Endoxifen for treatment of rare cancers

Abstract

Described herein are novel compositions and methods for the treatment of various cancers using (Z)-endoxifen. (Z)-endoxifen, either alone or in combination with other therapeutic agents, can be used to treat cancers such as glioblastoma, non-small cell lung cancer, melanoma, pancreatic carcinoma, and hormone-dependent cancers. The described compositions include anti-cancer compounds that, when combined with (Z)-endoxifen, show synergistic effectiveness for treating cancer. This innovative approach aims to improve cancer treatment outcomes by leveraging the synergistic potential of (Z)-endoxifen with other therapeutic agents, targeting multiple pathways and overcoming resistance mechanisms in cancer cells.

Description

ENDOXIFEN FOR TREATMENT OF RARE CANCERSCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 618,822, filed on January 8, 2024, U.S. Provisional Application No. 63 / 716,063, filed on November 4, 2024, and U.S. Provisional Application No. 63 / 730,390, filed on December 10, 2024, which applications are expressly incorporated herein by reference in their entirety.BACKGROUND

[0002] Cancer remains one of the leading causes of death worldwide. Traditional treatments like chemotherapy and radiation therapy, while effective in many cases, can have significant side effects and may not always provide optimal outcomes. This has led to increased interest in targeted therapies and combination approaches that may offer improved efficacy and reduced toxicity. Combination therapies have shown promise in improving treatment outcomes for various cancers. By targeting multiple pathways simultaneously, these approaches may enhance efficacy and potentially overcome resistance mechanisms. Synergistic compounds that work in concert with endocrine therapies may offer new avenues for treatment by targeting complementary physiological pathways to improve outcomes for patients. The development of optimized formulations and delivery systems for these therapies remains an important area of investigation in the ongoing effort to improve cancer treatment.SUMMARY

[0003] In various aspects, the present disclosure provides a combination formulation including (Z)-endoxifen and a therapeutic agent, where the (Z)-endoxifen includes a compound of Formula (I)Formula (I) or a pharmaceutically acceptable salt thereof, wherein at least 90% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof. In some aspects, the (Z)-endoxifen is an oral formulation. In some aspects, the (Z)-endoxifen is formulated as a suspension, a powder, an enteric tablet, an enteric caplet, an enteric capsule, a microparticle, or a nanoparticle. In some aspects, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of the compound of Formula (I) is (Z)-endoxifen or apharmaceutically acceptable salt thereof. In some aspects, the pharmaceutically acceptable salt of (Z)-endoxifen is selected from the group consisting of arecoline, besylate, bicarbonate, bitartrate, butylbromide, citrate, camsylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, isethionate, malate, mandelate, mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some aspects, the pharmaceutically acceptable salt of (Z)-endoxifen is (Z)-endoxifen gluconate.

[0004] In some aspects, the (Z)-endoxifen is (Z)-endoxifen free base. In some aspects, the (Z)-endoxifen includes less than 2%, less than 1.5%, less than 1%, or less than 0.5% 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 is stable for at least 3 months at 40 °C and 75% relative humidity. 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)-endoxifen 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. 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 tetrahydro furan, not more than 5000 ppm isopropanol, not more than 5000 ppm ethyl acetate, not more than 5000 ppm n-Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method. 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.

[0005] In some aspects, the (Z)-endoxifen includes less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities; is stable for at least 9 months at 25 °C and 60% relative humidity; is stable for at least 3 months at 40 °C and 75% relative humidity; has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL; has a water content of not more than 1.0% as tested by Method Ic of USP 921; has a water activity (Aw) of less than 0.9; has a residue on ignition of not more than 0.1% as tested by a method of USP 281; includes not more than 20 ppm of heavy metals as tested by Method II of USP 231; includes not more than 3000 ppm methanol, not more than 720 ppm tetrahydrofuran, not more than 5000 ppm isopropanol, notmore than 5000 ppm ethyl acetate; not more than 5000 ppm n-Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method; or any combination thereof.

[0006] In some aspects, the (Z)-endoxifen is a delayed-release formulation. In some aspects, the formulation further includes a sugar, salt, talc, calcium carbonate, microcrystalline cellulose, hydroxypropylmethyl 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.

[0007] In some aspects, the formulation includes from 1 mg to 200 mg, 1 mg to 80 mg, 1 mg to 40 mg, or 1 mg to 20 mg of (Z)-endoxifen. In some aspects, the formulation includes from 1 mg, 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg of (Z)-endoxifen.

[0008] 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. In some aspects, the suspension includes a syrup or an elixir. In some aspects, the suspension includes ethanol, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, vegetable oil, stearic acid, sodium lauryl sulfate, or a mixture thereof.

[0009] In some aspects, the therapeutic agent is a topoisomerase inhibitor, a tubulin polymerization inhibitor, a CDK inhibitor, an MTOR inhibitor, an AKT inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an HD AC inhibitor, an HSP inhibitor, a kinesin inhibitor, a MEK inhibitor, a PI3K inhibitor, a PLK inhibitor, a ribonucleotide reductase inhibitor, a nucleoside analog, a microtubule inhibitor, a bromodomain inhibitor, a proteasome inhibitor, an XIAP inhibitor, a kinesin-like spindle protein inhibitor, a Famesyltransferase inhibitor, a CHK inhibitor, an SRC inhibitor, a protein synthesis inhibitor, an epidermal growth factor receptor erbB 1 inhibitor, a vascular endothelial growth factor receptor inhibitor, a DNA topoisomerase I inhibitor, a programmed cell death protein 1 inhibitor, a vascular endothelial growth factor receptor 2 inhibitor, a programmed cell death protein 1 antagonist, a PI3 -kinase class I inhibitor, a tubulin inhibitor, a receptor protein-tyrosine kinase erbB2-2 inhibitor, a platelet-derived growth factor receptor inhibitor, an FK506-b inding protein 1 A inhibitor, a stem cell growth factor receptor inhibitor, an angiopoietin-2 inhibitor, an estrogen receptor alpha modulator, a hormone therapy molecule, a PDE inhibitor, a MAPK inhibitor, an FLT3 inhibitor, an HMGCR inhibitor, an ABL inhibitor, a DNA / thymidylate synthase inhibitor, an ALK inhibitor, an IGF-1inhibitor, or a dual mT0R / PI3K inhibitor. In some aspects, the therapeutic agent is selected from the group consisting of BAY-11 to 7082, Salinomycin (Procoxacin), Pimasertib (AS-703026), A66, RO5126766 (CH5126766), ASP3026, RO4987655, PD318088, K-Ras(G12C) inhibitor 12, PIK-93, Ravoxertinib, GDC-0994, Osimertinib, Gilteritinib, Cobimetinib, Duvelisib (IPI-145, INK1197), Tesevatinib, PD173074, Copanlisib, Binimetinib (MEK162, ARRY-162, ARRY- 438162), lodophenpropit, U-18666A, ZM-241385, AZD-8835, Trametinib, NVP-TAE226, Atiprimod, AZD4547, NVP-TNKS656, Alpelisib (BYL719), Afatinib (dimaleate), Saracatinib (AZD0530), Tenovin-6, Tubastatin A hydrochloride, L-778123 (hydrochloride), Ascomycin (FK520), AZD8186, GZD824 Dimesylate, Ro 48 to 8071 (fumarate), EW-7197, Dorsomorphin, BAX-channel-blocker, Erbstatin-analog, CH5132799, Hoechst 33258, AT13148, AZD5363, AZD8330, AZ5104, BMS-983970, Dasatinib, Bleomycin sulfate, Maxacalcitol, GSK1059615, Nexturastat A, Ribociclib (LEE011), Etoposide phosphate, NVP-ADW742, Voreloxin (Hydrochloride), Triciribine, LB42708, SM-164, Walrycin B, BMS-345541, Domiphen Bromide, RepSox, TAK-733, BX-912, LCL161, NVP-AEW541, Lonafarnib (SCH66336), Vorinostat (SAHA, MK0683), Quinacrine hydrochloride, Ipatasertib (GDC-0068), GDC-0152, Afuresertib, Falecalcitriol, PRT062607 (P505 to 15, PRT2607, BIIB057) HC1, Prexasertib (dihydrochloride), XL388, MLN8054, SU9516, BNTX, Fedratinib (SAR302503, TG101348), C-021, Taselisib, NSC-3852, Miransertib, MK-2206 dihydrochloride, Resminostat (RAS2410), 5-BrdU, CH55, Carmofur, Bimiralisib, JNJ-7706621, Rapamycin, Tosedostat, Idoxuridin, VS- 5584, Uprosertib, M344, Mycophenolate mofetil, XL888, PP-121, LMK-235, CPI-203, MK8745, Apitolisib (GDC-0980, RG7422), GSK690693, Tipifarnib (Zamestra), Etoposide, Mycophenolic Acid, PD 0332991 (Palbociclib) HC1, 1-BET151 (GSK1210151A), Pemetrexed, AZ20, Phortress, PHA-848125, MPI-0479605, OSI-027, Ingenol mebutate, Cevipabulin, FK- 866, APY-29, LY3023414, Ixazomib citrate, Belinostat (PXD101), Crenolanib (CP-868596), 6,7-Dihydroxy-l-(4-Hydroxybenzyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride, (+)-JQl, AZD3463, BET-BAY 002, GDC-0349, VX-680 (MK-0457, Tozasertib), GSK1070916, Gentian violet, Combretastatin-A4, UNC2025 (hydrochloride), Satraplatin, BMS-566419, Cycloheximide, Digitoxigenin, ABT-751 (E7010), 3-Deazaneplanocin A (DZNeP) HC1, Abemaciclib (LY2835219), AZD7762, WYE-687, AP26113, Hesperadin, PHA-680632, Basic fuchsin, Diphenyleneiodonium, MK-1775, Clofarabine, AZD6738, Bisacodyl, NVP-HSP990, NSC319726, Epothilone D, PHA-767491, AR-42 (HD AC-42), AMG 232, Barasertib (AZDI 152-HQPA), Teniposide, KW-2478, 1-BET-762, Strophantidin, Amsacrine, CC-115, Ganetespib (STA-9090), Filanesib, NMS-E973, BNC105, Torin 1, Aphidicolin, Vinorelbine (ditartrate), XL228, PF-05212384 (PKI-587), 17-AAG (Tanespimycin), 5-Fluoro-2- deoxycytidine, Trifluridine, GSK461364, Digoxigenin, Colchicine, MK-8776 (SCH 900776),SB-268262, R547, PF-03814735, Gemcitabine (elaidate), AT9283, Cyclocytidine HC1, Fosbretabulin (disodium), CGP-74514, VER-49009, Retaspimycin (Hydrochloride), BML-284, Cytarabine, Briciclib, Mivobulin, Ixazomib citrate (MLN9708), Verubulin, PF-3758309, LY2334737, Floxuridine, WYE-125132, Topotecan (hydrochloride), Torin-2, KX2 to 391, Ixazomib (MLN2238), Pevonedistat hydrochloride, Camptothecin, Gemcitabine, Irinotecan, Ispinesib (SB-715992), AZDI 152, TAK-901, NMS-1286937, Taltobulin (trifluoroacetate), Onalespib (AT13387), Danusertib (PHA-739358), 17-DMAG HC1 (Alvespimycin), PD-166285, Ixabepilone, Vincristine (sulfate), MLN8237 (Alisertib), Vinblastine (sulfate), Oprozomib (ONX 0912), Ansamitocin P-3, Vistusertib (AZD2014), CHIR-124, TAS- 103 (dihydrochloride), ER-27319 maleate, PU-H71, Vindesine Sulfate, Nampt-IN-1, Raltitrexed (Tomudex), BI6727 (Volasertib), Litronesib, Omipalisib (GSK2126458, GSK458), PF-04691502, PHA-793887, Luminespib, INK 128 (MLN0128), SNX-2112, SB-743921, CYT997, PF-04929113 (SNX- 5422), AZD5438, Proflavine hemisulfate, Patupilone (EPO906, Epothilone B), A-674563, LY2090314, Plinabulin, Talazoparib (BMN 673), Torkinib (PP242), Genz-644282, ARQ 621, Pralatrexate (Folotyn), Selinexor (KPT-330), R306465, and HMN-214.

[0010] In some aspects, the formulation includes from 0.01 mg to 1000 mg of the therapeutic agent. In some aspects, the formulation includes from 0.01 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 40 mg, 40 mg to 80 mg, 80 mg to 150 mg, 150 mg to 300 mg, 300 mg to 800 mg, 800 mg to 1000 mg of the therapeutic agent.

[0011] In some aspects, the therapeutic agent is formulated as an oral formulation, an intramuscular injection, a subcutaneous injection, an intrathecal injection, or an intravenous infusion. In some aspects, the therapeutic agent and the (Z)-endoxifen are administered in a single combination formulation. In some aspects, the therapeutic agent and the (Z)-endoxifen are administered in separate formulations.

[0012] In various aspects, the present disclosure provides a combination formulation including (Z)-endoxifen and a synergistic compound, wherein the (Z)-endoxifen includes a compound of Formula (I)Formula (I) or a pharmaceutically acceptable salt thereof, and at least 90% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof, wherein the (Z)-endoxifen is an oral formulation in the form of a suspension, a powder, an enteric tablet, an enteric caplet, an enteric capsule, a microparticle, or a nanoparticle.

[0013] In some aspects, the present disclosure describes a method of treating a disease or condition in a subject in need thereof, wherein the method includes administering the formulation, thereby treating the disease or condition. In some aspects, the administering of the formulation results in a plasma (Z)-endoxifen level greater than 40 nM per 1 mg of (Z)- endoxifen administered. In some aspects, the method includes administering 1 mg to 200 mg, 1 mg to 80 mg, 1 mg to 40 mg, or 1 mg to 20 mg of (Z)-endoxifen per day. In some aspects, the techniques described herein relate to a method, including administering a dose of 0.05 mg / kg to 10 mg / kg of (Z)-endoxifen per day. In some aspects, the techniques described herein relate to a method, including administering a dose of 0.05 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.8 mg / kg, 2 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.8 mg / kg, or 3 mg / kg of (Z)-endoxifen per day.

[0014] In some aspects, the techniques described herein relate to a method, wherein the administering of the formulation maintains a plasma level of (Z)-endoxifen of the subject at a steady state level above 30 nM. In some aspects, the administering of the formulation maintains the plasma level at a steady state level from 30 nM to 1000 nM.

[0015] In some aspects, the techniques described herein relate to a method, further including releasing no more than 10% of the (Z)-endoxifen in a stomach of the subject within 2 hours following the administering of the formulation. In some aspects, the method further includes releasing at least 50% of the (Z)-endoxifen in a small intestine of the subject within 8 hours following the administering of the formulation. In some aspects, the method further includes producing an area under the curve (AUCo-inf) of (Z)-endoxifen in the subject of from 200 hr* ng / mL to 10,000 hr* ng / mL per 4 mg of (Z)-endoxifen administered. In some aspects, the method further includes producing a maximum blood plasma concentration (Cmax) of (Z)- endoxifen in the subject of from 14 ng / mL to 62 ng / mL per 4 mg of (Z)-endoxifen administered.

[0016] In some aspects, the techniques described herein relate to a method, including administering from 0.01 mg to 1000 mg of the therapeutic agent per day. In some aspects, the method includes administering from 0.01 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 40 mg, 40 mg to 80 mg, 80 mg to 150 mg, 150 mg to 300 mg, 300 mg to 800 mg, 800 mg to 1000 mg of the therapeutic agent per day. In some aspects, the method includes administering from 0.01 mg / kg to 10 mg / kg of the therapeutic agent per day. In some aspects, the method includes administering from 0.01 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 1.5 mg / kg, 1.5 mg / kg to 2 mg / kg, 2 mg / kg to 2.5 mg / kg, or 2.5 to 3 mg / kg of the therapeutic agent per day. In some aspects, the therapeutic agent is administered every day, every other day, everythird day, biweekly, weekly, biweekly, monthly, bimonthly, every three months, every six months, or yearly.

[0017] In some aspects, the techniques described herein relate to a method of treating a disease or disorder, wherein the disease or disorder is a cancer. In some aspects, the cancer is glioblastoma, non-small cell lung cancer, melanoma, pancreatic carcinoma, medulloblastoma, pancreatic carcinoma, prostate carcinoma, gastric carcinoma, esophageal cancer, osteosarcoma, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, breast cancer, ductal carcinoma, lobular carcinoma, or urinary bladder cancer.

[0018] In some aspects, the disease or disorder is a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder. In some aspects, the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, ductal carcinoma in situ, lobular carcinoma in situ, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer. In some aspects, the hormonedependent breast disorder or the hormone-dependent reproductive tract disorder is tamoxifen- refractory or tamoxifen resistant.

[0019] In some aspects, the techniques described herein relate to a method, wherein the administering of the formulation results in a synergistic treatment of the disease or disorder. In some aspects, the method results in improvement of an objective response rate (ORR), complete response rate, partial response rate, overall survival, or progression-free survival compared to treatment with either compound alone. In some aspects, the method results in a reduction of a level of a biomarker associated with cancer progression by at least 20% compared to a baseline or reference level. In some aspects, the method results in an improvement of a level of a patient- reported quality of life score compared to a baseline or reference level.INCORPORATION BY REFERENCE

[0020] 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

[0021] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrativeembodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0022] FIG. 1A is an XRPD pattern obtained from a sample of Form I of (Z)-endoxifen.

[0023] FIG. IB is an XRPD pattern obtained from a sample of Form I of (Z)-endoxifen.

[0024] FIG. 2 is a schematic diagram showing the design of a 365 well plate, includingDMSO (DM), Positive controls with 10 pM doxorubicin (DOX), 0.5 pM (Z)-endoxifen plus 1 pM compounds (cells without text), 0.1 pM abemaciclib (AB), DMSO without (Z)-endoxifen (DMX), and empty cells (X).

[0025] FIGs. 3A and 3B are graphs illustrating the mean nuclei count per well for DMSO without (Z)-endoxifen.

[0026] FIGs. 4A and 4B describe plate uniformity of the quality control analyses with FIG. 4 A being a graph of Z’ -Prime values for each plate, and FIG. 4B being a graph illustrating Z’- factor measurement and distributions.

[0027] FIGs. 5A and 5B are graphs illustrating normalized viability for cells incubated with (Z)-endoxifen (0.5 uM, upper circles), abemaciclib (0.1 uM, middle circles) and doxorubicin (10 uM, lower circles).

[0028] FIGs. 6A and 6B are graphs illustrating normalized viability for compounds with a viability between (Z)-endoxifen and doxorubicin (red-shaded area in the graph) for Batch 1 (FIG. 6 A) and Batch 2 (FIG. 6B): includes the mean of (Z)-endoxifen plus 3 standard deviations and mean of doxorubicin plus 3 standard deviations. Batch 1 includes 141 synergistic and 7 antagonistic compounds, while Batch 2 includes 213 synergistic and 12 antagonistic compounds.

[0029] FIG. 7 is a pie chart illustrating the percentage of therapeutic agents grouped by method of action in Batch 1. Reading clockwise from the top, therapeutic agents included topoisomerase inhibitors (7%), tubulin polymerization inhibitors (8%), CDK inhibitors (7%), mTOR inhibitors (6%), AKT inhibitors (2%), Aurora kinase inhibitors (3%), EGFR inhibitors (3%), HD AC inhibitors (3%), HSP inhibitors (2%), kinesin inhibitors (2%), MEK inhibitors (3%), PI3K inhibitors (4%), PLK inhibitors (4%), ribonuclease reductase inhibitors, nucleoside analogs (4%), and others (42%).

[0030] FIG. 8 is a pie chart illustrating the percentage of therapeutic agents grouped by method of action in Batch 2. Reading clockwise from the top, therapeutic agents included (from most to least abundant): HD AC inhibitors, mTOR inhibitors, HSP inhibitors, PI3K inhibitors, Aurora kinase inhibitors, CDK inhibitors, AKT inhibitors, topoisomerase inhibitors, microtubule inhibitors, bromodomain inhibitors, MEK inhibitors, proteasome inhibitors, XIAP inhibitors, and others.

[0031] FIG. 9 is a graph illustrating the number of compounds per class for the total screen and the total number of compounds in the library.

[0032] FIG. 10 is a graph illustrating methods of calculating IC50 of (Z)-endoxifen.

[0033] FIG. 11 is a chart illustrating the distribution of drug types in glioblastoma clinical trials, which were tested with (Z)-endoxifen, including small molecules (176), antibodies (39), proteins (14), unknown (5), and oligonucleotides (1).

[0034] FIG. 12 is a chart illustrating mechanisms of action of drug types with potential use against glioblastoma in clinical trials.

[0035] FIG. 13 is a chart illustrating the numbers of compounds identified as complimentary or synergistic to (Z)-endoxifen and their pathway of action.

[0036] FIG. 14A is a chart and images showing the viability of cells in response to a doseresponse validation study of the inhibitory effect of a MEK inhibitor. Open dot symbols in the graph represent the MEK inhibitor alone, and closed dots represent the MEK inhibitor combined with 0.5 pM (Z)-endoxifen, and the values represent the mean ± SD of 3 wells. The images show cells defined by nuclei, which were stained with Hoechst and imaged at 4x magnification.

[0037] FIG. 14B is a chart and images showing the viability of cells in response to a doseresponse validation study of the inhibitory effect of a PI3K inhibitor. Open dot symbols in the graph represent the PI3K inhibitor alone, and closed dots represent the PI3K inhibitor combined with 0.5 pM (Z)-endoxifen, and the values represent the mean ± SD of 3 wells. The images show cells defined by nuclei, which were stained with Hoechst and imaged at 4x magnification.DETAILED DESCRIPTION

[0038] Efficacy of cancer therapies is highly dependent on cancer type, such that drugs that are highly effective in one cancer type may have limited efficacy in other cancers. Often, this results from drugs that target specific pathways disrupted or upregulated in one cancer type but not in others. The present disclosure provides compositions and methods for treating various cancers using (Z)-endoxifen and additional therapeutic agents chosen for their synergistic activity with (Z)-endoxifen. (Z)-endoxifen is an active metabolite of tamoxifen. In the liver, (Z)- endoxifen is broken down into active compounds or metabolites. One of the active tamoxifen metabolites is (Z)-endoxifen, also referred to as 4-hydroxy-A-desmethyltamoxifen. (Z)- endoxifen is a selective estrogen receptor modulator (SERM) that functions as a competitive partial agonist of estrogen receptors in a tissue-specific manner. (Z)-endoxifen has robust antitumor and anti-estrogenic activity compared to tamoxifen therapy and aromatase inhibitor therapy. (Z)-endoxifen may be beneficial in treating cancers in patients that are resistant to other hormone therapies, such as tamoxifen, aromatase inhibitors, or fulvestrant, in part because (Z)-endoxifen functions independently of metabolic enzymes such as CYP2D6. When combined with compounds chosen for their complementary mechanisms of action, treatment results are greatly improved, including in quality of life and other cancer-related outcome measures.

[0039] Cancers treated with the present methods include hormone-dependent cancers, such as an ER+ breast cancer, an ER+ / HER- breast cancer, or an ER+ / HER+ breast cancer. The cancer can also be a cancer such as a medulloblastoma or a glioblastoma. Diseases for treatment with the present compounds and formulations also include ovarian carcinoma, bipolar disorder, non-small cell lung carcinoma (NSCLC), endometrial carcinoma, melanoma, prostate carcinoma, pancreatic carcinoma, gastric carcinoma, esophageal cancer, osteosarcoma, and urinary bladder cancer.

[0040] Medulloblastoma is a cancerous brain tumor originating from the cerebellum. Medulloblastoma can spread through the cerebrospinal fluid to other areas around the brain and spinal cord. Medulloblastoma can occur at any age but most often occurs in young children (e.g., pediatric medulloblastoma). Medulloblastoma tumors may arise from cerebellar granule-like precursors that can have expression levels of estrogen receptors beta and alpha. In some embodiments, the expression of estrogen receptors in medulloblastoma may allow for cancer treatment by a composition or method described herein.

[0041] Glioblastoma (e.g., glioblastoma multiforme, grade IV astrocytoma, high-grade glioma, malignant glioma, or gliosarcoma) is a rare, aggressive cancer that is commonly deadly if left untreated. Glioblastomas may arise from gliomas and low-grade astrocytomas. Most often, glioblastomas occur in the frontal and temporal lobes of the brain. Glioblastomas may migrate to other locations in the brain or body. Glioblastoma most often occurs in adults (e.g., adult glioblastoma or adult glioblastoma multiforme) with a median age of diagnosis of 64 years. Hormonal factors may be involved in the development and progression of glioblastoma.Estrogen receptors may be involved in the malignancy of glioblastoma tumors. In some embodiments, the expression of estrogen receptors in glioblastoma may allow for cancer treatment by a composition or method described herein. Glioblastoma multiforme (GBM; CNS grade 4) is the most common malignant brain tumor in adult patients, with an estimated 5-year survival rate of less than 10%. Since 2005, the current standard of care has been intensive multimodal treatment, including neurosurgical resection, radiotherapy (RT), and concomitant and adjuvant chemotherapy (CT) with temozolomide (TMZ).

[0042] Many studies have investigated the involvement of estrogen receptors (ERs) in gliomas. Reduced expression of ERa and Erfi as malignancy of gliomas increases underlies the role of ERs in the progression and possible treatment of this disease. Despite extensive research,the role of ERs and estrogen in gliomas is not clear. Studies have shown associations between high expression of ERs and survival of glioblastoma patients.Glioblastoma

[0043] Glioblastoma is a highly aggressive form of brain cancer characterized by the dysregulation of numerous genes and signaling pathways. The analysis of bulk omics data and single-cell RNA sequencing has revealed several useful genes upregulated in glioblastoma and may contribute to its progression. These genes include TOP2A, SERPINA3, ANXA1, NUSAP1, EZH2, RAD51AP1, DEK, PBK, DLGAP5, NDC80, KIF15, NCAPG, CEP55, RAB31, BARD1, KNTC1, MAD2L1, CCT6A, MT2A, and HIF1A. Many of these genes are involved in cellular processes such as cell cycle regulation, DNA repair, and cell division, which may contribute to the rapid growth and invasiveness of glioblastoma tumors.

[0044] (Z)-Endoxifen, a metabolite of tamoxifen, has emerged as a potential therapeutic agent for glioblastoma due to its ability to modulate the expression of many of these genes. The analysis showed that (Z)-endoxifen treatment led to the downregulation of genes that were upregulated in glioblastoma, suggesting a potential reversal of the cancer-promoting gene expression profile. For instance, genes involved in the G2-M checkpoint, E2F targets, Myc targets, and mTORCl signaling pathways were found to be upregulated in glioblastoma but downregulated after (Z)-endoxifen treatment.

[0045] The mechanism of action of (Z)-endoxifen in glioblastoma may be multifaceted. While (Z)-endoxifen is known to act as a selective estrogen receptor modulator, its effects in glioblastoma may extend beyond estrogen receptor signaling. The analysis revealed that (Z)- endoxifen may affect the activity of transcription factors such as E2F7, E2F8, PRMT3, and CENPA, which are implicated in glioblastoma progression. Additionally, (Z)-endoxifen may modulate the activity of protein kinase C beta (PRKCB), which is involved in various cellular processes, including proliferation, apoptosis, and angiogenesis in glioblastoma.

[0046] Furthermore, the analysis identified several genes that may serve as potential biomarkers for (Z)-endoxifen response in glioblastoma. Genes such as RPA3, NFKBIZ, and HSPB1 were found to be associated with poor survival in glioblastoma patients and were downregulated by (Z)-endoxifen treatment. These genes may not only serve as prognostic markers but also as indicators of treatment efficacy.

[0047] The potential effectiveness of (Z)-endoxifen in glioblastoma is further supported by its ability to cross the blood-brain barrier, as demonstrated in preclinical studies. This property is useful for any drug targeting brain tumors. Moreover, (Z)-endoxifen has shown superior potencycompared to tamoxifen in various cancer models, suggesting it may be more effective in treating glioblastoma.

[0048] The comprehensive analysis of gene expression data, signaling pathways, and transcription factor activity provides a strong rationale for the use of (Z)-endoxifen in glioblastoma treatment. By targeting multiple oncogenic pathways and reversing cancer- associated gene expression patterns, (Z)-endoxifen may offer a novel therapeutic approach for this challenging malignancy. However, further preclinical and clinical studies are needed to fully elucidate the efficacy and safety of (Z)-endoxifen in glioblastoma patients. Genes involved in glioblastoma development and progression include TOP2A (DNA topoisomerase II alpha), SERPINA3 (serine protease inhibitor), ANXA1 (annexin Al), NUSAP1 (nucleolar and spindle- associated protein 1), EZH2 (enhancer of zeste homolog 2), RAD51AP1 (RAD51 -associated protein 1), DEK (DEK proto-oncogene), PBK (PDZ-binding kinase), DLGAP5 (discs large- associated protein 5), NDC80 (NDC80 kinetochore complex component), KIF15 (kinesin family member 15), NCAPG (non-SMC condensin I complex subunit G), CEP55 (centrosomal protein 55), RAB31 (Ras-related protein Rab-31), BARD1 (BRCA1 -associated RING domain protein 1), KNTC1 (kinetochore-associated 1), MAD2L1 (mitotic arrest deficient 2-like 1), CCT6A (chaperonin containing TCP1 subunit 6A), and MT2A (metallothionein 2A).

