Combination of nab-sirolimus and estrogen inhibitors for the treatment of hormone-dependent cancers

Abstract

This application relates, in certain embodiments, to a method and composition for treating hormone-dependent cancers (such as endometrial cancer (e.g., endometrioid endometrial cancer) or hormone receptor-positive breast cancer) by using a composition comprising nanoparticles containing sirolimus and albumin in combination with an estrogen inhibitor (such as letrozole or fulvestrant).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 531,511, filed on 8 August 2023, the entire contents of which are incorporated herein by reference for any purpose.

[0002] In certain embodiments, the present invention relates to a method and composition for treating hormone-dependent cancer by using a composition comprising an mTOR inhibitor (such as sirolimus) and albumin-containing nanoparticles in combination with an estrogen inhibitor (such as letrozole or fulvestrant). [Background technology]

[0003] Hormone-dependent cancers, such as endometrial cancer (e.g., endometrioid endometrial cancer) or hormone receptor-positive cancers (e.g., hormone receptor-positive breast cancer), are difficult to treat because most patients become resistant to standard endocrine therapy. Therefore, current standard treatments present a significant challenge in providing long-term care to patients.

[0004] mTOR inhibitors are widely used to treat a variety of conditions, including solid tumors, hematological malignancies, organ transplantation, restenosis, and rheumatoid arthritis. One such example is sirolimus (INN / USAN), also known as rapamycin, an immunosuppressant used to prevent organ transplant rejection. Sirolimus-eluting stents have been approved in the United States for the treatment of coronary artery restenosis. Furthermore, sirolimus has been demonstrated to effectively inhibit tumor growth in various cell lines and animal models. Other limus drugs, such as sirolimus analogs, are designed to improve upon the pharmacokinetic and pharmacodynamic properties of sirolimus. For example, temsirolimus is approved in the United States and Europe for the treatment of renal cell carcinoma. Everolimus is approved in the United States for the treatment of advanced breast cancer, pancreatic neuroendocrine tumors, advanced renal cell carcinoma, and subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis. The mechanism of action of sirolimus is by binding to the cytoplasmic protein FK-binding protein 12 (FKBP12), and the sirolimus-FKBP12 complex directly binds to mTOR complex 1 (mTORC1) and inhibits the mTOR pathway.

[0005] Albumin-based nanoparticle compositions have been developed as drug delivery systems for delivering substantially water-insoluble drugs. See, for example, U.S. Patents 5,916,596, 6,506,405, 6,749,868, 6,537,579, 7,820,788, and 7,923,536. Abraxane®, an albumin-stabilized nanoparticle formulation of paclitaxel, was approved in the United States in 2005 for the treatment of metastatic breast cancer and has since been approved in various other countries. More recently, it has been approved in the United States for the treatment of non-small cell lung cancer and has demonstrated therapeutic efficacy in various clinical trials for difficult-to-treat cancers such as bladder cancer and melanoma. Albumin derived from human blood is used in the manufacture of Abraxane® and various other albumin-based nanoparticle compositions. Albumin-based nanoparticle compositions containing sirolimus, such as nab-sirolimus or Fyarro®, are known, for example, in U.S. Patents 8,911,786 and 11,497,737.

[0006] In this field, there remains a continuing need for advanced treatments for certain difficult-to-treat hormone-dependent cancers, including endometrial cancer (e.g., endometrioid endometrial cancer) or hormone receptor-positive cancer (e.g., hormone receptor-positive breast cancer). [Brief explanation of the drawing]

[0007] [Figure 1] Figures 1A and 1B show histograms of the number of viable cells (Figure 1A) and cell death (Figure 1B) of MDA-MB-361 cells. [Figure 2] Figures 2A and 2B show histograms of the number of viable cells (Figure 2A) and cell death (Figure 2B) in MCF7 cells. [Figure 3] Western blot analyses of various markers (including p4EBP1 and AKT) from MCF7 cells treated with fulvestrant, nab-sirolimus, and a combination of fulvestrant and nab-sirolimus are shown. [Overview of the Initiative]

[0008] In certain embodiments, this application provides a method for treating hormone-dependent cancer in an individual requiring treatment for hormone-dependent cancer, the method comprising administering to the individual a composition comprising nanoparticles comprising sirolimus and albumin, and (b) an estrogen inhibitor.

[0009] In some embodiments, the estrogen inhibitor is a drug that suppresses estrogen production. In some embodiments, the estrogen inhibitor is an aromatase inhibitor. In some embodiments, the estrogen inhibitor is selected from the group consisting of letrozole, anastrozole, formestane, and exemestane. In some embodiments, the drug that suppresses estrogen production is letrozole. In some embodiments, the estrogen inhibitor is a drug that suppresses estrogen activity. In some embodiments, the estrogen inhibitor is an estrogen receptor antagonist. In some embodiments, the drug that suppresses estrogen activity is selected from the group consisting of fulvestrant, elastrant, tamoxifen, hydroxyprogesterone caprate, droloxifen, olmeroxifen, toremifene, faroxifen, raloxifen, and clomiphene. In some embodiments, the drug that suppresses estrogen activity is fulvestrant. In some embodiments, estrogen inhibitors are administered to an individual orally, intramuscularly, intravenously, intra-arterially, intraperitoneally, intrabladderally, subcutaneously, intrathecally, intrapulmonaryly, intratracheally, intraocularly, percutaneously, or by inhalation.

[0010] In some embodiments, the estrogen inhibitor is administered orally to the individual. In some embodiments, the estrogen inhibitor is administered intramuscularly to the individual.

[0011] In some embodiments, the estrogen inhibitor is letrozole, which is administered orally to the individual. In some embodiments, letrozole is administered to the individual in amounts ranging from approximately 0.1 mg to approximately 10 mg. In some embodiments, letrozole is administered to the individual daily.

[0012] In some embodiments, the estrogen inhibitor is fulvestrant, which is administered intramuscularly to the individual. In some embodiments, fulvestrant is administered to the individual in amounts ranging from approximately 100 mg to approximately 700 mg. In some embodiments, fulvestrant is administered to the individual on days 1, 15, and 29 of the initiation cycle, followed by monthly maintenance cycles.

[0013] In some embodiments, the hormone-dependent cancer is endometrioid endometrial carcinoma. In some embodiments, the hormone-dependent cancer is breast cancer. In some embodiments, the breast cancer is hormone receptor-positive breast cancer. In some embodiments, the hormone-dependent cancer is locally advanced, progressive, malignant, advanced malignant, or metastatic. In some embodiments, the hormone-dependent cancer is refractory, recurrent, recurrent, or resistant to prior treatment. In some embodiments, prior treatment comprises an mTOR inhibitor and / or a composition comprising nanoparticles comprising an mTOR inhibitor and albumin. In some embodiments, prior treatment comprises a platinum-based agent and / or a checkpoint inhibitor. In some embodiments, the individual has not been treated with an mTOR inhibitor and / or a composition comprising nanoparticles comprising an mTOR inhibitor and albumin. In some embodiments, the hormone-dependent cancer is stage III or stage IV.

[0014] In some embodiments, the individual is a human.

[0015] In other embodiments, this specification provides a method for treating endometrial cancer in an individual requiring treatment for endometrial cancer, the method comprising administering (a) a composition comprising nanoparticles comprising sirolimus and albumin, and (b) an estrogen inhibitor, the estrogen inhibitor being an aromatase inhibitor, and the estrogen inhibitor being administered to the individual in an amount of about 0.1 mg to about 10 mg. In some embodiments, the endometrial cancer is endometrioid endometrial cancer. In some embodiments, the estrogen inhibitor is letrozole. In some embodiments, the estrogen inhibitor is administered to the individual daily.

[0016] In other embodiments, this specification provides a method for treating hormone receptor-positive breast cancer in an individual requiring treatment for hormone receptor-positive breast cancer, the method comprising administering to the individual (a) a composition comprising nanoparticles comprising sirolimus and albumin, and (b) an estrogen inhibitor, the estrogen inhibitor being a selective estrogen receptor degrader (SERD), and the estrogen inhibitor being administered to the individual in an amount of about 200 mg to about 600 mg. In some embodiments, the estrogen inhibitor is fulvestrant. In some embodiments, the estrogen inhibitor is administered on days 1, 15, and 29 of the initiation cycle, and thereafter administered in monthly maintenance doses.

[0017] In some embodiments, the amount of sirolimus in the sirolimus nanoparticle composition is approximately 10 mg / m³. 2 ~about 150mg / m 2 It is administered in the amount of [amount]. In some embodiments, the amount of sirolimus in the sirolimus nanoparticle composition is about 100 mg / m². 2 It is administered in the amount of [amount]. In some embodiments, the amount of sirolimus in the sirolimus nanoparticle composition is about 75 mg / m². 2 It is administered in the amount of [amount]. In some embodiments, the amount of sirolimus in the sirolimus nanoparticle composition is about 56 mg / m². 2 It is administered in the amount of [amount]. In some embodiments, the amount of sirolimus in the sirolimus nanoparticle composition is about 45 mg / m². 2 It is administered in the amount of [amount]. In some embodiments, the amount of sirolimus in the sirolimus nanoparticle composition is about 30 mg / m³. 2 It is administered in that amount.

[0018] In some embodiments, the sirolimus nanoparticle composition is administered twice, every three weeks. In some embodiments, the sirolimus nanoparticle composition is administered on day 1 and day 8 of a 21-day cycle. In some embodiments, the average diameter of the nanoparticles in the composition is about 150 nm or less. In some embodiments, the average diameter of the nanoparticles in the composition is about 120 nm or less. In some embodiments, the weight ratio of albumin to sirolimus in the nanoparticle composition is about 9:1 or less. In some embodiments, the nanoparticles comprise sirolimus associated with albumin. In some embodiments, the nanoparticles comprise sirolimus coated with albumin.

[0019] In some embodiments, the sirolimus nanoparticle composition is administered intravenously.

[0020] In some embodiments, the sirolimus nanoparticle composition is administered in parallel with an estrogen inhibitor. In some embodiments, the sirolimus nanoparticle composition is administered sequentially with an estrogen inhibitor. In some embodiments, the sirolimus nanoparticle composition is administered simultaneously with an estrogen inhibitor.

[0021] All publications, patents, patent applications, and disclosures of published patent applications referenced herein are incorporated herein by reference in their entirety. [Modes for carrying out the invention]

[0022] This application provides, in certain embodiments, a treatment for hormone-dependent cancers (such as endometrial cancer (e.g., endometrioid endometrial cancer) or hormone receptor-positive cancers (e.g., hormone receptor-positive breast cancer)) in an individual requiring treatment for hormone-dependent cancer, the method comprising administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., sirolimus) and albumin, and (b) an estrogen inhibitor. In some embodiments, the estrogen inhibitor is an aromatase inhibitor, such as letrozole. In some embodiments, the estrogen inhibitor is a selective estrogen receptor depressant / degradant (SERD), such as fulvestrant.

[0023] The subject matter of this application is, at least in part, based on the inventors' unique perspective and findings that a combination of nab-sirolimus and an estrogen inhibitor, such as an estrogen-inhibiting agent (e.g., letrozole) or an estrogen receptor signaling inhibitor (e.g., fulvestrant), is useful in the treatment of hormone-dependent cancers and in overcoming commonly observed drug resistance to standard endocrine therapy. For example, as reported herein, monotherapy with fulvestrant increased phosphorylated 4E-binding protein 1 (p4EBP1), a protein species known to be a driving force of tumorigenesis and also associated with poor prognosis and drug resistance. Unexpectedly, the inventors demonstrated that treatment with nab-sirolimus and an estrogen inhibitor, i.e., fulvestrant, reduced p4EBP1. This finding is significant as it suggests that drug resistance problems are less likely to occur with the combination therapies described herein. Thus, these results demonstrate that the combination therapies described herein solve significant problems faced by currently available treatments.

[0024] Accordingly, in certain embodiments, this specification provides a method for treating hormone-dependent cancer in an individual requiring treatment for hormone-dependent cancer, the method comprising administering to the individual (a) a composition comprising nanoparticles comprising sirolimus and albumin, and (b) an estrogen inhibitor (e.g., an agent that suppresses estrogen by suppressing estrogen production, or an agent that suppresses the activity of estrogen receptors, such as an antagonist). In other embodiments, this specification provides a method for treating endometrial cancer in an individual requiring treatment for endometrial cancer, the method comprising administering (a) a composition comprising nanoparticles comprising sirolimus and albumin, and (b) an estrogen inhibitor, the estrogen inhibitor being an aromatase inhibitor, and the estrogen inhibitor being administered to the individual in an amount of about 0.1 mg to about 10 mg. In some embodiments, the endometrial cancer is endometrioid endometrial carcinoma. In some embodiments, the estrogen inhibitor is letrozole. In some embodiments, the estrogen inhibitor is administered to the individual daily.

[0025] In other embodiments, this specification provides a method for treating endometrial cancer in an individual requiring treatment for endometrial cancer, the method comprising administering (a) a composition comprising nanoparticles comprising sirolimus and albumin, and (b) an estrogen inhibitor, the estrogen inhibitor being an aromatase inhibitor, and the estrogen inhibitor being administered to the individual in an amount of about 0.1 mg to about 10 mg. In some embodiments, the endometrial cancer is endometrioid endometrial cancer. In some embodiments, the estrogen inhibitor is letrozole. In some embodiments, the estrogen inhibitor is administered to the individual daily.

[0026] In other embodiments, this specification provides a method for treating hormone receptor-positive breast cancer in an individual requiring treatment for hormone receptor-positive breast cancer, the method comprising administering to the individual (a) a composition comprising nanoparticles comprising sirolimus and albumin, and (b) an estrogen inhibitor, the estrogen inhibitor being a selective estrogen receptor degrader (SERD), and the estrogen inhibitor being administered to the individual in an amount of about 200 mg to about 600 mg. In some embodiments, the estrogen inhibitor is fulvestrant. In some embodiments, the estrogen inhibitor is administered on days 1, 15, and 29 of the initiation cycle, and thereafter administered in monthly maintenance doses.

[0027] I. Definition As used herein, “nab” refers to albumin-bound nanoparticles, and “nab-sirolimus” is an albumin-stabilized nanoparticle formulation of sirolimus, also known as nab-rapamycin, as previously described. See, for example, U.S. Patents 8,911,786 and 11,497,737, each of which is incorporated herein by reference.

[0028] As used herein, “treatment” or “to treat” refers to an approach to obtain beneficial or desirable outcomes, including clinical outcomes. For the purposes of the present invention, beneficial or desirable clinical outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms caused by the disease; reducing the severity of the disease; stabilizing the disease (e.g., preventing or delaying disease exacerbation); preventing or delaying the spread of the disease (e.g., metastasis); preventing or delaying disease recurrence; reducing the recurrence rate of the disease; delaying or slowing the progression of the disease; improving the state of the disease; achieving remission (partial or total) of the disease; reducing the dose of one or more other drugs required to treat the disease; delaying disease progression; improving quality of life; and / or extending survival. In some embodiments, the treatment reduces the severity of one or more cancer-related symptoms by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to the corresponding symptoms in the same subject before treatment, or compared to the corresponding symptoms in other untreated subjects. "Treatment" also includes mitigating the pathological effects of cancer. The methods of the present invention consider one or more of these embodiments of treatment.

[0029] The terms "recurrence," "relapse," or "recurrent" refer to the reappearance of cancer or disease after clinical assessment of disease clearance. A diagnosis of distant metastasis or local recurrence can be considered a recurrence.

[0030] The terms "refractory" or "resistant" refer to cancer or disease that does not respond to treatment.

[0031] As used herein, “delaying” cancer progression means slowing, preventing, slowing, delaying, stabilizing, and / or postponing the progression of the disease. This delay may be of varying duration depending on the medical history and / or the individual being treated. As will be apparent to those skilled in the art, sufficient or significant delay may substantially encompass prevention, in the sense that the individual does not develop the disease. A method of “delaying” cancer progression is a method that reduces the probability of disease progression within a particular period and / or reduces the severity of the disease within a particular period, compared to not using the method. Such comparisons are typically based on clinical studies using a statistically significant number of subjects. Cancer onset can be detected using standard methods, including, but not limited to, computed tomography (CAT scan), magnetic resonance imaging (MRI), ultrasound, coagulation tests, angiography, biopsy, urinalysis, and cystoscopy. Progression may also refer to the progression of cancer that may not be initially detected, and includes development, recurrence, and manifestation.

[0032] As used herein, the term “effective dose” refers to an amount of a compound or composition sufficient to treat a particular disorder, condition, or disease, for example, an amount that improves, alleviates, reduces, and / or delays one or more of its symptoms. In the context of cancer, an effective dose includes an amount sufficient to shrink a tumor and / or reduce its growth rate (such as inhibiting tumor proliferation), or an amount sufficient to prevent or delay other undesirable cell growth in cancer. In some embodiments, an effective dose is an amount sufficient to delay the onset of cancer. In some embodiments, an effective dose is an amount sufficient to prevent or delay recurrence. In some embodiments, an effective dose is an amount sufficient to reduce the recurrence rate in an individual. An effective dose may be administered in one or more doses. An effective amount of the drug or composition may (i) reduce the number of cancer cells, (ii) reduce the size of the tumor, (iii) inhibit, delay, slow to some extent, and preferably halt, the invasion of cancer cells into peripheral organs, (iv) inhibit (i.e., slow to some extent, and preferably halt) tumor metastasis, (v) inhibit tumor growth, (vi) prevent or delay the onset and / or recurrence of tumor, (vii) reduce the recurrence rate of tumor, and / or (viii) alleviate to some extent one or more symptoms associated with cancer.

[0033] As understood in the art, “effective dose” or “dose” can be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. An effective dose may be considered in the context of administering one or more therapeutic agents, and a nanoparticle composition (e.g., a composition comprising sirolimus and albumin) may be considered administered in an effective dose if, in combination with one or more other agents, a desirable or beneficial outcome can be achieved, or is achieved. The components in the combination therapy of the present invention (e.g., the first therapy and the second therapy) can be administered sequentially, simultaneously, or in parallel using the same or different routes of administration for each component. Therefore, the effective dose of the combination therapy includes the amount of the first therapy and the amount of the second therapy that produce the desired outcome when administered sequentially, simultaneously, or in parallel.

[0034] "In conjunction with" or "in combination with" refers to administering one treatment in addition to another, such as administering the nanoparticle composition described herein to the same individual in addition to administering other drugs under the same treatment plan. Therefore, "in conjunction with" or "in combination with" refers to administering one treatment before, during, or after administering another treatment to an individual.

[0035] As used herein, “concurrent administration” means that the first and second therapies in a combination therapy are administered within approximately 15 minutes, for example, within 10 minutes, 5 minutes, or 1 minute. When the first and second therapies are administered concurrently, they may be contained in the same composition (e.g., a composition containing both the first and second therapeutic agents) or in separate compositions (e.g., one composition containing the first therapy and another containing the second therapy).

[0036] As used herein, the term “sequential administration” means that the first and second therapies in combination therapy are administered at intervals of more than about 15 minutes, for example, more than about 20 minutes, more than 30 minutes, more than 40 minutes, more than 50 minutes, more than 60 minutes, or longer. Either the first or second therapy may be administered first. The first and second therapies are contained in separate compositions, which may be contained in the same or different packaging or kits.

[0037] As used herein, the term “concurrent administration” means that the administration of the first treatment and the administration of the second treatment in a combination therapy overlap.

[0038] As used herein, “pharmaceutically acceptable” or “pharmaceutically acceptable” means a material that is biologically or otherwise undesirable, for example, a material that may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effect or without adversely interacting with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients preferably meet the necessary criteria for toxicity and manufacturing testing and / or are listed in the Inactive Ingredient Guide prepared by the US Food and Drug Administration.

[0039] As used herein, the term “individual” refers to mammals, including but not limited to humans, cattle, horses, cats, dogs, rodents, mice, or primates. In some embodiments, the individual is a human individual.

[0040] As used herein, the terms “comprising,” “having,” “containing,” “including,” and other similar forms, and their grammatical synonyms, are equivalent in meaning and are intended to be unrestricted in that the items following any of these words are not intended to exhaustively list such items, nor are they intended to be limited to only the listed items. For example, an article “containing” components A, B, and C may consist of (i.e., contain only) components A, B, and C, or it may contain not only components A, B, and C but also one or more other components. So it is intended and understood that “~containing” and similar forms, and their grammatical equivalents, include disclosures of embodiments of “~essentially consisting of” or “~ comprising.”

[0041] Where a range of values ​​is provided, unless the context explicitly indicates otherwise, the values ​​between the upper and lower limits of that range, and the intermediate values ​​up to one-tenth of the lower limit in any other stated or intermediate values ​​within that stated range, are included within the scope of this disclosure and are subject to any restrictions specifically excluded within the stated scope. If the stated scope includes one or both limits, the scope excluding one or both of those included limits is also included in this disclosure.

[0042] In this specification, any reference to a value or parameter using the term "about" includes (and describes) variations relating to the value or parameter itself. For example, any reference to "about X" includes a description of "X".

[0043] As used herein, the singular “a,” “or,” and “the,” including in the appended claims, refer to multiple subjects unless the context clearly indicates otherwise.

[0044] Those skilled in the art will understand that several embodiments are possible within the scope and spirit of the present disclosure. The following description illustrates the present disclosure and, of course, should not be construed as limiting the scope of the invention described herein in any way.

[0045] II. Treatment Methods Disclosed herein is a method for treating hormone-dependent cancer in an individual who requires treatment for hormone-dependent cancer, the method comprising administering to the individual (a) a composition comprising nanoparticles comprising sirolimus and albumin, and (b) an estrogen inhibitor, such as an agent that suppresses the signaling of estrogen or an estrogen receptor.

