Combination therapy using mTOR inhibitors and multityrosine kinase inhibitors for the treatment of soft tissue sarcoma

Abstract

This application relates, in certain embodiments, to a method and composition for treating soft tissue sarcomas (STS, e.g., spindle cell sarcoma, solitary fibrous tumor, or leiomyosarcoma) using a composition comprising nanoparticles containing an mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and albumin in combination with a multityrosine kinase inhibitor (e.g., pazopanib).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 468,758, filed on 24 May 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 soft tissue sarcoma using a composition comprising nanoparticles containing an mTOR inhibitor and albumin in combination with a multityrosine kinase inhibitor. [Background technology]

[0003] Soft tissue sarcomas can present with many different histological subtypes and are generally difficult to treat. Soft tissue sarcomas have a low 5-year survival rate, especially when metastasis occurs, and many chemotherapy agents do not provide a significant benefit to patients. For example, pazopanib monotherapy did not show a significant difference in overall survival in patients with soft tissue sarcoma compared to placebo control.

[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, for example, nab-sirolimus or Fyarrao (additive), are known, for example, in U.S. Patents 8,911,786 and 11,497,737.

[0006] Despite the effectiveness of pazopanib or nabsirolimus monotherapy in certain cancer situations, there remains a need for advanced treatments for certain cancers, including difficult-to-treat soft tissue sarcomas. [Brief explanation of the drawing]

[0007] [Figure 1] This swimmer plot shows the total treatment duration for evaluable patients who received nabsilolimus in combination with pazopanib. [Figure 2] This shows a waterfall plot of responses in 18 evaluable patients who received nabsilolimus in combination with pazopanib. [Overview of the Initiative]

[0008] In a particular embodiment, the present application provides a method for treating soft tissue sarcoma (STS) in an individual requiring treatment for soft tissue sarcoma, the method comprising administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor and albumin, and (b) a multityrosine kinase inhibitor, wherein the multityrosine kinase inhibitor (e.g., pazopanib) is administered in amounts ranging from about 1 mg to about 2500 mg, for example, from about 200 mg to about 800 mg.

[0009] In some embodiments of any of the methods described herein, the soft tissue sarcoma is selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melanin schwannoma, and pleomorphic rhabdomyosarcoma.

[0010] In another embodiment, a method is provided for treating a soft tissue sarcoma in an individual requiring treatment for soft tissue sarcoma, the soft tissue sarcoma being selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melanin schwannoma, and pleomorphic rhabdomyosarcoma, and the method comprising administering to the individual (a) a composition comprising nanoparticles containing an mTOR inhibitor and albumin, and (b) a multityrosine kinase inhibitor (e.g., pazopanib).

[0011] In some embodiments of any of the methods described herein, the leiomyosarcoma is a uterine leiomyosarcoma. In some embodiments, the leiomyosarcoma is a non-uterine leiomyosarcoma.

[0012] In some embodiments of any of the methods described herein, the soft tissue sarcoma is locally progressive, progressive, malignant, progressive malignant, or metastatic. In some embodiments of any of the methods described herein, the soft tissue sarcoma is recurrent, refractory, or resistant to prior treatment. In some embodiments of any of the methods described herein, the prior treatment comprises a composition comprising an mTOR inhibitor and albumin nanoparticles.

[0013] In some embodiments of any of the methods described herein, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition administered to an individual is about 10 mg / m². 2 ~about 150mg / m 2 In some embodiments of any of the methods described herein, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition administered to an individual is approximately 10 mg / m 2 ~about 60mg / m 2 In some embodiments of any of the methods described herein, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition administered to an individual is 30 mg / m². 2 , 45 mg / m² 2 , or 60 mg / m² 2 That is the case.

[0014] In some embodiments of any of the methods described herein, the mTOR inhibitor nanoparticle composition is administered once or twice every three weeks. In some embodiments of any of the methods described herein, the mTOR inhibitor nanoparticle composition is administered on day 1 of a 21-day cycle. In some embodiments of any of the methods described herein, the mTOR inhibitor nanoparticle composition is administered on days 1 and 8 of a 21-day cycle.

[0015] In some embodiments of any of the methods described herein, the mTOR inhibitor is a limus drug. In some embodiments, the limus drug is sirolimus.

[0016] In some embodiments of any of the methods described herein, the average diameter of the nanoparticles in the composition is about 150 nm or less. In some embodiments of any of the methods described herein, the average diameter of the nanoparticles in the composition is about 120 nm or less. In some embodiments of any of the methods described herein, the weight ratio of albumin to mTOR inhibitor in the nanoparticle composition is about 9:1 or less. In some embodiments of any of the methods described herein, the nanoparticles comprise an mTOR inhibitor associated with albumin. In some embodiments of any of the methods described herein, the nanoparticles comprise an mTOR inhibitor coated with albumin.