[0049] DNA topoisomerase II alpha, encoded by TOP2A, may alter DNA topology by generating double-stranded breaks. TOP2A is overexpressed in glioblastoma and may be associated with poor prognosis. (Z)-Endoxifen treatment may downregulate TOP2A expression, potentially reducing tumor cell proliferation and improving chemosensitivity. SERPINA3 is a serine protease inhibitor that may be involved in inflammatory responses. In glioblastoma, SERPINA3 may promote tumor cell proliferation, invasion, and radioresistance. (Z)-Endoxifen treatment may decrease SERPINA3 expression, potentially inhibiting these effects. ANXA1 may regulate inflammatory processes and is overexpressed in glioblastoma. It may promote cell proliferation and invasion in glioblastoma. (Z)-Endoxifen treatment may reduce ANXA1 expression, potentially suppressing tumor growth and metastasis. NUSAP1 is a microtubule- associated protein that may be involved in spindle assembly and chromosome segregation. It is upregulated in glioblastoma and may be associated with poor prognosis. (Z)-Endoxifen treatment may downregulate NUSAP1, potentially inhibiting tumor cell division.

[0050] EZH2 is a histone methyltransferase that may regulate gene expression. In glioblastoma, EZH2 may promote tumor growth and invasion. (Z)-Endoxifen treatment may decrease EZH2 expression, potentially reversing these effects. RAD51AP1 may be involved in DNA repair and is upregulated in glioblastoma. (Z)-Endoxifen treatment may reduce RAD51AP1 expression, potentially sensitizing tumor cells to DNA-damaging therapies. DEKmay be involved in chromatin remodeling and transcriptional regulation. It is overexpressed in glioblastoma and may promote cell proliferation. (Z)-Endoxifen treatment may downregulate DEK, potentially inhibiting tumor growth. PBK is a serine / threonine kinase that may be involved in mitotic regulation. It is upregulated in glioblastoma and may be associated with poor prognosis. (Z)-Endoxifen treatment may decrease PBK expression, potentially suppressing tumor cell division. DLGAP5 may be involved in spindle assembly and chromosome segregation. It is overexpressed in glioblastoma and may promote tumor growth. (Z)-Endoxifen treatment may reduce DLGAP5 expression, potentially inhibiting cell division.

[0051] NDC80 is a component of the kinetochore complex and is upregulated in glioblastoma. (Z)-Endoxifen treatment may decrease NDC80 expression, potentially disrupting chromosome segregation in tumor cells. KIF15 is a motor protein that may be involved in spindle assembly. It is overexpressed in glioblastoma and may promote tumor growth. (Z)- Endoxifen treatment may downregulate KIF15, potentially inhibiting cell division. NCAPG may be involved in chromosome condensation and is upregulated in glioblastoma. (Z)-Endoxifen treatment may reduce NCAPG expression, potentially disrupting chromosome dynamics in tumor cells. CEP55 may be involved in cytokinesis and is overexpressed in glioblastoma. (Z)- Endoxifen treatment may decrease CEP55 expression, potentially inhibiting tumor cell division. RAB3 1 is a small GTPase that may be involved in vesicle trafficking. It is upregulated in glioblastoma and may promote tumor growth. (Z)-Endoxifen treatment may reduce RAB31 expression, potentially inhibiting tumor progression. BARD1 interacts with BRCA1 and may be involved in DNA repair. It is overexpressed in glioblastoma. (Z)-Endoxifen treatment may decrease BARD1 expression, potentially sensitizing tumor cells to DNA-damaging therapies.

[0052] KNTC1 may be involved in the mitotic checkpoint and is upregulated in glioblastoma. (Z)-Endoxifen treatment may reduce KNTC1 expression, potentially disrupting cell cycle progression in tumor cells. MAD2L1 is a component of the spindle assembly checkpoint and is overexpressed in glioblastoma. (Z)-Endoxifen treatment may decrease MAD2L1 expression, potentially disrupting mitotic progression. CCT6A may be involved in protein folding and is upregulated in glioblastoma. (Z)-Endoxifen treatment may reduce CCT6A expression, potentially affecting protein homeostasis in tumor cells. MT2A may be involved in metal homeostasis and is overexpressed in glioblastoma. (Z)-Endoxifen treatment may decrease MT2A expression, potentially affecting tumor cell metabolism. HIF1A is a transcription factor that may regulate cellular response to hypoxia. It is upregulated in glioblastoma and may promote tumor growth and angiogenesis. (Z)-Endoxifen treatment may reduce HIF1A expression, potentially inhibiting these effects.Pancreatic Cancer

[0053] Pancreatic carcinoma, also known as pancreatic cancer, is a disease of the exocrine pancreas. It may be referred to by synonyms such as carcinoma of the exocrine pancreas, pancreas carcinoma, exocrine pancreatic carcinoma, pancreatic cancer (not islets), exocrine pancreas carcinoma, carcinoma of the pancreas, or carcinoma of the pancreas.

[0054] Pancreatic carcinoma encompasses several disease subtypes, including pancreatic ductal adenocarcinoma (PDAC), familial pancreatic carcinoma, pancreatic adenocarcinoma, pancreatic large cell neuroendocrine carcinoma, invasive intraductal papillary mucinous neoplasm (IPMN), pancreatic neuroendocrine tumor (pNET), adenosquamous carcinoma, invasive mucinous cystic neoplasm (MCN), acinar cell carcinoma (ACC), squamous cell carcinoma (SCC), and invasive solid pseudopapillary tumor (SPT).

[0055] Pancreatic carcinoma belongs to the cancer pathology group and affects the digestive system. The prevalence is approximately 4.9 per 100,000 people. Factors that may increase susceptibility include age (over 60), lifestyle factors such as smoking, obesity, excessive consumption of red and processed meats, comorbidities like chronic pancreatitis and diabetes, familial history, and genetic risk factors. Some genetic risk factors may include mutations in genes such as KRAS (Kirsten rat sarcoma viral oncogene homolog), TP53 (tumor protein p53), CDKN2A (cyclin-dependent kinase inhibitor 2A), BRCA1 (breast cancer 1, early onset), BRCA2 (breast cancer 2, early onset), PALB2 (partner and localizer of BRCA2), ATM (ataxiatelangiectasia mutated), SMAD4 (SMAD family member 4), DPC4 (deleted in pancreatic cancer locus 4), and CCAT2 (colon cancer-associated transcript 2).

[0056] Estrogen receptor signaling may play a role in pancreatic carcinoma. Estrogen receptors, particularly ERa and ERfl, appear to have distinct roles in PDAC, potentially affecting tumor progression and gender-specific outcomes. Some studies suggest ERa may be associated with higher tumor grades, while ERfl may have a negative effect on patient survival in some cases. Activation of GPER1 (G protein-coupled estrogen receptor 1) has shown promise in inhibiting PDAC growth and enhancing immunotherapy responses in some studies, suggesting its potential as a therapeutic target. Interestingly, women may exhibit better PDAC survival rates in some cases, which could be influenced by estrogen signaling and GPER activation.

[0057] The competitive landscape for pancreatic carcinoma treatments includes approximately 310 drugs in development, with 9 in phase IV or approved. Common mechanisms of action for drugs in development include epidermal growth factor receptor erbB 1 inhibition, tubulin inhibition, programmed cell death protein 1 antagonism / inhibition, and vascular endothelial growth factor receptor inhibition. Fulvestrant, an estrogen receptor antagonist, is currently in a Phase 1 trial for pancreatic carcinoma.

[0058] Various in vitro and in vivo models are used to study pancreatic carcinoma. In vitro models may include established 2D cell lines, 3D models like spheroids, scaffolds or hydrogels, and organoids, as well as emerging models such as precision-cut tissue slices and pancreatic carcinoma-on-chip systems. In vivo models may include genetically engineered mouse models, chemically induced models, xenografts, and syngeneic mouse models. Each model type has advantages and limitations that should be considered when designing studies.

[0059] (Z)-Endoxifen, an active metabolite of tamoxifen, may have potential effects on pancreatic carcinoma. Analysis of gene expression data suggests that (Z)-endoxifen treatment may reverse the expression of genes that are dysregulated in pancreatic carcinoma. Pathway enrichment analysis identified several signaling pathways that may be upregulated in pancreatic carcinoma and reversed by (Z)-endoxifen treatment, including pathways related to cell cycle regulation, DNA replication, apoptosis, and inflammatory responses.

[0060] Transcription factor analysis revealed potential regulatory factors that may be involved in pancreatic carcinoma progression and affected by (Z)-endoxifen treatment. These include members of the E2F family, PRMT3 (protein arginine methyltransferase 3), and various zinc finger proteins. The roles of these factors in pancreatic carcinoma indicate that (Z)- endoxifen could be used to treat pancreatic cancer.

[0061] Single-cell RNA sequencing analysis of pancreatic carcinoma samples identified gene expression changes in epithelial cells that overlap with bulk RNA sequencing data and (Z)- endoxifen treatment effects. This analysis may provide insights into cell type-specific effects.

[0062] Survival analysis of pancreatic carcinoma patients based on expression of genes affected by (Z)-endoxifen treatment identified potential prognostic markers. Genes such as ITGA2 (integrin subunit alpha 2), ITGB1 (integrin subunit beta 1), DKK1 (Dickkopf WNT signaling pathway inhibitor 1), DCBLD2 (discoidin, CUB and LCCL domain containing 2), CD55 (CD55 molecule, decay accelerating factor for complement), EIF2AK2 (eukaryotic translation initiation factor 2 alpha kinase 2), NMI (N-myc and STAT interactor), IL18 (interleukin 18), DDX60 (DEAD-box helicase 60), ANXA1 (annexin Al), HMGB2 (high mobility group box 2), PMAIP1 (phorbol-12-myristate- 13 -acetate-induced protein 1), EZH2 (enhancer of zeste homolog 2), SQLE (squalene epoxidase), P4HA1 (prolyl 4-hydroxylase subunit alpha 1), LDHA (lactate dehydrogenase A), GNG7 (G protein subunit gamma 7), CERS4 (ceramide synthase 4), CIRBP (cold-inducible RNA binding protein), and TLE2 (transducin-like enhancer of split 2) are potential biomarkers or therapeutic targets.

[0063] The role of estrogen receptors in pancreatic carcinoma remains an area of active research. While some studies suggest ERfl may be a negative prognostic factor, other recent work has found positive correlations between ER expression and prognosis. The non-genomicestrogen receptor GPER1 has emerged as a potential therapeutic target, with activation showing promise in preclinical PDAC models.

[0064] Tamoxifen, a selective estrogen receptor modulator and precursor to (Z)-endoxifen, has shown some promising results in preclinical and early clinical studies of pancreatic carcinoma. Its effects may be mediated in part through GPER1 signaling and modulation of the tumor microenvironment. (Z)-Endoxifen has advantages over tamoxifen, including more consistent pharmacokinetics, independence from CYP2D6 metabolism, and potentially greater potency at estrogen receptors. (Z)-endoxifen formulations described herein will have increased effectiveness and can be combined with compounds that have synergistic mechanisms of action to treat cancer more quickly and thoroughly than either compound alone.

[0065] ITGA2 (Integrin alpha 2) encodes the alpha subunit of a transmembrane receptor for collagens and related proteins. In pancreatic carcinoma, high ITGA2 expression correlates with shorter progression-free and overall survival. ITGA2 may promote aggressive behavior and resistance to gemcitabine treatment in pancreatic cancer cells. (Z)-Endoxifen treatment appears to downregulate ITGA2 expression, which may contribute to its potential anti-tumor effects in pancreatic carcinoma.

[0066] ITGB1 (Integrin beta 1) encodes a cell surface receptor involved in cell adhesion and recognition processes. In pancreatic carcinoma, high ITGB1 expression is associated with poor clinical outcomes and may promote tumor progression through TGF-fl and WNT signaling pathways. (Z)-Endoxifen treatment appears to downregulate ITGB1 expression, potentially inhibiting these pro-tumorigenic effects.

[0067] DKK1 (Dickkopf WNT signaling pathway inhibitor 1) is a regulator of the Wnt signaling pathway and is overexpressed in pancreatic ductal adenocarcinoma (PDAC). High DKK1 expression correlates with poor patient outcomes and may promote tumor growth and metastasis. (Z)-Endoxifen treatment appears to downregulate DKK1 expression, which may contribute to its potential therapeutic effects in pancreatic carcinoma.

[0068] DCBLD2 (discoidin, CUB and LCCL domain containing 2) is a transmembrane protein involved in cell growth regulation and receptor signaling. In pancreatic carcinoma, elevated DCBLD2 expression is associated with poor clinical outcomes and may contribute to tumor aggressiveness and invasiveness. (Z)-Endoxifen treatment appears to downregulate DCBLD2 expression, potentially inhibiting these pro-tumorigenic effects.

[0069] CD55 (CD55 molecule, decay accelerating factor for complement) is a regulator of the complement system and plays a role in adaptive immunity. In pancreatic cancer, CD55 is upregulated and associated with lymph node involvement, metastasis, and vascular invasion.(Z)-Endoxifen treatment appears to downregulate CD55 expression, which may contribute to its potential anti-tumor effects.

[0070] EIF2AK2 (eukaryotic translation initiation factor 2 alpha kinase 2) encodes a protein kinase involved in the cellular stress response. In pancreatic cancer, high EIF2AK2 expression correlates with reduced overall survival and disease-specific survival. (Z)-Endoxifen treatment appears to downregulate EIF2AK2 expression, potentially inhibiting its pro-tumorigenic effects.

[0071] NMI (N-Myc and STAT interactor) interacts with transcription factors and enhances transcriptional responses to cytokines. In pancreatic cancer, high NMI expression is associated with poorer patient survival and may drive tumor progression. (Z)-Endoxifen treatment appears to downregulate NMI expression, which may contribute to its potential therapeutic effects.

[0072] IL 18 is a pro inflammatory cytokine that may promote pancreatic cancer cell proliferation and metastasis. High IL 18 expression in pancreatic cancer tissues is associated with shorter overall survival and increased invasion and metastasis. (Z)-Endoxifen treatment appears to downregulate IL 18 expression, potentially inhibiting these pro-tumorigenic effects.

[0073] DDX60 (DExD / H-Box helicase 60) functions as an antiviral factor and promotes RIG-I-like receptor-mediated signaling. In pancreatic carcinoma, DDX60 upregulation is associated with poor prognosis and may promote resistance to immunotherapy. (Z)-Endoxifen treatment appears to downregulate DDX60 expression, which may contribute to its potential anti-tumor effects.

[0074] ANXA1 is a membrane-localized protein with anti-inflammatory activity. In pancreatic cancer, ANXA1 expression is associated with epithelial-mesenchymal transition, cell proliferation, and drug response. (Z)-Endoxifen treatment appears to downregulate ANXA1 expression, potentially inhibiting these pro-tumorigenic effects.Non-Small Cell Lung Cancer

[0075] Lung cancer is a malignant tumor characterized by uncontrolled cell growth in tissues of the lung. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. NSCLC may develop and progress through various molecular mechanisms, including dysregulation of estrogen signaling pathways.

[0076] (Z)-Endoxifen may be an effective treatment for NSCLC due to its ability to modulate estrogen receptor (ER) signaling and other molecular pathways involved in cancer progression. (Z)-Endoxifen may act through both ER-dependent and ER-independent mechanisms to inhibit tumor growth and metastasis.

[0077] Several genes and their associated proteins are potential targets or indicators of (Z)- endoxifen’s efficacy in treating NSCLC, including LDHA (lactate dehydrogenase A), SFTPD(surfactant protein D), FBP1 (fructose-bisphosphatase 1), BTG2 (BTG anti-proliferation factor 2), MYEOV (myeloma overexpressed), PRR11 (proline rich 11), CENPK (centromere protein K), ECT2 (epithelial cell transforming 2), UHRF1 (ubiquitin like with PHD and ring finger domains 1), and HSP90B1 (heat shock protein 90 beta family member 1).

[0078] LDHA is often upregulated in NSCLC and associated with poor prognosis. (Z)- Endoxifen may downregulate LDHA expression, potentially reducing cancer cell metabolism and proliferation. Decreased expression of SFTPD in NSCLC may be associated with poor outcomes. (Z)-Endoxifen may upregulate SFTPD expression, potentially suppressing tumor progression. FBP1 is often downregulated in NSCLC. (Z)-Endoxifen may increase FBP1 expression, potentially inhibiting cancer cell proliferation and metastasis. BTG2 expression is frequently reduced in NSCLC. (Z)-Endoxifen may upregulate BTG2, potentially promoting cell cycle arrest and apoptosis in cancer cells. MYEOV is often overexpressed in NSCLC and associated with poor prognosis. (Z)-Endoxifen may downregulate MYEOV expression, potentially reducing tumor invasion and metastasis. PRR11 overexpression in NSCLC may be associated with poor survival. (Z)-Endoxifen may decrease PRR11 expression, potentially inhibiting cell cycle progression and tumor growth.

[0079] CENPK is often upregulated in NSCLC and associated with poor prognosis. (Z)- Endoxifen may downregulate CENPK expression, potentially reducing cancer cell proliferation and invasion. ECT2 overexpression in NSCLC may be associated with poor outcomes. (Z)- Endoxifen may decrease ECT2 expression, potentially inhibiting cancer cell division and metastasis. UHRF1 is often overexpressed in NSCLC. (Z)-Endoxifen may downregulate UHRF1, potentially reducing cancer cell proliferation and survival. HSP90B1 overexpression in NSCLC may be associated with poor prognosis. (Z)-Endoxifen may decrease HSP90B1 expression, potentially reducing cancer cell survival and drug resistance.

[0080] These genes and their associated proteins may be involved in various cellular processes, including cell cycle regulation, metabolism, DNA repair, and signal transduction. By modulating the expression or activity of these genes, (Z)-endoxifen may exert anti-tumor effects in NSCLC through multiple mechanisms.

[0081] In addition to its effects on individual genes, (Z)-endoxifen may also influence broader signaling pathways implicated in NSCLC progression. (Z)-Endoxifen may downregulate Myc-dependent gene expression, potentially inhibiting cancer cell growth and metabolism. (Z)-Endoxifen may also modulate mTORCl pathway activity, potentially affecting cancer cell growth, survival, and protein synthesis. The present disclosure shows that (Z)- Endoxifen may regulate estrogen-responsive genes, potentially altering cancer cell behavior and tumor microenvironment. In addition, (Z)-Endoxifen may influence cellular stress responsessuch as the unfolded protein response, potentially affecting cancer cell survival and drug sensitivity.

[0082] The present disclosure also shows that (Z)-Endoxifen may modulate genes involved in the epithelial-mesenchymal transition (EMT), potentially reducing cancer cell invasion and metastasis. Other targets that (Z)-endoxifen may regulate include expression of E2F-dependent genes, potentially affecting cell cycle progression and apoptosis. The ability of (Z)-endoxifen to potentially modulate multiple genes and pathways involved in NSCLC progression suggests that it may be an effective treatment option for this disease. Furthermore, (Z)-endoxifen’s effects on these molecular targets may complement or enhance the efficacy of existing therapies, such as chemotherapy or targeted therapies.Melanoma

[0083] In some aspects, the present disclosure relates to methods of treating melanoma using (Z)-endoxifen. Melanoma is a type of skin cancer that develops from melanocytes, the pigmentproducing cells in the skin. The development and progression of melanoma may involve dysregulation of various genes and signaling pathways.

[0084] Several useful genes and pathways may be involved in melanoma pathogenesis and progression, including KPNA2 (karyopherin subunit alpha 2), MYO5A (myosin VA), DTL (denticleless E3 ubiquitin protein ligase homolog), PRC1 (protein regulator of cytokinesis 1), ADAM 10 (ADAM metallopeptidase domain 10), E2F3 (E2F transcription factor 3), TBXAS1 (thromboxane A synthase 1), EIF2AK2 (eukaryotic translation initiation factor 2 alpha kinase 2), NFYA (nuclear transcription factor Y subunit alpha), and NARS2 (asparaginyl-TRNA synthetase 2).

[0085] KPNA2: This gene encodes a protein involved in nuclear transport. In melanoma, KPNA2 may be upregulated and associated with poor prognosis. (Z)-Endoxifen may help by potentially downregulating KPNA2 expression, which could inhibit melanoma cell proliferation and metastasis.

[0086] MYO5A: This gene encodes a protein involved in intracellular transport and cell motility. In melanoma, MYO5A may play a role in melanoma cell invasion and metastasis. (Z)- Endoxifen treatment may potentially reduce MY 05 A expression, which could help limit melanoma progression.

[0087] DTL: DTL is involved in cell cycle regulation and DNA replication. In melanoma, DTL upregulation may be associated with poor clinical outcomes. (Z)-Endoxifen may help by potentially downregulating DTL, which could inhibit melanoma cell growth and improve patient prognosis.

[0088] PRC1: This gene is involved in cell division and cytokinesis. In melanoma, PRC1 overexpression may contribute to tumor growth. (Z)-Endoxifen treatment may potentially reduce PRC 1 expression, which could help inhibit melanoma cell proliferation.

[0089] ADAMI 0: This gene encodes a protein involved in cell-cell interactions and cell signaling. In melanoma, ADAM 10 may be associated with increased cell proliferation and migration. (Z)-Endoxifen may help by potentially downregulating ADAM 10, which could limit melanoma progression and metastasis.

[0090] E2F3: This transcription factor plays a role in cell cycle regulation and proliferation.In melanoma, E2F3 overexpression may contribute to tumor growth. (Z)-Endoxifen treatment may potentially reduce E2F3 expression, which could help inhibit melanoma cell proliferation.

[0091] TBXAS1: This gene is involved in thromboxane biosynthesis and may play a role in inflammation and tumor progression. In melanoma, TBXAS 1 upregulation may be associated with enhanced inflammatory response in the tumor microenvironment. (Z)-Endoxifen may help by potentially downregulating TBXAS 1 , which could modulate the inflammatory response in melanoma.

[0092] EIF2AK2: This gene is involved in the cellular stress response and innate immune response. In melanoma, EIF2AK2 overexpression may be associated with poor prognosis. (Z)- Endoxifen treatment may potentially reduce EIF2AK2 expression, which could help improve patient outcomes.

[0093] NFYA: This transcription factor is involved in various cellular processes, including cell cycle regulation and apoptosis. In melanoma, NFYA may contribute to tumor angiogenesis. (Z)-Endoxifen may help by potentially downregulating NFYA, which could limit melanoma progression and metastasis.

[0094] NARS2: This gene is involved in protein synthesis. In melanoma, NARS2 mutations may be associated with immune checkpoint inhibitor therapy efficacy. (Z)-Endoxifen treatment may potentially modulate NARS2 expression, which could influence melanoma response to immunotherapy.

[0095] Several useful signaling pathways may be dysregulated in melanoma and potentially modulated by (Z)-endoxifen treatment:

[0096] G2-M Checkpoint: This cell cycle checkpoint ensures proper DNA repair before cell division. In melanoma, disruption of this checkpoint may contribute to genomic instability and tumor progression. (Z)-Endoxifen may help by potentially modulating the expression of genes involved in the G2-M checkpoint, which could help restore normal cell cycle control.

[0097] E2F Signaling Pathway: This pathway regulates cell cycle progression and DNA replication. In melanoma, dysregulation of E2F signaling may contribute to uncontrolled cellproliferation. (Z)-Endoxifen treatment may potentially modulate E2F signaling, which could help inhibit melanoma cell growth.

[0098] mTORCl Signaling: This pathway regulates cell growth, proliferation, and survival. In melanoma, mTORCl activation may contribute to tumor progression and drug resistance. (Z)-Endoxifen may help by potentially inhibiting mTORCl signaling, which could limit melanoma growth and enhance the efficacy of other treatments.

[0099] Interferon Alpha Response: This pathway is involved in the innate immune response against viruses and tumors. In melanoma, dysregulation of the interferon alpha response may contribute to immune evasion. (Z)-Endoxifen treatment may potentially modulate the interferon alpha response, which could enhance anti-tumor immunity.

[0100] Complement Activation: This pathway is part of the innate immune system and may play a role in tumor progression. In melanoma, complement activation may contribute to tumor growth and metastasis. (Z)-Endoxifen may help by potentially modulating complement activation, which could limit melanoma progression.

[0101] Interferon Gamma Response: This pathway is involved in adaptive immunity and tumor surveillance. In melanoma, dysregulation of the interferon gamma response may contribute to immune evasion and tumor progression. (Z)-Endoxifen treatment may potentially modulate the interferon-gamma response, which could enhance anti-tumor immunity and improve treatment outcomes.

[0102] In summary, (Z)-endoxifen may help treat melanoma by modulating the expression of useful genes and signaling pathways involved in melanoma pathogenesis and progression. These effects may include inhibition of cell proliferation, reduction of metastasis, modulation of immune responses, and enhancement of treatment efficacy. Further research may be needed to fully elucidate the mechanisms by which (Z)-endoxifen affects melanoma and to optimize its use in melanoma treatment.(Z)-Endoxifen in Combination with Therapeutic agents

[0103] Described herein are compositions comprising (Z)-endoxifen, or (Z)-endoxifen and a therapeutic agent such as an anti-cancer agent, that may be used for treating cancers such as breast cancer, medulloblastoma and glioblastoma. Medulloblastoma may include pediatric medulloblastoma. Glioblastoma may include glioblastoma multiforme (e.g., adult glioblastoma multiforme), grade IV astrocytoma, high-grade glioma, malignant glioma, or gliosarcoma. The (Z)-endoxifen composition may comprise (Z)-endoxifen, and polymorphs and salts thereof.

[0104] The compositions and methods described herein may be used in combination with other therapies (e.g., a chemotherapy, a drug, a radiation therapy, or surgery) to treat the canceror associated symptoms (e.g., pain, depression, anxiety, nausea, fatigue, or loss of appetite). For example, a (Z)-endoxifen composition may be administered in combination with an antidepressant (e.g., a serotonin reuptake inhibitor). In another example, a (Z)-endoxifen composition may be administered before, after, or concurrent with surgery to remove the cancer. A therapeutic agent may be formulated with the (Z)-endoxifen in a pharmaceutical composition or administered separately. In some embodiments, a therapeutic agent for use in combination with (Z)-endoxifen to treat a cancer may be identified using a drug screen.Benefits of Combination Treatment

[0105] (Z)-Endoxifen, a potent selective estrogen receptor modulator (SERM), has shown significant promise in treating various cancers, particularly those resistant to other hormone therapies. The efficacy of (Z)-endoxifen can be further enhanced when used in combination with therapeutic compounds that target complementary pathways. Several mechanisms of action have been identified that exhibit synergistic potential with (Z)-endoxifen, thereby improving its anticancer efficacy.

[0106] One notable mechanism involves the inhibition of the BCL2 family of proteins. (Z)- Endoxifen has been shown to down-regulate BCL2 expression, a pro-survival factor in cancer cells. This down-regulation can be leveraged by combining (Z)-endoxifen with drugs that target other BCL2 family members, such as BCL-XL, BCL-W, and MCL1. For instance, navitoclax, which targets BCL2, BCL-XL, and BCL-W, has demonstrated increased activity in (Z)- endoxifen-resistant models, further decreasing cancer cell viability. This combination exploits the vulnerability created by (Z)-endoxifen’s suppression of BCL2, leading to enhanced apoptosis and reduced likelihood of resistance development.

[0107] High-throughput screening has identified several classes of compounds that synergize with (Z)-endoxifen, enhancing its anti-cancer effects. These include inhibitors of microtubules, mTOR, proteasomes, XIAP, kinesin-like spindle proteins, PLK, farnesyltransferase, CDK, AKT, HSP, topoisomerase, Aurora kinase, MEK, CHK, HDAC, SRC, PI3K, bromodomain, and protein synthesis. For example, microtubule inhibitors disrupt the mitotic spindle, leading to cell cycle arrest and apoptosis, which complements (Z)-endoxifen’s ability to inhibit estrogen receptor signaling. Similarly, mTOR inhibitors, such as everolimus, can enhance the anti-proliferative effects of (Z)-endoxifen by blocking a pathway for cell growth and survival.