[0046] In some embodiments, a method for treating hormone-dependent cancer, such as endometrial cancer (e.g., endometrioid endometrial cancer), in an individual who requires treatment for hormone-dependent cancer is provided, the method comprising administering to the individual (a) a composition comprising nanoparticles comprising sirolimus and albumin, and (b) an estrogen inhibitor, wherein the estrogen inhibitor is an aromatase inhibitor, such as letrozole. In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the aromatase inhibitor is administered to the individual in an amount of about 0.1 mg to about 10 mg, such as about 2.5 mg. In some embodiments, the aromatase inhibitor is administered orally (i.e., the aromatase inhibitor, such as letrozole, is suitable for oral administration). In some embodiments, the aromatase inhibitor is administered daily. In some embodiments, the composition comprising nanoparticles comprising sirolimus and albumin, such as nab-sirolimus, is about 70 mg / m 2 ~ about 110 mg / m 2 、such as about 100 mg / m 2It is administered to the individual in a certain amount. In some embodiments, a composition comprising nanoparticles containing sirolimus and albumin, e.g., nab-sirolimus, is administered intravenously. In some embodiments, a composition comprising nanoparticles containing sirolimus and albumin, e.g., nab-sirolimus, is administered to the individual weekly, e.g., every three weeks for two weeks, e.g., on day 1 and day 8 of a 21-day cycle. In some embodiments, the individual is a human.

[0047] In some embodiments, a method is provided for treating hormone receptor-positive breast cancer, e.g., hormone-dependent cancer, in an individual requiring treatment for hormone receptor-positive breast cancer, the method comprising administering to the individual (a) a composition comprising nanoparticles comprising sirolimus and albumin, and (b) an estrogen inhibitor, the estrogen inhibitor being a selective estrogen receptor degrader (SERD), e.g., fulvestrant. In some embodiments, the SERD is administered to the individual in an amount of about 200 mg to about 600 mg, e.g., about 500 mg. In some embodiments, the SERD is administered intramuscularly (i.e., SERDs, e.g., fulvestrant, are suitable for intramuscular administration). In some embodiments, the SERD is administered on days 1, 15, and 29 of the initiation cycle, and thereafter administered at a maintenance dose monthly. In some embodiments, the composition comprising nanoparticles comprising sirolimus and albumin, e.g., nab-sirolimus, is administered at about 70 mg / m². 2 ~about 110mg / m 2 For example, approximately 100 mg / m² 2 It is administered to the individual in a certain amount. In some embodiments, a composition comprising nanoparticles containing sirolimus and albumin, e.g., nab-sirolimus, is administered intravenously. In some embodiments, a composition comprising nanoparticles containing sirolimus and albumin, e.g., nab-sirolimus, is administered to the individual weekly, e.g., every three weeks for two weeks, e.g., on day 1 and day 8 of a 21-day cycle. In some embodiments, the individual is a human.

[0048] Further descriptions of the methods and embodiments thereof described herein are provided in the following sections. Such modular discussions of components do not limit the scope of the invention, and those skilled in the art will readily understand how the specific features of the following sections can be combined to form the combination therapies and related subjects taught herein.

[0049] A. Hormone-dependent cancer In some embodiments, hormone-dependent cancer is hormone receptor-positive cancer, for example, estrogen receptor-positive and / or progesterone receptor-positive cancer. In some embodiments, hormone-dependent cancer is hormone-dependent, such as estrogen-dependent (e.g., dependent on hormone-induced development and / or growth). Techniques for determining hormone dependence and the presence of hormone receptors are known in the art, for example, using techniques such as immunohistochemistry (IHC) to take a biopsy to test for the presence of, for example, estrogen receptors or progesterone receptors. In some embodiments, hormone-dependent cancer is endometrial cancer, for example, endometrioid endometrial cancer (EEC), for example, estrogen-dependent endometrial cancer (including estrogen-dependent endometrioid endometrial cancer). In some embodiments, endometrial cancer (e.g., endometrioid endometrial cancer) is hormone receptor-positive endometrial cancer (e.g., endometrioid endometrial cancer), for example, estrogen receptor and / or progesterone receptor-positive endometrioid endometrial cancer. In some embodiments, hormone-dependent cancer is breast cancer. In some embodiments, breast cancer is hormone receptor-positive breast cancer, such as estrogen receptor and / or progesterone receptor-positive breast cancer.

[0050] In some embodiments, hormone-dependent cancer is locally advanced, progressive, malignant, advanced malignant, or metastatic. In some embodiments, advanced hormone-dependent cancer is unresectable or cannot be resected without an increased risk of serious injury or death. In some embodiments, hormone-dependent cancer is refractory, recurrent, relapsing, or resistant to prior treatment. In some embodiments, prior treatment includes an mTOR inhibitor (such as sirolimus) and / or a composition comprising nanoparticles containing an mTOR inhibitor (such as sirolimus) and albumin. In some embodiments, prior treatment includes chemotherapy, immunotherapy, targeted therapy, and / or checkpoint inhibitors. In some embodiments, chemotherapy includes a platinum-based agent. In some embodiments, prior treatment includes a platinum-based agent and / or a checkpoint inhibitor. In some embodiments, the individual has received zero or one or more prior treatments, e.g., zero to one or more chemotherapy regimens. In some embodiments, the individual has recurrent, locally advanced, or metastatic cancer. In some embodiments, the patient has received one or more chemotherapy regimens. In some embodiments, the patient has not received or is chemotherapy-naive. In some embodiments, the prior therapy is adjuvant therapy. In some embodiments, the prior adjuvant therapy is chemotherapy, hormone therapy, or a checkpoint inhibitor. In some embodiments, the adjuvant therapy is completed at least six months before treatment according to the method described herein. In some embodiments, the prior therapy is a non-chemotherapy-based treatment. In some embodiments, the prior non-chemotherapy-based treatment was completed at least four months before treatment according to the method described herein.

[0051] In some embodiments, individuals have not been treated with an mTOR inhibitor (such as sirolimus) and / or a composition comprising nanoparticles containing an mTOR inhibitor (such as sirolimus) and albumin.

[0052] In some embodiments, hormone-dependent cancer is stage III or stage IV according to the International Federation of Gynecology and Obstetrics (FIGO) staging classification.

[0053] In some embodiments, the hormone-dependent cancer is advanced or recurrent endometrial cancer (e.g., endometrioid endometrial cancer). In some embodiments, the advanced or recurrent endometrial cancer (e.g., endometrioid endometrial cancer) is unresectable FIGO stage III or IV. In some embodiments, the recurrent endometrial cancer (e.g., endometrioid endometrial cancer) is grade 3 or higher, and the individual has previously been treated with platinum-based and / or checkpoint inhibitors.

[0054] In some embodiments, the hormone-dependent cancer is ovarian cancer, for example, estrogen receptor-positive and / or progesterone receptor-positive ovarian cancer. In some embodiments, the hormone-dependent cancer is cervical cancer, for example, estrogen receptor-positive and / or progesterone receptor-positive cervical cancer.

[0055] B. Dosage and administration method The dose of an mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition) administered to an individual (e.g., a human) may vary depending on the specific composition, method of administration, the hormone-dependent cancer being treated, and the specific stage of the tumor being treated. The amount must be sufficient to produce the desired response, such as a therapeutic or prophylactic response against the tumor. In some embodiments, the amount of the mTOR inhibitor (e.g., limus drug, e.g., sirolimus or its derivatives) in the composition is below the level that induces a toxic effect (e.g., an effect exceeding clinically acceptable toxicity levels) or at a level where potential side effects are controlled or tolerable when the mTOR inhibitor nanoparticle composition is administered to an individual.

[0056] In some embodiments, when administering an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition), the mTOR inhibitor nanoparticle composition is administered to the individual simultaneously with an estrogen inhibitor (such as letrozole or fulvestrant) in at least one dose (for example, due to differences in the cycles of different drugs, certain doses may be able to be performed simultaneously, while others may not). For example, the mTOR inhibitor nanoparticle composition and the estrogen inhibitor (e.g., letrozole or fulvestrant) are administered within a time interval of approximately 15 minutes, for example, within approximately 10 minutes, 5 minutes, or 1 minute. In one example, if the compounds are in solution, simultaneous administration can be achieved by administering a solution containing the combination of compounds. In another example, simultaneous administration of separate solutions or compositions can be used, one containing the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and the other containing the estrogen inhibitor (such as letrozole or fulvestrant). In one example, simultaneous administration can be achieved by administering a composition containing the combination of compounds. In another example, simultaneous administration can be achieved by administering two separate compositions, one containing an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition administered intravenously) and the other containing an estrogen inhibitor (e.g., letrozole or fulvestrant). In some embodiments, simultaneous administration of an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) and an estrogen inhibitor (e.g., letrozole or fulvestrant) in a nanoparticle composition can be combined with additional administration of the mTOR inhibitor and / or estrogen inhibitor (e.g., letrozole or fulvestrant).

[0057] In other embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition) and the estrogen inhibitor (e.g., letrozole or fulvestrant) are not administered simultaneously in at least one dose. In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition) is administered before the estrogen inhibitor (e.g., letrozole or fulvestrant). In other embodiments, the estrogen inhibitor (e.g., letrozole or fulvestrant) is administered before the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition). The time difference when they are not administered simultaneously may exceed 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 24 hours, 36 hours, or 48 hours. In other embodiments, the first administered compound is given time to exert its effect on the patient before the second administered compound is administered. In some embodiments, the time difference does not exceed the time it takes for the first administered compound to complete its effect in the patient, or the time it takes for the first administered compound to be completely or substantially eliminated or inactivated in the patient.

[0058] In some embodiments, the administration of the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and the estrogen inhibitor (e.g., letrozole or fulvestrant) is simultaneous in at least one administration, i.e., the administration periods of the mTOR inhibitor nanoparticle composition and the estrogen inhibitor (e.g., letrozole or fulvestrant) overlap. In some embodiments, the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) is administered for at least one cycle (e.g., at least one of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles) prior to the administration of the estrogen inhibitor (e.g., letrozole or fulvestrant). In some embodiments, the estrogen inhibitor (e.g., letrozole or fulvestrant) is administered for at least one, two, three, or four weeks. In some embodiments, the administration of an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and an estrogen inhibitor (e.g., letrozole or fulvestrant) is initiated approximately simultaneously (e.g., within one of the following periods: day 1, day 2, day 3, day 4, day 5, day 6, week 1, week 2, or week 3). In some embodiments, the administration of an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and an estrogen inhibitor (e.g., letrozole or fulvestrant) is terminated approximately simultaneously (e.g., within one of the following periods: day 1, day 2, day 3, day 4, day 5, day 6, week 1, week 2, or week 3). In some embodiments, administration of an estrogen inhibitor (e.g., letrozole or fulvestrant) is continued even after the discontinuation of administration of an mTOR inhibitor nanoparticle composition (e.g., a sirolimus / albumin nanoparticle composition) (e.g., for one month, whichever is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months).In some embodiments, the administration of an estrogen inhibitor (e.g., letrozole or fulvestrant) is initiated after the initiation of the administration of an mTOR inhibitor nanoparticle composition (e.g., a sirolimus / albumin nanoparticle composition) (e.g., one month after approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the administration of the mTOR inhibitor nanoparticle composition (e.g., a sirolimus / albumin nanoparticle composition) and the estrogen inhibitor (e.g., letrozole or fulvestrant) is initiated and terminated almost simultaneously. In some embodiments, the administration of an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and an estrogen inhibitor (e.g., letrozole or fulvestrant) is initiated almost simultaneously, and after the discontinuation of the administration of the mTOR inhibitor nanoparticle composition, the administration of the estrogen inhibitor (e.g., letrozole or fulvestrant) is continued for one month (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, the administration of an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and an estrogen inhibitor (e.g., letrozole or fulvestrant) is discontinued almost simultaneously, and the administration of the estrogen inhibitor (e.g., letrozole or fulvestrant) is initiated after the commencement of the administration of the mTOR inhibitor nanoparticle composition (e.g., one month after about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months).

[0059] In some embodiments, the estrogen inhibitor (e.g., letrozole or fulvestrant) is administered according to the manufacturer's instructions for monotherapy or other combination therapy that does not include nab-sirolimus. In some embodiments, the dose of the estrogen inhibitor (e.g., letrozole or fulvestrant) is reduced due to patient considerations such as adverse events. In some embodiments, the dose reduction of the estrogen inhibitor (e.g., letrozole or fulvestrant) is made only for part of the treatment, for example, until the individual recovers (at least partially) from an adverse event. In some embodiments, the estrogen inhibitor (e.g., letrozole or fulvestrant) is administered at a dose considered to be less than the therapeutic dose in monotherapy of the estrogen inhibitor (for example, combination therapies taught herein can provide effective treatment using lower doses of one or both therapeutic agents).

[0060] In some embodiments, administration of a composition comprising an mTOR inhibitor and albumin and an estrogen inhibitor (e.g., letrozole or fulvestrant) is continued for at least one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 cycles.

[0061] In some embodiments, the administration of the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and the estrogen inhibitor (e.g., letrozole or fulvestrant) is not simultaneous. For example, in some embodiments, the administration of the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) is completed before the administration of the estrogen inhibitor (e.g., letrozole or fulvestrant). In other embodiments, the administration of the estrogen inhibitor (e.g., letrozole or fulvestrant) is completed before the administration of the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition). The interval between these two non-simultaneous administrations may range from about 2 to 8 weeks, such as about 4 weeks.

[0062] The frequency of administration of mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and estrogen inhibitors (e.g., letrozole or fulvestrant) may be adjusted during the course of treatment at the discretion of the administering physician. When administered separately, mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and estrogen inhibitors (such as letrozole or fulvestrant) may be administered at different frequencies or intervals. For example, an mTOR inhibitor nanoparticle composition (such as sirolimus / albumin nanoparticle compositions) may be administered once every three weeks, while an estrogen inhibitor (such as letrozole or fulvestrant) may be administered more frequently or less frequently, for example, daily. In some embodiments, sustained-release formulations of nanoparticles and / or estrogen inhibitors (e.g., letrozole or fulvestrant) may be used. Various formulations and devices for achieving sustained release are known in the art. Combinations of dosage forms described herein may also be used.

[0063] mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and estrogen inhibitors (such as letrozole or fulvestrant) can be administered using the same or different routes of administration. In some embodiments (for both simultaneous and sequential administration), the mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and the estrogen inhibitor (e.g., letrozole or fulvestrant) in the mTOR inhibitor nanoparticle composition are administered in a predetermined ratio.

[0064] The required dose of an mTOR inhibitor (limus drug, e.g., sirolimus or its derivatives) and / or estrogen inhibitor (e.g., letrozole or fulvestrant) in an mTOR inhibitor nanoparticle composition may be the same as, but not necessarily, the dose normally required when each drug is administered alone. Therefore, in some embodiments, the mTOR inhibitor (e.g., limus drug, e.g., sirolimus or its derivatives) and / or estrogen inhibitor (e.g., letrozole or fulvestrant) in the mTOR inhibitor nanoparticle composition may be less than a therapeutic dose. “Less than therapeutic dose” or “less than therapeutic level” refers to a dose less than therapeutic, i.e., less than the dose normally used when the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition) and / or estrogen inhibitor (e.g., letrozole or fulvestrant) is administered alone. The reduction may be reflected in the amount administered at a given time and / or the amount administered over a given period (reduction in frequency). For example, in some embodiments, this method involves a composition containing nanoparticles containing the mTOR inhibitor and albumin at approximately 100 mg / m². 2 Less than, for example, about 90 mg / m² 2 , 80 mg / m² 2 70 mg / m² 2 , 60 mg / m² 2 50 mg / m² 2 , 40 mg / m² 2 , 30 mg / m² 2 , 20 mg / m² 2 , or 10 mg / m² 2 This includes administering the drug in any of the following doses.

[0065] In some embodiments, a sufficient amount of an estrogen inhibitor (e.g., letrozole or fulvestrant) is administered so as to reduce the usual dose of the mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) in the mTOR inhibitor nanoparticle composition required to produce the same degree of therapeutic effect by at least about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% or more.

[0066] In some embodiments, the doses of both the mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and the estrogen inhibitor (e.g., letrozole or fulvestrant) in the mTOR inhibitor nanoparticle composition are reduced compared to the corresponding normal doses when each is administered alone. In some embodiments, both the mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and the estrogen inhibitor (e.g., letrozole, fulvestrant) in the mTOR inhibitor nanoparticle composition are administered at sub-thermal, i.e., reduced levels. In some embodiments, the doses of the mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and / or the estrogen inhibitor (e.g., letrozole or fulvestrant) in the mTOR inhibitor nanoparticle composition are substantially lower than the established maximum toxic dose (MTD). For example, the doses of mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and / or estrogen inhibitors (e.g., letrozole or fulvestrant) are less than 50%, 40%, 30%, 20%, or 10% of the MTD.

[0067] Combinations of management configurations described herein may be used. These combination therapies may be administered alone or in conjunction with other treatments such as surgery, radiotherapy, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and / or chemotherapy. Furthermore, individuals at high risk of developing hormone-dependent cancers may receive treatments to suppress and / or delay disease progression.

[0068] As those skilled in the art will understand, in some embodiments, an appropriate dose of the second agent is approximately equivalent to the dose already used in clinical treatment where an estrogen-suppressing agent (e.g., letrozole or fulvestrant) is administered alone or in combination with other chemotherapeutic agents. The dose will vary depending on the symptoms to be treated. As described above, in some embodiments, the second chemotherapeutic agent may be administered at lower levels.

[0069] In some embodiments, the amounts of the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and the estrogen inhibitor (e.g., letrozole or fulvestrant) are below the level at which the mTOR inhibitor nanoparticle composition and the estrogen inhibitor (e.g., letrozole or fulvestrant) would induce a toxic effect (i.e., an effect exceeding a clinically acceptable level of toxicity) when administered to an individual, or at a level at which potential side effects are controlled or tolerable.

[0070] In some embodiments, the amount of the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) is close to the maximum tolerated dose (MTD) of the composition when administered in combination with an estrogen inhibitor (e.g., letrozole or fulvestrant) according to the same dosing regimen. In some embodiments, the amount of the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) is greater than approximately 80%, 90%, 95%, or 98% of the MTD when administered in combination with an estrogen inhibitor (e.g., letrozole or fulvestrant).

[0071] As described herein, in some embodiments, the reference amount of a composition comprising nanoparticles containing an mTOR inhibitor and albumin is based on the amount of the mTOR inhibitor therein. In some embodiments, the amount of the mTOR inhibitor (e.g., limus, e.g., sirolimus) in the mTOR inhibitor nanoparticle composition is about 25 mg / m³ 2 , 30 mg / m² 2 , 45 mg / m² 2 50 mg / m² 2 , 56 mg / m² 2 , 60 mg / m² 2 75 mg / m² 2 , 80 mg / m² 2 90 mg / m² 2 , 100 mg / m² 2 , 120 mg / m² 2 , 160 mg / m² 2 , 175 mg / m² 2 , 180 mg / m² 2 , 200 mg / m² 2 , 210 mg / m² 2 , 220 mg / m² 2 , 250 mg / m² 2 , 260 mg / m² 2 , 300 mg / m² 2 , 350 mg / m² 2 , 400 mg / m² 2 500 mg / m² 2 540 mg / m² 2 750 mg / m² 2 , 1000 mg / m² 2 , or 1080 mg / m² 2 It is one of the TOR inhibitors. In some embodiments, the mTOR inhibitor nanoparticle composition is approximately 350 mg / mm³. 2 , 300 mg / m² 2 , 250 mg / m² 2 , 200 mg / m² 2 , 150 mg / m² 2 , 120 mg / m² 2 , 100 mg / m² 2 90 mg / m² 2 50 mg / m² 2 , or 30 mg / m² 2It contains any of the following mTOR inhibitors (e.g., rapamycin drugs such as sirolimus). In some embodiments, the amount of the mTOR inhibitor (e.g., rapamycin drug, e.g., sirolimus) per administration is about 40 mg / m 2 , 39 mg / m 2 , 38 mg / m 2 , 37 mg / m 2 , 36 mg / m 2 , 35 mg / m 2 , 34 mg / m 2 , 33 mg / m 2 , 32 mg / m 2 , 31 mg / m 2 , 30 mg / m 2 , 29 mg / m 2 , 28 mg / m 2 , 27 mg / m 2 , 26 mg / m<o000075>, 25 mg / m 2 , 24 mg / m 2 , 23 mg / m 2 , 22 mg / m 2 , 21 mg / m 2 , 20 mg / m 2 , 19 mg / m 2 , 18 mg / m 2 , 17 mg / m 2 , 16 mg / m 2 , 15 mg / m 2 , (14 mg / m 2 , 13 mg / m 2 , 12 mg / m 2 , 11 mg / m 2 , 10 mg / m 2 , 9 mg / m 2 , 8 mg / m 2 , 7 mg / m 2 , 6 mg / m 2 , 5 mg / m 2 , 4 mg / m 2 , 3 mg / m 2 , 2 mg / m 2 , or less than any of 1 mg / m 2 . In some embodiments, the mTOR inhibitor (e.g., rapamycin drug, e.g., sirolimus) in the mTOR inhibitor nanoparticle composition is about 1 to about 5 mg / m 2 , about 5 to about 10 mg / m 2 It should be noted that there seems to be a minor error in the original text where "14 mg / m" in line 52 has an extra closing parenthesis. This has been corrected in the translation as much as possible while maintaining the integrity of the overall text structure., about 10~25mg / m 2 , about 25~50mg / m 2 , about 50 to about 75mg / m 2 , about 75~100mg / m 2 , about 100~125mg / m 2 , about 125~150mg / m 2 , about 150~175mg / m 2 , about 175~200mg / m 2 , about 200~225mg / m 2 , about 225~250mg / m 2 , about 250~300mg / m 2 , about 300~350mg / m 2 , or approximately 350-400 mg / m² 2 It is included in any of the following ranges. In some embodiments, the mTOR inhibitor (e.g., limus drug, e.g., sirolimus) in the mTOR inhibitor nanoparticle composition is about 30 to about 300 mg / m 2 For example, approximately 100 to 150 mg / m² 2 , about 120mg / m2, about 130mg / m 2 , or approximately 140 mg / m² 2 In some embodiments, the amount of the mTOR inhibitor nanoparticle composition is administered every four weeks (e.g., on day 1 of a 28-day cycle). In some embodiments, the amount of the mTOR inhibitor nanoparticle composition is administered every three weeks (e.g., on day 1 of a 21-day cycle). In some embodiments, the amount of the mTOR inhibitor nanoparticle composition is administered every two weeks (e.g., on day 1 of a 14-day cycle). In some embodiments, the amount of the mTOR inhibitor nanoparticle composition is administered weekly. In some embodiments, the amount of the mTOR inhibitor nanoparticle composition is administered weekly, every two weeks out of three weeks. In some embodiments, the amount of the mTOR inhibitor nanoparticle composition is administered on days 8 and 15 of a 21-day cycle, day 1 or 8 of a 21-day cycle, day 15 and 21 of a 21-day cycle, day 1 and 15 of a 21-day cycle, or day 1 and 21 of a 21-day cycle.

