Endoxifen for the treatment of cancer

Abstract

Described herein are endoxifen compositions and methods of using endoxifen compositions for treating various cancers.Endoxifen compositions can be used to treat cancers such as skin cancer, digestive cancer, neuroblastoma, breast cancer, cervical cancer, or ovarian cancer.Methods of treating various cancers can include administering endoxifen to a subject with skin cancer, digestive cancer, neuroblastoma, breast cancer, cervical cancer, or ovarian cancer.In various aspects, the present disclosure provides a method of treating digestive cancer in a subject in need thereof, the method comprising administering a therapeutically effective amount of endoxifen to the subject, thereby treating the digestive cancer.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 272,869, entitled "ENDOXIFEN FOR TREATMENT OF CANCERS," filed on October 28, 2021, and is hereby incorporated by reference in its entirety for all purposes. [Background technology]

[0002] Although cancer survival rates have increased over the past several decades, cancer remains the second leading cause of death in the United States. Despite extensive research into treatment and prevention, drug resistance and recurrence remain limiting factors in the development of cancer therapies. To combat these and other factors, cancer therapies that can overcome drug resistance and prevent recurrence are needed. Summary of the Invention [Means for solving the problem]

[0003] In various aspects, the present disclosure provides a method of treating gastrointestinal cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of endoxifen, thereby treating the gastrointestinal cancer.

[0004] In some embodiments, the digestive cancer is colorectal cancer, gastric cancer, pancreatic cancer, esophageal cancer, rectal cancer, biliary tract cancer, bile duct cancer, or a combination thereof. In some embodiments, the digestive cancer is carcinoma. In some embodiments, the digestive cancer is adenocarcinoma. In some embodiments, the digestive cancer is colon cancer. In some embodiments, the digestive cancer is colon cancer. In some embodiments, the colon cancer is sigmoid colon cancer, adenocarcinoma of the colon, stage III colon cancer, stage IV colon cancer, or descending colon cancer. In some embodiments, the colon cancer is colon cancer, sigmoid colon cancer, adenocarcinoma of the colon, stage III colon cancer, stage IV colon cancer, or descending colon cancer.

[0005] In some embodiments, the gastrointestinal cancer is gastric cancer. In some embodiments, the gastrointestinal cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, or stage III metastatic pancreatic ductal adenocarcinoma.

[0006] In some aspects, the gastrointestinal cancer is esophageal cancer. In some aspects, the esophageal cancer is esophageal adenocarcinoma or metastatic esophageal cancer. In some aspects, the gastrointestinal cancer is rectal cancer. In some aspects, the rectal cancer is rectal adenocarcinoma. In some aspects, the gastrointestinal cancer is cholangiocarcinoma. In some aspects, the cholangiocarcinoma is metastatic cholangiocarcinoma. In some aspects, the gastrointestinal cancer is metastatic. In some aspects, the gastrointestinal cancer is recurrent.

[0007] In various aspects, the present disclosure provides a method of treating skin cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of endoxifen, thereby treating the skin cancer.

[0008] In some aspects, the skin cancer is melanoma. In some aspects, the melanoma is acral melanoma, recurrent acral melanoma, or anorectal melanoma. In some aspects, the skin cancer is metastatic. In some aspects, the skin cancer is recurrent.

[0009] In various aspects, the disclosure provides a method of treating neuroblastoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of endoxifen, thereby treating the neuroblastoma.

[0010] In some aspects, the neuroblastoma is metastatic. In some aspects, the neuroblastoma is recurrent.

[0011] In some embodiments, endoxifen is (Z)-endoxifen. In some embodiments, the (Z)-endoxifen has an isomeric purity of at least 90%. In some embodiments, endoxifen is administered orally, topically, rectally, intravenously, intraarterially, parenterally, transdermally, or by inhalation. In some embodiments, endoxifen is administered orally. In some embodiments, endoxifen is formulated as a sustained or delayed release composition. In some embodiments, endoxifen is formulated as a capsule or tablet. In some embodiments, endoxifen is administered topically or transdermally. In some embodiments, endoxifen is formulated as a cream, gel, cream, emulsion, lotion, ointment, solution, paste, patch, or oil.

[0012] In some embodiments, the method includes administering endoxifen to the subject daily. In some embodiments, the method includes administering endoxifen to the subject at a dose of 1 mg to 160 mg per day. In some embodiments, the method includes administering endoxifen to the subject at a dose of 1 mg to 40 mg per day. In some embodiments, the method includes administering endoxifen to the subject at a dose of 1 mg to 10 mg per day. In some embodiments, the method includes administering endoxifen to the subject at a dose of 2 mg to 5 mg per day. In some embodiments, the method includes administering endoxifen once, twice, three times, or four times per day. In some embodiments, the method includes administering endoxifen for at least 7 days, at least 14 days, at least 21 days, or at least 28 days.

[0013] In some embodiments, administration results in a systemic endoxifen C of about 0.01 μM to about 50 μM in the subject. max In some embodiments, administration achieves a systemic endoxifen C concentration of about 1 μM to about 10 μM in the subject. maxIn some embodiments, the administration maintains a systemic endoxifen concentration of at least 1 μM in the subject for at least one week.

[0014] In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises an anti-cancer agent. In some embodiments, the anti-cancer agent is selected from the group consisting of bicalutamide, enzalutamide, trastuzumab, atezolizumab, alpelisib, olaparib, talazoparib, ribociclib, neratinib, antineoplastic agents, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, fluorouracil, gemcitabine, methotrexate, paclitaxel, protein-bound paclitaxel, vinorelbine, eribulin, ixabepilone, immune checkpoint inhibitors, PD1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, and ATP cassette binding protein inhibitors. In some embodiments, the additional therapeutic agent comprises a selective serotonin reuptake inhibitor. In some embodiments, the selective serotonin reuptake inhibitor comprises citalopram, escitalopram, fluoxetine, paroxetine, sertraline, or vilazodone.

[0015] In some embodiments, the method further comprises surgical tumor removal. In some embodiments, administering a therapeutically effective amount of endoxifen occurs simultaneously, after, or both with surgical tumor removal. In some embodiments, the method further comprises radiation therapy. In some embodiments, administering a therapeutically effective amount of endoxifen occurs simultaneously, after, or both with radiation therapy.

[0016] Incorporation by Reference 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.

[0017] This patent or application contains at least one drawing executed in color. Copies of this patent or patent application publication containing color drawing(s) will be provided by the Patent Office upon request and payment of the necessary fee. 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 illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings in which: [Brief description of the drawings]

[0018] [Figure 1] Histograms showing the number of samples from patients diagnosed with various cancer types, including breast cancer (BRST), cervical cancer (CC), cholangiocarcinoma (CHOL), colorectal cancer (CRC), esophageal adenocarcinoma (EAC), endometrial cancer (EC), gastric cancer (GASC), leiomyosarcoma (LYMSC), myxofibrosarcoma (MFSC), melanoma (MLNM), neuroblastoma (NBL), ovarian cancer (OVA), pancreatic ductal adenocarcinoma (PDAC), primary peritoneal cancer (PPC), rectal cancer (RC), sarcoma (SC), and thyroid cancer (THYRD), that were screened for endoxifen response using a personalized cancer therapy screening assay. The shaded areas of the histogram bars represent the response category of the individual patient sample to endoxifen as determined by the personalized cancer therapy screening assay. [Diagram 2] A, B, C, and D show endoxifen dose-response curves for individual patients diagnosed with breast cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Diagram 3]A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with breast cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters such as SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 4] A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with breast cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters such as SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Diagram 5] A, B, and C show additional endoxifen dose-response curves for individual patients diagnosed with breast cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters such as SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 6] Endoxifen dose-response curves for patients diagnosed with cervical cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) derived from patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the insert. [Figure 7] A, B, and C show endoxifen dose-response curves for individual patients diagnosed with cholangiocarcinoma. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 8] A, B, and C show endoxifen dose-response curves for individual patients diagnosed with colorectal cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 9] A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with colon cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters such as SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 10] A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with colon cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters such as SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 11] A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with colon cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters such as SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 12]Endoxifen dose-response curves for patients diagnosed with esophageal cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) derived from the patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the insert. [Figure 13] Endoxifen dose-response curves for patients diagnosed with endometrial cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) derived from the patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the insert. [Figure 14] A and B show endoxifen dose-response curves for individual patients diagnosed with gastric cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the insert. [Figure 15] A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with gastric cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters such as SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 16] A, B, and C show endoxifen dose-response curves for individual patients diagnosed with leiomyosarcoma. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 17]Endoxifen dose-response curves for patients diagnosed with myxofibrosarcoma. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the insert. [Figure 18] A, B, C, and D show endoxifen dose-response curves for individual patients diagnosed with melanoma. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 19] A, B, and C show endoxifen dose-response curves for individual patients diagnosed with neuroblastoma. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 20] A, B, and C show endoxifen dose-response curves for individual patients diagnosed with ovarian cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 21] A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with ovarian cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 22] A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with ovarian cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 23] A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with ovarian cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 24] A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with ovarian cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Diagram 25] A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with ovarian cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 26]A, B, C, and D show additional endoxifen dose-response curves for individual patients diagnosed with ovarian cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 27] A and B show additional endoxifen dose-response curves for individual patients diagnosed with ovarian cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the insert. [Figure 28] A, B, and C show endoxifen dose-response curves for individual patients diagnosed with pancreatic cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) from individual patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the inserts. [Figure 29] Figure 1 shows the endoxifen dose-response curve for a patient diagnosed with primary peritoneal cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) derived from the patient. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the insert. [Diagram 30] Endoxifen dose-response curves for patients diagnosed with rectal cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) derived from the patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the insert. [Diagram 31] Endoxifen dose-response curves for patients diagnosed with sarcoma. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) derived from the patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the insert. [Diagram 32] Endoxifen dose-response curves for patients diagnosed with thyroid cancer. Endoxifen dose-response was measured using patient-derived tumor organoids (PDTO) derived from the patients. Response parameters including SEngine Precision Medicine (SPM) score, IC50, area under the curve (AUC), and goodness of fit of the response curve (GOF) are shown in the insert. [Diagram 33] Histograms showing the distribution of cancer types such as breast cancer (BRST), cervical cancer (CC), cholangiocarcinoma (CHOL), colorectal cancer (CRC), esophageal adenocarcinoma (EAC), endometrial cancer (EC), gastric cancer (GASC), leiomyosarcoma (LYMSC), myxofibrosarcoma (MFSC), melanoma (MLNM), neuroblastoma (NBL), ovarian cancer (OVA), pancreatic ductal adenocarcinoma (PDAC), primary peritoneal cancer (PPC), rectal cancer (RC), sarcoma (SC), and thyroid cancer (THYRD), which were screened for endoxifen response using the personalized cancer therapy screening assay. [Figure 34A] 1 is an XRPD pattern obtained from a sample of endoxifen Form I. [Figure 34B] 1 is an XRPD pattern obtained from a sample of endoxifen Form II. [Figure 34C] 1 is an XRPD pattern obtained from a sample of endoxifen Form III. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The effectiveness of cancer therapy is highly cancer type dependent, which makes drugs that are highly effective in one cancer type have limited effectiveness in other cancers. Often, this is caused by drugs targeting specific pathways that are disrupted or upregulated in one cancer type but not in other cancers. The present disclosure provides compositions and methods for treating various cancers using endoxifen. Endoxifen is the active metabolite of tamoxifen. In the liver, it is broken down into active compounds or metabolites. One of the active tamoxifen metabolites is endoxifen, also called 4-hydroxy-N-desmethyltamoxifen. Endoxifen (such as Z-endoxifen) is a selective estrogen receptor modulator (SERM) that functions as a competitive partial agonist of the estrogen receptor in a tissue-specific manner. Z-endoxifen has strong antitumor and antiestrogenic activity compared to tamoxifen therapy and aromatase inhibitor therapy. Endoxifen may be beneficial in treating cancer in patients whose cancer is resistant to other hormonal therapies, such as tamoxifen, aromatase inhibitors, and fulvestrant, in part because endoxifen functions independently of metabolic enzymes such as CYP2D6.

[0020] Described herein are compositions comprising endoxifen (e.g., Z-endoxifen) that can be used to treat various cancers (e.g., melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, bile duct cancer, breast cancer, cervical cancer, or ovarian cancer). Also described herein are methods of treating various cancers (e.g., melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, bile duct cancer, breast cancer, cervical cancer, or ovarian cancer) using endoxifen compositions. The methods of treating various cancers can include administering an endoxifen composition to a subject. The endoxifen composition can include Z-endoxifen, as well as polymorphs and salts thereof. In some embodiments, the endoxifen composition can be used in methods of treating melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, bile duct cancer, breast cancer, cervical cancer, or ovarian cancer. For example, the endoxifen compositions may be used to treat melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, or bile duct cancer. In some embodiments, the endoxifen compositions may be used to treat triple-negative breast cancer (e.g., breast cancer that lacks or has low levels of estrogen receptors, progesterone receptors, and HER2). In some embodiments, the endoxifen compositions described herein may be used to treat gastrointestinal cancer, such as colon cancer, gastric cancer, pancreatic cancer, esophageal cancer, rectal cancer, or bile duct cancer. In some embodiments, the endoxifen compositions described herein may be used to treat skin cancer, such as melanoma. In some embodiments, the endoxifen compositions described herein may be used to treat neuroblastoma.

[0021] The compositions and methods described herein may be used in combination with other therapies (e.g., chemotherapy, drug therapy, radiation therapy, or surgery) to treat cancer or related symptoms (e.g., pain, depression, anxiety, nausea, fatigue, or anorexia). For example, the endoxifen composition may be administered in combination with an antidepressant (e.g., a serotonin reuptake inhibitor). In another example, the endoxifen composition may be administered before, after, or simultaneously with surgery to remove cancer or cancerous tissue. In another example, the endoxifen composition may be administered in combination with an additional anticancer drug. The anticancer drug may be formulated with endoxifen in a pharmaceutical composition or may be administered separately. In some embodiments, anticancer drugs for use in combination with endoxifen to treat cancer may be identified using drug screening. For example, drug combinations including endoxifen that are effective in treating cancer (e.g., melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, bile duct cancer, breast cancer, cervical cancer, or ovarian cancer) may be identified using patient-derived tumor organoid (PDTO) screening.