[0108] Another promising combination involves the use of PI3K inhibitors, which target the PI3K / AKT / mTOR pathway, a driver of cancer cell proliferation and survival. By inhibiting this pathway, PI3K inhibitors can reduce cancer cell growth and enhance the sensitivity of cancercells to (Z)-endoxifen. Additionally, HD AC inhibitors, which modulate gene expression by altering chromatin structure, can also synergize with (Z)-endoxifen by promoting apoptosis and inhibiting cancer cell proliferation. These combinations not only improve the therapeutic efficacy of (Z)-endoxifen but also help in overcoming resistance mechanisms, providing a more robust and durable response in cancer treatment.

[0109] In summary, the combination of (Z)-endoxifen with various therapeutic agents targeting different mechanisms of action holds significant potential for enhancing cancer treatment outcomes. By strategically combining (Z)-endoxifen with these compounds, it is possible to exploit multiple vulnerabilities in cancer cells, leading to improved efficacy and reduced resistance.Methods of Treating Cancers

[0110] A method of treating a cancer (e.g., hormone-positive cancer, breast cancer, medulloblastoma, or glioblastoma) may comprise administering to a subject a therapy comprising a therapeutic agent and (Z)-endoxifen. In some embodiments, the therapeutic agent, the (Z)-endoxifen, or a combination thereof, is administered orally, topically, transdermally, rectally, intravenously, intramuscularly, subcutaneously, intra-arterially, intra-ovarianly, vaginally, parenterally, or via inhalation. In some embodiments, the (Z)-endoxifen is administered topically. In some embodiments, the (Z)-endoxifen is administered orally, topically, transdermally, rectally, intravenously, intra-arterially, intra-ovarianly, vaginally, parenterally, or via inhalation. In some embodiments, the (Z)-endoxifen is formulated as a sustained-release composition. A composition including (Z)-endoxifen may be administered 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day. In some embodiments, a composition including (Z)- endoxifen may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day. Treatment may be administered for at least 7, 14, 21, 28, 30, 35, 42, 49, 56, or 60 days. In some embodiments, treatment may be administered until a cancer is treated (e.g., by eliminating or reducing the size of a tumor). In some embodiments, treatment may be administered until unacceptable toxicity is observed in the subject. In some embodiments, (Z)-endoxifen may be administered to treat a cancer at a dose of from about 1 mg to about 160 mg, from about 1 mg to about 40 mg, from about 1 mg to about 10 mg, or from about 2 mg to about 5 mg per day. In some aspects, the (Z)- endoxifen is administered to the subject at a dose of no less than 1 mg and no more than 160 mg per day. In some aspects, the (Z)-endoxifen is administered to the subject at a dose of no less than 1 mg and no more than 40 mg per day. In some aspects, the (Z)-endoxifen is administered to the subject at a dose of no less than 1 mg and no more than 10 mg per day. In some aspects, the (Z)-endoxifen is administered to the subject at a dose of no less than 2 mg and no more than5 mg per day. In some aspects, the method includes administering the (Z)-endoxifen 1, 2, 3, or 4 times per day. In some aspects, the method includes administering the (Z)-endoxifen for at least 7, at least 14, at least 21, or at least 28 days.

[0111] The method of treating a cancer includes administering (Z)-endoxifen and a therapeutic agent. In some aspects, the therapeutic agent is selected from the group consisting of BAY-11-7082, salinomycin (Procoxacin), Pimasertib (AS-703026), A66, RO5126766 (CH5126766), ASP3026, RO4987655, PD318088, K-Ras(G12C) inhibitor 12, PIK-93, Ravoxertinib, GDC-0994, Osimertinib, Gilteritinib, Cobimetinib, Duvelisib (IPI-145, INK1197), Tesevatinib, PD173074, Copanlisib, Binimetinib (MEK162, ARRY-162, ARRY-438162), lodophenpropit, U-18666A, ZM-241385, AZD-8835, Trametinib, NVP-TAE226, Atiprimod, AZD4547, NVP-TNKS656, Alpelisib (BYL719), Afatinib (dimaleate), Saracatinib (AZD0530), Tenovin-6, Tubastatin A hydrochloride, L-778123 (hydrochloride), Ascomycin (FK520), AZD8186, GZD824 Dimesylate, Ro 48-8071 (fumarate), EW-7197, Dorsomorphin, BAX- channel-blocker, Erbstatin-analog, CH5132799, Hoechst 33258, AT13148, AZD5363, AZD8330, AZ5104, BMS-983970, Dasatinib, Bleomycin sulfate, Maxacalcitol, GSK1059615, Nexturastat A, Ribociclib (LEE011), Etoposide phosphate, NVP-ADW742, Voreloxin (Hydrochloride), Triciribine, LB42708, SM-164, Walrycin B, BMS-345541, Domiphen Bromide, RepSox, TAK-733, BX-912, LCL161, NVP-AEW541, Lonafarnib (SCH66336), Vorinostat (SAHA, MK0683), Quinacrine hydrochloride, Ipatasertib (GDC-0068), GDC-0152, Afuresertib, Falecalcitriol, PRT062607 (P505-15, PRT2607, BIIB057) HC1, Prexasertib (dihydrochloride), XL388, MLN8054, SU9516, BNTX, Fedratinib (SAR302503, TG101348), C-021, Taselisib, NSC-3852, Miransertib, MK-2206 dihydrochloride, Resminostat (RAS2410), 5-BrdU, CH55, Carmofur, Bimiralisib, JNJ-7706621, Rapamycin, Tosedostat, Idoxuridin, VS- 5584, Uprosertib, M344, Mycophenolate mofetil, XL888, PP-121, LMK-235, CPI-203, MK8745, Apitolisib (GDC-0980, RG7422), GSK690693, Tipifarnib (Zamestra), Etoposide, Mycophenolic Acid, PD 0332991 (Palbociclib) HC1, 1-BET151 (GSK1210151A), Pemetrexed, AZ20, Phortress, PHA-848125, MPI-0479605, OSI-027, Ingenol mebutate, Cevipabulin, FK- 866, APY-29, LY3023414, Ixazomib citrate, Belinostat (PXD101), Crenolanib (CP-868596), 6,7-Dihydroxy-l-(4-Hydroxybenzyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride, (+)-JQl, AZD3463, BET-BAY 002, GDC-0349, VX-680 (MK-0457, Tozasertib), GSK1070916, Gentian violet, Combretastatin-A4, UNC2025 (hydrochloride), Satraplatin, BMS-566419, Cycloheximide, Digitoxigenin, ABT-751 (E7010), 3-Deazaneplanocin A (DZNeP) HC1, Abemaciclib (LY2835219), AZD7762, WYE-687, AP26113, Hesperadin, PHA-680632, Basic fuchsin, Diphenyleneiodonium, MK-1775, Clofarabine, AZD6738, Bisacodyl, NVP-HSP990, NSC319726, Epothilone D, PHA-767491, AR-42 (HD AC-42), AMG 232, Barasertib(AZD1152-HQPA), Teniposide, KW-2478, 1-BET-762, Strophantidin, Amsacrine, CC-115, Ganetespib (STA-9090), Filanesib, NMS-E973, BNC105, Torin 1, Aphidicolin, Vinorelbine (ditartrate), XL228, PF-05212384 (PKI-587), 17-AAG (Tanespimycin), 5-Fluoro-2- deoxycytidine, Trifluridine, GSK461364, Digoxigenin, Colchicine, MK-8776 (SCH 900776), SB-268262, R547, PF-03814735, Gemcitabine (elaidate), AT9283, Cyclocytidine HC1, Fosbretabulin (disodium), CGP-74514, VER-49009, Retaspimycin (Hydrochloride), BML-284, Cytarabine, Briciclib, Mivobulin, Ixazomib citrate (MLN9708), Verubulin, PF-3758309, LY2334737, Floxuridine, WYE-125132, Topotecan (hydrochloride), Torin-2, KX2-391, Ixazomib (MLN2238), Pevonedistat hydrochloride, Camptothecin, Gemcitabine, Irinotecan, Ispinesib (SB-715992), AZDI 152, TAK-901, NMS-1286937, Taltobulin (trifluoroacetate), Onalespib (AT13387), Danusertib (PHA-739358), 17-DMAG HC1 (Alvespimycin), PD-166285, Ixabepilone, Vincristine (sulfate), MLN8237 (Alisertib), Vinblastine (sulfate), Oprozomib (ONX 0912), Ansamitocin P-3, Vistusertib (AZD2014), CHIR-124, TAS- 103 (dihydrochloride), ER-27319 maleate, PU-H71, Vindesine Sulfate, Nampt-IN-1, Raltitrexed (Tomudex), BI6727 (Volasertib), Litronesib, Omipalisib (GSK2126458, GSK458), PF-04691502, PHA-793887, Luminespib, INK 128 (MLN0128), SNX-2112, SB-743921, CYT997, PF-04929113 (SNX- 5422), AZD5438, Proflavine hemisulfate, Patupilone (EPO906, Epothilone B), A-674563, LY2090314, Plinabulin, Talazoparib (BMN 673), Torkinib (PP242), Genz-644282, ARQ 621, Pralatrexate (Folotyn), Selinexor (KPT-330), R306465, and HMN-214.

[0112] In some embodiments, a dosage of (Z)-endoxifen for treating a cancer may be selected based on an IC50 of (Z)-endoxifen determined in vitro for the cancer of interest. The IC50 may be determined as the concentration of (Z)-endoxifen that inhibits 50% of the tumor cells of that cancer type in vitro. For example, a dosage of (Z)-endoxifen may be selected to treat a cancer type such that an in vivo concentration is achieved within the subject (e.g., a maximum serum concentration (Cmax)) that is one tenth the IC50, at least one fifth the IC50, at least one third the IC50, at least half IC50, or at least the IC50. The IC50 of (Z)-endoxifen for the specific cancer type (e.g., pediatric medulloblastoma or adult glioblastoma multiforme) may be determined by generating a dose-response curve. In some embodiments, a dose-response curve may be generated using a patient-derived tumor model. In some embodiments, a dose-response curve may be generated using a cancer model (e.g., a cultured cell or tissue). In some embodiments, the IC50 may be patient-specific, cancer-type-specific, or both. In some embodiments, IC50 is calculated by incubating MCF-7 sigma cells for 4 days, 6 days, or 6 days at 1.25pM (Z)- endoxifen (FIG. 10).

[0113] Whether or not a subject is tamoxifen-refractory may be determined by dosing a subject with an initial dosage of tamoxifen and determining the subject’s plasma (Z)-endoxifensteady state level. Plasma (Z)-endoxifen steady-state levels in a subject dosed with tamoxifen serve as a biomarker for the tamoxifen-refractory subjects. The plasma (Z)-endoxifen levels (acute and / or steady state) may be determined by obtaining from the subject a test sample, which may be a blood sample collected from the subject after dosing the subject with tamoxifen. Plasma or serum may be obtained from blood samples to test the biomarker (Z)-endoxifen levels. The initial dosage may comprise administering tamoxifen daily for at least 1 day, 2 days, 3 days, 15 days, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months. The subject may also be administered with a first composition comprising tamoxifen daily for at least 1 day, 2 days, 3 days, 15 days, 1 week, 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, or 10 years.

[0114] A subject’s plasma (Z)-endoxifen steady-state level may be determined by measuring (Z)-endoxifen in a test sample. The subject’s plasma (Z)-endoxifen steady-state levels are compared to a reference plasma (Z)-endoxifen level. For the purposes of the present disclosure, the reference plasma level is 30 nM. If the subject’s plasma (Z)-endoxifen level is determined to be lower than 30 nM, then the subject is defined as tamoxifen-refractory. Such a tamoxifen- refractory subject may be treated by administering to the subject an oral composition comprising (Z)-endoxifen or a salt thereof disclosed herein or a polymorphic form of (Z)-endoxifen disclosed herein. In some embodiments, the composition administered to such a subject comprises (Z)-endoxifen free base. In other embodiments, the composition administered to such a subject comprises endoxifen gluconate selected from the group consisting of (Z)-endoxifen D- gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen D-gluconate, (E)-endoxifen L-gluconate, or a combination thereof. In other embodiments, the composition comprising (Z)-endoxifen is (Z)-endoxifen HC1 or (Z)-endoxifen citrate. The present disclosure also contemplates that a subject’s plasma (Z)-endoxifen levels are tracked or monitored periodically or as necessary. A subject who has been administered an initial dosage of tamoxifen may have his or her plasma (Z)-endoxifen steady-state levels adjusted by administering a composition comprising (Z)- endoxifen on an ongoing basis based on the test results.

[0115] In some aspects, the techniques described herein relate to a formulation, wherein the administering of the formulation maintains a plasma level of (Z)-endoxifen of the subject at a steady state level above 30 nM. In some aspects, the administering of the formulation maintains the plasma level at a steady state level from 30 nM to 300 nM. In some aspects, the techniques described herein relate to a formulation, further including releasing no more than 10% of the (Z)-endoxifen in a stomach of the subject within 2 hours following the administering of the formulation. In some aspects, the techniques described herein relate to a formulation, furtherincluding releasing at least 50% of the (Z)-endoxifen in a small intestine of the subject within 8 hours following the administering of the formulation. In some aspects, the techniques described herein relate to a formulation, further including producing an area under curve (AUCO-inf) of (Z)-endoxifen in the subject of from 200 hr*ng / mL to 10,000 hr*ng / mL per 4 mg of (Z)- endoxifen administered. In some aspects, the techniques described herein relate to a composition for use, further including producing a maximum blood plasma concentration (Cmax) of (Z)- endoxifen in the subject of from 14 ng / mL to 62 ng / mL per 4 mg of (Z)-endoxifen administered.

[0116] In some embodiments, the subject’s tamoxifen-refractory status may be determined by determining the subject’s tamoxifen-metabolites profile, which is compared with a reference tamoxifen-metabolite profile as seen in control or normal subjects. Subjects with low plasma (Z)-endoxifen levels in the subject’s tamoxifen-metabolite profile as compared to the reference tamoxifen-metabolite profile are administered a formulation comprising (Z)-endoxifen or a salt thereof. Such compositions may comprise synthetically prepared (Z)-endoxifen.

[0117] Plasma (Z)-endoxifen may be measured using any method known in the art. The levels of plasma (Z)-endoxifen in a test sample may be determined based on the subject’s genes, DNA, RNA, protein, tamoxifen-metabolite profile, or a combination thereof. The tamoxifen- metabolites profile can include at least tamoxifen, 4-OHT, N-desmethyltamoxifen, and / or (Z)- endoxifen. In some embodiments, the level of plasma (Z)-endoxifen and / or tamoxifen- metabolite profile in the test sample is measured by high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS / MS), immunohistochemistry (IHC), polymerase chain reaction (PCR), quantitative PCR (qPCR), and the like. In some embodiments, the tamoxifen-metabolites profile is predicted based on the subject’s genetic composition. In some embodiments, the subject’s CYP genotype includes, without limitation, analysis of CYP2D6, CYP3A4, and CYP2C9 genes. In some embodiments, a subject’s estrogen receptor levels may be analyzed. In other embodiments, the determination of plasma (Z)-endoxifen may be done by a third-party laboratory.

[0118] In another aspect, the subjects may have their test samples tested for their biomarker profile that may be indicative of cancer or used for monitoring cancer. Such biomarkers are known in the art and include, by way of non-limiting examples, biomarkers such as CYP2D6, BRCA-1, BRCA-2, ER, PR, Her2, uPA, PAI, Tf, p53, Ki67, cytokeratins, cancer tumor antigens, and other biomarkers measured by MAMMAPRINT®, ONCOTYPEDX®, PAM50®, ENDOXPREDICT®, MAMMOSTRAT®, and other diagnostic and predictive tests. A subject with a biomarker profile indicating that the subject has or is at risk of having cancer can be administered a composition disclosed herein. In one aspect, the present disclosure provides amethod of treating a subject having or at risk of having cancer, comprising determining the subject’s risk of cancer and administering to the subject a composition described herein.(Z)-Endoxifen

[0119] In some aspects, the techniques described herein relate to a method of treating a cancer in a subject in need thereof, the method including administering to the subject a composition including a therapeutically effective amount of a therapeutic agent and (Z)- endoxifen which is a compound of Formula (I)Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, thereby treating the cancer. In some aspects, the compound of Formula (I) is >90% (Z)-endoxifen. In some aspects, the compound of Formula (I) endoxifen is >95%, >96%, >97%, >98%, >99%, or >99.5% (Z)- endoxifen. In some aspects, the (Z)-endoxifen is a compound of Formula (II)Formula (II).

[0120] In some aspects, the (Z)-endoxifen is in a free base form. In some aspects, the pharmaceutically acceptable salt of the (Z)-endoxifen is selected from the group consisting of an: arecoline, besylate, bicarbonate, bitartrate, butylbromide, citrate, camsylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinol, hydralazine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc salt. In some aspects, the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen gluconate. In some aspects, the pharmaceutically acceptablesalt of the (Z)-endoxifen is (Z)-endoxifen citrate. In some aspects, the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen hydrochloride.

[0121] Unless specifically referred to by the prefix (Z), (E) or (E / Z), endoxifen used generally without a prefix is used herein to include to any or all endoxifen isoforms. A mixture of (E)-endoxifen and (Z)-endoxifen can be represented by Formula (I):Formula (I).

[0122] In an aspect, the present disclosure provides that the sustained-release compositions of the present disclosure specifically include, in some embodiments, polymorphic crystalline forms of endoxifen, such as Form I, Form II, or Form III, as described in Applicant’s patent publication W02019051416 (Al) (incorporated herein by reference).

[0123] In some cases, Formula (I) is primarily the (Z)-isomer. In some cases, Formula (I) is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% (Z)- endoxifen.

[0124] (Z)-endoxifen is an active metabolite of tamoxifen and is a selective estrogen receptor modulator (SERM) that functions as a competitive partial agonist of estrogen receptors in a tissue-specific manner. (Z)-Endoxifen has robust antitumor and anti-estrogenic activity compared to tamoxifen therapy and aromatase inhibitor therapy. (Z)-endoxifen may be beneficial in treating cancers in patients that are resistant to other hormone therapies, such as tamoxifen, aromatase inhibitors, or fulvestrant, in part because (Z)-endoxifen functions independently of metabolic enzymes such as CYP2D6. Moreover, (Z)-endoxifen has shown superior potency compared to tamoxifen in various cancer models, suggesting it may be more effective in treating cancers such as glioblastoma, among others.

[0125] (Z)-Endoxifen in the disclosed formulations may include less than about 2 wt. % of chemical impurities, such as less than about 2 wt. %, less than about 1 wt. %, less than about 0.5 wt. %, and so forth. Chemical impurities may include but are not limited to decomposition products, side products from the production of (Z)-endoxifen, and the like. The chemical purity of the (Z)-endoxifen may be measured by tools available to those skilled in the art, including but not limited to high-performance liquid chromatography (HPLC). In other words, the (Z)- endoxifen of the present disclosure may have a chemical purity of at least about 98%.

[0126] In some embodiments, the (Z)-endoxifen has a residual solvent content of not more than (NMT) about 3000 ppm methanol, NMT about 720 ppm tetrahydrofuran, NMT about 5000 ppm isopropanol, NMT about 5000 ppm heptane, NMT about 5000 ppm ethanol, or any combination thereof. Residual solvent content may be evaluated by methods including but not limited to HPLC or nuclear magnetic resonance (NMR) spectroscopy.

[0127] The (Z)-endoxifen of the present disclosure may, in some embodiments, be more stable than (Z)-endoxifen produced by other methods. It is contemplated that this improved stability is due to a different impurity and residual solvent profile. The (Z)-endoxifen may be stable at ambient temperature for at least 6 months, at least 9 months, at least 12 months, at least 18 months, or any value contained within a range formed by any two of the preceding values. In some embodiments, the (Z)-endoxifen is stable for at least 9 months at 25 °C at 60% relative humidity (25°C / 60% RH) and for at least 3 months at 40 °C / 75% RH.

[0128] In some embodiments, the (Z)-endoxifen compositions disclosed herein contain a ratio of (Z)-endoxifen to (E)-endoxifen of at least about 90:10, such as at least about 90:10, about 91:9, about 92:8, about 93:7, about 94:6, about 95:5, about 96:4, about 97:3, about 98:2, about 99:1, about 100:0, or any value contained within a range formed by any two of the preceding values. It will be understood that compositions having different ratios of (Z)- endoxifen to (E)-endoxifen may have different properties, including but not limited to stability and pharmacokinetic parameters. In some embodiments, compositions of endoxifen with a higher ratio of (Z)-endoxifen to (E)-endoxifen (that is, more (Z)-endoxifen) exhibit improved stability and superior pharmacokinetics relative to compositions containing higher amounts of (E)-endoxifen.

[0129] In some embodiments, the (Z)-endoxifen is produced in a particular crystalline form. For example, the (Z)-endoxifen produced may be in Crystalline Form I. FIG. 2 is an X-ray powder diffraction (XRPD) pattern of Crystalline Form I, according to an embodiment of the present disclosure. In some embodiments, the (Z)-endoxifen may be in a different crystalline form or mixture of crystalline forms. In some embodiments, the (Z)-endoxifen may have a polymorphic purity of at least about 70%, at least about 80%, at least about 90%, at least about 95%, or any value contained within a range formed by any two of the preceding values. For example, in some embodiments, the (Z)-endoxifen may have a polymorphic purity of at least about 90%, meaning that at least about 90% by mass of the crystalline (Z)-endoxifen is a particular crystalline form. In some embodiments, the polymorphic purity of the (Z)-endoxifen can be evaluated by an analytical method such as quantitative XRPD. In some embodiments, the polymorphic purity of the (Z)-endoxifen may be determined by evaluating the XRPD pattern and observing the absence of characteristic, non-overlapping peaks of other known crystalforms, and if no such peaks are present, the (Z)-endoxifen is considered to be polymorphically pure within the limit of detection of the instrument used to perform XRPD.

[0130] The terms “crystalline form”, “polymorph,” and “Form” may be used interchangeably herein and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. The compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0131] The term “substantially as shown in” when referring, for example, to an XRPD pattern, includes a pattern that 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 on 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 two theta (20) values. Accordingly, when a specified two theta angle is provided, it is to be understood that the specified two theta angle can vary by the specified value ± 0.5°, such as ± 0.4°, ± 0.3°, ± 0.2°, or ± 0.1°. 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.

[0132] All compounds disclosed herein are further understood to include all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of example, and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon includenC,13C, and14C.

[0133] In some embodiments, the (Z)-endoxifen may include one or more polymorphic forms, such as Form I, of (Z)-endoxifen. A polymorphic form may be distinguished by its X-ray powder diffraction pattern. In some embodiments, a method of treating cancer may comprise administering a pharmaceutical composition comprising (Z)-endoxifen predominantly as polymorph Form I. In some embodiments, polymorphic Form I is characterized by an X-ray powder diffraction pattern comprising major peaks at 16.8 ± 0.3°, 17.1 ± 0.3° and 21.8 ± 0.3° two theta. The crystalline form of Form I of the compound of (Z)-endoxifen can be characterizedby an XRPD pattern comprising major peaks at 16.8 ± 0.3°, 17.1 ± 0.3° and 21.8 ± 0.3° two theta. In some cases, the XRPD pattern further comprises at least one peak, or at least two peaks, at least three peaks selected from 16.0 ± 0.3°, 18.8 ± 0.3° and 26.5 ± 0.3° two theta. In some cases, the XRPD pattern further comprises at least one peak, or at least two peaks, at least three peaks selected from 12.4 ± 0.3°, 28.0 ± 0.3° and 29.0 ± 0.3° two theta. In some embodiments, polymorphic Form I of (Z)-endoxifen exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in WO2023 / 137044 (see FIG. 1A and FIG. IB).

[0134] In some embodiments, the (Z)-endoxifen of the present disclosure may have one or more properties selected from: an aerobic bacterial plate count of not more than 20,000 g / mL; a water content of not more than 1.0% as tested by Method Ic of the USP 921; a water activity (Aw) of less than 0.9, a residue on ignition of not more than 0.1% as tested by a method of USP 281; a heavy metal of not more than 20 ppm as tested by Method II of USP 231; a residual solvent content such that methanol is NMT 3000 ppm, tetrahydrofuran is NMT 720 ppm, isopropanol is NMT 5000 ppm, ethyl acetate is NMT 5000 ppm; n-Heptane is NMT 5000 ppm, and ethanol is NMT 5000 ppm as tested by a validated HPLC method, or any combinations thereof. In some embodiments, the (Z)-endoxifen produced by the present methods contains less than about 25 ppm of mesityl oxide, such as about 25 ppm, about 20 ppm, about 15 ppm, about 10 ppm, about 5 ppm, or any value contained within a range formed by any two of the preceding values. In some embodiments, the (Z)-endoxifen produced by the present methods does not contain mesityl oxide.

[0135] The (Z)-endoxifen of the present disclosure may be in the form of a free base or a salt. It will be understood that the conditions used to produce salts (such as suspending (Z)- endoxifen free base in aqueous acid) may lead to isomerization to a mixture of (Z)-endoxifen and (E)-endoxifen. Such isomerization may, in some embodiments, be undesirable and may be avoided by using (Z)-endoxifen free base. In other embodiments, endoxifen salts including a mixture of (Z)-endoxifen and (E)-endoxifen may be used or may be purified to isolate (Z)- endoxifen salts.

[0136] In some embodiments, the (Z)-endoxifen of the present disclosure has a mean halflife of in a subject ranging from about 30 hours to about 60 hours after administration, such as about 30 hours, about 35 hours, about 40 hours, about 45 hours, about 50 hours, about 55 hours, about 60 hours, or any value contained within a range formed by any two of the preceding values. In some embodiments, the (Z)-endoxifen of the present disclosure results in a mean area under the curve extrapolated to time infinity (AUCo-inf) of about 200 hr*ng / mL to about 10000 hr*ng / mL, such as about 300 hr*ng / mL to about 8000 hr*ng / mL, about 400 hr*ng / mL to about6000 hr*ng / mL, about 700 hr*ng / mL to about 6000 hr*ng / mL, or any value contained within a range formed by any two of the preceding values.

[0137] In some embodiments, administration of the (Z)-endoxifen of the present disclosure results in a steady state plasma level ranging from about 25 nM to about 300 nM, such as about 25 nM, about 50 nM, about 100 nM, about 150 nM, about 200 nM, about 250 nM, about 300 nM, or any value contained within a range formed by any two of the preceding values. It will be understood that frequency of administration, pharmaceutically acceptable excipients, and mode of administration may impact pharmacokinetic parameters.Endoxifen Free Base Compositions

[0138] In one aspect, the present disclosure provides stable (Z)-endoxifen free base or salts thereof and compositions comprising (Z)-endoxifen free base or salts thereof. In some embodiments, the pharmaceutical composition comprises endoxifen predominantly as (Z)- endoxifen free base.

[0139] In certain embodiments, compositions may comprise endoxifen as at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 1%, at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.99%, or 100% of (Z)-endoxifen free base wt / wt of total endoxifen in the composition. In at least one composition, the composition comprises >90% of (Z)-endoxifen free base wt / wt of the total endoxifen in the composition. In another embodiment, the composition comprises >95% of (Z)-endoxifen free base wt / wt of the total endoxifen in the composition. In yet another embodiment, the compositions comprise >96%, >97%, >98%, >99%, or >99.5% of (Z)-endoxifen free base wt / wt of the total endoxifen in the composition.

[0140] In other embodiments, compositions comprising endoxifen comprise 0.01% to 20%, 0.05% to 15%, or 0.1% to 10% of (Z)-endoxifen wt / wt or w / v of the composition. In at least one embodiment, the compositions comprising endoxifen comprise 0.01% to 20% of (Z)-endoxifen wt / wt or w / v of the composition. In various other embodiments, the compositions comprising endoxifen comprise 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 10%, or 20% of (Z)- endoxifen wt / wt of the composition.

[0141] In an aspect, the compositions comprising (Z)-endoxifen further comprise (E)- endoxifen. In some embodiments, the endoxifen in the composition has a ratio of (E)-endoxifen to (Z)-endoxifen (E / Z-ratio) of 1:99; 5:95; 10:90, 15:85; 20:80, 25:75; 30:70; 40:70, 45:55;50:50; 55:45; 60:40; 65:45; and 70:30. In other embodiments, the compositions comprise endoxifen having E / Z-ratio ranging from 10:90 to 70:30. In still other embodiments, compositions comprise endoxifen having E / Z-ratio ranging from 45:55 to 55:45.

