(z)-endoxifen for neoadjuvant treatment of er+ / her2- breast cancer in premenopausal women

Abstract

Described herein are (Z)-endoxifen compositions and methods using (Z)-endoxifen compositions for treating various cancers, such as hormone-dependent cancers. The (Z)-endoxifen compositions may be used to treat cancers such as breast cancer, medulloblastoma or glioblastoma. A method of treating various cancers may include administering (Z)-endoxifen to a subject having pediatric medulloblastoma or adult-glioblastoma multiforme.

Description

(Z)-ENDOXIFEN FOR NEOADJUVANT TREATMENT OF ER+ / HER2- BREAST CANCER IN PREMENOPAUSAL WOMENCROSS-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 / 733,393 filed on December 12, 2024 and U.S. Provisional Patent Application No. 63 / 730,391 filed on December 10, 2024. The disclosure of the prior application is considered part of and is herein incorporated by reference in the disclosure of this application in its entirety.BACKGROUND OF THE DISCLOSURE

[0002] Breast cancer is the most frequently diagnosed cancer in premenopausal women worldwide, with approximately 75% of cases being either luminal A or luminal B subtypes. These subtypes are typically treated with endocrine therapy, often combined with ovarian function suppression (OFS) and sometimes chemotherapy. Despite aggressive treatment, premenopausal women with breast cancer tend to have a less favorable prognosis compared to their postmenopausal counterparts.

[0003] The current standard of care for premenopausal women with estrogen receptor-positive (ER+) / human epidermal grow th factor receptor 2-negative (HER2-) breast cancer includes the use of aromatase inhibitors (AIs) combined with OFS. This regimen has been shown to improve disease-free survival compared to tamoxifen alone. However, the combination of AIs and OFS is associated with significant morbidity, including increased risks of cardiac disease, osteoporosis, and other health issues. Additionally, adherence to this treatment is often poor, particularly among younger women, due to the severe side effects associated with estrogen deprivation.

[0004] Tamoxifen, a selective estrogen receptor modulator (SERM). is another treatment option for premenopausal women who cannot tolerate OFS. However, tamoxifen monotherapy is less effective than the combination of AIs and OFS, with only about 41% of patients achieving endocrine sensitive disease (ESD) as indicated by a Ki-67 index of <10% after 4 weeks of treatment. 7 In contrast, approximately 70% of patients achieve ESD with AIs and OFS.

[0005] (Z)-endoxifen, a potent metabolite of tamoxifen, has emerged as a promising alternative for the treatment of ER+ / HER2- breast cancer. (Z)-endoxifen is significantly more potent than tamoxifen and has been shown to effectively target both estrogen receptor alpha (ERa) and protein kinase C beta 1 (PKCpi), a novel target implicated in breast cancer cell proliferation. Clinical1KTS Docket No. 116771 - 1531854-821 WO 1studies have demonstrated that (Z)-endoxifen can achieve steady-state plasma concentrations that are effective in inhibiting both ERa and PKC01, leading to significant antitumor activity.

[0006] The EVANGELINE study, a Phase 2 randomized trial, is currently evaluating the efficacy and safety of (Z)-endoxifen in combination with goserelin compared to exemestane plus goserelin as neoadjuvant treatment for premenopausal women with ER+ / HER2- breast cancer. Preliminary results from the pharmacokinetic (PK) run-in phase of the study have identified that a 40 mg / day dose of (Z)-endoxifen can achieve the desired plasma concentrations with acceptable safety and tolerability.

[0007] Given the limitations of current endocrine therapies and the promising results from early studies of (Z)-endoxifen, there is a significant need for new treatment options that can provide effective endocrine therapy without the side effects associated with OFS. (Z)-endoxifen has the potential to fill this gap, offering a more potent and well-tolerated alternative for premenopausal women with ER+ / HER2- breast cancer.BRIEF SUMMARY OF THE DISCLOSURE

[0008] In some aspects, the techniques described herein relate to a method of neoadjuvant treatment for a premenopausal subject with ER+ / HER2- breast cancer, the method including: (a) determining a pre-treatment Ki-67 level in the subject; (b) administering a composition including (Z)-endoxifen to the subject during a pre-surgical treatment period; (c) determining a posttreatment Ki-67 level in the subject; and (d) repeating steps (b) through (c) until the post-treatment Ki-67 level in the subject is less than 10% of the pre-treatment Ki -67 level. In some aspects, the method further includes surgically removing a breast cancer tissue from the subject following step (d). In some aspects, the pre-surgical treatment period is from 1 to 30 weeks, from 5 to 30 weeks, from 10 to 25 weeks, or from 20 to 30 weeks. In some aspects, step (a), step (c), or a combination thereof further includes obtaining a tumor biopsy sample from the subject. In some aspects, the post-treatment Ki-67 level includes obtaining the tumor biopsy sample at 1 to 20 weeks, 1 to 15 w eeks, 1 to 10 weeks, 2 to 7 weeks, or 3 to 5 weeks after administering (Z)-endoxifen.

[0009] In some aspects, the method further includes administering to the subject a composition including goserelin if the post-treatment Ki-67 level is greater than 10%. In some aspects, the (Z)- endoxifen is administered at a dose that achieves a steady-state plasma concentration of between 500 ng / mL and 1000 ng / mL. In some aspects, the subject has clinical Stage II A or IIB invasive breast cancer. In some aspects, the method further includes measuring one or more additional biomarkers selected from the group consisting of: ER, PgR, PKCpi, C-PARP, cyclin DI, E2F1, pAKT, AKT, and ESRI mutations. In some aspects, the method further includes performing2KTS Docket No. 116771 - 1531854-821 WO 1magnetic resonance imaging. In some aspects, the magnetic resonance imaging is performed between 2 to 20 weeks, 4 to 16 weeks, or 10 to 14 weeks after administering (Z)-endoxifen.

[0010] In some aspects, the techniques described herein relate to a method of treating an ER+ / HER2- breast cancer in a premenopausal subject, the method including: (a) determining a pre-treatment level of one or more biomarkers selected from the group consisting of: Ki-67, ER, PgR, PKCpi, C-PARP, cyclin DI, E2F1, pAKT, AKT, ESRI mutations, tumor transcriptome, and / or tumor whole exome DNA; (b) administering (Z)-endoxifen during a pre-surgical treatment period; (c) determining a post-treatment level of the one or more biomarkers of step (a); and (d) repeating steps (b) through (c) until the post-treatment level of the one or more biomarkers reaches a target level. In some aspects, the method further includes surgically removing a breast cancer tissue from the subject following step (d). In some aspects, the pre-surgical treatment period is from 1 to 30 weeks, from 5 to 30 weeks, from 10 to 25 weeks, or from 20 to 30 weeks. In some aspects, step (a), step (c), or a combination thereof further includes obtaining a tumor biopsy sample from the subject. In some aspects, determining the post-treatment Ki-67 level includes obtaining the tumor biopsy sample at 1 to 20 weeks, 1 to 15 weeks, 1 to 10 weeks, 2 to 7 weeks, or 3 to 5 weeks after administering (Z)-endoxifen.

[0011] In some aspects, the method further includes administering to the subject a composition including goserelin if the post-treatment biomarker level is greater than 10%. In some aspects, the goserelin is administered at a dose of 3 to 5 mg / month.

[0012] In some aspects, the techniques described herein relate to a method, wherein the (Z)- endoxifen is administered at a dose that achieves a steady-state plasma concentration of between 500 ng / mL and 1000 ng / mL. In some aspects, the method further includes performing surgery’ within 2 to 15 days after a final dose of (Z)-endoxifen. In some aspects, the subject has clinical Stage II A or IIB invasive breast cancer. In some aspects, the breast cancer has a tumor size greater than 2.0 cm. In some aspects, the method further includes performing magnetic resonance imaging at about 12 weeks after initiating (Z)-endoxifen treatment.

[0013] In some aspects, the method further includes measuring a level of serum thymidine kinase 1 (TK1), estrone (El), estradiol (El), or a combination thereof in a pre-treatment blood sample. In some aspects, the method further includes measuring a level of TK1, estrone (El), estradiol (El), or a combination thereof in a post-treatment blood sample.

[0014] In some aspects, the (Z)-endoxifen is administered at a dose of 20 to 100 mg / day, 40 mg / day, 20 mg / day, or 80 mg / day. In some aspects, the (Z)-endoxifen is administered at a dose that achieves a steady-state plasma concentration of between 500 ng / mL and 1000 ng / mL.3KTS Docket No. 116771 - 1531854-821 WO 1

[0015] In some aspects, the method further includes determining the level of one or more biomarkers in tumor biopsies, serum, or circulating tumor DNA (ctDNA) at one or more of a first, second, third, fourth, fifth, sixth, seventh, or eighth time prior to surgery. In some aspects, the first, second, third, fourth, fifth, sixth, seventh, or eighth time is between 1 to 30 weeks prior to surgery.

[0016] In some aspects, the one or more biomarkers include ER, progesterone receptor (PgR), protein kinase C beta 1 (PKC01), cleaved poly (ADP-ribose) polymerase (C-PARP), cyclin DI, E2F transcription factor 1 (E2F1), phosphory lated AKT (pAKT), AKT, and estrogen receptor 1 (ESRI) mutations. In some aspects, the one or more biomarkers include serum thymidine kinase 1 (TK1), estrone (El), estradiol (E2), and ctDNA. In some aspects, the one or more biomarkers include cholesterol, lipid panel, and coagulation biomarkers. In some aspects, the one or more biomarkers include C-telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1N1), bonespecific alkaline phosphatase, and osteocalcin.

[0017] In some aspects, the (Z)-endoxifen includes less than 25 ppm of mesityl oxide. In some aspects, the (Z)-endoxifen has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL. In some aspects, the (Z)-end oxifen has a water content of not more than 1.0% as tested by Method Ic of USP 921. In some aspects, the (Z)-endoxifen has a water activity (Aw) of less than 0.9.

[0018] In some aspects, the (Z)-endoxifen has a residue on ignition of not more than 0.1% as tested by a method of USP 281. In some aspects, the (Z)-endoxifen includes not more than 20 ppm of heavy metals as tested by Method II of USP 231. In some aspects, the (Z)-endoxifen includes not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate, not more than 5000 ppm heptane, and not more than 5000 ppm ethanol, as tested by a validated HPLC method.

[0019] In some aspects, the (Z)-endoxifen includes an isomeric purity of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% of (Z)-endoxifen. by weight. In some aspects, the (Z)-endoxifen includes less than 2% of an impurity having m / z of 511. In some aspects, the (Z)-endoxifen includes less than 1.5% of an impurity having m / z of 402.

[0020] In some aspects, the (Z)-endoxifen is formulated as an oral formulation including (Z)- endoxifen or a pharmaceutically acceptable salt thereof, wherein the oral formulation is in a form of an enteric tablet, an enteric caplet, or an enteric capsule. In some aspects, the (Z)-endoxifen includes less than 2% impurities. In some aspects, the (Z)-endoxifen is stable for at least 9 months at 25°C and 60% relative humidity. In some aspects, the (Z)-endoxifen includes no more than 3000 ppm methanol, no more than 720 ppm tetrahydrofuran, no more than 5000 ppm isopropanol, no more than 5000 ppm ethyl acetate; no more than 5000 ppm n-Heptane, no more than 5000 ppm ethanol, or any combination thereof. In some aspects, a water content of the (Z)-endoxifen is not4KTS Docket No. 116771 - 1531854-821 WO 1more than 1.0%. In some aspects, the (Z)-endoxifen includes no more than 20 ppm of heavy metals. In some aspects, the (Z)-endoxifen is stable for at least 3 months at 40°C and 75% relative humidity.

[0021] In some aspects, the pharmaceutically acceptable salt of (Z)-endoxifen 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 (Z)-endoxifen is (Z)-endoxifen gluconate.

[0022] In some aspects, the formulation is a delayed-release formulation. In some aspects, the formulation is resistant to dissolution in an acidic environment for at least 2 hours, as measured in a dissolution test. In some aspects, the formulation releases no more than 10% of the (Z)- endoxifen over 2 hours in gastric fluid, as measured in a dissolution test performed. In some aspects, the formulation releases at least 50% of the (Z)-endoxifen within 8 hours in intestinal fluid, as measured in a dissolution test.

[0023] In some aspects, the formulation further includes hydroxypropylmethyl cellulose. In some aspects, the formulation further includes a sugar, salt, talc, calcium carbonate, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, or combinations thereof. In some aspects, the formulation further includes a disintegrant. In some aspects, the formulation further includes calcium stearate, magnesium stearate, zinc stearate, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil, ethyl oleate, ethyl laureate, agar, or combinations thereof.

[0024] In some aspects, the formulation includes from 1 mg to 20 mg of (Z)-endoxifen. In some aspects, the formulation includes from 1 mg to 4 mg of (Z)-endoxifen. In some aspects, the formulation includes 40 mg, 20 mg and 80 mg of (Z)-endoxifen. In some aspects, the formulation is uncoated. In some aspects, the formulation further includes an enteric coating. In some aspects, the formulation is formulated as a suspension of one or more of the enteric capsule.

[0025] In some aspects, the present disclosure describes a treatment wherein a level of quality of life of the subject is improved over a baseline level of quality of life. In some aspects, the quality5KTS Docket No. 116771 - 1531854-821 WO 1of life indicator comprises at least one of headache, nausea, abdominal distension, hot flash, upper respiratory tract infection, fatigue, sweating, difficulty sleeping, decrease in sexual desire, vaginal dryness, vaginal bleeding, back pain, abdominal pain, tension headache, menstruation delayed, dysmenorrhea, arthralgia, irritability, dry’ mouth, or night sweats.

[0026] In one aspect, the present disclosure provides a method of neoadjuvant treatment for a premenopausal subject in need thereof with ER+ / HER2- breast cancer, the method comprising the follow ing steps: (a) determining a pre-treatment Ki-67 level in the premenopausal subject in need thereof; (b) administering a therapeutically effective amount of a composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof to the premenopausal subject in need thereof during a pre-surgical treatment period; (c) determining a post-treatment Ki-67 level in the premenopausal subject in need thereof; and (d) repeating steps (b) through (c) until the posttreatment Ki-67 level in the premenopausal subject in need thereof is less than 10% of the pretreatment Ki-67 level.

[0027] In another aspect, the present disclosure provides method of treating an ER+ / HER2- breast cancer in a premenopausal subject in need thereof, the method comprising the following steps: (a) determining a pre-treatment level of one or more biomarkers selected from the group consisting of: Ki-67, ER, PgR, PKC01, C-PARP, cyclin DI, E2F1, pAKT, AKT, ESRI mutations, tumor transcriptome, and tumor whole exome DNA; (b) administering a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof during a pre-surgical treatment period; (c) determining a post-treatment level of the one or more biomarkers of step (a); and (d) repeating steps (b) through (c) until the post-treatment level of the one or more biomarkers reaches a target level.

[0028] In some aspects, the method further comprises surgically removing a breast cancer tissue from the premenopausal subject in need thereof following step (d).

[0029] In some aspects, the pre-surgical treatment period is from 1 to 30 weeks, from 5 to 30 weeks, from 10 to 25 weeks, or from 20 to 30 weeks.

[0030] In some aspects, step (a), step (c), or a combination thereof further comprises obtaining a tumor biopsy sample from the premenopausal subject in need thereof.

[0031] In some aspects, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 1 to 20 w eeks, 1 to 15 weeks, 1 to 10 weeks, 2 to 7 weeks, or 3 to 5 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.6KTS Docket No. 116771 - 1531854-821 WO 1

[0032] In some aspects, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is greater than 10%.

[0033] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration between 500 ng / mL and 1000 ng / mL of (Z)-endoxifen.

[0034] In some aspects, the premenopausal subject in need thereof has clinical Stage IIA invasive breast cancer or clinical Stage IIB invasive breast cancer.