[0072] In some embodiments, the estrogen inhibitor (e.g., letrozole or fulvestrant) is administered in doses ranging from about 0.1 mg to about 2,500 mg, which includes any of the following: about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, or about 200 mg to about 400 mg. In some embodiments, the estrogen inhibitor (e.g., letrozole or fulvestrant) is approximately 2,500 mg or less, for example, approximately 2,250 mg or less, 2,000 mg or less, 1,750 mg or less, 1,500 mg or less, 1,250 mg or less, 1,000 mg or less, 750 mg or less, 700 mg or less, 650 mg or less, 600 mg or less, 550 mg or less, 500 mg or less, 450 mg or less, 400 mg or less, 350 mg or less, 300 mg or less, 250 mg or less, 200 mg or less, 150 mg or less, 100 mg or less, 9 It is administered in any of the following amounts: 0 mg or less, 80 mg or less, 70 mg or less, 60 mg or less, 50 mg or less, 40 mg or less, 30 mg or less, 20 mg or less, 10 mg or less, 9 mg or less, 8 mg or less, 7 mg or less, 6 mg or less, 5 mg or less, 4.5 mg or less, 4 mg or less, 3.5 mg or less, 3 mg or less, 2.5 mg or less, 2 mg or less, 1.5 mg or less, 1 mg or less, 0.9 mg or less, 0.8 mg or less, 0.7 mg or less, 0.6 mg or less, 0.5 mg or less, 0.4 mg or less, 0.3 mg or less, 0.2 mg or less, or 0.1 mg or less.In some embodiments, the estrogen inhibitor (e.g., letrozole or fulvestrant) is present in doses of approximately 2,500 mg, 2,400 mg, 2,300 mg, 2,200 mg, 2,100 mg, 2,000 mg, 1,900 mg, 1,800 mg, 1,700 mg, 1,600 mg, 1,500 mg, 1,400 mg, 1,300 mg, 1,200 mg, 1,100 mg, 1,000 mg, 900 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, and 500 mg. It is administered in one of the following doses: 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4.5 mg, 4 mg, 3.5 mg, 3 mg, 2.5 mg, 2 mg, 1.5 mg, 1 mg, 0.9 mg, 0.8 mg, 0.7 mg, 0.6 mg, 0.5 mg, 0.4 mg, 0.3 mg, 0.2 mg, or 0.1 mg.

[0073] In some embodiments, the administration frequency of the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) includes, but is not limited to, daily, every two days, every three days, every four days, every five days, every six days, weekly (without breaks), every three weeks out of four weeks (such as days 1, 8, and 15 of a 28-day cycle), once every three weeks, once every two weeks, or twice out of three weeks. In some embodiments, the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) is administered approximately once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks. In some embodiments, the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) is administered at least approximately once, twice, three times, four times, five times, six times, or seven times per week (i.e., daily). In some embodiments, the interval between doses is less than approximately 6 months, 3 months, 1 month, 20 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, or 1 day. In some embodiments, the interval between doses is greater than approximately 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months. In some embodiments, there is no interruption in the dosing schedule. In some embodiments, the interval between doses is less than approximately 1 week.

[0074] In some embodiments, the administration frequency is once, once, twice, three times, four times, five times, six times, seven times, eight times, nine times, ten times, or eleven times every two days. In some embodiments, the administration frequency is once every two days or five times. In some embodiments, the mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) is administered over a period of at least 10 days, with intervals between each administration being approximately two days or less, and the dose of the mTOR inhibitor at each administration being approximately 0.25 mg / m² 2 ~about 250mg / m 2 , about 0.25mg / m 2 ~about 150mg / m 2 , about 0.25mg / m 2 ~about 75mg / m 2 For example, approximately 0.25 mg / m²2 ~about 25mg / m 2 , or approximately 25 mg / m² 2 ~about 50mg / m 2 That is the case.

[0075] The administration of mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) can be carried out over a long period of time, ranging from approximately one month to approximately seven years. In some embodiments, the mTOR inhibitor nanoparticle composition (such as sirolimus / albumin nanoparticle compositions) is administered for at least one of the following periods: approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 48, 60, 72, or 84 months.

[0076] In some embodiments, the dose of the mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) in the nanoparticle composition is 5 to 400 mg / m² when administered on a 3-week schedule. 2 The range is 5-250 mg / m² when administered on a once-weekly schedule. 2 2 (For example, 80-150 mg / m²) 2 For example, 100-120 mg / m² 2 The dosage may be within the range of ). For example, the amount of mTOR inhibitors (e.g., limus drugs, e.g., sirolimus or its derivatives) may be approximately 60 to 300 mg / m² over a 3-week schedule. 2 (For example, approximately 260 mg / m²) 2 )

[0077] In some embodiments, an exemplary dosing schedule for administering an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) is 100 mg / m². 2 (Weekly, without interruption), 10 mg / m² 2 (Weekly, for 3 weeks out of 4 weeks (e.g., day 1, day 8, day 15 of a 28-day cycle)), 45 mg / m² 2 (Weekly, for 3 weeks out of 4 weeks (e.g., day 1, day 8, day 15 of a 28-day cycle)), 75 mg / m² 2(Weekly, for 3 weeks out of 4 weeks (e.g., day 1, day 8, day 15 of a 28-day cycle)), 100 mg / m² 2 (Weekly, for 3 out of 4 weeks), 125 mg / m² 2 (Weekly, for 3 out of 4 weeks), 125 mg / m² 2 (Weekly, for 2 weeks out of 3), 130 mg / m² 2 (Weekly, uninterrupted), 175 mg / m² 2 (Once every two weeks), 260 mg / m² 2 (Once every two weeks), 260 mg / m² 2 (Once every 3 weeks), 180-300 mg / m² 2 (Every 3 weeks), 60-175 mg / m² 2 (Weekly, without interruption), 20-150 mg / m² 2 (Twice a week), and 150-250 mg / m² 2 This includes, but is not limited to, administration twice a week. The frequency of administration of mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) may be adjusted during the course of treatment at the discretion of the administering physician.

[0078] In some embodiments, the individual receives treatment for at least one, two, three, four, five, six, seven, eight, nine, or ten treatment cycles.

[0079] The mTOR inhibitor nanoparticle compositions described herein (such as sirolimus / albumin nanoparticle compositions) enable the injection of the mTOR inhibitor nanoparticle compositions into an individual with an injection time shorter than approximately 24 hours. For example, in some embodiments, the mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) are administered over injection periods of approximately 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or less than 10 minutes. In some embodiments, the mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) are administered over an injection period of approximately 30 minutes.

[0080] In some embodiments, the exemplary dose of the mTOR inhibitor (in some embodiments, a limus drug, e.g., sirolimus) in the mTOR inhibitor nanoparticle composition is about 10 mg / m³ 2 , 20 mg / m² 2 , 30 mg / m² 2 , 40 mg / m² 2 50 mg / m² 2 , 60 mg / m² 2 75 mg / m² 2 , 80 mg / m² 2 90 mg / m² 2 , 100 mg / m² 2 , 120 mg / m² 2 , 160 mg / m² 2 , 175 mg / m² 2 , 200 mg / m² 2 , 210 mg / m² 2 , 220 mg / m² 2 , 260 mg / m² 2 , and 300 mg / m² 2 This includes, but is not limited to, any of the following. For example, the dose of an mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) in a nanoparticle composition is approximately 20-400 mg / m² when administered on a 3-week schedule. 2 The range is approximately 10-250 mg / m² when administered on a weekly schedule. 2 It may also be within that range.

[0081] In some embodiments, the dose of the mTOR inhibitor (e.g., limus, e.g., sirolimus) is about 100 mg to about 400 mg, for example, about 100 mg, about 200 mg, about 300 mg, or about 400 mg. In some embodiments, the limus is administered at doses of about 100 mg weekly, about 200 mg weekly, about 300 mg weekly, about 100 mg twice weekly, or about 200 mg twice weekly. In some embodiments, a monthly maintenance dose (the same as or different from the weekly dose) is administered after the initial administration.

[0082] In some embodiments, when the mTOR nanoparticle composition is administered intravenously, the dose of the mTOR inhibitor (e.g., limus drug, e.g., sirolimus) in the nanoparticle composition may range from about 30 mg to about 400 mg. The mTOR inhibitor nanoparticle compositions described herein (such as sirolimus / albumin nanoparticle compositions) allow for the infusion of the mTOR inhibitor nanoparticle composition into an individual with an infusion time shorter than about 24 hours. For example, in some embodiments, the mTOR inhibitor nanoparticle composition (such as sirolimus / albumin nanoparticle compositions) is administered over infusion periods of about 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or less than 10 minutes. In some embodiments, the mTOR inhibitor nanoparticle composition (such as sirolimus / albumin nanoparticle compositions) is administered over infusion periods of about 30 minutes to about 40 minutes.

[0083] In some embodiments, exemplary dosing schedules for administering estrogen inhibitors, such as drugs that inhibit estrogen or estrogen receptor signaling, are the same as or similar to the dosing schedules for such drugs when administered alone. For example, in some embodiments, the estrogen inhibitor is letrozole and is administered daily. In some embodiments, letrozole is administered to the individual daily in amounts of about 0.1 mg to about 10 mg, e.g., 2.5 mg. In some embodiments, the estrogen inhibitor, e.g., a drug that inhibits estrogen receptor signaling, is fulvestrant and is administered to the individual on days 1, 15, and 29 of the initiation cycle, followed by a monthly maintenance dose. In some embodiments, the estrogen inhibitor, e.g., a drug that inhibits estrogen receptor signaling, is fulvestrant and is administered to the individual on days 1, 15, and 29 of the initiation cycle, followed by a monthly maintenance dose of about 100 mg to about 700 mg, e.g., 500 mg.

[0084] mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and estrogen inhibitors (e.g., letrozole or fulvestrant) can be administered in pure form or as suitable pharmaceutical compositions by any acceptable mode of administration or agent known in the art. Compositions and / or agents can be administered, for example, parenterally (e.g., intravenously). Dosage forms may be solid, semi-solid, lyophilized powder, or liquid dosage forms, such as tablets, pills, soft elastic or hard gelatin capsules, powders, solutions, suspensions, suppositories, or aerosols, preferably unit dosage forms suitable for easy administration of precise doses.

[0085] As discussed above, mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and estrogen inhibitors (e.g., letrozole or fulvestrant) can be administered in a single unit dose or in separate dosage forms. Therefore, the term “pharmaceutical combination” includes combinations of two drugs in either a single dosage form or separate dosage forms, i.e., the pharmaceutically acceptable carriers and excipients described throughout the application can be combined with mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and estrogen inhibitors (e.g., letrozole or fulvestrant) in a single unit dose, as well as individually with mTOR inhibitor nanoparticle compositions and estrogen inhibitors (e.g., letrozole or fulvestrant) when these compounds are administered separately.

[0086] Auxiliaries and adjuvants may include, for example, preservatives, humectants, suspending agents, sweeteners, flavorings, fragrances, emulsifiers, and dispersants. Prevention of microbial action is generally carried out by various antimicrobial and antifungal agents such as parabens, chlorobutanol, phenol, and sorbic acid. Isotonic agents such as sugars and sodium chloride may also be included. The use of absorption-delaying agents such as aluminum monostearate and gelatin can result in prolonged absorption of injectable drugs. Auxiliaries may also include humectants, emulsifiers, pH buffers, and antioxidants, such as citric acid, sorbitan monolaurate, triethanolamine oleate, and butylated hydroxytoluene.

[0087] Solid dosage forms can be prepared using enteric coatings and other coatings and shells known in the art. These dosage forms may contain sedatives and have compositions that delay the release of the active compound at specific sites in the intestinal tract. Examples of usable embedding compositions are polymeric substances and waxes. The active compound may, where appropriate, be in a microencapsulated form with one or more of the excipients described above.

[0088] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared by dissolving or dispersing, for example, an mTOR inhibitor nanoparticle composition described herein (such as a sirolimus / albumin nanoparticle composition) or an estrogen inhibitor (e.g., letrozole or fulvestrant)), or a pharmaceutically acceptable salt thereof, and an optional pharmaceutical adjuvant, in a carrier such as water, physiological saline, aqueous dextrose, glycerol, or ethanol, a solubilizer and emulsifier such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, or dimethylformamide, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, or mixtures thereof, to form a solution or suspension.

[0089] In some embodiments, depending on the intended mode of administration, the pharmaceutically acceptable composition contains about 1% to about 99% by weight of the compound described herein or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a pharmaceutically acceptable excipient. In one example, the composition contains about 5% to about 75% by weight of the compound described herein or a pharmaceutically acceptable salt thereof, with the remainder being a suitable pharmaceutically acceptable excipient.

[0090] The practical methods for preparing such dosage forms will be known or obvious to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990).

[0091] mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) can be administered to individuals (such as humans) via various routes, including intravenous administration. In some embodiments, a sustained-release formulation of the composition may be used. In some embodiments, the composition is administered intravenously.

[0092] Estrogen inhibitors, such as drugs that suppress estrogen or estrogen receptor signaling (e.g., letrozole or fulvestrant), can be administered to an individual (e.g., a human) via various routes, including, for example, oral, intramuscular, intravenous, intra-arterial, intraperitoneal, intrapulmonary, inhalation, intravesical, intratracheal, subcutaneous, intraocular, intrathecal, transmucosal, and transdermal. In some embodiments, the estrogen inhibitor is letrozole and is administered orally. In some embodiments, the estrogen inhibitor is fulvestrant and is administered intramuscularly.

[0093] C. Treatment of hormone-dependent cancers In some embodiments, a method is provided for treating hormone-dependent cancer in an individual requiring treatment for hormone-dependent cancer, wherein the hormone-dependent cancer is selected from the group consisting of endometrial cancer (e.g., endometrioid endometrial cancer) and hormone receptor-positive breast cancer, and the method comprises administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor and albumin, and (b) an estrogen inhibitor, such as an agent that suppresses estrogen or estrogen receptor signaling (e.g., letrozole or fulvestrant).

[0094] Endometrioid endometrial carcinoma (EEC) is a type of endometrial cancer that develops in the endometrium of the uterus. It typically originates in the glandular cells of the endometrium. Endometrial cancer is classified into estrogen-dependent type I and estrogen-independent type II. Type I endometrial tumors, also known as low-grade endometrioids, account for the majority of endometrial cancer cases (approximately 85%), are low-grade tumors with glandular structures, usually express high levels of estrogen receptor α (ER), and are thought to be hormone-induced. Type II tumors include high-grade endometrioid tumors, serous tumors, clear cell tumors, carcinosarcomas, and mixed histological tumors. The main subtypes of endometrioid endometrial carcinoma are defined by the genetic characteristics of the cells, such as mutations in the POLE gene, high levels of "microsatellite instability," microsatellite stability, and high copy numbers of specific DNA sections. Examples of non-endometrioid endometrial carcinomas include papillary serous carcinoma, clear cell tumors, and carcinosarcomas. EECs are typically cystic and solid tumors with necrotic and hemorrhagic foci. EECs are morphologically similar to typical types of endometrial adenocarcinoma and are classified using the same criteria. Squamous differentiation may be seen in EECs. There are many subtypes of EECs, including adenocarcinomas (such as those with squamous differentiation), adenocautalocytes, adenosquamous cell carcinomas (or mixed cell types), secretory carcinomas, ciliary carcinomas, and chorioadoneocarcinomas. In some embodiments, EECs are estrogen-dependent EECs. Techniques for determining hormone dependence and the presence of hormone receptors are known in the art, for example, using techniques such as immunohistochemistry (IHC) to take biopsies to examine the presence of, for example, estrogen receptors or progesterone receptors.

[0095] In some embodiments, a method is provided for treating endometrial cancer (e.g., endometrioid endometrial carcinoma) in an individual (such as a human), the method comprising administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, and (b) an estrogen inhibitor (e.g., letrozole). In some embodiments, the method comprises administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, wherein the mTOR inhibitor in the nanoparticles is associated with (e.g., coated with) albumin, and (b) an estrogen inhibitor (e.g., letrozole). In some embodiments, the method involves administering to an individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, wherein the nanoparticles have an average particle size of about 150 nm or less (e.g., about 120 nm or less), and (b) an estrogen inhibitor (e.g., letrozole). In some embodiments, the method comprises administering to an individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, wherein the nanoparticles comprise the mTOR inhibitor associated (e.g., coated) with albumin, the nanoparticles have an average particle size of about 150 nm or less (e.g., about 120 nm or less, e.g., about 100 nm), and the weight ratio of albumin to mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 9:1 or less (e.g., about 9:1 or about 8:1), and (b) an estrogen inhibitor (e.g., letrozole). In some embodiments, the mTOR inhibitor is a limus drug.In some embodiments, the mTOR inhibitor is sirolimus or a derivative thereof. In some embodiments, the mTOR inhibitor nanoparticle composition comprises nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is nab-sirolimus. In some embodiments, the estrogen inhibitor is letrozole. In some embodiments, the mTOR inhibitor nanoparticle composition is administered weekly, such as twice every three weeks, on days 1 and 8, 1 and 15, 1 and 21, or 8 and 15 of a 21-day cycle. In some embodiments, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg / m². 2 ~about 150mg / m 2 For example, approximately 100 mg / m² 2 75 mg / m² 2 , 56 mg / m² 2 , 45 mg / m² 2 , or 30 mg / m² 2 It is one of the following. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition is administered over an infusion period of about 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or less than 10 minutes. In some embodiments, the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) is administered over an infusion period of about 30 minutes. In some embodiments, the estrogen inhibitor (e.g., letrozole) is administered daily. In some embodiments, the amount of the estrogen inhibitor (e.g., letrozole) is about 0.1 mg to about 10 mg, for example, about 2.5 mg. In some embodiments, the estrogen inhibitor (e.g., letrozole) is administered orally. In some embodiments, the estrogen inhibitor (e.g., letrozole) is administered orally daily in amounts of about 0.1 mg to about 10 mg, including about 2.5 mg. In some embodiments, a method is provided for treating endometrial cancer (e.g., endometrioid endometrial carcinoma) in an individual (such as a human), the method comprising (a) a composition comprising nanoparticles containing sirolimus and albumin, administered for two weeks every three weeks (e.g., on day 1 and day 8 of a 21-day cycle) at a dose of approximately 10 mg / m²2 ~about 150mg / m 2 For example, approximately 100 mg / m² 2 (b) administering intravenously to the individual in an amount of (a) letrozole orally to the individual daily in an amount of about 0.1 mg to about 10 mg, for example, about 2.5 mg. In some embodiments, the endometrial cancer (e.g., endometrioid endometrial cancer) is either advanced endometrial cancer (unresectable International Federation of Gynecology and Obstetrics (FIGO) stage III or IV) or recurrent endometrial cancer (e.g., endometrioid endometrial cancer).

[0096] In some embodiments, endometrial cancer (e.g., endometrioid endometrial carcinoma) is refractory, recurrent, recurrent, or resistant to prior treatment. In some embodiments, prior treatment includes chemotherapy. In some embodiments, prior treatment includes platinum-based agents, immunotherapy, targeted therapy, and / or checkpoint inhibitors. In some embodiments, prior treatment includes platinum-based agents and / or checkpoint inhibitors. In some embodiments, the individual has received zero or one or more prior treatments, e.g., zero to one or more chemotherapy regimens. In some embodiments, the individual has recurrent, progressive, or metastatic cancer. In some embodiments, the patient has received one or more chemotherapy regimens. In some embodiments, the patient has not received or is chemotherapy-naive. In some embodiments, prior therapy is adjuvant therapy. In some embodiments, prior adjuvant therapy is chemotherapy, hormone therapy, or checkpoint inhibitors. In some embodiments, adjuvant therapy is completed at least six months before treatment according to the method described herein. In some embodiments, prior therapy is a non-chemotherapy-based treatment. In some embodiments, prior non-chemotherapy-based treatment was completed at least four months before treatment according to the method described herein.

[0097] In some embodiments, the individual has not previously received treatment for cancer, such as the cancer treated by the method described herein. In some embodiments, the cancer is endometrial cancer. In some embodiments, the individual has recurrent, progressive, or metastatic cancer. In some embodiments, the patient has not previously received chemotherapy. In some embodiments, prior treatment includes platinum-based agents, immunotherapy, targeted therapy, and / or checkpoint inhibitors. In some embodiments, the patient has not previously received platinum-based agents and / or checkpoint inhibitors. In some embodiments, the patient has not previously received adjuvant therapy after surgery. In some embodiments, the patient has not previously received any treatment other than chemotherapy.

[0098] Hormone receptor-positive breast cancer is breast cancer that expresses estrogen receptors, progesterone receptors, or both estrogen and progesterone receptors. The presence of such receptors plays a role in stimulating growth in the presence of estrogen and / or progesterone (in a receptor-dependent manner). In some embodiments, hormone receptor-positive breast cancer may have other clinically relevant markers, such as HER2. Techniques for determining hormone dependence and the presence of hormone receptors are known in the art, for example, using techniques such as immunohistochemistry (IHC) to take biopsies to test for the presence of, for example, estrogen receptors or progesterone receptors.