[0017] In some embodiments of any of the methods described herein, the mTOR inhibitor nanoparticle composition is administered intravenously.

[0018] In some embodiments of any of the methods described herein, the multityrosine kinase inhibitor inhibits two or more of the following: vascular endothelial growth factor receptor (VEGFR)-1, -2, or -3, platelet-derived growth factor receptor (PDGFR)-α or -β, interleukin-2 receptor-induced T cell kinase (ITK), leukocyte-specific protein tyrosine kinase (LCK), colony-stimulating factor-1 receptor (c-fms), fibroblast growth factor receptor (FGFR)-1, -3, or -4, or stem cell factor receptor c-Kit.

[0019] In some embodiments of any of the methods described herein, the multityrosine kinase inhibitor is pazopanib or a pharmaceutically acceptable salt thereof. In some embodiments of any of the methods described herein, the multityrosine kinase inhibitor is pazopanib hydrochloride. In some embodiments of any of the methods described herein, the multityrosine kinase inhibitor is administered in an amount of about 400 mg. In some embodiments of any of the methods described herein, the multityrosine kinase inhibitor is administered daily or every other day. In some embodiments of any of the methods described herein, the multityrosine kinase inhibitor is administered orally. In some embodiments of any of the methods described herein, the multityrosine kinase inhibitor is administered without food.

[0020] In some embodiments of any of the methods described herein, when the mTOR inhibitor nanoparticle composition is administered, a multityrosine kinase inhibitor is administered concurrently. In some embodiments of any of the methods described herein, when the mTOR inhibitor nanoparticle composition is administered, a multityrosine kinase inhibitor is administered sequentially. In some embodiments of any of the methods described herein, when the mTOR inhibitor nanoparticle composition is administered, a multityrosine kinase inhibitor is administered simultaneously.

[0021] In some embodiments of any of the methods described herein, the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is approximately 30 mg / m³ on day 1 of a 21-day cycle. 2 The drug is administered intravenously in a dose of [amount missing], while multi-tyrosine kinase inhibitors are administered orally at a dose of approximately 400 mg per day.

[0022] In some embodiments of any of the methods described herein, the individual is a human.

[0023] 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]

[0024] In certain embodiments, this application provides a treatment for soft tissue sarcoma (e.g., spindle cell sarcoma, solitary fibrous tumor, or leiomyosarcoma) comprising a combination of (a) a composition comprising nanoparticles containing an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin (e.g., nab-sirolimus) and (b) a multityrosine kinase inhibitor (e.g., pazopanib).

[0025] The subject matter of this application is based, at least in part, on the discovery that nab-sirolimus, a composition comprising nanoparticles containing the mTOR inhibitor sirolimus and albumin, and (b) the multityrosine kinase inhibitor pazopanib, are safe and effective in treating patients with soft tissue sarcoma. Soft tissue sarcomas, such as spindle cell sarcoma, solitary fibrous tumor, and leiomyosarcoma, are very difficult cancers to treat, and patients diagnosed with such cancers have a poor prognosis even with approved therapies. For example, soft tissue sarcoma patients treated with pazopanib monotherapy showed an objective response rate of approximately 6%, and there was no significant improvement in overall survival compared to placebo controls. As described in more detail in the Examples section, the dose and schedule of the nab-sirolimus and pazopanib combination proved to be safe and effective in benefiting patients with soft tissue sarcoma. For example, 16 out of 18 evaluated patients treated with the nab-sirolimus and pazopanib combination showed disease stability or partial response. Because soft tissue sarcomas are particularly difficult to treat, finding disease stabilization is crucial. Furthermore, the combination of nabushirolimus and pazopanib has yielded long-term patient benefits, with some patients experiencing progression-free survival for more than one year. Such findings, even relatively short-term results of disease stabilization, let alone the long-term results reported in the Case Studies section, represent a significant advance in the treatment of soft tissue sarcomas and represent a substantial improvement over existing treatments.

[0026] Thus, in certain aspects, the present specification provides a method of treating soft tissue sarcoma in an individual who requires treatment for soft tissue sarcoma, the method comprising administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor and albumin, and (b) a multi-kinase inhibitor (e.g., pazopanib). In some embodiments, the soft tissue sarcoma is selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melanotic schwannoma, and pleomorphic rhabdomyosarcoma. In some embodiments, the multi-kinase inhibitor (e.g., pazopanib) is administered at about 1 mg to about 2500 mg, such as about 200 mg to about 800 mg, such as about 400 mg. In some embodiments, the composition comprising nanoparticles comprising an mTOR inhibitor and albumin is administered at about 10 mg / m 2 to about 100 mg / m 2 , such as about 30 mg / m 2 , about 45 mg / m 2 , or about 60 mg / m 2 . In some embodiments, the composition comprising nanoparticles comprising an mTOR inhibitor and albumin is administered once every three weeks, such as on day 1 of a 21-day cycle. In some embodiments, the composition comprising nanoparticles comprising an mTOR inhibitor and albumin is administered twice every three weeks, such as on day 1 and day 8 of a 21-day cycle. In some embodiments, the multi-kinase inhibitor (e.g., pazopanib) is administered orally at about 400 mg per day, and the composition comprising nanoparticles comprising an mTOR inhibitor and albumin is administered intravenously at about 30 mg / m 2 once every three weeks, such as on day 1 of a 21-day cycle.

