciclib to (Z)-endoxifen is between about 1: 1 to 1:5. In some aspects, the ratio is between about 1:5 to 1:10. In some aspects, the ratio is about 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0287] In one aspect, rapid achievement of maximal and steady state plasma levels of endoxifen is a particular aspect of the present disclosure. The present disclosure provides compositions that achieve a maximal plasma level of endoxifen ranging within 2 to 30 hours, within 3 to 20 hours, within 2 to 10 hours or within 4 to 8 hours after administration of the compositions. Accordingly, in some embodiments, time to maximal (peak) plasma level of endoxifen ranges from 2 to 10 hours after administration of the composition. In someembodiments, the time to maximal plasma level of endoxifen ranges from 4 to 8 hours after administration of a composition disclosed herein.

[0288] In one aspect, rapid achievement of maximal and steady state plasma levels of abemaciclib is a particular aspect of the present disclosure. The present disclosure provides compositions that achieve a maximal plasma level of abemaciclib ranging within 2 to 30 hours, within 3 to 20 hours, within 2 to 10 hours or within 4 to 8 hours after administration of the compositions. Accordingly, in some embodiments, time to maximal (peak) plasma level of abemaciclib ranges from 2 to 10 hours after administration of the composition. In some embodiments, the time to maximal plasma level of abemaciclib ranges from 4 to 8 hours after administration of a composition disclosed herein.

[0289] In an aspect, the present disclosure provides that circulating endoxifen released from a composition disclosed herein is cleared faster than tamoxifen. Terminal elimination half-life of tamoxifen is 5-7 days and peak concentration time of tamoxifen is approximately 5 hours post-dose. In some embodiments, (Z)-endoxifen released from a composition disclosed herein has a terminal elimination half-life ranging from 30 to 60 hours, significantly lower than tamoxifen. In some embodiments, the mean half -life ranges from 40 to 53 hours. The mean ratio of AUC24hr (Day 21) / AUC0-inf (Dayl) typically ranges from 0.7 to 1.2 for compositions including 1 mg to 4 mg (Z)-endoxifen, or a salt thereof. Thus, accumulation of endoxifen released from a composition disclosed herein does not significantly vary over continued treatment.

[0290] In another aspect, a composition described herein achieves absorption of (Z)-endoxifen that is therapeutically effective.

[0291] Area under Curve AUC(0-24hr) (“AUC24hr”) describes the total exposure of the subject to a drug from time of dosing (0 hr) over a 24-hour period. Compositions including (Z)-endoxifen or a salt thereof typically achieve mean (AUC24hr) of 150 hr*ng / mL to 600 hr*ng / mL on Day 1 of initial (first) dose of a composition including 1 mg to 4 mg of (Z)-endoxifen. Compositions including (Z)-endoxifen or a salt thereof typically achieve mean AUC24hr of 400 hr*ng / mL to 2500 hr*ng / mL on Day 21 of initial (first) dose of compositions including 1 mg to 4 mg of (Z)-endoxifen.

[0292] AUCO-inf ("‘AUCO-inf’), a time-averaged concentration of drug circulating in the body fluid analyzed (normally plasma, blood or serum), describes the total exposure of the subject to a drug. The present disclosure provides that the exposure of a subject to endoxifen (AUCO-inf) is dose proportional. In some embodiments. AUCO-inf ranges from 200hr*ng / mL to 10000 hr*ng / mL. In other embodiments, the AUCO-inf ranges from 300 hr*ng / mL to 8000 hr*ng / mL. In certain embodiments, the AUCO-inf ranges from 400 hr*ng / mL to 6000 hr*ng / mL over the dosing range of 1 mg to 4 mg of (Z)-endoxifen.

[0293] Dissolution of the oral dosage forms disclosed herein is tested by the dissolution tests according to the current methods of USP 711. In some embodiments, the oral dosage forms disclosed herein are protected from the acidic environment of the stomach and do not dissolve for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, 6 hours, at least 7 hours or at least 8 hours. In at least one embodiment, the oral dosage forms do not release endoxifen for at least 6 hours. In another embodiment, the oral dosage forms do not release endoxifen or a salt thereof for at least 2 hours.

[0294] In other embodiments, less than 10% of (Z)-endoxifen in a composition including endoxifen or a salt thereof disclosed herein is released in the stomach after 2 hours after administration; or wherein less than 40% of (Z)-endoxifen is released in the stomach after 4 hours of administration; or less than 50% of (Z)-endoxifen is released in the stomach after 6 hours of administration, as tested by a method of USP 711.

[0295] In another embodiment, a composition disclosed herein releases in the stomach less than 10% of (Z)-endoxifen in 2 hours after administration, less than 40% of (Z)-endoxifen in 4 hours after administration; and less than 50% of (Z)-endoxifen in 6 hours after administration, as tested by a method of USP 711.

[0296] In yet another embodiment, the composition is formulated to release in the small intestine, such that at least 10% of endoxifen is released after 4 hours after administration; or at least 30% of endoxifen is released after 6 hours after administration; or at least 40% of endoxifen is released after 7 hours after administration; or at least 50% of endoxifen is released after 8 hours after administration, as tested by a method of USP 711.

[0297] In a further embodiment, as determined by a method of USP 711, the composition is formulated to release in the colon at least 50% of endoxifen after 8 hours after administration.

[0298] In still further embodiments, the composition is formulated to release in the colon at least 20% of endoxifen after 4 hours after administration; at least 40% of endoxifen after 6 hours after administration; at least 60% of endoxifen after 7 hours after administration; or at least 80% of endoxifen after 8 hours after administration.

[0299] In another embodiment, a composition disclosed herein releases in the stomach less than 10% of abemaciclib in 2 hours after administration, less than 40% of abemaciclib in 4hours after administration; and less than 50% of abemaciclib in 6 hours after administration, as tested by a method of USP 711.

[0300] In yet another embodiment, the composition is formulated to release in the small intestine, such that at least 10% of abemaciclib is released after 4 hours after administration; or at least 30% of abemaciclib is released after 6 hours after administration; or at least 40% of abemaciclib is released after 7 hours after administration; or at least 50% of abemaciclib is released after 8 hours after administration, as tested by a method of USP 711.

[0301] In a further embodiment, as determined by a method of USP 711, the composition is formulated to release in the colon at least 50% of abemaciclib after 8 hours after administration.

[0302] In still further embodiments, the composition is formulated to release in the colon at least 20% of abemaciclib after 4 hours after administration; at least 40% of abemaciclib after 6 hours after administration; at least 60% of abemaciclib after 7 hours after administration; or at least 80% of abemaciclib after 8 hours after administration.Oral Dosage Forms

[0303] In some embodiments, a pharmaceutical composition of the present disclosure is formulated for oral delivery. In some aspects, compositions intended for oral use are prepared in solid or fluid unit dosage forms. In at least some embodiments, the compositions are formulated for oral delivery as tablets, caplets, capsules, pills, powders, troches, elixirs, suspensions, syrups, wafers, chewing gums, dragees, lozenges, and the like.