[0099] In some embodiments, a method is provided for treating hormone receptor-positive breast cancer in an individual (such as a human), the method comprising administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, and (b) an estrogen inhibitor (e.g., fulvestrant). In some embodiments, the method comprises administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, wherein the mTOR inhibitor in the nanoparticles is associated with (e.g., coated) albumin, and (b) an estrogen inhibitor (e.g., fulvestrant). In some embodiments, the method comprises administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, wherein the nanoparticles have an average particle size of about 150 nm or less (e.g., about 120 nm or less), and (b) an estrogen inhibitor (e.g., fulvestrant). In some embodiments, the method comprises administering to an individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, wherein the nanoparticles comprise the mTOR inhibitor associated with (e.g., coated with) albumin, and the nanoparticles have an average particle size of about 150 nm or less (e.g., about 120 nm or less), and (b) an estrogen inhibitor (e.g., fulvestrant). In some embodiments, the method comprises administering to an individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, wherein the nanoparticles comprise the mTOR inhibitor associated (e.g., coated) with albumin, the nanoparticles have an average particle size of about 150 nm or less (e.g., about 120 nm or less, e.g., about 100 nm), and the weight ratio of albumin to mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 9:1 or less (e.g., about 9:1 or about 8:1), and (b) an estrogen inhibitor (e.g., fulvestrant). In some embodiments, the mTOR inhibitor is a limus drug.In some embodiments, the mTOR inhibitor is sirolimus or a derivative thereof. In some embodiments, the mTOR inhibitor nanoparticle composition comprises nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is nab-sirolimus. In some embodiments, the estrogen inhibitor is fulvestrant. In some embodiments, the mTOR inhibitor nanoparticle composition is administered weekly, such as twice every three weeks, on days 1 and 8, 1 and 15, 1 and 21, or 8 and 15 of a 21-day cycle. In some embodiments, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg / m². 2 ~about 150mg / m 2 For example, approximately 100 mg / m² 2 75 mg / m² 2 , 56 mg / m² 2 , 45 mg / m² 2 , or 30 mg / m² 2 It is one of the following. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the estrogen inhibitor (e.g., fulvestrant) is administered using an initiation cycle and one or more subsequent maintenance cycles (e.g., fulvestrant is administered to the individual on days 1, 15, and 29 of the initiation cycle, and then one or more monthly maintenance doses are administered thereafter). In some embodiments, the amount of the estrogen inhibitor (e.g., fulvestrant) is about 100 mg to about 700 mg, for example, 500 mg. In some embodiments, the estrogen inhibitor (e.g., fulvestrant) is administered intramuscularly. In some embodiments, the estrogen inhibitor (e.g., fulvestrant) is administered intramuscularly using an initiation cycle and one or more subsequent maintenance cycles at about 100 mg to about 700 mg, for example, 500 mg. In some embodiments, a method is provided for treating hormone receptor-positive breast cancer in an individual (e.g., a human), the method comprising (a) a composition comprising nanoparticles containing sirolimus and albumin, administered for two weeks every three weeks (e.g., on day 1 and day 8 of a 21-day cycle) at a dose of approximately 10 mg / m². 2 ~about 150mg / m 2For example, approximately 100 mg / m² 2 (b) administering the amount intravenously to the individual, and (b) administering fulvestrant intramuscularly to the individual using an initiation cycle and one or more subsequent maintenance cycles of approximately 100 mg to approximately 700 mg, for example, 500 mg.

[0100] III. Composition containing nanoparticles containing an mTOR inhibitor The mTOR inhibitor nanoparticle compositions described herein include nanoparticles comprising an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) and albumin (e.g., human serum albumin) (in various embodiments, substantially consisting of or comprising these). Note that the terms sirolimus and rapamycin are used interchangeably herein. Nanoparticles of poorly water-soluble drugs (such as macrolides) are disclosed, for example, in U.S. Patent Nos. 5,916,596, 6,506,405, 6,749,868, 6,537,579, 7,820,788, 8,911,786, and 11,497,737, as well as U.S. Patent Publication Nos. 2006 / 0263434 and 2007 / 0082838, PCT Patent Application No. W008 / 137148 and U.S. Patent Application No. 62 / 927,047, all of which are incorporated herein by reference.

[0101] In some embodiments, the composition comprises nanoparticles having an average diameter or diameter of about 1000 nanometers (nm) or less, for example, about 900, 800, 700, 600, 500, 400, 300, 200, and 100 nm or less. In some embodiments, the average diameter or diameter of the nanoparticles is about 200 nm or less. In some embodiments, the average diameter or diameter of the nanoparticles is about 150 nm or less. In some embodiments, the average diameter or diameter of the nanoparticles is about 100 nm or less. In some embodiments, the average diameter or diameter of the nanoparticles is about 10 to about 400 nm. In some embodiments, the average diameter or diameter of the nanoparticles is about 10 to about 150 nm. In some embodiments, the average diameter or diameter of the nanoparticles is about 40 to about 120 nm. In some embodiments, the average diameter or diameter of the nanoparticles is about 50 nm or more. In some embodiments, the nanoparticles are sterile and filterable.

[0102] Methods for determining average particle size are known in the art, and for example, dynamic light scattering (DLS) is routinely used to determine the size of submicrometer-sized particles. See the international standard ISO 22412 Particle size analysis - dynamic light scattering, International Organization for Standardization (ISO) 2008 and definitions of general terms for dynamic light scattering (Malvern Instruments Limited, 2011). In some embodiments, particle size is measured as the volume-weighted average particle size (Dv50) of nanoparticles in a composition.

[0103] In some embodiments, the nanoparticles contain an mTOR inhibitor associated with albumin. In some embodiments, the nanoparticles contain an mTOR inhibitor coated with albumin.

[0104] In some embodiments, the albumin has sulfidyl groups capable of forming disulfide bonds. In some embodiments, at least about 5% of the albumin in the nanoparticle portion of the composition (e.g., including at least about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%) is crosslinked (e.g., crosslinked via one or more disulfide bonds).

[0105] In some embodiments, nanoparticles containing an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) are associated with (e.g., coated with) albumin (e.g., human albumin or human serum albumin). In some embodiments, the composition contains an mTOR inhibitor (e.g., a limus drug, e.g., rapamycin or a derivative thereof) in both nanoparticle and non-nanoparticle forms (e.g., in the form of a solution or a soluble albumin / nanoparticle complex), where at least about 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the mTOR inhibitor in the composition is in the form of nanoparticles. In some embodiments, the mTOR inhibitor (e.g., a limus drug, e.g., rapamycin or a derivative thereof) in the nanoparticles constitutes one or more of about 50%, 60%, 70%, 80%, 90%, 95%, or 99% by weight of the nanoparticles. In some embodiments, the nanoparticles have a nonpolymer matrix. In some embodiments, the nanoparticles comprise a core of an mTOR inhibitor (e.g., a limus drug, e.g., rapamycin or a derivative thereof) that is substantially free of polymer material (e.g., a polymer matrix).

[0106] In some embodiments, the composition comprises albumin in both the nanoparticle portion and the non-nanoparticle portion of the composition, with at least one of approximately 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the albumin in the composition present in the non-nanoparticle portion of the composition.

[0107] In some embodiments, the weight ratio of albumin to the mTOR inhibitor (e.g., limus drugs, e.g., rapamycin or its derivatives) in the mTOR inhibitor nanoparticle composition is such that a sufficient amount of the mTOR inhibitor binds to or is transported by the cell. The weight ratio of albumin to the mTOR inhibitor (e.g., limus drugs, e.g., rapamycin or its derivatives) needs to be optimized for various combinations of albumin and mTOR inhibitor, but generally, the weight ratio (w / w) of albumin to the mTOR inhibitor (e.g., limus drugs, e.g., rapamycin or its derivatives) is about 0.01:1 to about 100:1, about 0.02:1 to about 50:1, about 0.05:1 to about 20:1, about 0.1:1 to about 20:1, about 1:1 to about 18:1, about 2:1 to about 15:1, about 3:1 to about 12:1, about 4:1 to about 10:1, about 5:1 to about 9:1, or about 9:1. In some embodiments, the weight ratio of albumin to an mTOR inhibitor (e.g., a limus drug, e.g., rapamycin or its derivatives) is one of the following: approximately 18:1 or less, 15:1 or less, 14:1 or less, 13:1 or less, 12:1 or less, 11:1 or less, 10:1 or less, 9:1 or less, 8:1 or less, 7:1 or less, 6:1 or less, 5:1 or less, 4:1 or less, and 3:1 or less. In some embodiments, the weight ratio of albumin (e.g., human albumin or human serum albumin) to an mTOR inhibitor (e.g., limus drugs, e.g., rapamycin or its derivatives) in the composition is one of the following: about 1:1 to about 18:1, about 1:1 to about 15:1, about 1:1 to about 12:1, about 1:1 to about 10:1, about 1:1 to about 9:1, about 1:1 to about 8:1, about 1:1 to about 7:1, about 1:1 to about 6:1, about 1:1 to about 5:1, about 1:1 to about 4:1, about 1:1 to about 3:1, about 1:1 to about 2:1, or about 1:1 to about 1:1.

[0108] In some embodiments, the composition comprises nanoparticles containing an mTOR inhibitor and albumin, with a weight ratio of albumin to mTOR inhibitor in the composition being about 0.01:1 to about 100:1. In some embodiments, the composition comprises nanoparticles containing an mTOR inhibitor (such as rapamycin) and albumin, with a weight ratio of albumin to mTOR inhibitor (such as rapamycin) in the composition being about 18:1 or less (for example, including any of about 1:1 to about 18:1, about 2:1 to about 15:1, about 3:1 to about 12:1, about 4:1 to about 10:1, about 5:1 to about 9:1, and about 9:1). In some embodiments, the composition comprises nanoparticles containing rapamycin or a derivative thereof and albumin, wherein the weight ratio of albumin to rapamycin or a derivative thereof in the composition is about 18:1 or less (e.g., including any of about 1:1 to about 18:1, about 2:1 to about 15:1, about 3:1 to about 12:1, about 4:1 to about 10:1, about 5:1 to about 9:1, and about 9:1). In some embodiments, the mTOR inhibitor (such as rapamycin) is coated with albumin.

[0109] In some embodiments, the mTOR inhibitor nanoparticle composition (such as a rapamycin / albumin nanoparticle composition) includes one or more of the above-described properties.

[0110] The nanoparticles described herein may exist as a dry formulation (such as a lyophilized composition) or suspended in a biocompatible medium. Suitable biocompatible mediums include, but are not limited to, water, buffered aqueous media, physiological saline, buffered saline, optionally buffered amino acid solutions, optionally buffered protein solutions, optionally buffered sugar solutions, optionally buffered vitamin solutions, optionally buffered synthetic polymer solutions, and lipid-containing emulsions.

[0111] In some embodiments, the pharmaceutically acceptable carrier includes albumin (such as human albumin or human serum albumin). The albumin may be of natural origin or synthetic. In some embodiments, the albumin is human albumin or human serum albumin. In some embodiments, the albumin is recombinant albumin.

[0112] Human serum albumin (HSA) is M r HSA is a highly soluble globular protein with a weight of 65K and consists of 585 amino acids. HSA is the most abundant protein in plasma, accounting for 70-80% of the colloid osmotic pressure of human plasma. The amino acid sequence of HSA contains a total of 17 disulfide crosslinks, one free thiol (Cys 34), and one tryptophan (Trp 214). Intravenous administration of HSA solution is indicated for the prevention and treatment of hypovolemic shock (see, e.g., Tullis, JAMA, 237:355-360, 460-463, (1977) and Houser et al., Surgery, Gynecology and Obstetrics, 150:811-816 (1980)), and is also indicated for use in combination with exchange transfusion in the treatment of neonatal hyperbilirubinemia (see, e.g., Finlayson, Seminars in Thrombosis and Hemostasis, 6, 85-120, (1980)). Other albumins, such as bovine serum albumin, should also be considered. The use of such non-human albumins may be appropriate in the context of the use of these compositions in non-human mammals, for example, in veterinary medicine (including in the pet and agricultural sectors). Human serum albumin (HSA) has multiple hydrophobic binding sites (a total of eight for fatty acids, which are the endogenous ligands of HSA), and binds to a variety of drugs, particularly neutral and negatively charged hydrophobic compounds (Goodman et al., The Pharmacological Basis of Therapeutics, 9 thed, McGraw-Hill New York (1996)). Two high-affinity binding sites have been proposed for the HSA subdomains IIA and IIIA, which are very elongated hydrophobic pockets with charged lysine and arginine residues near the surface that function as attachment sites for polar ligands (e.g., Fehske et al., Biochem. Pharmcol., 30, 687-92 (198a), Vorum, Dan. Med. Bull., 46, 379-99 (1999), Kragh-Hansen, Dan. Med. Bull., 1441, 131-40 (1990), Curry et al., Nat. Struct. Biol., 5, 827-35 (1998), Sugio et al., Protein. Eng., 12, 439-46 (1999), He et al., Nature, 358, 209-15 (199b), and Carter et al. al., Adv. Protein. Chem., 45, 153-203 (1994). Rapamycin and propofol have been shown to bind to HSA (see, for example, Paal et al., Eur. J. Biochem., 268(7), 2187-91(200a), Purcell et al., Biochem. Biophys. Acta, 1478(a), 61-8(2000), Altmayer et al., Arzneimittelforschung, 45, 1053-6(1995), and Garrido et al., Rev. Esp. Anestestiol. Reanim., 41, 308-12(1994)). Furthermore, docetaxel has been shown to bind to human plasma proteins (see, for example, Urien et al., Invest. New Drugs, 14(b), 147-51 (1996)).

[0113] mTOR inhibitors (e.g., limus drugs, e.g., rapamycin or its derivatives) are considered "stabilized" in aqueous suspension if they remain suspended in an aqueous medium for an extended period (e.g., without visible precipitation or sedimentation), and this period is at least about 0.1, 0.2, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 36, 48, 60, or 72 hours. Suspensions are generally suitable, but not always, for administration to an organism (such as a human). The stability of a suspension is generally (but not always) assessed at the storage temperature (room temperature (e.g., 20-25°C) or refrigerated conditions (e.g., 4°C)). For example, a suspension is stable at the storage temperature if it is visible to the naked eye about 15 minutes after preparation, or if no cottony sediment or particle aggregation is observed using a 1000x optical microscope. Stability can also be evaluated under accelerated testing conditions, such as temperatures above approximately 40°C.

[0114] The compositions described herein may be stable aqueous suspensions of mTOR inhibitors at any of the following concentrations: approximately 0.1 to approximately 200 mg / ml, approximately 0.1 to approximately 150 mg / ml, approximately 0.1 to approximately 100 mg / ml, approximately 0.1 to approximately 50 mg / ml, approximately 0.1 to approximately 20 mg / ml, approximately 1 to approximately 10 mg / ml, approximately 2 mg / ml to approximately 8 mg / ml, approximately 4 to approximately 6 mg / ml, and approximately 5 mg / ml. In some embodiments, the concentration of the mTOR inhibitor is at least about 0.2 mg / ml, 1.3 mg / ml, 1.5 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 100 mg / ml, 150 mg / ml, or 200 mg / ml.

[0115] In some embodiments, albumin is present in an amount sufficient to stabilize an mTOR inhibitor (e.g., a limus drug, e.g., rapamycin or its derivatives) in an aqueous suspension at a specific concentration. For example, the concentration of the mTOR inhibitor (e.g., a limus drug, e.g., rapamycin or its derivatives) in the composition is about 0.1 to about 100 mg / ml, and includes, for example, about 0.1 to about 50 mg / ml, about 0.1 to about 20 mg / ml, about 1 to about 10 mg / ml, about 2 mg / ml to about 8 mg / ml, about 4 to about 6 mg / ml, or about 5 mg / ml. In some embodiments, the concentration of the mTOR inhibitor (e.g., limus drugs, e.g., rapamycin or its derivatives) is at least one of the following: 1.3 mg / ml, 1.5 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 40 mg / ml, and 50 mg / ml. In some embodiments, albumin is present in amounts that avoid the use of surfactants (e.g., cremophor), so the composition is surfactant-free (e.g., cremophor) or substantially surfactant-free.

[0116] In some embodiments, the composition in liquid form contains about 0.1% to about 50% (w / v) of albumin (e.g., about 0.5% (w / v), about 5% (w / v), about 10% (w / v), about 15% (w / v), about 20% (w / v), about 30% (w / v), about 40% (w / v), or about 50% (w / v)).

[0117] In some embodiments, albumin enables the administration of the composition to an individual (such as a human) without serious side effects. In some embodiments, the amount of albumin (such as human serum albumin or human albumin) is effective in mitigating one or more side effects when an mTOR inhibitor (e.g., a Limus drug, e.g., rapamycin or its derivatives) is administered to a human. The term "mitigating one or more side effects" of the administration of an mTOR inhibitor (e.g., a Limus drug, e.g., rapamycin or its derivatives) refers to the mitigation, mitigation, elimination, or avoidance of one or more undesirable effects caused by the mTOR inhibitor and side effects caused by the delivery medium used to deliver the mTOR inhibitor (e.g., a solvent that makes the Limus drug suitable for injection). Such side effects include, for example, myelosuppression, neurotoxicity, hypersensitivity, inflammation, venous irritation, phlebitis, pain, skin irritation, peripheral neuropathy, neutropenic fever, anaphylactic reactions, venous thrombosis, extravasation, and combinations thereof. However, these side effects are merely examples, and other side effects, or combinations of side effects, associated with limus drugs (e.g., limus drugs such as rapamycin or its derivatives) can be mitigated.

[0118] In some embodiments, the composition is a dry (e.g., lyophilized) composition that can be reconstituted, resuspended, or rehydrated to form a generally stable aqueous suspension of nanoparticles containing an mTOR inhibitor and albumin. In some embodiments, the composition is a liquid (e.g., aqueous) composition obtained by reconstituting or resuspending the dry composition. In some embodiments, the composition is a dry (e.g., lyophilized) intermediate liquid (e.g., aqueous) composition.

[0119] A. mTOR inhibitors The methods described herein include, in some embodiments, the administration of a nanoparticle composition of an mTOR inhibitor. As used herein, “mTOR inhibitor” refers to an inhibitor of mTOR. mTOR is a serine / threonine-specific protein kinase located downstream of the phosphatidylinositol 3-kinase (PI3K) / Akt (protein kinase B) pathway and is a key regulator of cell survival, proliferation, stress, and metabolism. Dysregulation of the mTOR pathway has been found in many human cancers, and mTOR inhibition has shown a significant inhibitory effect on tumor progression.

[0120] Mammalian target of rapamycin (mTOR) (also known as the mechanistic target protein of rapamycin, or FK506-binding protein 12-rapamycin-related protein 1 (FRAP1)) is an atypical serine / threonine protein kinase present in two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is composed of mTOR, mTOR regulatory-related protein (Raptor), mammalian lethal protein (MLST8) with SEC13 protein 8, PRAS40, and DEPTOR (Kim et al. (2002). Cell 110:163-75; Fang et al. (2001). Science 294(5548):1942-5). mTORC1 integrates four major signaling inputs: nutrients (amino acids and phosphatidic acid, etc.), growth factors (insulin), energy, and stress (hypoxia and DNA damage, etc.). The availability of amino acids is signaled to mTORC1 via a pathway involving Rag and Ragulator (LAMTOR1-3) growth factors and hormones (such as insulin), and Akt inactivates TSC2, preventing inhibition of mTORC1. Alternatively, low ATP levels lead to AMPK-dependent TSC2 activation and raptor phosphorylation, reducing mTORC1 signaling proteins.

[0121] Active mTORC1 has many downstream biological effects, including mRNA translation via phosphorylation of downstream targets (4E-BP1 and p70 S6 kinase), repression of autophagy (Atg13, ULK1), ribosome biosynthesis, and activation of transcription leading to mitochondrial metabolism or adipogenesis. Therefore, mTORC1 activity promotes cell growth under favorable conditions and facilitates catabolic processes under stress or unfavorable conditions.

[0122] mTORC2 is composed of mTOR, rapamycin-insensitive mTOR companion (RICTOR), GβL, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1). In contrast to mTORC1 (see above), many upstream signals and cellular functions are defined, relatively little is known about the biology of mTORC2. mTORC2 regulates cytoskeletal organization by stimulating F-actin stress fibers, paxilin, RhoA, Rac1, Cdc42, and protein kinase Cα (PKCα). Knockdown of mTORC2 components has been observed to affect actin polymerization and disrupt cell morphology (Jacinto et al. (2004). Nat. Cell Biol. 6, 1122-1128; Sarbassov et al. (2004). Curr. Biol. 14, 1296-1302). This suggests that mTORC2 regulates the actin cytoskeleton by promoting the phosphorylation of protein kinase Cα (PKCα), the phosphorylation and relocalization of paxil to adhesion plaques, and the GTP loading of RhoA and Rac1. The molecular mechanisms by which mTORC2 controls these processes remain unclear.

[0123] In some embodiments, the mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) is an inhibitor of mTORC1. In some embodiments, the mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) is an inhibitor of mTORC2. In some embodiments, the mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) is an inhibitor of both mTORC1 and mTORC2.

[0124] In some embodiments, the mTOR inhibitor is a limus drug, including sirolimus and its analogs. Examples of limus drugs include, but are not limited to, temsirolimus (CCI-779), everolimus (RAD001), lidaforolimus (AP-23573), deforolimus (MK-8669), zotarolimus (ABT-578), pimecrolimus, and tacrolimus (FK-506). In some embodiments, the limus drug is selected from the group consisting of temsirolimus (CCI-779), everolimus (RAD001), lidaforolimus (AP-23573), deforolimus (MK-8669), zotarolimus (ABT-578), pimecrolimus, and tacrolimus (FK-506). In some embodiments, the mTOR inhibitor is an mTOR kinase inhibitor such as CC-115 or CC-223.

[0125] In some embodiments, the mTOR inhibitor is sirolimus. Sirolimus is a macrolide antibiotic that forms a complex with FKBP-12 and binds to mTORC1, thereby inhibiting the mTOR pathway.

[0126] In some embodiments, the mTOR inhibitor is sirolimus (rapamycin), BEZ235 (NVP-BEZ235), everolimus (RAD001, also known as Zotres, Certican, Afinitor), AZD8055, temsirolimus (CCI-779, also known as Tricel), CC-115, CC-223, PI-103, Ku-0063794, INK128, AZD2014, NVP-BGT226, PF- The group is selected from 04691502, CH5132799, GDC-0980 (RG7422), Trin-1, WAY-600, WYE-125132, WYE-687, GSK2126458, PF-05212384 (PKI-587), PP-121, OSI-027, Palomid529, PP242, XL765, GSK1059615, WYE-354, and ridafololimus (also known as defololimus).