[0035] In some aspects, the method further comprises measuring one or more additional biomarkers selected from the group consisting of: ER, PgR, PKC(31, C-PARP, cyclin DI, E2F1, pAKT, AKT, and ESRI mutations.

[0036] In some aspects, the method further comprises performing magnetic resonance imaging.

[0037] In some aspects, the magnetic resonance imaging is performed between 2 to 20 weeks, 4 to 16 weeks, or 10 to 14 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

[0038] In some aspects, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 10%.

[0039] In some aspects, the composition comprising goserelin is administered at a dose of 3 to 5 mg / month.

[0040] In some aspects, the method further comprises performing surgery within 2 to 15 days after a final dose of the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

[0041] In some aspects, the breast cancer has a tumor size greater than 2.0 cm.

[0042] In some aspects, the method further comprises performing magnetic resonance imaging at 12 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

[0043] In some aspects, the method further comprises measuring a serum level of thymidine kinase 1 (TK1), estrone (El), estradiol (El), or a combination thereof in a pre- treatment blood sample.

[0044] In some aspects, the method further comprises measuring a serum level of thymidine kinase 1 (TK1), estrone (El), estradiol (El), or a combination thereof in a post-treatment blood sample.7KTS Docket No. 116771 - 1531854-821 WO 1

[0045] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 20 to 100 mg / day, 40 mg / day, 20 mg / day, or 80 mg / day.

[0046] In some aspects, the method further comprises determining the level of the one or more biomarkers in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA) for 1, 2, 3, 4, 5, 6, 7, or 8 times prior to surgery.

[0047] In some aspects, the 1, 2, 3, 4, 5, 6, 7, or 8 times prior to surgery is between 1 to 30 weeks prior to surgery;

[0048] In some aspects, the one or more biomarkers comprise ER. progesterone receptor (PgR), protein kinase C beta 1 (PK.C01), cleaved poly (ADP-ribose) polymerase (C-PARP), cyclin DI, E2F transcription factor 1 (E2F1), phosphorylated AKT (pAKT), AKT, or estrogen receptor 1 (ESRI) mutations.

[0049] In some aspects, the one or more biomarkers comprise thymidine kinase 1 (TK1), estrone (El), estradiol (E2), or ctDNA.

[0050] In some aspects, the one or more biomarkers comprise a cholesterol biomarker, a lipid panel biomarker, or a coagulation biomarker.

[0051] In some aspects, the one or more biomarkers comprise C-telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1N1), bone-specific alkaline phosphatase, or osteocalcin.

[0052] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof comprises less than 25 ppm of mesityl oxide.

[0053] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof has an aerobic bacterial plate count of 0.05 g / mL to 20.000 g / mL.

[0054] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof has a water content of not more than 1.0% as tested by Method Ic of USP 921.

[0055] In some aspects, the composition comprising (Z)-endoxifen has or a pharmaceutically acceptable salt thereof a water activity (Aw) of less than 0.9.

[0056] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof having a residue on ignition of not more than 0.1% as tested by a method of USP 281.

[0057] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof comprising not more than 20 ppm of heavy metals as tested by Method II of USP 231.8KTS Docket No. 116771 - 1531854-821 WO 1

[0058] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof comprises not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate, not more than 5000 ppm heptane, and not more than 5000 ppm ethanol, as tested by a validated HPLC method.

[0059] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof comprises an isomeric purity of (Z)-endoxifen of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% of (Z)-endoxifen by weight (wt%).

[0060] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof comprises less than 2% of an impurity having m / z of 51 1

[0061] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof comprises less than 1.5% of an impurity having m / z of 402.

[0062] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.

[0063] In some aspects, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is formulated as an oral formulation comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof, wherein the oral formulation is an enteric tablet, an enteric caplet, or an enteric capsule.

[0064] In some aspects, the oral formulation comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof comprises less than 2% of (Z)-endoxifen impurities.

[0065] In some aspects, the oral formulation comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is stable for at least 9 months at 25°C and 60% relative humidity.

[0066] In some aspects, the oral formulation comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof comprises no more than 3000 ppm methanol, no more than 720 ppm tetrahydrofuran, no more than 5000 ppm isopropanol, no more than 5000 ppm ethyl acetate; no more than 5000 ppm n-Heptane. no more than 5000 ppm ethanol, or any combination thereof.

[0067] In some aspects, the oral formulation comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof has a water content of the (Z)-endoxifen is not more than 1.0%.

[0068] In some aspects, wherein the oral formulation comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof comprises no more than 20 ppm of heavy metals.

[0069] In some aspects, the oral formulation comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is stable for at least 3 months at 40°C and 75% relative humidity.9KTS Docket No. 116771 - 1531854-821 WO 1

[0070] In some aspects, the pharmaceutically acceptable salt of (Z)-endoxifen 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 salt

[0071] In some aspects, the pharmaceutically acceptable salt of (Z)-endoxifen is (Z)-endoxifen gluconate.

[0072] In some aspects, the oral formulation is a delayed-release formulation

[0073] In some aspects, the oral formulation is resistant to dissolution in an acidic environment for at least 2 hours, as measured in a dissolution test.

[0074] In some aspects, the oral formulation releases no more than 10% of the (Z)-endoxifen over 2 hours in gastric fluid, as measured in a dissolution test performed.

[0075] In some aspects, the oral formulation releases at least 50% of the (Z)-endoxifen within 8 hours in intestinal fluid, as measured in a dissolution test.

[0076] In some aspects, the oral formulation further comprises hydroxypropylmethyl cellulose.

[0077] In some aspects, the oral formulation further comprises a sugar, salt, talc, calcium carbonate, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, or combinations thereof.

[0078] In some aspects, the oral formulation further comprises a disintegrant.

[0079] In some aspects, the oral formulation further comprises calcium stearate, magnesium stearate, zinc stearate, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil, ethyl oleate, ethyl laureate, agar, or combinations thereof.

[0080] In some aspects, the oral formulation comprises from 1 mg to 20 mg of (Z)-endoxifen.

[0081] In some aspects, the oral formulation comprises from 1 mg to 4 mg of (Z)-endoxifen.

[0082] In some aspects, the oral formulation comprises 40 mg, 20 mg, or 80 mg of (Z)-endoxifen.

[0083] In some aspects, the oral formulation is uncoated.

[0084] In some aspects, the oral formulation further comprises an enteric coating.

[0085] In some aspects, the oral formulation is an enteric capsule, an enteric coated capsule, or an enteric coated enteric capsule.10KTS Docket No. 116771 - 1531854-821 WO 1

[0086] In some aspects, the method further comprises an improvement in one or more quality of life indicators post-treatment relative to the pre-treatment.

[0087] In some aspects, the one or more quality-of-life indicators comprise at least one of headache, nausea, abdominal distension, hot flash, upper respiratory’ tract infection, fatigue, sweating, difficulty sleeping, decrease in sexual desire, vaginal dryness, vaginal bleeding, back pain, abdominal pain, tension headache, menstruation delayed, dysmenorrhea, arthralgia, irritability’, dry’ mouth, or night sweats.INCORPORATION BY REFERENCE

[0088] 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.BRIEF DESCRIPTION OF THE DRAWINGS

[0089] 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:

[0090] FIG. 1 is a schematic diagram illustrating the Phase 2 non-inferiority trial design comparing (Z)-endoxifen + goserelin versus exemestane + goserelin in premenopausal women with ER+ / HER2- breast cancer, showing the PK run-in phase followed by the randomized treatment phase;

[0091] FIG. 2 is a diagram depicting the single-arm Phase 2 study design evaluating (Z)- endoxifen + goserelin in premenopausal women with Stage IIA or IIB ER+ / HER2- breast cancer, highlighting the 4-week endocrine sensitive disease (ESD) rate assessment;

[0092] FIG. 3 is a graph showing the percentage distribution of women achieving steady-state (Z)-endoxifen plasma concentrations (Css) between 500-1000 ng / mL. The left column show’s subjects in the (Z)-endoxifen 40 mg Arm. The middle column shows subjects in the (Z)-endoxifen 80 mg Arm. The right column shows subjects in the (Z)-endoxifen 80 mg Arm + OFS. OFS = Ovarian functional suppresion;

[0093] FIG. 4 is a correlation plot demonstrating the relationship betw een plasma (Z)-endoxifen concentration on C1D28 and tumor (Z)-endoxifen concentration under two conditions: (Z)- endoxifen 80mg alone and (Z)-endoxifen 80mg + OFS. C1D28 = Cycle 1 Day 28. OFS = Ovarian functional suppresion;11KTS Docket No. 116771 - 1531854-821 WO 1

[0094] FIG. 5 is a graph showing tumor reduction as measured by MRI at week 12 of treatment; and

[0095] FIG. 6 displays three parallel graphs illustrating temporal changes in Ki-67 expression levels under different treatment regimens: (Z)-endoxifen 40 mg / day without ovarian function suppression (OFS), (Z)-endoxifen 80 mg / day without OFS, and (Z)-endoxifen 80 mg / day with OFS. C1D1 = Cycle 1 Day 1. C1D28 = Cycle 1 Day 28. C6D28 = Cycle 6 Day 28.DETAILED DESCRIPTION OF THE DISCLOSURE

[0096] The present disclosure relates to compositions and methods for treating breast cancer, particularly using (Z)-endoxifen, an active metabolite of tamoxifen that functions as a selective estrogen receptor modulator (SERM). (Z)-endoxifen is formed when tamoxifen is metabolized in the liver through CYP2D6-mediated processes. Studies have demonstrated that (Z)-endoxifen exhibits substantially greater antitumor activity compared to tamoxifen and aromatase inhibitor therapy, particularly in premenopausal women with ER+ / HER2- breast cancer. The enhanced efficacy appears to be due to (Z)-end oxifen’s dual mechanism of action targeting both estrogen receptor alpha (ERa) and protein kinase C beta 1 (PKC 1). Independent laboratories have demonstrated that tamoxifen and its primary metabolites only partially inhibit the stimulant effects of premenopausal estrogen levels, while the addition of (Z)-endoxifen fully inhibits estrogen actions at concentrations of 1 pM or greater.

[0097] Using a screen of 336 kinases (HOTSPOT™ Panel, Reaction Biology) with confirmatory in vitro kinase assays, PKC 1 was identified as a novel target for (Z)-endoxifen with an IC50 of 350 nM, compared to nearly 5 pM for tamoxifen. Surface plasmon resonance experiments confirmed direct binding of (Z)-endoxifen to PKCpi with an association constant of approximately 100 nM. Importantly, (Z)-endoxifen demonstrated specificity for PKCpi and did not interact with PKC(32, the other isoform produced from the PRKCB gene. In a separate unbiased global mass spectrometry analysis evaluating the effects of three different (Z)-endoxifen concentrations on the MCF7AC1 phospho-proteome, 5 pM (Z)-endoxifen concentrations more potently inhibited phospho-residues of proteins regulated by PKCs compared to 10 and 100 nM (concentrations that only target ER). PKCpi was identified as the top predicted upstream kinase inhibited by (Z)-endoxifen.

[0098] The effects of PKCpi knockdown in MCF7AC1 cells were assessed using two independent PKCpi siRNAs and an shRNA targeting different regions of the transcript. PKCpi knockdown resulted in robust inhibition of cell proliferation and identified 455 commonly regulated genes implicated in cell cycle related pathways. Cell cycle profiling confirmed that both12KTS Docket No. 116771 - 1531854-821 WO 1PKCpi knockdown and (Z)-endoxifen treatment induce G1 arrest. PKC 1 knockdown resulted in near ablation of ER and suppression of critical cell cycle related oncoproteins including cyclin DI, E2F1 and Rb in multiple cell lines, effects that were mimicked by (Z)-endoxifen but not tamoxifen or enzastaurin treatment.

[0099] In clinical studies, (Z)-endoxifen has been studied at doses of 1 to 360 mg in single and repeat dose studies across multiple centers, with approximately 388 people exposed totaling an estimated 20,576 exposure patient days. Phase 1 studies found (Z)-endoxifen to be well tolerated with substantial bioavailability, acceptable toxicity', reductions in total cholesterol, and promising antitumor activity in endocrine treatment-resistant breast cancer. A Phase 2 trial randomizing postmenopausal patients with metastatic endocrine therapy resistant ER+ / HER2- breast cancer to either (Z)-endoxifen (80 mg / day) or tamoxifen (20 mg / day) showed prolonged progression-free survival with (Z)-endoxifen (7.2 months vs 2.4 months, HR 0.42, 95% CI 0.22-0.80, p=0.002) in patients without prior cyclin-dependent kinase (CDK) 4 / 6 inhibitor exposure.

[0100] The present disclosure provides methods for treating hormone receptor positive breast cancer in premenopausal subjects comprising administering an effective amount of (Z)-endoxifen. In some embodiments, (Z)-endoxifen is administered as neoadjuvant therapy for approximately 4-24 weeks prior to surgical resection. The methods include monitoring treatment response through assessment of Ki-67 levels in tumor biopsies, with Ki-67 <10% indicating endocrine sensitive disease. Studies have demonstrated that in women with early-stage ER+ / HER2- breast cancer treated with 2 to 4 weeks of endocrine therapy, Ki-67 is prognostic in both premenopausal and postmenopausal women. Patients with inadequate Ki-67 response (Ki-67>10%) after perioperative aromatase inhibitor therapy had 5-year recurrence rates of 21.5% compared to patients with baseline high Ki-67 response rates that decreased to <10% (5-year recurrence rates of 8.4%).

[0101] In some aspects, the techniques described herein relate to a method of neoadjuvant treatment for a premenopausal subject with ER+ / HER2- breast cancer, comprising (a) determining a first Ki-67 level; (b) administering (Z)-endoxifen during a pre-surgical treatment period; (c) determining a second Ki-67 level; and (d) repeating steps (a) through (b) until the second Ki-67 level is less than 10%. In some aspects, the pre-surgical treatment period is from 1 to 30 weeks, from 5 to 30 weeks, from 10 to 25 weeks, or from 20 to 30 weeks. In some aspects, the method further includes obtaining a tumor biopsy sample from the subject. In some aspects, the method includes obtaining the tumor biopsy sample at 1 to 20 weeks, 1 to 15 weeks, 1 to 10 weeks. 2 to 7 weeks, or 3 to 5 weeks after administering (Z)-endoxifen.

[0102] Pharmaceutical compositions comprising (Z)-endoxifen are formulated for oral administration, ty pically as delayed release capsules containing 10 mg or 40 mg of active drug.13KTS Docket No. 116771 - 1531854-821 WO 1The delayed release formulation protects (Z)-endoxifen from acid degradation in the stomach. Daily doses between 20-80 mg are administered to achieve target steady state plasma concentrations of 500-1000 ng / mL. These concentrations are necessary to target PKCpi for degradation, which results in multiple anticancer effects including apoptosis and protein reductions in pAKT, ER, PR, Cyclin DI, and E2F1. Dose modifications may be implemented based on tolerability and plasma drug level monitoring.

[0103] The PK Run-in cohort of clinical studies evaluates the pharmacokinetics of (Z)-endoxifen in premenopausal women with Grade 1 or 2 ER+ / HER2- breast cancer after 4 weeks of 40 mg / day dosing. Additional 20 mg / day or 80 mg / day oral doses may be explored based on steady-state concentrations and observed toxicities. Pharmacokinetic analyses are generated on Day 1 and Day 28 of treatment and at surgery based on multiple sampling timepoints. Subjects demonstrating endocrine sensitive disease (Ki-67<10%) at Week 4 are eligible to continue treatment for up to 24 weeks prior to surgery.

[0104] Grade 3 and 4 symptoms reported at doses equal to or less than 80 mg / day include Grade 3 and Grade 4 hypertriglyceridemia, Grade 3 pulmonary embolus, and Grade 4 thromboembolic events. Common treatment emergent symptoms occurring in >10% of subjects include headache, nausea, abdominal distension, hot flash, upper respiratory' tract infection, fatigue, back pain, abdominal pain, tension headache, menstruation delayed, dy smenorrhea, arthralgia, irritability, dry mouth, and night sweats.