[0022] How to Treat Cancer Methods of treating various cancers may include administering to a subject a therapy comprising endoxifen (e.g., Z-endoxifen). In some embodiments, endoxifen is administered orally. In some embodiments, endoxifen is administered topically. In some embodiments, endoxifen is administered orally, topically, transdermally, rectally, intravenously, intraarterially, intraovarianly, intravaginally, parenterally, or by inhalation. In some embodiments, endoxifen is formulated as a sustained release composition. A composition comprising endoxifen may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day. In some embodiments, a composition comprising endoxifen may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times per day. The therapy may be administered for at least 7 days, 14 days, 21 days, 28 days, 30 days, 35 days, 42 days, 49 days, 56 days, or 60 days. In some embodiments, treatment may be administered until the cancer is treated (e.g., by causing the tumor to disappear or decrease in size). In some embodiments, treatment may be administered until unacceptable toxicity is observed in the subject. In some embodiments, endoxifen (e.g., Z-endoxifen) may be administered at a dose of about 1 mg to about 160 mg, about 1 mg to about 40 mg, about 1 mg to about 10 mg, or about 2 mg to about 5 mg per day to treat cancer.

[0023] In some embodiments, the method of treating cancer may include administering endoxifen in combination with an additional therapeutic agent. For example, the method of treating cancer may include administering endoxifen and an additional anti-cancer agent. In some embodiments, the anti-cancer agent may be bicalutamide, enzalutamide, trastuzumab, atezolizumab, alpelisib, olaparib, talazoparib, ribociclib, neratinib, antineoplastic agent, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, fluorouracil, gemcitabine, methotrexate, paclitaxel, protein-bound paclitaxel, vinorelbine, eribulin, ixabepilone, immune checkpoint inhibitors, PD1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, or ATP cassette binding protein inhibitors. In some embodiments, methods of treating cancer can include administering endoxifen and a selective serotonin reuptake inhibitor (e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline, or vilazodone).

[0024] In some embodiments, the dose of endoxifen to treat a particular cancer type is determined based on the IC50 of endoxifen measured in vitro for the cancer type of interest. 50 The IC 50 The C concentration can be determined as the concentration of endoxifen that inhibits 50% of tumor cells in a given cancer type in vitro. For example, the dose of endoxifen can be determined by the in vivo concentration (e.g., maximum serum concentration (C)) required to treat a given cancer type. max )) (i.e., IC 50 1 / 10th of IC 50 At least one-fifth of I.C. 50 At least one-third of the IC 50 Half of the total, or at least the IC 50The IC of endoxifen for a particular cancer type (e.g., melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, bile duct cancer, breast cancer, cervical cancer, or ovarian cancer) can be selected so as to achieve in the subject an IC of endoxifen. 50 can be determined by generating dose-response curves using patient-derived tumor organoids (PDTOs). In some embodiments, the IC 50 can be patient-specific, cancer type-specific, or both. In some embodiments, the dosage for treating a subject is determined based on the IC measured in tumor organoids derived from the subject. 50 can be adjusted based on

[0025] (i) Method for treating gastrointestinal cancer A surprising discovery disclosed herein is that endoxifen may be effective in the treatment of gastrointestinal cancer, which as used herein may refer to cancer originating in the gastrointestinal (GI) tract or digestive accessory organs, including a broad range of cellular malignancies, such as cancer of the pharynx, esophagus, stomach, biliary system, pancreas, small intestine, large intestine, rectum, anus, spleen, liver, gallbladder, peritoneum, and specific cell and tissue cancers associated therewith. Although endoxifen is not expected to treat malignancies in some gastrointestinal tissues, such as those in which estrogen receptor beta agonism affects apparent tumor suppression (Y. Niv. Eur J Gastroenterol Hepatol, 2015;27(12):1438-42) or those with low estrogen receptor and estrogen receptor complex protein distribution, organoid studies (e.g., those outlined in Examples 5-8 and 17-19) have confirmed that endoxifen may exhibit significant systemic clearance of cancer cells from gastrointestinal tissues. Furthermore, the organoid studies disclosed herein show that endoxifen effectively treats gastrointestinal cancers in the absence of immune-mediated apoptosis and clearance, suggesting that endoxifen may be ideal for treating multiple refractory and metastatic gastrointestinal cancers, such as those that are immunosuppressive, anoikis-resistant, or have a high incidence of circulating tumor cell (CTC) formation.

[0026] Taking advantage of these observations, an aspect of the present disclosure provides a method for treating digestive cancer, comprising administering a therapeutically effective amount of endoxifen to a subject in need of such treatment.In some cases, the digestive cancer is esophageal cancer, gastric cancer, small intestine cancer, appendix cancer, colon cancer, anal cancer, liver cancer, biliary tract cancer (e.g., bile duct cancer), pancreatic cancer, peritoneal cancer, or a combination thereof.In some cases, the digestive cancer is colon cancer, gastric cancer, pancreatic cancer, esophageal cancer, rectal cancer, biliary tract cancer, bile duct cancer, or a combination thereof.In some cases, the digestive cancer is metastatic.In some cases, the digestive cancer is recurrent.

[0027] In some cases, the gastrointestinal cancer is a carcinoma. In some cases, the gastrointestinal cancer is an adenocarcinoma. In some cases, the adenocarcinoma is a colonic adenocarcinoma, a pancreatic ductal adenocarcinoma, a rectal adenocarcinoma, or a combination thereof. In some cases, the carcinoma is metastatic (e.g., metastatic adenocarcinoma). In some cases, the carcinoma is recurrent.

[0028] In some cases, the gastrointestinal cancer is colorectal cancer. In some cases, the colorectal cancer is cecum cancer, ascending colon cancer, transverse colon cancer, descending colon cancer, sigmoid colon cancer, or rectum cancer, or a combination thereof. In some cases, the colorectal cancer is colon cancer. In some cases, the colon cancer is sigmoid colon cancer, colon adenocarcinoma, descending colon cancer, or a combination thereof. In some cases, the colorectal cancer is metastatic. In some cases, the colorectal cancer is recurrent.

[0029] In some cases, the gastric cancer is gastric cancer. In some cases, the gastric cancer is gastric carcinoma, gastric adenocarcinoma, gastrointestinal stromal carcinoma, signet ring cell carcinoma, gastric lymphoma, gastritis plastica, hereditary diffuse gastric cancer, mucosa-associated lymphoid tissue, or a combination thereof. In some cases, the gastric cancer is adenocarcinoma. In some cases, the gastric cancer is metastatic. In some cases, the gastric cancer is recurrent.

[0030] In some cases, the gastrointestinal cancer is pancreatic cancer. In some cases, the pancreatic cancer is exocrine pancreatic cancer, cystic neoplasm, serous microcystic adenoma, pancreatoblastoma, intraductal papillary mucinous neoplasm, pseudopapillary neoplasm, mucinous cystic neoplasm, or a combination thereof. In some cases, the pancreatic cancer is exocrine pancreatic cancer. In some cases, the pancreatic cancer is pancreatic adenocarcinoma. In some cases, the adenocarcinoma is pancreatic ductal adenocarcinoma. In some cases, the adenocarcinoma is metastatic pancreatic ductal adenocarcinoma. In some cases, the pancreatic cancer is metastatic. In some cases, the pancreatic cancer is recurrent.

[0031] (ii) Methods for Treating Skin Cancer An embodiment of the present disclosure provides a method for treating skin cancer, comprising administering a therapeutically effective amount of endoxifen to a subject in need of skin cancer treatment.Skin cancer may reduce the expression of estrogen receptor alpha, and therefore skin cancer may be poorly responsive to selective estrogen receptor modulators such as endoxifen.Nevertheless, the present invention hypothesizes that endoxifen may be active against some forms of skin cancer.This hypothesis is supported by the finding that endoxifen IC is less than 10 μM for multiple skin cancers. 50 The value of endoxifen was confirmed by skin cancer organoid assays (e.g., as outlined in Example 20) that identified endoxifen activity in skin cancer. Because organoids were substantially free of immune cells, these assays further demonstrated that endoxifen activity in skin cancer may be independent of immune inhibition and cancer cell elimination.

[0032] In some cases, the skin cancer is carcinoma, melanoma, cutaneous T-cell lymphoma, dermatofibrosarcoma, or a combination thereof. In some cases, the skin cancer is a carcinoma. In some cases, the carcinoma is selected from the group consisting of cutaneous T-cell lymphoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma, sebaceous gland carcinoma, basal cell carcinoma, squamous cell carcinoma, or a combination thereof. In some cases, the skin cancer is a cutaneous T-cell lymphoma. In some cases, the skin cancer is a dermatofibrosarcoma. In some cases, the skin cancer is metastatic. In some cases, the skin cancer is recurrent.

[0033] In some cases, the skin cancer is melanoma. In some cases, the melanoma is superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral melanoma, mucosal melanoma, linear melanoma, uveal melanoma, vaginal melanoma, polypoid melanoma, or a combination thereof. In some cases, the melanoma is acral melanoma, recurrent acral melanoma, anorectal melanoma, or a combination thereof. In some cases, the melanoma is acral melanoma. In some cases, the acral melanoma is recurrent acral melanoma. In some cases, the melanoma is anorectal melanoma. In some cases, the melanoma is recurrent melanoma. In some cases, the melanoma is metastatic.

[0034] (iii) Methods for treating neuroblastoma An aspect of the present disclosure provides a method for treating neuroblastoma, comprising administering a therapeutically effective amount of endoxifen to a subject in need of neuroblastoma treatment. Neuroblastoma typically arises from neuroblasts in sympathetic nervous tissue and can arise in various locations, such as the neck, chest, and spine. Neuroblastoma often exhibits high cellular heterogeneity, making it difficult to treat when in advanced stages and after dissemination. As disclosed herein (e.g., Example 10), endoxifen has a low IC for some neuroblastomas. 50 and thus provide an effective means for treating and maintaining remission of neuroblastoma. In some methods of treating neuroblastoma disclosed herein, the neuroblastoma is metastatic. In some methods of treating neuroblastoma disclosed herein, the neuroblastoma is recurrent.

[0035] (iv) Administration of cancer treatment In some embodiments, the dosage of endoxifen to treat melanoma (e.g., acral melanoma, recurrent acral melanoma, or anorectal melanoma) is a C of at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM in the subject. max (e.g., systemic C max In some embodiments, the dosage of endoxifen for treating melanoma (e.g., acral melanoma, recurrent acral melanoma, or anorectal melanoma) may be selected to achieve a C of about 0.01 μM to about 50 μM, about 0.01 μM to about 0.1 μM, about 0.1 μM to about 0.5 μM, about 0.1 μM to about 1 μM, about 0.1 μM to about 2 μM, about 0.5 μM to about 1 μM, about 0.5 μM to about 2 μM, about 1 μM to about 2 μM, about 1 μM to about 5 μM, or about 1 μM to about 10 μM in the subject. max may be selected to achieve

[0036] In some embodiments, the dosage of endoxifen for treating colorectal cancer is from about 0.01 μM to about 10 μM C ​​in a subject. maxIn some cases, the colon cancer is colon cancer, sigmoid colon cancer, adenocarcinoma of the colon, stage III colon cancer, stage IV colon cancer, or descending colon cancer. The dosage of endoxifen is selected to achieve a C of at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM in the subject. max In some embodiments, the dosage of endoxifen for treating colorectal cancer (e.g., colon cancer, sigmoid colon cancer, adenocarcinoma of the colon, stage III colon cancer, stage IV colon cancer, or descending colon cancer) can be selected to achieve a C of about 0.01 μM to about 50 μM, about 0.01 μM to about 0.1 μM, about 0.1 μM to about 0.5 μM, about 0.1 μM to about 1 μM, about 0.1 μM to about 2 μM, about 0.5 μM to about 1 μM, about 0.5 μM to about 2 μM, about 1 μM to about 2 μM, about 1 μM to about 5 μM, or about 1 μM to about 10 μM in a subject. max In some embodiments, the method for treating colon cancer maintains a systemic endoxifen concentration of greater than about 0.1 μM for at least one week. In some embodiments, the method for treating colon cancer maintains a systemic endoxifen concentration of greater than about 0.5 μM for at least one week. In some embodiments, the method for treating colon cancer maintains a systemic endoxifen concentration of greater than about 1 μM for at least one week. In some embodiments, the method for treating colon cancer maintains a systemic endoxifen concentration of greater than about 2 μM for at least one week.

[0037] In some embodiments, the dosage of endoxifen to treat gastric cancer provides a C of at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM in a subject. max In some embodiments, the dose of endoxifen for treating gastric cancer may be selected to achieve a C of about 0.01 μM to about 50 μM, about 0.01 μM to about 0.1 μM, about 0.1 μM to about 0.5 μM, about 0.1 μM to about 1 μM, about 0.1 μM to about 2 μM, about 0.5 μM to about 1 μM, about 0.5 μM to about 2 μM, about 1 μM to about 2 μM, about 1 μM to about 5 μM, or about 1 μM to about 10 μM in the subject. max In some embodiments, the method for treating gastric cancer maintains a systemic endoxifen concentration of greater than about 0.1 μM for at least one week. In some embodiments, the method for treating gastric cancer maintains a systemic endoxifen concentration of greater than about 0.5 μM for at least one week. In some embodiments, the method for treating gastric cancer maintains a systemic endoxifen concentration of greater than about 1 μM for at least one week. In some embodiments, the method for treating gastric cancer maintains a systemic endoxifen concentration of greater than about 2 μM for at least one week.