[0142] Unless specifically referred to by the prefix (Z), (E) or (E / Z), endoxifen used generally without a prefix is used herein to include to any or all endoxifen isoforms.(Z)-Endoxifen Salt Compositions

[0143] In some embodiments, the present disclosure provides compositions comprising salts of (Z)-endoxifen. In some embodiments, the present disclosure provides compositions comprising pharmaceutically acceptable salts of (Z)-endoxifen. Provided herein in certain embodiments are compositions comprising 1%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.99% or 100% of (Z)-endoxifen salt.

[0144] As used herein, the term “pharmaceutically acceptable salt” refers to any salt (e.g., obtained by reaction with an acid or a base) of a compound of the present disclosure that is physiologically tolerated in a subject (e.g., a mammal, and / or in vivo, ex-vivo, in vitro cells, tissues, or organs). A “salt” of a compound of the present disclosure may be derived from inorganic or organic acids and bases.

[0145] In some embodiments, the salt is selected from the group consisting of arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, Teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some embodiments, the salt is (Z)-endoxifen gluconate. (Z)- endoxifen gluconate can be selected from the group consisting of (Z)-endoxifen D-gluconate, (E)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, (E)-endoxifen L-gluconate or a combination thereof.

[0146] In some embodiments, a composition comprising (Z)-endoxifen gluconate is comprised of 10% to 100% of (Z)-endoxifen D-gluconate on a wt / wt basis of total (Z)-endoxifen gluconate in the composition. In some embodiments, a composition comprising (Z)-endoxifen gluconate is comprised of 10% to 100% of (Z)-endoxifen L-gluconate on a wt / wt basis of total (Z)-endoxifen in the composition.

[0147] In other embodiments, a composition comprising (Z)-endoxifen gluconate is comprised of 10%, 20%, 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.75%, 99.99%, or 100% of (Z)-endoxifen D- gluconate or (Z)-endoxifen L-gluconate with respect to total (Z)-endoxifen gluconate. In some embodiments, the compositions comprise at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.99% of (Z)-endoxifen D-gluconate, (Z)-endoxifen L- gluconate or a combination thereof.

[0148] Provided herein in some embodiments are compositions comprising (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate. (Z)-endoxifen D-gluconate and (E)-endoxifen D- gluconate may be present in the compositions at ratios ranging from 10:90 to 99:1 wt / wt or v / v, respectively. In some embodiments, the ratio of (Z)-endoxifen D-gluconate to (E)-endoxifen D- gluconate is (wt / wt or v / v) 10:90 to 99:1 (e.g., 45:55, 50:50, 60:40, 70:30, 80: 20, 90:10; 91:9; 92:8; 93:7; 94:8; 95:5, 96:4, 97:3, 98:2, 99:1, 99.5:0.5, or 99.99:0.01) respectively. In certain embodiments, the ratio of (Z)-endoxifen D-gluconate to (E)-endoxifen D-gluconate (wt / wt or v / v) is 90:10; 91:9; 92:8; 93:7; 94:8; 95:5, 96:4, 97:3, 98:2, 99:1, 99.5:0.5, or 99.99:0.01. One of skill in the art will recognize that other combinations of (Z)-endoxifen gluconate isomers are encompassed in the present disclosure.

[0149] In some embodiments, a composition comprising (Z)-endoxifen gluconate comprises 0.01%, 0.05%, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% (Z)-endoxifen gluconate (wt / wt) or (w / v) of the composition. In some embodiments, a composition comprising (Z)- endoxifen gluconate comprises 0.01%, 0.05%, 0.01%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% (Z)-endoxifen gluconate (wt / wt) or (w / v) of the composition.

[0150] All compounds disclosed herein are further understood to include all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of example, and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon includenC,13C, and14C.

[0151] 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 combinations 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., areexpressly 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 the weight percent of each ingredient in the component.Pharmaceutical Excipients

[0152] Compositions of the present disclosure may comprise a (Z)-endoxifen composition comprising (Z)-endoxifen and one or more therapeutic agents as described herein and a pharmaceutically acceptable carrier or diluent. In some embodiments, a pharmaceutical composition may comprise a (Z)-endoxifen (Formula (I)) and a pharmaceutically acceptable carrier or diluent. In some embodiments, a pharmaceutical composition may comprise a (Z)- endoxifen and a pharmaceutically acceptable carrier or diluent.

[0153] In one aspect, the present disclosure relates to a composition comprising (Z)- endoxifen formulated for oral, intra-arterial, intravenous administration, parenteral, topical, transdermal, intranasal, administration via inhalation, rectal, or intraductal delivery. In some embodiments, a (Z)-endoxifen composition may be formulated as an oral dosage form, which can be 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.

[0154] A composition of the present disclosure may be formulated as a pharmaceutical composition for topical or transdermal delivery. In some embodiments, a 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 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, a topical 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 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-ethoxyethoxy)ethanol (e.g., TRANSCUTOL®), isopropanol, a fully saturated emollient triester (e.g., CRODAMOL™ GTCC), and mineral oil. A topical (Z)-endoxifen formulation can be administered at the same time as or at a different time than a therapeutic agent.

[0155] An oral dosage form can be of any shape suitable for oral administration, such as spherical (0.05 - 5 mL), oval (0.05 - 7 mL), ellipsoidal, pear (0.3 - 5 mL), cylindrical, cubic, regular, and / or irregular shaped. An oral dosage form may be of any size suitable for oral administration, for example, size 0, size 2, and the like.

[0156] One of skill in the art will further recognize that compositions disclosed herein may include one or more of the excipients known in the art and disclosed herein in any combination appropriate for a desired formulation or preparation. Additional excipients may generally be found in Remington’s The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia / National Formulary. One of skill in the art will be able to select suitable excipients necessary for the preparation of the formulations and appropriate dosage forms compatible with the route of administration based on his or her skill and knowledge in the art and the disclosures made herein. In all cases, the dosage form should be sterile and stable under the conditions of manufacture and storage.

[0157] In some embodiments, the present disclosure relates to a composition formulated for oral administration comprising: 1 mg to 200 mg of (Z)-endoxifen or a pharmaceutically acceptable salt, solvate, or tautomer thereof, per unit dose. In some aspects, the composition formulated for oral administration comprises from 1 mg to 80 mg per unit dose, from 2 mg to 80 mg per unit dose, from 4 mg to 80 mg per unit dose, or from 4 mg to 40 mg per unit dose, of (Z)-endoxifen or a pharmaceutically acceptable salt, solvate, or tautomer thereof. The composition for oral delivery can be a tablet, a caplet, a capsule, a pill, a powder, a troche, an elixir, a suspension, a syrup, a wafer, a chewing gum, a dragee, or a lozenge.

[0158] As used herein, the term “pharmaceutical composition” means a combination of the active agent (e.g., an active pharmaceutical compound or ingredient, API) with a carrier, inert or active (e.g., a phospholipid), making the compositions particularly suitable for diagnostic or therapeutic uses in vitro, in vivo, or ex vivo.

[0159] As used herein, the terms “subject,” “patient,” “participant,” and “individual” may be used interchangeably herein and refer to a mammal such as a human. Mammals also include pet animals, such as dogs and cats; laboratory animals, such as rats and mice, and farm animals, such as cows and horses. Unless otherwise specified, a mammal may be of any gender or sex.

[0160] In various embodiments, a pharmaceutical composition provided herein includes from about 1% to about 99.99%, about 5% to about 95%, about 5% to about 90%, about 10% toabout 80%, about 15% to about 70%, about 20% to about 60%, from about 30% to about 95%, from about 50% to about 90%, from about 60% to about 90%, from about 60% to about 80%, from about 70% to about 90%, or from about 70% to about 80% by weight of one or more excipients. In certain embodiments, the composition provided herein includes about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80% by weight of one or more excipients. In certain embodiments, the composition provided herein includes about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, or about 79% by weight of one or more excipients.

[0161] Examples of excipients that can be used in the compositions formulated for oral administration are provided herein and can include, but are not limited to, one or more bulking agents, binders, fillers, disintegrating agents, lubricants, glidants, control release agents, enteric coatings, film-forming agents, plasticizers, colorants, sweeteners, flavoring agents and the like, or any combination thereof.

[0162] 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 ormore of the compounds of the present disclosure from one tissue, organ, or portion of the body or across the skin.

[0163] Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, sucrose, starches such as corn starch, potato starch, or starches such as starch paste, pregelatinized starch, and starch 1500, PEG 6000, METHOCEL™, WALOCEL® HM, LUVITEC®, Luvicaparolactam, AVICEL®, SMCC, UNIPURE®, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include but are not limited to, the materials sold as AVICEL® PH 101, AVICEL® PH 103, AVICEL® RC 581, AVICEL® PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. In some embodiments, the binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL® PH 103 and Starch 1500 LM.

[0164] Examples of fillers suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), sugars such as dextrose, sucrose, lactose, a salt such as calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starches, microcrystalline cellulose, powdered cellulose, cellulosic bases such as methyl cellulose, carboxymethyl cellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0165] One or more binders or fillers in compositions are typically present from about 10% to about 99% (wt / wt) of the composition or the dosage form. In some embodiments, binders and / or fillers in a composition include about 15% to 99%, about 20% to 60%, about 25% to 55%, about 30% to 50%, about 35% to 60%, about 50% to 99% (wt / wt) of the composition. In some embodiments, binders and / or fillers are present at about 1% to 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 70% to 75%, about 75% to 80%, about 80% to 85%, about 85% to 90%, or about 90% to 95% (wt / wt) of the composition. In some embodiments, binders and / or fillers are present at about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, 81%, about 82%, about 83%, about 84%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% of the composition.

[0166] For example, a composition may comprise from about 50% to about 95% microcrystalline cellulose by weight of the total fill weight of the composition.

[0167] Disintegrants can be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients is 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.

[0168] A disintegrant may be included in a composition of the present disclosure to inhibit crosslinking between an active agent and an encapsulating layer (e.g., capsule). In some embodiments, a disintegrant may comprise croscarmellose sodium, agar, alginic acid, calcium carbonate, microcrystalline cellulose, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, or a combination thereof. For example, croscarmellose sodium may be included in a (Z)-endoxifen composition to inhibit crosslinking between (Z)-endoxifen and an enteric-resistant delayed-release capsule encapsulating the (Z)-endoxifen composition.

[0169] In some embodiments, compositions include from 0.5% to 15% (wt / wt) of disintegrant. In some embodiments, compositions include from 1% to 5% (wt / wt) of disintegrant in the composition. In another embodiment, the disintegrant is 1% to 25%, 2% to 20%, 5% to 15%, 8% to 12%, or about 10% (wt / wt) of the composition. In some embodiments, compositions include a disintegrant present at about 1% to 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 70% to 75%, about 75% to 80%, about 80% to 85%, about 85%to 90%, or about 90% to 95% (wt / wt) of the composition. In some embodiments, compositions include disintegrant at about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% (wt / wt) of the composition.

[0170] The disintegrant (e.g., croscarmellose sodium) may be included in a (Z)-endoxifen composition of the present disclosure at an amount of at least about 0.1%, at least about 0.5%, at least about 0.8%, at least about 1.0%, at least about 1.2%, at least about 1.4%, at least about 1.5%, at least about 1.6%, at least about 1.8%, at least about 2.0%, at least about 2.2%, at least about 2.4%, at least about 2.5%, at least about 2.6%, at least about 2.8%, or at least about 2.9%, by weight, of the total fill weight of the composition. For example, a (Z)-endoxifen composition may comprise at least about 2% croscarmellose sodium by weight of the total fill weight of the composition.

[0171] In some embodiments, the disintegrant (e.g., croscarmellose sodium) may be included in a (Z)-endoxifen composition of the present disclosure at an amount of from about 0.1% to about 10%, from about 1.0% to about 10%, from about 1.5% to about 10%, from about 2.0% to about 10%, from about 2.5% to about 10%, from about 2.6% to about 10%, from about 2.8% to about 10%, from about 2.9% to about 10%, from about 0.1% to about 8.0%, from about 1.0% to about 8.0%, from about 1.5% to about 8.0%, from about 2.0% to about 8.0%, from about 2.5% to about 8.0%, from about 2.6% to about 8.0%, from about 2.8% to about 8.0%, from about 2.9% to about 8.0%, from about 0.1% to about 5.0%, from about 1.0% to about 5.0%, from about 1.5% to about 5.0%, from about 2.0% to about 5.0%, from about 2.5% to about 5.0%, from about 2.6% to about 5.0%, from about 2.8% to about 5.0%, from about 2.9% to about 5.0%, from about 0.1% to about 4.0%, from about 1.0% to about 4.0%, from about 1.5% to about 4.0%, from about 2.0% to about 4.0%, from about 2.5% to about 4.0%, from about 2.6% to about 4.0%, from about 2.8% to about 4.0%, from about 2.9% to about 4.0%, from about 0.1% to about 3.0%, from about 1.0% to about 3.0%, from about 1.5% to about 3.0%, from about 2.0% to about 3.0%, from about 2.5% to about 3.0%, from about 2.6% to about 3.0%, from about 2.8% to about 3.0%, or from about 2.9% to about 3.0%, by weight, of the total fill weight of the composition. For example, a (Z)-endoxifen composition may comprise from about 1% to about 4% croscarmellose sodium by weight of the total fill weight of the composition.

[0172] In some embodiments, a lubricant may be included in a (Z)-endoxifen composition of the present disclosure. Examples of lubricants include but are not limited to, magnesium stearate, calcium 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, corn oil, and soybean oil), zinc stearate, magnesium stearate or potassium stearate, ethyl oleate, ethyl laureate, agar, and combinations thereof. Additional lubricants include, for example, a syloid silica gel (e.g., AEROSIL® 200, manufactured by W.R. GRACE® Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (e.g., marketed by DEGUSSA® Co. of Plano, Tex.), a fumed silica (e.g., CAB-O-SIL®, a pyrogenic silicon dioxide product sold by CABOT® Co. of Boston, Mass.), a silicon fluid (e.g., Q7-9120 manufactured by DOW CORNING®), and combinations thereof.

[0173] The lubricant (e.g., magnesium stearate) may be included in a (Z)-endoxifen composition of the present disclosure at an amount of at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.5%, at least about 0.6%, at least about 0.8%, at least about 0.8%, or at least about 1.0%, by weight, of the total fill weight of the composition. For example, a (Z)-endoxifen composition may comprise at least about 0.8% magnesium stearate by weight of the total fill weight of the composition.

[0174] In some embodiments, the lubricant (e.g., magnesium stearate) may be included in a (Z)-endoxifen composition of the present disclosure at an amount of from about 0.1% to about 5.0%, from about 0.2% to about 5.0%, from about 0.3% to about 5.0%, from about 0.4% to about 5.0%, from about 0.5% to about 5.0%, from about 0.6% to about 5.0%, from about 0.7% to about 5.0%, from about 0.8% to about 5.0%, from about 0.9% to about 5.0%, from about 1.0% to about 5.0%, from about 0.1% to about 4.0%, from about 0.2% to about 4.0%, from about 0.3% to about 4.0%, from about 0.4% to about 4.0%, from about 0.5% to about 4.0%, from about 0.6% to about 4.0%, from about 0.7% to about 4.0%, from about 0.8% to about 4.0%, from about 0.9% to about 4.0%, from about 1.0% to about 4.0%, from about 0.1% to about 3.0%, from about 0.2% to about 3.0%, from about 0.3% to about 3.0%, from about 0.4% to about 3.0%, from about 0.5% to about 3.0%, from about 0.6% to about 3.0%, from about 0.7% to about 3.0%, from about 0.8% to about 3.0%, from about 0.9% to about 3.0%, from about 1.0% to about 3.0%, from about 0.1% to about 2.0%, from about 0.2% to about 2.0%, from about 0.3% to about 2.0%, from about 0.4% to about 2.0%, from about 0.5% to about 2.0%, from about 0.6% to about 2.0%, from about 0.7% to about 2.0%, from about 0.8% to about 2.0%, from about 0.9% to about 2.0%, from about 1.0% to about 2.0%, from about 0.1% to about 1.5%, from about 0.2% to about 1.5%, from about 0.3% to about 1.5%, from about0.4% to about 1.5%, from about 0.5% to about 1.5%, from about 0.6% to about 1.5%, from about 0.7% to about 1.5%, from about 0.8% to about 1.5%, from about 0.9% to about 1.5%, from about 1.0% to about 1.5%, from about 0.1% to about 1.2%, from about 0.2% to about 1.2%, from about 0.3% to about 1.2%, from about 0.4% to about 1.2%, from about 0.5% to about 1.2%, from about 0.6% to about 1.2%, from about 0.7% to about 1.2%, from about 0.8% to about 1.2%, from about 0.9% to about 1.2%, or from about 1.0% to about 1.2%, by weight, of the total fill weight of the composition. For example, a (Z)-endoxifen composition may comprise from about 0.5% to about 2% magnesium stearate by weight of the total fill weight of the composition.

[0175] Plasticizers may be added to control the softness or pliability of oral dosage forms such as the shell of a capsule, caplet, or tablet, and thus, may improve the mechanical properties of the pH-sensitive materials of the coatings on the oral dosage forms. Suitable plasticizers include, without limitation, petroleum oils (e.g., a paraffinic process oil, a naphthenic process oil, and an aromatic process oil), squalene, squalane, plant oils, (e.g., olive oil, camelia oil, castor oil, tall oil, and a peanut oil), silicon oils, dibasic acid esters, (e.g., dibutyl phthalate, and dioctyl phthalate), liquid rubbers (e.g., polybutene and a liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), hexyl laurate, diethyl sebacate, and diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycols, polypropylene glycol, phthalates, sorbitol, glycol salicylate, crotaminton, and glycerin or mixtures thereof. The amount of plasticizer may vary depending upon the chemical composition of the pharmaceutical preparation. In one embodiment, the at least one plasticizer is sorbitol, dimethyl isosorbide, or a glycerol. In another embodiment, the plasticizer is about 1% to 10%, such as about 3% to 5% (wt / wt) of the composition. In some embodiments, the plasticizer is present at about 1% to 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, or about 35% to 40% of the composition. In some embodiments, the plasticizer is present at about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% (wt / wt) of the composition.

[0176] Examples of glidants include but are not limited to, colloidal silicone dioxide, cellulose, calcium phosphate, di or tri-basic, and the like. In some embodiments, the glidant is present at about 0.01% to 0.05%, about 0.05% to 0.1%, about 0.1% to 0.5%, about 0.5% to about 1%, 1% to 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, or about 35% to 40% of the composition. In someembodiments, the glidant is present from about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% (wt / wt) of the composition.

[0177] As an example of sweeteners or sweetening agents, these can include sucrose, saccharin, dextrose, maltose, sugar substitutes, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, acesulfame K, and the like.

[0178] Examples of flavoring agents include peppermint, methyl salicylate, peppermint, spearmint, methyl salicylate, raspberry, red berry, strawberry, pineapple, orange, cherry, and the like.

[0179] Additional agents that may be included in the (Z)-endoxifen compositions of the present disclosure include binders, fillers, lubricants, and other pharmaceutically acceptable excipients. Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, sucrose, starches such as corn starch, potato starch, or starches such as starch paste, pregelatinized starch, and starch 1500, PEG 6000, METHOCEL®, WALOCEL® HM, LUVITEC®, caprolactam, AVICEL®, SMCC, UNI-PURE®, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL® PH 101, AVICEL® PH 103 AVICEL® RC 581, AVICEL® PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. In some embodiments, the binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL® PH 103 and Starch 1500 LM.Enteric-Resistant Delay ed-Release (Z)-endoxifen Compositions

[0180] Compositions formulated for oral delivery as disclosed herein, for example, tablets, caplets, and capsules, may be coated with one or more enteric coating agents, control release agents or film-forming agents 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, thetablet can be an enteric tablet, the caplet can be an enteric caplet, or the capsule can be an enteric capsule. The enteric tablets, enteric caplets, or enteric capsules of the present disclosure may be prepared by techniques known in the art.

[0181] In an aspect of the present disclosure, 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.

[0182] In various embodiments, the enteric tablet is a hard tablet made with free-flowing powder of (Z)-endoxifen or a polymorph or a salt thereof. In various embodiments, the enteric capsule is a capsule made with free-flowing powder of (Z)-endoxifen or a polymorph 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.

[0183] The (Z)-endoxifen compositions described herein may be formulated as entericresistant delayed-release formulations for oral delivery. An enteric-resistant delayed-release (Z)- endoxifen formulation may be resistant to dissolution in the acidic environment of the stomach following oral administration, slowing or preventing release of (Z)-endoxifen in the stomach, and may readily dissolve in the less acidic environment of the intestines, releasing most of the (Z)-endoxifen in the intestines. The enteric-resistant delayed-release formulations of the present disclosure may facilitate delivery of (Z)-endoxifen by protecting the (Z)-endoxifen from the acidic environment of the stomach and preventing isomerization into (E)-endoxifen.

[0184] For time delay or delayed-release pharmaceutical preparations of oral dosage forms, glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, for example polymethacrylate pH-sensitive polymer-based coatings can be used, (e.g., as coating material, such as 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 can 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 can release at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80% at least 85%, or at least 90% of the (Z)-endoxifen or salts thereof in the intestines (small intestines, large intestine / colon, etc.).

[0185] Enteric-resistant and delayed-release properties of a (Z)-endoxifen composition may be assessed using a dissolution assay, which may be performed using a variety of techniques. In some embodiments, dissolution properties of a (Z)-endoxifen composition may be quantifiedusing the dissolution assay. A (Z)-endoxifen composition, such as a (Z)-endoxifen formulation encapsulated in an enteric-resistant delayed-release capsule, may be placed in an acidic solution comprising a pH of less than about 2 for about 120 minutes, stirring at a temperature of about 37 ± 0.5°C. Dissolution rates under acidic conditions, mimicking the stomach environment, may be assessed by measuring the concentration of (Z)-endoxifen in the solution at multiple time points (e.g., at 30 minutes, 60 minutes, 90 minutes, 120 minutes, or combinations thereof). After about 120 minutes, the acidic solution may be replaced with a buffered solution comprising a pH of about 6.8 and about 0.75% polysorbate 80 and stirred for about 90 minutes at a temperature of about 37 ± 0.5°C. Dissolution rates under less acidic conditions, mimicking the intestinal environment, may be assessed by measuring the concentration of (Z)-endoxifen in the solution at multiple time points (e.g., at 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or combinations thereof). Alternatively, dissolution rates may be measured using a US pharmacopoeia (USP) dissolution method or a Japanese pharmacopoeia (JP) dissolution method.

[0186] An enteric-resistant delayed-release formulation may release no more than about 1%, no more than about 2%, no more than about 3%, no more than about 4%, no more than about 5%, no more than about 6%, no more than about 7%, no more than about 8%, no more than about 9%, no more than about 10%, no more than about 15%, no more than about 20%, no more than about 25%, no more than about 30%, no more than about 35%, or no more than about 40% of (Z)-endoxifen in the composition within about 2 hours in an acidic solution comprising a pH of less than about 2. In some embodiments, an enteric-resistant delayed-release formulation may release from about 0% to about 1%, from about 0% to about 2%, from about 0% to about 3%, from about 0% to about 4%, from about 0% to about 5%, from about 0% to about 10%, from about 0% to about 15%, from about 0% to about 20%, from about 1% to about 2%, from about 1% to about 3%, from about 1% to about 4%, from about 1% to about 5%, from about 1% to about 10%, from about 1% to about 15%, from about 1% to about 20%, from about 3% to about 3%, from about 3% to about 4%, from about 3% to about 5%, from about 3% to about 10%, from about 3% to about 15%, from about 3% to about 20%, from about 4% to about 5%, from about 4% to about 10%, from about 4% to about 15%, from about 4% to about 20%, from about 5% to about 10%, from about 5% to about 15%, from about 5% to about 20%, from about 10% to about 20%, or from about 15% to about 20% of (Z)-endoxifen in the composition within about 2 hours in an acidic solution comprising a pH of less than about 2.

[0187] In some embodiments, an enteric-resistant delayed-release formulation may release no more than about 1%, no more than about 2%, no more than about 3%, no more than about 4%, no more than about 5%, no more than about 6%, no more than about 7%, no more than about 8%, no more than about 9%, no more than about 10%, no more than about 15%, no morethan about 20%, no more than about 25%, no more than about 30%, no more than about 35%, or no more than about 40% of (Z)-endoxifen in the composition within about 2 hours under acidic conditions. In some embodiments, an enteric-resistant delayed-release formulation may release from about 0% to about 1%, from about 0% to about 2%, from about 0% to about 3%, from about 0% to about 4%, from about 0% to about 5%, from about 0% to about 10%, from about 0% to about 15%, from about 0% to about 20%, from about 1% to about 2%, from about 1% to about 3%, from about 1% to about 4%, from about 1% to about 5%, from about 1% to about 10%, from about 1% to about 15%, from about 1% to about 20%, from about 3% to about 3%, from about 3% to about 4%, from about 3% to about 5%, from about 3% to about 10%, from about 3% to about 15%, or from about 3% to about 20% of (Z)-endoxifen in the composition within about 2 hours under acidic conditions.

[0188] An enteric-resistant delayed-release formulation may release at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of (Z)-endoxifen in the composition within about 1.5 hours in a solution comprising a pH of about 6.8 at about 0.75% polysorbate 80. In some embodiments, an enteric-resistant delayed-release formulation may release from about 50% to about 95%, from about 60% to about 95%, from about 70% to about 95%, from about80% to about 95%, from about 85% to about 95%, from about 86% to about 95%, from about87% to about 95%, from about 88% to about 95%, from about 89% to about 95%, from about90% to about 95%, from about 91% to about 95%, from about 92% to about 95%, from about93% to about 95%, from about 94% to about 95%, from about 50% to about 97%, from about60% to about 97%, from about 70% to about 97%, from about 80% to about 97%, from about85% to about 97%, from about 86% to about 97%, from about 87% to about 97%, from about88% to about 97%, from about 89% to about 97%, from about 90% to about 97%, from about91% to about 97%, from about 92% to about 97%, from about 93% to about 97%, from about94% to about 97%, from about 95% to about 97%, from about 50% to about 99%, from about60% to about 99%, from about 70% to about 99%, from about 80% to about 99%, from about85% to about 99%, from about 86% to about 99%, from about 87% to about 99%, from about88% to about 99%, from about 89% to about 99%, from about 90% to about 99%, from about91% to about 99%, from about 92% to about 99%, from about 93% to about 99%, from about94% to about 99%, from about 95% to about 99%, from about 50% to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, fromabout 85% to about 100%, from about 86% to about 100%, from about 87% to about 100%, from about 88% to about 100%, from about 89% to about 100%, from about 90% to about 100%, from about 91% to about 100%, from about 92% to about 100%, from about 93% to about 100%, from about 94% to about 100%, or from about 95% to about 100% of (Z)- endoxifen in the composition within about 1.5 hours in a solution comprising a pH of about 6.8 at about 0.75% polysorbate 80.

[0189] In some embodiments, an enteric-resistant delayed-release formulation may release at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% of (Z)-endoxifen in the composition within about 1.5 hours in a solution comprising a pH of about 6.8 at about 0.75% polysorbate 80. In some embodiments, an enteric-resistant delayed-release formulation may release from about 50% to about 95%, from about 60% to about 95%, from about 70% to about 95%, from about 80% to about 95%, from about 85% to about 95%, from about 86% to about95%, from about 87% to about 95%, from about 88% to about 95%, from about 89% to about95%, from about 90% to about 95%, from about 91% to about 95%, from about 92% to about95%, from about 93% to about 95%, from about 94% to about 95%, from about 50% to about97%, from about 60% to about 97%, from about 70% to about 97%, from about 80% to about97%, from about 85% to about 97%, from about 86% to about 97%, from about 87% to about97%, from about 88% to about 97%, from about 89% to about 97%, from about 90% to about97%, from about 91% to about 97%, from about 92% to about 97%, from about 93% to about97%, from about 94% to about 97%, from about 95% to about 97%, from about 50% to about99%, from about 60% to about 99%, from about 70% to about 99%, from about 80% to about99%, from about 85% to about 99%, from about 86% to about 99%, from about 87% to about99%, from about 88% to about 99%, from about 89% to about 99%, from about 90% to about99%, from about 91% to about 99%, from about 92% to about 99%, from about 93% to about99%, from about 94% to about 99%, from about 95% to about 99%, from about 50% to about100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 85% to about 100%, from about 86% to about 100%, from about 87% to about 100%, from about 88% to about 100%, from about 89% to about 100%, from about 90% to about 100%, from about 91% to about 100%, from about 92% to about 100%, from about 93% to about 100%, from about 94% to about 100%, or from about 95% to about 100% of(Z)-endoxifen in the composition within about 1.5 hours in a solution comprising a pH of about 6.8 at about 0.75% polysorbate 80.