[0027] In other embodiments, this specification provides a method for treating soft tissue sarcoma in an individual requiring treatment for soft tissue sarcoma, the method comprising administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor and albumin, and (b) a multityrosine kinase inhibitor (e.g., pazopanib), the multityrosine kinase inhibitor being administered in doses of about 1 mg to about 2500 mg, for example, about 200 mg to about 800 mg, for example, about 400 mg. In some embodiments, the soft tissue sarcoma is selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melanin schwannoma, and pleomorphic rhabdomyosarcoma. In some embodiments, the composition comprising nanoparticles comprising an mTOR inhibitor and albumin is about 10 mg / m 2 ~about 100mg / m 2 For example, approximately 30 mg / m² 2 , 45 mg / m² 2 , or 60 mg / m² 2 In some embodiments, the composition comprising nanoparticles containing an mTOR inhibitor and albumin is administered once every three weeks, such as on day 1 of a 21-day cycle. In some embodiments, the composition comprising nanoparticles containing an mTOR inhibitor and albumin is administered twice every three weeks, such as on day 1 and day 8 of a 21-day cycle. In some embodiments, a multikinase inhibitor (e.g., pazopanib) is administered orally at a dose of approximately 400 mg daily, and the composition comprising nanoparticles containing an mTOR inhibitor and albumin is administered at a dose of approximately 30 mg / m³ every three weeks, such as on day 1 of a 21-day cycle. 2 It is administered intravenously.

[0028] In other embodiments, a method is provided for treating soft tissue sarcoma in an individual requiring treatment for soft tissue sarcoma, the soft tissue sarcoma being selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melanin schwannoma, and pleomorphic rhabdomyosarcoma, and the method comprises administering to the individual (a) a composition comprising nanoparticles containing an mTOR inhibitor and albumin, and (b) a multityrosine kinase inhibitor (e.g., pazopanib). In some embodiments, the multikinase inhibitor is administered in doses of about 1 mg to about 2500 mg, for example, about 200 mg to about 800 mg, for example, 400 mg. In some embodiments, the composition comprising nanoparticles containing an mTOR inhibitor and albumin is administered in doses of about 10 mg / m 2 ~about 100mg / m 2 For example, approximately 30 mg / m² 2 , about 45mg / m 2 , or approximately 60 mg / m² 2 In some embodiments, the composition comprising nanoparticles containing an mTOR inhibitor and albumin is administered once every three weeks, such as on day 1 of a 21-day cycle. In some embodiments, the composition comprising nanoparticles containing an mTOR inhibitor and albumin is administered twice every three weeks, such as on day 1 and day 8 of a 21-day cycle. In some embodiments, a multikinase inhibitor (e.g., pazopanib) is administered orally at a dose of approximately 400 mg daily, and the composition comprising nanoparticles containing an mTOR inhibitor and albumin is administered at a dose of approximately 30 mg / m³ every three weeks, such as on day 1 of a 21-day cycle. 2 It is administered intravenously.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] The terms "refractory" or "resistant" refer to cancer or disease that does not respond to treatment.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] "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.

[0037] 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).

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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.”

[0043] 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.

[0044] 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".

[0045] As used herein, the singular “a,” “or,” and “the,” including in the appended claims, refer to multiple subjects unless the context clearly indicates otherwise.

[0046] Those skilled in the art will understand that several embodiments are possible within the scope and spirit of this disclosure. The following description is illustrative of this disclosure and should not be construed as limiting the scope of the inventions described herein.

[0047] II. Treatment method This specification provides a method for treating soft tissue sarcoma in an individual requiring treatment for soft tissue sarcoma, the method comprising administering to the individual a combination of (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., limus drug, e.g., sirolimus or a derivative thereof) and albumin, and (b) a multityrosine kinase inhibitor (e.g., pazopanib) for soft tissue sarcoma (e.g., spindle cell sarcoma, solitary fibrous tumor, or leiomyosarcoma).