[0304] In some embodiments, an oral dosage form is of any shape suitable for oral administration, such as spherical (0.05 - 5 mL), oval (0.05 - 7 mL), ellipsoidal, pear (0.3 - 5 mL), cylindrical, cubic, regular and / or irregular shaped. An oral dosage form may be of any size suitable for oral administration, for example, size 0, size 2, and the like.

[0305] One of skill in the art will further recognize that compositions disclosed herein may include one or more of the excipients known in the art and disclosed herein in any combination appropriate for a desired formulation or preparation. Additional excipients may generally be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia / National Formulary. One of skill in the art will be able to select suitable excipients necessary' for the preparation of the formulations and appropriate dosage forms compatible with the route of administration based on his or her skill and knowledge in the art and the disclosures made herein. In all cases, the ultimate dosage form should be sterile and stable under the conditions of manufacture and storage.

[0306] For formulations of the solid dosage compositions disclosed herein, as the water activity (Aw) is less than 0.75, testing Total Aerobic Plate Count (TAC) and USP indicator organism is typically not necessar. The publication, "Microbial Bioburden on Oral Solid Dosage Form,” by Jose E. Martinez, Pharmaceutical Technology, February 2002, pages 58 to 70, is hereby incorporated by reference in its entirety'.

[0307] In some embodiments, the compounds described herein are administered orally. In some embodiments, the compounds described herein are administered intravenously. In other embodiments, other routes of administration are used or even preferred. For example, transdermal administration is very desirable for patients who are forgetful or petulant about taking oral medicine. In additional aspects, compounds of the present invention are administered by the percutaneous, intramuscular, intranasal or intrarectal route in particular circumstances. In some aspects, the route of administration is any appropriate route, as limited by the physical properties of the drugs, the convenience of the patient and the caregiver, and other relevant circumstances.

[0308] In some embodiments, the oral dosage forms are solid oral dosage forms such as tablets, caplets, and capsules. In some embodiments, the capsule is a hard capsule or a soft capsule. In other embodiments, the capsule is a gelatin capsule, gelatin-free capsule, a “capin-cap” capsule, alginate capsule, hydroxypropylmethyl cellulose (HPMC) capsule, a polyvinyl alcohol (PVA) capsule, a hypromellose capsule, or a starch capsule.

[0309] In some embodiments, the compositions of the disclosure, e.g., (Z)-endoxifen or a salt thereof and a CDK4 / 6 inhibitor or a salt thereof, further includes one or more excipients. Accordingly, compositions designed for oral administration are made with an inert or active excipient or with an edible carrier as disclosed herein.

[0310] In various embodiments, the composition provided herein includes from about 1% to about 99.99%, about 5% to about 95%, about 5% to about 90%, about 10% to about 80%, about 15% to about 70%, about 20% to about 60%, from about 30% to about 95%, from about 50% to about 90%, from about 60% to about 90%, from about 60% to about 80%, or from about 70% to about 80% by weight of one or more excipients. In certain embodiments, the composition provided herein includes about 99.99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% by weight of one or more excipients. In certain embodiments, the composition provided herein includes about 99.99%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%. about 92%, about 91%, about 90%, about 89%, about 88%. about 87%,about 86%, or about 85% by weight of one or more excipients. In certain embodiments, the composition provided herein includes about 85%, about 84%. about 83%, about 82%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, or about 65% by weight of one or more excipients. In certain embodiments, the composition provided herein includes about 55%, about 54%, about 53%, about 52%, about 51%, about 50%, about 49%, about 48%, about 47%, about 46%, or about 45% by weight of one or more excipients. In certain embodiments, the composition provided herein includes about 30%, about 29%, about 28%, about 27%, about 26%, about 25%, about 24%, about 23%, about 22%, about 21%, or about 20% by weight of one or more excipients.

[0311] Examples of excipients that are used in the compositions formulated for oral administration are provided herein and include, but are not limited to, one or more of bulking agents, binders, fdlers, disintegrating agents, lubricants, glidants, control release agents, enteric coatings, film-forming agents, plasticizers, colorants, sweeteners, flavoring agents and the like, or any combination thereof.

[0312] Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, sucrose, starches such as com starch, potato starch, or starches such as starch paste, pregelatinized starch, and starch 1500, PEG 6000, methocel, walocel HM, Luvitec, Luvicaparolactam, Avicel, SMCC, UNIPURE, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum. cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, polyvinyl pyrrolidone, hydroxy propyl methyl cellulose, (e g., Nos. 2208, 2906, 2910), sodium stearyl fumarate, microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. In some embodiments, the binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103 and Starch 1500 LM.

[0313] Examples of fdlers suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), sugars such as dextrose, sucrose, lactose, lactose monohydrate, a salt such as calciumcarbonate, calcium phosphate, sodium carbonate, sodium phosphate, starches, microcrystalline cellulose, powdered cellulose, cellulosic bases such as methyl cellulose, carboxymethyl cellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0314] One or more binder or fdler in compositions is ty pically present in from about 10% to about 99% wt / wt of the composition or the dosage form. In some embodiments, binders and / or fillers in a composition include about 15% to 99%, about 20% to 60%, about 25% to 55%, about 30% to 50%, about 35% to 60%, about 50% to 99% wt / wt of the composition.

[0315] In some aspects, disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. In some embodiments, disintegrants used in the present composition include starches, modified starches, sodium starch glycolate. microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, alginates, guar gum, xanthan gum, and resins. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. In some embodiments, the disintegrant is deep in the oral solid dosage form to delay disintegration. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

[0316] Typical compositions include from 0.5% to 15% wt / wt of disintegrant. In some embodiments, compositions include from 1% to 5% wt / wt of disintegrant in the composition. In another embodiment, the disintegrant is 1% to 25%, 2% to 20%, 5% to 15%, 8% to 12%, or about 10% wt / wt of the composition.

[0317] Disintegrants that are used in the pharmaceutical compositions provided herein include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystallme cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0318] Lubricants that are used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium laury l sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, magnesium stearate or potassiumstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a SYLOID silica gel (AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), silicon dioxide, Q7-9120 (Dow Coming), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than 1% wt / wt of the compositions or dosage forms into which they are incorporated. In yet another embodiment, the lubricant is 0.1% to 3%, such as 0.5% to 1% wt / wt, of the composition.