[0127] BEZ235 (NVP-BEZ235) is an imidazokilonine derivative that acts as an mTORC1 catalytic inhibitor (Roper J, et al. PLoS One, 2011, 6(9), e25132). Everolimus is a 40-O-(2-hydroxyethyl) derivative of sirolimus that binds to cyclophylline FKBP-12, and this complex also binds to mTORC1. AZD8055 is a small molecule that inhibits the phosphorylation of mTORC1 (p70S6K and 4E-BP1). Temsirolimus is a small molecule that forms a complex with FK506-binding protein and inhibits mTOR activation when present within the mTORC1 complex. PI-103 is a small molecule that inhibits the activation of the rapamycin-sensitive (mTORC1) complex (Knight et al. (2006) Cell. 125:733-47). KU-0063794 is a small molecule that inhibits the phosphorylation of Ser2448 of mTORC1 in a dose-dependent and time-dependent manner. INK128, AZD2014, NVP-BGT226, CH5132799, and WYE-687 are small molecule inhibitors of mTORC1, respectively. PF-04691502 inhibits mTORC1 activity. GDC-0980 is an orally available small molecule that inhibits class I PI3 kinase and TORC1. Trrin-1 is a potent small molecule inhibitor of mTOR. WAY-600 is a potent ATP-competitive and selective mTOR inhibitor. WYE-125132 is an ATP-competitive small molecule inhibitor of mTORC1. GSK2126458 is an inhibitor of mTORC1. PKI-587 is a very potent dual inhibitor of PI3Kα, PI3Kγ, and mTOR. PP-121 is a multi-target inhibitor of PDGFR, Hck, mTOR, VEGFR2, Src, and Abl. OSI-027 is a selective and potent dual inhibitor of mTORC1 and mTORC2, with IC50 values ​​of 22 nM and 65 nM, respectively. Paromide 529 is a small molecule inhibitor of mTORC1 that lacks affinity for ABCB1 / ABCG2 and has excellent brain penetration (Lin et al. (2013) Int J Cancer DOI:10.1002 / ijc.28126 (e-published ahead of print)). PP242 is a selective mTOR inhibitor.XL765 is a dual mTOR / PI3k inhibitor against mTOR, p110α, p110β, p110γ, and p110δ. GSK1059615 is a novel dual inhibitor of PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, and mTOR. WYE-354 inhibits mTORC1 in HEK293 cells (0.2 μM to 5 μM) and HUVEC cells (10 nM to 1 μM). WYE-354 is a potent, specific, and ATP-antagonistic inhibitor of mTOR. Defololimus (ridafololimus, AP23573, MK-8669) is a selective mTOR inhibitor.

[0128] B. Other components in the nanoparticle composition In some embodiments, this composition is suitable for administration to humans. In some embodiments, this composition is suitable for administration to mammals such as pets and farm animals from a veterinary standpoint. The following formulations and methods are merely illustrative and not limiting. Formulations suitable for oral administration may consist of (a) a liquid solution such as an effective amount of the compound dissolved in a diluent such as water, saline, or orange juice; (b) capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient as a solid or granule; (c) a suspension in a suitable liquid; and (d) a suitable emulsion. Tablet forms may contain lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and one or more other excipients, colorants, diluents, buffers, wetting agents, preservatives, flavoring agents, and pharmacologically suitable excipients. The lozenge form may include the active ingredients of the flavoring, usually sucrose and acacia or tragacanth, as well as pastilles containing the active ingredients in an inert base such as gelatin or glycerin, or emulsions, gels, etc., containing the active ingredients plus minor components known in the industry, such as sucrose and acacia.

[0129] Examples of suitable carriers, excipients, and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline, syrup, methylcellulose, methyl hydroxybenzoate and propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The formulation may further contain lubricants, wetting agents, emulsifiers and suspending agents, preservatives, sweeteners, or flavoring agents.

[0130] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bactericides, and solutes to make the formulation compatible with the blood of the intended target, as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. The formulations can be supplied in sealed containers of unit or multiple doses, such as ampoules and vials, and can be stored in a freeze-dried state simply by adding a sterile liquid excipient, such as water for injection, immediately before use. Immediate injection solutions and suspensions can be prepared from the aforementioned types of sterile powders, granules, and tablets. Injectable formulations are preferred.

[0131] In some embodiments, the composition is formulated to have a pH range of about 4.5 to about 9.0, including, for example, one of the pH ranges of about 5.0 to about 8.0, about 6.5 to about 7.5, and about 6.5 to about 7.0. In some embodiments, the pH of the composition is formulated to be about 6 or higher, for example, one of the following (e.g., about 6.5, 7, or 8). The composition may also be made isotonic with blood by adding a suitable tonicity modifier such as glycerol.

[0132] Albumin-based nanoparticle composition of C. sirolimus The methods described herein are particularly suitable for albumin-based nanoparticle compositions, which are described in more detail herein. In some embodiments, the nanoparticle compositions comprise (a) nanoparticles comprising rapamycin and albumin, and (b) non-nanoparticle portions comprising rapamycin and albumin. The rapamycin and albumin in the nanoparticles are associated with each other within the nanoparticles. For example, the nanoparticles may comprise a coating having albumin surrounding a core comprising rapamycin. In the non-nanoparticle portions of the composition, rapamycin and albumin may or may not be associated with each other (i.e., rapamycin may be in a reversible binding equilibrium with albumin), but they do not associate with each other in a manner that would form nanoparticles. That is, the nanoparticle composition may comprise nanoparticle-bound albumin and nanoparticle-bound rapamycin in the nanoparticle portion of the composition, and non-nanoparticle albumin and non-nanoparticle rapamycin in the non-nanoparticle portion of the composition. Where used herein, “in nanoparticles” is used synonymously with “in nanoparticle portions.” Albumin in nanoparticles can be further distinguished from albumin in the non-nanoparticle portion of the composition; for example, the oligomeric profile of albumin in nanoparticles may differ from the oligomeric profile of albumin in the non-nanoparticle portion of the composition. The oligomeric profile refers to the percentage of various albumin species compared to the total albumin in the composition. The types of albumin species include albumin monomers, dimers, trimers, oligomers, and polymers.As used herein, “albumin monomer” or “monomer albumin” refers to an albumin species having one or only one albumin unit; “albumin dimer” or “dimer albumin” refers to an albumin species having two or only two albumin units; “albumin trimer” or “trimer albumin” refers to an albumin species having three or only three albumin units; “albumin polymer” refers to an albumin species with a molecular weight higher than that of albumin monomers and albumin dimers; and “albumin oligomer” or “oligomeric albumin” refers to a low molecular weight polymer albumin species that associates with a UV-based size exclusion chromatography peak observed between the peak associated with albumin dimers and the high molecular weight polymer albumin species.

[0133] The albumin in the nanoparticles associates with the rapamycin in the nanoparticles, resulting in a nanoparticle suspension containing a high concentration of rapamycin, which makes it possible to use this composition as a pharmaceutical composition for the treatment of certain diseases, such as cancer. The manufactured nanoparticles (for example, those prepared using the method described herein) can be formulated, filtered, or otherwise processed to obtain a pharmaceutical composition suitable for medical use in human organisms.

[0134] Generally, to prepare the rapamycin pharmaceutical compositions described herein, rapamycin is dissolved in an organic solvent. Suitable organic solvents include, for example, ketones, esters, ethers, chlorinated solvents, and other solvents known in the art. For example, the organic solvent may be methylene chloride / ethanol, chloroform / ethanol, or a mixture of chloroform / tert-butanol (e.g., any one ratio of about 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1, or any one ratio of about 3:7, 5:7, 4:6, 5:5, 6:5, 8:5, 9:5, 9.5:5, 5:3, 7:3, 6:4, or 9.5:0.5). In some embodiments, the organic solvent contains about 10% to about 50% tert-butanol by volume. In some embodiments, the organic solvent contains about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by volume of tert-butanol. In some embodiments, the organic solvent contains about 10–15%, 15–20%, 20–25%, 25–30%, 30–35%, 35–40%, 40–45%, or 45–50% by volume of tert-butanol, or any combination of such ranges. In some embodiments, the organic solvent contains about 50%–90% by volume of chloroform. In some embodiments, the organic solvent contains about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% by volume of chloroform. In some embodiments, the organic solvent comprises chloroform in an amount of about 50–55%, 55–60%, 60–65%, 65–70%, 70–75%, 75–80%, 80–85%, or 85–90% by volume, or any combination of such ranges. In some embodiments, the organic solvent comprises about 10%–50% by volume of tert-butanol and about 50%–90% by volume of chloroform. In some embodiments, the organic solvent comprises chloroform and tert-butanol in a volume ratio of about 1:1–1:9, for example, about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, and 9:1.

[0135] Albumin (e.g., recombinant albumin, e.g., NOVOZYMETM® recombinant albumin or INTRIVIA® recombinant albumin disclosed herein) is dissolved in an aqueous solution (such as water) and mixed with rapamycin solution to form a crude emulsion. The mixture is subjected to high-pressure homogenization (e.g., using an Avestin, APV Gaulin, MICROFLUIDIZER®, e.g., a MICROFLUIDIZER® Processor M-110EH from Microfluidics, Stansted, or an Ultra Turrax homogenizer). The emulsion can be circulated through the high-pressure homogenizer for about 2 to about 100 cycles, e.g., about 5 to about 50 cycles or about 6 to about 20 cycles (e.g., any one of about 6, 8, 10, 12, 14, 16, 18, or 20 cycles). Next, the organic solvent can be evaporated and removed using a known and suitable instrument for this purpose that can be operated in batch mode or continuous operation, such as a rotary evaporator, a drip-film evaporator, a wiped-film evaporator, or a spray dryer. In some embodiments, the evaporator is a wiped-film evaporator. The solvent can be removed under reduced pressure (e.g., any one of about 25 mmHg, 30 mmHg, 40 mmHg, 50 mmHg, 100 mmHg, 200 mmHg, or 300 mmHg). The time used to remove the solvent under reduced pressure can be adjusted based on the volume of the formulation. For example, in the case of a formulation manufactured on a 300 mL scale, the solvent can be removed at a pressure of approximately 1 to 300 mmHg (e.g., any one of approximately 5 to 100 mmHg, 10 to 50 mmHg, 20 to 40 mmHg, or 25 mmHg) for approximately 5 to 60 minutes (e.g., any one of approximately 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 25, or 30 minutes). The resulting dispersion can then be freeze-dried.

[0136] The nanoparticle compositions described herein (such pharmaceutical compositions) may have distinct characteristics with respect to one or more of the following (any combination): (1) the oligomeric state of albumin associated with (e.g., in) the nanoparticles, e.g., the percentage of albumin monomers, dimers, and / or polymers (or trimers) of albumin associated with (e.g., in) the nanoparticles; (2) the oligomeric state of albumin associated with (e.g., in) the non-nanoparticle portion of the composition, e.g., the percentage of albumin monomers, dimers, and / or polymers (or trimers) of albumin associated with (e.g., in) the non-nanoparticle portion of the composition; (3) the oligomeric state of total albumin in the composition. (4) Grammar state, e.g., the percentage of albumin monomers, dimers, and / or polymers (or trimers) of total albumin in the composition; (5) Particle size profile of the nanoparticles, e.g., average particle size, polydispersity index, and / or particle size distribution; (6) the portion of the nanoparticles that is albumin (e.g., weight percentage) and / or the portion of the nanoparticles that is rapamycin (e.g., weight percentage); (7) the weight ratio of albumin to rapamycin in the nanoparticles; (8) the weight ratio of albumin to rapamycin in the non-nanoparticle portion of the composition. (9) the weight ratio of albumin to rapamycin in the non-nanoparticle portion of the composition, (10) the weight ratio of total albumin to total rapamycin in the composition, (11) the portion of rapamycin contained in the nanoparticles (or the non-nanoparticle portion of the composition) compared to total rapamycin in the composition (e.g., by weight percentage), (12) the portion of albumin contained in the non-nanoparticle portion (or within the nanoparticles) compared to total albumin in the composition (e.g., by weight percentage), (13) the concentration of albumin in the composition, (14) the weight ratio of albumin to rapamycin in the non-nanoparticle portion of the composition (14) Concentration of albumin in the composition associated with nanoparticles (e.g., within them), (15) Concentration of rapamycin in the composition, (16) Concentration of rapamycin in the non-nanoparticle portion of the composition, (17) Concentration of rapamycin in the composition associated with nanoparticles (e.g., within them), (18) Osmotic pressure of the composition, (19) Viscosity of the composition, (20) pH of the composition, (21) Stability of nanoparticles in the composition, (22) Amount of residual solvent in the composition, (23) Zeta potential of nanoparticles in the composition, (24) Crystalline state of rapamycin in nanoparticles,(25) Particle morphology of the nanoparticles, e.g., shape, sphericity, coating thickness, and / or surface area to volume ratio; (26) Weight percentage of seco-rapamycin in the nanoparticles compared to the total weight of seco-rapamycin and rapamycin; (27) Presence, percentage, or concentration of albumin stabilizers (such as sodium caprylate and / or N-acetyltryptophanic acid) in the composition; (28) Recovery rate of rapamycin after filtration; (29) In vitro release kinetics of the nanoparticles; (30) Total rapamycin portion of the composition that is in the non-nanoparticle portion of the composition and not bound to albumin, and / or (31) Weight percentage of seco-rapamycin in the composition compared to the total weight of seco-rapamycin and rapamycin. In some embodiments, the oligomeric state of nanoparticles, non-nanoparticle portions, or the total composition (e.g., percentages of albumin monomers, dimers, polymers (or trimers)) is evaluated by size exclusion chromatography using a saline mobile phase combined with a multi-angle light scattering (MALS) detector.

[0137] The nanoparticle compositions described herein (such pharmaceutical compositions) may have distinct characteristics with respect to one or more of the following (any combination): (1) the oligomeric state of albumin associated with (e.g., in) the nanoparticles, e.g., the percentage of albumin monomers, dimers, oligomers, and / or polymers (other than oligomers) of albumin associated with (e.g., in) the nanoparticles; (2) the oligomeric state of albumin associated with (e.g., in) the non-nanoparticle portion of the composition, e.g., the percentage of albumin monomers, dimers, oligomers, and / or polymers (other than oligomers) of albumin associated with (e.g., in) the non-nanoparticle portion of the composition; (3) a set (4) The oligomeric state of total albumin in the product, e.g., the percentage of albumin monomers, dimers, oligomers, and / or polymers (other than oligomers) of the total albumin in the composition; (5) The particle size profile of the nanoparticles, e.g., average particle size, polydispersity index, and / or particle size distribution; (6) The portion of the nanoparticles that is albumin (e.g., weight percentage) and / or the portion of the nanoparticles that is rapamycin (e.g., weight percentage); (7) The weight ratio of albumin to rapamycin in the nanoparticles; (8) The portion of the non-nanoparticle portion of the composition (8) the weight ratio of albumin to rapamycin, (9) the weight ratio of albumin to rapamycin in the non-nanoparticle portion of the composition, (10) the portion of rapamycin contained in the nanoparticles (or the non-nanoparticle portion of the composition) compared to the total rapamycin in the composition (e.g., by weight percentage), (11) the portion of albumin contained in the non-nanoparticle portion (or in the nanoparticles) compared to the total albumin in the composition (e.g., by weight percentage), (12) the concentration of albumin in the composition. (13) Concentration of albumin in the non-nanoparticle portion of the composition, (14) Concentration of albumin in the composition associated with (e.g., in) the nanoparticles, (15) Concentration of rapamycin in the composition, (16) Concentration of rapamycin in the non-nanoparticle portion of the composition, (17) Concentration of rapamycin in the composition associated with (e.g., in) the nanoparticles, (18) Osmotic pressure of the composition, (19) Viscosity of the composition, (20) pH of the composition, (21) Stability of the nanoparticles in the composition, (22) Amount of residual solvent in the composition, (23) Zeta potential of the nanoparticles in the composition.(24) the crystalline state of rapamycin in the nanoparticles, (25) the particle morphology of the nanoparticles, e.g., shape, sphericity, coating thickness, and / or surface area to volume ratio, (26) the weight percentage of seco-rapamycin in the nanoparticles compared to the total weight of seco-rapamycin and rapamycin, (27) the presence, percentage, or concentration of albumin stabilizers (such as sodium caprylate and / or N-acetyltryptophanic acid) in the composition, (28) the recovery rate of rapamycin after filtration, (29) the in vitro release kinetics of the nanoparticles, (30) the portion of total rapamycin in the composition that is in the non-nanoparticle portion of the composition and not bound to albumin, and / or (31) the weight percentage of seco-rapamycin in the composition compared to the total weight of seco-rapamycin and rapamycin. As used herein, “albumin oligomer” or “oligomeric albumin” refers to a low molecular weight polymer albumin species associated with a size exclusion chromatography peak based on UV absorbance observed between a peak associated with an albumin dimer and a high molecular weight polymer albumin species. In some embodiments, the oligomeric state of the nanoparticles, non-nanoparticle portions, or total composition (e.g., percentages of albumin monomers, dimers, oligomers, or polymers (non-oligomeric)) is evaluated by size exclusion chromatography using a mobile phase containing an aqueous portion and a miscible organic portion (e.g., an aqueous buffer containing 7.5% methanol) and a UV detector. In some embodiments, the percentage of albumin in the nanoparticle portions in the form of monomers, dimers, oligomers, or polymer albumins (non-oligomeric albumins) is determined by separating the nanoparticles from the non-nanoparticle portion, dissolving the nanoparticles, and subjecting the dissolved nanoparticles to size exclusion chromatography. In some embodiments, size exclusion chromatography uses a mobile phase containing an aqueous portion and a miscible organic portion (e.g., an aqueous buffer containing 7.5% methanol) and a UV detector. ,

[0138] In some embodiments, the composition of the nanoparticles has one or more distinct characteristics: (1) about 80% to about 95% (or as further provided herein) of the total albumin in the composition is in the form of monomeric albumin; (2) about 4% to about 15% (or as further provided herein) of the total albumin in the composition is in the form of dimer albumin; (3) about 0.5% to about 5% (or as further provided herein) of the total albumin in the composition is in the form of polymeric albumin (or trimer albumin); (4) the weight ratio of total albumin to total rapamycin in the composition is about 1:1 to about 10:1 (or as further provided herein); (5) about 90% or more (or as further provided herein) of the total rapamycin in the composition is in nanoparticles; and (6) about 90% or more (or as further provided herein) of the total albumin in the composition is non-nanoparticles of the nanoparticles. (7) The composition comprises tert-butanol at a concentration of less than about 10 μg / ml or less than about 10 ppm (or as further provided herein), (8) the composition comprises chloroform at a concentration of less than about 5 μg / ml or less than about 5 ppm (or as further provided herein), (9) the composition comprises an albumin stabilizer (such as sodium caprylate and / or N-acetyltryptophanate), (10) at least about 80% or more of the rapamycin in the composition (or as further provided herein) is recoverable after filtering the composition through a 0.2 micron filter, (11) the composition is stable for at least 24 hours, and (12) less than about 5% of the total rapamycin in the composition is in the non-nanoparticle portion of the composition and is not bound to albumin in the non-nanoparticle portion of the composition. In some embodiments, the nanoparticle composition may be a nanoparticle suspension, and the nanoparticle composition may have one or more of the following distinct characteristics (in addition to or instead of any of the characteristics described above):(1) The concentration of albumin in the composition is about 30 mg / mL to about 100 mg / mL (or as further provided herein), (2) The concentration of rapamycin in the composition is about 1 mg / mL to about 15 mg / mL (or as further provided herein, about 1 mg / mL to about 7 mg / mL), (3) The osmotic pressure of the composition is about 300 mOsm / kg to about 350 mOsm / kg (or as separately provided herein), (4) The viscosity of the composition is about 1.2 cP to about 1.5 cP (or as separately provided herein), and / or (5) The pH of the composition is about 6.0 to about 7.5 (or as separately provided herein).

[0139] In some embodiments, the nanoparticles of the composition have one or more of the following distinct characteristics: (1) about 70% to about 85% of the albumin in the nanoparticles (or as otherwise provided herein) is in the form of albumin monomers; (2) about 9% to about 20% of the albumin in the nanoparticles (or as otherwise provided herein) is in the form of albumin dimers; (3) about 5% to about 15% of the albumin in the nanoparticles (or as otherwise provided herein) is in the form of albumin polymers (or albumin trimers); and (4) the nanoparticles are about 200 nm or less (or about 50 nm as otherwise provided herein, for example). (5) The nanoparticles have a volume-weighted average particle size and / or Z-average particle size of ~approximately 200 nm, (6) the polydispersity index is less than approximately 0.2 (or approximately 0.03 to approximately 0.2 as separately provided herein), (7) the nanoparticles are approximately 25% to approximately 45% by weight of albumin (or as separately provided herein), and (8) the nanoparticles are approximately 55% to approximately 75% by weight of rapamycin (or as separately provided herein). (9) The weight ratio of albumin to rapamycin in the nanoparticles is about 1:1 to about 1:4 (or as otherwise provided herein), (10) The zeta potential of the nanoparticles in the composition is about -25mV to about -50mV (or as otherwise provided herein), (11) The nanoparticles have an amorphous form, (12) The rapamycin in the nanoparticles has an amorphous form, (13) The vinyl chain of rapamycin in the nanoparticles interacts with the albumin in the nanoparticles, and (14) At least A portion (for example, at least 20%, or as otherwise provided herein) is non-spherical, and (15) the nanoparticles contain less than about 2.5% by weight of seco-rapamycin (or, as otherwise provided herein, for example, about 0.2% to about 2.5% by weight) compared to the combined weight of seco-rapamycin and rapamycin, and / or (16) the composition contains less than 3% by weight of seco-rapamycin (or, as otherwise provided herein, for example, about 0.2% to about 2.5% by weight) compared to the combined weight of seco-rapamycin and rapamycin.In some embodiments, the nanoparticle composition may be a nanoparticle suspension, and in some embodiments, the concentration of albumin in the nanoparticle suspension is about 1.8 mg / mL to about 3 mg / mL (or as otherwise provided herein).