[0105] In some aspects, the present disclosure describes a treatment wherein a level of quality' of life of the subject is improved over a baseline level of quality of life. In some aspects, the quality' of life indicator comprises at least one of headache, nausea, abdominal distension, hot flash, upper respiratory tract infection, fatigue, sweating, difficulty sleeping, decrease in sexual desire, vaginal drymess, vaginal bleeding, back pain, abdominal pain, tension headache, menstruation delayed, dysmenorrhea, arthralgia, irritability, dry' mouth, or night sweats.Definitions

[0106] 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 w hich this invention belongs. As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below:

[0107] 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’.14KTS Docket No. 116771 - 1531854-821 WO 1

[0001] As used herein and unless otherwise specified, the term “consisting essentially of’ when used herein in connection with a compound, composition, use, or method, denotes that additional elements, method steps or both additional elements and method steps may be present, but that these additions do not materially affect the manner in which the recited composition, method, or use functions.

[0002] As used herein and unless otherwise specified, the term “consisting of’ when used herein in connection with a compound, composition, use, or method, excludes the presence of additional elements and / or method steps.

[0003] 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.

[0004] 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, an XRPD 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 ± 0.5 ° 2-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.

[0005] Whenever the term “about,” “at least,” “greater than,” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “about,” “at least,” “greater than,” or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, “greater than or equal to 1, 2, or 3” is equivalent to “greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3”.

[0006] Whenever the term “no more than,” “at most,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “at most,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, “less than or equal to 3, 2, or 1” is equivalent to “less than or equal to 3, less than or equal to 2, or less than or equal to 1”.15KTS Docket No. 116771 - 1531854-821 WO 1

[0007] As used herein, the terms “weight percent,” “wt%,” and “percent by weight” are used interchangeably to refer to the concentration of a substance as the weight of that substance divided by the total weight of the composition or of the mixture and multiplied by 100.

[0008] 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.

[0009] 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%. Yet 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 or from 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.16KTS Docket No. 116771 - 1531854-821 WO 1

[0010] 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 non-claimed element as essential to practice of the invention as used herein.

[0011] The term “modulate,” “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.

[0012] The term “agonism” as used herein refers to the activation of a receptor or enzy me by a modulator, or agonist, to produce a biological response.

[0013] The term “agonist” as used herein refers to a modulator that binds to a receptor or target enzyme and activates the receptor or enzyme to produce a biological response. By way of example, “GPR40 agonist” can be used to refer to a compound that exhibits an EC 50 with respect to GPR40 activity of no more than about 100 pM, as measured in the as measured in the inositol phosphate accumulation assay. In some embodiments, the term “agonist” includes full agonists or partial agonists.

[0014] The term “full agonist” refers to a modulator that binds to and activates a receptor or target enzyme with the maximum response that an agonist can elicit at the receptor or enzyme.

[0015] The term “partial agonist” refers to a modulator that binds to and activates a receptor or target enzyme, but has partial efficacy, that is, less than the maximal response, at the receptor or enzyme relative to a full agonist.

[0016] The terms “inhibit,” “block,” “suppress,” and grammatical variants thereof are used interchangeably herein and refer to any statistically significant decrease in biological activity, including full blocking of the activity. In some embodiments, “inhibition” refers to a decrease of about 10%, about 20%, about 30%, about 40%. about 50%, about 60%, about 70%. about 80%, about 90% or about 100% in biological activity. Accordingly, when the terms “inhibition” or “suppression” are applied to describe, e.g., an effect on the enzy matic activity' of a target, the term refers to the ability of a compound disclosed herein to statistically significantly decrease the activity of the target.

[0017] 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.17KTS Docket No. 116771 - 1531854-821 WO 1

[0018] 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.

[0019] The phrase “pharmaceutically acceptable” is employed 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 relatively nontoxic, 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 w hich it is contained.

[0020] 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.

[0021] In some embodiments, the composition described herein is a “pharmaceutical composition”. A pharmaceutical composition comprises at least one active agent (e.g., at least one active pharmaceutical compound or ingredient, API or salt thereof) with an excipient. Excipients include carriers, inerts or actives (e.g.. a phospholipid), making the compositions suitable for diagnostic or therapeutic uses in vitro, in vivo, or ex vivo.

[0022] 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 or18KTS Docket No. 116771 - 1531854-821 WO 1organic 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, secondary7, and tertiary7amines, 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.

[0023] 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.

[0024] 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, methylsulfate, mucate, napsylate,19KTS Docket No. 116771 - 1531854-821 WO 1nitrate, 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.

[0025] The term “solvate,” as used herein, means a molecular complex between compounds of the disclosed herein and solvent molecules. Examples of solvates include, but are not limited to, compounds disclosed herein in combination water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term “hydrate” can be used when said solvent is water. In some embodiments, one solvent molecule can be associated with one molecule of the compounds disclosed herein, such as a hydrate. In some embodiments, more than one solvent molecule may be associated with one molecule of the compounds disclosed herein, such as a dihydrate. In some embodiments, less than one solvent molecule may be associated with one molecule of the compounds disclosed herein, such as a hemihydrate. In some embodiments, solvates of compounds of disclosed herein retain the biological effectiveness of the non-hydrate form of the compounds (referred to as pharmaceutically acceptable solvates).

[0026] The term “prevent” or “preventing”, as used herein, as related to a disease or disorder may refer to a compound or a pharmaceutically acceptable salt thereof 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 the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample. In some embodiments, the terms “prevent,” “preventing”, or “prevention” are used interchangeably refer to prevention of a particular disorder or the occurrence or onset of one or more symptoms associated with the particular disease or disorder and does not necessarily mean the complete prevention of the disease or disorder. For example, the term “prevent,” “preventing” and “prevention” means the administration of therapy on a prophylactic or preventative basis to a subject in need thereof who may ultimately manifest at least one symptom of a disease or disorder but who has not yet done so. Such a subject in need thereof can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease. Alternatively, prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of at least one symptom can also be considered prevention or prophylaxis.20KTS Docket No. 116771 - 1531854-821 WO 1

[0027] 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. In one aspect, the subject is a human. In some embodiments, the subject suffers from a relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to a disease, disorder, or condition. In some embodiments, the subject displays one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a mammal with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, the human is an infant, a child, an adult, or a senior citizen (i.e., the subject is of advanced age, such as older than 50). In some embodiments, a child refers to a human that is between 0 and 2 years of age. In some embodiments, a child refers to a human that is between 2 and 18 years of age. In some embodiments, an adult refers to a human that is from 18 to 50 years of age.

[0028] As used herein, the phrase “a subject in need thereof’ and “in need of treatment” are used interchangeably to refer to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof described herein. In some embodiments, the phrase “a subject in need thereof’ and “in need of treatment” are used interchangeably when referring to treatment refer to a judgment made by a caregiver (e.g. physician, nurse, nurse practitioner, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver’s expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by the compounds of the invention. Accordingly, the compounds of the invention can be used in a protective or preventive manner; or compounds of the invention can be used to alleviate, inhibit, or ameliorate the disease, condition or disorder.

[0029] 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 disease21KTS Docket No. 116771 - 1531854-821 WO 1condition being treated, e.g., the weight 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 ordinary7skill 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 with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried. The term an “effective amount” or “therapeutically effective” amount can also refer 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. The term an “effective amount” or “therapeutically effective” amount can also refer any amount which results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

[0030] 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 some embodiments, 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 include22KTS Docket No. 116771 - 1531854-821 WO 1reducing 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.

[0031] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic benefit includes preventing, delaying, or eliminating the appearance of a disease or condition, preventing, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, preventing, or reversing the progression of a disease or condition, or any combination thereof.

[0032] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery' of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0033] As used herein, the terms “active pharmaceutical ingredient” (API), “active ingredient,” “drug,” and “therapeutic agent” are used interchangeably to refer to the pharmaceutically active compound(s) in a pharmaceutical composition and are intended for use in diagnosis, cure, mitigation, treatment, and / or prevention of disease in a human or another mammal. This is in contrast to other ingredients in the compositions, such as excipients, which are substantially or completely pharmaceutically inert. The therapeutic agent as used herein includes the active compounds and their salts, isomers, polymorphs, prodrugs, and metabolites.

[0034] 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 transdermal23KTS Docket No. 116771 - 1531854-821 WO 1administration selected from ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and patches.

[0035] 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. A “unit dose” is a dose of any therapeutic or active agent administered in one dose / at one time / single route / single point of contact, i.e., one administration event. As used herein, "split dose” refers to (1) dosing regimens in which one or more active agents are administered to a patient at least twice daily; (2) once daily administration of a pharmaceutical composition containing one or more active agent in which a portion of the active agent is formulated for immediate release and a portion of the active agent is formulated for delayed or pulsatile release; and (3) once daily administration of a pharmaceutical composition containing an active agent formulated for controlled or sustained release.

[0036] As used herein, “preventive therapy” refers to a therapy that is administered to healthy individuals at increased risk of breast cancer in order to decrease the risk of being diagnosed with breast cancer.

[0037] As used herein, “adjuvant therapy” refers to a therapy that follows a primary therapy of breast cancer and that is administered to patients to decrease the risk of relapsing. Adjuvant systemic therapy in case of breast cancer usually begins soon after primary therapy to delay recurrence, prolong survival or cure a subject.

[0038] As used herein, “neo-adjuvant therapy” refers to a therapy that precedes surgery for breast cancer and is administered to patients in order to decrease the tumor burden.

[0039] As used herein, “breast cancer” refers to any malignant tumor of breast cells. Breast cancer may be at any stage of breast cancer, including stages of a pre-cancer, an early-stage cancer, a non-metastatic cancer, a pre-metastatic cancer, a locally advanced cancer, and a metastatic cancer. Breast cancer can be invasive breast cancer or in situ breast cancer. There are several types of breast cancer. Exemplary breast cancers include, but are not limited to, 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, HER2+ breast cancer, triple negative breast cancer (TNBC), adenoid cystic (adenocystic) carcinoma, low-grade adenosquamatous carcinoma, medullary carcinoma, mucinous (or colloid)24KTS Docket No. 116771 - 1531854-821 WO 1carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, or micropapillary carcinoma. A single breast cancer tumor can be a combination of these types or be a mixture of invasive and in situ cancer.

[0040] As used herein, the term ‘“combination therapy” refers to the use of a composition described herein in combination with one or more additional treatment. Treatment in combination therapy can be any treatment such as any prophylactic agent, therapeutic agent (such as chemotherapy), radiotherapy, surgery and the like. The combination can refer to inclusion of a therapeutic or prophylactic agent in a same composition as a composition disclosed herein (for example, in the same capsule, tablet, ointment, etc.) or in separate compositions (for example, in 2 separate capsules). The separate compositions may be 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. Compositions of the present disclosure can be 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, 4 wk, 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. Combination therapy as used herein can also refer to treatment of a subject having a single disease or multiple diseases, for example, prostate cancer in men and gynecomastia.

[0041] As used herein, the term “pharmaceutically acceptable carrier” or “carrier” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting one or more of the compounds of the present disclosure from one tissue, organ, or portion of the body or across the skin.

[0042] 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-(l,2-diphenyl- l-butenyl)phenoxy]-N,N-dimethylethanamine) 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.25KTS Docket No. 116771 - 1531854-821 WO 1

[0043] As used herein, the terms '‘4-hydroxytamoxifen”, “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.

[0044] 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- 1 -en- 1 -yl)phenol). Unless otherwise specified, “endoxifen”, also referred to as “(ZZE)-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 aZ: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 a Z: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.

[0045] As used herein, unless otherwise specified, “endoxifen” refers to the free base (i.e., not a salt) of endoxifen. Therefore, “endoxifen”, “endoxifen free base”, “(ZZE)-endoxifen”, and “(Z / E)- endoxifen free base” are all equivalent terms. By way of example only:26KTS Docket No. 116771 - 1531854-821 WO 1p ;((Z / E)-endoxifen).

[0046] As used herein, the term “(Z)-endoxifen” is isomeric pure (100% of one alkene isomer)(Z)-endoxifen. (Z)-endoxifen is represented by the structure

[0047] As used herein, the term “(E)-endoxifen” is isomeric pure (100% of one alkene isomer)(E)-endoxifen. (E)-endoxifen is represented by the structure

[0048] As used throughout the present disclosure, the wiggly line ( ^ ) 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:KTS Docket No. 116771 - 1531854-821 WO 1

[0049] 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 to asrepresentations of (Z)-endoxifen hydrochloride (also referred to as (Z)-endoxifen hydrochloride):embodiments, the salt is a pharmaceutically acceptable salt.

[0050] As used herein, “In some embodiments,” and “In some cases,” are used interchangeably herein and mean that a particular feature, structure, characteristic, step, or element described in connection with the embodiment is included in at least one aspect of the present disclosure. Thus, the phrases “in some embodiments” and “in some cases” in various places throughout this specification are not necessarily all referring to the same embodiment or the same aspect of the present disclosure, but they could be referring to the same embodiment or the same aspect of the present disclosure. Furthermore, the particular features, structures, characteristics, steps, or elements disclosed may be combined in any suitable manner or combination in one or more embodiments or aspects of the present disclosure. Such combinations of the features, structures,28KTS Docket No. 116771 - 1531854-821 WO 1characteristics, steps, or elements are expressly and unambiguously contemplated in the present disclosure. Unless otherwise indicated, the features, structures, characteristics, steps, or elements described in relation to any aspect or embodiment of the present disclosure may be used in combination with the features, structures, characteristics, steps, or elements of any other aspect or embodiment. Unless the context clearly dictates otherwise, the features, structures, characteristics, or elements of any method or use disclosed herein are mutually compatible. Unless the context clearly dictates otherwise, the features, structures, characteristics, or elements of a compound or pharmaceutically acceptable salt of any Formula of the present disclosure, or a composition or a pharmaceutical composition thereof, are mutually compatible. For instance, if a Formula (Ill- alpha) or Formula (Ill-beta) comprises a R1and a R2and a paragraph exists in the specification for each R1and R2such as “In some embodiments, for a method of the present disclosure or for a compound or pharmaceutically acceptable salt of Formula (Ill-alpha) or Formula (Ill-beta), ... ” then each and every one of the combinations of R1and R2are expressly and unambiguously contemplated in the present disclosure. By way of example only, if the following sentences exist: “In some embodiments, R1is selected from halogen.”, “In some embodiments, R2is selected from -CN, -OH, Ci-3 alkyl, and Cs-6 cycloalkyl. ”, and “In some embodiments, R2is selected from -CN, -OH, and Ci-3 alkyl” then the following is expressly and unambiguously contemplated: “In some embodiments, R1is selected from halogen; and R2is selected from -CN, -OH, C1-3 alkyl, and C3- 6 cycloalkyl.” and “In some embodiments, R1is selected from halogen; and R2is selected from - CN, -OH, and C1-3 alkyl”. This logic regarding R1and R2applies to other features, structures, characteristics, or elements that a Formula, a composition, or a pharmaceutical composition may comprise. Furthermore, this logic applies to “In some embodiments, for a method or a use of the present disclosure, . .. ”. As used herein, the phrases “In some embodiments, for a method or a use of the present disclosure, ... ” and “In some embodiments, for a method of the present disclosure, ... ” are used interchangeably. Unless indicated otherwise, any aspect or embodiment of the present disclosure can be combined with any other aspect or embodiment of the present disclosure.

[0051] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.Further Forms

[0052] 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.29KTS Docket No. 116771 - 1531854-821 WO 1

[0053] '‘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 unknown can 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. Compounds described herein may contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0054] The carbon-carbon or carbon-heteroatom bonds of the compounds of the present disclosure may be depicted herein using a solid line ( ''' ), a solid wedge (or a hashed wedge(••*'' ). The use of a solid line to depict bonds to asymmetric center is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or hashed wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. Compounds of the present disclosure may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds disclosed herein can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or hashed wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. 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.30KTS Docket No. 116771 - 1531854-821 WO 1

[0055] 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.