[0319] Plasticizers may be added to control the softness or pl iabi 1 i ty of oral dosage forms such as shell of a capsule, caplet or a tablet and thus, may improve the mechanical properties of the pH-sensitive materials of the coatings on the oral dosage forms. Suitable plasticizers, include, without limitation, petroleum oils (for e.g., a paraffinic process oil, a naphthenic process oil, and an aromatic process oil), squalene, squalane, plant oils, (e.g., olive oil, camelia oil, castor oil, tall oil, and a peanut oil), silicon oils, dibasic acid esters, (e.g., dibutyl phthalate, and dioctyl phthalate), liquid rubbers (e.g., polybutene and a liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), hexyl laurate, diethyl sebacate, and diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycols, polypropylene glycol, phthalates, sorbitol, glycol salicylate, crotaminton, and glycerin or mixtures thereof. The amount of plasticizer may vary depending upon the chemical composition of the pharmaceutical preparation. In one embodiment, the at least one plasticizer is sorbitol, dimethyl isosorbide, or a glycerol. In another embodiment, the plasticizer is 1% to 10%, such as 3% to 5% wt / wt of the composition.

[0320] Examples of glidants include, but are not limited to, colloidal silicone dioxide, cellulose, calcium phosphate, di or tri-basic and the like.

[0321] As an example of sweeteners or sweetening agents include sucrose, saccharin, dextrose, maltose, sugar substitutes, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, acesulfame K and the like.

[0322] Examples of flavoring agents include peppermint, methyl salicylate, peppermint, spearmint, methyl salicylate, raspberry, red berry, strawberry, pineapple, orange, cherry and the like.Types of Cancer for Treatment

[0323] Several types of breast cancer are treated with the methods and compositions disclosed herein. In some embodiments, breast cancers treated with the discussed methodsand compositions include ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), invasive (or infiltrating) lobular carcinoma (ILC), invasive (or infiltrating) ductal carcinoma (IDC), microinvasive breast carcinoma (MIC), inflammatory breast cancer, ER-positive (ER+) breast cancer, ER-negative (ER-) breast cancer, hormone epidermal growth factor receptor 2 (HER2) positive breast cancer, HER2 negative breast cancer, triple negative breast cancer (TNBC), adenoid cystic (adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, or micropapillary carcinoma. In some embodiments, a single breast cancer tumor is a combination of these types or be a mixture of invasive and in situ cancer. In other embodiments, breast cancers treated with the discussed methods and compositions include any malignant tumor of breast cells. In some aspects, the breast cancer discussed herein is at any stage of breast cancer, including stages of a precancer, an early stage cancer, a non-metastatic cancer, a pre-metastatic cancer, a locally advanced cancer, and a metastatic cancer. In various aspects, the breast cancer is stage 0, 1, II, III, or IV cancer. The cancer can be node-positive, early stage, resected hormone receptor positive (HR+), HER2- breast cancer at high risk of recurrence. High risk of recurrence can be determined by a subject having four or more node positive axillary lymph nodes and with a grade 3 tumor, a size of a tumor that is greater than 5 centimeters, or a combination thereof. Subjects with Ki67 values between about 20% to 29% also can have high risk of recurrence. An early stage cancer is generally a cancer that has not spread or metastasized, or a cancer that may have spread to nearby lymph nodes but not metastasized to distant tissues of the subject.

[0324] In some embodiments, the types of cancer treated with the present methods and compositions include ER+ endometrial and ER+ ovarian carcinoma. In some aspects, the ER+ endometrial cancer is low grade endometrial cancer. In other aspects, the ER+ ovarian carcinoma is low grade serous ovarian carcinoma.

[0325] In some embodiments, the subject is premenopausal. In some embodiments, the subject is postmenopausal. As used herein, the term “menopause” is used to refer to a stage or a condition in a subject whose ovaries have stopped making estrogen and other sex hormones and / or the subject has had no menstrual cycle (periods) for 12 months in a row. Any period of time before menopause is herein referred to as “premenopausal” and any time after menopause is referred to as “post-menopausal.” In some embodiments, premenopausal subjects include adults with at least 1 menses within 12 months of screening and / or adultswith no menses within 12 months of screening but with serum estradiol and FSH level confirmed as being within the standard laboratory reference range for premenopausal subjects.

[0326] In some embodiments, the breast cancer is DCIS. DCIS is the most common non-invasive breast cancer. It involves the cell lining of the breast ducts. In DCIS, the cells have not spread beyond the walls of the duct into the surrounding breast tissue. About 1 in 5 new breast cancer cases will be DCIS. LCIS is a pre-cancerous neoplasia. In some aspects, LCIS is indicative of a predisposition for invasive cancer. LCIS only accounts for about 15% of the in situ (ductal or lobular) breast cancers.

[0327] In some embodiments, the breast cancer is infiltrating ductal carcinoma. Infiltrating ductal carcinoma (IDC) is the most invasive breast cancer. As the name applies, it is a carcinoma that begins in the breast ducts and then invades the surrounding fatty tissue. About 8 to 10 invasive breast cancers are IDCs. Infiltrating ductal carcinoma is often treated by surgery to excise the cancerous tissue, and radiation therapy. In addition, chemotherapy combined with immunotherapy (e.g., tamoxifen and trastuzumab) is often used to treat IDC. If the tumor is larger than 4 cm, then a radical mastectomy is performed.

[0328] In some embodiments, the breast cancer is invasive lobular carcinoma, which is a cancer that develops in the lobules of the breast and has invaded the surrounding tissue. About 1 in 10 invasive breast cancer is an ILC, which is treated by surgery to excise the cancerous tissue and is also treated with radiation therapy. In addition, chemotherapy and immunotherapy combinations (e g., tamoxifen and trastuzumab) are often used as an adjuvant therapy to treat ILC.

[0329] In some embodiments, the breast cancer is inflammatory breast cancer, which accounts for about 1% to 3% of all breast cancers. In inflammatory breast cancer, cancer cells block lymph vessels in the skin, resulting in the beast turning red and feeling warm. The affected breast may become larger or firmer, tender, or itchy. Inflammatory breast cancer is treated with chemotherapy, immunotherapy, radiation therapy and in some cases, surgery.

[0330] In some embodiments, the subject has hormone receptor positive (HR+) breast cancer. As used herein, the term "HR positive’7breast cancer is used to refer to breast cancer / tumors that contain or express estrogen and / or progesterone receptors. In some embodiments the subject has breast cancer lacking expression of estrogen receptors (ER) and which is herein referred to as an “ER negative breast cancer.” Breast cancers lacking expression of bothIllestrogen and progesterone receptors are herein referred to as hormone receptor negative (HR negative) breast cancers.