[0190] In some embodiments, a (Z)-endoxifen formulation (e.g., a dose oral (Z)-endoxifen formulation) is in the form of solid dosage forms such as capsules, tablets, mini-tablets, beads, microbeads, granules, spheres particles, multi-particulates, and the like. The (Z)-endoxifen compositions of the present disclosure can be formulated to target release in the intestines and colon. Accordingly, in some embodiments, the (Z)-endoxifen compositions are in the form of enteric-resistant delayed-release capsules, enteric-coated delayed-release tablets, enteric-coated delayed-release tablet-in-tablets, enteric-coated delayed-release tablet-in-capsules, beads-in- capsules, spheres-in capsules, and the like. For example, a (Z)-endoxifen formulation may be encapsulated in an enteric-resistant delayed-release capsule, such as a hydroxypropyl methylcellulose (also referred to as HPMC or hypromellose) capsule to form an enteric-resistant delayed-release (Z)-endoxifen composition. In some embodiments, (Z)-endoxifen may be dispersed in the (Z)-endoxifen compositions homogeneously.

[0191] 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 can also be utilized. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen free base or salts thereof is filled neat into the capsule. In such API-in-capsule oral dosage forms, the active ingredient, a therapeutic agent, (Z)-endoxifen or salts thereof, or a combination 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. In some aspects, the composition is formulated as a delayed-release composition.

[0192] An enteric-resistant delayed-release capsule, also referred to as an enteric-resistant delayed-release capsule, may encapsulate a (Z)-endoxifen formulation of the present disclosure. In some embodiments, an enteric-resistant delayed-release capsule may comprise hydroxypropyl methylcellulose, gellan gum, gelatin, hydroxypropyl methylcellulose phthalate, a coloring agent, an opacifier, or any combination thereof. An enteric-resistant delayed-release capsule may comprise at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% hydroxypropyl methylcellulose by weight, relative to total capsule weight (e.g.,not including the (Z)-endoxifen formulation filling). In some embodiments, an enteric-resistant delayed-release capsule may comprise from about 50% to about 99%, from about 55% to about 99%, from about 60% to about 99%, from about 65% to about 99%, from about 70% to about99%, from about 75% to about 99%, from about 80% to about 99%, from about 85% to about99%, from about 50% to about 95%, from about 55% to about 95%, from about 60% to about95%, from about 65% to about 95%, from about 70% to about 95%, from about 75% to about95%, from about 80% to about 95%, from about 85% to about 95%, from about 50% to about90%, from about 55% to about 90%, from about 60% to about 90%, from about 65% to about90%, from about 70% to about 90%, from about 75% to about 90%, from about 80% to about90%, or from about 85% to about 90% hydroxypropyl methylcellulose by weight, relative to total capsule weight.

[0193] An enteric-resistant delayed-release capsule may comprise at least about 1 %, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10% gellan gum, gelatin, or a combination thereof by weight, relative to total capsule weight. In some embodiments, an enteric-resistant delayed-release capsule may comprise from about 1% to about 10%, from about 2% to about 10%, from about 3% to about 10%, from about 4% to about 10%, from about 5% to about 10%, from about 1% to about 9%, from about 2% to about 9%, from about 3% to about 9%, from about 4% to about 9%, from about 5% to about 9%, from about 1% to about 8%, from about 2% to about 8%, from about 3% to about 8%, from about 4% to about 8%, from about 5% to about 8%, from about 1% to about 7%, from about 2% to about 7%, from about 3% to about 7%, from about 4% to about 7%, from about 5% to about 7%, from about 1% to about 6%, from about 2% to about 6%, from about 3% to about 6%, from about 4% to about 6%, from about 5% to about 6%, from about 1% to about 5%, from about 2% to about 5%, from about 3% to about 5%, or from about 4% to about 5% gellan gum, gelatin, or a combination thereof by weight, relative to total capsule weight.

[0194] An example of an enteric-resistant delayed-release (Z)-endoxifen composition may comprise an enteric-resistant delayed-release capsule comprising from about 65% to about 95% hydroxypropyl methylcellulose by weight and from about 3% to about 10% gellan gum by weight, relative to total unfilled capsule weight, encapsulating a (Z)-endoxifen formulation comprising from about 10% to about 30% (Z)-endoxifen by weight, from about 1% to about 5% croscarmellose sodium by weight, from about 60% to about 95% microcrystalline cellulose by weight, and from about 0.5% to about 3% magnesium stearate by weight, relative to total fill weight of the composition. In some embodiments, the enteric-resistant delayed-release (Z)-endoxifen composition may be formulated in a dosage form comprising about 10 mg, about 20 mg, about 40 mg, or about 80 mg of (Z)-endoxifen per capsule.Sustained-Release

[0195] Compositions formulated for oral delivery as disclosed herein, for example, tablets, caplets, and capsules, may be coated with one or more enteric coating agents, control release agents, or film-formin agents 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.

[0196] Pharmaceutical preparations 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. In some embodiments, the controlled-release agent is present at about 0.01% to 0.05%, about 0.05% to 0.1%, about 0.1% to 0.5%, about 0.5% to about 1%, 1% to 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, or about 35% to 40% of the composition. In some embodiments, the controlled-release agent is present from about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% (wt / wt) of the composition.

[0197] In some embodiments, a pharmaceutical composition comprising (Z)-endoxifen may be formulated as a sustained-release composition. A sustained-release agent present in a sustained-release composition of the present disclosure may be any sustained-release agentknown in the art to slow the release of a hydrophobic drug such as (Z)-endoxifen or a polymorph or a salt thereof.

[0198] 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, 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, at least one sustained-release agent is a pH sustained-release agent, such as acidinsoluble polymers, which become increasingly soluble and permeable above pH 5.0 but remain impermeable below pH 5.0. Such controlled-release polymers target the upper small intestines and / or colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, alginic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methacrylic 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)) - alone or in any combination thereof to achieve the desired permeability for sustained-release.

[0199] 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 certain embodiments, the viscosity of the at least sustained-release agent ranges from about 1000 mPa.s to about 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 about 1000 mPa.s to about 10,000 mPa.s, from about 10,000 mPa.s to about 70,000 mPa.s, from about 70,000 mPa.s to about 150,000 mPa.s. or a combination thereof. In some embodiments, the present disclosure provides that the sustained- release delivery 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 about 1000 mPa.s to about 10,000 mPa.s, while another sustained-release agent may have a viscosity of about 10,000 mPa.s to about 70,000 mPa.s or about 70,000 mPa.s to about 150,000 mPa.s.

[0200] 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 molecular weight average of about 20,000-500,000. In some embodiments, hypromellose has a molecular weight average of generally 20,000 - 250,000. Hypromellose is commercially available from DowChemicals 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.

[0201] 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 is about 15,000 Daltons.

[0202] 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 about 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 about 2 hours to about 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 about 1 hour, at least about 1.1 hours, at least about 1.2 hours, at least about 1.3 hours, at least about 1.4 hours, at least about 1.5 hours, at least about 1.6 hours, at least about 1.7 hours, at least about 1.8 hours, at least about 1.9 hours, at least about 2 hours, at least about 2.1 hours, at least about 2.2 hours, at least about 2.3 hours, at least about 2.4 hours, or at least about 2.5 hours post-dose, as compared with the reference product.

[0203] When a sustained-release composition shows percentage dissolution ranging from about 0% to 35% at 3 hours, from about 35% to about 55% at 12 hours, and from about 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 disclosurein amounts from about 0.1% to about 99%, from about 0.1% to about 90%, from about 5% to about 90%, from about 5% to about 80%, from about 5% to about 70%, and from about 5% to about 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, carboxymethyl cellulose) may be present in an amount of from about 10% to about 40%, from about 10% to about 50%, from about 10% to about 60%, from about 20% to about 40%, from about 20% to about 50%, from about 20% to about 60%. In some embodiments, the sustained-release agent may be present in an amount of at least about 10%, at least about 20%, at least about 30%, or at least about 40%. In some embodiments, the sustained- release agent is present at about 0.01% to 0.05%, about 0.05% to 0.1%, about 0.1% to 0.5%, about 0.5% to about 1%, 1% to 5%, about 5% to 10%, about 10% to 15%, or about 15% to 20% of the composition. In some embodiments, the sustained-release agent is present at about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% (wt / wt) of the composition.

[0204] 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.

[0205] In some embodiments, compositions may comprise one or more pH-dependent polymers, such as acid-insoluble polymers. The pH-dependent polymers become increasingly permeable above pH 5.0 but are impermeable at pH below 5.0, whereas acid- insoluble polymers become soluble in neutral to weakly alkaline conditions. Such control-release polymers target the 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® LI 00-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S100, EUDRAGIT® S 12,5, EUDRAGIT® FS 30D, EUDRAGIT® E100, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment, the composition comprises EUDRAGIT® L100-55. EUDRAGIT® RS and RL and EUDRAGIT® NE and NM are also useful polymers for the purpose of this disclosure. In some embodiments, the composition comprises EUDRAGIT® L30D 55. In another embodiment, the preparation comprises EUDRAGIT® FS 30D. One of skill in the art will recognize that at least some acid-insoluble polymers listed herein will also be biodegradable.

[0206] Commercially available delayed-release capsules, such as those available from Capsugel (e.g., VCAPS® Plus enteric capsules), can be used to prepare enteric-resistant delayed- release capsules and are encompassed in the present disclosure. In some embodiments, the enteric delayed-release capsules can be non-animal-based capsules, such as a hypromellose capsule (for example, commercially available self-gelling VCAPS®, VCAPS® Plus, VCAPS® Enteric, other enteric capsules made using XCELLODOSE®, DRCAPS®, Encap Colonic Delivery (ENCODE®), and ENTRINSIC™ drug delivery technology from CAPSUGEL®). Other technologies known in the art and available commercially (for example, QUALICAPS®, USA, NUTRASCIENCE®, USA, etc.) for the formulating enteric forms of oral solid dosage forms can also be utilized. For example, the (Z)-endoxifen formulations of the present disclosure may be encapsulated in a DRCAPS® enteric-resistant delayed-release capsule. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen free base or salts thereof is filled neat into the capsule. In such API-in-capsule oral dosage forms, the active ingredient (Z)-endoxifen or salts thereof can be free-flowing powders or micronized powders. When the dosage form is a capsule, in at least one embodiment, the capsule can be a seamless capsule or a banded capsule.

[0207] An example of an enteric-resistant delayed-release (Z)-endoxifen composition may comprise an enteric-resistant delayed-release capsule comprising from about 65% to about 95% hydroxypropyl methylcellulose by weight and from about 3% to about 10% gellan gum by weight, relative to total unfilled capsule weight, encapsulating a (Z)-endoxifen formulation comprising from about 10% to about 30% (Z)-endoxifen by weight, from about 1% to about 5% croscarmellose sodium by weight, from about 60% to about 95% microcrystalline cellulose by weight, and from about 0.5% to about 3% magnesium stearate by weight, relative to total fill weight of the composition. In some embodiments, the enteric-resistant delayed-release (Z)- endoxifen composition may be formulated in a dosage form comprising about 10 mg, about 20 mg, about 40 mg, or about 80 mg of (Z)-endoxifen per capsule.

[0208] A further example of a (Z)-endoxifen composition may comprise from about 15% to about 20% (Z)-endoxifen by weight, from about 2% to about 4% croscarmellose sodium by weight, from about 70% to about 80% microcrystalline cellulose by weight, and from about 0.5% to about 2% magnesium stearate by weight, relative to total fill weight of the composition. The composition may be encapsulated in an enteric-resistant delayed-release capsule, such as a capsule comprising from about 85% to about 97% hydroxypropyl methylcellulose and from about 3% to about 7% gellan gum. In some embodiments, the (Z)-endoxifen formulation may be formulated in a dosage form comprising about 10 mg, about 20 mg, about 40 mg, or about 80 mg of (Z)-endoxifen per dosage unit (e.g., per capsule).(Z)-Endoxifen Particles

[0209] The present disclosure relates to nanoparticle and microparticle (Z)-endoxifen formulations. In aspects, the present disclosure provides a particle containing a (Z)-endoxifen composition (e.g., powdered or micro crystalline (Z)-endoxifen, optionally including a formulary on an excipient) and a pharmaceutically acceptable coating. The particle can be formulated as a powder which can be added to food, beverages, and other administrable compositions. The coating can prevent the (Z)-endoxifen composition from degrading or isomerizing while in an administrable composition or a physiological location not intended for (Z)-endoxifen delivery. In particular, the coating may be stable in the administrable composition (e.g., in a syrup suspension or in a yogurt) and in the stomach but may release (Z)-endoxifen in the small intestine.

[0210] The particle can be amenable to oral administration. The particle can be provided in the form of a powder (e.g., a plurality of instances of the particle), which can be added to food, drinks (e.g., juice, milkshakes, or water), lozenges, gels, creams, or syrups. For example, the powder can be added to a yogurt, nut butter, or salad dressing to ease ingestion. The powder may be amenable for use in a broad range of vehicles, such that a subject can choose a new beverage or food to mix with the powder during each incidence of administration. The powder can be provided in dry form, for example, as a single dose in a breakable capsule or sachet. The powder can also be preformulated within an edible medium, such as a food or drink. For example, a pharmacist may generate a syrup suspension with the powder upon prescription to a subject.

[0211] In some aspects, the plurality of microparticles includes between them a total of from about 0.01 mg to about 200 mg of (Z)-endoxifen, such as about 0.01 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1.0 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, or any value contained within a range formed by any two of the preceding values.

[0212] In some aspects, a dose of the formulation is 0.01 mL to 10 mL of the aqueous solution per kg body weight. In some aspects, the dose of the formulation is 0.01 mL, 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1 mL of the aqueous solution per kg body weight. In some aspects, a dose of (Z)-endoxifen of 0.01 to 3 mg / kg of body weight. In some aspects, the techniques described herein relate to a formulation, including a dose of (Z)-endoxifen of 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / .kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, or 3 mg / kg of body weight.

[0213] In some aspects, the formulation is administered once daily for at least 28 days. In some aspects, the techniques described herein relate to a method, further including administering a therapeutically effective amount of an antidepressant. In some aspects, the techniques described herein relate to a method, further including administering a therapeutically effective amount of a second therapeutic agent. In some aspects, the techniques described herein relate to a method, including an effective amount of the second therapeutic agent from 0.5 to 2500 mg. In some aspects, the second therapeutic agent is ataluren, prednisone, or deflazacort. In some aspects, the daily dosage of ataluren is from 10 mg / kg to 40 mg / kg. In some aspects, the effective amount of ataluren is administered once daily, twice daily, three times daily, or four times daily to achieve a daily dosage. In some aspects, the techniques described herein relate to a method, including a daily dosage of prednisone of from 0.1 mg / kg / day to 3 mg / kg / day or 10 mg / kg / weekend. In some aspects, the techniques described herein relate to a method, including a daily dosage of prednisone of 0.75 mg / kg / day, 0.3 mg / kg / day, or 1.5 mg / kg / day. In some aspects, the techniques described herein relate to a method, including a daily dosage of deflazacort from 0.5 to 5 mg / kg / day. In some aspects, the techniques described herein relate to a method, including a daily dosage of deflazacort of 0.9 mg / kg / day.

[0214] In some aspects, the coating is a capsule. In some aspects, the capsule is an enteric capsule. In some aspects, the enteric capsule comprises hydroxypropylmethyl cellulose. In some aspects, the formulation is formulated for addition to a beverage, a solid food, a cream, a gel, a colloid, a syrup, or a combination thereof. In some aspects, the formulation is formulated for suspension in liquid. In some aspects, the liquid is an aqueous solution.

[0215] In some aspects, a dose of the formulation is 0.01 mL to 10 mL of the aqueous solution per kg body weight. In some aspects, the dose of the formulation is 0.01 mL, 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, or 1 mL of the aqueous solution per kg body weight. In some aspects, a dose of (Z)-endoxifen of 0.01 to 3 mg / kg of body weight. In some aspects, the techniques described herein relate to a formulation, including a dose of (Z)-endoxifen of 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / .kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, or 3 mg / kg of body weight. In some aspects, the aqueous solution comprises a sugar, a sugar alcohol, a sweetener, a flavoring, an alcohol, glycerol, propylene glycol, or combinations thereof. In some aspects, the liquid is viscous.

[0216] The particle can be a nanoparticle or a microparticle. In many cases, the coating defines an exterior surface of the particle and an inner cavity or space that contains the (Z)- endoxifen composition. The coating can surround a single (Z)-endoxifen solid, a (Z)-endoxifen powder, a (Z)-endoxifen suspension, a (Z)-endoxifen composition, a (Z)-endoxifen solution, or a combination thereof. In some cases, the coating is a thin layer encompassing the (Z)-endoxifen composition. In some cases, the coating defines a surface of a sphere surrounding the (Z)- endoxifen composition. For example, the coating may be a capsule, a spun-on polymeric coating, a sprayed-on hard sugar coating, or combinations thereof. The (Z)-endoxifen composition can also be interspersed throughout the coating. In such cases, the coating may be formed as a continuous material with the (Z)-endoxifen composition inclusions and may be formed from a suspension of the (Z)-endoxifen composition in pre-hardened coating material.

[0217] In some cases, a microparticle may be no more than about 500 pm, no more than about 300 pm, no more than about 200 pm, no more than about 150 pm, no more than about 100 pm, no more than about 75 pm, no more than about 50 pm, or no more than about 25 pm in diameter as measured by microscopy, scanning electron microscopy, transmission electron microscopy, dynamic light scattering, laser diffraction, Coulter counter, or sedimentation. In some aspects, a coating on the nanoparticle is from 1 nm to 100 nm thick. In some aspects, the coating is from about 1 nm to 10 nm, from 20 nm to 30 nm, from 30 nm to 40 nm, from 40 nm to 50 nm, from 50 nm to 60 nm, from 60 nm to 70 nm, from 70 nm to 80 nm, from 80 nm to 90 nm, or from 90 nm to 100 nm thick. In some aspects, the coating is from 1 nm to 30 nm, from 30nm to 60 nm, from 40 nm to 80 nm, or from 70 nm to lOOnm thick. In some aspects, a coating on the nanoparticle is from 1 pm to 100 pm thick. In some aspects, the coating is from 1 pm to 10 pm, from 20 pm to 30 pm, from 30 pm to 40 pm, from 40 pm to 50 pm, from 50 pm to 60 pm, from 60 pm to 70 pm, from 70 pm to 80 pm, from 80 pm to 90 pm, or from 90 pm to 100 pm thick. In some aspects, the coating is from 1 pm to 30 pm, from 30 pm to 60 pm, from 40 pm to 80 pm, or from 70 pm to 100 pm thick.

[0218] In some cases, a population of microparticles may be uniform in size. A uniform population of microparticles may vary in diameter by no more than about 50%, no more than about 40%, no more than about 30%, no more than about 20%, no more than about 10%, no more than about 5%, or no more than about 2%. A uniform population of microparticles may vary in volume by no more than about 50%, no more than about 40%, no more than about 30%, no more than about 20%, no more than about 10%, no more than about 5%, or no more than about 2%.

[0219] In many cases, the pharmaceutically acceptable coating is an enteric coating. The enteric coating can enable transit through the stomach without (Z)-endoxifen degradation or isomerization and release the (Z)-endoxifen in the intestines, thereby increasing its potency and limiting side effects. The enteric coating can be configured to last in the stomach for at least 30 minutes, at least 1 hour, at least 1.5 hours, at least 2 hours, at least 3 hours, or at least 4 hours without dissolving or degrading. The enteric coating can then release the (Z)-endoxifen in the small intestines with a half-life of about 3 hours to 100 hours, about 3 hours to 15 hours, about 5 hours to 20 hours, about 10 hours to 30 hours, or about 20 to 100 hours.

[0220] The coating can be any pharmaceutically acceptable coating disclosed herein. In some cases, the coating comprises glyceryl monostearate, glyceryl distearate, polymethacrylate, hypromellose (HPMC), polyacrylate, 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, synthetic waxes, microcrystalline waxes, paraffin wax, carnauba wax, beeswax, polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl mono-, di-tribemates, glyceryl monostearate, glyceryl distearate, such as stearyl alcohol, cetyl alcohol, polyethylene glycol, copolymers thereof, and mixtures thereof.

[0221] The particle may be nanometer, micron, or millimeter dimensioned. In some cases, the particle has a largest dimension of between about 10 nm and 2 mm (correspondingly, a plurality of instances of the particle can have a mean or median largest dimension of between about 10 nm and 2 mm). In some cases, the particle has a largest dimension of between about 10and 100 nm, between about 25 and 250 nm, between about 50 and 500 nm, between about 100 and 500 nm, between about 200 nm and 1 pm, between about 1 and 25 pm, between about 10 and 100 pm, between about 25 and 250 pm, between about 50 and 500 pm, between about 100 and 500 pm, between about 200 pm and 1 mm, or between about 400 pm and 2 mm. In some cases, the particle is substantially spherical. In some cases, the particle has an oblong or irregular structure. In some cases, the particle is a nanoparticle. In some cases, the particle is a microparticle.

[0222] In some cases, a microparticle may be no more than 500 pm, no more than 300 pm, no more than 200 pm, no more than 150 pm, no more than 100 pm, no more than 75 pm, no more than 50 pm, or no more than 25 pm in diameter. In some cases, a population of microparticles may be uniform in size. A uniform population of microparticles may vary in diameter by no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, or no more than 2%. A uniform population of microparticles may vary in volume by no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 5%, or no more than 2%.

[0223] In some aspects, the (Z)-endoxifen has a half-life of between 4 to 24 hours in pH 1.2 simulated gastric fluid at 37°C. In some aspects, the (Z)-endoxifen has a half-life of between 2 to 72 hours in pH 6.7 simulated intestinal fluid at 37°. In some aspects, the (Z)-endoxifen has a half-life of between 12 to 144 hours in pH 7.0 deionized water at 25°C.

[0224] A plurality of instances of the particle (e.g., a powder comprising the particle) can be uniform or heterogeneous. For example, a plurality of instances of the particle can be characterized by a polydispersity index (PDI) of less than about 5, less than about 4.5, less than about 4, less than about 3.5, less than about 3, less than about 2.5, less than about 2, less than about 1.5, less than about 1, less than about 0.75, less than about 0.5, less than about 0.25, or less than about 0.1. In some cases, a plurality of instances of the particle can be characterized by a polydispersity index of at least about 0.1, at least about 0.25, at least about 0.5, at least about 0.75, at least about 1, at least about 1.5, at least about 2, at least about 2.5, at least about 3, at least about 3.5, at least about 4, at least about 4.5, or at least about 5.

[0225] In some cases, the pharmaceutically acceptable coating is about 5% to 95% of the weight of the particle. In some cases, the pharmaceutically acceptable coating is about 5% to 25%, about 10% to 30%, about 20% to 50%, about 30% to 60%, about 40% to 80%, about 50% to 90%, or about 60% to 95% of the weight of the particle.

[0226] In some cases, the particle includes a plasticizer. A plasticizer may control the softness or pliability of the particle and may improve its mechanical properties for administration and enteric delivery. Suitable plasticizers include, without limitation, petroleumoils (for e.g., a paraffinic process oil, a naphthenic process oil, and an aromatic process oil), squalene, squalane, plant oils (e.g., olive oil, camelia oil, castor oil, tall oil, and a peanut oil), silicon oils, dibasic acid esters, (e.g., dibutyl phthalate, and dioctyl phthalate), liquid rubbers (e.g., polybutene and a liquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl mynstate 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 on the chemical composition of the pharmaceutical preparation. In one embodiment, the coating contains sorbitol, dimethyl isosorbide, or glycerol. In another embodiment, the plasticizer is 1% to 10%, such as 3% to 5% (wt / wt), of the coating. In another embodiment, the plasticizer is 1% to 10%, such as 3% to 5% (wt / wt), of the particle.

[0227] The particle can include a disintegrant. Disintegrants can enhance particle disintegration upon exposure to an aqueous environment. Particles that contain too much disintegrant may disintegrate in storage or upon formulation in an aqueous medium, such as a syrup, while those that contain too little disintegrant may not disintegrate at a desired rate or under the desired conditions (e.g., disintegrate enterically). Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used in a particle formulation. In some embodiments, the disintegrant is buried within a particle to delay disintegration. The amount of disintegrant used varies based on the type of formulation and is readily discernible to those of ordinary skill in the art.

[0228] A particle can contain between 0.5% to 15% (wt / wt) of the disintegrant. In some cases, the particle contains between 1% and 5% (wt / wt) of the disintegrant. In another embodiment, the particle contains between 1% to 25%, 2% to 20%, 5% to 15%, 8% to 12%, or about 10% (wt / wt) of the disintegrant. Disintegrants that can be used in the particles provided herein include but are not limited to, 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 mixtures thereof.

[0229] The particle can include a control release agent. Examples of control release agent suitable for use include without limitation, pH-dependent polymers, acid-insoluble polymers, methyl aery late-methacry lie 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, carnaubawax, and beeswax; polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl mono-, ditribemates, 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.

[0230] The particle can contain a pH-dependent polymer, such as an acid-insoluble polymer. The pH-dependent polymer can become increasingly permeable above pH 5.0 and impermeable at pH below 5.0. Alternatively, the pH-dependent polymer can become increasingly permeable below pH 5.0 and increasingly permeable at pH above 5.0. pH-dependent polymers can configure the particle to release (Z)-endoxifen in the colon and upper small intestines. The pH- dependent polymer may prevent (Z)-endoxifen release in the high pH environment of the stomach and become permeable in the higher pH environment of the small intestines, thereby ensuring (Z)-endoxifen release following transit through the stomach. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, alginic 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® LI 00-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S 100, EUDRAGIT® S12, 5, EUDRAGIT® FS 30D, EUDRAGIT® El 00, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment, the composition comprises EUDRAGIT® LI 00-55.

[0231] EUDRAGIT® RS and RL and EUDRAGIT®NE and NM polymers may also be included in a particle of the present disclosure. In some embodiments, the particle comprises EUDRAGIT® L30D 55. In another embodiment, the particle comprises EUDRAGIT® FS 30D. One of skill in the art will recognize that at least some acid-insoluble polymers listed herein will also be biodegradable.

[0232] In some cases, the particle contains at least one sustained-release agent. Non-limiting examples of sustained-release agents compatible with particles of the present disclosure include hypromellose (HPMC), acrylic resins, methacrylic resins, polyvinyl pyrrolidine, hydroxyalkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl celluloses, carboxyalkyl cellulose, and carboxymethyl cellulose. The sustained-release agent may be present in from about 0.1% to about 99%, from about 0.1% to about 90%, from about 5% toabout 90%, from about 5% to about 80%, from about 5% to about 70%, and from about 5% to about 60% w / w of the particle. In some embodiments, the sustained-release agent is present in an amount of from about 10% to about 40%, from about 10% to about 50%, from about 10% to about 60%, from about 20% to about 40%, from about 20% to about 50%, from about 20% to about 60%. In some embodiments, the sustained-release agent is present in an amount of at least about 10%, at least about 20%, at least about 30%, or at least about 40% (w / w).

[0233] In some cases, the particle contains a lubricant. Exemplary lubricants include but are not limited to, stearic acid, calcium stearate, magnesium stearate, zinc stearate, potassium stearate, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, talc, ethyl oleate, ethyl laureate, agar, waxes, and combinations 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, TX), CAB O SIL® (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), Q7- 9120 (Dow Coming), and combinations thereof. In some embodiments, the lubricant is magnesium stearate. The lubricant can reduce the friction between the (Z)-endoxifen, coating, and optionally other ingredients (e.g., filler in the (Z)-endoxifen composition) during particle formation. The particle can include at least one lubricant in an amount ranging from about 0.01% to about 5%, from about 0.2% to about 2%, or from about 0.5% to about 1.5% on a w / w basis relative to the weight of the sustained-release composition. In certain embodiments, the particle includes magnesium stearate in an amount ranging from about 0.01% to about 5%, from about 0.2% to about 2%, or from about 0.5% to about 1.5% on a w / w basis.

[0234] The particle can exhibit a sustained-release profile. In some cases, the particle releases (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. In some embodiments, the therapeutic agent in the sustained-release composition is released over a period of from 6 hours to 48 hours. In some embodiments, the (Z)-endoxifen is released over a period of from 2 hours to 72 hours as tested by the USP II 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. In some embodiments, the particle has a half-life of between about 4 and 24 hours, between about 6 and 48 hours, between about 2 and 12 hours, between about 16 and 72 hours, or between about 48 and 280 hours in pH 1.2 simulated gastric fluid at 37°C. In some embodiments, the particle has ahalf-life of between about 2 and 72 hours, between about 6 and 48 hours, between about 2 and 12 hours, between about 16 and 72 hours, or between about 48 and 280 hours in pH 6.7 simulated intestinal fluid at 37°C.