[0038] In some embodiments, the dosage of endoxifen to treat neuroblastoma is at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM C ​​in the subject. max In some embodiments, the dose of endoxifen for treating neuroblastoma can be selected to achieve a C of about 0.01 μM to about 50 μM, about 0.01 μM to about 0.1 μM, about 0.1 μM to about 0.5 μM, about 0.1 μM to about 1 μM, about 0.1 μM to about 2 μM, about 0.5 μM to about 1 μM, about 0.5 μM to about 2 μM, about 1 μM to about 2 μM, about 1 μM to about 5 μM, or about 1 μM to about 10 μM in the subject. max In some embodiments, the method for treating neuroblastoma maintains a systemic endoxifen concentration of greater than about 0.1 μM for at least one week. In some embodiments, the method for treating neuroblastoma maintains a systemic endoxifen concentration of greater than about 0.5 μM for at least one week. In some embodiments, the method for treating neuroblastoma maintains a systemic endoxifen concentration of greater than about 1 μM for at least one week. In some embodiments, the method for treating neuroblastoma maintains a systemic endoxifen concentration of greater than about 2 μM for at least one week.

[0039] In some embodiments, the dosage of endoxifen for treating pancreatic cancer (e.g., pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, or stage III metastatic pancreatic ductal adenocarcinoma) is a C of at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM in the subject. max In some embodiments, the dosage of endoxifen for treating pancreatic cancer (e.g., pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, or stage III metastatic pancreatic ductal adenocarcinoma) can be selected to achieve a C of about 0.01 μM to about 50 μM, about 0.01 μM to about 0.1 μM, about 0.1 μM to about 0.5 μM, about 0.1 μM to about 1 μM, about 0.1 μM to about 2 μM, about 0.5 μM to about 1 μM, about 0.5 μM to about 2 μM, about 1 μM to about 2 μM, about 1 μM to about 5 μM, or about 1 μM to about 10 μM in the subject. max In some embodiments, the method for treating pancreatic cancer maintains a systemic endoxifen concentration of greater than about 0.1 μM for at least one week. In some embodiments, the method for treating pancreatic cancer maintains a systemic endoxifen concentration of greater than about 0.5 μM for at least one week. In some embodiments, the method for treating pancreatic cancer maintains a systemic endoxifen concentration of greater than about 1 μM for at least one week. In some embodiments, the method for treating pancreatic cancer maintains a systemic endoxifen concentration of greater than about 2 μM for at least one week.

[0040] In some embodiments, the dosage of endoxifen for treating esophageal cancer (e.g., esophageal adenocarcinoma or metastatic esophageal cancer) is a C of at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM in a subject. max In some embodiments, the dosage of endoxifen for treating esophageal cancer (e.g., esophageal adenocarcinoma or metastatic esophageal cancer) can be selected to achieve a C of about 0.01 μM to about 50 μM, about 0.01 μM to about 0.1 μM, about 0.1 μM to about 0.5 μM, about 0.1 μM to about 1 μM, about 0.1 μM to about 2 μM, about 0.5 μM to about 1 μM, about 0.5 μM to about 2 μM, about 1 μM to about 2 μM, about 1 μM to about 5 μM, or about 1 μM to about 10 μM in the subject. max In some embodiments, the method for treating esophageal cancer maintains a systemic endoxifen concentration of greater than about 0.1 μM for at least one week. In some embodiments, the method for treating esophageal cancer maintains a systemic endoxifen concentration of greater than about 0.5 μM for at least one week. In some embodiments, the method for treating esophageal cancer maintains a systemic endoxifen concentration of greater than about 1 μM for at least one week. In some embodiments, the method for treating esophageal cancer maintains a systemic endoxifen concentration of greater than about 2 μM for at least one week.

[0041] In some embodiments, the dosage of endoxifen to treat rectal cancer (e.g., rectal adenocarcinoma) provides a C of at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM in a subject. max In some embodiments, the dose of endoxifen for treating rectal cancer (e.g., rectal adenocarcinoma) may be selected to achieve a C of about 0.01 μM to about 50 μM, about 0.01 μM to about 0.1 μM, about 0.1 μM to about 0.5 μM, about 0.1 μM to about 1 μM, about 0.1 μM to about 2 μM, about 0.5 μM to about 1 μM, about 0.5 μM to about 2 μM, about 1 μM to about 2 μM, about 1 μM to about 5 μM, or about 1 μM to about 10 μM in the subject. max In some embodiments, the method for treating rectal cancer maintains a systemic endoxifen concentration of greater than about 0.1 μM for at least one week. In some embodiments, the method for treating rectal cancer maintains a systemic endoxifen concentration of greater than about 0.5 μM for at least one week. In some embodiments, the method for treating rectal cancer maintains a systemic endoxifen concentration of greater than about 1 μM for at least one week. In some embodiments, the method for treating rectal cancer maintains a systemic endoxifen concentration of greater than about 2 μM for at least one week.

[0042] In some embodiments, the dosage of endoxifen for treating cholangiocarcinoma (e.g., metastatic cholangiocarcinoma) is a C of at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM in a subject. max In some embodiments, the dosage of endoxifen for treating cholangiocarcinoma (e.g., metastatic cholangiocarcinoma) may be selected to achieve a C of about 0.01 μM to about 50 μM, about 0.01 μM to about 0.1 μM, about 0.1 μM to about 0.5 μM, about 0.1 μM to about 1 μM, about 0.1 μM to about 2 μM, about 0.5 μM to about 1 μM, about 0.5 μM to about 2 μM, about 1 μM to about 2 μM, about 1 μM to about 5 μM, or about 1 μM to about 10 μM in the subject. max In some embodiments, the method for treating cholangiocarcinoma maintains a systemic endoxifen concentration of greater than about 0.1 μM for at least one week. In some embodiments, the method for treating cholangiocarcinoma maintains a systemic endoxifen concentration of greater than about 0.5 μM for at least one week. In some embodiments, the method for treating cholangiocarcinoma maintains a systemic endoxifen concentration of greater than about 1 μM for at least one week. In some embodiments, the method for treating cholangiocarcinoma maintains a systemic endoxifen concentration of greater than about 2 μM for at least one week.

[0043] In some embodiments, the dosage of endoxifen for treating breast cancer (e.g., triple-negative breast cancer, metastatic breast cancer, or HER2+ breast cancer) is a C of at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM in a subject. max In some embodiments, the dosage of endoxifen for treating breast cancer (e.g., triple-negative breast cancer, metastatic breast cancer, or HER2+ breast cancer) may be selected to achieve a C of about 0.01 μM to about 50 μM, about 0.01 μM to about 0.1 μM, about 0.1 μM to about 0.5 μM, about 0.1 μM to about 1 μM, about 0.1 μM to about 2 μM, about 0.5 μM to about 1 μM, about 0.5 μM to about 2 μM, about 1 μM to about 2 μM, about 1 μM to about 5 μM, or about 1 μM to about 10 μM in the subject. max In some embodiments, the method for treating breast cancer maintains a systemic endoxifen concentration of greater than about 0.1 μM for at least one week. In some embodiments, the method for treating breast cancer maintains a systemic endoxifen concentration of greater than about 0.5 μM for at least one week. In some embodiments, the method for treating breast cancer maintains a systemic endoxifen concentration of greater than about 1 μM for at least one week. In some embodiments, the method for treating breast cancer maintains a systemic endoxifen concentration of greater than about 2 μM for at least one week.

[0044] In some embodiments, the dosage of endoxifen to treat cervical cancer (e.g., cervical carcinoma) provides a C of at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM in a subject. max In some embodiments, the dosage of endoxifen for treating cervical cancer (e.g., cervical carcinoma) may be selected to achieve a C of about 0.01 μM to about 50 μM, about 0.01 μM to about 0.1 μM, about 0.1 μM to about 0.5 μM, about 0.1 μM to about 1 μM, about 0.1 μM to about 2 μM, about 0.5 μM to about 1 μM, about 0.5 μM to about 2 μM, about 1 μM to about 2 μM, about 1 μM to about 5 μM, or about 1 μM to about 10 μM in the subject. max In some embodiments, the method for treating cervical cancer maintains a systemic endoxifen concentration of greater than about 0.1 μM for at least one week. In some embodiments, the method for treating cervical cancer maintains a systemic endoxifen concentration of greater than about 0.5 μM for at least one week. In some embodiments, the method for treating cervical cancer maintains a systemic endoxifen concentration of greater than about 1 μM for at least one week. In some embodiments, the method for treating cervical cancer maintains a systemic endoxifen concentration of greater than about 2 μM for at least one week.

[0045] In some embodiments, the dosage of endoxifen to treat ovarian cancer (e.g., malignant endometrioid ovarian cancer, stage IIIC poorly differentiated serous adenocarcinoma, fallopian tube cancer, stage IV ovarian cancer, ovarian granulosa cell tumor, high grade Mullerian / primary ovarian cancer, platinum resistant recurrent ovarian cancer, high grade serous carcinoma, ovarian mucinous adenocarcinoma, metastatic ovarian cancer, low grade serous ovarian cancer, recurrent ovarian cancer, or peritoneal carcinomatosis) is at least about 0.01 μM, at least about 0.05 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.4 μM, at least about 0.6 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 0.1 μM, at least about 0.2 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 0.9 μM, at least about 0.1 ...3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0. At least about 0.3 μM, at least about 0.4 μM, at least about 0.5 μM, at least about 0.6 μM, at least about 0.7 μM, at least about 0.8 μM, at least about 0.9 μM, at least about 1 μM, at least about 1.5 μM, at least about 2 μM, at least about 2.5 μM, at least about 3 μM, at least about 3.5 μM, at least about 4 μM, at least about 4.5 μM, at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 μM, or at least about 10 μM. max may be selected to achieve In some embodiments, the dosage of endoxifen for treating ovarian cancer (e.g., malignant endometrioid ovarian cancer, stage IIIC poorly differentiated serous adenocarcinoma, fallopian tube cancer, stage IV ovarian cancer, ovarian granulosa cell tumor, high grade Mullerian / primary ovarian cancer, platinum resistant recurrent ovarian cancer, high grade serous carcinoma, ovarian mucinous adenocarcinoma, metastatic ovarian cancer, low grade serous ovarian cancer, recurrent ovarian cancer, or peritoneal carcinomatosis) is from about 0.01 μM to about 50 μM, from about 0.01 μM to about 0.1 μM, from about 0.1 μM to about 0.5 μM, from about 0.1 μM to about 1 μM, from about 0.1 μM to about 2 μM, from about 0.5 μM to about 1 μM, from about 0.5 μM to about 2 μM, from about 1 μM to about 2 μM, from about 1 μM to about 5 μM, or from about 1 μM to about 10 μM C ​​in the subject. maxIn some embodiments, the method for treating ovarian cancer maintains a systemic endoxifen concentration of greater than about 0.1 μM for at least one week. In some embodiments, the method for treating ovarian cancer maintains a systemic endoxifen concentration of greater than about 0.5 μM for at least one week. In some embodiments, the method for treating ovarian cancer maintains a systemic endoxifen concentration of greater than about 1 μM for at least one week. In some embodiments, the method for treating ovarian cancer maintains a systemic endoxifen concentration of greater than about 2 μM for at least one week.

[0046] In some embodiments, a method of treating cancer (e.g., melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, bile duct cancer, breast cancer, cervical cancer, or ovarian cancer) may include administering (e.g., orally, topically, or via inhalation) an endoxifen composition to a subject at a plasma endoxifen steady-state level of greater than 30 nM, such as a level in the range of 30 nM to 80 nM, or a level in the range of 30 nM to 300 nM. In some embodiments, the plasma steady-state endoxifen level is maintained greater than 40 nM. Maintaining such plasma endoxifen at a steady-state level of greater than 30 nM is advantageous in that the likelihood of recurrence (relapse) of hormone-dependent breast disorder or hormone-dependent reproductive tract disorder at plasma endoxifen levels less than 30 nM is reduced. It is particularly advantageous to administer the compositions disclosed herein to subjects who are poor metabolizers of tamoxifen (plasma endoxifen levels less than 16nM), intermediate metabolizers of tamoxifen (plasma endoxifen levels less than 27nM).It is also advantageous to subjects who are being treated or will be treated with antidepressants, such as SSRI drugs, such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil, Pexeva), sertraline (Zoloft), vilazodone (Vibride), for example, subjects who suffer from depression or may suffer from depression.

[0047] In some embodiments, the steady-state endoxifen level (e.g., steady-state plasma endoxifen level) is indicative of an IC for a cancer type of interest (e.g., melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, cholangiocarcinoma, breast cancer, cervical cancer, or ovarian cancer). 50 For example, the steady state of endoxifen can be maintained at any level relative to the IC 50 or greater than 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or greater than 0.01. In some embodiments, plasma levels of endoxifen may be maintained for at least 7 days, at least 14 days, at least 21 days, or at least 28 days, thereby treating cancer (e.g., melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, bile duct cancer, breast cancer, cervical cancer, or ovarian cancer).

[0048] Whether a subject is tamoxifen refractory can be determined by administering an initial dose of tamoxifen to the subject and determining the subject's plasma endoxifen steady-state level. The plasma endoxifen steady-state level in a subject administered tamoxifen serves as a biomarker for tamoxifen refractory subjects. Plasma endoxifen level (acute and / or steady-state) can be determined by obtaining a test sample (which can be a blood sample taken from the subject) from the subject after administering tamoxifen to the subject. Plasma or serum can be obtained from the blood sample to test the biomarker endoxifen level. The initial dose can include daily administration of tamoxifen 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 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.