[0331] In certain embodiments, the present methods and claims are directed to treatment of a disorder. In some aspects, the disorder is a hormone-dependent breast disorder. In other embodiments, the disorder is hormone-dependent reproductive tract disorder. In still other embodiments, the subj ect has both a hormone-dependent breast disorder and a hormonedependent reproductive tract disorder. In some embodiments, the hormone dependent disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, DCIS, LCIS, breast cancer, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer or vulvar cancer.

[0332] In some embodiments, the breast disorder is increased breast density. For example, the breast disorder is a class B (formerly Class II), class C (formerly class III) or class D (formerly class IV) breast density. In some embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is precocious puberty. In other embodiments, the hormone-dependent breast disorder or hormone-dependent reproductive tract disorder is McCune- Albright Syndrome.

[0333] In some embodiments, the breast disorder is gynecomastia. In some embodiments, gynecomastia is presented secondarily to an underlying disease. Accordingly in some embodiments, the subject also has underlying disease selected from the group consisting of prostate cancer, cirrhosis and liver disease, male hypogonadism, hyperthyroidism, renal failure and in subjects undergoing hemodialysis, or type I diabetes mellitus. In certain embodiments, the subject has prostate cancer as the underlying disease, wherein the subject has or is at risk of having gynecomastia.

[0334] The present disclosure contemplates the use of the compounds and compositions disclosed herein at various stages in tumor development and progression, including the treatment of advanced and / or aggressive neoplasms, i.e., overt disease in a subject that is not amenable to cure by local modalities of treatment such as surgery or radiotherapy, metastatic disease, or locally advanced disease. Accordingly in some embodiments, the breast cancer is a pre-cancer, an early-stage cancer, a non-metastatic cancer, a pre-metastatic cancer, or a locally advanced cancer. In at least one embodiment, the breast cancer is metastatic cancer.

[0335] In certain aspects, the present disclosure provides certain patient populations that would benefit from such methods of treatment. In some embodiments, the patient population is a tamoxifen-refractory or tamoxifen resistant population. In certain embodiments, thesubject has tamoxifen-refractory or tamoxifen resistant hormone-dependent breast disorder or hormone-dependent reproductive tract disorder. In other embodiments, the patient population includes subjects that are or will be treated with an SSRI drug selected from the group consisting of citalopram, escitaloram, fluoxetine, paroxetine, sertraline, and vilazodone.

[0336] In some embodiments, the subject has a condition for which aromatase inhibitors (Al) are contraindicated or not recommended. In some embodiments, the subject is hypersensitive to AIs. In some aspects, hypersensitivity presents as anaphylaxis, angioedema, and / or urticaria. In some embodiments, the subject is pregnant, and AIs are contraindicated because AIs can harm the fetus or cause miscarriage. In some embodiments, AIs are contraindicated for a subject because the subject is premenopausal. In some embodiments, the subject is resistant or refractory to treatment by AIs. In some aspects, resistance to Al is due to inherent tumor insensitivity to estrogen, ineffective inhibition of aromatase, sources of estrogenic hormones independent of aromatase, activation of signaling by non-endocrine pathways, enhanced cell survival and selection of hormone-insensitive cellular clones during treatment. In some embodiments, the subject has a co-morbidity occurring with their breast cancer. In some embodiments, the co-morbidity is a cardiovascular condition, hyperlipidemia, diabetes, arthritis, a rheumatologic disease, chronic obstructive pulmonary disease, osteoporosis, pain and / or pain-inflammation.Outcomes of Breast Cancer Treatment

[0337] Outcomes of cancer treatment include the objective response rate (ORR), defined as the proportion of patients who achieve a complete or partial response according to response evaluation criteria in solid tumors (RECIST) criteria, progression-free survival (PFS), overall survival (OS), percent partial mastectomy, disease-free survival (DFS), and safety. RECIST criteria include complete response (CR), where the tumor disappears completely; partial response (PR), where the tumor shrinks significantly; stable disease (SD), where the tumor size remains relatively unchanged; and progressive disease (PD) where the tumor grows or metastasizes. As used herein, the terms ‘"treat” or "‘treatment” refer to methods of treating a cancer, which methods include the administration of at least one compound or composition, at one or multiple dosages and times of administration, which reduces the frequency of, delays the onset of, or reduce the intensity of, a symptom. In some aspects, treatment also includes reducing, reversing, easing, or arresting the symptoms, clinical presentation, or physiological responses to treatment, related treatments, or co-administered treatments. The methods disclosed herein describe administration of a combination of (Z)-endoxifen with a CDK4 / 6inhibitor, where administration has the effect of inhibition of tumor cell proliferation, shrinkage of the tumor, causing apoptosis of cancer cells, or a combination thereof.

[0338] Effects of neoadjuvant treatment include reduction of the extent of tumors in the breast and axilla, and an increase in the rate of breast conservation while avoiding complete axillary dissections. Effects of (Z)-endoxifen; exemestane + goserelin; and (Z)-endoxifen + goserelin on endocrine-sensitive disease rates are measured based on select biomarker levels, including PK. C01, ER, PgR, cyclin DI, E2F1, pAKT, total AKT, Ki-67, c-PARP. and serum TK1 at 4 weeks and at time of surgery in all subjects, and in those subjects with and without ESD. Biomarkers are evaluated by pairing tumor biopsies and blood sampling; biomarkers correlated with disease progression are used to determine treatment regimes, and biomarkers correlated with disease treatment are used to determine treatment regimes. Treatment regimens include surgery, chemotherapy, radiation therapy, hormone therapy, targeted therapy, or immunotherapy.

[0339] Outcomes of treatment include objective response rate (ORR), progression-free survival (PFS), overall survival (OS), percent partial mastectomy, disease-free survival, and safety. In some aspects, the outcome of treatment with a combination of (Z)-endoxifen with a CDK4 / 6 inhibitor results in higher rates of PFS, OS, percent partial mastectomy, or disease-free survival (DFS). In some aspects, the ORR, PFS, OS, or DFS is at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% higher in subjects treated without a CDK4 / 6 inhibitor. In some aspects, the ORR, PFS, OS, or DFS is about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%. 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, greater in a subject treated with a combination of endoxifen and a CDK4 / 6 inhibitor than in a subject treated with endoxifen without a CDK4 / 6 inhibitor.Treatment Prior to Surgery

[0340] The present disclosure provides methods of treating a subject having or at risk of having breast cancer. In some embodiments, such methods include administering a combination of abemaciclib and (Z)-endoxifen to a subject contraindicated for aromatase inhibitor therapy and / or ovarian suppression therapy. In some embodiments, such methodsinclude administering a combination of (Z)-endoxifen and a CDK4 / 6 inhibitor to a subject contraindicated for aromatase inhibitor therapy and / or ovarian suppression therapy.