[0140] In some embodiments, the nanoparticles of the composition have one or more of the following distinct properties: (1) about 25% to about 50% of the albumin in the nanoparticles (or as otherwise provided herein) is in the form of albumin monomers; (2) about 5% to about 16% of the albumin in the nanoparticles (or as otherwise provided herein) is in the form of albumin dimers; (3) about 1% to about 4.5% of the albumin in the nanoparticles (or as otherwise provided herein) is in the form of albumin oligomers; (4) about 42% to about 60% of the albumin in the nanoparticles (or as otherwise provided herein) (5) The nanoparticles are in the form of albumin polymers (other than oligomers), (6) the nanoparticles have a volume-weighted average particle size and / or Z-average particle size of about 200 nm or less (or about 50 nm to about 200 nm as separately provided herein), (7) the nanoparticles have a polydispersity index of less than about 0.2 (or about 0.03 to about 0.2 as separately provided herein), (8) the particle size distribution range ((Dv95-Dv5) / Dv50) is about 0.8 to about 1.2 (or as separately provided herein), and (9) The nanoparticles are approximately 25% to 45% by weight of albumin (or as otherwise provided herein), (10) The nanoparticles are approximately 55% to 75% by weight of rapamycin (or as otherwise provided herein), (11) The weight ratio of albumin to rapamycin in the nanoparticles is approximately 1:1 to 1:4 (or as otherwise provided herein), (12) The zeta potential of the nanoparticles in the composition is approximately -25mV to -50mV (or as otherwise provided herein), and (13) The nanoparticles are (13) The rapamycin in the nanoparticles has an amorphous form, (14) The vinyl chain of rapamycin in the nanoparticles interacts with albumin in the nanoparticles, (15) At least a portion of the nanoparticles in the composition (e.g., at least 20%, or as otherwise provided herein) are non-spherical, and (16) The nanoparticles contain less than about 2.5% by weight of seco-rapamycin (or, as otherwise provided herein, e.g., about 0.2% by weight to about 2%) compared to the total weight of seco-rapamycin and rapamycin.(17) The composition contains 5% by weight of seco-rapamycin and / or (17) the composition contains less than 3% by weight of seco-rapamycin (or, as otherwise provided herein, for example, about 0.2% to about 3% by weight) compared to the total weight of seco-rapamycin and rapamycin. In some embodiments, the nanoparticle composition may be a nanoparticle suspension, and in some embodiments, the concentration of albumin in the nanoparticle suspension in the nanoparticles is about 1.8 mg / mL to about 3 mg / mL (or, as otherwise provided herein).

[0141] In some embodiments, the non-nanoparticle portion of the composition has one or more of the following distinct characteristics: (1) about 80% to about 95% (or as otherwise provided herein) of the albumin in the non-nanoparticle portion of the composition is in the form of albumin monomers; (2) about 5% to about 14% (or as otherwise provided herein) of the albumin in the non-nanoparticle portion of the composition is in the form of albumin dimers; and / or (3) about 1% to about 5% (or as otherwise provided herein) of the albumin in the non-nanoparticle portion of the composition is in the form of albumin polymers (or albumin trimers). In some embodiments, the nanoparticle composition may be a nanoparticle suspension, and the non-nanoparticle portion of the nanoparticle suspension may have one or more of the following distinct characteristics (in addition to or instead of any of the characteristics described above). (1) The concentration of albumin in the non-nanoparticle portion of the composition is about 30 mg / mL to about 100 mg / mL (or as otherwise provided herein), and / or (2) The concentration of rapamycin in the non-nanoparticle portion is about 20 μg / mL to about 55 μg / mL (or as otherwise provided herein).

[0142] In some embodiments, the non-nanoparticle portion of the composition has one or more of the following distinct characteristics: (1) about 80% to about 95% (or as otherwise provided herein) of the albumin in the non-nanoparticle portion of the composition is in the form of albumin monomers; (2) about 5% to about 16% (or as otherwise provided herein) of the albumin in the non-nanoparticle portion of the composition is in the form of albumin dimers; about 0.5% to about 4% (or as otherwise provided herein) of the albumin in the non-nanoparticle portion of the composition is in the form of albumin oligomers; and / or (4) about 0.5% to about 3% (or as otherwise provided herein) of the albumin in the non-nanoparticle portion of the composition is in the form of albumin polymers (other than oligomers). In some embodiments, the nanoparticle composition may be a nanoparticle suspension, and the non-nanoparticle portion of the nanoparticle suspension may have one or more of the following distinct characteristics (in addition to or instead of any of the characteristics described above). (1) The concentration of albumin in the non-nanoparticle portion of the composition is about 30 mg / mL to about 100 mg / mL (or as otherwise provided herein), and / or (2) The concentration of rapamycin in the non-nanoparticle portion is about 20 μg / mL to about 55 μg / mL (or as otherwise provided herein).

[0143] The compositions described herein (such as pharmaceutical compositions) may be in liquid (e.g., nanoparticle suspension) or powder form. For example, in some embodiments, the composition is a liquid nanoparticle suspension (e.g., before lyophilization). In some embodiments, the composition is a reconstituted suspension (e.g., an aqueous solution such as physiological saline). In some embodiments, the composition is dried by lyophilization or the like. In some embodiments, the composition is sterilized. In some embodiments, the composition is contained in a sealed container such as a sealed vial (e.g., a glass vial) or a sealed bag.

[0144] In some embodiments, the nanoparticle composition comprises (a) nanoparticles containing rapamycin and albumin (such as human albumin), and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin. In some embodiments, about 0.5% to about 5% of the albumin in the non-nanoparticle portion or the total albumin in the nanoparticle composition is in the form of polymer albumin (or trimer albumin). In some embodiments, about 4% to about 14% of the albumin in the non-nanoparticle portion or the total albumin in the nanoparticle composition is in the form of dimer albumin. In some embodiments, about 80% to about 95% of the albumin in the non-nanoparticle portion or the total albumin in the nanoparticle composition is in the form of monomer albumin. In some embodiments, the weight ratio of albumin to rapamycin in the composition is about 1:1 to about 10:1. In some embodiments, about 90% or more of the albumin in the composition is in the non-nanoparticle portion. In some embodiments, about 90% or more of the rapamycin in the composition is in the nanoparticles. In some embodiments, the concentration of albumin in the nanoparticle composition in the non-nanoparticle portion, or the total albumin concentration in the nanoparticle composition, is about 30 mg / mL to about 100 mg / mL. In some embodiments, the osmotic concentration of the composition is about 300 mOsm / kg to about 350 mOsm / kg. In some embodiments, the viscosity of the composition is about 1.2 cP to about 1.5 cP. In some embodiments, the pH of the composition is about 6.0 to about 7.5. In some embodiments, the composition is stable at 4°C and / or 25°C for at least 24 hours. In some embodiments, the rapamycin in the nanoparticles has an amorphous form. In some embodiments, the nanoparticle composition is a nanoparticle suspension. In some embodiments, the nanoparticle composition is a dried composition. In some embodiments, the nanoparticle composition is sterilized, for example, by filtration. In some embodiments, the nanoparticle composition is contained in a sealed container such as a sealed vial or sealed bag. In some embodiments, the nanoparticle composition contains less than 10 μg / mL of tert-butanol and / or less than 5 μg / mL of chloroform.

[0145] In some embodiments, the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), wherein about 70% to about 85% of the albumin in the nanoparticles is in the form of monomeric albumin, and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0146] In some embodiments, the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), wherein about 25% to about 50% of the albumin in the nanoparticles is in the form of monomeric albumin, and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0147] In some embodiments, the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), wherein about 5% to about 15% of the albumin in the nanoparticles is in the form of polymer albumin (or trimer albumin), and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0148] In some embodiments, the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), wherein about 25% to about 50% of the albumin in the nanoparticles is in the form of polymer albumin (other than oligomeric albumin), and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0149] In some embodiments, the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), wherein about 9% to about 20% of the albumin in the nanoparticles is in the form of dimer albumin, and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0150] In some embodiments, the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), wherein about 5% to about 16% of the albumin in the nanoparticles is in the form of dimer albumin, and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0151] In some embodiments, the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), wherein about 70% to about 85% of the albumin in the nanoparticles is in the form of monomeric albumin, about 9% to about 20% of the albumin in the nanoparticles is in the form of dimer albumin, and about 5% to about 15% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin. In some embodiments, the nanoparticle composition comprises (a) nanoparticles containing rapamycin and albumin (such as human albumin), wherein about 25% to about 50% of the albumin in the nanoparticles is in the form of monomeric albumin, about 1% to about 4.5% of the albumin in the nanoparticles is in the form of oligomeric albumin, about 5% to about 16% of the albumin in the nanoparticles is in the form of dimeric albumin, and about 25% to about 50% of the albumin in the nanoparticles is in the form of polymeric albumin (other than oligomeric albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0152] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (e.g., about 50 nm to about 200 nm) and containing rapamycin and albumin (such as human albumin), wherein about 70% to about 85% of the albumin in the nanoparticles is in the form of monomeric albumin, about 9% to about 20% of the albumin in the nanoparticles is in the form of dimer albumin, and about 5% to about 15% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0153] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (e.g., about 50 nm to about 200 nm) and comprising a coating containing albumin (e.g., human albumin) and a core containing rapamycin, wherein about 70% to about 85% of the albumin in the nanoparticles is in the form of monomeric albumin, about 9% to about 20% of the albumin in the nanoparticles is in the form of dimeric albumin, and about 5% to about 15% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimeric albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0154] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (e.g., about 50 nm to about 200 nm) and containing about 55% to about 65% (by weight) of rapamycin and about 25% to about 45% (by weight) of albumin (e.g., human albumin), wherein about 70% to about 85% of the albumin in the nanoparticles is in the form of monomeric albumin, about 9% to about 20% of the albumin in the nanoparticles is in the form of dimeric albumin, and about 5% to about 15% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimeric albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0155] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (e.g., about 50 nm to about 200 nm) and comprising a coating containing albumin (e.g., human albumin) and a core containing rapamycin, wherein the albumin constitutes about 25% to about 45% by weight of the nanoparticles, and the rapamycin constitutes about 55% to about 75% by weight of the nanoparticles, wherein about 70% to about 85% of the albumin in the nanoparticles is in the form of monomeric albumin, about 9% to about 20% of the albumin in the nanoparticles is in the form of dimeric albumin, and about 5% to about 15% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimeric albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0156] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (e.g., about 50 nm to about 200 nm) and containing about 55% to about 75% (by weight) of rapamycin and about 25% to about 45% (by weight) of albumin (e.g., human albumin), wherein about 70% to about 85% of the albumin in the nanoparticles is in the form of monomeric albumin, about 9% to about 20% of the albumin in the nanoparticles is in the form of dimer albumin, and about 5% to about 15% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is about 1 mg / mL to about 100 mg / mL (e.g., about 1 mg / mL to about 15 mg / mL).

[0157] In some embodiments, the nanoparticle composition is a nanoparticle having a Z-average particle diameter of about 200 nm or less (e.g., about 50 nm to about 200 nm), comprising a coating containing albumin (e.g., human albumin) and a core containing rapamycin, wherein the albumin constitutes about 25% to about 45% by weight of the nanoparticle, and the rapamycin constitutes about 55% to about 75% by weight of the nanoparticle, and about 70% to about 85% of the albumin in the nanoparticle is in the form of monomeric albumin. The nanoparticle comprises (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is approximately 1 mg / mL to approximately 100 mg / mL (for example, approximately 1 mg / mL to approximately 15 mg / mL).

[0158] In some embodiments, the nanoparticle composition is a nanoparticle having a Z-average particle size of about 200 nm or less (e.g., about 50 nm to about 200 nm) and a zeta potential of about -25 mV to about -50 mV, comprising about 55% to about 75% (by weight) of rapamycin and about 25% to about 45% (by weight) of albumin (e.g., human albumin), wherein about 70% to about 85% of the albumin in the nanoparticle is in the form of monomeric albumin, and the albumin in the nanoparticle is The nanoparticles consist of (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is approximately 1 mg / mL to approximately 100 mg / mL (e.g., approximately 1 mg / mL to approximately 15 mg / mL).

[0159] In some embodiments, the nanoparticle composition comprises nanoparticles having a Z-average particle diameter of about 200 nm or less (e.g., about 50 nm to about 200 nm) and a zeta potential of about -25 mV to about -50 mV, and comprising a coating containing albumin (e.g., human albumin) and a core containing rapamycin, wherein the albumin constitutes about 25% to about 45% by weight of the nanoparticles, and the rapamycin constitutes about 55% to about 75% by weight of the nanoparticles, and about 70% to about 85% of the albumin in the nanoparticles is monomeric albumin. The nanoparticles consist of (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is approximately 1 mg / mL to approximately 100 mg / mL (for example, approximately 1 mg / mL to approximately 15 mg / mL).

[0160] In some embodiments, the nanoparticle composition is a nanoparticle having a Z-average particle size of about 200 nm or less (e.g., about 50 nm to about 200 nm) and a zeta potential of about -25 mV to about -50 mV, comprising about 55% to about 75% (by weight) of rapamycin and about 25% to about 45% (by weight) of albumin (e.g., human albumin), wherein about 70% to about 85% of the albumin in the nanoparticle is in the form of monomeric albumin, and about 9% to about 20% of the albumin in the nanoparticle is dyma - Nanoparticles in the form of albumin, where approximately 5% to approximately 15% of the albumin in the nanoparticles is in the form of polymer albumin (or trimer albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is approximately 1 mg / mL to approximately 100 mg / mL (for example, approximately 1 mg / mL to approximately 15 mg / mL), and approximately 3% or less of the rapamycin in the nanoparticle composition is free rapamycin.

[0161] In some embodiments, the nanoparticle composition is a nanoparticle comprising (a) a Z-average particle diameter of about 200 nm or less (e.g., about 50 nm to about 200 nm) and a zeta potential of about -25 mV to about -50 mV, having a coating containing albumin (e.g., human albumin) and a core containing rapamycin, wherein the albumin constitutes about 25% to about 45% by weight of the nanoparticle, and the rapamycin constitutes about 55% to about 75% by weight of the nanoparticle, and about 70% to about 85% of the albumin in the nanoparticle is in the form of monomeric albumin, and The nanoparticles consist of (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is approximately 1 mg / mL to approximately 100 mg / mL (e.g., approximately 1 mg / mL to approximately 15 mg / mL), and approximately 3% or less of the rapamycin in the nanoparticle composition is free rapamycin.

[0162] In some embodiments, the nanoparticle composition is a nanoparticle having a Z-average particle size of about 200 nm or less (e.g., about 50 nm to about 200 nm) and a zeta potential of about -25 mV to about -50 mV, comprising about 55% to about 75% (by weight) of rapamycin and about 25% to about 45% (by weight) of albumin (e.g., human albumin), wherein about 70% to about 85% of the albumin in the nanoparticle is in the form of monomeric albumin, and about 9% to about 20% of the albumin in the nanoparticle is in the form of dimeric albumin. The composition comprises (b) nanoparticles in which approximately 5% to approximately 15% of the albumin is in the form of polymer albumin (or trimer albumin), and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is approximately 1 mg / mL to approximately 100 mg / mL (e.g., approximately 1 mg / mL to approximately 15 mg / mL), and the total weight of seco-rapamycin and rapamycin in the nanoparticles is less than 3% by weight (e.g., approximately 0.2% to approximately 3%) of seco-rapamycin. In some embodiments, the total weight of seco-rapamycin and rapamycin in the composition is less than 3% by weight (e.g., approximately 0.2% to approximately 3%) of seco-rapamycin.

[0163] In some embodiments, the nanoparticle composition comprises nanoparticles having a Z-average particle diameter of about 200 nm or less (e.g., about 50 nm to about 200 nm) and a zeta potential of about -25 mV to about -50 mV, and comprising a coating containing albumin (e.g., human albumin) and a core containing rapamycin, wherein the albumin constitutes about 25% to about 45% by weight of the nanoparticles, and the rapamycin constitutes about 55% to about 75% by weight of the nanoparticles, and about 70% to about 85% of the albumin in the nanoparticles is in the form of monomeric albumin, and about 9% to about 20% of the albumin in the nanoparticles is die The nanoparticles include (b) nanoparticles in the form of polymer albumin, where about 5% to about 15% of the albumin in the nanoparticles is in the form of polymer albumin (or trimer albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is about 1 mg / mL to about 100 mg / mL (e.g., about 1 mg / mL to about 15 mg / mL), and the total weight of seco-rapamycin and rapamycin in the nanoparticles is less than 3% by weight of seco-rapamycin (e.g., about 0.2% to about 3% by weight). In some embodiments, seco-rapamycin is less than 3% (e.g., about 0.2% to about 3%) of the total of seco-rapamycin and rapamycin in the composition.

[0164] In some embodiments, the nanoparticle composition comprises (a) nanoparticles containing rapamycin and albumin (such as human albumin), wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin. In some embodiments, about 1.5% to about 3% of the albumin in the non-nanoparticle portion or of the total albumin in the nanoparticle composition is in the form of polymeric albumin (or trimer albumin). In some embodiments, about 7% to about 11% of the albumin in the non-nanoparticle portion of the nanoparticle composition is in the form of dimer albumin. In some embodiments, about 7% to about 11% of the total albumin in the nanoparticle composition is in the form of dimer albumin. In some embodiments, about 83% to about 92% of the albumin in the non-nanoparticle portion or of the total albumin in the nanoparticle composition is in the form of monomeric albumin. In some embodiments, the weight ratio of albumin to rapamycin in the composition is about 7:1 to about 9:1. In some embodiments, more than 95% of the albumin in the composition is in the non-nanoparticle portion. In some embodiments, about 98% to about 99.5% of the rapamycin in the composition is in the nanoparticles. In some embodiments, the concentration of albumin in the nanoparticle composition in the non-nanoparticle portion, or the concentration of total albumin in the nanoparticle composition, is about 35 mg / mL to about 45 mg / mL.

[0165] In some embodiments, the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), wherein about 7% to about 11% of the albumin in the nanoparticles is in the form of polymer albumin (or trimer albumin), and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0166] In some embodiments, the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), wherein about 12% to about 17% of the albumin in the nanoparticles is in the form of dimer albumin, and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0167] In some embodiments, the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, about 12% to about 17% of the albumin in the nanoparticles is in the form of dimer albumin, and about 7% to about 11% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0168] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm and containing rapamycin and albumin (such as human albumin), and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0169] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm and containing rapamycin and albumin (such as human albumin), wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, about 12% to about 17% of the albumin in the nanoparticles is in the form of dimer albumin, and about 7% to about 11% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0170] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm, comprising a coating containing albumin (e.g., human albumin) and a core containing rapamycin, wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, about 12% to about 17% of the albumin in the nanoparticles is in the form of dimer albumin, and about 7% to about 11% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0171] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a zeta potential of about -33 mV to about -39 mV and containing rapamycin and albumin (such as human albumin), and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0172] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a zeta potential of about -33 mV to about -39 mV and comprising a coating containing albumin (such as human albumin) and a core containing rapamycin, and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0173] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a zeta potential of about -33 mV to about -39 mV and containing rapamycin and albumin (such as human albumin), wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, about 12% to about 17% of the albumin in the nanoparticles is in the form of dimer albumin, and about 7% to about 11% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0174] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a zeta potential of about -33 mV to about -39 mV and comprising a coating containing albumin (e.g., human albumin) and a core containing rapamycin, wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, about 12% to about 17% of the albumin in the nanoparticles is in the form of dimeric albumin, and about 7% to about 11% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimeric albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0175] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm and a zeta potential of about -33 mV to about -39 mV, and containing rapamycin and albumin (such as human albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0176] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm and a zeta potential of about -33 mV to about -39 mV, and comprising a coating containing albumin (such as human albumin) and a core containing rapamycin, and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.

[0177] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm and a zeta potential of about -33 mV to about -39 mV, and containing rapamycin and albumin (such as human albumin), wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, about 12% to about 17% of the albumin in the nanoparticles is in the form of dimer albumin, and about 7% to about 11% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0178] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm and a zeta potential of about -33 mV to about -39 mV, comprising a coating containing albumin (e.g., human albumin) and a core containing rapamycin, wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, about 12% to about 17% of the albumin in the nanoparticles is in the form of dimer albumin, and about 7% to about 11% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0179] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm and containing about 62% to about 68% (by weight) of rapamycin and about 32% to about 38% (by weight) of albumin (e.g., human albumin), wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, about 12% to about 17% of the albumin in the nanoparticles is in the form of dimer albumin, and about 7% to about 11% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin.

[0180] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm and containing about 62% to about 68% (by weight) of rapamycin and about 32% to about 38% (by weight) of albumin (e.g., human albumin), wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, about 12% to about 17% of the albumin in the nanoparticles is in the form of dimer albumin, and about 7% to about 11% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is about 1 mg / mL to about 100 mg / mL (e.g., about 1 mg / mL to about 15 mg / mL).

[0181] In some embodiments, the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm and a zeta potential of about -33 mV to about -39 mV, and comprising about 62% to about 68% (by weight) of rapamycin and about 32% to about 38% (by weight) of albumin (e.g., human albumin), wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, about 12% to about 17% of the albumin in the nanoparticles is in the form of dimer albumin, and about 7% to about 11% of the albumin in the nanoparticles is in the form of polymeric albumin (or trimer albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is about 1 mg / mL to about 100 mg / mL (e.g., about 1 mg / mL to about 15 mg / mL).

[0182] In some embodiments, the nanoparticle composition is a nanoparticle having a Z-average particle size of about 85 nm to about 95 nm and a zeta potential of about -33 mV to about -39 mV, comprising about 62% to about 68% (by weight) of rapamycin and about 32% to about 38% (by weight) of albumin (e.g., human albumin), wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, and about 12% to about 17% of the albumin in the nanoparticles is in the form of dimeric albumin. The nanoparticles consist of (b) a non-nanoparticle portion containing albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is approximately 1 mg / mL to approximately 100 mg / mL (for example, approximately 1 mg / mL to approximately 15 mg / mL), and approximately 1% or less of the rapamycin in the nanoparticle composition is free rapamycin.

[0183] In some embodiments, the nanoparticle composition is a nanoparticle having a Z-average particle size of about 85 nm to about 95 nm and a zeta potential of about -33 mV to about -39 mV, comprising about 62% to about 68% (by weight) of rapamycin and about 32% to about 38% (by weight) of albumin (e.g., human albumin), wherein about 74% to about 80% of the albumin in the nanoparticles is in the form of monomeric albumin, and about 12% to about 17% of the albumin in the nanoparticles is in the form of dimeric albumin. The composition comprises (b) nanoparticles, in which approximately 7% to approximately 11% are in the form of polymer albumin (or trimer albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin, wherein the concentration of rapamycin in the nanoparticle composition is approximately 1 mg / mL to approximately 100 mg / mL (e.g., approximately 1 mg / mL to approximately 15 mg / mL), and the total weight of seco-rapamycin and rapamycin in the nanoparticles is less than 1% by weight (e.g., approximately 0.5% to approximately 1%) of seco-rapamycin. In some embodiments, seco-rapamycin is more than approximately 0.2% of the total weight of seco-rapamycin and rapamycin in the composition (e.g., approximately 0.2% to approximately 3%).