[0056] In certain embodiments, compositions of the disclosure may comprise two or more enantiomers or diastereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers.

[0057] 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 cry stallization 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.

[0058] A “tautomer’7refers 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,31KTS Docket No. 116771 - 1531854-821 WO 1including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0059] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. 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.

[0060] 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 hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0061] 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,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all32KTS Docket No. 116771 - 1531854-821 WO 1contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0062] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. 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.

[0063] 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 Discovers’ 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.

[0064] 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.

[0065] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0066] 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. The compounds described herein may be in the form of pharmaceutically acceptable salts. 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 unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. 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 is33KTS Docket No. 116771 - 1531854-821 WO 1referred to as a pseudopolymorph. Both unsolvate and solvate forms of the compounds presented herein are also considered to be disclosed herein

[0067] 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).

[0068] The terms “amorphous” and “amorphous form” are used interchangeably herein to refer to a solid having no long range order in the position of its atoms. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement and no long range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. An amorphous solid is a solid that is characterized as having no sharp peak(s) in its X-ray powder diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). An XRPD pattern of an amorphous form may one or several broad peaks (e.g., halos). Broad peaks (e.g., halos) are characteristic of an amorphous solid. An amorphous solid system may be composed of a single chemical entity or may be a multi-component system containing, e.g.. an API, polymer, and other excipients, without stoichiometric composition. Amorphous solids may possess crystal like short range molecular arrangement, but no long-range order of molecular packing.

[0069] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.34KTS Docket No. 116771 - 1531854-821 WO 1

[0070] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0071] In some embodiments, the design of a prodrug increases the lipophilicity7of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g.. Fedorak et al., Am. J Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., BiomedChrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J Pharmaceutics , 37, 87 (1987); J. Larsen et al., Int. J Pharmaceutics , 47, 103 (1988); Sinkula et al., J Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0072] 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).Compounds for Treating / Preventing Cancer(Z)-Endoxifen, a Potent Selective Estrogen Receptor Modulator

[0108] 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 a competitive partial agonist of estrogen receptor in a tissue-specific manner. (Z)-endoxifen has robust antitumor and antiestrogenic 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 as35KTS Docket No. 116771 - 1531854-821 WO 1tamoxifen, aromatase inhibitors, or fulvestrant, in part because endoxifen functions independently of metabolic enzymes such as CYP2D6.

[0109] 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 (1):or a pharmaceutically acceptable salt thereof.

[0110] In another aspect, the present disclosure provides a compound of Formula (I-Z):or a pharmaceutically acceptable salt thereof.

[0073] In another aspect, the present disclosure provides a compound of Formula (I-E):Formula (I-E), or a pharmaceutically acceptable salt thereof.

[0074] 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).

[0075] 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, the crystalline Form I is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 16.8±0.3° 2-Theta, about 17. l±0.3° 2-Theta. and about 21.8±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form I is further characterized as having one additional peak selected from about 16.0±0.3° 2-Theta, about 18.8±0.3° 2-Theta, and about 26.5±0.3° 2- Theta as measured by Cu Ka radiation. In some embodiments, the cry stalline Form I is further characterized as having one additional peak selected from about 12.3±0.3° 2-Theta, about 28.0±0.3° 2-Theta, and about 29.0±0.3° 2-Theta as measured by Cu Ka radiation. In some36KTS Docket No. 116771 - 1531854-821 WO 1embodiments, the crystalline Form I is further characterized as having 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 as measured by Cu Ka radiation.

[0076] In some embodiments, for a compound or salt of Formula (I) or Formula (I-Z), the compound is crystalline Form II of (Z)-endoxifen. In some embodiments, the crystalline Form II is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 7.0±0.3° 2-Theta, about 11.9±0.3° 2-Theta, and about 14.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having one additional peak selected from about 18.4±0.3° 2-Theta and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having peaks at about 18.4±0.3° 2-Theta and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having one additional peak selected from about 6.6±0.3° 2-Theta, 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having two additional peaks selected from about 6.6±0.3° 2-Theta, about 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having peaks at about 6.6±0.3° 2-Theta. about 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having two additional peaks selected from about 6.6±0.3° 2-Theta, about 13.3 ± 0.3° 2-Theta, about 20.0±0.3° 2-Theta, and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation.

[0077] In some embodiments, for a compound or salt of Formula (I) or Formula (I-Z), the compound is crystalline Form V of (Z)-endoxifen. In some embodiments, the crystalline Form V is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 8.9± 0.3° 2-Theta, 12.5± 0.3° 2-Theta, and 19.6± 0.3° 2-Theta, as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having one additional peak selected from 21.7± 0.3° 2-Theta, 20.8± 0.3° 2-Theta. 19.8± 0.3° 2-Theta, and 16.0± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having two additional peak selected from 21.7± 0.3° 2-Theta, 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta, and 16.0± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having one additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having two additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as37KTS Docket No. 116771 - 1531854-821 WO 1measured by Cu Kot radiation. In some embodiments, crystalline Form V is further characterized as having three additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, or 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, cry stalline Form V is further characterized as having four additional peak selected from 21 ,7± 0.3° 2-Theta. 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta, 16.0± 0.3° 2-Theta, 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation.

[0078] In some embodiments, for a compound or salt of Formula (I) or Formula (I-Z), the compound is a crystalline Form selected from Form I, Form II, Form V, and any combinations thereof. In some embodiments, the compound is a crystalline Form selected from Form I, Form II, and a combination thereof. In some embodiments, the compound is a crystalline Form selected from Form I, Form V, and a combination thereof. In some embodiments, the crystalline Form I is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 16.8±0.302-Theta, about 17. l±0.3° 2-Theta, and about 21.8±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form I is further characterized as having one additional peak selected from about 16.0±0.3° 2-Theta, about 18.8±0.3° 2-Theta, and about 26.5±0.3° 2- Theta as measured by Cu Ka radiation. In some embodiments, the cry stalline Form I is further characterized as having one additional peak selected from about 12.3±0.3° 2-Theta, about 28.0±0.3° 2-Theta, and about 29.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the cry stalline Form I is further characterized as having peaks at 12.3±0.3° 2-Theta, 16.0±0.3° 2-Theta, I8.8±0.3°, 26.5±0.3° 2-Theta, 28.0±0.3° 2-Theta, and 29.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the cry stalline Form II is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 7.0±0.3° 2-Theta. about 11.9±0.3° 2-Theta, and about 14.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having one additional peak selected from about 18.4±0.3° 2-Theta and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the cry stalline Form II is further characterized as having peaks at about 18.4±0.3° 2-Theta and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having one additional peak selected from about 6.6±0.3° 2-Theta, 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having tyvo additional peaks selected from about 6.6±0.3° 2-Theta, about 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the crystalline Form II is further characterized as having peaks at about 6.6±0.3° 2-Theta, about 13.3±0.3° 2-Theta, and 20.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the cry stalline38KTS Docket No. 116771 - 1531854-821 WO 1Form II is further characterized as having two additional peaks selected from about 6.6±0.3° 2- Theta, about 13.3 ± 0.3° 2-Theta, about 20.0±0.3° 2-Theta, and about 22.0±0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, the cry stalline Form V is characterized as having an x-ray powder diffraction (XRPD) pattern with peaks at about 8.9± 0.3° 2-Theta, 12.5± 0.3° 2-Theta, and 19.6± 0.3° 2-Theta. as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having one additional peak selected from 21.7± 0.3° 2-Theta, 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta, and 16.0± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, cry stalline Form V is further characterized as having two additional peak selected from 21.7± 0.3° 2-Theta, 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta. and 16.0± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having one additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having two additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having three additional peak selected from 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, or 14.4± 0.3° 2-Theta as measured by Cu Ka radiation. In some embodiments, crystalline Form V is further characterized as having four additional peak selected from 21.7± 0.3° 2-Theta. 20.8± 0.3° 2-Theta, 19.8± 0.3° 2-Theta. 16.0± 0.3° 2-Theta, 22.0± 0.3° 2-Theta, 13.5± 0.3° 2-Theta, and 14.4± 0.3° 2-Theta as measured by Cu Ka radiation.

[0079] 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,39KTS Docket No. 116771 - 1531854-821 WO 1hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxy napthanoate, isethionate, malate, mandelate, mesylate, methylbromide, 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 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.

[0080] 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 combination thereof. 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)-end oxifen 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, the40KTS Docket No. 116771 - 1531854-821 WO 1compound or salt of Formula (I) is (Z)-endoxifen. In some embodiments, the compound or salt of Formula (I) is (E)-endoxifen.

[0081] 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 (1-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.

[0082] 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.

[0083] 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, the compound 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,41KTS Docket No. 116771 - 1531854-821 WO 1the 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.

[0084] In some embodiments, endoxifen or salt thereof is a cry stalline 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, 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.

[0085] In some embodiments, (Z)-endoxifen or salt thereof is a cr stal line 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 cry stalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the cry stalline 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, (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.

[0086] In some embodiments, (E)-endoxifen or salt thereof is a cry stalline 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 cry stalline 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 some42KTS Docket No. 116771 - 1531854-821 WO 1embodiments, 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

[0087] 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 crystalline 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.Pharmaceutical Formulations / Compositions[OHl] In certain embodiments, the present disclosure provides a composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the composition is a pharmaceutical composition.

[0112] In certain embodiments, a compound or a pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E) is formulated into pharmaceutical composition.

[0113] In some embodiments, a compound or pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E), or a pharmaceutical composition of the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E) is useful for the treatment of a disease or disorder. In some embodiments, the pharmaceutical composition is effective at treating a disease or disorder. In some embodiments, the compound is effective at treating a disease or disorder. In some embodiments, the pharmaceutical acceptable salt is effective at treating a disease or disorder.

[0114] Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Pharmaceutical compositions may 43KTS Docket No. 116771 - 1531854-821 WO 1be formulated using one or more physiologically acceptable excipients including earners and auxiliaries. 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), herein incorporated by reference for such disclosure.

[0115] In some embodiments, a compound or a pharmaceutically acceptable salt thereof disclosed herein is administered either alone or in combination with pharmaceutically acceptable excipients, including carriers and auxiliaries, in a pharmaceutical composition. In some embodiments the compound or the pharmaceutically acceptable salt thereof is formulated into a pharmaceutical composition. Administration of the compounds, the pharmaceutically acceptable salts, and pharmaceutical compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. In some embodiments, these methods include oral administration.

[0116] The compounds or pharmaceutically acceptable salts thereof disclosed herein, the pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts thereof disclosed herein, and the methods disclosed herein may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human. In some embodiments, the subject is a non-human mammal. When administered to a 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 excipient (excipients include carriers and auxiliaries). 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. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppositor , injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye44KTS Docket No. 116771 - 1531854-821 WO 1drop. The composition can also be suitable for nasal delivery. The composition can also be suitable for inhalation.

[0117] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units (also referred to as “dosage unit forms”) such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. The predetermined amount can be in the form of a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

[0118] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0119] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, inhalation, nasal delivery, or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be45KTS Docket No. 116771 - 1531854-821 WO 1enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. A liquid pharmaceutical composition may be delivered / administered orally.

[0120] For oral formulations, at least one of the compounds or pharmaceutically acceptable salts thereof 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 delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation.

[0121] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

[0122] 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 a physiologically acceptable agent, depends, for example, on the route of administration of the composition.

[0123] 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 ordinary7skill 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.

[0124] 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 w eight, and other factors apparent to46KTS Docket No. 116771 - 1531854-821 WO 1a 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. Dosage amount and interval / regimen can be adjusted individually to provide levels that are sufficient to maintain the desired therapeutic effects. It is possible that the interval / regimen may comprise an infrequent administration (<?.g. monthly, as opposed to daily) to achieve the desired therapeutic effect.

[0125] 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)), herein incorporated by reference for such disclosure.. 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).

[0126] Preservatives can be used to prevent the growth 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..

[0127] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound of Formula (I), Formula (I-Z), or Formula (I-E). 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%47KTS Docket No. 116771 - 1531854-821 WO 1(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.

[0128] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). 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.48KTS Docket No. 116771 - 1531854-821 WO 1

[0129] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen 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 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 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 compnses (Z)-endoxifen and (E)-endoxifen in a Z: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 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 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 a Z: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, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z: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.

[0130] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition may comprise one or more crystalline forms of a49KTS Docket No. 116771 - 1531854-821 WO 1compound or salt of Formula (I), Formula (I-Z), or Formula (I-E). 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 crystalline 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% of a 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.

[0131] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition may comprise one or more polymorphic forms of a compound or salt of Formula (I), Formula (I-Z). or Formula (I-E). 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. In some 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 a50KTS Docket No. 116771 - 1531854-821 WO 1single 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.

[0132] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). 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% crystalline 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 weight of 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% cry stalline 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.

[0133] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (I-E). In some embodiments, the pharmaceutical composition comprises from 0.01 mg to 200 mg of crystalline 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 cry stalline Form I of (Z)-endoxifen . In some51KTS Docket No. 116771 - 1531854-821 WO 1embodiments, the pharmaceutical composition comprises about 4 mg crystalline Form I of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 6 mg cry stalline 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 composes 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.

[0134] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). 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)-52KTS Docket No. 116771 - 1531854-821 WO 1endoxifen. 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 to 40 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.

[0135] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z). or Formula (I-E). 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)-53KTS Docket No. 116771 - 1531854-821 WO 1endoxifen 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% to 30% 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.

[0136] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z). or Formula (I-E). 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 delay disintegration 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 some54KTS Docket No. 116771 - 1531854-821 WO 1embodiments, the caplet is an enteric caplet. In some embodiments, 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.

[0137] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). 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 further comprises a capsule, a caplet, or a tablet. In some embodiments, the pharmaceutical composition further comprises a capsule. In some55KTS Docket No. 116771 - 1531854-821 WO 1embodiments, 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 some embodiments, 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 pharmaceutical56KTS Docket No. 116771 - 1531854-821 WO 1composition 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 comprises 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.

[0138] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), the enteric capsule is a capsule comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). 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.

[0139] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), the enteric coated capsule is a capsule comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E), 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 is57KTS Docket No. 116771 - 1531854-821 WO 1formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0140] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (1), Formula (1-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition is formulated as an enteric capsule. 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 delay ed-release capsule. In some embodiments, the enteric capsule is further coated with an enteric coating. In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0141] 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 entenc capsules made using Xcellodose, ENCODE colonic delivery technology, and EnTrinsicTM drug delivery7technology' 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 dosage form is an enteric capsule, wherein the enteric capsule is further coated an enteric coating. In some embodiments, the capsule is a seamless capsule. In some embodiments, the capsule is a banded capsule. In some embodiments, the capsule is an enteric, seamless capsule. In some embodiments, the capsule is an enteric, banded capsule. In some embodiments, the capsule is an enteric coated, seamless capsule. In some embodiments, the capsule is an enteric coated, banded capsule. In some embodiments, the capsule is a Capsugel Enprotect capsule. In some embodiments, the Capsugel Enprotect capsule comprises EIMPC-AS. In some embodiments, the Capsugel Enprotect capsule comprises HMPC. In some embodiments, the Capsugel Enprotect capsule comprises HMPC and HPMC-AS. In some embodiments, the capsule is an Eudracap enteric capsule. In some embodiments, the Eudracap enteric capsule comprises a methacrylic acid and ethyl acry late58KTS Docket No. 116771 - 1531854-821 WO 1copolymer. In some embodiments, the Eudracap enteric capsule comprises EUDRAGIT® L 30 D-55. In some embodiments, the Eudracap enteric capsule comprises EUDRAGIT® NM 30 D. In some embodiments, the Eudracap enteric capsule comprises EUDRAGIT® NM 30 D and EUDRAGIT® L 30 D-55. In some embodiments, the Eudracap enteric capsule comprises HMPC, EUDRAGIT® NM 30 D, EUDRAGIT® L 30 D-55. In some embodiments, the Eudracap enteric capsule comprises HMPC.