[0049] The subject's plasma endoxifen steady state level can be determined by measuring endoxifen in a test sample. The subject's plasma endoxifen steady state level is compared to a reference plasma endoxifen level. For the purposes of this disclosure, the reference plasma level is 30 nM. If the subject's plasma endoxifen level is determined to be less than 30 nM, the subject is defined as tamoxifen refractory. Tamoxifen refractory subjects who may have or be at risk of having hormone-dependent breast disorder or hormone-dependent reproductive tract disorder are treated by administering to the subject an oral composition comprising (Z)-endoxifen or a salt thereof disclosed herein, or a polymorphic form of endoxifen disclosed herein. In some embodiments, the composition administered to such subjects comprises (Z)-endoxifen free base. In other embodiments, the composition administered to such subjects comprises an 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 endoxifen is endoxifen HCl or endoxifen citrate. The present disclosure also contemplates that the subject's plasma endoxifen level is tracked or monitored periodically or as needed. If necessary, the subject who has been administered the initial dose of tamoxifen may have their plasma endoxifen steady-state level adjusted based on the test results by continuing to administer a composition comprising endoxifen.

[0050] In some embodiments, the tamoxifen-refractory state of a subject can be determined by determining the tamoxifen-metabolite profile of the subject, compared to the reference tamoxifen-metabolite profile found in control or normal subjects.A subject having a low plasma endoxifen level in the tamoxifen metabolite profile of the subject compared to the reference tamoxifen-metabolite profile is administered an oral composition comprising endoxifen or a salt thereof.Such a composition can comprise synthetically prepared endoxifen.

[0051] Plasma endoxifen may be measured by any method known in the art. The plasma endoxifen level in the test sample may be determined based on the subject's genetic, DNA, RNA, protein, tamoxifen-metabolite profile, or a combination thereof. The tamoxifen-metabolite profile may include at least tamoxifen, 4-OHT, N-desmethyltamoxifen, and / or endoxifen. In some embodiments, the plasma endoxifen level 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), etc. In some embodiments, the tamoxifen-metabolite profile is predicted based on the subject's genetic composition. In some embodiments, the subject's CYP genotype includes, but is not limited to, the analysis of CYP2D6 gene, CYP3A4 gene, CYP2C9 gene.In some embodiments, the subject's estrogen receptor level can be analyzed.In other embodiments, the measurement of plasma endoxifen can be performed by a third-party laboratory.

[0052] Thus, provided herein is a method of maintaining plasma endoxifen levels at levels greater than 30 nM in a subject in need thereof by administering to the subject a composition comprising endoxifen or a salt thereof. In some embodiments, the subject's plasma endoxifen levels are maintained at a steady state level greater than 30 nM. In some embodiments, the subject's plasma endoxifen levels are maintained at a steady state level in the range of 30 nM to 300 nM (e.g., 30 nM to 200 nM, or 30 nM to 80 nM). In some embodiments, the subject's plasma endoxifen levels are maintained at a steady state level greater than 40 nM. In some embodiments, the plasma levels of endoxifen can be maintained for at least 7 days, at least 14 days, at least 21 days, or at least 28 days, thereby treating cancer (e.g., melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, bile duct cancer, breast cancer, cervical cancer, or ovarian cancer).

[0053] In another aspect, the subject may have a test sample tested for a biomarker profile that may indicate or monitor a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both. Such biomarkers are known in the art, and non-limiting examples include biomarkers such as CYP2D6, BRCA-1, BRCA-2, ER, PR, Her2, uPA, PAI, Tf, p53, Ki67, cytokeratin, cancer tumor antigens, and other biomarkers measured by Mammaprint, OncotypeDx, PAM50, EndoxPredict, MammoStrat, and other diagnostic and predictive tests. The compositions disclosed herein can be administered to a subject having a biomarker profile that indicates that the subject has or is at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both. In one aspect, the disclosure provides a method of treating a subject having or at risk of having a hormone-dependent breast disorder, a hormone-dependent reproductive tract disorder, or both, the method comprising determining the subject's tamoxifen-refractory or tamoxifen-resistant status and administering to the subject a composition described herein.

[0054] (v) Metastatic cancer Aspects of the present disclosure provide a method of treating metastatic cancer, comprising administering a therapeutically effective amount of endoxifen to a subject in need of such treatment. A surprising discovery disclosed herein is that endoxifen can be effective in treating certain metastatic cancers, such as some metastatic skin cancers, metastatic gastrointestinal cancers, and metastatic neuroblastoma. Metastatic cancers often exhibit tumor genetic and phenotypic heterogeneity, wide tissue distribution, and lack of response to first-line treatments. These characteristics can limit the effectiveness of targeted and immunomodulatory therapies, and thus necessitate the use of potent anticancer drugs. Endoxifen has been shown to be effective in treating many of the cancers disclosed herein, including some metastatic cancers (e.g., metastatic pancreatic ductal adenocarcinoma, as outlined in Example 12), with IC 50The low levels observed suggest that endoxifen may be an effective treatment option for some metastatic cancers.

[0055] (vi) Intraoperative and postoperative endoxifen course In another example, the endoxifen composition can be administered in combination with surgical or radiation therapy. In many of the methods disclosed herein, endoxifen is administered before, at the same time as, or after surgical tumor or organ resection (e.g., cholecystectomy) or radiation therapy. Cancer recurrence after such treatment is often due to residual small metastases, incomplete removal of cancerous tissue, or residual portions of cancerous or precancerous tissue. Endoxifen has been shown to be effective in treating many cancers through IC. 50 Its low activity makes it an effective means of eliminating remaining cancer cells after surgery or radiation treatment.

[0056] Endoxifen can be an effective post-operative treatment to remove remaining cancer cells in cancers where other treatments cannot remove remaining cancer parts. Often, treatments that rely on immune-mediated cancer cell removal, such as some immune activation therapies and certain chemotherapy for PD-L1 and CD155 positive cancers, have low effectiveness against pre-cancerous cells and small metastases with low immune cell density. As identified herein, endoxifen can directly affect the killing and removal of cancer cells without the concomitant activation or involvement of immune cells. For these cancers, endoxifen administration can be a preferred method to remove remaining cancer cells or suppress further metastasis after surgery and / or radiation therapy.

[0057] The methods disclosed herein can include administering a therapeutically effective amount of endoxifen and an additional therapy to a subject. In some cases, the additional therapy is surgical tumor removal, radiation therapy, or a combination thereof. In some cases, administering a therapeutically effective amount of endoxifen is before surgical tumor removal and / or radiation therapy, simultaneously with surgical tumor removal and / or radiation therapy, after surgical tumor removal and / or radiation therapy, or a combination thereof. In some cases, administering a therapeutically effective amount of endoxifen is after surgical tumor removal and / or radiation therapy.

[0058] Surgical tumor removal may include complete (e.g., "total resection") or partial (e.g., "resection") removal of tumor and / or cancerous tissue in a subject. In some cases, surgical tumor removal includes cryosurgery, which may hereinafter refer to a method of killing or weakening cancerous tissue by cooling. In some cases, surgical tumor removal includes laser removal, which uses high-energy coherent light to damage, kill, or remove cancerous tissue. In some cases, surgical tumor removal is a laparoscopic procedure.

[0059] Radiation therapy as disclosed herein may include, but is not limited to, external beam radiation therapy, brachytherapy (e.g., implant-based radiation therapy), total body radiation therapy, stereotactic radiosurgery, and combinations thereof. In some cases, radiation therapy uses X-rays or gamma rays. In some embodiments, radiation therapy utilizes particles (electrons, protons, neutrons, carbon ions, alpha particles, and / or beta particles). In some cases, radiation therapy utilizes about 1 to about 100 Gray ("Gy", 10 2rem (roentgen equivalent man). As used herein, cumulative external radiation dose may refer to the total amount of radiation provided to a subject or treatment area over the entire course of treatment. In some cases, radiation therapy provides a cumulative external radiation dose of about 1 to about 20 Gy, about 1 to about 40 Gy, about 5 to about 30 Gy, about 10 to about 40 Gy, about 10 to about 50 Gy, about 20 to about 60 Gy, or about 5 to about 25 Gy. In some cases, radiation therapy is administered in a single dose. In some cases, radiation therapy is administered in 1 to 5 doses, 1 to 10 doses, 3 to 10 doses, 4 to 15 doses, 6 to 20 doses, 4 to 12 doses, or 6 to 15 doses (e.g., isodose). These doses can be administered hourly, daily, once every 1 to 10 days, once every 1 to 14 days, once every 3 to 14 days, once every 7 to 31 days, or once every 14 to 31 days.

[0060] Endoxifen preparations A method for treating cancer may include administering to a subject a composition comprising endoxifen. Endoxifen is also known as 4-hydroxy-N-desmethyl-tamoxifen and may include polymorphs, salts, free bases, cocrystals, or solvates of endoxifen. In some embodiments, endoxifen may include one or more polymorphic forms, such as form I, form II, or form III of endoxifen. Polymorphic forms may be distinguished by powder X-ray diffraction patterns. In some embodiments, a method for treating cancer may include administering a pharmaceutical composition comprising endoxifen predominantly as polymorphic form I. In some embodiments, the pharmaceutical composition comprises endoxifen predominantly as polymorphic form II. In some embodiments, the pharmaceutical composition comprises endoxifen predominantly as polymorphic form III.

[0061] In some embodiments, polymorph 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° 2-theta. In some embodiments, crystalline form I is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 34A. In some embodiments, polymorph form II is characterized by an X-ray powder diffraction pattern comprising major peaks at 7.0±0.3°, 11.9±0.3°, 14.0±0.3°, and 18.4±0.3° 2-theta. In some embodiments, crystalline form II is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 34B. In some embodiments, polymorph form III is characterized by an X-ray powder diffraction pattern comprising major peaks at 11.9±0.3°, 13.9±0.3°, 17.1±0.3°, and 17.7±0.3° 2-theta. In some embodiments, crystalline Form III is characterized by an X-ray powder diffraction pattern substantially as shown in Figure 34C.

[0062] In some embodiments, the composition comprises endoxifen in an amount of at least 0.1 wt / wt%, at least 0.2 wt / wt%, at least 0.3 wt / wt%, at least 0.4 wt / wt%, at least 0.5 wt / wt%, at least 1 wt / wt%, at least 5 wt / wt%, at least 10 wt / wt%, at least 20 wt / wt%, at least 25 wt / wt%, at least 30 wt / wt%, at least 40 wt / wt%, at least 50 wt / wt%, at least 60 wt / wt%, at least 70 wt / wt% of the total endoxifen in the composition. %, at least 80 wt / wt%, at least 90 wt / wt%, at least 91 wt / wt%, at least 92 wt / wt%, at least 93 wt / wt%, at least 94 wt / wt%, at least 95 wt / wt%, at least 96 wt / wt%, at least 97 wt / wt%, at least 98 wt / wt%, at least 99 wt / wt%, at least 99.5 wt / wt%, at least 99.99 wt / wt%, or 100 wt / wt% of endoxifen as a single polymorphic form, such as Form I, Form II, or Form III. In some embodiments, the compositions for treating various cancers comprise 90 wt / wt% or more of the total endoxifen in the composition as a single polymorphic form, such as Form I, Form II, or Form III. In another embodiment, the composition comprises 95 wt / wt% or more of the total endoxifen in the composition in a single polymorphic form of endoxifen, such as Form I, Form II, or Form III. In some embodiments, the composition comprises 96% or more, 97% or more, 98% or more, 99% or more, or 99.5% or more of the total endoxifen in the composition in a single polymorphic form of endoxifen, such as Form I, Form II, or Form III. When a particular weight percent of endoxifen is a single polymorphic form, the remaining endoxifen in the composition may be amorphous endoxifen and / or any combination of one or more polymorphic forms of endoxifen excluding a single polymorphic form. When polymorphic endoxifen is defined as one particular form of endoxifen, the remainder may be comprised of amorphous endoxifen and / or one or more polymorphic forms other than the specified particular form.Examples of single polymorphs include endoxifen Forms I, II, and III, as well as descriptions of single polymorphs characterized by one or more properties described herein.

[0063] In other embodiments, the compositions comprising endoxifen comprise between 0.01% and 20%, between 0.05% and 15%, or between 0.1% and 10% (wt / wt or w / v) of the composition of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III. In at least one embodiment, the compositions comprising endoxifen comprise between 0.01% and 20% (wt / wt or w / v) of the composition of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III. In various other embodiments, the composition comprising endoxifen comprises 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 the composition of a single polymorphic form of endoxifen, such as Form I, Form II, or Form III. In one aspect, the composition comprising a single polymorphic form of endoxifen, such as Form I, Form II, or Form III, further comprises a second polymorphic form of endoxifen.

[0064] In some embodiments, the endoxifen composition may comprise no more than 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% (wt / wt) E-endoxifen relative to total endoxifen. In some embodiments, the endoxifen composition may comprise 99.9%, 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, or 70% or more (wt / wt) Z-endoxifen relative to total endoxifen. In some embodiments, the endoxifen composition may contain impurities not exceeding 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% (wt / wt) of Z-endoxifen. In some embodiments, the endoxifen composition may contain 99.9%, 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, or 70% or more (wt / wt) of Z-endoxifen based on the total composition. In some embodiments, the endoxifen composition comprises 99.9%, 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, or 70% or more (wt / wt) Z-endoxifen relative to total endoxifen (e.g., in the case of (Z)-endoxifen, an isomeric purity of at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9%).

[0065] Pharmaceutical Compositions The composition for treating various cancers can be formulated as a pharmaceutical composition. For example, the composition containing endoxifen (e.g., Z-endoxifen) can be formulated as a pharmaceutical composition. In some embodiments, the composition for treating various cancers (e.g., melanoma, colon cancer, gastric cancer, neuroblastoma, pancreatic cancer, esophageal cancer, rectal cancer, bile duct cancer, breast cancer, cervical cancer or ovarian cancer) can contain endoxifen (e.g., Z-endoxifen). In some embodiments, the pharmaceutical composition can further contain additional therapeutic agents. For example, the pharmaceutical composition can contain anti-cancer agents. In some embodiments, the anti-cancer agent can be bicalutamide, enzalutamide, trastuzumab, atezolizumab, alpelisib, olaparib, talazoparib, ribociclib, neratinib, antineoplastic agents, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, fluorouracil, gemcitabine, methotrexate, paclitaxel, protein-bound paclitaxel, vinorelbine, eribulin, ixabepilone, immune checkpoint inhibitors, PD1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, or ATP cassette binding protein inhibitors. In some embodiments, the pharmaceutical compositions may include a selective serotonin reuptake inhibitor (eg, citalopram, escitalopram, fluoxetine, paroxetine, sertraline, or vilazodone).