[0184] Furthermore, this specification also provides commercially available batches of nanoparticle compositions (such as pharmaceutical compositions) for use in any one of the processing methods described herein. As used herein, “commercial batch” refers to a batch size of at least about 20 grams (mass of rapamycin). Commercial batches are produced on a larger scale than experimental or bench-scale batches. The increase in scale is associated with an increase in production time, such as by extending steps (such as an evaporation step) or by extending the hold time between steps.

[0185] In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered subcutaneously. In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered at a dose of approximately 1 mg / m². 2 ~about 150mg / m 2 , about 5mg / m 2 ~about 75mg / m 2 The dose is administered, for example, by intravenous infusion. In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered at doses of approximately 5, 7.5, 10, 15, 30, 56, 75, or 100 mg / m². 2It is administered, for example, by intravenous infusion, in any one of the following doses. In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered to an individual with cancer in one or more 21-day cycles (e.g., 3-week cycles). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered to the individual once in each 21-day cycle (e.g., 3-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered in the first, second, or third week of each 21-day cycle (e.g., 3-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered on day 1, day 8, or day 15 of each 21-day cycle (e.g., 3-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered to the individual twice in each 21-day cycle (e.g., a 3-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered in the first and second weeks of each 21-day cycle (e.g., a 2-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered in the second and third weeks of each 21-day cycle (e.g., a 3-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered in the first and third weeks of each 21-day cycle (e.g., a 3-week cycle). In some embodiments, an mTOR inhibitor nanoparticle composition (e.g., a sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered on days 1 and 8 of each 21-day cycle (e.g., a 3-week cycle).In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered on days 1 and 15 of each 21-day cycle (e.g., a 3-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered on days 8 and 15 of each 21-day cycle (e.g., a 3-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered to the individual three times in each 21-day cycle (e.g., a 3-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered in weeks 1, 2 and 3 of each 21-day cycle (e.g., a 3-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is administered on days 1, 8, and 15 of each 21-day cycle (e.g., a 3-week cycle). In some embodiments, the dose of the mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., FYARRO®) is modified (e.g., if an individual experiences one or more adverse events). Details regarding dose modifications of FYARRO® and the circumstances under which dose modifications are made are described in www(dot)accessdata(dot)fda(dot)gov / drugsatfda_docs / label / 2021 / 213312lbl.pdf.

[0186] IV. Estrogen inhibitors The therapeutic methods described herein include administering estrogen inhibitors. As taught herein, estrogen inhibitors may act as agents that suppress estrogen or as agents that suppress signaling at estrogen receptors. Therefore, it will be readily apparent to those skilled in the art that the range of agents included in estrogen inhibitors includes agents with various mechanisms of action. For example, estrogen inhibitors include, for example, one or more agents that reduce (including inhibit) estrogen production, agents that bind to estrogen, agents that reduce (including inhibit) estrogen binding to estrogen receptors, or agents that reduce (including inhibit) downstream events resulting from estrogen binding to receptors. The biology of human estrogen production and pathways is well known in the art, for example, Cui et al., Trends Mol Med, 19, 013, which is incorporated herein by reference in its entirety.

[0187] As used herein, the term “estrogen” can be used interchangeably to describe one or more of many estrogen compounds, including estrone, estradiol, and estriol. Estrogen inhibitors, such as drugs that suppress estrogen, can inhibit one or more of the compounds referred to herein as estrogen. In some embodiments, estrogen inhibitors inhibit estrone. In some embodiments, estrogen inhibitors inhibit estradiol. In some embodiments, estrogen inhibitors inhibit estriol.

[0188] In some embodiments, an estrogen inhibitor is a drug that suppresses estrogen production. In some embodiments, an estrogen inhibitor is a drug that suppresses estrogen activity, for example, a drug that suppresses estrogen receptor signaling.

[0189] In some embodiments, the agent that inhibits estrogen production is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is a type I inhibitor that has a steroid structure similar to androgens and inactivates aromatase by irreversibly blocking the substrate binding site (in certain embodiments, such compounds are also called aromatase inactivators). In some embodiments, the aromatase inhibitor is a nonsteroidal type II inhibitor that reversibly binds to aromatase (e.g., letrozole). In some embodiments, the type II aromatase inhibitor is a triazole derivative. In some embodiments, the agent that inhibits estrogen production is selected from the group consisting of letrozole, anastrozole, formestane, and exemestane. In some embodiments, the agent that inhibits estrogen production is letrozole.

[0190] In some embodiments, estrogen inhibitors are agents that suppress estrogen activity, such as by inhibiting estrogen receptor signaling. In some embodiments, agents that suppress estrogen activity are estrogen receptor antagonists. Those skilled in the art will readily understand that there are many forms of estrogen receptor antagonists with different mechanisms of action. For example, in some embodiments, estrogen receptor antagonists are pure anti-estrogen agents that inhibit the function of estrogen. In some embodiments, estrogen receptor antagonists are selective estrogen receptor depressants / degraders (SERDs), such as fulvestrant. In some embodiments, estrogen receptor antagonists are selective estrogen receptor modulators (SERMs), which typically selectively modulate estrogen receptors depending on the type of tissue. In some embodiments, estrogen receptor antagonists are dual-mechanism estrogen receptor inhibitors. In some embodiments, estrogen receptor antagonists are antagonists of estrogen receptor binding. In some embodiments, the estrogen receptor antagonist is an estradiol analog (e.g., fulvestrant). In some embodiments, the agent that inhibits estrogen activity is selected from the group consisting of fulvestrant, elastrant, tamoxifen, hydroxyprogesterone caprate, droloxifen, olmeroxifen, toremifene, faroxifen, raloxifen, and clomiphene. In some embodiments, the agent that inhibits estrogen activity is fulvestrant.

[0191] In some embodiments, the estrogen receptor antagonist is not a SERM.

[0192] Exemplary doses, routes of administration, and administration schedules for estrogen inhibitors are described in other sections of this specification. To illustrate the teachings provided herein, specific additional embodiments relating to estrogen receptor antagonists are provided below. For example, in some embodiments, the estrogen inhibitor is letrozole. In some embodiments, the estrogen inhibitor is letrozole, which is administered orally to the individual. In some embodiments, letrozole is administered to the individual in any amount from about 0.1 mg to about 10 mg, for example, about 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg. In some embodiments, letrozole is administered to the individual daily.

[0193] In some embodiments, the estrogen inhibitor is fulvestrant. In some embodiments, the estrogen inhibitor is fulvestrant, which is administered intramuscularly to the individual. In some embodiments, fulvestrant is administered to the individual in any amount from about 100 mg to about 700 mg, for example, about 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, or 700 mg. In some embodiments, fulvestrant is administered to the individual using an initiation cycle and a maintenance cycle. In some embodiments, fulvestrant is administered to the individual on days 1, 15, and 29 of the initiation cycle, followed by a maintenance cycle lasting one month or more.

[0194] V. Manufactured Articles and Kits In some embodiments, a manufactured article is provided containing a substance useful for the treatment of hormone-dependent cancers (including endometrial cancer (e.g., endometrioid endometrial cancer) or hormone receptor-positive breast cancer), the manufactured article comprising, for example, a drug or combination of drugs, an mTOR inhibitor nanoparticle composition (e.g., sirolimus / albumin nanoparticle composition, e.g., nab-sirolimus) and an estrogen inhibitor (e.g., letrozole or fulvestrant). The manufactured article may include a container and a label or accompanying documentation on or attached to the container. Suitable containers include, for example, bottles, vials, syringes, etc. Containers may be formed from a variety of materials such as glass or plastic. Generally, the container may hold a composition effective for treating the disease or disorder described herein and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper that can be punctured with a subcutaneous needle). At least one activator in the composition is (a) a nanoparticle formulation of an mTOR inhibitor (e.g., nab-sirolimus), or (b) an estrogen inhibitor (e.g., letrozole or fulvestrant). The label or accompanying leaflet indicates that the composition is used to treat specific symptoms in an individual, as described herein. The label or accompanying leaflet further includes instructions for use for administering the composition to an individual according to the methods described herein. Manufactured articles and kits containing the combination therapies described herein are also to be considered.

[0195] A package insert is a document typically included with the marketed packaging of a therapeutic drug, and it contains information regarding the indications, method of use, dosage, administration, contraindications, and / or warnings regarding the use of that drug. In some embodiments, the package insert states that the composition is used for the treatment of hormone-dependent cancers (e.g., endometrial cancer (e.g., endometrioid endometrial cancer) or hormone receptor-positive breast cancer).

[0196] Furthermore, the manufactured article may further include a second container containing a pharmaceutically acceptable buffer such as sterile water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or glucose solution. It may further include other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0197] Furthermore, kits useful for a variety of purposes are also provided, such as the treatment of hormone-dependent cancers (e.g., endometrial cancer (e.g., endometrioid endometrial cancer) or hormone receptor-positive breast cancer). The kits of the present invention comprise one or more containers containing an mTOR inhibitor nanoparticle composition (e.g., a sirolimus / albumin nanoparticle composition) (or a unit dosage form and / or manufactured article), and in some embodiments further comprise instructions for use according to an estrogen inhibitor (e.g., letrozole or fulvestrant) and / or any of the methods described herein. The kits may further comprise instructions for selecting individuals suitable for treatment. The instructions provided in the kits of the present invention are typically instructions for use written on a label or accompanying document (e.g., a paper sheet included in the kit), but machine-readable instructions for use (e.g., instructions recorded on a magnetic or optical storage disk) are also acceptable.

[0198] The kit of the present invention comes in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, and flexible packaging (e.g., sealed Mylar or plastic bags). The kit may optionally provide additional components, such as buffers and explanatory information. Accordingly, this application also provides manufactured articles including vials (such as sealed vials), bottles, jars, and flexible packaging.

[0199] Instructions for use of mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and estrogen inhibitors (e.g., letrozole or fulvestrant) typically include information regarding the intended therapeutic dose, administration schedule, and route of administration. Containers may be unit doses, bulk packages (e.g., multi-dose packages), or subunit doses. For example, kits may be provided that contain a sufficient dose of an mTOR inhibitor nanoparticle composition (such as sirolimus / albumin nanoparticle compositions) and an estrogen inhibitor (e.g., letrozole or fulvestrant), as disclosed herein, to provide effective treatment of an individual over a long period, such as 1 week, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or longer. The kit includes multiple unit doses of mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and estrogen inhibitors (e.g., letrozole or fulvestrant), along with instructions for use, and is packaged in quantities sufficient for storage and use in pharmacies such as hospital pharmacies and dispensing pharmacies.

[0200] Those skilled in the art will understand that several embodiments are possible within the scope and spirit of the present invention. The present invention is described in more detail hereby by reference to the following non-limiting embodiments. The following examples further illustrate the present invention, but of course should not be construed as limiting the scope of the present invention. [Examples]

[0201] Example 1 This example demonstrates a study using a combination of nab-sirolimus and fulvestrant (a selective estrogen receptor degrader, SERD) to treat hormone receptor-positive breast cancer cell lines.

[0202] Series of monotherapy with fulvestrant or nab-sirolimus, and combination therapy with fulvestrant and nab-sirolimus, were applied separately to aliquots of hormone receptor-positive breast cancer cell lines (MCF7 or MDA-MB-361). This series included various concentrations of nab-sirolimus (20 nM or 80 nM) and fulvestrant (0.98 nM to 1000 nM). After application of each treatment, cell aliquots were incubated for 5 days. The antiproliferative and cytotoxic effects of monotherapy and combination therapy were then evaluated using an automated trypan blue elimination assay.

[0203] Studies have shown that nab-sirolimus enhances the cytotoxicity of fulvestrant. Adding 20 nM and 80 nM nab-sirolimus to all tested fulvestrant doses significantly reduced cell viability and nearly doubled cell death in both MCF7 and MDA-MB-361 cells (Figures 1A and 1B for MDA-MB-361 cells: "ful" is fulvestrant, abi-009 is nab-sirolimus, and the bars are arranged in the order of saline, abi-009 20 nM, and abi-009 80 nM, with the DMSO data point on the far right representing saline treatment). Figures 2A and 2B for MCF7 cells: abi-009 is nab-sirolimus, and the bars are arranged in the order of saline, abi-009 20 nM, and abi-009 80 nM.

[0204] Western blot analysis was performed to evaluate p4EBP1 in MCF7 cells. Western blot (Figure 3) showed a dose-dependent increase in p4EBP1 in response to fulvestrant (reversed by concomitant use with nab-sirolimus). Therefore, adding nab-sirolimus to endocrine-based therapies such as fulvestrant may overcome resistance mechanisms.

[0205] Western blot analysis was performed to evaluate pAKT in MCF7 cells. Western blot (Figure 3) showed an increase in pAKT in response to nab-sirolimus (which was reversed in a dose-dependent manner by co-administration with fulvestrant). Therefore, adding fulvestrant to mTOR-targeting drugs such as nab-sirolimus may overcome resistance mechanisms.

[0206] Example 2 Phase 2 multicenter open-label trial of nabsirolimus in combination with letrozole in patients with advanced or recurrent endometrioid endometriometrial cancer. A prospective, open-label, multicenter phase 2 trial is planned to evaluate the efficacy and safety of nab-sirolimus plus letrozole in patients with advanced (unresectable International Federation of Gynecology and Obstetrics [FIGO] stage III or IV) or recurrent endometrioid endometriometrial carcinoma (EEC) grade 3 or lower who have received both platinum-based drugs and checkpoint inhibitors (unless the drugs are contraindicated or intolerant). Patients who have received prior treatment must have achieved a response to at least one prior treatment. Patients with advanced or recurrent EEC should receive nab-sirolimus (100 mg / m² on days 1 and 8 of a 21-day cycle). 2 Treatment involves administering (and) in combination with letrozole (2.5 mg orally, daily). Eligible patients will be treated until unacceptable toxicity or disease progression occurs, or until the investigator determines that the patient is not benefiting from the treatment, or at the patient's discretion.

[0207] One cycle consists of 21 days. Patients receive 100 mg / mm³ on days 1 and 8 of the 21-day cycle (2 / 3-week schedule). 2Nab-sirolimus is administered by intravenous (IV) infusion over 30 (+10) minutes (i.e., 30-40 minute infusion) at the specified dose. Letrozole is administered orally at 2.5 mg daily every 21-day cycle. For the management of adverse events (AEs), nab-sirolimus is reduced by up to four consecutive doses (75, 56, 45, and 35 mg / m²). 2 If, among the initially treated patients, 3 out of 6 or 4 out of 10 need to reduce their nab-sirolimus dose within the first 4 months, the starting dose for all patients subsequently enrolled will be 75 mg / mm³. 2 This is nab-sirolimus (further dose increases are not permitted).

[0208] Approximately 29 patients are expected to be enrolled in this study at about eight facilities in the United States. The study period will be approximately 24 months, from the enrollment of the first patient to the follow-up of the last patient, which includes an enrollment period of approximately 18 months (from the first patient to the last patient). All enrolled patients will receive a minimum of 6 months of treatment, 28 days of screening, and 28 days (4 weeks) of safety follow-up after the last dose.

[0209] The end-of-treatment (EOT) date for a patient is defined as the date of the last administration of nab-sirolimus. The end-of-treatment visit (EOT visit) is a safety follow-up visit in which safety assessments and procedures are performed 28–35 days after the last administration of nab-sirolimus. The end-of-study (EOS) date for a patient is defined as the date of the last follow-up. EOS is defined as the date the last patient last visited the hospital to complete the study, or the date the last data point from the last patient required for primary, secondary, and / or exploratory analyses was received, as pre-specified in the protocol.

[0210] The follow-up period begins after the end-of-treatment (EOT) visit. All patients who discontinue research treatment and have not withdrawn their full consent to participate in the study will participate in a follow-up phase regarding survival and the initiation of new treatment, including surgery or anti-cancer therapy. If a patient is able to undergo surgical resection of her primary tumor for curative purposes after nab-sirolimus treatment, a record will be made regarding the outcome and whether the patient is disease-free or stable. Follow-up will continue approximately every 12 (±3) weeks until death, withdrawal of consent, or termination of the study, whichever comes first. This assessment may be made by reviewing records and / or by telephone.

[0211] The primary endpoint is to determine the ORR (complete or partial response) in patients with advanced or relapsed EEC receiving combination therapy with nab-sirolimus and letrozole. Based on previous trials of mTOR inhibitors and letrozole in previously treated patients, the benchmark is a 5% ORR, and a 20% ORR is targeted to be considered a signal of meaningful clinical benefit. In this study, Simon's optimal two-stage design is used to test a clinically meaningful difference of 5%–20% of the estimated historical ORR, with a type 1 error rate of 0.05 and a statistical power of 80% requiring a total sample size of 29 efficacy-evaluable patients (10 in stage 1 and an additional 19 in stage 2). An interim analysis (Simon's stage 1) will be performed after 10 efficacy-evaluable patients have received treatment for 6 months and have undergone at least one post-baseline scan. If 0 of the 10 patients show a response, the treatment will be considered ineffective. If one or more patients achieve a response, 19 additional patients whose effectiveness can be evaluated can be enrolled, bringing the total number of enrolled patients to 29. If four or more responses are observed among the 29 patients, the null hypothesis is rejected.

[0212] The secondary objectives are to evaluate the duration of response (DOR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), and overall survival (OS) of the combination of nab-sirolimus and letrozole in EEC, and to establish the safety profile of the combination of nab-sirolimus and letrozole in EEC. Secondary endpoints include: a) DOR: Determination of patients with BOR who have confirmed CR or PR; b) DCR: BOR for CR or PR (regardless of the time period) or stable disease (SD) confirmed at 2:12 weeks after the start of the study treatment; c) TTR: Time from the start of the study treatment to the first measurement of CR or PR (after which CR or PR is confirmed); d) PFS: Number of months from the start of the study treatment to the date of disease progression or death due to any cause, or to the last tumor assessment date if the study was discontinued; e) OS: Number of months from the start of the study treatment to the date of death due to any cause or to the last follow-up date if the patient is alive; and f) Incidence and severity of adverse events and treatment-related adverse events (AEs) that occurred during treatment as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

[0213] The exploratory objective is to evaluate the relationship between baseline molecular biomarkers and genomics, and molecular / genomic profiles and clinical outcomes. Exploratory endpoints include: a) from baseline tumor tissue (archive or fresh biopsy) and blood (peripheral blood mononuclear cells [PBMCs]), (1) evaluating the expression of pS6 and other relevant markers by immunohistochemistry; (2) determining the expression status of estrogen (ER) and progesterone receptor (PgR), tumor mutation burden (TMB), copy number variation (CNA), microsatellite instability (MSI), and polymerase epsilon (POLE) mutation status; (3) determining the mutation profile by next-generation sequencing and understanding the relationship between the mutation profile and clinical outcomes; and b) circulating tumor DNA (ctDNA) at baseline and its change from baseline during treatment.

[0214] Efficacy is assessed by radiological evaluation using CT or MRI scans performed by the principal investigator, based on RECIST v1.1. Patients are evaluated for complete response (CR), partial response (PR), stable disease (SD), or progression (PD) by CT images or MRI. The same imaging method is used throughout the study. Baseline scan results are accepted from external institutions but must be performed within 4 weeks of the start of treatment and must include chest, abdominal, and pelvic (CAP) CT or MRI (if clinically indicated). The initial response assessment by CT or MRI scans recording the target lesion is performed 6 weeks (±7 days) after the first treatment, repeated every 6 weeks (±7 days) for the first year, and thereafter every 12 weeks (±7 days) until disease progression is observed. If an initial observation of an objective response (CR or PR) is made, a confirmatory scan is performed 6 weeks (±1) weeks after the initial observation. Scans continue on schedule regardless of delays in nab-sirolimus administration. BOR and DCR are reported with accurate 95% CI calculated by the Clopper-Pearson method. For PFS, OS, and DOR, KM estimates and corresponding two-sided 95% confidence intervals (CIs) for the median and quartiles are provided. KM plots may also be provided.

[0215] Safety and tolerability are monitored through continuous reporting of the incidence of treatment-related adverse events and treatment-related adverse events, particularly noteworthy adverse events (AESIs), abnormal laboratory values, and patients experiencing dose changes, delayed / missed doses, interruptions, and / or early discontinuation of IP due to AEs. All AEs are recorded by the principal investigator from the time the patient signs informed consent until 28 days after the last dose of IP. Adverse events are classified according to NCI CTCAE v5.0. Physical examination, vital signs, laboratory values ​​(e.g., serological tests, hematological tests, lipid panels, thyroid function), and performance status are monitored. All serious AEs (SAEs, regardless of their relationship to IP) are followed until resolved. Analysis is performed at local laboratories according to the study schedule. Safety (incidence and severity of AEs and significant abnormal laboratory values) is a secondary endpoint and is analyzed using the Full Analysis Set. Patient incidence of all adverse events occurring during treatment is summarized in tables by organ system and priority term. Tables are provided for fatal adverse events, serious adverse events, treatment-related AEs, grade 3 or 4 AEs, particularly noteworthy adverse events, and adverse events leading to discontinuation of the investigational drug, as well as AEs leading to death. The Medical Dictionary for Regulatory Activities (MedDRA) is used to code adverse events, and NCI CTCAE version 5.0 is used to classify the severity of adverse events and experimental toxicity. For nab-sirolimus exposure, summary statistics such as total doses, mean dose, and duration of treatment are provided, but are not limited to these. For selected laboratory parameters, changes in laboratory values ​​over time (e.g., changes from baseline summary statistics), grade shifts in laboratory values ​​from baseline to the worst values ​​during the study, and grade 3 or higher laboratory toxicity are summarized.