[0142] In some embodiments, the enteric tablets, enteric caplets, and enteric capsules may be uncoated. Hard uncoated capsules with enteric capability using intrinsically enteric capsule technology (for example, ENTRINSICT® Drug Delivery available from Capsugel) are suitable for the purpose of the present disclosure.

[0143] In various embodiments, the enteric tablet is a hard tablet made with free-flowing powder of (Z)-endoxifen or a salt thereof. In various embodiments, the enteric capsule is a capsule made with free-flowing powder of (Z)-endoxifen or a salt thereof. In various embodiments, the enteric tablet is a hard tablet made with free-flowing powder of (Z)-endoxifen or a polymorph thereof. In various embodiments, the enteric capsule is a capsule made with free-flowing powder of (Z)- endoxifen or a polymorph thereof.

[0144] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition comprises 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 beesw ax; polyethoxylated castor oil derivatives, hydrogenated oils, 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, a time delay material such as glyceryl 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, glyceryl59KTS Docket No. 116771 - 1531854-821 WO 1monostearate, glyceryl distearate, long chain alcohols, such as stearyl alcohol, cet l 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.

[0145] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition comprises is a sustained release agent. In some embodiments, the pharmaceutical composition is a sustained release pharmaceutical 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, methacrylic 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, 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, hydroxyethyl 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 release60KTS Docket No. 116771 - 1531854-821 WO 1agents 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 EVONIK® 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 acrylic acid- methylacrylic acid copolymers such as EUDRAGIT® sustained release polymers EUDRAGIT® RL, EUDRAGIT® RS, and EUDRAGIT® NM 30D. In some embodiments, 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® L 100-55, EUDRAGIT® L30 D-55, EUDRAGIT® L 100, EUDRAGIT® L 100 12,5, EUDRAGIT® S100, EUDRAGIT® S 12, 5, EUDRAGIT® FS 30D, EUDRAGIT® E 100, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In some embodiments, the acid-insoluble polymers are selected from EUDRAGIT® L 100-55, EUDRAGIT® RS, EUDRAGIT® RL, EUDRAGIT® NE, EUDRAGIT® NM 30 D, 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® L 100-55, 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® L 100-55, EUDRAGIT® RS. EUDRAGIT® RL, EUDRAGIT® NE, and EUDRAGIT® NM, and any combination thereof. In some embodiments, the pH sustained release agent is EUDRAGIT® L30 D-55. One of skill in the art will recognize that at least some acid insoluble polymers listed herein will also be biodegradable.61KTS Docket No. 116771 - 1531854-821 WO 1

[0146] In some embodiments, a pharmaceutical composition of the present disclosure may comprise 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 a pH below 5.0. In contrast, 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® L 100-55, EUDRAGIT® L30 D-55, EUDRAGIT® L 100, EUDRAGIT® L 100 12,5, EUDRAGIT® S 100, EUDRAGIT® S 12,5, EUDRAGIT® FS 30 D. EUDRAGIT® E 100, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment, the composition comprises EUDRAGIT® L 100-55. EUDRAGIT® RS, EUDRAGIT® RL, EUDRAGIT® NE, and EUDRAGIT® NM are also useful polymers for the purpose of pharmaceutical compositions of the present disclosure. In some embodiments, a pharmaceutical composition comprises EUDRAGIT® L30 D-55. In some embodiments, a pharmaceutical composition comprises EUDRAGIT® FS 30 D. In some embodiments, a pharmaceutical composition comprises EUDRAGIT® FS 30 D and EUDRAGIT® L30 D-55. One of skill in the art will recognize that at least some acid insoluble polymers listed herein will also be biodegradable.

[0147] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition further comprises a delayed-release agent. Examples of delayed-release agents include glyceryl monostearate, glyceryl distearate, and acidinsoluble 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 oral dosage forms release at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the62KTS Docket No. 116771 - 1531854-821 WO 1(Z)-endoxifen or salts thereof or elagolix or salts thereof in the intestines (small intestines, large intestine / colon etc.).

[0148] 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. In some embodiments, the enteric delayed release capsules can be non-ammal-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 EudraCap® capsule. In some embodiments, the capsule is an enteric coated Eudracap capsule. In some embodiments, the capsule is an Eudracap capsule. In at least one embodiment, the capsule is an APLin-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.

[0149] 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 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 are also be utilized. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen or a pharmaceutically acceptable salt thereof is filled neat into the capsule.

[0150] In some embodiments, for a pharmaceutical composition disclosed herein, a pharmaceutical composition comprises an enteric coated capsule. In some embodiments, the pharmaceutical composition comprises an enteric capsule. In some embodiments, the pharmaceutical composition comprises an enteric capsule with an enteric coating. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising from 10 mg to 80 mg (Z)-endoxifen per capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 10 mg of (Z)-endoxifen per63KTS Docket No. 116771 - 1531854-821 WO 1capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 20 mg of (Z)-endoxifen per capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 30 mg of (Z)- endoxifen per capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 40 mg of (Z)-endoxifen per capsule. In some embodiments, the pharmaceutical composition may be formulated in a dosage form comprising about 50 mg of (Z)-endoxifen per capsule. In some embodiments, the 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.

[0151] For a delayed-released pharmaceutical composition, glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, for example polymethacrylate pH-sensitive polymer- based coatings, may be 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.

[0152] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z). or Formula (I-E). 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% or from 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,64KTS Docket No. 116771 - 1531854-821 WO 1film-forming agents, plasticizers, colorants, sweeteners, flavoring agents, or any combination thereof.

[0153] 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 microcry stalline 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.

[0154] 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.

[0155] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). 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, the65KTS Docket No. 116771 - 1531854-821 WO 1pharmaceutical 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.

[0156] 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.

[0157] 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 active66KTS Docket No. 116771 - 1531854-821 WO 1ingredients 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.

[0158] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). 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 composition comprises 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 sodium67KTS Docket No. 116771 - 1531854-821 WO 1starch 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.

[0159] 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.

[0160] 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 pliability 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,68KTS Docket No. 116771 - 1531854-821 WO 1dibasic acid esters, (e.g., dibutyl phthalate, and dioctyl phthalate), liquid rubbers (e.g., polybutene and ali quid 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.

[0161] 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.

[0162] In some embodiments, for a pharmaceutical composition of the present disclosure, the pharmaceutical composition comprises one or more excipients. In some embodiments, the one or more excipients is selected from a bulking agent, a binder, a filler, a disintegrating agent, a lubricant, a glidant, a control release agent, an enteric coating, a film-forming agent, a plasticizer, a colorant, a sweetener, a flavoring agent, and any combinations thereof.

[0163] 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) or Formula (I-Z). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition 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.

[0164] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). Area under Curve AUC(0-24hr) (“AUC24hr”) describes the total exposure of the subject in need thereof to a69KTS Docket No. 116771 - 1531854-821 WO 1drug from time of dosing (0 hr) over a 24-hour period. The pharmaceutical composition achieves mean (AUC24hr) of 150 hr*ng / mL to 600 hr*ng / mL of (Z)-endoxifen on Day 1 of initial (first) dose of the pharmaceutical composition including 1 mg to 4 mg of (Z)-endoxifen. In some embodiments, the compositions achieves mean AUC24hr of 400 hr*ng / mL to 2500 hr*ng / mL of (Z)-endoxifen on Day 21 of initial (first) dose of compositions including 1 mg to 4 mg of (Z)- endoxifen.

[0165] AUCo-inf is 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) isdose proportional. In some embodiments, AUCo-inf ranges from 200 hr*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.

[0166] Dissolution of a formulated pharmaceutical composition disclosed herein is tested by the dissolution tests. In some embodiments, the dissolutions tests are dissolution tests of USP 711. In some embodiments, the formulated pharmaceutical composition is 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 some embodiments, the formulated pharmaceutical composition do not release endoxifen for at least 6 hours. In some embodiments, the formulated pharmaceutical composition do not release endoxifen or a salt thereof for at least 2 hours. In some embodiments, the formulated pharmaceutical composition releases less than 10% of (Z)-endoxifen in the stomach after 2 hours after administration. In some embodiments, the formulated pharmaceutical composition releases less than 40% of (Z)- endoxifen in the stomach after 4 hours after administration. In some embodiments, the formulated pharmaceutical composition releases less than 50% of (Z)-endoxifen in the stomach after 6 hours after administration.

[0167] In some embodiments, for a formulated pharmaceutical composition disclosed herein, the formulated pharmaceutical composition provides that circulating (Z)-endoxifen released from the formulated pharmaceutical composition is cleared faster than tamoxifen. In some embodiments,, 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 formulated pharmaceutical composition disclosed herein provides a terminal elimination half-life ranging from 30 to 60 hours. This is 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 (Day 1) typically ranges from70KTS Docket No. 116771 - 1531854-821 WO 10.7 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.

[0168] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical releases at least 10% of endoxifen in the small intestine after 4 hours after administration. In some embodiments, the pharmaceutical composition releases at least 30% of endoxifen after 6 hours after administration. In some embodiments, the pharmaceutical composition releases at least 40% of endoxifen after 7 hours after administration. In some embodiments, the pharmaceutical composition releases at least 50% of endoxifen after 8 hours after administration. In some embodiments, the pharmaceutical composition releases at least 20% of endoxifen in the colon after 4 hours after administration. In some embodiments, the pharmaceutical composition releases at least 40% of endoxifen in the colon after 6 hours after administration. In some embodiments, the pharmaceutical composition releases at least 80% of endoxifen in the colon after 8 hours after administration.

[0169] 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.

[0170] 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 dosage71KTS Docket No. 116771 - 1531854-821 WO 1forms. 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.

[0171] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition compnses 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 necessary' for solid formulations (see “Microbial Bioburden on Oral Solid Dosage Form,” by Jose E. Martinez, Pharmaceutical Technology, February 2002, pages 58 to 70). For other formulations, such as liquid or fluid formulations with water activity of less than 0.75, Tests for Specified Microorganisms (S. aureus, Ps. aeruginosa, Salmonella, C. albicans, Clostridia, E. coli and Bile Tolerant Gram negative bacteria) in compliance with USP Guidelines Chapter 62 may not need to be performed. 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 capsule. In some embodiments, the solid dosage is an enteric capsule. In some embodiments, the solid dosage is an enteric capsule with an enteric coating. An enteric capsule with an enteric coating is a capsule that is made of enteric materials that further comprises an enteric coating on the surface of the enteric capsule.

[0172] A (Z)-endoxifen composition of the present disclosure may be formulated as a pharmaceutical composition for topical or transdermal delivery'. In some embodiments, a (Z)- endoxifen composition for topical or transdermal delivery may be formulated as a cream, a gel, a cream, an emulsion, a lotion, an ointment, a solution, a paste, a patch, or an oil. A (Z)-endoxifen composition for topical or transdermal delivery may be applied to the skin of a subject to treat a cancer (e.g., melanoma, esophageal cancer, or breast cancer). The topical or transdermal composition may be applied to a region of skin at or near a location of a caner. For example, a72KTS Docket No. 116771 - 1531854-821 WO 1topical (Z)-endoxifen composition may be applied at the site of a cancerous skin growth in a subject with melanoma, thereby treating the melanoma. In another example, a topical (Z)- endoxifen composition may be applied to the skin around the throat of a subject with esophageal cancer, thereby treating the esophageal cancer. In some embodiments, a pharmaceutical composition for topical or transdermal administration may comprise (Z)-endoxifen, 2-(2- ethoxyethoxyjethanol (e.g., TRANSCUTOL®), isopropanol, a fully saturated emollient triester (e.g., CRODAMOL™ GTCC), and mineral oil.

[0173] In some embodiments, a pharmaceutical composition comprising (Z)-endoxifen (e.g., (Z)- endoxifen) may be formulated as a sustained release composition. In some embodiments, a pharmaceutical composition comprising a phosphoinositide 3-kinase inhibitor (e.g., alpelisib) may be formulated as a sustained release composition. 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 polymorph or a salt thereof.

[0174] Examples of sustained release agents include cellulosic ethers, gums, acrylic resins such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methylacrylate, and combinations thereof, polyvinyl pyrrolidine, and protein-derived compounds. Examples of cellulosic ethers include hydroxyalkyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropylmethyl celluloses (HPMC or hypromellose, for example Nos. 2208, 2906, 2910), carboxyalkyl celluloses, and carboxymethyl celluloses. In some embodiments, the at least one sustained release agent is a pH sustained release agent such as 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 Evonik or Rohm ((EUDRAGIT® sustained release polymers, EUDRAGIT® RL (high permeability), Eudragit® RS (low permeability) and EUDRAGIT® NM 30D (low permeability)) - alone or in any combination thereof to achieve the desired permeability for sustained release. The viscosity of sustained release agents may be any viscosity suitable for sustained release of (Z)-endoxifen or a polymorph or a salt thereof. In some embodiments, the viscosity of the at least sustained release agent ranges from 1000 mPa.s to 150,000 mPa.s. In some embodiments, the sustained release delivery system includes one or more SR / release rate controlling agents with viscosity ranging from 1000 mPa.s to 10,000 mPa.s, from73KTS Docket No. 116771 - 1531854-821 WO 110,000 mPa.s to 70,000 mPa.s, from 70,000 mPa.s to 150,000 mPa.s. or a combination thereof. In some embodiments, the present disclosure provides that the sustained release deliver}' system includes two or more sustained release agents. Each sustained release agent may have the same viscosity or a differing viscosity, for example one sustained release agent may have a viscosity ranging from 1000 mPa.s to 10,000 mPa.s, while other sustained release agent may have a viscosity of 10,000 mPa.s to 70,000 mPa s or 70,000 mPa.s to 150,000 rnPa s.

[0175] In some embodiments, the sustained release agent is HPMC / hypromellose (e.g., Nos. 2208, 2906, 2910). Hypromellose to be used in the present disclosure has a weight molecular average of 20,000-500,000. In some embodiments, hypromellose has a molecular weight average of generally 20,000 - 250,000. Hypromellose is commercially available from Dow Chemicals under the trade name METHOCELL™, for example, METHOCELL™ KI 00 (average molecular weight 26,000, 2% viscosity; 75,000 - 140,000 mPa.s); METHOCELL™ K15M (average molecular weight 120,000, 2% viscosity; 15.000 cP, 13275 - 24,780 mPa.s); METHOCELL™ K4M (average molecular weight 86,000, 2% viscosity; 4,000 cP, 75,000 - 140,000 mPa.s). Hypromellose of one grade may be used alone or in combination with another grade.

[0176] When a sustained release composition showing release of (Z)-endoxifen or a polymorph or a salt thereof in a sustained manner for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours is obtained, in some embodiments the sustained release agent, such as Hypromellose, has an average molecular weight generally ranging from 15,000 to 140,000 Daltons. In at least one embodiment, the average molecular weight of 15.000 Daltons.

[0177] The amount of sustained release agent in the composition may be any amount effective to delay the release of the therapeutic agent (Z)-endoxifen, or a polymorph or a salt thereof, for 2 hours post-dose to protect the therapeutic agent from the acidic environment of the stomach and allow passage of the therapeutic agent through the stomach into the intestines and prolong such release for a period of 2 hours to 72 hours. The amount of sustained release agent in the composition may be any amount effective to provide a slower rate of release of the therapeutic agent (Z)-endoxifen, or a polymorph or a salt thereof as compared with the reference product. In some embodiments, the amount of sustained release agent in the composition may be any amount effective to delay the release of the therapeutic agent (Z)-endoxifen, or a polymorph or a salt thereof, for at least 1 hour, at least 1. 1 hours, at least 1.2 hours, at least 1.3 hours, at least 1.4 hours, at least 1.5 hours, at least 1.6 hours, at least 1.7 hours, at least 1.8 hours, at least 1.9 hours, at least74KTS Docket No. 116771 - 1531854-821 WO 12 hours, at least 2.1 hours, at least 2.2 hours, at least 2.3 hours, at least 2.4 hours, or at least 2.5 hours post-dose, as compared with the reference product.