[0341] In some embodiments, the methods described herein include administering the composition at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks prior to surgery.

[0342] In some embodiments, the compositions of the present disclosure are used as a primary therapy. In some aspects, the combinations are used as a part of a neo-adjuvant therapy to primary therapy, or as part of adjuvant therapy regimen, where the intention is to ameliorate or cure a subject having or at risk of having a hormone-dependent breast disorder, hormone-dependent reproductive tract disorder, or both. In some aspects, the compositions of the present disclosure are used as a therapy prior to surgery, to decrease the size of the tumor, or to reduce the extent of surgery. In some aspects, the composition is administered at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks prior to surgery.Combination Therapy

[0343] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of Formula (I). Formula (II- A), Formula (II), or a combination thereof. In some embodiments, the pharmaceutical composition comprises a first dosage form and a second dosage form. In some embodiments, the pharmaceutical composition comprises a single dosage form. In some embodiments, the first dosage form comprises a compound or pharmaceutically acceptable salt of Formula (I). In some embodiments, the first dosage form comprises endoxifen. In some embodiments, the endoxifen is greater than or equal to 90% (Z)-endoxifen by wt% of the endoxifen. In some embodiments, the endoxifen is greater than or equal to 95% (Z)-endoxifen by wt% of the endoxifen. In some embodiments, the endoxifen is greater than or equal to 98% (Z)-endoxifen by wt% of the endoxifen. In some embodiments, the endoxifen is greater than or equal to 99% (Z)-endoxifen by wt% of the endoxifen. In some embodiments, the first dosage form comprises (Z)-endoxifen. In some embodiments, the second dosage form comprises a CDK4 / 6 inhibitor. In some embodiments, the second dosage form comprises a compound or pharmaceutically acceptable salt of Formula (II-A) or Formula (II). In some embodiments, the second dosage form comprises a compound or pharmaceutically acceptable salt of Formula(II). In some embodiments, the second dosage form comprises a compound or pharmaceutically acceptable salt of Formula (II-A). In some embodiments, the second dosage form comprises abemaciclib. In some embodiments, the single dose form comprises a compound or pharmaceutically acceptable salt of Formula (I) and a compound or pharmaceutically acceptable salt of Formula (II-A) or Formula (II). In some embodiments, the single dose form comprises a compound or pharmaceutically acceptable salt of Formula (I) and a compound or pharmaceutically acceptable salt of Formula (II). In some embodiments, the single dose form comprises a compound or pharmaceutically acceptable salt of Formula (I) and a compound or pharmaceutically acceptable salt of Formula (II-A). In some embodiments, the single dose form comprises endoxifen and a CDK4 / 6 inhibitor. In some embodiments, the single dose form comprises endoxifen and abemaciclib. In some embodiments, the endoxifen is greater than or equal to 90% (Z)-endoxifen by wt% of the endoxifen. In some embodiments, the endoxifen is greater than or equal to 95% (Z)-endoxifen by wt% of the endoxifen. In some embodiments, the endoxifen is greater than or equal to 98% (Z)-endoxifen by wt% of the endoxifen. In some embodiments, the endoxifen is greater than or equal to 99% (Z)-endoxifen by wt% of the endoxifen. In some embodiments, the single dose form comprises (Z)-endoxifen and a CDK4 / 6 inhibitor. In some embodiments, the single dose form comprises (Z)-endoxifen and abemaciclib. In some embodiments, the CDk4 / 6 inhibitor is abemaciclib.

[0344] In some embodiments, the present pharmaceutical composition includes administration of a pharmaceutical composition described herein in combination with one or more additional treatments. In several aspects, treatment in combination therapy is any treatment such as any prophylactic agent, therapeutic agent (such as chemotherapy), radiotherapy, surgery and the like. In various aspects, the combination refers to inclusion of a therapeutic or prophylactic agent in a same composition as a pharmaceutical composition disclosed herein (for example, in the same capsule, tablet, ointment, etc.) or in separate pharmaceutical compositions (for example, in two separate capsules). In some aspects, the separate pharmaceutical compositions are in a different dosage form. The use of the terms ■’combination therapy” and "in combination with” does not restrict the order in which a composition described herein, and prophylactic and / or therapeutic agent and / or treatment are administered to a subject in need thereof. In some aspects, compositions of the present disclosure are administered prior to (e.g., 1 minute (min), 5 min, 15 min, 30 min, 45 min, 1 hour (h), 2 h, 4 h. 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, 48 h, 72 h. 96 h. 1 week (wk). 2 wk, 3 wk, 4wk, 5 wk, 6 wk, 8 wk, 12 wk, 6 months (m), 9 m, or 1 year before), concomitant with, or subsequent to (e.g.. 1 minute (min), 5 min. 15 min, 30 min, 45 min, 1 hour (h), 2 h. 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 1 week (wk), 2 wk, 3 wk, 4 wk, 5 wk, 6 wk, 8 wk, 12 wk, 6 months (m), 9 m, or 1 year after) administration of one or more prophylactic and / or therapeutic agent and / or treatment to a subject in thereof. In several aspects, combination therapy as used herein also refers to treatment of a subject having a single disease or multiple disease...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a subject having a hormone receptor positive (HR+) cancer, the method comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of endoxifen which is a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof; anda therapeutically effective amount of a CDK4 / 6 inhibitor or a pharmaceutically acceptable salt thereof, thereby treating the subject having the hormone receptor positive (HR+) cancer.

2. The method of claim 1, wherein the endoxifen is >90% (Z)-endoxifen.

3. The method of claim 1 or claim 2, wherein the endoxifen is >95%, >96%, >97%, >98%, >99%, or >99.5% (Z)-endoxifen.

4. The method of any one of claims 1 to 3, wherein the endoxifen is in a free base form.

5. The method of any one of claims 1 to 4, wherein the pharmaceutically acceptable salt of the (Z)-endoxifen is selected from the group consisting of an: arecoline, besylate, bicarbonate, bitartrate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate. hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

6. The method of any one of claims 1 to 5, wherein the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen gluconate.

7. The method of any one of claims 1 to 5, wherein the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen citrate.

8. The method of any one of claims 1 to 5, wherein the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen hydrochloride.

9. The method of any one of claims 1 to 8, wherein the CDK4 / 6 inhibitor is palbociclib, abemaciclib, ribociclib, trilaciclib, SHR-6390. FCN-437c. lerociclib, milciclib, PF- 06873600, XZP-3287, zotiraciclib, BEBT-209, BPI- 16350, CS-3002, fadraciclib, HS- 10342, ON-123300, PF-06842874, TQ-05510, BPI-1178, JS-101, NUV-422, AU-294, CCT-68127, ETH-155008, HEC-80797, JRP- 890, JS-104, NEOS-518, PF-07104091, PF- 07220060, RMC-4550. SRX-3177, VS-2370, or VS- 2370.