[0216] Eligible individuals must meet all of the following inclusion criteria: a) have clinically confirmed advanced (FIGO stage III or IV) or recurrent endometrioid endometriometrial carcinoma (EEC) (histological documentation of recurrence is recommended but not required); b) have one or more measurable target lesions at baseline as determined by computed tomography (CT, or magnetic resonance imaging (MRI) if CT scanning is contraindicated) according to the definition of RECIST version 1.1; c) have metastatic or locally advanced EEC for which surgical resection is not an option or is unlikely to cause serious complications; d) have completed adjuvant therapy at least 6 months prior to the start of the study treatment, and are permitted to receive chemotherapy, hormone therapy, checkpoint inhibitors, and / or other therapies; e) be 18 years of age or older; and f) be from Eastern Cooperative Oncology. Group (ECOG) performance status is 0 or 1, and g) adequate liver function is defined as follows: (1) total bilirubin ≤ 1.5x upper limit of normal (ULN) (≤ 3x ULN unless due to Gilbert's syndrome), (2) aspartate aminotransferase (AST): S2.5x ULN (S5x ULN if due to liver metastasis), h) adequate renal function: creatinine clearance (CrCL) 2.30 mL / min, Cockcroft-Gold

number

[0217] The exclusion criteria are as follows: a) prior treatment with mTOR inhibitors including nab-sirolimus; b) patients with known inactivating mutations in TSC1 or TSC2 (based on tissue or fluid next-generation sequencing [NGS]) unless enrollment in the PRECISION 1 trial (NCT05103358) has been completed; c) patients with a severe (grade 3 or higher) ongoing infection requiring parenteral or oral anti-infective therapy that occurred or was completed within 7 days prior to enrollment; d) patients with primary refractory disease (i.e., patients who have not achieved a complete or partial response to prior treatment) are ineligible to participate in the study; e) patients with the following conditions are excluded: (1) known or suspected brain metastases; (2) unstable angina, New York Heart (3) Severe heart disease as defined by Association (NYHA) Class III or IV congestive heart failure, myocardial infarction within 6 months of the first study treatment, severe uncontrolled arrhythmia, or other clinically significant heart disease; (4) Severe lung disease as defined by carbon monoxide diffusing capacity (DLCO) ≤ 50% of normal and / or resting room air oxygen saturation ≤ 88% (Note: Spirometry and pulmonary function tests (PFT) are not required unless clinically instructed); (5) Non-malignant disease that is uncontrolled or may be threatened with control by administration of the investigational drug; (6) History of malignant tumors other than those being treated (except in cases where the patient has been disease-free for more than 5 years since completion of treatment administered for curative purposes). Controlled non-melanoma skin cancer, cervical carcinoma in situ, resected incidental prostate cancer, certain low-grade hematological malignancies (e.g., chronic lymphocytic leukemia (CLL), follicular lymphoma, etc.), or other appropriately treated carcinomas in situ may be eligible after consultation with medical monitors; (6) patients with uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and / or diastolic blood pressure ≥ 100 mmHg), (7) patients with a history of interstitial lung disease and / or pneumonitis, or pulmonary hypertension, and (8) individuals known to have human immunodeficiency virus (HIV) infection are excluded from this study due to the potential for significant pharmacokinetic interactions with concomitant antiretroviral therapy.Furthermore, these individuals are at increased risk of severe infections due to the immunosuppressive effects of mTOR inhibition, and if they have active hepatitis B or C with a detectable viral load, or if concomitant medications with strong CYP3A4 interactions (induction or inhibition) are required, their use should be discontinued (strong inhibitors include ketoconazole, itraconazole, voriconazole, erythromycin, clarithromycin, telithromycin, and strong inducers include rifampicin and rifabutin), and these medications should be discontinued prior to the first administration of nab-sirolimus.

[0218] Unless otherwise specified, the following evaluations and actions are performed on Day 1 of each cycle before nab-sirolimus administration: physical examination, vital signs (temperature, systolic and diastolic blood pressure, heart rate) according to standard care, weight evaluation, calculation of body surface area (BSA) based on actual weight (calculated only on Cycle 1 / Day 1 according to the facility's standard method and recalculated only if weight changes by more than 10% in subsequent cycles), ECG (only in Cycle 1 and Cycle 3), evaluation of concomitant medications and concomitant treatments, ECOG performance status evaluation, baseline blood of biomarkers before infusion on Day 1 of Cycle 1 (for registered patients only), then performed every 12 weeks for up to 1 year, biomarker pre-treatment tissue (archived or fresh, only in Cycle 1, for registered patients only), clinical chemistry panel, CBC, white blood cell fraction, platelet count, thyroid function defined by TSH (and T3 and T4 if available), fasting lipids (triglycerides, total cholesterol, HDL, and LDL cholesterol) in even cycles starting from Cycle 2, evaluation of adverse events, administration of nab-sirolimus, initiation of daily letrozole administration. If the screening evaluation is performed within 3 days from Day 1 of Cycle 1, the evaluation on Day 1 of Cycle 1 can be omitted. Clinical laboratory evaluations include chemistry tests, hematology tests, pregnancy tests (for women of childbearing potential, including tubal ligation). Refer to Table 1 for the analytes tested for the clinical laboratory tests required on Day 1.

[0219] Unless otherwise specified, on the 8th day of each cycle before nab-sirolimus administration, the following evaluations and treatments are performed: vital signs (body temperature, systolic and diastolic blood pressure, and heart rate), evaluation of concomitant medications and treatments, evaluation of adverse events, dose of nab-sirolimus, CBC, white blood cell fraction, and platelet count (refer to Table 1 for the analysis targets to be included). [Table 1]

[0220] The patient's visit is completed after the EOT visit. The EOT visit is a safety follow-up visit conducted at least 4 weeks (+7 days) after the last administration of nab-sirolimus. All efforts should be made to conduct this visit. If the EOT visit cannot be conducted, the efforts to complete the visit should be documented.

[0221] As specified in the evaluation schedule (Table 2), the following procedures are completed at the EOT visit: physical examination, vital signs (body temperature, systolic and diastolic blood pressure, heart rate), weight, evaluation of concomitant medications and treatments, ECOG performance evaluation, evaluation of adverse events, evaluation of clinical tests: chemistry tests, CBC, white blood cell fraction, platelet count, pregnancy test (for women of childbearing potential) (refer to Table 2 for the analysis targets to be included), tissue samples for biomarker analysis (optional, storage), blood samples for biomarker analysis (storage), image evaluation: CT / MRI is performed at the end of the study visit only for patients who discontinued treatment for reasons other than disease progression, in accordance with RECIST v1.1. [Table 2-1] [Table 2-2]

[0222] Tumor response is assessed by CT or MRI scans of the chest, abdomen, and pelvis (with or without contrast agent, according to the standard procedures of each institution). Image preparation and evaluation are conducted in accordance with RECIST v1.1, and the same modality (CT or MRI) is used at screening and throughout the entire study period. Blood samples for biomarker analysis are collected at baseline, every 12 (±1) weeks in conjunction with scans during the first year, and at EOT visits / disease progression. CT / MRI scans are performed up to 28 days prior to C1D1 (screening), then every 6 weeks (±7 days) after C1D1 for the first year, and thereafter every 12 weeks (±7 days) until disease progression is observed. CT / MRI scans at the end of treatment are performed only for patients who discontinue treatment for reasons other than disease progression. Unplanned scans may be performed at any time if disease progression is suspected. However, it is important to adhere to the planned imaging schedule regardless of delays in administration, unplanned evaluations, or missed evaluations. The determination of disease progression for the clinical management of patients in the study will be evaluated at the local facility. If an initial observation of an objective response (CR or PR) is made, a confirmatory scan will be performed 6 (±1) weeks after the initial observation. If a biopsy is performed when the disease has progressed, a tumor sample should be taken if possible. The surgical pathology report will be submitted along with the tumor tissue sample.

[0223] Post-treatment survival and subsequent initiation of anticancer therapy will be collected approximately every 12 (±3) weeks from the EOT visit, or more frequently as needed, until death, withdrawal of consent, or termination of the study, whichever comes first. If, after nab-sirolimus treatment, the patient is able to undergo surgical resection of his / her primary tumor for curative purposes, a record will be made of the outcome and disease-free or stable condition. This assessment can be made by reviewing the records and / or by telephone.

[0224] Baseline tissue (archive or fresh biopsy) consisting of up to 20 slides, if possible, and blood samples are required from all patients. The primary objectives of baseline tissue profiling for exploratory biomarker analysis and baseline blood biomarker analysis (PBMC) are to assess the expression of pS6 and other relevant markers by immunohistochemistry, to understand the expression status of ER and PgR, the status of TMB, CNA, and MSI, and the POLE mutation status, to understand the mutation profile by next-generation sequencing and to understand the relationship between the mutation profile and clinical outcomes, and to assess ctDNA at baseline and changes from baseline during treatment. The primary objective of longitudinal blood biomarker analysis during treatment is to assess genomic changes due to treatment. Blood samples are collected at baseline on day 1 of cycle 1 (pre-infusion), every 12 (±1) weeks for the first year, and at EOT visits or as disease progresses, according to RECIST v1.1.

[0225] Before administering nab-sirolimus on days 1 and 8, the patient must meet the following hematological requirements prior to administration: ANC ≥ 1.0x0 9 / L, platelet count ≥100x10 9 / L, and hemoglobin ≥ 8.0 g / dL. If treatment cannot be administered on the scheduled appointment date, nabushiromus may be administered ±3 days from the scheduled date, but not for 4 days or less since the previous dose. If necessary, administration can be delayed up to 21 days from the scheduled date. To resume research treatment after an interruption of more than 21 days (counting from the original scheduled date), approval from the medical monitor is required.

[0226] If the dose is not administered within ±3 days of the scheduled day 1, the cycle will start when the first dose of the cycle is actually administered. If the dose on day 8 is not administered within ±3 days of the scheduled date, that week will be a rest week. The next dose (if counting and chemical properties allow) will be day 1 of the new cycle (i.e., if the day 8 dose cannot be administered by day 11 of any cycle, the day 8 dose of that cycle should be skipped, and day 1 of the next cycle should be planned to start 14 days after the previous dose).

[0227] For hematological and non-hematological toxicity, dose reduction should be clinically indicated and shown in Table 3. For the management of adverse events, up to four consecutive dose reductions (75, 56, 45, and 35 mg / m²) may be performed. 2 ) may be observed. If the patient is experiencing multiple toxic symptoms simultaneously, refer to the following guidelines. Changes / discontinuation of administration (see general guidelines and Table 4 below) should be made according to the highest level of toxicity, and if the toxicity grades are the same, follow the most conservative guidelines. Toxicity / AEs are classified using NCI CTCAE v5.0.

[0228] Guidelines for modifying and discontinuing administration to manage common toxicity associated with the investigational treatment(s) are provided below. General guidelines: If a clinically significant AE(s) occurs, treatment should be discontinued and clinically directed supportive care should be provided. Treatment may be resumed if the toxicity or event is not Grade 3 or 4 and resolves to baseline or Grade 1 within 21 days of discontinuing treatment.

[0229] If there is intolerable toxicity at any grade, the dose of nab-sirolimus can be reduced at the discretion of the treating physician. If two dose reductions are thought to be the only safe way to resume treatment by IP, the responsible investigator must consult with the medical monitor before continuing treatment by IP. If toxicity does not improve to Grade 1 or baseline within 21 days, it is recommended to discontinue treatment by IP. However, if the responsible investigator, the patient, and the Aadi Medical Monitor agree that further treatment would be beneficial to the patient, treatment can be continued with dose reduction.

Table 3

[0230] If AE resolves to Grade 1 or baseline with dose reduction and no additional toxicity is observed during the next nab-sirolimus dosing cycle with dose reduction, the dose can be increased to the previous dose at the discretion of the treating physician. The nab-sirolimus dose change guidelines for clinically important toxicities determined by the responsible investigator to be relevant are outlined in Tables 3 and 4. The dosing schedule is described in the assessment schedule (Table 2).

Table 4-1

Table 4-2

Table 4-3

Table 4-4

Table 4-5

Table 4-6

[0231] If another cause for abnormal liver function test values ​​(ALT, AST, alkaline phosphatase) and / or elevated total bilirubin levels is found and the abnormal values ​​improve to normal or baseline, a re-challenge may be considered. The decision to re-administer nabsirolimus to a patient after discontinuation due to potential hepatotoxicity will be discussed and unanimously agreed upon by the patient, the principal investigator, and Aadi Medical Monitor. If signs or symptoms recur after re-administration, nabsirolimus will be discontinued completely. Patients who clearly meet the criteria for permanent discontinuation will not be re-administered.

[0232] For each dose, an overdose is defined as exceeding the nabsirolimus dose specified in the protocol assigned to a particular patient by 10%, regardless of any associated adverse events or sequelae. Based on schedule or frequency, an overdose is defined as occurring more frequently than the schedule or frequency required in the protocol. Based on infusion rate, an overdose is defined as occurring faster than the rate specified in the protocol for each infusion over a 30-minute period.

[0233] Nab-sirolimus is reconstituted by a designated researcher according to the instructions in the Pharmacy Manual and administered to the patient at the research site. The principal investigator or designated researcher calculates the patient's BSA according to the site's standard method to determine the total amount of nab-sirolimus to be administered. The dose is 2m 2 The BSA is restricted. The calculated dose of 5 mg / mL (rounded to the nearest mL) of recomposed nabsirolimus suspension is administered by IV infusion over 30 minutes (+10 minute time frame).

[0234] The letrozole used in this study is a commercially available product.

[0235] During the study period, patients will receive full supportive care in accordance with institutional guidelines, including transfusions of blood and blood products, treatment with antibiotics, antiemetics, antidiarrheals, analgesics, and other care deemed appropriate. White blood cells (WBCs) and platelet growth factor may be administered at the discretion of the principal investigator in accordance with institutional guidelines. Palliative radiotherapy or palliative surgery will not be initiated during participation in the protocol with approval from Medical Monitor, except for the first 8 weeks of treatment, and will only be permitted if the response of other unirradiated lesions in addition to the irradiated lesion(s) is followed up. If radiotherapy or palliative surgery needs to be initiated beyond 8 weeks, it will be considered a non-protocol treatment and therefore a treatment failure. If contraceptives (combined or progesterone alone) are used, extreme caution is necessary as it is unknown whether they may inhibit / induce enzymes that affect the metabolism of estrogen and / or progestins.

[0236] Certain pharmaceuticals and illegal drugs are not permitted to be used before the first dose of IP and during the study period within five times their half-life or 28 days (whichever is shorter). The following drug and non-drug therapies are prohibited during nab-sirolimus administration: other anticancer therapies during treatment in this study, except as described in the paragraph above; antiretroviral drugs (patients with known HIV infection are not eligible to participate in the study); herbal therapies (e.g., St. John's wort) unless approved by Medical Monitor (products containing tetrahydrocannabinol [THC] and cannabidiol [CBD] are permitted); and the use of potent CYP3A4 inhibitors and inducers within five half-lives prior to the first dose of nab-sirolimus. Sirolimus is primarily metabolized by CYP3A4 (potent inhibitors or inducers of CYP3A4 may only be used in special circumstances (e.g., single use for treatment) while treatment with nab-sirolimus is interrupted, and the list may change based on new data), and the use of known CYP3A4 substrates with a narrow therapeutic range (such as fentanyl, alfentanyl, astemizole, dihydroergotamine, pimozide, quinidine, or terfenadine) within five times the half-life prior to the first dose of nab-sirolimus is prohibited unless discussed and agreed upon with Medical Monitor (single doses of fentanyl and similar drugs are permitted if necessary for treatment).

Claims

1. A method for treating hormone-dependent cancer in an individual requiring treatment for hormone-dependent cancer, wherein the method provides the individual with (a) A composition comprising nanoparticles containing sirolimus and albumin, and (b) The method comprising administering an estrogen inhibitor.

2. The method according to claim 1, wherein the estrogen inhibitor is a drug that suppresses the production of estrogen.

3. The method according to claim 2, wherein the estrogen inhibitor is an aromatase inhibitor.

4. The method according to claim 2 or 3, wherein the estrogen inhibitor is selected from the group consisting of letrozole, anastrozole, formestane, and exemestane.

5. The method according to any one of claims 2 to 4, wherein the agent that suppresses estrogen production is letrozole.

6. The method according to claim 1, wherein the estrogen inhibitor is a drug that inhibits the activity of estrogen.

7. The method according to claim 6, wherein the estrogen inhibitor is an estrogen receptor antagonist.

8. The method according to claim 6 or 7, wherein the agent that inhibits estrogen activity is selected from the group consisting of fulvestrant, elastrant, tamoxifen, hydroxyprogesterone caprate, droloxifen, olmeroxifen, toremifene, faroxifen, raloxifen, and clomiphene.

9. The method according to any one of claims 6 to 8, wherein the agent that inhibits estrogen activity is fulvestrant.

10. The method according to any one of claims 1 to 9, wherein the estrogen inhibitor is administered to the individual by oral, intramuscular, intravenous, intraarterial, intraperitoneal, intrabladder, subcutaneous, intrathecal, intrapulmonary, intratracheal, intraocular, transdermal, or inhalation.

11. The method according to claim 10, wherein the estrogen inhibitor is administered orally to the individual.

12. The method according to claim 10, wherein the estrogen inhibitor is administered intramuscularly to the individual.

13. The method according to any one of claims 1 to 10, wherein the estrogen inhibitor is letrozole, and the letrozole is administered orally to the individual.

14. The method according to claim 13, wherein letrozole is administered to the individual in an amount of about 0.1 mg to about 10 mg.

15. The method according to claim 13 or 14, wherein letrozole is administered to the individual daily.

16. The method according to any one of claims 1 to 11, wherein the estrogen inhibitor is fulvestrant, and the fulvestrant is administered intramuscularly to the individual.

17. The method according to claim 16, wherein fulvestrant is administered to the individual in an amount of approximately 100 mg to approximately 700 mg.

18. The method according to claim 16 or 17, wherein fulvestrant is administered to the individual on days 1, 15, and 29 of the initiation cycle, followed by monthly maintenance cycles.

19. The method according to any one of claims 1 to 18, wherein the hormone-dependent cancer is endometrioid endometrial carcinoma.

20. The method according to any one of claims 1 to 18, wherein the hormone-dependent cancer is breast cancer.

21. The method according to claim 20, wherein the breast cancer is hormone receptor-positive breast cancer.

22. The method according to any one of claims 1 to 21, wherein the hormone-dependent cancer is locally advanced, progressive, malignant, advanced malignant, or metastatic.

23. The method according to any one of claims 1 to 22, wherein the hormone-dependent cancer is refractory, recurrent, recurrent, or resistant to previous treatments.

24. The method according to claim 23, wherein the aforementioned prior treatment comprises an mTOR inhibitor and / or a composition comprising nanoparticles comprising an mTOR inhibitor and albumin.

25. The method according to claim 23, wherein the aforementioned prior treatment comprises a platinum-based agent and / or a checkpoint inhibitor.

26. The method according to any one of claims 1 to 23, wherein the individual has not been treated with an mTOR inhibitor and / or a composition comprising nanoparticles comprising an mTOR inhibitor and albumin.

27. The method according to any one of claims 1 to 26, wherein the hormone-dependent cancer is stage III or stage IV.

28. The method according to any one of claims 1 to 27, wherein the individual is a human.

29. A method for treating endometrial cancer in an individual requiring treatment for endometrial cancer, wherein the method involves the individual, (a) A composition comprising nanoparticles containing sirolimus and albumin, and (b) Including administering an estrogen inhibitor, The estrogen inhibitor is an aromatase inhibitor. The method wherein the estrogen inhibitor is administered to the individual in an amount of approximately 0.1 mg to approximately 10 mg.

30. The method according to claim 29, wherein the endometrial cancer is endometrioid endometrial carcinoma.

31. The method according to claim 29 or 30, wherein the estrogen inhibitor is letrozole.

32. The method according to any one of claims 29 to 31, wherein the estrogen inhibitor is administered to the individual daily.

33. A method for treating hormone receptor-positive breast cancer in an individual requiring treatment for hormone receptor-positive breast cancer, wherein the method involves the individual, (a) A composition comprising nanoparticles containing sirolimus and albumin, and (b) Including administering an estrogen inhibitor, The estrogen inhibitor is a selective estrogen receptor degrader (SERD), The method wherein the estrogen inhibitor is administered to the individual in an amount of approximately 200 mg to approximately 600 mg.

34. The method according to claim 33, wherein the estrogen inhibitor is fulvestrant.

35. The method according to claim 33 or 34, wherein the estrogen inhibitor is administered to the individual on day 1, day 15, and day 29 of the initiation cycle, and thereafter administered at a maintenance dose every month.

36. The amount of sirolimus in the sirolimus nanoparticle composition is approximately 10 mg / m³ ２ ~Approx. 150mg / m ２ The method according to any one of claims 1 to 35, administered in an amount.

37. The amount of sirolimus in the sirolimus nanoparticle composition is approximately 100 mg / m². ２ The method according to claim 36, administered in an amount.

38. The amount of sirolimus in the sirolimus nanoparticle composition is approximately 75 mg / m². ２ The method according to claim 36, administered in an amount.

39. The amount of sirolimus in the sirolimus nanoparticle composition is approximately 56 mg / m². ２ The method according to claim 36, administered in an amount.

40. The amount of sirolimus in the sirolimus nanoparticle composition is approximately 45 mg / m². ２ The method according to claim 36, administered in an amount.

41. The amount of sirolimus in the sirolimus nanoparticle composition is approximately 30 mg / m². ２ The method according to claim 36, administered in an amount.

42. The method according to any one of claims 1 to 41, wherein the sirolimus nanoparticle composition is administered twice, every three weeks.

43. The method according to any one of claims 1 to 42, wherein the sirolimus nanoparticle composition is administered on day 1 and day 8 of a 21-day cycle.

44. The method according to any one of claims 1 to 43, wherein the average diameter of the nanoparticles in the composition is about 150 nm or less.

45. The method according to claim 44, wherein the average diameter of the nanoparticles in the composition is about 120 nm or less.

46. The method according to any one of claims 1 to 45, wherein the weight ratio of albumin to sirolimus in the nanoparticle composition is about 9:1 or less.

47. The method according to any one of claims 1 to 46, wherein the nanoparticles include sirolimus associated with albumin.

48. The method according to claim 47, wherein the nanoparticles include sirolimus coated with albumin.

49. The method according to any one of claims 1 to 48, wherein the sirolimus nanoparticle composition is administered intravenously.

50. The method according to any one of claims 1 to 49, wherein the sirolimus nanoparticle composition is administered in parallel with the estrogen inhibitor.

51. The method according to any one of claims 1 to 49, wherein the sirolimus nanoparticle composition is administered sequentially with the estrogen inhibitor.

52. The method according to any one of claims 1 to 49, wherein the sirolimus nanoparticle composition is administered simultaneously with the estrogen inhibitor.

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