[0178] When a sustained release composition shows percentage dissolution ranging from 0% to 35% at 3 hours, from 35% to 55% at 12 hours, and from 65% to 85% at 24 hours in a dissolution test according to the 75 RPM USP paddle method and using pH 1.2 at 37°C for 2 hours in simulated gastric fluid and pH 6.8 at 37°C for 24 hours in simulated intestinal fluid as a test medium, at least one sustained release agent, such as Hypromellose (HPMC), may generally be present in a sustained release composition of the present disclosure in amounts from 0. 1% to 99%, from 0.1% to 90%, from 5% to 90%, from 5% to 80%, from 5% to 70%, and from 5% to 60% w / w of the sustained release composition. In some embodiments, the sustained release agent (e.g., a gum, an acrylic resin, methacrylic acid, methyl acrylate, methyl methylacrylate, polyvinyl pyrrolidine, a protein-derived compound, a hydroxyalkyl cellulose, a hydroxyethyl cellulose, a hydroxypropyl cellulose, a hydroxypropylmethyl celluloses, a carboxyalkyl cellulose, or. a carboxymethyl cellulose) may be present in an amount of from 10% to 40%, from 10% to 50%, from 10% to 60%, from 20% to 40%, from 20% to 50%, from 20% to 60%. In some embodiments, the sustained release agent may be present in an amount of at least 10%, at least 20%, at least 30%, or at least 40%. Such sustained release compositions of the present disclosure as disclosed herein release (Z)-endoxifen or polymorphs or salts thereof in a sustained manner for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 12 hours, at least 14 hours, at least 16 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours.

[0179] A pharmaceutical composition of the present disclosure may be for treatment of various cancers (e.g., medulloblastoma or glioblastoma). In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises an anti-cancer agent. In some embodiments, the anti-cancer agent is selected from bical utamide, enzalutamide, trastuzumab, atezolizumab, alpelisib, olaparib, talazoparib, ribociclib, neratinib, an antineoplastic, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, fluorouracil, gemcitabine, methotrexate, paclitaxel, protein-bound paclitaxel, vinorelbine, eribulin, ixabepilone, an immune checkpoint inhibitor, a PD1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, or an ATP-cassette binding protein inhibitor. In some embodiments, the anti-cancer agent is selected from bicalutamide, enzalutamide, trastuzumab, atezolizumab, alpelisib, olaparib, talazoparib, ribociclib, neratinib, an antineoplastic, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin,75KTS Docket No. 116771 - 1531854-821 WO 1fluorouracil, gemcitabine, methotrexate, paclitaxel, protein-bound paclitaxel, vinorelbine, eribulin, ixabepilone, an immune checkpoint inhibitor, a PD1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, or an ATP-cassette binding protein inhibitor, any any combinations thereof. In some embodiments, the additional therapeutic agent comprises a selective serotonin reuptake inhibitor. In some embodiments, the selective serotonin reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, paroxetine, sertraline, vilazodone, and any combinations thereof. In some embodiments, the selective serotonin reuptake inhibitor is selected from citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and vilazodone.

[0180] In some embodiments, a pharmaceutical composition of the present disclosure may be formulated for oral, topical, rectal, intravenous, intra-arterial, parenteral, or transdermal administration, or for administration via inhalation. In some embodiments, a (Z)-endoxifen composition may be formulated as a sustained-release composition or a delayed release composition. In some embodiments, a (Z)-endoxifen composition may be formulated as a capsule or a tablet. In some embodiments, a (Z)-endoxifen composition may be formulated as a cream, a gel, a cream, an emulsion, a lotion, an ointment, a solution, a paste, a patch, or an oil.

[0181] In various embodiments, a pharmaceutical composition provided herein comprises from 1% to 99.99%. 5% to 95%, 5% to 90%, 10% to 80%, 15% to 70%, 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 one or more excipients. In some embodiments, the composition provided herein comprises 99.99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% by weight of one or more excipients. In some embodiments, the composition provided herein comprises 99.99%, 99%, 98%, 97%. 96%, 95%, 94%. 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, or 85% by weight of one or more excipients. In some embodiments, the composition provided herein comprises 85%, 84%, 83%, 82%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, or 65% by weight of one or more excipients. In some embodiments, the composition provided herein comprises 55%. 54%. 53%, 52%, 51%, 50%, 49%, 48%, 47%, 46%, or 45% by weight of one or more excipients. In some embodiments, the composition provided herein comprises 30%, 29%, 28%, 27%, 26%, 25%, 24%, 23%, 22%, 21%, or 20% by weight of one or more excipients.

[0182] Pharmaceutical compositions formulated for oral delivery as disclosed herein include, for example, tablets, caplets, and capsules, may be 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 comprising (Z)-endoxifen 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 can be an enteric tablet, the caplet can be an enteric caplet, or the capsule can be an enteric76KTS Docket No. 116771 - 1531854-821 WO 1capsule. The enteric tablets, enteric caplets, or enteric capsules of the present disclosure may be prepared by techniques known in the art.

[0183] A pharmaceutical composition disclosed herein may comprise 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, glyceryl mono-, di- tribenates, glyceryl monostearate, glyceryl 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.

[0184] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z). or Formula (I-E). 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 mg77KTS Docket No. 116771 - 1531854-821 WO 1to 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 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 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 form78KTS Docket No. 116771 - 1531854-821 WO 1of (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 every 5, 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 admrmstered 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.

[0185] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), the 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. In some embodiments, 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.Methods and Uses

[0186] In one aspect, the present disclosure provides a method of neoadjuvant treatment for a premenopausal subject in need thereof with ER+ / HER2- breast cancer, the method comprising the following steps: (a) determining a pre-treatment Ki-67 level in the premenopausal subject in need thereof; (b) administering a therapeutically effective amount of a composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof to the premenopausal subject in need thereof during a pre-surgical treatment period; (c) determining a post-treatment Ki-67 level in the premenopausal subject in need thereof; and (d) repeating steps (b) through (c) until the post- 79KTS Docket No. 116771 - 1531854-821 WO 1treatment Ki-67 level in the premenopausal subject in need thereof is less than 10% of the pretreatment Ki-67 level.

[0187] In another aspect, the present disclosure provides a method of neoadjuvant treatment for a premenopausal subject in need thereof with ER+ / HER2- breast cancer, the method comprising the following steps: (a) determining a pre-treatment Ki-67 level in the premenopausal subject in need thereof; (b) administering a therapeutically effective amount of a composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof to the premenopausal subject in need thereof during a pre-surgical treatment period; (c) determining a post-treatment Ki-67 level in the premenopausal subject in need thereof; and (d) repeating steps (b) through (c) until the posttreatment Ki -67 level in the premenopausal subject in need thereof is less than the pre-treatment Ki-67 level.

[0188] In one aspect, the present disclosure provides a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof for use in a neoadjuvant treatment for a premenopausal subject in need thereof with ER+ / HER2- breast cancer, wherein the neoadjuvant treatment comprises the following steps: (a) determining a pre-treatment Ki-67 level in the premenopausal subject in need thereof; (b) administering the therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof to the premenopausal subject in need thereof during a pre-surgical treatment period; (c) determining a post-treatment Ki-67 level in the premenopausal subject in need thereof; and (d) repeating steps (b) through (c) until the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 10% of the pre-treatment Ki-67 level.

[0189] In another aspect, the present disclosure provides a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof for use in a neoadjuvant treatment for a premenopausal subject in need thereof with ER+ / HER2- breast cancer, wherein the neoadjuvant treatment comprises the following steps: (a) determining a pre-treatment Ki-67 level in the premenopausal subject in need thereof; (b) administering the therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof to the premenopausal subject in need thereof during a pre-surgical treatment period; (c) determining a post-treatment Ki-67 level in the premenopausal subj ect in need thereof; and (d) repeating steps (b) through (c) until the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than the pre-treatment Ki-67 level.

[0190] In one aspect, the present disclosure provides a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for a neoadjuvant treatment for a premenopausal subject in need80KTS Docket No. 116771 - 1531854-821 WO 1thereof with ER+ / HER2- breast cancer, wherein the neoadjuvant treatment comprises the following steps: (a) determining a pre-treatment Ki-67 level in the premenopausal subject in need thereof; (b) administering the therapeutically effective amount of a composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof to the premenopausal subject in need thereof during a pre-surgical treatment period; (c) determining a post-treatment Ki-67 level in the premenopausal subject in need thereof; and (d) repeating steps (b) through (c) until the posttreatment Ki-67 level in the premenopausal subject in need thereof is less than 10% of the pretreatment Ki-67 level.

[0191] In another aspect, the present disclosure provides a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for a neoadjuvant treatment for a premenopausal subject in need thereof with ER+ / HER2- breast cancer, wherein the neoadjuvant treatment comprises the following steps: (a) determining a pre-treatment Ki-67 level in the premenopausal subject in need thereof; (b) administering the therapeutically effective amount of a composition compnsing (Z)- endoxifen or a pharmaceutically acceptable salt thereof to the premenopausal subject in need thereof during a pre-surgical treatment period; (c) determining a post-treatment Ki-67 level in the premenopausal subject in need thereof; and (d) repeating steps (b) through (c) until the posttreatment Ki-67 level in the premenopausal subject in need thereof is less than the pre-treatment Ki-67 level.

[0192] In one aspect, the present disclosure provides a method of treating an ER+ / HER2- breast cancer in a premenopausal subject in need thereof, the method comprising the following steps: (a) determining a pre-treatment level of one or more biomarkers selected from the group consisting of: Ki-67, ER, PgR, PKC01, C-PARP, cyclin DI, E2F1, pAKT, AKT, ESRI mutations, tumor transcriptome, and tumor whole exome DNA; (b) administering a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof during a pre-surgical treatment period; (c) determining a post-treatment level of the one or more biomarkers of step (a); and (d) repeating steps (b) through (c) until the post-treatment level of the one or more biomarkers reaches a target level.

[0193] In another aspect, the present disclosure provides a method of treating an ER+ / HER2- breast cancer in a premenopausal subject in need thereof, the method comprising the following steps: (a) determining a pre-treatment level of one or more biomarkers selected from the group consisting of: Ki-67, ER, PgR, PKC01, C-PARP, cyclin DI, E2F1, pAKT, AKT, ESRI mutations, tumor transcriptome, and tumor whole exome DNA; (b) administering a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof81KTS Docket No. 116771 - 1531854-821 WO 1during a pre-surgical treatment period; (c) determining a post-treatment level of the one or more biomarkers of step (a); and (d) repeating steps (b) through (c) until the post-treatment level of the one or more biomarkers is less than the pre-treatment level of the one or more biomarkers.

[0194] In one aspect, the present disclosure provides a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof for use in treating an ER+ / HER2- breast cancer in a premenopausal subject in need thereof, wherein the treating comprising the following steps: (a) determining a pre-treatment level of one or more biomarkers selected from the group consisting of: Ki-67, ER, PgR, PKCpi, C-PARP, cyclin DI, E2F1, pAKT, AKT, ESRI mutations, tumor transcriptome, and tumor whole exome DNA; (b) administering a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof during a pre-surgical treatment period; (c) determining a post-treatment level of the one or more biomarkers of step (a); and (d) repeating steps (b) through (c) until the post-treatment level of the one or more biomarkers reaches a target level.

[0195] In another aspect, the present disclosure provides a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof for use in treating an ER+ / HER2- breast cancer in a premenopausal subject in need thereof, wherein the treating comprising the following steps: (a) determining a pre-treatment level of one or more biomarkers selected from the group consisting of: Ki-67, ER. PgR. PKCpi, C-PARP, cyclin DI, E2F1, pAKT, AKT, ESRI mutations, tumor transcriptome, and tumor whole exome DNA; (b) administering a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof during a pre-surgical treatment period; (c) determining a post-treatment level of the one or more biomarkers of step (a); and (d) repeating steps (b) through (c) until the post-treatment level of the one or more biomarkers is less than the pre-treatment level of the one or more biomarkers.

[0196] In one aspect, the present disclosure provides a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating an ER+ / HER2- breast cancer in a premenopausal subject in need thereof, wherein the treating comprising the following steps: (a) determining a pre-treatment level of one or more biomarkers selected from the group consisting of: Ki-67, ER, PgR, PKCpi, C-PARP, cyclin DI, E2F1, pAKT, AKT, ESRI mutations, tumor trans criptome, and tumor whole exome DNA; (b) administering a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof during a pre- surgical treatment period; (c) determining a post-treatment level of the one or more biomarkers of82KTS Docket No. 116771 - 1531854-821 WO 1step (a); and (d) repeating steps (b) through (c) until the post-treatment level of the one or more biomarkers reaches a target level.

[0197] In another aspect, the present disclosure provides a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating an ER+ / HER2- breast cancer in a premenopausal subject in need thereof, wherein the treating comprising the following steps: (a) determining a pre-treatment level of one or more biomarkers selected from the group consisting of: Ki-67, ER, PgR, PKCpi, C-PARP, cyclin DI, E2F1, pAKT, AKT, ESRI mutations, tumor transcriptome, and tumor whole exome DNA; (b) administering a therapeutically effective amount of a composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof during a pre- surgical treatment period; (c) determining a post-treatment level of the one or more biomarkers of step (a); and (d) repeating steps (b) through (c) until the post-treatment level of the one or more biomarkers is less than the pre-treatment level of the one or more biomarkers.

[0198] In some embodiments, for a method or a use of the present disclosure, the method further comprises surgically removing a breast cancer tissue from the premenopausal subject in need thereof following step (d).

[0199] In some embodiments, for a method or a use of the present disclosure, the pre-surgical treatment period is from 1 to 50 weeks. In some embodiments, the pre-surgical treatment period is from 1 to 30 weeks, from 5 to 30 weeks, from 10 to 25 weeks, or from 20 to 30 weeks. In some embodiments, the pre-surgical treatment period is from 1 to 30 weeks, from 5 to 30 weeks, from 10 to 25 weeks, or from 20 to 30 weeks. In some embodiments, the pre-surgical treatment period is from about 1 week to about 30 weeks. In some embodiments, the pre-surgical treatment period is from about 5 weeks to about 30 weeks. In some embodiments, the pre-surgical treatment period is from about 10 weeks to about 25 weeks. In some embodiments, the pre-surgical treatment period is from about 20 weeks to about 30 weeks. In some embodiments, the pre-surgical treatment period is from 1 to 30 weeks. In some embodiments, the pre-surgical treatment period is from 5 to 30 weeks. In some embodiments, the pre-surgical treatment period is from 10 to 25 weeks. In some embodiments, the pre-surgical treatment period is from 20 to 30 weeks.

[0200] In some embodiments, for a method or a use of the present disclosure, the method further comprises obtaining a tumor biopsy sample from the premenopausal subject in need thereof. In some embodiments, step (a), step (c). or a combination thereof further comprises obtaining a tumor biopsy sample from the premenopausal subject in need thereof. In some embodiments, step (a) further comprises obtaining a tumor biopsy sample from the premenopausal subject in need thereof. In some embodiments, step (c) further comprises obtaining a tumor biopsy sample from83KTS Docket No. 116771 - 1531854-821 WO 1the premenopausal subject in need thereof. In some embodiments, step (a) and step (c) further comprises obtaining a tumor biopsy sample from the premenopausal subject in need thereof.