[0066] In some embodiments, a pharmaceutical composition (e.g., a pharmaceutical composition comprising endoxifen) may be formulated for oral, topical, rectal, intravenous, intraarterial, parenteral or transdermal administration, or for administration by inhalation. In some embodiments, an endoxifen composition may be formulated as a sustained or delayed release composition. In some embodiments, an endoxifen composition may be formulated as a capsule or tablet. In some embodiments, an endoxifen composition may be formulated as a cream, gel, cream, emulsion, lotion, ointment, solution, paste, patch, or oil.

[0067] In various embodiments, the pharmaceutical compositions provided herein comprise from about 1% to about 99.99%, about 5% to about 95%, about 5% to about 90%, about 10% to about 80%, about 15% to about 70%, about 20% to about 60%, about 30% to about 95%, about 50% to about 90%, about 60% to about 90%, about 60% to about 80%, or about 70% to about 80% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise from about 99.99%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 99.99%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 89%, about 88%, about 87%, about 86%, or about 85% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 85%, about 84%, about 83%, about 82%, about 80%, about 79%, about 78%, about 77%, about 76%, about 75%, about 74%, about 73%, about 72%, about 71%, about 70%, about 69%, about 68%, about 67%, about 66%, or about 65% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 55%, about 54%, about 53%, about 52%, about 51%, about 50%, about 49%, about 48%, about 47%, about 46%, or about 45% by weight of one or more excipients. In certain embodiments, the compositions provided herein comprise about 30% by weight, about 29% by weight, about 28% by weight, about 27% by weight, about 26% by weight, about 25% by weight, about 24% by weight, about 23% by weight, about 22% by weight, about 21% by weight, or about 20% by weight of one or more excipients.

[0068] Examples of excipients that can be used in compositions formulated for oral administration are provided herein and may include, but are not limited to, one or more of a bulking agent, binder, filler, disintegrant, lubricant, glidant, release controlling agent, enteric coating, film former, plasticizer, colorant, sweetener, flavoring agent, etc., or any combination thereof.

[0069] Non-limiting examples of 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, 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, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, methylcellulose, polyvinylpyrrolidone, hydroxypropyl methylcellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (sold by 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 carboxymethylcellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103 and Starch 1500 LM.

[0070] Examples of fillers that are suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, talc, calcium carbonate (e.g., granular or powdered), sugars such as dextrose, sucrose, lactose, salts such as calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starch, microcrystalline cellulose, powdered cellulose, cellulose bases such as methylcellulose, carboxymethylcellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0071] The one or more binders or fillers in a composition are typically present at about 10% to about 99% (wt / wt) of the composition or dosage form, in some embodiments, the binder and / or filler in a composition comprises about 15% to 99%, about 20% to 60%, about 25% to 55%, about 30% to 50%, about 35% to 60%, or about 50% to 99% (wt / wt) of the composition.

[0072] Disintegrants can be used in the composition to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate during storage, while tablets that contain too little may not disintegrate at the desired speed or under the desired conditions. Therefore, a sufficient amount of disintegrant, not too much or too little, that does not adversely alter the release of active ingredients, should be used to form a solid oral dosage form. In some embodiments, the disintegrant is present deep in the oral solid dosage form to slow down disintegration. The amount of disintegrant used varies based on the type of formulation and is easily discernible to those skilled in the art.

[0073] In some embodiments, the composition comprises 0.5%-15% (wt / wt) of disintegrant. In some embodiments, the composition comprises 1%-5% (wt / wt) of disintegrant in the composition. In other embodiments, the disintegrant is 1%-25%, 2%-20%, 5%-15%, 8%-12%, or about 10% (wt / wt) of the composition.

[0074] Disintegrants that may be used in the pharmaceutical compositions 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, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0075] Lubricants that may be used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (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 laurate, agar, and mixtures thereof. Additional lubricants include, for example, syloid silica gel (AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore, Md.), coagulated aerosol of synthetic silica (available from Degussa Co. of Plano, Tex.), CAB O SIL (a pyrogenic silicon dioxide product available from Cabot Co. of Boston, Mass.), Q7-9120 (Dow Corning), and mixtures thereof. When lubricants are used, they are typically used in an amount of less than 1% (wt / wt) of the composition or dosage form in which they are incorporated. In yet another embodiment, the lubricant is 0.1% to 3%, e.g., 0.5% to 1% (wt / wt) of the composition.

[0076] Plasticizers can be added to control the softness or flexibility of oral dosage forms, such as capsules, caplets, or tablet shells, and thus improve the mechanical properties of pH-sensitive materials of coatings of oral dosage forms.Suitable plasticizers include, but are not limited to, petroleum oils (e.g., paraffinic processing oils, naphthenic processing oils, and aromatic processing oils), squalene, squalane, vegetable oils (e.g., olive oil, camellia oil, castor oil, tall oil, peanut oil), silicone oils, dibasic acid esters (e.g., dibutyl phthalate and dioctyl phthalate), liquid rubbers (e.g., polybutene, 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 glycol, polypropylene glycol, phthalate esters, sorbitol, glycol salicylate, crotamine, and glycerin, or mixtures thereof. The amount of plasticizer may vary depending on the chemical composition of the pharmaceutical preparation. In one embodiment, at least one plasticizer is sorbitol, dimethyl isosorbide, or glycerol. In another embodiment, the plasticizer is 1% to 10%, for example 3% to 5% (wt / wt) of the composition.

[0077] Examples of glidants include, but are not limited to, colloidal silicon dioxide, cellulose, calcium phosphate, dibasic or tribasic, and the like.

[0078] Examples of sweeteners or sweetening agents include sucrose, saccharin, dextrose, maltose, sugar replacers, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, acesulfame K, and the like.

[0079] Examples of flavoring agents include peppermint, methyl salicylate, peppermint, spearmint, methyl salicylate, raspberry, red berry, strawberry, pineapple, orange, cherry, and the like.

[0080] The compositions disclosed herein, for example tablets, caplets, and capsules, formulated for oral delivery, may be coated with one or more enteric coating agents, release control agents, or film-forming agents to control or delay the disintegration and absorption of the compositions comprising endoxifen or its salt in the gastrointestinal tract, thereby providing a sustained effect over a long period of time.Thus, in some embodiments, the tablet may be an enteric coated tablet, the caplet may be an enteric coated caplet, or the capsule may be an enteric coated capsule.The enteric coated tablets, caplets, or capsules of the present disclosure may be prepared by techniques known in the art.

[0081] The pharmaceutical preparations disclosed herein may also include controlled release agents. Examples of release control agents suitable for use include, but are not limited to, pH-dependent polymers, acid-insoluble polymers, methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate) polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, waxes such as synthetic waxes, microcrystalline wax, paraffin wax, carnauba wax, beeswax wax; polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl monobenate, glyceryl dibenate, glyceryl tribenate, 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, for example, glyceryl monostearate or glyceryl distearate may be employed, hi other embodiments, the controlled release agent is a digestible waxy substance such as hard paraffin wax.

[0082] In some embodiments, a pharmaceutical composition comprising endoxifen (e.g., (Z)-endoxifen) may be formulated as a sustained release composition. In some embodiments, a pharmaceutical composition comprising a phosphoinositide 3-kinase inhibitor (e.g., alpelisib) may be formulated as a sustained release composition. The sustained release agent present in the sustained release composition of the present disclosure may be any sustained release agent known in the art for slowing the release of a hydrophobic drug, such as (Z)-endoxifen or a polymorph or salt thereof.

[0083] Examples of sustained release agents include cellulose ethers, gums, acrylic resins such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate, and combinations thereof, polyvinylpyrrolidine, and protein-derived compounds. Examples of cellulose-based ethers include hydroxyalkylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose, e.g. No. 2208, 2906, 2910), carboxyalkylcellulose, and carboxymethylcellulose. In some embodiments, at least one sustained release agent is a pH sustained release agent, such as an acid-insoluble polymer that becomes more soluble and permeable above pH 5.0, but remains impermeable below pH 5.0. Such release-controlling polymers target the upper small intestine and / or colon. Non-limiting examples of acid insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, alginates such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers, available from Evonik or Rohm (Eudragit® sustained release polymers Eudragit® RL (high permeability), Eudragit® RS (low permeability), and Eudragit® NM30D (low permeability), either alone or in any combination thereof. The combination is such that the desired permeability for sustained release is achieved. The viscosity of the sustained release agent can be any viscosity suitable for sustained release of (Z)-endoxifen or a polymorph or salt thereof. In certain embodiments, the viscosity of at least the 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 having a viscosity ranging from about 1000 mPa.s to about 10,000 mPa.s, about 10,000 mPa.s to about 70,000 mPa.s, 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 or different viscosity, for example, one sustained release agent may have a viscosity in the range of about 1000 mPa.s to about 10,000 mPa.s, and another sustained release agent may have a viscosity in the range of about 10,000 mPa.s to about 70,000 mPa.s or about 70,000 mPa.s to about 150,000 mPa.s.

[0084] In some embodiments, the sustained release agent is HPMC / hypromellose (e.g., No. 2208, 2906, 2910). The hypromellose used in the present disclosure has an average molecular weight of about 20,000 to 500,000. In some embodiments, the hypromellose generally has an average molecular weight of 20,000 to 250,000. Hypromellose is available from Dow Chemicals under the trade name Methocell™, e.g., Methocell™ K100 (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). One grade of hypromellose may be used alone or in combination with another.

[0085] In some embodiments, the sustained release agent, such as hypromellose, generally has an average molecular weight in the range of 15,000 to 140,000 daltons, and in at least one embodiment, the average molecular weight is about 15,000 daltons, where the sustained release composition exhibits a sustained release of (Z)-endoxifen or a polymorph or salt thereof 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.

[0086] The amount of sustained release agent in the composition can be any amount effective to delay release of the therapeutic agent (Z)-endoxifen, or a polymorph or salt thereof, for about 2 hours after administration of the therapeutic agent, to protect the therapeutic agent from the acidic environment of the stomach, thereby allowing the therapeutic agent to pass through the stomach and enter the intestine, and to extend such release for about 2 hours to about 72 hours. The amount of sustained release agent in the composition can be any amount effective to result in a slower release rate of the therapeutic agent (Z)-endoxifen, or a polymorph or salt thereof, as compared to a reference product. In some embodiments, the amount of sustained release agent in the composition can be any amount effective to delay the release of the therapeutic agent (Z)-endoxifen, or a polymorph or salt thereof, by 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 after administration compared to a reference product.

[0087] In a dissolution test by 75 RPM USP paddle method, using simulated gastric fluid at pH 1.2 at 37° C. for 2 hours and simulated intestinal fluid at pH 6.8 at 37° C. for 24 hours as the test medium, if the sustained release composition exhibits a dissolution rate in the range of about 0% to 35% at 3 hours, about 35% to about 55% at 12 hours, and about 65% to 85% at 24 hours, at least one sustained release agent, for example, hypromellose (HPMC), may generally be present in the sustained release composition of the present disclosure in an amount of about 0.1% to about 99%, about 0.1% to about 90%, about 5% to about 90%, about 5% to about 80%, about 5% to about 70%, and about 5% to about 60% w / w of the sustained release composition. In some embodiments, the sustained release agent (e.g., gum, acrylic resin, methacrylic acid, methyl acrylate, methyl methyl acrylate, polyvinylpyrrolidine, protein-derived compound, hydroxyalkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxyalkyl cellulose, or carboxymethyl cellulose) may be present in an amount of about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 20% to about 40%, about 20% to about 50%, or 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%. The sustained release compositions of the present disclosure disclosed herein release (Z)-endoxifen or a polymorph or 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 hours, at least 18 hours, at least 24 hours, at least 48 hours, and at least 72 hours.

[0088] In some embodiments, the composition may include one or more pH-dependent polymers, such as acid-insoluble polymers. pH-dependent polymers are more permeable above pH 5.0 and impermeable below pH 5.0, while acid-insoluble polymers are soluble in neutral to slightly alkaline conditions. Such release-controlling polymers target the upper small intestine and colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, algenates, such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers (commercially available under the trade names EUDRAGIT® L and EUDRAGIT® S (Rohm America Inc., Piscataway, NJ), as a powder or a 30% aqueous dispersion; or EASTACRYL® (Eastman Chemical Co., Kingsport, TN), as a 30% dispersion). Additional examples include EUDRAGIT® L100-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S100, EUDRAGIT® S12,5, EUDRAGIT® FS 30D, EUDRAGIT® E100, EUDRAGIT® E 12,5, and EUDRAGIT® PO. In at least one embodiment, the composition comprises EUDRAGIT® L100-55. EUDRAGIT® RS and RL, as well as EUDRAGIT® NE and NM, are also useful polymers for purposes of the present disclosure. In some embodiments, the composition comprises EUDRAGIT® L30D 55. In another embodiment, the formulation comprises EUDRAGIT® FS 30D. One of ordinary skill in the art will recognize that at least some of the acid-insoluble polymers listed herein are also biodegradable.

[0089] For time-delayed or delayed release pharmaceutical preparations of oral dosage forms, glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, such as polymethacrylate, pH-sensitive polymer-based coatings can be used (e.g., as coating materials for enteric coatings, capsules, caplets, and tablets, etc.). Delayed release oral dosage forms are commercially available, such as DRCaps (Capsugel, USA) made of hypromellose (HPMC). Such delayed release oral dosage forms can be acid-resistant and resistant to the acidity found in the stomach for at least 30 minutes, such as at least 1 hour, at least 1.5 hours, or at least 2 hours. Such delayed release oral dosage forms can release at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of endoxifen or its salt in the intestine (such as small intestine, large intestine / colon).