[0235] In some cases, (Z)-endoxifen is about 5% to 95% of the weight of the particle. In some cases, the (Z)-endoxifen is about 5% to 25%, about 10% to 30%, about 20% to 50%, about 30% to 60%, about 40% to 80%, about 50% to 90%, or about 60% to 95% of the weight of the particle. In some cases, the (Z)-endoxifen is a powder. In some cases, the (Z)-endoxifen is microcrystalline. In some cases, the (Z)-endoxifen is nanocrystalline.

[0236] In some cases, the (Z)-endoxifen is isomerically pure. In some cases, the (Z)- endoxifen is at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% (Z)-endoxifen.

[0237] The (Z)-endoxifen composition can include a filler. The filler may stabilize the (Z)- endoxifen, prevent cross-reaction of the (Z)-endoxifen with the coating or another constituent of the (Z)-endoxifen composition, act as a pharmaceutical excipient, or affect its release profile. Non-limiting examples of fillers include talc, calcium carbonate, a sugar, a salt, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and combinations thereof.

[0238] The pharmaceutically acceptable coating can have a high aqueous stability, enabling formulation of the particle within an aqueous medium. In some cases, the particle is dispersed within an aqueous medium, such as a beverage or a syrup, a gel such as gelatin, a colloid such as a fruit preserve or nut butter, or a cream such as cake icing. The particle can have an aqueous half-life of between about 5 and 25 hours, between about 10 and 50 hours, between about 20 and 100 hours, or between about 50 and 250 hours. The particle can have a substantially enhanced half-life in room-temperature water relative to human body temperature water. For example, the particle can have a half-life of between about 50 and 250 hours in 25°C simulated intestinal fluid and a half-life of between about 10 and 50 hours in 37°C simulated intestinal fluid. In some cases, the particle is configured to release less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 12%, less than about 10%, less than about 8%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% of the (Z)-endoxifen following 1 month of storage in pH 7 water at 25 °C. In some cases, the particle is configured to release at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 8%, at least about 10%, at least about 12%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, atleast about 40%, or at least about 50% of the (Z)-endoxifen following 1 day of storage in pH 7 water at 37°C.Sustained-Release Particles

[0239] The (Z)-endoxifen of the present disclosure can be in a sustained-release particle.The particle can be configured for controlled and sustained release. The particle can release (Z)- endoxifen over a span of hours, days, weeks, or months. The particle can be designed to release (Z)-endoxifen following administration. In many cases, the particle provides prolonged release in the intestines after the passage of the compositions from the stomach to allow for uptake of the therapeutic agent ((Z)-endoxifen or a polymorph or a salt thereof) from the intestines and / or colon into the bloodstream of a subject. The rate of release of (Z)-endoxifen, or a polymorph or a salt thereof, from the particle can be slower than that observed for the reference product (the Capsule), which has been described in W02019051416A1. The particles can provide a controlled and prolonged exposure of the subject to the (Z)-endoxifen over a time period from at least about 2 hours to about 270 hours following administration. Sustained (Z)-endoxifen release can reduce the frequency of dosing and / or the rate of uptake of the (Z)-endoxifen agent into the bloodstream, which can improve tolerance to the (Z)-endoxifen by the patient. Intermittent dosing facilitated by the sustained-release particles can also increase patient convenience and compliance by decreasing self-administration requirements. The slow and prolonged (or sustained) release can lower peak systemic levels of the (Z)-endoxifen, which may reduce local and / or systemic side effects, toxicity, and (Z)-endoxifen accumulation as compared with other dosage forms such as the reference product.

[0240] A sustained-release agent present in a particle 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. In some cases, the sustained-release agent constitutes at least about 25%, at least about 50%, at least about 75%, at least about 90%, or at least about 95% of the coating by weight. In some cases, the sustained-release agent constitutes at least about 25%, at least about 50%, at least about 75%, at least about 90%, or at least about 95% of the particle by weight.

[0241] 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. Insome embodiments, 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 remain impermeable below pH 5.0. Such controlled-release polymers target the upper small intestines and / or colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, alginic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methacrylic 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 certain embodiments, the viscosity of the at least sustained- release agent ranges from about 1000 mPa.s to about 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 about 1000 mPa.s to about 10,000 mPa.s, from about 10,000 mPa.s to about 70,000 mPa.s, from about 70,000 mPa.s to about 150,000 mPa.s. or a combination thereof. In some embodiments, the present disclosure provides that the sustained-release delivery 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 about 1000 mPa.s to about 10,000 mPa.s, while another sustained-release agent may have a viscosity of about 10,000 mPa.s to about 70,000 mPa.s or about 70,000 mPa.s to about 150,000 mPa.s.

[0242] 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 molecular weight average of about 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.

[0243] A sustained-release agent, such as hypromellose, can have an average molecular weight generally ranging from 15,000 to 140,000 Daltons. In at least one embodiment, the average molecular weight is about 15,000 Daltons.

[0244] The amount of sustained-release agent in the particle may be any amount effective to delay the release of the therapeutic agent (Z)-endoxifen, or a polymorph or a salt thereof, for about 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 about 2 hours to about 72 hours. The amount of sustained- release agent in the particle 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 about 1 hour, at least about 1.1 hours, at least about 1.2 hours, at least about 1.3 hours, at least about 1.4 hours, at least about 1.5 hours, at least about 1.6 hours, at least about 1.7 hours, at least about 1.8 hours, at least about 1.9 hours, at least about 2 hours, at least about 2.1 hours, at least about 2.2 hours, at least about 2.3 hours, at least about 2.4 hours, or at least about 2.5 hours post-dose, as compared with the reference product.

[0245] A particle may exhibit a sustained-release profile. For example, the particle can have a dissolution ranging from about 0% to 35% at 3 hours, from about 35% to about 55% at 12 hours, and from about 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. A particle can be suspended in a liquid for ease of administration, such as for administration to a child.Administration of (Z)-Endoxifen Compositions

[0246] In some embodiments, the compositions including (Z)-endoxifen or a (Z)-endoxifen salt or polymorph are administered to the subject at a dose of 0.01 mg to 200.0 mg of (Z)- endoxifen per unit dose. In other embodiments, the oral compositions including (Z)-endoxifen or a (Z)-endoxifen salt or polymorph are administered to the subject at a dose of 1 mg to 200.0 mg of (Z)-endoxifen. In some embodiments, the oral compositions including (Z)-endoxifen or a (Z)- endoxifen salt or polymorph are administered to the subject at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg,22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg,47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg,72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg,97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, or 200 mg of (Z)-endoxifen per unit dose. In certain embodiments, the oral compositions include at least 90% (Z)-endoxifen (wt / wt) and are administered at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg,28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg,53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg,78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, or 200 mg of (Z)-endoxifen per unit dose. In some embodiments, the compositions include (Z)-endoxifen gluconate and are administered at a dose ranging from 0.01 to 20 mg of (Z)-endoxifen per unit dose. In some embodiments, a composition including (Z)-endoxifen D-gluconate is administered at 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 3 mg, 4 mg, 5mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg,116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg,127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg,138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg,149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg,160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg,171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg,182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg,193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, or 200 mg of (Z)-endoxifen per unit dose. In some embodiments, a composition including 1 mg of (Z)-endoxifen D-gluconate is administered. In other embodiments, a composition including 1 mg of (Z)-endoxifen L- gluconate is administered. In yet other embodiments, a composition including 2 mg of (Z)- endoxifen D-gluconate and (E)-endoxifen D-gluconate is administered. In certain embodiments, an oral composition including at least 90% of a polymorph of (Z)-endoxifen (wt / wt) is administered at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, or 200 mg per unit dose. In some embodiments, a composition including a polymorphic form of (Z)- endoxifen is administered at a dose ranging from 0.01 mg to 20 mg per unit dose.

[0247] In some embodiments, a dosage of (Z)-endoxifen for treating cancer in combination with a therapeutic agent may be selected to achieve a Cmax in the subject of at least about 0.01 pg / mL, at least about 0.05 pg / mL, at least about 0.1 pg / mL, at least about 0.2 pg / mL, at least about 0.3 pg / mL, at least about 0.4 pg / mL, at least about 0.5 pg / mL, at least about 0.6 pg / mL, at least about 0.7 pg / mL, at least about 0.8 pg / mL, at least about 0.9 pg / mL, at least about 1 pg / mL, at least about 1.5 pg / mL, at least about 2 pg / mL, at least about 2.5 pg / mL, at least about 3 pg / mL, at least about 3.5 pg / mL, at least about 4 pg / mL, at least about 4.5 pg / mL, at least about 5 pg / mL, at least about 6 pg / mL, at least about 7 pg / mL, at least about 8 pg / mL, at least about 9 pg / mL, or at least about 10 pg / mL. In some embodiments, a dosage of (Z)-endoxifen for treating cancer in combination with a therapeutic agent may be selected to achieve a Cmax in the subject of from about 0.01 pg / mL to about 0.1 pg / mL, from about 0.1 pg / mL to about 0.5 pg / mL, from about 0.1 pg / mL to about 1 pg / mL, from about 0.1 pg / mL to about 2 pg / mL, from about 0.5 pg / mL to about 1 pg / mL, from about 0.5 pg / mL to about 2 pg / mL, from about 1 pg / mL to about 2 pg / mL, from about 1 pg / mL to about 5 pg / mL, or from about 1 pg / mL to about 10 pg / mL.

[0248] In some embodiments, a method of treating cancer may include administering (e.g., orally, topically, or via inhalation) a (Z)-endoxifen composition to the subject’s plasma (Z)- endoxifen levels at a steady state level greater than 30 nM, for example, at levels ranging from 30 nM to 80 nM or at levels ranging from 30 nM to 300 nM. In some embodiments, the plasma steady-state (Z)-endoxifen level is maintained at >40 nM. It also advantageous for subjects being treated or to be treated with antidepressant drugs such as SSRI drugs such as citalopram, escital opram, fluoxetine, paroxetine, sertraline, vilazodone, and the like; for example, a subject having or likely to have depression.

[0249] The plasma (Z)-endoxifen may be measured by any of the methods known in the art. The levels of plasma (Z)-endoxifen in a test sample may be determined based on the subject’s genes, DNA, RNA, protein, tamoxifen-metabolite profile, or a combination thereof. The tamoxifen-metabolite profile can include at least tamoxifen, 4-OHT, N-desmethyltamoxifen, and / or (Z)-endoxifen. In some embodiments, the level of plasma (Z)-endoxifen and / ortamoxifen-metabolite profile in the test sample is measured by high-performance liquid chromatography (HPLC), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-tandem mass spectrometry (LC-MS / MS), immunohistochemistry (IHC), polymerase chain reaction (PCR), quantitative PCR (qPCR), and the like. In some embodiments, the tamoxifen-metabolites profile is predicted based on the subject’s genetic composition. In some embodiments, the subject’s CYP genotype includes, without limitation, analysis of CYP2D6, CYP3A4, CYP2C9 genes. In some embodiments, the subject’s estrogen receptor levels may be analyzed. In other embodiments, the determination of plasma (Z)-endoxifen may be done by a third-party laboratory.

[0250] Accordingly, provided herein are methods of maintaining a plasma (Z)-endoxifen at a level greater than 30 nM in a subject in need thereof by administering to the subject a composition comprising (Z)-endoxifen or a salt thereof. In some embodiments, the subject’s plasma (Z)-endoxifen level is maintained at a steady state level greater than 30 nM. In some embodiments, the subject’s plasma (Z)-endoxifen levels are maintained at a steady state level ranging from 30 nM to 300 nM (for example, from 30 nM to 200 nM, or from 30 nM to 80 nM). In some embodiments, the subject’s plasma (Z)-endoxifen levels are maintained at a steady state level >40 nM. In some embodiments, the plasma level of (Z)-endoxifen may be maintained for at least 7, at least 14, at least 21, or at least 28 days, thereby treating cancer in the subject.

[0251] In some aspects, the techniques described herein relate to a method, further including producing an area under curve (AUCo-inf) of (Z)-endoxifen in the subject of from 200 hr* ng / mL to 10,000 hr*ng / mL per 4 mg of (Z)-endoxifen administered. In some aspects, the techniques described herein relate to a method, further including producing a maximum blood plasma concentration (Cmax) of (Z)-endoxifen in the subject of from 14 ng / mL to 62 ng / mL per 4 mg of (Z)-endoxifen administered.

[0252] The duration of (Z)-endoxifen administration can vary depending on the gene mutation involved, cancer stage, severity, and progression, as well as on the long-term safety and efficacy of (Z)-endoxifen. The composition including (Z)-endoxifen can be administered from 1 to 120 days, 0 to 120 months, 0 to 10 years or longer, 1 to 10 days, 10 to 20 days, 20 to 30 days, 30 to 40 days, 40 to 50 days, 50 to 60 days, 1 to 6 months, 6 to 12 months, 1 year to 5 years, or 1 year to 10 years or longer. In some aspects, the method includes administering the composition for 1 to 160 days. In some aspects, the method includes administering the composition for 1 to 10 days, 10-20 days, 20-30 days, 30-40 days, 40-50 days, 50-60 days, 60- 70 days, 70-80 days, 80-90 days, 90-100 days, or 100-160 days. The (Z)-endoxifen can be administered orally once, twice, three times or four times daily for at least 7, 14, 28, 30, 45, 60days or longer, until the cancer reduces in size or distribution, or until treatment is no longer needed.

[0253] The (Z)-endoxifen 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 therapeutic agents to a subject in thereof.

[0254] As used herein, the terms “about” and “approximately,” in reference to a number, are used herein to include numbers that fall within a range of 10%, 5%, or 1% in either direction (greater than or less than) the number unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

[0255] 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 combinations 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%. In 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.

[0256] As used herein, the terms “active pharmaceutical ingredient,” “active ingredient,” “API,” “drug,” “active,” “actives,” or “therapeutic agent” may be used interchangeably to refer to the pharmaceutically active compound(s) in a pharmaceutical composition. This is in contrast to other ingredients in the compositions, such as excipients, which are substantially or completely pharmaceutically inert. A suitable API in accordance with the present disclosure is one where there are or likely may be patient compliance issues for treating a disease, condition, or disorder. The therapeutic agent as used herein includes the active compound and its salts,prodrugs, and metabolites. As used herein, the term “drug” means a compound intended for use in the diagnosis, cure, mitigation, treatment, and / or prevention of disease in man or other animals.

[0257] As used herein, “adjuvant therapy” refers to a therapy that follows a primary therapy and that is administered to subjects at risk of relapsing. Adjuvant systemic therapy in case of breast cancer or reproductive tract cancer, for example with tamoxifen, usually begins soon after primary therapy to delay recurrence, prolong survival or cure a subject.

[0258] Embodiments that reference throughout this specification to “a compound”, such as the compound of Formula (I), include the polymorphic, salt, free base, co-crystal, and solvate forms of the formulas and / or compounds disclosed herein. Thus, the appearances of the phrases “a compound” and “compounds of Formula (I)” include crystalline Form I of the compound of Formula (I), the free base of the compound of Formula (I), and / or the gluconate salts as described herein.

[0259] The terms “crystalline form”, “polymorph” and “Form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0260] The term “substantially as shown in” when referring, for example, to an XRPD pattern, includes a pattern that 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 on 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 two theta (20) values. Accordingly, when a specified two theta angle is provided, it is to be understood that the specified two theta angle can vary by the specified value ± 0.5°, such as ± 0.4°, ± 0.3°, ± 0.2°, or ± 0.1°. 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.

[0261] All compounds disclosed herein are further understood to include all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of example, and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon includenC,13C and14C.Therapeutic Agents for Combination Treatment

[0262] The present disclosure provides compositions and methods for treating cancer and hormone-dependent diseases or disorders through treatment with a combination of (Z)- endoxifen and a synergistic compound or therapeutic agent. The synergistic compound, in some aspects, is also referred to as a therapeutic agent. Due to the physiological pathways involved in the described diseases, the pathways influenced by (Z)-endoxifen, and the pathways influenced by the different compounds described herein, the treatment results from the combination treatments described are greater than those seen through treatment with either compound alone.

[0263] For purposes herein, the definition of “therapeutic agent” is a compound that, when combined with (Z)-endoxifen, produces a viability of more than 3 standard deviations (StD) below the mean (Z)-endoxifen line. As can be seen in these two experiments, both the mean (Z)- endoxifen and the 3 StD line can vary from one experiment to another, but the use of this methodology compensates for this variability and provides a clear definition of a therapeutic agent.

[0264] In some aspects, the therapeutic agent is a topoisomerase inhibitor, a tubulin polymerization inhibitor, a CDK inhibitor, an MTOR inhibitor, an AKT inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an HD AC inhibitor, an HSP inhibitor, a kinesin inhibitor, a MEK inhibitor, a PI3K inhibitor, a PLK inhibitor, a ribonucleotide reductase inhibitor, a nucleoside analog, a microtubule inhibitor, a bromodomain inhibitor, a proteasome inhibitor, an XIAP inhibitor, a kinesin-like spindle protein inhibitor, a Famesyltransferase inhibitor, a CHK inhibitor, an SRC inhibitor, a protein synthesis inhibitor, an epidermal growth factor receptor erbB 1 inhibitor, a vascular endothelial growth factor receptor inhibitor, a DNA topoisomerase I inhibitor, a programmed cell death protein 1 inhibitor, a vascular endothelial growth factor receptor 2 inhibitor, a programmed cell death protein 1 antagonist, a PI3 -kinase class I inhibitor, a tubulin inhibitor, a receptor protein-tyrosine kinase erbB2-2 inhibitor, a platelet-derived growth factor receptor inhibitor, an FK506-b inding protein 1 A inhibitor, a stem cell growth factor receptor inhibitor, an angiopoietin-2 inhibitor, an estrogen receptor alpha modulator, a hormone therapy molecule, a PDE inhibitor, a MAPK inhibitor, an FLT3 inhibitor, an HMGCR inhibitor, an ABL inhibitor, a DNA / thymidylate synthase inhibitor, an ALK inhibitor, an IGF-1 inhibitor, or a dual mTOR / PI3K inhibitor. In some aspects, the therapeutic agent is selected fromthe group consisting of BAY-11 to 7082, Salinomycin (Procoxacin), Pimasertib (AS-703026), A66, RO5126766 (CH5126766), ASP3026, RO4987655, PD318088, K-Ras(G12C) inhibitor 12, PIK-93, Ravoxertinib, GDC-0994, Osimertinib, Gilteritinib, Cobimetinib, Duvelisib (IPI-145, INK1197), Tesevatinib, PD173074, Copanlisib, Binimetinib (MEK162, ARRY-162, ARRY- 438162), lodophenpropit, U-18666A, ZM-241385, AZD-8835, Trametinib, NVP-TAE226, Atiprimod, AZD4547, NVP-TNKS656, Alpelisib (BYL719), Afatinib (dimaleate), Saracatinib (AZD0530), Tenovin-6, Tubastatin A hydrochloride, L-778123 (hydrochloride), Ascomycin (FK520), AZD8186, GZD824 Dimesylate, Ro 48 to 8071 (fumarate), EW-7197, Dorsomorphin, BAX-channel-blocker, Erbstatin-analog, CH5132799, Hoechst 33258, AT13148, AZD5363, AZD8330, AZ5104, BMS-983970, Dasatinib, Bleomycin sulfate, Maxacalcitol, GSK1059615, Nexturastat A, Ribociclib (LEE011), Etoposide phosphate, NVP-ADW742, Voreloxin (Hydrochloride), Triciribine, LB42708, SM-164, Walrycin B, BMS-345541, Domiphen Bromide, RepSox, TAK-733, BX-912, LCL161, NVP-AEW541, Lonafarnib (SCH66336), Vorinostat (SAHA, MK0683), Quinacrine hydrochloride, Ipatasertib (GDC-0068), GDC-0152, Afuresertib, Falecalcitriol, PRT062607 (P505 to 15, PRT2607, BIIB057) HC1, Prexasertib (dihydrochloride), XL388, MLN8054, SU9516, BNTX, Fedratinib (SAR302503, TG101348), C-021, Taselisib, NSC-3852, Miransertib, MK-2206 dihydrochloride, Resminostat (RAS2410), 5-BrdU, CH55, Carmofur, Bimiralisib, JNJ-7706621, Rapamycin, Tosedostat, Idoxuridin, VS- 5584, Uprosertib, M344, Mycophenolate mofetil, XL888, PP-121, LMK-235, CPI-203, MK8745, Apitolisib (GDC-0980, RG7422), GSK690693, Tipifarnib (Zamestra), Etoposide, Mycophenolic Acid, PD 0332991 (Palbociclib) HC1, 1-BET151 (GSK1210151A), Pemetrexed, AZ20, Phortress, PHA-848125, MPI-0479605, OSI-027, Ingenol mebutate, Cevipabulin, FK- 866, APY-29, LY3023414, Ixazomib citrate, Belinostat (PXD101), Crenolanib (CP-868596), 6,7-Dihydroxy-l-(4-Hydroxybenzyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride, (+)-JQl, AZD3463, BET-BAY 002, GDC-0349, VX-680 (MK-0457, Tozasertib), GSK1070916, Gentian violet, Combretastatin-A4, UNC2025 (hydrochloride), Satraplatin, BMS-566419, Cycloheximide, Digitoxigenin, ABT-751 (E7010), 3-Deazaneplanocin A (DZNeP) HC1, Abemaciclib (LY2835219), AZD7762, WYE-687, AP26113, Hesperadin, PHA-680632, Basic fuchsin, Diphenyleneiodonium, MK-1775, Clofarabine, AZD6738, Bisacodyl, NVP-HSP990, NSC319726, Epothilone D, PHA-767491, AR-42 (HD AC-42), AMG 232, Barasertib (AZDI 152-HQPA), Teniposide, KW-2478, 1-BET-762, Strophantidin, Amsacrine, CC-115, Ganetespib (STA-9090), Filanesib, NMS-E973, BNC105, Torin 1, Aphidicolin, Vinorelbine (ditartrate), XL228, PF-05212384 (PKI-587), 17-AAG (Tanespimycin), 5-Fluoro-2- deoxycytidine, Trifluridine, GSK461364, Digoxigenin, Colchicine, MK-8776 (SCH 900776), SB-268262, R547, PF-03814735, Gemcitabine (elaidate), AT9283, Cyclocytidine HC1,Fosbretabulin (disodium), CGP-74514, VER-49009, Retaspimycin (Hydrochloride), BML-284, Cytarabine, Briciclib, Mivobulin, Ixazomib citrate (MLN9708), Verubulin, PF-3758309, LY2334737, Floxuridine, WYE-125132, Topotecan (hydrochloride), Torin-2, KX2 to 391, Ixazomib (MLN2238), Pevonedistat hydrochloride, Camptothecin, Gemcitabine, Irinotecan, Ispinesib (SB-715992), AZDI 152, TAK-901, NMS-1286937, Taltobulin (trifluoroacetate), Onalespib (AT13387), Danusertib (PHA-739358), 17-DMAG HC1 (Alvespimycin), PD-166285, Ixabepilone, Vincristine (sulfate), MLN8237 (Alisertib), Vinblastine (sulfate), Oprozomib (ONX 0912), Ansamitocin P-3, Vistusertib (AZD2014), CHIR-124, TAS- 103 (dihydrochloride), ER-27319 maleate, PU-H71, Vindesine Sulfate, Nampt-IN-1, Raltitrexed (Tomudex), BI6727 (Volasertib), Litronesib, Omipalisib (GSK2126458, GSK458), PF-04691502, PHA-793887, Luminespib, INK 128 (MLN0128), SNX-2112, SB-743921, CYT997, PF-04929113 (SNX- 5422), AZD5438, Proflavine hemisulfate, Patupilone (EPO906, Epothilone B), A-674563, LY2090314, Plinabulin, Talazoparib (BMN 673), Torkinib (PP242), Genz-644282, ARQ 621, Pralatrexate (Folotyn), Selinexor (KPT-330), R306465, or HMN-214.

[0265] In some aspects, the formulation includes from 0.01 mg to 1000 mg of the therapeutic agent. In some aspects, the formulation includes from 0.01 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 40 mg, 40 mg to 80 mg, 80 mg to 150 mg, 150 mg to 300 mg, 300 mg to 800 mg, 800 mg to 1000 mg of the therapeutic agent. In some aspects, the therapeutic agent is formulated as a formulation, an intramuscular injection, a subcutaneous injection, an intrathecal injection, or an intravenous infusion. In some aspects, the therapeutic agent and the (Z)-endoxifen are administered in a single combination formulation. In some aspects, the therapeutic agent and the (Z)-endoxifen are administered in separate formulations.

[0266] The present disclosure describes a method of treating a disease or condition in a subject in need thereof, including administering a formulation described herein that includes (Z)- endoxifen and a synergistic compound or therapeutic agent, thereby treating the disease or condition. In some aspects, the administering of the formulation results in a plasma (Z)- endoxifen level greater than 40 nM per 1 mg of (Z)-endoxifen administered. In some aspects, the method includes administering 1 mg to 200 mg, 1 mg to 80 mg, 1 mg to 40 mg, or 1 mg to 20 mg of (Z)-endoxifen per day. In some aspects, the techniques described herein relate to a method, including administering a dose of 0.05 mg / kg to 10 mg / kg of (Z)-endoxifen per day. In some aspects, the techniques described herein relate to a method, including administering a dose of 0.05 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.8 mg / kg, 2 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.8 mg / kg, or 3 mg / kg of (Z)-endoxifen per day. In some aspects, the administering of the combination formulation maintains a plasma level of (Z)-endoxifen of the subject at a steady state level above 30 nM. In some aspects, the administering of the formulation maintains theplasma level at a steady state level from 30 nM to 1000 nM. In some aspects, administering of the combination formulation releases no more than 10% of the (Z)-endoxifen in a stomach of the subject within 2 hours following the administering of the formulation. In some aspects, the method further includes releasing at least 50% of the (Z)-endoxifen in a small intestine of the subject within 8 hours following the administering of the formulation. In some aspects, the method further includes producing an area under the curve (AUCo-inf) of (Z)-endoxifen in the subject of from 200 hr*ng / mL to 10,000 hr*ng / mL per 4 mg of (Z)-endoxifen administered. In some aspects, the method further includes producing a maximum blood plasma concentration (Cmax) of (Z)-endoxifen in the subject of from 14 ng / mL to 62 ng / mL per 4 mg of (Z)-endoxifen administered.

[0267] A dose of the therapeutic agent or synergistic compound can range from 0.01 mg to 1000 mg of the therapeutic agent per day. In some aspects, the dose ranges from 0.01 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 40 mg, 40 mg to 80 mg, 80 mg to 150 mg, 150 mg to 300 mg, 300 mg to 800 mg, 800 mg to 1000 mg of the therapeutic agent per day. In some aspects, dose of the therapeutic agent or synergistic compound ranges from 0.01 mg / kg to 10 mg / kg per day. In some aspects, the dose is from about 0.01 mg / kg to 0.5 mg / kg, about 0.5 mg / kg to 1 mg / kg, about 1 mg / kg to 1.5 mg / kg, about 1.5 mg / kg to 2 mg / kg, about 2 mg / kg to 2.5 mg / kg, or about 2.5 to 3 mg / kg of the therapeutic agent per day. In some aspects, the therapeutic agent is administered every day, every other day, every third day, biweekly, weekly, biweekly, monthly, bimonthly, every three months, every six months, or yearly.

[0268] The disease or disorder treated with the compositions and methods described herein can be a cancer. In some aspects, the cancer is glioblastoma, non-small cell lung cancer, melanoma, pancreatic carcinoma, medulloblastoma, pancreatic carcinoma, prostate carcinoma, gastric carcinoma, esophageal cancer, osteosarcoma, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, breast cancer, ductal carcinoma, lobular carcinoma, or urinary bladder cancer.

[0269] The disease or disorder treated with the compositions and methods described herein can be a hormone-dependent breast disorder or a hormone-dependent reproductive tract disorder. In some aspects, the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, ductal carcinoma in situ, lobular carcinoma in situ, breast cancer, precocious puberty, McCune-Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer. In some aspects, the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is tamoxifen-refractory or tamoxifen resistant.

[0270] The present disclosure provides compositions and methods for treating a disease or disorder such as breast cancer or glioblastoma, wherein administering of a combination of (Z)- endoxifen and a synergistic compound results in greatly improved treatment of the disease or disorder compared to treatment results seen from either compound alone. In some aspects, the method results in improvement of a level of an objective response rate (ORR), complete response rate, partial response rate, overall survival, or progression-free survival compared to a level observed from treatment with either compound alone. Biomarkers associated with the improvement of cancer or disease treatment include Ki-67, ERa, PR, PKCpi, C-PARP, Cyclin DI, pAKT / total AKT, and ESRI mutations. Other biomarkers are used as appropriate. Additional analyses can include tumor transcriptome sequencing, whole exome sequencing, thymidine kinase levels, E1 / E2 ratios, ctDNA, and lipid / coagulation / bone markers. These biomarkers are assessed at baseline, during treatment, and at surgery to evaluate treatment response and resistance mechanisms. In some aspects, the method results in a reduction of a level of a biomarker associated with cancer progression by at least 10%, 15%, 20%. 25%, 30%, 35%, 40% or greater compared to a baseline or reference level.