[0201] In some embodiments, for a method or a use of the present disclosure, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 1 to 20 weeks, 1 to 15 weeks, 1 to 10 weeks, 2 to 7 weeks, or 3 to 5 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 10 to 20 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment Ki-67 level comprises obtaining a tumor biopsy sample at 5 to 10 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining atumor biopsy sample at 15 to 20 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 1 to 20 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 1 to 15 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki -67 level comprises obtaining a tumor biopsy sample at 1 to 10 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 2 to 7 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki -67 level comprises obtaining a tumor biopsy sample at 3 to 5 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 3 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 4 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 5 weeks after administering the composition84KTS Docket No. 116771 - 1531854-821 WO 1comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 6 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 7 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 8 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 9 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 10 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 11 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 12 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 13 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 14 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, for a method or a use of the present disclosure, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is greater than 10%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is greater than 5%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is greater than 15%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition85KTS Docket No. 116771 - 1531854-821 WO 1comprising goserelin if the post-treatment Ki-67 level is greater than 20%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is greater than 25%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is greater than 30%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is greater than 35%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is greater than a percent selected from about 10% to about 50%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is greater than a percent selected from about 5% to about 10%.

[0203] In some embodiments, for a method or a use of the present disclosure, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post- treatment Ki-67 level is not less than the pre-treatment Ki-67 level. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is not less than 10% of the pre-treatment Ki-67 level. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is not less than 5% of the pre-treatment Ki-67 level. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post -treatment Ki-67 level is not less than 15% of the pre-treatment Ki-67 level. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is not less than 20% of the pre-treatment Ki-67 level. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is not less than 25% of the pretreatment Ki-67 level. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is not less than 30% of the pre-treatment Ki-67 level. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a86KTS Docket No. 116771 - 1531854-821 WO 1composition comprising goserelin if the post-treatment Ki-67 level is not less than 35% of the pretreatment Ki-67 level. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is not less than 40% of the pre-treatment Ki-67 level. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is not less than 50% of the pretreatment Ki-67 level. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is not less than 45% of the pre-treatment Ki-67 level.

[0204] In some embodiments, for a method or a use of the present disclosure, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 5% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 10% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 15% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 20% of the pre-treatment Ki- 67 level. In some embodiments, the post-treatment Ki -67 level in the premenopausal subject in need thereof is less than 25% of the pre-treatment Ki-67 level. In some embodiments, the posttreatment Ki-67 level in the premenopausal subject in need thereof is less than 30% of the pretreatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 35% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 40% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 45% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 50% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 55% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 60% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 70% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 80% of the pre-treatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 90% of the pre-treatment Ki-87KTS Docket No. 116771 - 1531854-821 WO 167 level. In some embodiments, the post-treatment Ki -67 level in the premenopausal subject in need thereof is less than 100% of the pre-treatment Ki-67 level. In some embodiments, the posttreatment Ki-67 level in the premenopausal subject in need thereof is less than 150% of the pretreatment Ki-67 level. In some embodiments, the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 200% of the pre-treatment Ki-67 level.

[0205] In some embodiments, for a method or a use of the present disclosure, the post-treatment level of the one or more biomarkers is less than the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 5% of the pre-treatment level of the one or more biomarkers. In some embodiments, the posttreatment level of the one or more biomarkers is less than 10% of the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 15% of the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 20% of the pretreatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 25% of the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 30% of the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 35% of the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 40% of the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 45% of the pretreatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 50% of the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 55% of the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 100% of the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 150% of the pre-treatment level of the one or more biomarkers. In some embodiments, the post-treatment level of the one or more biomarkers is less than 200% of the pretreatment level of the one or more biomarkers.

[0206] In some embodiments, for a method or a use of the present disclosure, the post-treatment level of the additional biomarker is less than the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 5% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of88KTS Docket No. 116771 - 1531854-821 WO 1the additional biomarker is less than 10% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 15% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 20% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 25% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 30% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 40% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 50% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 75% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 100% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 150% of the pre-treatment level of the additional biomarker. In some embodiments, the post-treatment level of the additional biomarker is less than 200% of the pre-treatment level of the additional biomarker.

[0207] In some embodiments, for a method or a use of the present disclosure, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration between 500 ng / mL and 1000 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration between 750 ng / mL and 1000 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration between 500 ng / mL and 750 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration between 500 ng / mL and 800 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration between 700 ng / mL and 1000 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a89KTS Docket No. 116771 - 1531854-821 WO 1steady-state plasma concentration from about 500 ng / mL to about 1000 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration from about 750 ng / mL to about 1000 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration from about 500 ng / mL to about 750 ng / mL of (Z)-endoxifen. In some embodiments, the dose is a therapeutically effective amount.

[0208] In some embodiments, for a method or a use of the present disclosure, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount that achieves a steady-state plasma concentration of (Z)- endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount that achieves a steady -state plasma concentration between 500 ng / mL and 1000 ng / mL of (Z)- endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount that achieves a steady -state plasma concentration between 750 ng / mL and 1000 ng / mL of (Z)- endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount that achieves a steady-state plasma concentration between 500 ng / mL and 750 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount that achieves a steadystate plasma concentration between 500 ng / mL and 800 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount that achieves a steady-state plasma concentration between 700 ng / mL and 1000 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount that achieves a steady-state plasma concentration from about 500 ng / mL to about 1000 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount that achieves a steady-state plasma concentration from about 750 ng / mL to about 1000 ng / mL of (Z)-endoxifen. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt90KTS Docket No. 116771 - 1531854-821 WO 1thereof is administered at a therapeutically effective amount that achieves a steady-state plasma concentration from about 500 ng / mL to about 750 ng / mL of (Z)-endoxifen.

[0209] In some embodiments, for a method or a use of the present disclosure, premenopausal subject in need thereof has a breast cancer. In some embodiments, the breast is an invasive breast cancer. In some embodiments, the invasive breast cancer is a clinical Stage 11A invasive breast cancer or a clinical Stage IIB invasive breast cancer. In some embodiments, the premenopausal subject in need thereof has invasive breast cancer. In some embodiments, the premenopausal subject in need thereof has clinical Stage IIA invasive breast cancer or clinical Stage IIB invasive breast cancer. In some embodiments, the premenopausal subject in need thereof has clinical Stage IIA invasive breast cancer. In some embodiments, the premenopausal subject in need thereof has clinical Stage IIB invasive breast cancer. In some embodiments, the breast cancer has a tumor size greater than 2.0 cm. In some embodiments, the invasive breast cancer has a tumor size greater than 2.0 cm. In some embodiments, clinical Stage IIA invasive breast cancer has a tumor size greater than 2.0 cm. In some embodiments, clinical Stage IIB invasive breast cancer has a tumor size greater than 2.0 cm. In some embodiments, the breast cancer has a tumor size greater than 3 cm. In some embodiments, the invasive breast cancer has a tumor size greater than 3 cm. In some embodiments, clinical Stage IIA invasive breast cancer has a tumor size greater than 3 cm. In some embodiments, clinical Stage IIB invasive breast cancer has a tumor size greater than 3 cm. In some embodiments, the breast cancer has a tumor size greater than 1 cm. In some embodiments, the invasive breast cancer has a tumor size greater than 1 cm. In some embodiments, clinical Stage IIA invasive breast cancer has a tumor size greater than 1 cm. In some embodiments, clinical Stage IIB invasive breast cancer has a tumor size greater than 1 cm. In some embodiments, the breast cancer has a tumor size less than 5 cm. In some embodiments, the invasive breast cancer has a tumor size less than 5 cm. In some embodiments, clinical Stage IIA invasive breast cancer has a tumor size less than 5 cm. In some embodiments, clinical Stage IIB invasive breast cancer has a tumor size less than 5 cm. In some embodiments, the breast cancer has a tumor size less than 10 cm. In some embodiments, the invasive breast cancer has a tumor size less than 10 cm. In some embodiments, clinical Stage IIA invasive breast cancer has a tumor size less than 10 cm. In some embodiments, clinical Stage IIB invasive breast cancer has a tumor size less than 10 cm.

[0210] In some embodiments, for a method or a use of the present disclosure, the method further comprises measuring one or more additional biomarkers. In some embodiments, the method further comprises an additional biomarker. In some embodiments, the method further comprises measuring one or more additional biomarkers selected from the group consisting of: ER, PgR, PKC|31, C-PARP, cyclin DI, E2F1, pAKT, AKT, and ESRI mutations. In some embodiments, the91KTS Docket No. 116771 - 1531854-821 WO 1one or more additional biomarkers is selected from ER, PgR, PKC01, C-PARP, cyclin DI, E2F1, pAKT, AKT, and ESRI mutations. In some embodiments, the additional biomarker is selected from ER, PgR, PKC01, C-PARP, cyclin DI, E2F1, pAKT, AKT, and ESRI mutations. In some embodiments, one or more additional biomarkers is selected from ER, PgR, PKC01, C-PARP, cyclin DI, E2F1, pAKT, AKT, ESRI mutations, and any combinations thereof. In some embodiments, the additional biomarker is a ER mutation. In some embodiments, the additional biomarker is a PgR mutation. In some embodiments, the additional biomarker is a PKC01 mutation. In some embodiments, the additional biomarker is a C-PARP mutation. In some embodiments, the additional biomarker is a cyclin DI mutation. In some embodiments, the additional biomarker is a pAKT mutation. In some embodiments, the additional biomarker is an E2F1 mutation. In some embodiments, the additional biomarker is an ESRI mutation.

[0211] In some embodiments, for a method or a use of the present disclosure, the method further comprises performing magnetic resonance imaging. In some embodiments, the magnetic resonance imaging is performed between 2 to 20 weeks, 4 to 16 weeks, or 10 to 14 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the magnetic resonance imaging is performed between 2 to 20 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the magnetic resonance imaging is performed between 4 to 16 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the magnetic resonance imaging is performed between 10 to 14 weeks after administering the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the magnetic resonance imaging is performed between 10 to 20 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the magnetic resonance imaging is performed between 15 to 20 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the magnetic resonance imaging is performed between 1 to 5 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the magnetic resonance imaging is performed between 5 to 10 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the magnetic resonance imaging is performed between 10 to 16 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.92KTS Docket No. 116771 - 1531854-821 WO 1

[0212] In some embodiments, for a method or a use of the present disclosure, the method further comprises performing magnetic resonance imaging. In some embodiments, the method further comprises performing magnetic resonance imaging at 12 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing magnetic resonance imaging from about 2 weeks to about 20 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing magnetic resonance imaging from about 10 weeks to about 20 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing magnetic resonance imaging from about 2 weeks to about 15 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing magnetic resonance imaging from about 2 weeks to about 10 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing magnetic resonance imaging from about 10 weeks to about 15 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, for a method or a use of the present disclosure, the determining the post-treatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample. In some embodiments, the determining the post-treatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 1 to 20 weeks, 1 to 15 weeks, 1 to 10 weeks, 2 to 7 weeks, or 3 to 5 weeks after administering the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 10 to 20 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 5 to 10 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 15 to 20 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 1 to 20 weeks after administering the composition comprising (Z)-endoxifen or a93KTS Docket No. 116771 - 1531854-821 WO 1pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 1 to 15 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 1 to 10 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 2 to 7 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 3 to 5 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 3 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 4 weeks after administering the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the post-treatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 5 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 6 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 7 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 8 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsysample at 9 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy94KTS Docket No. 116771 - 1531854-821 WO 1sample at 10 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 11 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 12 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsysample at 13 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the determining the posttreatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsysample at 14 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

[0214] In some embodiments, for a method or a use of the present disclosure, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 10%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is not less than 5% of the pre-treatment biomarker level of the one or more biomarkers. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is not less than 15% of the pre-treatment biomarker level of the one or more biomarkers. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is not less than 20% of the pre-treatment biomarker level of the one or more biomarkers. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is not less than 25% of the pretreatment biomarker level of the one or more biomarkers. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is not95KTS Docket No. 116771 - 1531854-821 WO 1less than 30% of the pre-treatment biomarker level of the one or more biomarkers. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is not less than 35% of the pre-treatment biomarker level of the one or more biomarkers. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is not less than 40% of the pre-treatment biomarker level of the one or more biomarkers. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is not less than 45% of the pretreatment biomarker level of the one or more biomarkers. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is not less than 50% of the pre-treatment biomarker level of the one or more biomarkers.

[0215] In some embodiments, for a method or a use of the present disclosure, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 10%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 5%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the posttreatment biomarker level of the one or more biomarkers is greater than 15%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 20%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 25%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 30%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 35%. In some96KTS Docket No. 116771 - 1531854-821 WO 1embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 40%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 45%. In some embodiments, the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 50%.

[0216] In some embodiments, for a method or a use of the present disclosure, the composition comprising goserelin is administered at a dose of 1 to 15 mg / month. In some embodiments, the composition comprising goserelin is administered at a dose of 1 to 10 mg / month. In some embodiments, the composition comprising goserelin is administered at a dose of 3 to 5 mg / month. In some embodiments, the composition comprising goserelin is a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises goserelin and one or more pharmaceutically acceptable excipients.

[0217] In some embodiments, for a method or a use of the present disclosure, the method further comprises performing surgery after a final dose of the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing surgery within 2 to 15 days after a final dose of the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing surgery within 1 to 7 days after a final dose of the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing surgery within 7 to 15 days after a final dose of the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing surgery within 1 to 4 days after a final dose of the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing surgery within 1 to 3 days after a final dose of the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing surgery7within 1 to 6 days after a final dose of the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing surgery within 2 to 4 days after a final dose of the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing surgery within 2 to 3 days after a final dose of the composition comprising (Z)-endoxifen or a97KTS Docket No. 116771 - 1531854-821 WO 1pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises performing surgery within 2 to 5 days after a final dose of the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, for a method or a use of the present disclosure, the method further comprises measuring a serum level in a pre-treatment blood sample. In some embodiments, the serum level is selected from a thymidine kinase 1 (TK1) serum level, an estrone (El) serum level, an estradiol (El) serum level, and any combinations thereof. In some embodiments, the serum level is a thymidine kinase 1 (TK1) serum level. In some embodiments, the serum level is an estrone (El) serum level. In some embodiments, the serum level is an estradiol (El) serum level. In some embodiments, the method further comprises measuring a serum level of thymidine kinase 1 (TK1), estrone (El), estradiol (El), or a combination thereof in a pre-treatment blood sample. In some embodiments, the method further comprises measuring a serum level selected from a thymidine kinase 1 (TK1) serum level, an estrone (El) serum level, an estradiol (El) serum level, and any combinations thereof in a pre-treatment blood sample. In some embodiments, the serum level is an estradiol (El) serum level. In some embodiments, the method further comprises measuring a serum level of thymidine kinase 1 (TK1) in a pre-treatment blood sample. In some embodiments, the serum level is an estradiol (El) serum level. In some embodiments, the method further comprises measuring a serum level of estrone (El) in a pre-treatment blood sample.

[0219] In some embodiments, for a method or a use of the present disclosure, the method further comprises measuring a serum level in a post-treatment blood sample. In some embodiments, the serum level is selected from a thymidine kinase 1 (TK1) serum level, an estrone (El) serum level, an estradiol (El) serum level, and any combinations thereof. In some embodiments, the serum level is a thymidine kinase 1 (TK1) serum level. In some embodiments, the serum level is an estrone (El) serum level. In some embodiments, the serum level is an estradiol (El) serum level. In some embodiments, the method further comprises measuring a serum level of thymidine kinase 1 (TK1), estrone (El), estradiol (El), or a combination thereof in a post-treatment blood sample. In some embodiments, the method further comprises measuring a serum level selected from a thymidine kinase 1 (TK1) serum level, an estrone (El) serum level, an estradiol (El) serum level, and any combinations thereof in a post-treatment blood sample. In some embodiments, the serum level is an estradiol (El) serum level. In some embodiments, the method further comprises measuring a serum level of thymidine kinase 1 (TK1) in a post-treatment blood sample. In some embodiments, the serum level is an estradiol (El) serum level. In some embodiments, the method further comprises measuring a serum level of estrone (El) in a post-treatment blood sample.98KTS Docket No. 116771 - 1531854-821 WO 1

[0220] In some embodiments, for a method or a use of the present disclosure, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose from about 1 mg / day to about 100 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 20 to 100 mg / day, 40 mg / day, 20 mg / day, or 80 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 20 to 100 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 20 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 40 mg / day. In some embodiments, the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 80 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 2 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 4 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 10 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 8 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose from about 4 mg / day to about 40 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose from about 10 mg / day to about 40 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose from about 20 mg / day to about 40 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose from about 4 mg / day to about 10 mg / day.