[0090] In one aspect of the present disclosure, enteric coated tablets, enteric coated caplets, and enteric coated capsules may be uncoated. Uncoated hard capsules that have enteric capabilities inherently using enteric capsule technology (e.g., EnTrinsic Drug Delivery available from Capsugel) are suitable for the purposes of the present disclosure.

[0091] In various embodiments, the enteric coated tablet is a hard tablet made with a free-flowing powder of (Z)-endoxifen or a salt thereof. In various embodiments, the enteric coated capsule is a capsule made with a free-flowing powder of (Z)-endoxifen or a salt thereof. In various embodiments, the enteric coated tablet is a hard tablet made with a free-flowing powder of endoxifen or a polymorph thereof. In various embodiments, the enteric coated capsule is a capsule made with a free-flowing powder of endoxifen or a polymorph thereof.

[0092] In some embodiments, the enteric capsule is a non-animal capsule, such as a hypromellose capsule (e.g., commercially available self-gelling Vcaps, VCaps Plus, VCaps enteric capsules, Xcellodose, ENCODE colonic delivery technology, and other enteric capsules made using EnTrinsic™ drug delivery technology (Capsugel)). Other technologies known in the art and commercially available (e.g., Qualicaps, USA, Nutrascience, USA, etc.) are also available for formulating enteric forms of oral solid dosage forms. In at least one embodiment, the capsule is an API-in-capsule, which means that the (Z)-endoxifen free base or a salt thereof is loaded directly into the capsule. In such API-in-capsule oral dosage forms, the active ingredient, (Z)-endoxifen or a salt thereof, can be a free-flowing powder or a micronized powder. When the dosage form is a capsule, in at least one embodiment, the capsule can be a seamless capsule or a banded capsule.

[0093] The oral dosage form can be of any shape suitable for oral administration, such as spherical (0.05-5 mL), elliptical (0.05-7 mL), oval, pear-shaped (0.3-5 mL), cylindrical, cubic, regular and / or irregular shapes, etc. The oral dosage form can be of any size suitable for oral administration, e.g., size 0, size 2, etc.

[0094] The endoxifen composition of the present disclosure may be formulated as a pharmaceutical composition for topical or transdermal delivery. In some embodiments, the endoxifen composition for topical or transdermal delivery may be formulated as a cream, gel, cream, emulsion, lotion, ointment, solution, paste, patch, or oil. The endoxifen composition for topical or transdermal delivery may be applied to the skin of a subject to treat cancer (e.g., melanoma, esophageal cancer, or breast cancer). The topical or transdermal composition may be applied to a skin area at or near the location of the cancer. For example, a topical endoxifen composition may be applied to a cancerous skin growth site in a subject with melanoma, thereby treating the melanoma. In another example, a topical endoxifen composition may be applied to the skin around the throat of a subject with esophageal cancer, thereby treating the esophageal cancer. In some embodiments, pharmaceutical compositions for topical or transdermal administration may include (Z)-endoxifen, 2-(2-ethoxyethoxy)ethanol (e.g., transcutol), isopropanol, a fully saturated emollient triester (e.g., crodamol GTCC), and mineral oil.

[0095] Those skilled in the art will further recognize that the compositions disclosed herein may contain one or more of the excipients known in the art and disclosed herein in any combination that is appropriate for the desired formulation or preparation. Additional excipients are generally described in Remington's The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia. Those skilled in the art will be able to select the appropriate excipients required for the preparation of the formulation and the appropriate dosage form that is compatible with the route of administration based on their skills and knowledge and the disclosure made herein. In all cases, the final dosage form shall be sterile and stable under the conditions of manufacture and storage.

[0096] For the formulations of solid dosage compositions disclosed herein, total aerobic count (TAC) and USP indicator organism testing is typically not required since the water activity (Aw) is less than 0.75. The publication "Microbial Bioburden on Oral Solid Dosage Form" (Jose E. Martinez, Pharmaceutical Technology, February 2002, pages 58-70) is incorporated herein by reference in its entirety.

[0097] For other preparations, such as liquid or fluid preparations with a water activity of less than 0.75, testing for certain microorganisms (S. aureus, Ps. aeruginosa, Salmonella, C. albicans, Clostridia, E. coli, and bile-resistant gram-negative organisms) in accordance with USP Guideline Chapter 62 may not be required.

[0098] How to detect cancer Methods for treating cancer may include detection, diagnosis, and staging of cancer or precancerous tissue in a subject. Cancer detection can identify the type, distribution, stage, and severity of cancer, and can be used to determine the optimal course of treatment for a subject in need of it. Cancer detection can also be used to actively monitor cancer during and after treatment. In some cases, cancer detection is used to monitor a subject in remission.

[0099] In some cases, the cancer detection method (e.g., as part of a treatment method) includes tumor imaging. In some cases, the tumor imaging includes computed tomography, magnetic resonance imaging, positron emission tomography, ultrasound, X-ray imaging, or a combination thereof.

[0100] In some cases, the method of detecting cancer includes genetic testing. Tissues that are known to be cancerous or may be cancerous can be screened for genetic predisposition (e.g., genetic mutations) or mutations resulting from cancer or increased risk of developing cancer. In some cases, the method of monitoring or detecting colorectal cancer includes detecting mutations in one or more of APC, DCC, TP53, serine / threonine protein kinase B-Raf (BRAF), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), tumor protein P53 (P53), kisspeptin protein (KISS1), Rho family alpha serine / threonine protein kinase (AKT1), SMAD4, KRAS, HRAS, and catenin beta 1 (CTNNB1). In some cases, the method of monitoring or detecting melanoma includes detecting mutations in KRAS, HRAS, NRAS, BRAF, CDK4, or combinations thereof. In some cases, the method of monitoring or detecting neuroblastoma includes detecting mutations in anaplastic lymphoma kinase (ALK), PHOX2B, FLJ22536, BARD1, NBPF23, or a combination thereof.

[0101] In some cases, the method of detecting cancer includes expression profiling. In some cases, the method of monitoring or detecting colorectal cancer includes identifying overexpression of one or more of HER2, FOXQ1, CDCP1, NEDD4, human leukocyte antigen E protein (HLA-E), HOXC10, HsAIRK1, HsAIRK3, PLAGL2, and CK2α. In some cases, the method of monitoring or detecting melanoma includes identifying overexpression of KRAS, HRAS, NRAS, cyclin D1, HDM2, NF1, or a combination thereof. In some cases, the method of monitoring or detecting neuroblastoma includes identifying overexpression of ALK, MYCN, or TFAP4, decreased expression of NF1, or a combination thereof.

[0102] As used herein, the terms "about" and "approximately" in reference to numerical values ​​are used herein to include numerical values ​​that fall within 10%, 5%, or 1% of that numerical value in either direction (greater or smaller), unless otherwise stated or clear from the context (except where such numerical value exceeds 100% of its possible values).

[0103] As used herein, the terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0104] Any numerical value cited herein includes all values ​​from the lower limit to the upper limit, i.e., all possible combinations of numerical values ​​between the lowest and highest values ​​recited are considered to be expressly recited in this application, and all range endpoints are included within this range and are specifically understood to be independently combinable. For example, if a concentration range or useful range is recited as 1%-50%, it is intended herein to explicitly recite values ​​such as 2%-40%, 10%-30%, or 1%-3%. It is also understood that when a concentration or dose is recited as a specific value such as 1 mg or 10 mg, it is intended to include a 10% variation. As another example, when a concentration is recited as 20%, it is intended to include values ​​of ±10%. As yet another example, if a ratio of 1:10-10:1 is recited, it is intended that 1:9-9:1, 1:8-8:1, 1:7-7:1, 1:6-6:1, 1:5-5:1, 1:4-4:1, 1:3-3:1, 1:2-2:1, 1:1-2:1, or 2:5-3:5, etc., are specifically contemplated. Only some examples are given of what is specifically contemplated. Unless otherwise specified, values ​​for components or ingredients of a composition are expressed as the weight percent of each ingredient in that composition.

[0105] As used herein, the terms "active pharmaceutical ingredient", "active ingredient", "API", "drug", "active substance", "active substance(s)", or "therapeutic agent" may be used interchangeably to refer to a pharma- ceutically active compound(s) in a pharmaceutical composition. This is in contrast to other components in the composition, such as excipients, which are substantially or completely pharma- ceutically inactive. Suitable APIs according to the present disclosure are those for which there is or may be a patient compliance issue for treating a particular disease, condition, or disorder. Therapeutic agents as used herein include active compounds and their salts, prodrugs, and metabolites. The term "drug" as used herein means a compound intended for use in the diagnosis, cure, mitigation, treatment, and / or prevention of disease in humans or other animals.

[0106] As used herein, "adjuvant therapy" refers to therapy administered to subjects at risk of recurrence after primary therapy.In the case of breast cancer or reproductive cancer, adjuvant systemic therapy, for example with tamoxifen, is usually initiated immediately after primary therapy to delay recurrence, prolong survival, or cure the subject.

[0107] Throughout this specification, embodiments referring to "compounds," such as compounds of Formula (I), Formula (II), Formula (III) and Formula (IV), include polymorphs, salts, free bases, co-crystals, and solvate forms of the formulas and / or compounds disclosed herein. Thus, occurrences of the phrases "compound," "compound of Formula (I)," "compound of Formula (II)," "compound of Formula (III)," and "compound of Formula (IV)" include Form I of compound of Formula (IV), Forms II-III of compound of Formula (III), the free base of compound of Formula (IV), the free base of compound of Formula (III), and / or the gluconate salt, as described herein.

[0108] The terms "crystalline form", "polymorph" and "form" may be used interchangeably herein and are meant to include all crystalline and amorphous forms of a compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, nonsolvated polymorphs (including anhydrous), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of these compounds, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, nonsolvated polymorphs (including anhydrous), conformational polymorphs, and amorphous forms, and mixtures thereof, of the compounds.

[0109] It is further understood that all compounds disclosed herein include all possible isotopes of atoms present in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of example and without limitation, isotopes of hydrogen include tritium and deuterium, isotopes of carbon include tritium and deuterium, and isotopes of carbon include tritium and deuterium. 11 C. 13 C, and 14 C is an example.

[0110] The terms "comprising," "containing," and "including" as used in the specification and claims are inclusive and open-ended and do not exclude additional, unrecited elements, components, or method steps. Thus, the terms "comprising" and "including" encompass the more restrictive terms "consisting of" and "consisting essentially of."

[0111] As used herein, the term "combination therapy" refers to the use of the compositions described herein in combination with one or more additional treatments. The treatment in the combination therapy can be any treatment, such as any prophylactic agent, therapeutic agent (such as chemotherapy), radiation therapy, surgery, etc. Combination can refer to the inclusion of a therapeutic or prophylactic agent in the same composition (e.g., in the same capsule, tablet, ointment, etc.) or in separate compositions (e.g., in two separate capsules) as the compositions disclosed herein. The separate compositions may be in different dosage forms. The use of the terms "combination therapy" and "in combination with" does not limit the order in which the compositions, prophylactic and / or therapeutic agents and / or treatments described herein are administered to a subject in need thereof. Compositions of the disclosure may be administered orally or intravenously prior to administration of one or more prophylactic and / or therapeutic agents and / or treatments to a subject (e.g., 1 minute (min), 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour (hr), 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 96 hours, 1 week (wk), 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, 6 months (months), The combination therapy may be administered 1 min (min), 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 1 wk (wk), 2 wk, 3 wk, 4 wk, 5 wk, 6 wk, 8 wk, 12 wk, 6 mo (mo), 9 mo, or 1 y (y). Combination therapy as used herein may also refer to the treatment of a subject with one disease or multiple diseases, such as prostate cancer and gynecomastia in men.

[0112] As used herein, the term "pharmaceutically acceptable carrier" or "carrier" means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting one or more of the compounds of the present disclosure through a tissue, organ, or part of the body, or across the skin.

[0113] As used herein, the term "pharmaceutical acceptable salt" refers to any salt of a compound of the present disclosure (e.g., obtained by reaction with an acid or base) that is physiologically acceptable in a subject (e.g., a mammal, and / or in a cell, tissue, or organ in vivo, ex-vivo, or in vitro). The "salts" of the compounds of the present disclosure may be derived from inorganic or organic acids and bases. Suitable anionic salts include arecoline, besylate, bicarbonate, bitartrate, butyl bromide, citrate, camysylate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methyl bromide, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate / diphosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, fatty acid anions, and triethiodide.

[0114] Suitable cations include benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc.

[0115] As used herein, the term "pharmaceutical composition" means a combination of an active agent (e.g., an active pharmaceutical compound or ingredient, API) with an inert or active carrier (e.g., phospholipids) that makes the composition particularly suitable for diagnostic or therapeutic use in vitro, in vivo, or ex vivo.

[0116] 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, mammals may be of any gender or sex.

[0117] All methods described herein may be performed in any suitable order unless otherwise indicated or clearly contradicted by context. Any and all examples provided herein, or the use of exemplary language (e.g., "such as" and "the like"), are intended merely to illustrate the invention and do not impose limitations on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating that any non-claimed element, as used herein, is essential to the practice of the invention.

[0118] As used herein, the term "cancer" may refer to the presence of cells exhibiting abnormal growth within an organism. The cells often exhibit a recognizable expression profile and morphology, as well as behaviors such as uncontrolled growth and proliferation, metastatic potential, and immortality. Cancer cells may exist within a tumor, within non-cancerous tissue, or away from other cells (e.g., in the circulation or lymphatic spaces). EXAMPLES

[0119] The invention is further illustrated by the following non-limiting examples.