10. The method of any one of claims 1 to 9, wherein the pharmaceutically acceptable salt of the CDK4 / 6 inhibitor is selected from the group consisting of an: arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate. hexylresorcinate. hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

11. The method of any one of claims 1 to 10, wherein the pharmaceutically acceptable salt of the CDK4 / 6 inhibitor is the hydrochloride salt.

12. The method of any one of claims 1 to 10, wherein the pharmaceutically acceptable salt of the CDK4 / 6 inhibitor is the mesylate salt.

13. The method of any one of claims 1 to 12, wherein the CDK4 / 6 inhibitor is abemaciclib which is a compound of Formula (II):Formula (II), or a pharmaceutically acceptable salt or tautomer thereof.

14. The method of any one of claims 1 to 13, wherein the therapeutically effective amount of the (Z)-endoxifen is from about 0.01 to 360 mg.

15. The method of any one of claims 1 to 14, wherein the therapeutically effective amount of the (Z)-endoxifen is from about 0.01 mg to 200 mg, from 0.1 mg to 100 mg, from 0.1 mg to 50 mg, from 0.1 mg to 20 mg, from 1 mg to 20 mg, from 20 mg to 50 mg, from 50 mg to 100 mg, from 100 mg to 200 mg, or from 200 mg to 360 mg.

16. The method of any one of claims 1 to 15, wherein the therapeutically effective amount of the (Z)-endoxifen is from about 1 and 80 mg.

17. The method of any one of claims 1 to 16, wherein the (Z)-endoxifen is administered at a unit dose from about 0.05 to 0.5 mg / kg, about 0.5 to 1 mg / kg, about 1 to 1.5 mg / kg, about 1.5 to 2 mg / kg, about 2 to 5 mg / kg, or about 5 to 10 mg / kg.

18. The method of any one of claims 1 to 17, wherein the (Z)-endoxifen is administered at a unit dose of about 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2.0 mg / kg.

19. The method of any one of claims 1 to 18, wherein the (Z)-endoxifen is administered once a day. twice a day, three times a day. four times a day. every’ other day, once every three days, or once every four days.

20. The method of any one of claims 1 to 19, wherein the (Z)-endoxifen is administered for at least 1 month to 5 years.

21. The method of any one of claims 1 to 20, wherein the therapeutically effective amount of the CDK4 / 6 inhibitor is from about 0.1 mg to 600 mg.

22. The method of any one of claims 1 to 21, wherein the therapeutically effective amount of the CDK4 / 6 inhibitor is from 50 mg to 200 mg, from 200 mg to 400 mg, or 400 mg to 600 mg.

23. The method of any one of claims 1 to 22, wherein the CDK4 / 6 inhibitor is administered at a unit dose of about 1 to 5 mg / kg or about 5 to 10 mg / kg.

24. The method of any one of claims 1 to 24, wherein the CDK4 / 6 inhibitor is administered once a day, twice a day, three times a day, four times a day, every other day, once every three days, or once every four days.

25. The method of any one of claims 1 to 25, wherein the CDK4 / 6 inhibitor is administered for at least 1 month to 5 years.

26. The method of any one of claims 1 to 25, wherein the (Z)-endoxifen is administered in a first dosage form and the CDK4 / 6 inhibitor is administered in a second dosage form.

27. The method of claim 26, wherein the first dosage form is administered orally.

28. The method of claim 26 or claim 27, wherein the first dosage form is formulated as an enteric formulation or as a delayed release formulation.

29. The method of any one of claims 26 to 28, wherein the first dosage form is formulated as an enteric caplet, an enteric capsule, a delayed-release tablet, a delay ed-release caplet, or a delay ed-release capsule.

30. The method of any one of claims 26 to 29, wherein the first dosage form comprises hydroxypropyl methyl cellulose.

31. The method of any one of claims 26 to 30, wherein the first dosage form comprises a therapeutically effective amount from 0.01 to 360 mg of the (Z)-endoxifen.

32. The method of any one of claims 26 to 31, wherein the first dosage form comprises a therapeutically effective amount from 0.01 mg to 200 mg, from 0.1 mg to 100 mg, from 0.1 mg to 50 mg, from 0.1 mg to 20 mg, from 1 mg to 20 mg, from 20 mg to 50 mg, from 50 mg to 100 mg, from 100 mg to 200 mg, or from 200 mg to 360 mg of the (Z)- endoxifen.

33. The method of any one of claims 26 to 32, wherein the first dosage form comprises a therapeutically effective amount of between about 1 and 80 mg of the (Z)-endoxifen.

34. The method of any one of claims 26 to 33, wherein the first dosage form comprises a unit dose of 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2.0 mg / kg of the (Z)- endoxifen.

35. The method of any one of claims 26 to 34, wherein the first dosage form is administered at a unit dose of about 0.05 to 0.5 mg / kg, about 0.5 to 1 mg / kg, about 1 to 1.5 mg / kg, about 1.5 to 2 mg / kg. about 2 to 5 mg / kg, or about 5 to 10 mg / kg of the (Z)-endoxifen.

36. The method of any one of claims 26 to 35, wherein the first dosage form is administered at a unit dose of 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2.0 mg / kg of the (Z)-endoxifen.

37. The method of any one of claims 26 to 36, wherein the first dosage form is administered once a day, twice a day, three times a day, four times a day, every other day, once every three days, or once every four days.

38. The method of any one of claims 26 to 37, wherein the first dosage form is administered for at least 1 month to 5 years.

39. The method of any one of claims 26 to 38, wherein the second dosage form comprises about 0.1 to 600 mg of the CDK4 / 6 inhibitor.

40. The method of claim 39, wherein the CDK4 / 6 inhibitor is abemaciclib.

41. The method of claim 40, wherein the second dosage form comprises a therapeutically effective amount between about 0.1 mg to 600 mg of the abemaciclib.

42. The method of claim 40 or claim 41, wherein the second dosage form comprises a therapeutically effect amount of 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg of the abemaciclib.

43. The method of any one of claims 40 to 42. wherein the second dosage form is administered at a unit dose of 25 to 600 mg daily of the abemaciclib.

44. The method of any one of claims 40 to 43, wherein the second dosage form is administered at a unit dose from 0.1 to 5 mg / kg, 5 to 10 mg / kg, 10 to 20 mg / kg, 20 to 30 mg / kg, 30 to 40 mg / kg, 40 to 50 mg / kg, 50 to 60 mg / kg, 60 to 70 mg / kg, 70 to 80 mg / kg, 80 to 90 mg / kg, or 90 to 100 mg / kg of the abemaciclib.