[0221] In some embodiments, for a method or a use of the present disclosure, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount from about 1 mg / day to about 100 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount of 20 to 100 mg / day. 40 mg / day. 20 mg / day. or 80 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount of 20 to 100 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a99KTS Docket No. 116771 - 1531854-821 WO 1pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount of 20 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount of 40 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount of 80 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount of 2 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount of 4 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount of 10 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount of 8 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount from about 4 mg / day to about 40 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount from about 10 mg / day to about 40 mg / day. In some embodiments, the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount from about 20 mg / day to about 40 mg / day. In some embodiments, the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is administered at a therapeutically effective amount from about 4 mg / day to about 10 mg / day.

[0222] In some embodiments, for a method or a use of the present disclosure, the method further comprises determining the level of the one or more biomarkers in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA). In some embodiments, the method further comprises determining the level of the one or more biomarkers in a tumor biopsy. In some embodiments, the method further comprises determining the level of the one or more biomarkers in a serum. In some embodiments, the method further comprises determining the level of the one or more biomarkers in a circulating tumor DNA (ctDNA). In some embodiments, the method further comprises determining the level of the one or more biomarkers in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA) for 1, 2, 3, 4, 5, 6, 7, or 8 times prior to surgery In some embodiments, the method further comprises determining the level of the one or more biomarkers in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA) 1 time prior to surgery. In some embodiments, the method further comprises determining the level of the one or more biomarkers100KTS Docket No. 116771 - 1531854-821 WO 1in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA) at least 2 times prior to surgery. In some embodiments, the method further comprises determining the level of the one or more biomarkers in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA) at least 3 times prior to surgery. In some embodiments, the method further comprises determining the level of the one or more biomarkers in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA) at least 4 times prior to surgery. In some embodiments, the method further comprises determining the level of the one or more biomarkers in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA) no more than 4 times prior to surgery. In some embodiments, the method further comprises determining the level of the one or more biomarkers in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA) no more than 6 times prior to surgery. In some embodiments, the method further comprises determining the level of the one or more biomarkers in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA) no more than 3 times prior to surgery. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 times prior to surgery is between 1 to 30 weeks prior to surgery. In some embodiments, times prior to surgery is between 1 to 30 weeks pnor to surgery. In some embodiments, the time prior to surgery is between 1 to 30 weeks prior to surgery. In some embodiments, times prior to surgery is between 1 to 16 weeks prior to surgery'. In some embodiments, the time prior to surgery is between 1 to 16 weeks prior to surgery. In some embodiments, times prior to surgery is between 1 to 8 weeks prior to surgery. In some embodiments, the time prior to surgery is between 1 to 8 weeks prior to surgery7. In some embodiments, times prior to surgery is between 1 to 5 weeks prior to surgery7. In some embodiments, the time prior to surgery is between 1 to 5 weeks prior to surgery. In some embodiments, times prior to surgery is between 10 to 30 weeks prior to surgery. In some embodiments, the time prior to surgery is between 10 to 30 weeks prior to surgery7. In some embodiments, times prior to surgery is between 1 to 20 weeks prior to surgery7. In some embodiments, the time prior to surgery7is between 1 to 20 weeks prior to surgery.

[0223] In some embodiments, for a method or a use of the present disclosure, the one or more biomarkers comprise a mutation. In some embodiments, the mutation is a gene mutation. In some embodiments, the mutation is a gen...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of neoadjuvant treatment for a premenopausal subject in need thereof with ER+ / HER2- breast cancer, the method comprising the following steps:(a) determining a pre-treatment Ki-67 level in the premenopausal subject in need thereof;(b) administering a therapeutically effective amount of a composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof to the premenopausal subject in need thereof during a pre-surgical treatment period;(c) determining a post-treatment Ki-67 level in the premenopausal subject in need thereof; and(d) repeating steps (b) through (c) until the post-treatment Ki-67 level in the premenopausal subject in need thereof is less than 10% of the pre-treatment Ki-67 level.

2. The method of claim 1, wherein the method further comprises surgically removing a breast cancer tissue from the premenopausal subject in need thereof following step (d).

3. The method of claim 1 or claim 2. wherein the pre-surgical treatment period is from 1 to 30 weeks, from 5 to 30 weeks, from 10 to 25 weeks, or from 20 to 30 weeks.

4. The method of any one of claims 1 to 3, wherein step (a), step (c), or a combination thereof further comprises obtaining a tumor biopsy sample from the premenopausal subject in need thereof.

5. The method of any one of claims 1 to 4, wherein the determining the post-treatment Ki-67 level comprises obtaining a tumor biopsy sample at 1 to 20 weeks, 1 to 15 weeks, 1 to 10 weeks, 2 to 7 weeks, or 3 to 5 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1 to 5, wherein the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment Ki-67 level is greater than 10%.

7. The method of any one of claims 1 to 6, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration between 500 ng / mL and 1000 ng / mL of (Z)-endoxifen.

8. The method of any one of claims 1 to 7, wherein the premenopausal subject in need thereof has clinical Stage IIA invasive breast cancer or clinical Stage IIB invasive breast cancer.146KTS Docket No. 116771 - 1531854-821 WO 19. The method of any one of claims 1 to 8, wherein the method further comprises measuring one or more additional biomarkers selected from the group consisting of: ER, PgR, PKCpi, C- PARP, cyclin DI, E2F1, pAKT, AKT, and ESRI mutations.

10. The method of any one of claims 1 to 9, wherein the method further comprises performing magnetic resonance imaging.

11. The method of claim 10. wherein the magnetic resonance imaging is performed between 2 to 20 weeks, 4 to 16 weeks, or 10 to 14 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

12. A method of treating an ER+ / HER2- breast cancer in a premenopausal subject in need thereof, the method comprising the following steps:(a) determining a pre-treatment level of one or more biomarkers selected from the group consisting of: Ki-67, ER, PgR, PKCpi , C-PARP, cyclin DI , E2F1, pAKT, AKT, ESRI mutations, tumor trans criptome, and tumor whole exome DNA;(b) administering a therapeutically effective amount of a composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof during a pre-surgical treatment period;(c) determining a post-treatment level of the one or more biomarkers of step (a); and(d) repeating steps (b) through (c) until the post-treatment level of the one or more biomarkers reaches a target level.

13. The method of claim 12, wherein the method further comprises surgically removing a breast cancer tissue from the premenopausal subject in need thereof following step (d).

14. The method of claim 12 or claim 13, wherein the pre-surgical treatment period is from 1 to 30 weeks, from 5 to 30 weeks, from 10 to 25 weeks, or from 20 to 30 weeks.

15. The method of any one of claims 12 to 14, wherein step (a), step (c), or a combination thereof further comprises obtaining a tumor biopsy sample from the premenopausal subject in need thereof.

16. The method of any one of claims 12 to 15, wherein the determining the post-treatment biomarker level of the one or more biomarkers comprises obtaining a tumor biopsy sample at 1 to 20 weeks, 1 to 15 weeks, 1 to 10 weeks, 2 to 7 weeks, or 3 to 5 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.147KTS Docket No. 116771 - 1531854-821 WO 117. The method of any one of claims 12 to 16, wherein the method further comprises administering to the premenopausal subject in need thereof a composition comprising goserelin if the post-treatment biomarker level of the one or more biomarkers is greater than 10%.

18. The method of claim 6 or claim 17, wherein the composition comprising goserelin is administered at a dose of 3 to 5 mg / month.

19. The method of any one of claims 12 to 18, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration between 500 ng / mL and 1000 ng / mL of (Z)-endoxifen.

20. The method of any one of claim 12 to 19, wherein the method further comprises performing surgery' within 2 to 15 days after a final dose of the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof.

21. The method of any one of claim 12 to 20, wherein the premenopausal subject in need thereof has clinical Stage IIA invasive breast cancer or clinical Stage IIB invasive breast cancer.

22. The method of any one of claim 1 to 21 , wherein the breast cancer has a tumor size greater than 2.0 cm.

23. The method of any one of claim 12 to 22, wherein the method further comprises performing magnetic resonance imaging at 12 weeks after administering the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof.

24. The method of any one of claim 1 to 23, wherein the method further comprises measuring a serum level of thymidine kinase 1 (TK1), estrone (El), estradiol (El), or a combination thereof in a pre-treatment blood sample.

25. The method of any one of claim 1 to 24, wherein the method further comprises measuring a serum level of thymidine kinase 1 (TK1), estrone (El), estradiol (El), or a combination thereof in a post-treatment blood sample.

26. The method of any one of claims 1 to 25, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose of 20 to 100 mg / day, 40 mg / day, 20 mg / day, or 80 mg / day.

27. The method of any one of claims 1 to 26, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is administered at a dose that achieves a steady-state plasma concentration between 500 ng / mL and 1000 ng / mL of (Z)-endoxifen.148KTS Docket No. 116771 - 1531854-821 WO 128. The method of any one of claims 12 to 27, wherein the method further comprises determining the level of the one or more biomarkers in a tumor biopsy, a serum, or a circulating tumor DNA (ctDNA) for 1, 2, 3, 4, 5, 6, 7, or 8 times prior to surgery.

29. The method of claim 28, wherein the 1 , 2, 3, 4, 5, 6, 7, or 8 times prior to surgery is between 1 to 30 weeks prior to surgery.

30. The method of claim 28. wherein the one or more biomarkers comprise ER, progesterone receptor (PgR), protein kinase C beta 1 (PKC[31 ), cleaved poly (ADP-ribose) polymerase (C- PARP), cyclin DI, E2F transcription factor 1 (E2F1), phosphorylated AKT (pAKT), AKT, or estrogen receptor 1 (ESRI) mutations.

31. The method of claim 28, wherein the one or more biomarkers comprise thymidine kinase 1 (TK1), estrone (El), estradiol (E2), or ctDNA.

32. The method of claim 28, wherein the one or more biomarkers comprise a cholesterol biomarker, a lipid panel biomarker, or a coagulation biomarker.

33. The method of claim 28, wherein the one or more biomarkers comprise C-telopeptide (CTX), procollagen type 1 N-terminal propeptide (P1N1), bone-specific alkaline phosphatase, or osteocalcin.

34. The method of any one of claims 1 to 33, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof comprises less than 25 ppm of mesityl oxide.

35. The method of any one of claims 1 to 34, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL.

36. The method of any one of claims 1 to 35, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof has a water content of not more than 1.0% as tested by Method Ic of USP 921.

37. The method of any one of claims 1 to 36, wherein the composition comprising (Z)- endoxifen has or a pharmaceutically acceptable salt thereof a water activity (Aw) of less than 0.9.

38. The method of any one of claims 1 to 37, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof has a residue on ignition of not more than 0. 1 % as tested by a method of USP 281.149KTS Docket No. 116771 - 1531854-821 WO 139. The method of any one of claims 1 to 38, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof comprises not more than 20 ppm of heavy metals as tested by Method II of USP 231.

40. The method of any one of claims 1 to 39, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof comprises not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate, not more than 5000 ppm heptane, and not more than 5000 ppm ethanol, as tested by a validated HPLC method.

41. The method of any one of claims 1 to 40, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof comprises an isomeric purity of (Z)- endoxifen of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% of (Z)-endoxifen by weight (wt%).

42. The method of any one of claims 1 to 41, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof comprises less than 2% of an impurity having m / z of 511.

43. The method of any one of claims 1 to 42, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof comprises less than 1.5% of an impurity having m / z of 402.

44. The method of any one of claims 1 to 43, wherein the composition comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof is a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.

45. The method of any one of claims 1 to 43, wherein the composition comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is formulated as an oral formulation comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof, wherein the oral formulation is an enteric tablet, an enteric caplet, or an enteric capsule.

46. The method of claim 44, wherein the oral formulation comprising (Z)-endoxifen or a pharmaceutically acceptable salt thereof comprises less than 2% of (Z)-endoxifen impurities.

47. The method of claim 44 or claim 45. wherein the oral formulation comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is stable for at least 9 months at 25°C and 60% relative humidity.150KTS Docket No. 116771 - 1531854-821 WO 148. The method of any one of claims 44 to 46, wherein the oral formulation comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof comprises no more than 3000 ppm methanol, no more than 720 ppm tetrahydrofuran, no more than 5000 ppm isopropanol, no more than 5000 ppm ethyl acetate; no more than 5000 ppm n-Heptane, no more than 5000 ppm ethanol, or any combination thereof.

49. The method of any one of claims 44 to 47, wherein the oral formulation comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof has a water content of the (Z)-endoxifen is not more than 1.0%.

50. The method of any one of claims 44 to 48, wherein the oral formulation comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof comprises no more than 20 ppm of heavy metals.

51. The method of any one of claims 44 to 49, wherein the oral formulation comprising (Z)- endoxifen or a pharmaceutically acceptable salt thereof is stable for at least 3 months at 40°C and 75% relative humidity.

52. The method of any one of claims 1 to 49, wherein the pharmaceutically acceptable salt of (Z)-endoxifen is selected from arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamme, 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.53 The method of any one of claims 1 to 52, wherein the pharmaceutically acceptable salt of (Z)-endoxifen is (Z)-endoxifen gluconate.

54. The method of any one of claims 44 to 53, wherein the oral formulation is a delayed- release formulation.

55. The method of any one of claims 44 to 54, wherein the oral formulation is resistant to dissolution in an acidic environment for at least 2 hours, as measured in a dissolution test.151KTS Docket No. 116771 - 1531854-821 WO 156. The method of any one of claims 44 to 55, wherein the oral formulation releases no more than 10% of the (Z)-endoxifen over 2 hours in gastric fluid, as measured in a dissolution test performed.

57. The method of any one of claims 44 to 56, wherein the oral formulation releases at least 50% of the (Z)-endoxifen within 8 hours in intestinal fluid, as measured in a dissolution test.

58. The method of any one of claims 44 to 57, wherein the oral formulation further comprises hydroxypropylmethyl cellulose.

59. The method of any one of claims 44 to 58. wherein the oral formulation further comprises a sugar, salt, talc, calcium carbonate, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, or combinations thereof.

60. The method of any one of claims 44 to 59. wherein the oral formulation further comprises a disintegrant.

61. The method of any one of claims 44 to 60, wherein the oral formulation further comprises calcium stearate, magnesium stearate, zinc stearate, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil, ethyl oleate, ethyl laureate, agar, or combinations thereof.

62. The method of any one of claims 44 to 61, wherein the oral formulation comprises from 1 mg to 20 mg of (Z)-endoxifen.

63. The method of any one of claims 44 to 62. wherein the oral formulation comprises from 1 mg to 4 mg of (Z)-endoxifen.

64. The method of any one of claims 44 to 63, wherein the oral formulation comprises 40 mg, 20 mg, or 80 mg of (Z)-endoxifen.

65. The method of any one of claims 44 to 64, wherein the oral formulation is uncoated.

66. The method of any one of claims 44 to 64, wherein the oral formulation further comprises an enteric coating.

67. The method of any one of claims 44 to 66, wherein the oral formulation is an enteric capsule, an enteric coated capsule, or an enteric coated enteric capsule.152KTS Docket No. 116771 - 1531854-821 WO 168. The method of any one of claims 1 to 67, wherein the method further comprises an improvement in one or more quality of life indicators post-treatment relative to the pre-treatment.

69. The method of claim 68, wherein the one or more quality-of-life indicators comprise at least one of headache, nausea, abdominal distension, hot flash, upper respiratory tract infection, fatigue, sweating, difficulty sleeping, decrease in sexual desire, vaginal dryness, vaginal bleeding, back pain, abdominal pain, tension headache, menstruation delayed, dysmenorrhea, arthralgia, irritability, dry mouth, or night sweats.153KTS Docket No. 116771 - 1531854-821 WO 1

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