[0271] In some aspects, the method results in an improvement of the level of a patient- reported quality of life score compared to a baseline or reference level. 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 includes 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. In some aspects, the method results in the improvement of a quality of life indicator by at least 10%, 15%, 20%. 25%, 30%, 35%, 40% or greater compared to a baseline or reference level.EXAMPLES

[0272] The invention is further illustrated by the following non-limiting examples.EXAMPLE 1Treatment of Pediatric Medulloblastoma Using (Z)-Endoxifen

[0273] This example describes the treatment of pediatric medulloblastoma using (Z)- endoxifen. A pediatric patient diagnosed with pediatric medulloblastoma is administered (Z)- endoxifen and a therapeutic agent. The (Z)-endoxifen is formulated for oral delivery. The (Z)- endoxifen is administered orally once daily for at least 28 days, until the tumor shrinks, untilmetastasis slows, or until unacceptable toxicity is observed. Administration of the (Z)-endoxifen and the therapeutic agent treats the pediatric medulloblastoma in the patient.EXAMPLE 2Treatment of Adult Glioblastoma Multiforme Using (Z)-Endoxifen

[0274] This example describes treatment of adult glioblastoma multiforme using (Z)- endoxifen and a therapeutic agent that targets the MEK, PI3K or mTOR pathways. An adult patient diagnosed with adult glioblastoma multiforme is administered (Z)-endoxifen and the therapeutic agent. The (Z)-endoxifen is formulated for oral delivery. The (Z)-endoxifen is administered orally once daily for at least 28 days, and the therapeutic agent is also administered, until the tumor shrinks, until metastasis slows, or until unacceptable toxicity is observed. Administration of the combination treats the adult glioblastoma multiforme in the patient.

[0275] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.EXAMPLE 3Evaluate the Efficacy of BH3 Mimetics in Combination with (Z)-Endoxifen

[0276] This example describes experiments demonstrating that (Z)-endoxifen silences BCL2 expression in breast cancer cells, and that targeting other BCL2 family members may enhance the efficacy of (Z)-endoxifen and overcome resistance, leading to potential combinatorial therapies.

[0277] Through RNA sequencing of short-term and long-term (Z)-endoxifen treated breast cancer cells, it was found that (Z)-endoxifen quickly and robustly silences BCL2 expression, an effect that persists for the duration of (Z)-endoxifen treatment. Further, (Z)-endoxifen resistant cells also show complete loss of BCL2 expression. BCL2 is a pro-survival factor in cells, suggesting that down-regulation by (Z)-endoxifen may contribute to the initial beneficial effects of this treatment. Using an unbiased and genome -wide CRISPR screen, it was also discovered that silencing the expression of other BCL2 family members (i.e., other anti-apoptotic / pro- survival factors) such as BCL-XL, BCL-W and MCL1, is lethal in the presence of (Z)-endoxifentreatment. These data indicate that strategies to inhibit these BCL2 family members may be more beneficial in models of (Z)-endoxifen resistance compared to sensitive cells and that such strategies may also synergize with (Z)-endoxifen to elicit improved initial responses and decrease the likelihood that a cancer cell escapes the anti-cancer activity of (Z)-endoxifen. Venetoclax, a drug that specifically targets the BCL2 protein, had little to no activity in (Z)- endoxifen resistant cells where BCL2 expression was lost, and did not synergize with (Z)- endoxifen. This is due in part to one of the effects of (Z)-endoxifen, which is to down-regulate BCL2 expression, thereby reducing the target of venetoclax. However, navitoclax, a drug that targets BCL2, BCL-XL and BCL-W, exhibited increased activity in (Z)-endoxifen resistant models and was shown to further decrease viability of cancer cells when combined with (Z)- endoxifen. To further support development of treatment formulations, the contribution of BCL2 family members and related pro-survival factors was characterized in view of mediating resistance to (Z)-endoxifen therapy.

[0278] Efficacy of combinatorial therapies with (Z)-endoxifen was tested first in vitro using multiple estrogen receptor positive cell lines and patient-derived organoids in 2D and 3D culture systems. For those combinatorial approaches that are most effective / promising, we will pursue mechanistically driven approaches to elucidate the basis for the enhanced anti-cancer activity of the combination vs. single agents alone. Such studies will allow us to understand useful factors and nodes of signaling pathways that drive enhanced anti-cancer activity. These pathway members represent predictive / prognostic biomarkers that can inform patient stratification to such treatment regimens and represent mechanisms of escape or resistance following an initial durable response. Towards the goal of studying combination therapies with (Z)-endoxifen in patients, in vivo pre-clinical studies will be performed, aimed at determining treatment schedules, identifying toxicity profiles, developing a tolerable treatment plan, and confirming enhanced efficacy of the combination using multiple cell line and patient-derived xenograft models.EXAMPLE 4Identify Distinct Genomic and Transcriptomic Signatures of (Z)-Endoxifen Persister Cells with Single-Cell Resolution.

[0279] This example describes methods for analyzing genomic and transcriptomic signatures of cells that survive treatment with (Z)-endoxifen.

[0280] (Z)-endoxifen(Z)-endoxifen treatment is cytostatic in nature. (Z)-endoxifen inhibits breast cancer progression by inhibiting cancer cell division. Given the late recurrences observed in patients treated with many different endocrine therapies, as well as in vitro and in vivo data, itis seen that a small population of ER+ breast cancer cells are able to persist for long periods of time despite chronic exposure to (Z)-endoxifen. These persister cells are held in check, but not eliminated, by(Z)-endoxifen treatment, and eventually are able to escape their dormancy prior to or upon termination of treatment, leading to recurrence of the cancer. Characterizing the properties of the small fraction of persister cells following (Z)-endoxifen(Z)-endoxifen treatment helps design strategies to eliminate this persister cell population.

[0281] Understanding the mechanisms of (Z)-endoxifen resistance provides insights into potential therapeutic vulnerabilities. By strategically combining (Z)-endoxifen with agents that target these resistance mechanisms, it is possible to enhance treatment efficacy and overcome resistance. Combination therapies hold promise for improving outcomes in patients with ER+ breast cancer who have developed resistance treatment. To identify (Z)-endoxifen persister cells, an expressed barcoding strategy is used. Briefly, a lentiviral library encoding over 1 million unique and expressed barcodes is applied to cultures of ER+ breast cancer cells followed by immediate randomization to vehicle control or (Z)-endoxifen treatment using an IC90 dose of (Z)-endoxifen. Following chronic exposure, cells are collected and processed in parallel with baseline samples for single cell DNA, RNA and ATAC sequencing using the 10X Genomics platform. Customized bioinformatic pipelines are applied to identify genomic, transcriptomic and epigenetic characteristics of persister cells, as well as to identify the population of cells that are sensitive to (Z)-endoxifen (i.e. those cells that are completely eliminated from the cultures over time).EXAMPLE 5Identify FDA-Approved Drugs that Synergize with (Z)-Endoxifen and Identify Distinct Genomic and Transcriptomic Signatures of (Z)-Endoxifen Persister Cells with Single-Cell Resolution.

[0282] In this example, a “Drug Repurposing Hub” is used to identify compounds that enhance (Z)-endoxifen treatment efficacy in ER+ breast cancer cells, and to validate the findings in additional models. A high throughput approach identifies compounds that enhance the efficacy of (Z)-endoxifen treatment. Regarding the chemical library, a “Drug Repurposing Hub” is used, which is a set of -5,280 compounds, including medically approved drugs, plus preclinical compounds and many others that were safe in initial clinical trials but failed to show efficacy in the disease tested. These compounds ware used to treat ER+ breast cancer cells alone or in combination with (Z)-endoxifen to identify molecules that more potently inhibit / kill breast cancer cells compared to single agent treatments. Following identification of top hits, subsequent studies determine the most effective ratio of drugs and the minimum concentrationsof each drug that elicit potent treatment effects. Subsequently, the validity of the drug combinations will be confirmed in additional ER+ cell lines and patient-derived models.EXAMPLE 6Identify Drug Combinations that Potentiate the Cytotoxic Activity of (Z)-Endoxifen in Breast Cancer through Hi-Content Microscopy Screens

[0283] In this example, drug combinations with (Z)-endoxifen are tested against breast cancer cells and analyzed using high-content microscopy. Effective doses of (Z)-endoxifen are determined in several BC cell lines (including MCF7 and T47D). Effective doses are doses that lead to toxicity and / or cell arrest in a manner that is sufficient to efficiently complete chemical screens in secondary steps. Doses around 1-2 pM are tested in MCF7 cells, and administered for 72-96 hrs.

[0284] The screening is conducted using 384-well plates and a library of medically approved compounds, using an In-Cell HCM system. At the end of the screen, a report is delivered with a prioritized list of drug combinations.

[0285] The conditions for the compound screen include cytotoxicity of (Z)-endoxifen, which is tested in 384-well plates using several ER+ breast cancer cell lines (MCF7, T47D). Nuclei are counted with a DNA staining die, and quantification is performed using an HCM microscope. This part of the project defines the Z-score and assay window, parameters necessary to define the robustness of the assay. A dose of 1-2 pM of (Z)-endoxifen is used.

[0286] A validation screen is conducted with selected hits, including a dose response.

[0287] To screen compounds for synergy with (Z)-endoxifen, 5251 compounds were grown on 18 x 384 well plates in triplicate, for a total of 54 plates in two batches of 27 plates each. MCF-7 cells were seeded in the plates for about 5 hours, then exposed to (Z)-endoxifen at IpM for 96 hours. Cells were then fixed, and nuclei were stained with Hoechst dye. Plates were subjected to high-throughput microscopy, viability was measured, compounds were ranked, and hits were identified. Results are shown in FIG. 3A and FIG. 3B.

[0288] In 364 well plates (see FIG. 2), cells were incubated with compounds and (Z)- endoxifen and positive and negative controls were included (see FIG. 4A and FIG. 4B). Therapeutic agents for Batch 1 and Batch 2 are listed by method of action in TABLE 2. Results for (Z)-endoxifen, abemaciclib and doxorubicin are shown in FIG. 5 A and FIG. 5B. There were 354 compounds identified as synergistic. When all synergistic hit compounds are considered, some of the methods of action include epidermal growth factor receptor erbB 1 inhibitors, vascular endothelial growth factor receptor inhibitors, DNA topoisomerase I inhibitors, programmed cell death protein 1 inhibitors, vascular endothelial growth factor receptor 2inhibitors, programmed cell death protein 1 antagonists, pI3-kinase class I inhibitors, tubulin inhibitors, receptor protein-tyrosine kinase erbB-2 inhibitors, platelet-derived growth factor receptor inhibitors, FK506-binding protein 1 A inhibitors, stem cell growth factor receptor inhibitors, angiopoietin-2 inhibitors, and estrogen receptor alpha modulators, microtubule inhibitors, mTOR inhibitors, proteasome inhibitors, XIAP inhibitors, kinesin-like spindle protein inhibitors, PLK inhibitors, farnesyltransferase inhibitors, CDK inhibitors, AKT inhibitors, HSP inhibitors, topoisomerase inhibitors, Aurora kinase inhibitors, MEK inhibitors, CHK inhibitors, HDAC inhibitors, SRC inhibitors, PI3K inhibitors, bromodomain inhibitors, protein synthesis inhibitors, and EGFR inhibitors (see FIG. 11 and FIG. 12).

[0289] As shown in FIG. 13, additional compounds were identified acting in hormone therapy pathways, PDE inhibitors, HDAC inhibitors, EGFR inhibitors, FLT3 inhibitors, DNA / thymidylate synthase inhibitors, ALK inhibitors, IGF-1 inhbitors, ABL inhibitors, AKT inhibitors, HMGCR inhibitors, MAPK inhibitors, ABL inhibitors, and dual mTOR / PI3K inhibitors; these are all compounds that exhibit synergy in combination with (Z)-endoxifen.

[0290] Drugs that can treat glioblastoma were tested for interaction with (Z)-endoxifen. 236 drugs were identified that are under investigation for glioblastoma in clinical trials and only 4 drugs are in Phase IV / approved: temozolomide, carmustine, bevacizumab, pembrolizumab.Type of drugs included small molecules (176), antibodies (39), proteins (14), unknown (5), and oligonucleotides (1) (see FIG. 11). Methods of action of glioblastoma drugs in clinical trials include EGFR inhibitors, VEGFR inhibitors, DNA topoisomerase inhibitors, PD-1 inhibitors / antagonists, PI3K inhibitors, Tubulin inhibitors etc. Tamoxifen is the only selective estrogen receptor modulator (SERM) tested up to phase II for glioblastoma (see FIG. 12).

[0291] The combination of a MEK inhibitor and (Z)-endoxifen led to a significant decrease in cancer cell viability (FIG. 14A), as did the combination of a PI3K inhibitor and (Z)-endoxifen (FIG. 14B). Although either compound alone had some inhibitory effect, the combination of (Z)-endoxifen with either an MEK inhibitor or a PI3K inhibitor led to significantly improved and synergistic inhibition.

[0292] There were 59 genes in the G2-M checkpoint signaling pathway which were upregulated in glioblastoma and downregulated after (Z)-endoxifen treatment.

[0293] Antagonistic compounds are compounds that reduce the effect of (Z)-endoxifen, leading to increasing viability of breast cancer cells. Such compounds include estrogen receptor agonists, RAF inhibitors, and some tyrosine kinase inhibitors (see TABLE 1).

[0294] TABLE 1 includes identification about the compounds identified in one of the screening plates as being synergistic with (Z)-endoxifen in breast cancer cells. Results are also summarized in FIG. 7, FIG. 8 and FIG. 9.

[0295] In summary, in the screen of medically approved compounds, therapeutic agents included those that were inhibitors of microtubules, CDK and topoisomerases. Compounds that antagonized the effect of (Z)-endoxifen included estrogen receptor agonists and RAF inhibitors. Compounds were screened at IpM in the presence or absence of 0.5pM (Z)-endoxifen for 4 days.

[0296] TABLE 2 includes viability results from testing of the compounds identified as being synergistic to (Z)-endoxifen in breast cancer cells.

[0297] TABLE 3 includes normalized viabilities and viability ratios of the compounds identified as being synergistic to (Z)-endoxifen in breast cancer cells.

[0298] TABLE 4 is a list of antagonistic compounds grouped by method of action.

[0299] TABLE 5 includes compounds that were identified as antagonistic to (Z)-endoxifen.-Ill-to (Z)-endoxifen.

[0301] TABLE 7 includes normalized measurements for compounds identified as antagonistic to (Z)-endoxifen.EXAMPLE 7Identify Drugs that Synergize with (Z)-Endoxifen

[0302] A high throughput approach to identify compounds that enhance the efficacy of (Z)- endoxifen treatment was conducted. Regarding the chemical library, the “Drug Repurposing Hub” was used, which is a set of about 5,280 compounds defined by the Broad Institute at MIT, and which contains medically approved drugs, plus preclinical compounds and many others that were safe in initial clinical trials but failed to show efficacy in the disease tested.

[0303] These compounds were used to treat ER+ breast cancer cells alone or in combination with (Z)-endoxifen, to identify molecules that more potently inhibit / kill breast cancer cells compared to single agent treatments. Following identification of top hits, subsequent studies were conducted to determine the most effective ratio of drugs, and the minimum concentrations of each drug that elicited potent synergistic effects. Subsequently, we confirmed the validity of the drug combination in additional ER+ cell line and patient derived models.

[0304] Compounds were found that were both effective in combination as well as compounds that were ineffective in combination.

[0305] Results are shown in FIG. 6 A and FIG. 6B for two experiments. On the Y-axis is normalized viability, from a high of 100% to 0%. On the X-axis are the compounds tested for synergy, numbered 1-3000. (Z)-Endoxifen is at a concentration of 0.5 uM while all compounds (expect abemaciclib at 0.1 uM and doxorubicin) are at a concentration of 1 uM. The compounds are ordered from highest combined viability to lowest, and a pattern of about 60% viability for most compounds and only a small number of compounds where the combined viability is low. The mean viability for (Z)-endoxifen for the non-synergistic is determined and shown as a dotted line ‘mean (Z)-endoxifen. ’

[0306] For purposes herein, the definition of “therapeutic agent” is a compound that, when combined with (Z)-endoxifen, produces a viability of more than 3 standard deviations (StD) below the mean (Z)-endoxifen line. As can be seen in these two experiments, both the mean (Z)- endoxifen and the 3 StD line can vary from one experiment to another, but the use of this methodology compensates for this variability and provides a clear definition of a therapeutic agent.EXAMPLE 7Treatment of Glioblastoma with Combination Therapy

[0307] This example describes treatment of glioblastoma with (Z)-endoxifen and an MEK inhibitor, according to the list of synergistic compounds discussed in the present application.

[0308] A 55 -year-old male patient diagnosed with glioblastoma multiforme is selected for a combination therapy involving (Z)-endoxifen and pimasertib. The patient presents with a tumor located in the frontal lobe, confirmed through MRI and biopsy, which reveals the presence of high-grade glioma cells. The patient has undergone initial surgical resection to remove the bulk of the tumor, followed by standard radiotherapy. Despite these interventions, residual tumor cells remain, necessitating further treatment.

[0309] The treatment regimen involves administering (Z)-endoxifen orally at a dose of 20 mg per day. This dosage is chosen based on previous studies indicating its efficacy in crossing the blood-brain barrier and modulating estrogen receptor activity within the brain. Concurrently, the patient receives pimasertib, a MEK inhibitor, at a dose of 60 mg twice daily. Pimasertib is selected for its ability to inhibit the MEK pathway, which is often upregulated in glioblastoma, contributing to tumor cell proliferation and survival.

[0310] The combination therapy is expected to provide a synergistic effect, enhancing the anti-tumor activity of (Z)-endoxifen through the inhibition of complementary pathways. (Z)- Endoxifen downregulates estrogen receptor signaling and modulates the expression of genesinvolved in cell cycle regulation and apoptosis. Pimasertib, on the other hand, inhibits the MEK / ERK pathway, reducing tumor cell proliferation and inducing apoptosis.

[0311] The patient is monitored closely for any adverse effects, with regular blood tests and imaging studies to assess tumor response and overall health. Initial outcomes are promising, with MRI scans showing a reduction in tumor size and decreased metabolic activity within the tumor, as evidenced by PET scans. The patient reports improved neurological function and a reduction in symptoms such as headaches and cognitive impairment.

[0312] Over the course of the treatment, the combination therapy continues to demonstrate efficacy, with further reductions in tumor size and stabilization of the disease. The patient experiences manageable side effects, primarily mild gastrointestinal discomfort and fatigue, which are addressed with supportive care. The overall quality of life improves, and the patient is able to resume daily activities with minimal limitations.