[0120] Example 1 Screening endoxifen in patient-derived tumor organoids This example describes the screening of endoxifen in patient-derived tumor organoids. Endoxifen was tested as a single agent on tumor organoids derived from patients diagnosed with various cancer types using a personalized cancer treatment screening assay (PARIS® Test, SEngine Precision Medicine). This screen utilizes patient-derived tumor organoids (PDTOs) with high-throughput drug screening and machine learning-based data analysis to quantify the efficacy of endoxifen on samples derived from individual patients diagnosed with various cancer types. PDTOs are self-organizing three-dimensional organoid structures that recapitulate the structural, functional, and genomic aspects of in vivo organs. PDTOs are grown in culture from patient tumor biopsy samples.

[0121] Fresh patient biopsy samples received after surgery were washed and purified. To establish pure PDTO for endoxifen testing, immune cells (e.g., lymphocytes, blood cells), cancer-associated fibroblasts, and other non-tumor cells were removed. Tumor organoids were grown and expanded by supplying organ- and patient-specific growth factors and nutrients. PDTO were treated with increasing concentrations of endoxifen ranging from about 30 nM to about 10 μM, and drug response was measured using luminescence readouts. Lower luminescence indicates stronger drug response.

[0122] The results were analyzed using the "SEngine Precision Medicine" (SPM) scoring system to assess the sensitivity and individualization of each tumor organoid to endoxifen. The SPM score correlates with clinical outcome, such that the higher the SPM score of a particular PDTO-drug combination, the more favorable the clinical outcome after treatment of the corresponding patient with the test drug.

[0123] Example 2 A study of the efficacy of endoxifen against 17 different types of cancer This example describes a method to test the efficacy of endoxifen against 17 different cancer types in patient-derived tumor organoids (PDTOs). Screening of PDTOs was performed as described in Example 1. For each PDTO sample, luminescence readings at a range of endoxifen concentrations were used to measure drug response. Drug response was evaluated based on the fitted area under the dose-response curve (AUC) and the SPM scoring system. AUC values ​​were normalized for each PDTO. Briefly, the data points for each drug concentration were first normalized to the negative control, and then a dose-response drug curve was fitted using a four-parameter logistic model that was fitted to the normalized data points. The area under the curve was calculated from the normalized curve. Normalization allowed comparison of AUC values ​​between patient samples. The SPM score was based on a machine learning model that incorporated values ​​for how well the drug killed the patient's cells (sensitivity metrics), the patient's relative drug response to all other patients in the sample database (individualization metrics), and knowledge of the patient's clinical outcome as assessed by a personalized cancer screening assay (PARIS® Test, SEngine Precision Medicine).

[0124] The SPM scoring system assessed whether PDTOs were non-responsive or responsive to endoxifen, and the degree of drug response for PDTOs that were responsive to endoxifen. The SPM scoring system generated a metric, the SPM score, that predicted clinical outcome, overall drug response (response category), drug sensitivity (sensitivity category), and drug individualization (individualization category). SPM scores range from 1 to 15 and correspond to the following drug response categories: no response (SPM1–8), poor response (SPM9), moderate response (SPM10–11), good response (SPM12–13), and excellent response (SPM14–15). Drugs that exhibit excellent response (SPM14–15) often indicate that the drug has clinical relevance as a monotherapy. Moderate to good drug response (SPM10–13) may indicate that the drug has clinical relevance, possibly in combination with other drugs. The sensitivity category is determined from the sensitivity metrics and is a measure of the overall cell death of the patient's cells in response to the six concentrations of endoxifen. Sensitivity categories range from high, good, moderate, poor, and none. The personalized category is determined from the personalized metrics and is a measure of how well the PDTO responded to endoxifen compared to other PDTOs evaluated using the same personalized cancer screening assay. Personalized categories range from high, good, moderate, poor, and none.

[0125] As shown in Figure 1 and Table 1, endoxifen induced drug responses in samples from patients with breast, cervical, bile duct, colon, esophageal, gastric, melanoma, neuroblastoma, ovarian, pancreatic ductal, and rectal cancer. Figure 1 shows the number of samples tested for each cancer type and the drug response category for each sample. The SPM score, sensitivity category, individualized category, and response category for each sample are shown in Table 1. Table 1 for each sample lists the concentration of endoxifen that inhibits 50% of tumor cells in vitro (IC 50 ), AUC, and goodness of fit (GOF) of a four-parameter logistic curve to the six experimental data points are also shown. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0126] The number of patient samples tested for each cancer type is summarized in Figure 33. Patient-specific results for individual cancer types are described in more detail in Examples 3-13. No responses were observed in test samples from patients with endometrial cancer (Figure 13), leiomyosarcoma (Figures 16A, 16B, and 16C), myxofibrosarcoma (Figure 17), primary peritoneal cancer (Figure 29), sarcoma (Figure 31), or thyroid cancer (Figure 32). However, the sample sizes for these cancer types were too small to rule out the possibility that a drug response to endoxifen could have been observed.

[0127] Example 3 Breast cancer response to endoxifen in patient-derived samples This example describes the response of breast cancer to endoxifen measured in patient-derived tumor organoids (PDTOs). Screening of PDTOs was performed as described in Example 1. PDTOs from 15 different breast cancer patients were screened for response to endoxifen. Individual dose-response curves for each patient are shown in Figures 2A, 2B, 2C, 2D, 3A, 3B, 3C, 3D, 4A, 4B, 4C, 4D, 5A, 5B, and 5C. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided for each dose-response curve. IC 50 (μM) is provided where possible calculated by a four-parameter logistic model. IC 50 If the IC is not within the range of drug concentrations tested, 50 was not extrapolated. The diagnosis of each breast cancer patient and the sensitivity, individualized, and response categories for the PDTO endoxifen response are summarized in Table 2. Further details of each patient sample are provided in Table 1 and Example 2. [Table 2]

[0128] One breast cancer patient sample was classified as having an excellent response to endoxifen, two samples were classified as having a good response, two samples were classified as having a moderate response, and three samples were classified as having a poor response. In particular, of the samples from patients diagnosed with triple-negative breast cancer (patients 11, 12, 15, 16, 36, and 45), one was classified as having an excellent response, one was classified as having a good response, and one was classified as having a poor response. Taken together, these data suggest that endoxifen may be an effective treatment for various breast cancers, including triple-negative breast cancer.

[0129] Example 4 Cervical cancer response to endoxifen in patient-derived samples This example describes the response of cervical cancer to endoxifen measured in patient-derived tumor organoids (PDTOs). Screening of PDTOs was performed as described in Example 1. PDTOs derived from a cervical cancer patient (patient 10) were screened for response to endoxifen. The dose-response curve is shown in Figure 6. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided. IC 50 (μM) was calculated by a four-parameter logistic model. The patient was diagnosed with cervical carcinoma. The sensitivity of the endoxifen response was classified as low, the individualization of the response was classified as good, and the response was classified as moderate. Further details of the patient sample are shown in Table 1 and Example 2. This data suggests that endoxifen may be an effective treatment for cervical cancer.

[0130] Example 5 Cholangiocarcinoma response to endoxifen in patient-derived samples This example describes the response of cholangiocarcinoma to endoxifen measured in patient-derived tumor organoids (PDTO). PDTO screening was performed as described in Example 1. PDTO from three different cholangiocarcinoma patients were screened for response to endoxifen. Individual dose-response curves for each patient are shown in Figure 7A, Figure 7B, and Figure 7C. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided for each dose-response curve. IC 50 (μM) is provided where possible calculated by a four-parameter logistic model. IC 50 If the IC is not within the range of drug concentrations tested, 50 was not extrapolated. The diagnosis of each cholangiocarcinoma patient and the sensitivity, individualized, and response categories for the PDTO endoxifen response are summarized in Table 3. Further details of each patient sample are provided in Table 1 and Example 2. [Table 3]

[0131] One cholangiocarcinoma patient sample was classified as having a low response to endoxifen. This data suggests that endoxifen may be an effective treatment for cholangiocarcinoma.

[0132] Example 6 Colorectal cancer response to endoxifen in patient-derived samples This example describes the response of colon cancer to endoxifen measured in patient-derived tumor organoids (PDTO). Screening of PDTO was performed as described in Example 1. PDTO from 15 different colon cancer patients was screened for response to endoxifen. Individual dose-response curves of each patient are shown in Figure 8A, Figure 8B, Figure 8C, Figure 9A, Figure 9B, Figure 9C, Figure 9D, Figure 10A, Figure 10B, Figure 10C, Figure 10D, Figure 11A, Figure 11B, Figure 11C, and Figure 11D. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided for each dose-response curve. IC 50 (μM) is provided where possible calculated by a four-parameter logistic model. IC 50 If the IC is not within the range of drug concentrations tested, 50 was not extrapolated. The diagnosis of each colon cancer patient and the sensitivity, individualized, and response categories for the PDTO endoxifen response are summarized in Table 4. Further details of each patient sample are provided in Table 1 and Example 2. [Table 4]

[0133] Two colon cancer patient samples were classified as having a moderate response to endoxifen and two samples were classified as having a poor response. Taken together, these data suggest that endoxifen may be an effective treatment for colon cancer.

[0134] Example 7 Esophageal cancer response to endoxifen in patient-derived samples This example describes the response of esophageal cancer to endoxifen measured in patient-derived tumor organoids (PDTOs). Screening of PDTOs was performed as described in Example 1. PDTOs derived from a patient with esophageal adenocarcinoma (patient 14) were screened for response to endoxifen. The dose-response curve is shown in Figure 12. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided. IC 50 (μM) was calculated by a four-parameter logistic model. The patient was diagnosed with metastatic esophageal cancer. The sensitivity of the endoxifen response was classified as low, the individualization of the response was classified as good, and the response was classified as moderate. Further details of the patient sample are shown in Table 1 and Example 2. This data suggests that endoxifen may be an effective treatment for esophageal adenocarcinoma.

[0135] Example 8 Gastric cancer response to endoxifen in patient-derived samples This example describes the response of gastric cancer to endoxifen measured in patient-derived tumor organoids (PDTO). Screening of PDTO was performed as described in Example 1. PDTO from six different gastric cancer patients was screened for response to endoxifen. Individual dose-response curves of each patient are shown in Figure 14A, Figure 14B, Figure 15A, Figure 15B, Figure 15C, and Figure 15D. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided for each dose-response curve. IC 50 (μM) is provided where possible calculated by a four-parameter logistic model. IC 50 If the IC is not within the range of drug concentrations tested, 50 was not extrapolated. The diagnosis of each gastric cancer patient and the sensitivity, individualized, and response categories for the PDTO endoxifen response are summarized in Table 5. Further details of each patient sample are provided in Table 1 and Example 2. [Table 5]

[0136] Two gastric cancer patient samples were classified as having a good response to endoxifen, two samples were classified as having a moderate response, and one sample was classified as having a poor response. Taken together, these data suggest that endoxifen may be an effective treatment for gastric cancer.

[0137] Example 9 Melanoma response to endoxifen in patient-derived samples This example describes the response of melanoma to endoxifen measured in patient-derived tumor organoids (PDTOs). PDTOs were screened as described in Example 1. PDTOs from four different melanoma patients were screened for response to endoxifen. Individual dose-response curves for each patient are shown in Figure 18A, Figure 18B, Figure 18C, and Figure 18D. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided for each dose-response curve. IC 50 (μM) is provided where possible calculated by a four-parameter logistic model. IC 50 If the IC is not within the range of drug concentrations tested, 50 was not extrapolated. The diagnosis of each melanoma patient and the sensitivity, individualized, and response categories for the PDTO endoxifen response are summarized in Table 6. Further details of each patient sample are provided in Table 1 and Example 2. [Table 6]

[0138] One melanoma patient sample was classified as having a good response to endoxifen, two samples were classified as having a moderate response, and one sample was classified as having a poor response. Taken together, these data suggest that endoxifen may be an effective treatment for melanoma.

[0139] Example 10 Neuroblastoma response to endoxifen in patient-derived samples This example describes the response of neuroblastoma to endoxifen measured in patient-derived tumor organoids (PDTO). PDTO screening was performed as described in Example 1. PDTO from three different neuroblastoma patients were screened for response to endoxifen. Individual dose-response curves of each patient are shown in Figure 19A, Figure 19B, and Figure 19C. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided for each dose-response curve. IC 50 (μM) is provided where possible calculated by a four-parameter logistic model. IC 50 If the IC is not within the range of drug concentrations tested, 50 The diagnosis of each neuroblastoma patient and the sensitivity, individualized, and response categories for the PDTO endoxifen response are summarized in Table 7. Further details of each patient sample are provided in Table 1 and Example 2. [Table 7]

[0140] One neuroblastoma patient sample was classified as having a moderate response to endoxifen and one sample was classified as having a poor response. Taken together, these data suggest that endoxifen may be an effective treatment for neuroblastoma.

[0141] Example 11 Ovarian cancer response to endoxifen in patient-derived samples This example describes the response of ovarian cancer to endoxifen measured in patient-derived tumor organoids (PDTO). PDTO screening was performed as described in Example 1. PDTO from 29 different ovarian cancer patients was screened for response to endoxifen. Individual dose-response curves of each patient are shown in Figure 20A, Figure 20B, Figure 20C, Figure 21A, Figure 21B, Figure 21C, Figure 21D, Figure 22A, Figure 22B, Figure 22C, Figure 22D, Figure 23A, Figure 23B, Figure 23C, Figure 23D, Figure 24A, Figure 24B, Figure 24C, Figure 24D, Figure 25A, Figure 25B, Figure 25C, Figure 25D, Figure 26A, Figure 26B, Figure 26C, Figure 26D, Figure 27A, and Figure 27B. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided for each dose-response curve. I C 50 (μM) is provided where possible calculated by a four-parameter logistic model. IC 50 If the IC is not within the range of drug concentrations tested, 50 was not extrapolated. The diagnosis of each ovarian cancer patient and the sensitivity, individualized, and response categories for the PDTO endoxifen response are summarized in Table 8. Further details of each patient sample are provided in Table 1 and Example 2. [Table 8]

[0142] Four ovarian cancer patient samples were classified as having a moderate response to endoxifen, and six samples were classified as having a poor response. Taken together, these data suggest that endoxifen may be an effective treatment for ovarian cancer.