45. The method of any one of claims 40 to 44, wherein the second dosage form is administered at a unit dose of 25 mg / kg, 50 mg / kg, 50 mg / kg. or 100 mg / kg of the abemaciclib.

46. The method of any one of claims 40 to 45, wherein the second dosage form is administered once a day, twice a day, three times a day, four times a day, every other day, once every three days, or once every four days.

47. The method of any one of claims 40 to 46, wherein the second dosage form is administered in an amount of 50 mg twice daily. 100 mg twice daily, 150 mg twice daily, or 200 mg twice daily of the abemaciclib.

48. The method of claim 40 to 47, wherein the second dosage form of is administered in an amount of 150 mg or 200 mg twice daily of the abemaciclib.

49. The method of any one of claims 1 to 26, wherein the (Z)-endoxifen and the CDK4 / 6 inhibitor are administered in a single dosage form.

50. The method of claim 49, wherein the (Z)-endoxifen and the abemaciclib are administered in a single dosage form.

51. The method of claim 49 or claim 50, wherein the single dosage form is formulated as a suspension, a tablet, a capsule, a caplet, a liquid, or a gel.

52. The method of any one of claims 49 to 51, wherein the single dosage form is formulated as an enteric formulation or as a delayed release formulation.

53. The method of any one of claims 49 to 52, wherein the single dosage form is formulated as an enteric caplet, an enteric capsule, a delayed-release tablet, a delay ed-release caplet, or a delayed-release capsule.

54. The method of any one of claims 49 to 53, wherein the single dosage form comprises hydroxypropyl methyl cellulose.

55. The method of any one of claims 49 to 54. wherein the single dosage form is administered orally.

56. The method of any one of claims 49 to 55, wherein the single dosage form is administered at an amount of 0.01 mg to 200 mg of the (Z)-endoxifen.

57. The method of any one of claims 49 to 56, wherein the single dosage form comprises a therapeutically effective amount from about 0.01 mg to 200 mg, about 0.1 mg to 100 mg, about 0.1 mg to 50 mg. about 0.1 mg to 20 mg, or about 1 mg to 20 mg of the (Z)- endoxifen.

58. The method of any one of claims 49 to 57, wherein the single dosage form is administered at a unit dose of 0.05 to 0.5 mg / kg, 0.5 to 1 mg / kg, 1 to 1.5 mg / kg, 1.5 to 2 mg / kg, 2 to 5 mg / kg, 5 to 10 mg / kg, or 10 to 20 mg / kg of the (Z)-endoxifen.

59. The method of any one of claims 49 to 58. wherein the single dosage form is administered at a unit dose of 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2.0 mg / kg of the (Z)-endoxifen.

60. The method of any one of claims 50 to 59, wherein the single dosage form comprises a therapeutically effective amount of 50 mg, 100 mg, 150 mg, or 200 mg of the abemaciclib.

61. The method of any one of claims 50 to 60, wherein the single dosage form comprises a therapeutically effective amount from about 0.1 to 400 mg of the abemaciclib.

62. The method of any one of claims 50 to 61, wherein the single dosage form comprises a therapeutically effective amount of 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg of the abemaciclib.

63. The method of any one of claims 50 to 62, wherein the single dosage form is administered at a unit dose from about 25 to 800 mg daily of the abemaciclib.

64. The method of any one of claims 50 to 63. wherein the single dosage form is administered at a unit dose from about 0.1 to 5 mg / kg, 5 to 10 mg / kg, 10 to 20 mg / kg, 20 to 30 mg / kg, 30 to 40 mg / kg, 40 to 50 mg / kg, 50 to 60 mg / kg, 60 to 70 mg / kg, 70 to 80 mg / kg, 80 to 90 mg / kg, or 90 to 100 mg / kg of the abemaciclib.

65. The method of any one of claims 50 to 64, wherein the single dosage form is administered at a unit dose of 25 mg / kg, 50 mg / kg, 50 mg / kg, or 100 mg / kg of the abemaciclib.

66. The method of any one of claims 49 to 65, wherein the single dosage form is administered once a day, twice a day, three times a day, four times a day, every other day, every two days, every three days, or every four days.

67. The method of any one of claims 1 to 66, wherein at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released in the intestines.

68. The method of any one of claims 1 to 67, wherein the administration of the pharmaceutical composition achieves a mean area under the curve extrapolated to time infinity' (AUCO-inf) of (Z)-endoxifen of 200 hr*ng / mL to 10000 hr*ng / mL, of 300 hr*ng / mL to 8000 hr*ng / mL, of 400 hr*ng / mL to 6000 hr*ng / mL or of 700 hr*ng / mL to 6000 hr*ng / mL.

69. The method of any one of claims 1 to 68, wherein a steady state plasma level of endoxifen in the subject is greater than 30 nM.

70. The method of any one of claims 1 to 69, wherein a steady state plasma level of endoxifen is achieved within 7 to 21 days of a first administration of the pharmaceutical composition.

71. The method of any one of claims 1 to 70, wherein a time to maximum plasma levels of endoxifen is from 2 hours to 10 hours or from 4 hours to 8 hours after administering the pharmaceutical composition.

72. The method of any one of claims 1 to 71, wherein prior to administering the pharmaceutical composition, a biomarker measurement of the subject is at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% higher than a baseline biomarker measurement of a subject without cancer.

73. The method of any one of claims 1 to 72, wherein after at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 3 months, at least 4 months, at least 5 months, or at least 6 months of administering the composition, a biomarker measurement of the subject is at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% lower than an initial biomarker measurement of a subject without cancer.

74. The method of claim 72 or claim 73, wherein the biomarker is PKCpi, Ki-67, ER, PgR, cyclin DI, E2F1, pAKT, total AKT, c-PARP, BCL2, or serum TK1.

75. The method of claim 74, wherein the biomarker is Ki-67.

76. The method of claim 75, wherein the subject has a Ki-67 level of at most 10% at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks prior to surgery’.

77. The method of any one of claims 1 to 76, wherein the method further comprises administering the pharmaceutical composition at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks prior to surgery.

78. The method of any one of claims 1 to 77, wherein the administering the pharmaceutical composition continues after surgery.

79. The method of any one of claims 1 to 78, wherein the HR+ cancer is estrogen receptor positive (ER+) cancer.

80. The method of claim 79, wherein the ER+ cancer is breast cancer, endometrial cancer, prostate cancer, uterine cancer, gastric cancer, lung cancer or ovarian cancer.

81. The method of claim 79 or claim 80, wherein the ER+ cancer is low grade endometrial or low grade serous ovarian carcinoma.