[0313] In summary, the combination of (Z)-endoxifen and pimasertib offers a promising therapeutic approach for treating glioblastoma, leveraging the synergistic effects of targeting both estrogen receptor signaling and the MEK / ERK pathway. This treatment regimen not only reduces tumor burden but also enhances the patient's quality of life, providing a viable option for managing this aggressive form of brain cancer.NUMBERED EMBODIMENTS1. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an oral formulation comprising a therapeutically effective amount of (Z)-endoxifen which is a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof; wherein at least 90% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof, thereby treating the cancer, wherein the cancer is selected from the group consisting of glioblastoma, non-small cell lung cancer, melanoma, pancreatic carcinoma, and medulloblastoma.2. The method of claim 1, wherein the subject is a pediatric subject.3. The method of claim 2, wherein the medulloblastoma is pediatric medulloblastoma.4. The method of claim 1, wherein the glioblastoma is adult glioblastoma multiforme.5. The method of any one of claims 1 to 4, wherein the compound of Formula (I) is >90%(Z)-endoxifen.6. The method of any one of claims 1 to 5, wherein the compound of Formula (I) is >95%, >96%, >97%, >98%, >99%, or >99.5% (Z)-endoxifen.7. The method of any one of claims 1 to 6, wherein the (Z)-endoxifen is in a free base form.8. The method of any one of claims 1 to 7, wherein the pharmaceutically acceptable salt of the (Z)-endoxifen is selected from the group consisting of an: arecoline, besylate, bicarbonate, bitartrate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc salt.9. The method of any one of claims 1 to 8, wherein the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen gluconate.10. The method of any one of claims 1 to 9, wherein the oral formulation is formulated as an enteric formulation.11. The method of any one of claims 1 to 10, wherein the oral formulation is formulated as an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed-release capsule.12. The method of any one of claims 1 to 11, wherein the oral formulation comprises hydroxypropyl methyl cellulose.13. The method of any one of claims 1 to 11, wherein the oral formulation is formulated as a delayed-release composition.14. The method of any one of claims 1 to 13, wherein the oral formulation comprises from 0.01 mg to 200 mg, from 0.1 mg to 100 mg, from 0.1 mg to 50 mg, from 0.1 mg to 20 mg, or from 1 mg to 20 mg of the (Z)-endoxifen.15. The method of any one of claims 1 to 14, further comprising administering an additional therapeutic agent.16. The method of claim 15, wherein the additional therapeutic agent comprises an anticancer agent.17. The method of claim 16, wherein the anti-cancer agent is selected from the group consisting of bicalutamide, 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, and an ATP-cassette binding protein inhibitor.18. The method of claim 15, wherein the additional therapeutic agent comprises a selective serotonin reuptake inhibitor.19. The method of claim 18, wherein the selective serotonin reuptake inhibitor comprises citalopram, escitalopram, fluoxetine, paroxetine, sertraline, or vilazodone.20. A combination formulation comprising (Z)-endoxifen and a therapeutic agent, wherein: (i) the (Z)-endoxifen comprises a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof; and(ii) at least 90% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof, wherein the (Z)-endoxifen is an oral formulation in a form of an enteric tablet, an enteric caplet, an enteric capsule, a microparticle, or a nanoparticle.21. The formulation of claim 20, wherein at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof.22. The formulation of any one of claims 20 to 21, wherein the pharmaceutically acceptable salt of (Z)-endoxifen is selected from the group consisting of: arecoline, besylate, bicarbonate, bitartrate, butylbromide, citrate, camsylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, isethionate, malate, mandelate, mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.23. The formulation of any one of claims 20 to 22, wherein the pharmaceutically acceptable salt of (Z)-endoxifen is (Z)-endoxifen gluconate.24. The formulation of any one of claims 20 to 23, wherein the (Z)-endoxifen is (Z)- endoxifen free base.25. The formulation of any one of claims 20 to 24, wherein the (Z)-endoxifen comprises less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities.26. The formulation of any one of claims 20 to 25, wherein the (Z)-endoxifen is stable for at least 9 months at 25 °C and 60% relative humidity.27. The formulation of any one of claims 20 to 26, wherein the (Z)-endoxifen is stable for at least 3 months at 40 °C and 75% relative humidity.28. The formulation of any one of claims 20 to 27, wherein the (Z)-endoxifen has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL.29. The formulation of any one of claims 20 to 28, wherein the (Z)-endoxifen has a water content of not more than 1.0% as tested by Method Ic of USP 921.30. The formulation of any one of claims 20 to 29, wherein the (Z)-endoxifen has a water activity (Aw) of less than 0.9.31. The formulation of any one of claims 20 to 30, wherein the (Z)-endoxifen has a residue on ignition of not more than 0.1% as tested by a method of USP 281.32. The formulation of any one of claims 20 to 31, wherein the (Z)-endoxifen comprises not more than 20 ppm of heavy metals as tested by Method II of USP 231.33. The formulation of any one of claims 20 to 32, wherein the (Z)-endoxifen 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 n-Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method.34. The formulation of any one of claims 20 to 33, wherein the (Z)-endoxifen 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.35. The formulation of any one of claims 20 to 34, wherein the (Z)-endoxifen: comprises less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities; is stable for at least 9 months at 25 °C and 60% relative humidity; is stable for at least 3 months at 40 °C and 75% relative humidity; has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL; has a water content of not more than 1.0% as tested by Method Ic of USP 921; has a water activity (Aw) of less than 0.9; has a residue on ignition of not more than 0.1% as tested by a method of USP 281; comprises not more than 20 ppm of heavy metals as tested by Method II of USP 231; 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 n-Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method; or any combination thereof.36. The formulation of any one of claims 20 to 35, wherein the (Z)-endoxifen is a delayed- release formulation.37. The formulation of any one of claims 20 to 36, further comprising a sugar, salt, talc, calcium carbonate, microcrystalline cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, or combinations thereof.38. The formulation of any one of claims 20 to 37, further comprising a disintegrant.39. The formulation of any one of claims 20 to 38, further comprising 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.40. The formulation of any one of claims 20 to 39, comprising from 1 mg to 200 mg, 1 mg to 80 mg, 1 mg to 40 mg, or 1 mg to 20 mg of (Z)-cndoxifcn.41. The formulation of any one of claims 20 to 40, comprising from 1 mg, 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg of (Z)-cndoxifcn.42. The formulation of any one of claims 20 to 41, wherein the formulation is uncoated.43. The formulation of any one of claims 20 to 42, further comprising an enteric coating.44. The formulation of any one of claims 20 to 43, wherein the formulation is a suspension.45. The formulation of claim 44, wherein the suspension comprises a syrup or an elixir.46. The formulation of claim 44, wherein the suspension comprises ethanol, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, vegetable oil, stearic acid, sodium lauryl sulfate, or a mixture thereof.47. The formulation of any one of claims 20 to 46, wherein the therapeutic agent is a topoisomerase inhibitor, tubulin polymerization inhibitor, CDK inhibitor, MTOR inhibitor, AKT inhibitor, Aurora kinase inhibitor, EGFR inhibitor, HD AC inhibitor, HSP inhibitor, kinesin inhibitor, MEK inhibitor, PI3K inhibitor, PLK inhibitor, ribonucleotide reductase inhibitor nucleoside analog, microtubule inhibitor, bromodomain inhibitor, proteasome inhibitor, XIAP inhibitor, kinesin-like spindle protein inhibitor, Farnesyltransferase inhibitor, CHK inhibitor, SRC inhibitor, protein synthesis inhibitor, epidermal growth factor receptor erbB 1 inhibitor, vascular endothelial growth factor receptor inhibitor, DNA topoisomerase I inhibitor, programmed cell death protein 1 inhibitor, vascular endothelial growth factor receptor 2 inhibitor, programmed cell death protein 1 antagonist, PI3 -kinase class I inhibitor, tubulin inhibitor, receptor protein-tyrosine kinase erbB2-2 inhibitor, platelet-derived growth factor receptor inhibitor, FK506-b inding protein 1 A inhibitor, stem cell growth factor receptor inhibitor, angiopoietin-2 inhibitor, estrogen receptor alpha modulator, hormone therapy molecule, PDE inhibitor, MAPK inhibitor, FLT3 inhibitor, HMGCR inhibitor, ABL inhibitor, DNA / thymidylate synthase inhibitor, ALK inhibitor, IGF-1 inhibitor, or dual mTOR / PI3K inhibitor.48. The formulation of any one of claims 20 to 47, wherein the therapeutic agent is selected from the group consisting of BAY-11 to 7082, Salinomycin (Procoxacin), Pimasertib (AS- 703026), A66, RO5126766 (CH5126766), ASP3026, RO4987655, PD318088, K-Ras(G12C) inhibitor 12, PIK-93, Ravoxertinib, GDC-0994, Osimertinib, Gilteritinib, Cobimetinib, Duvelisib (IPI-145, INK1197), Tesevatinib, PD173074, Copanlisib, Binimetinib (MEK162, ARRY-162, ARRY-438162), lodophenpropit, U-18666A, ZM-241385, AZD-8835, Trametinib, NVP-TAE226, Atiprimod, AZD4547, NVP-TNKS656, Alpelisib (BYL719), Afatinib (dimaleate), Saracatinib (AZD0530), Tenovin-6, Tubastatin A hydrochloride, L-778123 (hydrochloride), Ascomycin (FK520), AZD8186, GZD824 Dimesylate, Ro 48 to 8071 (fumarate), EW-7197, Dorsomorphin, BAX-channel-blocker, Erbstatin-analog, CH5132799, Hoechst 33258, AT13148, AZD5363, AZD8330, AZ5104, BMS-983970, Dasatinib, Bleomycin sulfate, Maxacalcitol, GSK1059615, Nexturastat A, Ribociclib (LEE011), Etoposide phosphate, NVP-ADW742, Voreloxin (Hydrochloride), Triciribine, LB42708, SM-164, Walrycin B, BMS- 345541, Domiphen Bromide, RepSox, TAK-733, BX-912, LCL161, NVP-AEW541, Lonafamib (SCH66336), Vorinostat (SAHA, MK0683), Quinacrine hydrochloride, Ipatasertib (GDC-0068), GDC-0152, Afuresertib, Falecalcitriol, PRT062607 (P505 to 15, PRT2607, BIIB057) HC1, Prexasertib (dihydrochloride), XL388, MLN8054, SU9516, BNTX, Fedratinib (SAR302503, TG101348), C-021, Taselisib, NSC-3852, Miransertib, MK-2206 dihydrochloride, Resminostat (RAS2410), 5-BrdU, CH55, Carmofur, Bimiralisib, JNJ-7706621, Rapamycin, Tosedostat, Idoxuridin, VS-5584, Uprosertib, M344, Mycophenolate mofetil, XL888, PP-121, LMK-235, CPI-203, MK8745, Apitolisib (GDC-0980, RG7422), GSK690693, Tipifarnib (Zarnestra), Etoposide, Mycophenolic Acid, PD 0332991 (Palbociclib) HC1, 1-BET151 (GSK1210151A), Pemetrexed, AZ20, Phortress, PHA-848125, MPI-0479605, OSI-027, Ingenol mebutate, Cevipabulin, FK-866, APY-29, LY3023414, Ixazomib citrate, Belinostat (PXD101), Crenolanib (CP-868596), 6,7-Dihydroxy-l-(4-Hydroxybenzyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride, (+)-JQl, AZD3463, BET-BAY 002, GDC-0349, VX-680 (MK-0457, Tozasertib), GSK1070916, Gentian violet, Combretastatin-A4, UNC2025 (hydrochloride), Satraplatin, BMS-566419, Cycloheximide, Digitoxigenin, ABT-751 (E7010), 3- Deazaneplanocin A (DZNeP) HC1, Abemaciclib (LY2835219), AZD7762, WYE-687, AP26113, Hesperadin, PHA-680632, Basic fuchsin, Diphenyleneiodonium, MK-1775, Clofarabine, AZD6738, Bisacodyl, NVP-HSP990, NSC319726, Epothilone D, PHA-767491, AR-42 (HDAC-42), AMG 232, Barasertib (AZDI 152-HQPA), Teniposide, KW-2478, 1-BET-762, Strophantidin, Amsacrine, CC-115, Ganetespib (STA-9090), Filanesib, NMS-E973, BNC105, Torin 1, Aphidicolin, Vinorelbine (ditartrate), XL228, PF-05212384 (PKI-587), 17-AAG (Tanespimycin), 5 -Fluoro-2-deoxy cytidine, Trifluridine, GSK461364, Digoxigenin, Colchicine,MK-8776 (SCH 900776), SB-268262, R547, PF-03814735, Gemcitabine (elaidate), AT9283, Cyclocytidine HC1, Fosbretabulin (disodium), CGP-74514, VER-49009, Retaspimycin (Hydrochloride), BML-284, Cytarabine, Briciclib, Mivobulin, Ixazomib citrate (MLN9708), Verubulin, PF-3758309, LY2334737, Floxuridine, WYE-125132, Topotecan (hydrochloride), Torin-2, KX2 to 391, Ixazomib (MLN2238), Pevonedistat hydrochloride, Camptothecin, Gemcitabine, Irinotecan, Ispinesib (SB-715992), AZDI 152, TAK-901, NMS-1286937, Taltobulin (trifluoroacetate), Onalespib (AT13387), Danusertib (PHA-739358), 17-DMAG HC1 (Alvespimycin), PD-166285, Ixabepilone, Vincristine (sulfate), MLN8237 (Alisertib), Vinblastine (sulfate), Oprozomib (ONX 0912), Ansamitocin P-3, Vistusertib (AZD2014), CHIR-124, TAS-103 (dihydrochloride), ER-27319 maleate, PU-H71, Vindesine Sulfate, Nampt- IN-1, Raltitrexed (Tomudex), BI6727 (Volasertib), Litronesib, Omipalisib (GSK2126458, GSK458), PF-04691502, PHA-793887, Luminespib, INK 128 (MLN0128), SNX-2112, SB- 743921, CYT997, PF-04929113 (SNX-5422), AZD5438, Proflavine hemisulfate, Patupilone (EPO906, Epothilone B), A-674563, LY2090314, Plinabulin, Talazoparib (BMN 673), Torkinib (PP242), Genz-644282, ARQ 621, Pralatrexate (Folotyn), Selinexor (KPT-330), R306465, and HMN-214.49. The formulation of claim 48, comprising from 0.01 mg to 1000 mg of the therapeutic agent.50. The formulation of claim 49, comprising from 0.01 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 40 mg, 40 mg to 80 mg, 80 mg to 150 mg, 150 mg to 300 mg, 300 mg to 800 mg, 800 mg to 1000 mg of the therapeutic agent.51. The formulation of claim 48 or 49, wherein the therapeutic agent is formulated as an oral formulation, an intramuscular injection, a subcutaneous injection, an intrathecal injection, or an intravenous infusion.52. The oral formulation of any one of claims 20 to 51, wherein the therapeutic agent and the (Z)-endoxifen are administered in a single combination formulation.53. The oral formulation of any one of claims 20 to 52, wherein the therapeutic agent and the (Z)-endoxifen are administered in separate formulations.54. A combination formulation comprising (Z)-endoxifen and a synergistic compound, wherein: the (Z)-endoxifen comprises a compound of Formula (I):or a pharmaceutically acceptable salt thereof; and at least 90% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof, wherein the (Z)-endoxifen is an oral formulation in a form of an enteric tablet, an enteric caplet, an enteric capsule, microparticles, or nanoparticles.55. A method of treating a disease or condition in a subject in need thereof, comprising administering the oral formulation of any one of claims 20 to 54, thereby treating the disease or condition.56. The method of claim 55, wherein the administering of the formulation results in a plasma (Z)-cndoxi fen level greater than 40 nM per 1 mg of (Z)-endoxifen administered.57. The method of any one of claims 55 to 56, comprising administering 1 mg to 200 mg, 1 mg to 80 mg, 1 mg to 40 mg, or 1 mg to 20 mg of (Z)-endoxifen per day.58. The method of any one of claims 55 to 57, comprising administering 1 mg, 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg of (Z)- endoxifen per day.59. The method of any one of claims 55 to 58, comprising administering a dose of 0.05 mg / kg to 10 mg / kg of (Z)-endoxifen per day.60. The method of claim 59, comprising administering a dose of 0.05 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.8 mg / kg, 2 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.8 mg / kg, or 3 mg / kg of (Z)-endoxifen per day.61. The method of any one of claims 55 to 60, wherein the administering of the formulation maintains a plasma level of (Z)-endoxifen of the subject at a steady state level above 30 nM.62. The method of claim 61, wherein the administering of the formulation maintains the plasma level at a steady state level from 30 nM to 1000 nM.63. The method of any one of claims 55 to 62, further comprising releasing no more than 10% of the (Z)-cndoxifcn in a stomach of the subject within 2 hours following the administering of the oral formulation.64. The method of any one of claims 55 to 63, further comprising releasing at least 50% of the (Z)-cndoxifcn in a small intestine of the subject within 8 hours following the administering of the oral formulation.65. The method of any one of claims 55 to 64, further comprising producing an area under curve (AUCo-inf) of (Z)-endoxifen in the subject of from 200 hr* ng / mL to 10,000 hr* ng / mL per 4 mg of (Z)-endoxifen administered.66. The method of any one of claims 55 to 65, further comprising producing a maximum blood plasma concentration (Cmax) of (Z)-endoxifen in the subject of from 14 ng / mL to 62 ng / mL per 4 mg of (Z)-endoxifen administered.67. The method of any one of claims 55 to 66, comprising administering from 0.01 mg to 1000 mg of the therapeutic agent per day.68. The method of claim 67, comprising administering from 0.01 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 40 mg, 40 mg to 80 mg, 80 mg to 150 mg, 150 mg to 300 mg, 300 mg to 800 mg, 800 mg to 1000 mg of the therapeutic agent per day.69. The method of claim 67 or 68, comprising administering from 0.01 mg / kg to 10 mg / kg of the therapeutic agent per day.70. The method of any one of claims 67 to 69, comprising administering from 0.01 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 1.5 mg / kg, 1.5 mg / kg to 2 mg / kg, 2 mg / kg to 2.5 mg / kg, or 2.5 to 3 mg / kg of the therapeutic agent per day.71. The method of any one of claims 67 to 70, wherein the therapeutic agent is administered every day, every other day, every third day, biweekly, weekly, biweekly, monthly, bimonthly, every three months, every six months, or yearly.72. The method of any one of claims 55 to 71, wherein the disease or disorder is a cancer.73. The method of claim 72, wherein the cancer is glioblastoma, non-small cell lung cancer, melanoma, pancreatic carcinoma, medulloblastoma, pancreatic carcinoma, prostate carcinoma, gastric carcinoma, esophageal cancer, osteosarcoma, endometrial cancer, ovarian cancer, uterinecancer, cervical cancer, vaginal cancer, vulvar cancer, breast cancer, ductal carcinoma, lobular carcinoma, or urinary bladder cancer.74. The method of any one of claims 55 to 66, wherein the disease or disorder is a hormonedependent breast disorder or a hormone-dependent reproductive tract disorder.75. The method of claim 74, wherein the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, ductal carcinoma in situ, lobular carcinoma in situ, breast cancer, precocious puberty, McCune- Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.76. The method of claim 74 or claim 46, wherein the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is tamoxifen-refractory or tamoxifen resistant.77. The method of any one of claims 55 to 76, wherein the administering of the formulation results in a synergistic treatment of the disease or disorder.78. The method of any one of claims 55 to 77, wherein the method results in improvement of an objective response rate (ORR), complete response rate, partial response rate, overall survival, or progression-free survival compared to treatment with either compound alone.79. The method of any one of claims 55 to 77, wherein the method results in a reduction of a level of a biomarker associated with cancer progression by at least 20% compared to a baseline or reference level.80. The method of any one of claims 55 to 77, wherein the method results in an improvement of a level of a patient-reported quality of life score compared to a baseline or reference level.

[0314] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of theinvention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWhat is claimed is:

1. A combination formulation comprising (Z)-endoxifen and a therapeutic agent, wherein: the (Z)-endoxifen comprises a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof; and at least 90% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof, wherein the (Z)-endoxifen is an oral formulation.

2. The combination formulation of claim 1, wherein the (Z)-endoxifen is formulated as a suspension, a powder, an enteric tablet, an enteric caplet, an enteric capsule, a microparticle, or a nanoparticle.

3. The combination formulation of claim 1 or 2, wherein at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9% by weight of the compound of Formula (I) is (Z)- endoxifen or a pharmaceutically acceptable salt thereof.

4. The combination formulation of any one of claims 1 to 3, wherein the pharmaceutically acceptable salt of (Z)-endoxifen is selected from the group consisting of: arecoline, besylate, bicarbonate, bitartrate, butylbromide, citrate, camsylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, isethionate, malate, mandelate, mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

5. The combination formulation of any one of claims 1 to 4, wherein the pharmaceutically acceptable salt of (Z)-endoxifen is (Z)-endoxifen gluconate.

6. The combination formulation of any one of claims 1 to 5, wherein the (Z)-endoxifen is (Z)-endoxifen free base.

7. The combination formulation of any one of claims 1 to 6, wherein the (Z)-endoxifen comprises less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities.

8. The combination formulation of any one of claims 1 to 7, wherein the (Z)-endoxifen is stable for at least 9 months at 25 °C and 60% relative humidity.

9. The combination formulation of any one of claims 1 to 8, wherein the (Z)-endoxifen is stable for at least 3 months at 40 °C and 75% relative humidity.

10. The combination formulation of any one of claims 1 to 9, wherein the (Z)-endoxifen has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL.

11. The combination formulation of any one of claims 1 to 10, wherein the (Z)-endoxifen has a water content of not more than 1.0% as tested by Method Ic of USP 921.

12. The combination formulation of any one of claims 1 to 11, wherein the (Z)-endoxifen has a water activity (Aw) of less than 0.9.

13. The combination formulation of any one of claims 1 to 12, wherein the (Z)-endoxifen has a residue on ignition of not more than 0.1% as tested by a method of USP 281.

14. The combination formulation of any one of claims 1 to 13, wherein the (Z)-endoxifen comprises not more than 20 ppm of heavy metals as tested by Method II of USP 231.

15. The combination formulation of any one of claims 1 to 14, wherein the (Z)-endoxifen 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 n- Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method.

16. The combination formulation of any one of claims 1 to 15, wherein the (Z)-endoxifen 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.

17. The combination formulation of any one of claims 1 to 16, wherein the (Z)-endoxifen: comprises less than 2%, less than 1.5%, less than 1%, or less than 0.5% impurities; is stable for at least 9 months at 25 °C and 60% relative humidity;is stable for at least 3 months at 40 °C and 75% relative humidity; has an aerobic bacterial plate count of 0.05 g / mL to 20,000 g / mL; has a water content of not more than 1.0% as tested by Method Ic of USP 921; has a water activity (Aw) of less than 0.9; has a residue on ignition of not more than 0.1% as tested by a method of USP 281; comprises not more than 20 ppm of heavy metals as tested by Method II of USP 231; 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 n-Heptane, not more than 5000 ppm ethanol, or any combination thereof, as tested by a validated HPLC method; or any combination thereof.

18. The combination formulation of any one of claims 1 to 17, wherein the (Z)-endoxifen is a delayed-release formulation.

19. The combination formulation of any one of claims 1 to 18, further comprising a sugar, salt, talc, calcium carbonate, microcrystalline cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, or a combination thereof.

20. The combination formulation of any one of claims 1 to 19, further comprising a disintegrant.

21. The combination formulation of any one of claims 1 to 20, further comprising 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 a combination thereof.

22. The combination formulation of any one of claims 1 to 21, comprising from 1 mg to 200 mg, 1 mg to 80 mg, 1 mg to 40 mg, or 1 mg to 20 mg of (Z)-endoxifen.

23. The combination formulation of any one of claims 1 to 22, comprising from 1 mg, 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg of (Z)- endoxifen.

24. The combination formulation of any one of claims 1 to 23, wherein the oral formulation is uncoated.

25. The combination formulation of any one of claims 1 to 24, wherein the oral formulation further comprises an enteric coating.

26. The combination formulation of any one of claims 1 to 25, wherein the oral formulation is formulated as a suspension.

27. The combination formulation of claim 26, wherein the suspension comprises a syrup or an elixir.

28. The combination formulation of claim 26 or 27, wherein the suspension comprises ethanol, mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, vegetable oil, stearic acid, sodium lauryl sulfate, or a mixture thereof.

29. The combination formulation of any one of claims 1 to 28, wherein the therapeutic agent is a topoisomerase inhibitor, a tubulin polymerization inhibitor, a CDK inhibitor, an MTOR inhibitor, an AKT inhibitor, an Aurora kinase inhibitor, an EGFR inhibitor, an HD AC inhibitor, an HSP inhibitor, a kinesin inhibitor, a MEK inhibitor, a PI3K inhibitor, a PLK inhibitor, a ribonucleotide reductase inhibitor, a nucleoside analog, a microtubule inhibitor, a bromodomain inhibitor, a proteasome inhibitor, an XIAP inhibitor, a kinesin-like spindle protein inhibitor, a Famesyltransferase inhibitor, a CHK inhibitor, an SRC inhibitor, a protein synthesis inhibitor, an epidermal growth factor receptor erbB 1 inhibitor, a vascular endothelial growth factor receptor inhibitor, a DNA topoisomerase I inhibitor, a programmed cell death protein 1 inhibitor, a vascular endothelial growth factor receptor 2 inhibitor, a programmed cell death protein 1 antagonist, a PI3 -kinase class I inhibitor, a tubulin inhibitor, a receptor protein-tyrosine kinase erbB2-2 inhibitor, a platelet- derived growth factor receptor inhibitor, an FK506-binding protein 1 A inhibitor, a stem cell growth factor receptor inhibitor, an angiopoietin-2 inhibitor, an estrogen receptor alpha modulator, a hormone therapy molecule, a PDE inhibitor, a MAPK inhibitor, an FLT3 inhibitor, an HMGCR inhibitor, an ABL inhibitor, a DNA / thymidylate synthase inhibitor, an ALK inhibitor, an IGF-1 inhibitor, or a dual mT0R / PI3K inhibitor.

30. The combination formulation of any one of claims 1 to 29, wherein the therapeutic agent is selected from the group consisting of BAY- 11 to 7082, Salinomycin (Procoxacin), Pimasertib (AS-703026), A66, RO5126766 (CH5126766), ASP3026, RO4987655, PD318088, K- Ras(G12C) inhibitor 12, PIK-93, Ravoxertinib, GDC-0994, Osimertinib, Gilteritinib, Cobimetinib, Duvelisib (IPI-145, INK1197), Tesevatinib, PD173074, Copanlisib, Binimetinib (MEK162, ARRY-162, ARRY-438162), lodophenpropit, U-18666A, ZM-241385, AZD-8835,Trametinib, NVP-TAE226, Atiprimod, AZD4547, NVP-TNKS656, Alpelisib (BYL719), Afatinib (dimaleate), Saracatinib (AZD0530), Tenovin-6, Tubastatin A hydrochloride, L-778123 (hydrochloride), Ascomycin (FK520), AZD8186, GZD824 Dimesylate, Ro 48 to 8071 (fumarate), EW-7197, Dorsomorphin, BAX-channel-blocker, Erbstatin-analog, CH5132799, Hoechst 33258, AT13148, AZD5363, AZD8330, AZ5104, BMS-983970, Dasatinib, Bleomycin sulfate, Maxacalcitol, GSK1059615, Nexturastat A, Ribociclib (LEE011), Etoposide phosphate, NVP-ADW742, Voreloxin (Hydrochloride), Triciribine, LB42708, SM-164, Walrycin B, BMS- 345541, Domiphen Bromide, RepSox, TAK-733, BX-912, LCL161, NVP-AEW541, Lonafamib (SCH66336), Vorinostat (SAHA, MK0683), Quinacrine hydrochloride, Ipatasertib (GDC-0068), GDC-0152, Afuresertib, Falecalcitriol, PRT062607 (P505 to 15, PRT2607, BIIB057) HC1, Prexasertib (dihydrochloride), XL388, MLN8054, SU9516, BNTX, Fedratinib (SAR302503, TG101348), C-021, Taselisib, NSC-3852, Miransertib, MK-2206 dihydrochloride, Resminostat (RAS2410), 5-BrdU, CH55, Carmofur, Bimiralisib, JNJ-7706621, Rapamycin, Tosedostat, Idoxuridin, VS-5584, Uprosertib, M344, Mycophenolate mofetil, XL888, PP-121, LMK-235, CPI-203, MK8745, Apitolisib (GDC-0980, RG7422), GSK690693, Tipifarnib (Zarnestra), Etoposide, Mycophenolic Acid, PD 0332991 (Palbociclib) HC1, 1-BET151 (GSK1210151A), Pemetrexed, AZ20, Phortress, PHA-848125, MPI-0479605, OSI-027, Ingenol mebutate, Cevipabulin, FK-866, APY-29, LY3023414, Ixazomib citrate, Belinostat (PXD101), Crenolanib (CP-868596), 6,7-Dihydroxy-l-(4-Hydroxybenzyl)-l,2,3,4-tetrahydroisoquinoline hydrochloride, (+)-JQl, AZD3463, BET-BAY 002, GDC-0349, VX-680 (MK-0457, Tozasertib), GSK1070916, Gentian violet, Combretastatin-A4, UNC2025 (hydrochloride), Satraplatin, BMS-566419, Cycloheximide, Digitoxigenin, ABT-751 (E7010), 3-Deazaneplanocin A (DZNeP) HC1, Abemaciclib (LY2835219), AZD7762, WYE-687, AP26113, Hesperadin, PHA-680632, Basic fuchsin, Diphenyleneiodonium, MK-1775, Clofarabine, AZD6738, Bisacodyl, NVP-HSP990, NSC319726, Epothilone D, PHA-767491, AR-42 (HDAC-42), AMG 232, Barasertib (AZDI 152-HQPA), Teniposide, KW-2478, 1-BET-762, Strophantidin, Amsacrine, CC-115, Ganetespib (STA-9090), Filanesib, NMS-E973, BNC105, Torin 1, Aphidicolin, Vinorelbine (ditartrate), XL228, PF-05212384 (PKI-587), 17-AAG (Tanespimycin), 5 -Fluoro-2-deoxy cytidine, Trifluridine, GSK461364, Digoxigenin, Colchicine, MK-8776 (SCH 900776), SB-268262, R547, PF-03814735, Gemcitabine (elaidate), AT9283, Cyclocytidine HC1, Fosbretabulin (disodium), CGP-74514, VER-49009, Retaspimycin (Hydrochloride), BML-284, Cytarabine, Briciclib, Mivobulin, Ixazomib citrate (MLN9708), Verubulin, PF-3758309, LY2334737, Floxuridine, WYE-125132, Topotecan (hydrochloride), Torin-2, KX2 to 391, Ixazomib (MLN2238), Pevonedistat hydrochloride, Camptothecin, Gemcitabine, Irinotecan, Ispinesib (SB-715992), AZDI 152, TAK-901, NMS-1286937,Taltobulin (trifluoroacetate), Onalespib (AT13387), Danusertib (PHA-739358), 17-DMAG HC1 (Alvespimycin), PD-166285, Ixabepilone, Vincristine (sulfate), MLN8237 (Alisertib), Vinblastine (sulfate), Oprozomib (ONX 0912), Ansamitocin P-3, Vistusertib (AZD2014), CHIR-124, TAS-103 (dihydrochloride), ER-27319 maleate, PU-H71, Vindesine Sulfate, Nampt- IN-1, Raltitrexed (Tomudex), BI6727 (Volasertib), Litronesib, Omipalisib (GSK2126458, GSK458), PF-04691502, PHA-793887, Luminespib, INK 128 (MLN0128), SNX-2112, SB- 743921, CYT997, PF-04929113 (SNX-5422), AZD5438, Proflavine hemisulfate, Patupilone (EPO906, Epothilone B), A-674563, LY2090314, Plinabulin, Talazoparib (BMN 673), Torkinib (PP242), Genz-644282, ARQ 621, Pralatrexate (Folotyn), Selinexor (KPT-330), R306465, and HMN-214.

31. The combination formulation of claim 30, comprising from 0.01 mg to 1000 mg of the therapeutic agent.

32. The combination formulation of claim 31, comprising from 0.01 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 40 mg, 40 mg to 80 mg, 80 mg to 150 mg, 150 mg to 300 mg, 300 mg to 800 mg, 800 mg to 1000 mg of the therapeutic agent.

33. The combination formulation of claim 30 or 31, wherein the therapeutic agent is formulated as an oral formulation, an intramuscular injection, a subcutaneous injection, an intrathecal injection, or an intravenous infusion.

34. The combination formulation of any one of claims 1 to 33, wherein the therapeutic agent and the (Z)-endoxifen are administered in a single combination formulation.

35. The combination formulation of any one of claims 1 to 33, wherein the therapeutic agent and the (Z)-endoxifen are administered in separate formulations.

36. A combination formulation comprising (Z)-endoxifen and a synergistic compound, wherein: the (Z)-endoxifen comprises a compound of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof; andat least 90% by weight of the compound of Formula (I) is (Z)-endoxifen or a pharmaceutically acceptable salt thereof, wherein the (Z)-endoxifen is an oral formulation.

37. The combination formulation of claim 36, wherein the (Z)-endoxifen is formulated as a suspension, a powder, an enteric tablet, an enteric caplet, an enteric capsule, a microparticle, or a nanoparticle.

38. A method of treating a disease or condition in a subject in need thereof, comprising administering the combination formulation of any one of claims 1 to 37, thereby treating the disease or condition.

39. The method of claim 38, wherein the administering of the combination formulation results in a plasma (Z)-endoxifen level greater than 40 nM per 1 mg of (Z)-endoxifen administered.

40. The method of claim 38 or 39, comprising administering 1 mg to 200 mg, 1 mg to 80 mg, 1 mg to 40 mg, or 1 mg to 20 mg of (Z)-endoxifen per day.

41. The method of any one of claims 38 to 40, comprising administering 1 mg, 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg of (Z)- endoxifen per day.

42. The method of any one of claims 38 to 41, comprising administering a dose of 0.05 mg / kg to 10 mg / kg of (Z)-endoxifen per day.

43. The method of claim 42, comprising administering a dose of 0.05 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.8 mg / kg, 2 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.8 mg / kg, or 3 mg / kg of (Z)-endoxifen per day.

44. The method of any one of claims 38 to 43, wherein the administering of the combination formulation maintains a plasma level of (Z)-endoxifen of the subject at a steady state level above 30 nM.

45. The method of claim 44, wherein the administering of the combination formulation maintains the plasma level at a steady state level from 30 nM to 1000 nM.

46. The method of any one of claims 38 to 45, further comprising releasing no more than 10% of the (Z)-cndoxifcn in a stomach of the subject within 2 hours following the administering of the combination formulation.

47. The method of any one of claims 38 to 46, further comprising releasing at least 50% of the (Z)-cndoxifcn in a small intestine of the subject within 8 hours following the administering of the combination formulation.

48. The method of any one of claims 38 to 47, further comprising producing an area under curve (AUCo-inf) of (Z)-endoxifen in the subject of from 200 hr* ng / mL to 10,000 hr* ng / mL per 4 mg of (Z)-endoxifen administered.

49. The method of any one of claims 38 to 48, further comprising producing a maximum blood plasma concentration (Cmax) of (Z)-endoxifen in the subject of from 14 ng / mL to 62 ng / mL per 4 mg of (Z)-endoxifen administered.

50. The method of any one of claims 38 to 49, comprising administering from 0.01 mg to 1000 mg of the therapeutic agent per day.

51. The method of claim 50, comprising administering from 0.01 mg to 5 mg, 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 40 mg, 40 mg to 80 mg, 80 mg to 150 mg, 150 mg to 300 mg, 300 mg to 800 mg, 800 mg to 1000 mg of the therapeutic agent per day.

52. The method of claim 50 or 51, comprising administering from 0.01 mg / kg to 10 mg / kg of the therapeutic agent per day.

53. The method of any one of claims 50 to 52, comprising administering from 0.01 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 1.5 mg / kg, 1.5 mg / kg to 2 mg / kg, 2 mg / kg to 2.5 mg / kg, or 2.5 to 3 mg / kg of the therapeutic agent per day.

54. The method of any one of claims 50 to 53, wherein the therapeutic agent is administered every day, every other day, every third day, biweekly, weekly, biweekly, monthly, bimonthly, every three months, every six months, or yearly.

55. The method of any one of claims 38 to 54, wherein the disease or disorder is a cancer.

56. The method of claim 55, wherein the cancer is glioblastoma, non-small cell lung cancer, melanoma, pancreatic carcinoma, medulloblastoma, pancreatic carcinoma, prostate carcinoma, gastric carcinoma, esophageal cancer, osteosarcoma, endometrial cancer, ovarian cancer, uterinecancer, cervical cancer, vaginal cancer, vulvar cancer, breast cancer, ductal carcinoma, lobular carcinoma, or urinary bladder cancer.

57. The method of any one of claims 38 to 49, wherein the disease or disorder is a hormonedependent breast disorder or a hormone-dependent reproductive tract disorder.

58. The method of claim 57, wherein the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is a benign breast disorder, hyperplasia, atypia, atypical ductal hyperplasia, atypical lobular hyperplasia, increased breast density, gynecomastia, ductal carcinoma in situ, lobular carcinoma in situ, breast cancer, precocious puberty, McCune- Albright Syndrome, endometrial cancer, ovarian cancer, uterine cancer, cervical cancer, vaginal cancer, or vulvar cancer.

59. The method of claim 57 or claim 46, wherein the hormone-dependent breast disorder or the hormone-dependent reproductive tract disorder is tamoxifen-refractory or tamoxifen resistant.

60. The method of any one of claims 38 to 59, wherein the administering of the combination formulation results in a synergistic treatment of the disease or disorder.

61. The method of any one of claims 38 to 60, wherein the method results in improvement of an objective response rate (ORR), complete response rate, partial response rate, overall survival, or progression-free survival compared to treatment with either compound alone.

62. The method of any one of claims 38 to 60, wherein the method results in a reduction of a level of a biomarker associated with cancer progression by at least 20% compared to a baseline or reference level.

63. The method of any one of claims 38 to 60, wherein the method results in an improvement of a level of a patient-reported quality of life score compared to a baseline or reference level.

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