[0143] Example 12 Pancreatic cancer response to endoxifen in patient-derived samples This example describes the response of pancreatic cancer to endoxifen measured in patient-derived tumor organoids (PDTOs). PDTOs were screened as described in Example 1. PDTOs from three different pancreatic cancer patients were screened for response to endoxifen. Individual dose-response curves for each patient are shown in Figure 28A, Figure 28B, and Figure 28C. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided for each dose-response curve. IC 50 (μM) is provided where possible calculated by a four-parameter logistic model. IC 50 If the IC is not within the range of drug concentrations tested, 50 was not extrapolated. The diagnosis of each pancreatic cancer patient and the sensitivity, individualized, and response categories for the PDTO endoxifen response are summarized in Table 9. Further details of each patient sample are provided in Table 1 and Example 2. [Table 9]

[0144] One pancreatic cancer patient sample was classified as having a moderate response to endoxifen and one sample was classified as having a poor response. Taken together, these data suggest that endoxifen may be an effective treatment for pancreatic cancer.

[0145] Example 13 Response of rectal cancer to endoxifen in patient-derived samples This example describes the response of rectal cancer to endoxifen measured in patient-derived tumor organoids (PDTOs). Screening of PDTOs was performed as described in Example 1. PDTOs derived from a rectal cancer patient (patient 19) were screened for response to endoxifen. The dose-response curve is shown in Figure 30. Curve metrics such as area under the curve (AUC) and goodness of fit (GOF) are provided. IC 50(μM) was calculated by a four-parameter logistic model. The patient was diagnosed with rectal adenocarcinoma. The sensitivity of the endoxifen response was classified as low, the individualization of the response was classified as low, and the response was classified as low. Further details of the patient sample are shown in Table 1 and Example 2. This data suggests that endoxifen may be effective in treating rectal cancer.

[0146] Example 14 Treating Triple-Negative Breast Cancer with Endoxifen This example describes the treatment of triple-negative breast cancer using endoxifen. Patients diagnosed with triple-negative breast cancer are administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is orally administered once a day for at least 28 days until tumor shrinkage, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat triple-negative breast cancer. Administration of Z-endoxifen treats triple-negative breast cancer in patients.

[0147] Example 15 Treating Cervical Cancer with Endoxifen This example describes the treatment of cervical cancer using endoxifen. A patient diagnosed with cervical cancer is administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is administered orally once a day for at least 28 days until tumor shrinkage, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat cervical cancer. Administration of Z-endoxifen treats cervical cancer in the patient.

[0148] Example 16 Treating Bile Duct Cancer with Endoxifen This example describes the treatment of cholangiocarcinoma using endoxifen. Patients diagnosed with cholangiocarcinoma are administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is orally administered once a day for at least 28 days until tumor shrinkage, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat cholangiocarcinoma. Administering Z-endoxifen treats cholangiocarcinoma in patients.

[0149] Example 17 Treating colon cancer with endoxifen This example describes the treatment of colon cancer with endoxifen. A patient diagnosed with colon cancer is administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is administered orally once a day for at least 28 days until tumors shrink, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapies are used in combination with endoxifen to treat colon cancer. Administration of Z-endoxifen treats colon cancer in the patient.

[0150] Example 18 Treating Esophageal Cancer with Endoxifen This example describes the treatment of esophageal cancer using endoxifen. A patient diagnosed with esophageal cancer is administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is administered orally once a day for at least 28 days until tumor shrinkage, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat esophageal cancer. Administration of Z-endoxifen treats esophageal cancer in the patient.

[0151] Example 19 Treating Gastric Cancer with Endoxifen This example describes the treatment of gastric cancer using endoxifen. A patient diagnosed with gastric cancer is administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is administered orally once a day for at least 28 days until tumor shrinkage, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat gastric cancer. Administration of Z-endoxifen treats gastric cancer in the patient.

[0152] Example 20 Treating Melanoma with Endoxifen This example describes the treatment of melanoma using endoxifen. Patients diagnosed with melanoma are administered Z-endoxifen. Z-endoxifen is formulated for local delivery. Z-endoxifen is administered locally once a day for at least 28 days until tumor shrinks, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat melanoma. Administration of Z-endoxifen treats melanoma in patients.

[0153] Example 21 Treating Neuroblastoma with Endoxifen This example describes the treatment of neuroblastoma using endoxifen. Patients diagnosed with neuroblastoma are administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is orally administered once a day for at least 28 days until tumor shrinkage, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat neuroblastoma. Administration of Z-endoxifen treats neuroblastoma in patients.

[0154] Example 22 Treating ovarian cancer with endoxifen This example describes the treatment of ovarian cancer using endoxifen. A patient diagnosed with ovarian cancer is administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is administered orally once a day for at least 28 days until tumor shrinkage, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat ovarian cancer. Administration of Z-endoxifen treats ovarian cancer in a patient.

[0155] Example 23 Treating pancreatic cancer with endoxifen This example describes the treatment of pancreatic cancer using endoxifen. A patient diagnosed with pancreatic cancer is administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is administered orally once a day for at least 28 days until tumor shrinkage, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat pancreatic cancer. Administration of Z-endoxifen treats pancreatic cancer in the patient.

[0156] Example 24 Treating rectal cancer with endoxifen This example describes the treatment of rectal cancer with endoxifen. A patient diagnosed with rectal cancer is administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is administered orally once a day for at least 28 days until tumor shrinkage, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat rectal cancer. Administration of Z-endoxifen treats rectal cancer in a patient.

[0157] Example 25 Treatment of gastrointestinal adenocarcinoma with endoxifen This example describes the treatment of gastrointestinal adenocarcinoma with endoxifen. A patient diagnosed with gastrointestinal adenocarcinoma cancer is administered Z-endoxifen. Z-endoxifen is formulated for oral delivery. Z-endoxifen is administered orally once daily for at least 28 days until tumor shrinkage, metastasis slows, or unacceptable toxicity is observed. Optionally, additional anti-cancer therapies are used in combination with endoxifen to treat gastrointestinal adenocarcinoma. Administration of Z-endoxifen treats gastrointestinal adenocarcinoma.

[0158] Example 26 Treating Metastatic Skin Cancer with Endoxifen In this example, the treatment of metastatic skin cancer using endoxifen is described. The onset of skin cancer is confirmed to be metastatic. A subject with skin cancer is orally administered Z-endoxifen once a day for at least 28 days until the rate of metastasis slows, as measured by the reduction in the subject's cell-free DNA (cfDNA) and circulating tumor cell count. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat metastatic skin cancer. The administration of Z-endoxifen treats the subject's metastatic skin cancer.

[0159] Example 27 Treatment of metastatic gastrointestinal cancer with endoxifen In this example, the treatment of metastatic gastrointestinal cancer using endoxifen is described. The occurrence of gastrointestinal cancer is confirmed to be metastatic. Subjects with gastrointestinal cancer are orally administered Z-endoxifen once a day for at least 28 days until metastasis slows, as measured by a decrease in tumor marker levels by urine testing. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat metastatic gastrointestinal cancer. The administration of Z-endoxifen treats the subject's metastatic gastrointestinal cancer.

[0160] Example 28 Dual treatment of gastrointestinal cancer with endoxifen and radiotherapy This example describes the treatment of gastrointestinal cancer using endoxifen and radiation therapy. The subject is diagnosed with gastrointestinal cancer. High incidence sites of gastrointestinal cancer are irradiated multiple times per month to a total cumulative radiation dose of 1-100 Gy. The subject is simultaneously administered Z-endoxifen orally once per day during radiation therapy and optionally after radiation therapy is completed. Optionally, an additional anti-cancer therapy is used in combination with endoxifen to treat the gastrointestinal cancer. A combined radiation therapy, Z-endoxifen course treats the subject's gastrointestinal cancer.

[0161] Example 29 Endoxifen Treatment After Surgical Melanocytic Tumor Removal In this example, endoxifen treatment after surgical tumor removal is described. A melanocytic tumor is surgically removed from a melanoma patient. The patient is then administered endoxifen to ensure removal of residual cancer cells. The subject is orally administered Z-endoxifen once a day until melanoma is no longer detectable or until unacceptable toxicity is observed. Optionally, additional anti-cancer therapy is used in combination with endoxifen to treat melanoma. Administration of Z-endoxifen treats melanoma in the patient.

[0162] 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 is understood that various alternatives to the embodiments of the invention described herein may be employed in the practice of 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, are covered thereby.

Claims

1. 1. A composition for use in a method for treating gastrointestinal cancer in a subject in need thereof, the composition comprising a therapeutically effective amount of endoxifen.

2. The composition of claim 1 , wherein the gastrointestinal cancer is colon cancer, gastric cancer, pancreatic cancer, esophageal cancer, rectal cancer, biliary tract cancer, cholangiocarcinoma, or a combination thereof.

3. The digestive system cancer is (a) is a carcinoma; (b) adenocarcinoma; (c) colorectal cancer, optionally wherein the gastrointestinal cancer is colon cancer, and further optionally wherein the colon cancer is sigmoid colon cancer, adenocarcinoma of the colon, stage III colon cancer, stage IV colon cancer, or descending colon cancer, or gastric cancer; (d) gastric cancer; (e) pancreatic cancer, optionally wherein the pancreatic cancer is pancreatic ductal adenocarcinoma, metastatic pancreatic ductal adenocarcinoma, or stage III metastatic pancreatic ductal adenocarcinoma; (f) esophageal cancer, optionally wherein the esophageal cancer is esophageal adenocarcinoma or metastatic esophageal cancer; (g) rectal cancer, optionally wherein the rectal cancer is rectal adenocarcinoma; (h) biliary tract cancer. (i) cholangiocarcinoma, optionally wherein the cholangiocarcinoma is metastatic cholangiocarcinoma; or (j) a combination thereof; The composition according to claim 1 or claim 2.

4. 3. The composition of claim 1 or claim 2, wherein the gastrointestinal cancer is metastatic, recurrent, or a combination thereof.

5. 1. A composition for use in a method for treating skin cancer in a subject in need thereof, the composition comprising a therapeutically effective amount of endoxifen.

6. the skin cancer is melanoma, and optionally (a) the melanoma is acral melanoma, recurrent acral melanoma, or anorectal melanoma, or a combination thereof; or (b) the skin cancer is metastatic, or recurrent, or a combination thereof.

7. 1. A composition for use in a method for treating neuroblastoma in a subject in need thereof, the composition comprising a therapeutically effective amount of endoxifen.

8. 8. The composition of claim 7, wherein the neuroblastoma is metastatic, recurrent, or a combination thereof.

9. 8. The composition of any one of claims 1, 5, and 7, wherein the endoxifen is (Z)-endoxifen.

10. 10. The composition of claim 9, wherein the (Z)-endoxifen has an isomeric purity of at least 90%.

11. 8. The composition of any one of claims 1, 5, and 7, wherein the composition is administered orally, topically, rectally, intravenously, intraarterially, parenterally, transdermally, or by inhalation.

12. The composition of claim 11, wherein the composition is administered orally.

13. 8. The composition of any one of claims 1, 5, and 7, wherein the composition is formulated as a sustained release composition, or a delayed release composition, or a combination thereof.

14. 8. The composition of any one of claims 1, 5, and 7, wherein the composition is formulated as a capsule or tablet.

15. The composition is administered to the subject: (a) endoxifen at a dose of 1 mg or more and 160 mg or less per day; (b) endoxifen at a dose of 1 mg or more and 40 mg or less per day; (c) endoxifen at a dose of 1 mg to 10 mg per day, or (d) endoxifen at a dose of 2 mg to 5 mg per day; 8. The composition of any one of claims 1, 5 and 7, which is administered daily.

16. 12. The composition of claim 11, wherein the composition is administered once, twice, three times, or four times per day.

17. 12. The composition of claim 11, wherein the composition is administered for at least 7 days, at least 14 days, at least 21 days, or at least 28 days.

18. Administration of the composition results in a systemic endoxifen C of about 0.01 to about 50 μM in the subject. ｍａｘ is achieved, or administration of the composition achieves a systemic endoxifen C max of about 1 to about 10 μM in the subject; or 8. The composition of any one of claims 1, 5, and 7, wherein administration of the composition maintains a systemic endoxifen concentration of at least 1 μM in the subject for at least one week.

19. The composition described in any one of claims 1, 5, and 7, characterized in that the composition is administered in combination with an additional therapeutic agent.

20. 20. The composition of claim 19, wherein the additional therapeutic agent comprises an anti-cancer agent, optionally wherein the anti-cancer agent is selected from the group consisting of bicalutamide, enzalutamide, trastuzumab, atezolizumab, alpelisib, olaparib, talazoparib, ribociclib, neratinib, antineoplastic agents, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, pegylated liposomal doxorubicin, epirubicin, fluorouracil, gemcitabine, methotrexate, paclitaxel, protein-bound paclitaxel, vinorelbine, eribulin, ixabepilone, immune checkpoint inhibitors, PD1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, and ATP cassette binding protein inhibitors.

21. 20. The composition of claim 19, wherein the additional therapeutic agent comprises a selective serotonin reuptake inhibitor, wherein the selective serotonin reuptake inhibitor comprises citalopram, escitalopram, fluoxetine, paroxetine, sertraline, or vilazodone, or a combination thereof.

22. The composition of any one of claims 1, 5, and 7, wherein the method further comprises surgical tumor removal and / or radiation therapy, and optionally administration of the composition is performed simultaneously with, after, or simultaneously and after the surgical tumor removal, or radiation therapy, or a combination thereof.

23. The composition of claim 9, wherein the (Z)-endoxifen has an isomeric purity of at least 95%.

24. The composition of claim 13, wherein the composition is formulated as an enteric-coated tablet, enteric-coated caplet, or enteric-coated capsule.

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