82. The method of any one of claims 79 to 81, wherein the ER+ cancer is human epidermal growth factor receptor 2 negative (HER2-) breast cancer.

83. The method of any one of claims 1 to 82, wherein the subject has metastatic breast cancer.

84. The method of any one of claims 1 to 83, wherein the subject in need thereof has or is at risk for developing a breast cancer-associated co-morbidity.

85. The method of any one of claims 1 to 84, wherein the subject in need thereof is tamoxifen-refractory or tamoxifen-resistant.

86. The method of any one of claims 1 to 85, wherein the subject in need thereof is contraindicated for aromatase inhibitor therapy.

87. The method of any one of claims 1 to 86, wherein an additional aromatase inhibitor is not administered.

88. The method of any one of claims 1 to 87, wherein the subject in need thereof is contraindicated for ovarian suppression therapy.

89. The method of any one of claims 1 to 88, wherein the ovarian suppression therapy is not administered.

90. The method of any one of claims 1 to 89, wherein the subject in need thereof is premenopausal.

91. The method of any one of claims 1 to 90, wherein the subject in need thereof is postmenopausal.

92. The method of any one of claims 1 to 91, wherein administering the composition continues after surgery.

93. The method of any one of claims 1 to 92, wherein the administration results in rates of disease-free survival (DFS) at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% higher compared to treatment with abemaciclib, with (Z)-endoxifen and abemaciclib, or with (Z)-endoxifen alone.

94. The method of any one of claims 1 to 93, wherein the administration results in rates of partial mastectomy at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, or at least 10% higher compared to treatment with abemaciclib, with (Z)-endoxifen and abemaciclib, or with (Z)-endoxifen alone.

95. The method of any one of claims 1 to 94, wherein the administration results in rates of full mastectomy at least 80%, at least 85%, at least 90%, at least 95%, or at least 98% lower compared to treatment with abemaciclib, with (Z)-endoxifen and abemaciclib, or with (Z)-endoxifen alone.

96. The method of any one of claims 1 to 95, wherein the administration results in increased treatment of the cancer compared to treatment with abemaciclib, with (Z)-endoxifen and abemaciclib, or with (Z)-endoxifen alone.

97. The method of any one of claims 1 to 96, wherein the method further comprises administration of a chemotherapy.

98. The method of any one of claims 1 to 97, wherein the administration results in synergistic treatment of the cancer.

99. The method of any one of claims 1 to 98, wherein the administration results in an increase in effectiveness compared to treatment with abemaciclib, with (Z)-endoxifen and abemaciclib, or with (Z)-endoxifen alone.

100. The method of any one of claims 1 to 99, wherein the subject in need thereof is disease-free for 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months. 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 36 months, 37 months, 38 months, 39 months, 40 months, 41 months, 42 months, 43 months, 44 months, 45 months, 46 months, 47 months, 48 months, 49 months, 50 months, 51 months, 52 months, 53 months, 54 months, 55 months, 56 months, 57 months, 58 months, 59 months, 60 months, 61 months, 62 months, 63 months, 64 months, 65 months, 66 months, 67 months, 68 months, 69 months, 70 months, 71 months, 72 months, or greater.

101. The method of any one of claims 1 to 100, wherein the subject in need thereof has an objective response rate of at least 10%.

102. A method of treating a subject having or at risk of having an HR+ HER2- breast cancer, the method comprising administering an oral composition comprising a combination of a therapeutically effective amount of (Z)-endoxifen or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of abemaciclib or a pharmaceutically acceptable salt thereof, wherein administration of the composition achieves:a mean half-life of endoxifen in the subject ranging from 30 hours to 60 hours after administration;a time to maximum plasma levels of endoxifen ranging from 4 hours to 8 hours after administration;a steady state plasma level of endoxifen greater than 30 nM;a mean half-life of abemaciclib in the subject ranging from 8 to 65 hours after administration; anda time to maximum plasma levels of abemaciclib ranging from 0-11 hours after administration, thereby treating the subject having or at risk of having the HR+ HER2- breast cancer.

103. A method of treating a subject having or at risk of having an HR+ endometrial or ovarian cancer, the method comprising administering an oral composition comprising a combination of a therapeutically effective amount of (Z)-endoxifen or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of abemaciclib or a pharmaceutically acceptable salt thereof, thereby treating the subject having or at risk of having the HR+ endometrial or ovarian cancer.

104. A method of treating a subj ect having or at risk of having an HR+ cancer, the method comprising administering an oral composition comprising a combination of a therapeutically effective amount of (Z)-endoxifen or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of abemaciclib or a pharmaceutically acceptable salt thereof, wherein the cancer is HR+, and has failed previous CDK4 / 6inhibitor therapy, thereby treating the subject having or at risk of having the HR+ cancer.

105. A method for treating an HR+ cancer in a subject in need thereof, comprising:determining that a biopsy or tissue sample from the subject has a positive or high score for a biomarker comprising PKCpi. Ki-67, ER, PgR, cyclin DI, E2F1. pAKT. total AKT, c-PARP, BCL2, or serum TK1; and administering a therapeutically effective amount of (Z)-endoxifen or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of abemaciclib or a pharmaceutically acceptable salt thereof, thereby treating the HR+ cancer in the subject in need thereof.

106. The method of claim 105, wherein the Ki-67 score is 20% or higher.

107. The method of claim 105 or claim 106, wherein the Ki-67 score is a number of Ki-67 staining viable cancer cells in the biopsy or tissue sample divided by a total number of cancer cells in the biopsy or tissue sample, multiplied by 100.

108. The method of any one of claims 10 to 107. wherein the method comprises administering the (Z)-endoxifen or a pharmaceutically acceptable salt thereof concurrently, at separate times, or in sequential times with the abemaciclib or pharmaceutically acceptable salt thereof.

109. The method of any one of claims 10 to 107. wherein the method comprises administering the (Z)-endoxifen or a pharmaceutically acceptable salt thereof sequentially with the abemaciclib or pharmaceutically acceptable salt thereof.

110. The method of any one of claims 10 to 109. wherein the method comprises administering the (Z)-endoxifen or a pharmaceutically acceptable salt thereof and the abemaciclib or pharmaceutically acceptable salt thereof for a length of time, wherein progression-free survival of the subject is improved over a previous treatment.

111. The method of any one of claims 1 to 110, wherein the subject has previously undergone treatment with a CDK4 / 6 inhibitor.

112. The method of any one of claims 1 to 111, wherein the cancer increased in size or metastasized upon previous treatment with a CDK4 / 6 inhibitor.

113. The method of any one of claims 1 to 112, wherein the cancer comprises an ESRI mutation.

114. The method of claim 113, wherein the (Z)-endoxifen inhibits transcriptional activity of the ESRI mutation in the cancer.

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