[0048] In some embodiments, a method is provided for treating soft tissue sarcoma in an individual requiring treatment for soft tissue sarcoma, the method comprising administering to the individual (a) a composition comprising nanoparticles containing an mTOR inhibitor and albumin (e.g., nabsirolimus), and (b) pazopanib. In some embodiments, the soft tissue sarcoma is selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melanin schwannoma, and pleomorphic rhabdomyosarcoma. In some embodiments, pazopanib is administered in doses of about 1 mg to about 2500 mg, for example, about 200 mg to about 800 mg, for example, about 400 mg. In some embodiments, pazopanib is administered orally. In some embodiments, pazopanib is administered daily. In some embodiments, the composition comprising nanoparticles containing an mTOR inhibitor and albumin is about 10 mg / m² 2 ~about 100mg / m 2 For example, approximately 30 mg / m² 2In some embodiments, the composition comprising nanoparticles containing an mTOR inhibitor and albumin is administered intravenously. In some embodiments, the composition comprising nanoparticles containing an mTOR inhibitor and albumin is administered every three weeks. In some embodiments, pazopanib is administered orally at a dose of approximately 400 mg daily, and the composition comprising nanoparticles containing an mTOR inhibitor and albumin is administered at a dose of approximately 30 mg / m³ every three weeks, such as on day 1 of a 21-day cycle. 2 It is administered intravenously.

[0049] In some embodiments, the soft tissue sarcoma is selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melaninous schwannoma, and pleomorphic rhabdomyosarcoma. In some embodiments, the leiomyosarcoma is uterine leiomyosarcoma. In some embodiments, the leiomyosarcoma is non-uterine leiomyosarcoma.

[0050] In some embodiments, the soft tissue sarcoma is locally progressive, progressive, malignant, progressive malignant, or metastatic. In some embodiments, the soft tissue sarcoma is recurrent, refractory, or resistant to prior treatment. In some embodiments, prior treatment includes a composition comprising nanoparticles containing an mTOR inhibitor and albumin.

[0051] The methods provided herein are applicable to all stages of soft tissue sarcoma, including stages I, II, III, and IV according to the American Joint Committee on Cancer (AJCC) staging classification group. In some embodiments, the soft tissue sarcoma is early-stage cancer, non-metastatic cancer, primary cancer, advanced cancer, locally advanced cancer, metastatic cancer, cancer in remission, cancer receiving adjuvant therapy, or cancer receiving neoadjuvant therapy. In some embodiments, the soft tissue sarcoma is locally resectable, locally unresectable, or unresectable. In some embodiments, the soft tissue sarcoma is locally resectable or borderline resectable.

[0052] In some embodiments of any of the methods described herein, a composition comprising nanoparticles containing an mTOR inhibitor and albumin, as well as a multityrosine kinase inhibitor, is administered in an effective amount for the treatment of soft tissue sarcoma.

[0053] A. 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, the method of administration, 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., a 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.

[0054] In some embodiments, when an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) is administered, the mTOR inhibitor nanoparticle composition is administered to the individual simultaneously with a multityrosine kinase inhibitor (e.g., pazopanib). For example, the mTOR inhibitor nanoparticle composition and the multityrosine kinase inhibitor (e.g., pazopanib) are administered within approximately 15 minutes, for example, within 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 multityrosine kinase inhibitor (such as pazopanib). In one example, simultaneous administration can be achieved by administering a composition containing the combination of compounds. In another example, co-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 another containing a multityrosine kinase inhibitor (such as pazopanib administered orally). In some embodiments, co-administration of an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) and a multityrosine kinase inhibitor (e.g., pazopanib) in a nanoparticle composition can be combined with additional administration of the mTOR inhibitor and / or the multityrosine kinase inhibitor (e.g., pazopanib).

[0055] In other embodiments, the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and the multityrosine kinase inhibitor (such as pazopanib) are not administered simultaneously. In some embodiments, the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) is administered before the multityrosine kinase inhibitor (such as pazopanib). In other embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered before the mTOR inhibitor nanoparticle composition (such as a 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 compound administered is given time to exert its effect on the patient before the second 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.

[0056] In some embodiments, the administration of an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and a multityrosine kinase inhibitor (e.g., pazopanib) are parallel, i.e., the administration periods of the mTOR inhibitor nanoparticle composition and the multityrosine kinase inhibitor (e.g., pazopanib) 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 multityrosine kinase inhibitor (e.g., pazopanib). In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered for at least one week, two weeks, three weeks, or four weeks. In some embodiments, the administration of an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and a multityrosine kinase inhibitor (e.g., pazopanib) 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 a multityrosine kinase inhibitor (e.g., pazopanib) 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, the administration of the multityrosine kinase inhibitor (e.g., pazopanib) is continued after the termination of the administration of the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) (e.g., for one month, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months). In some embodiments, administration of a multityrosine kinase inhibitor (e.g., pazopanib) is initiated after the start of 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 an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and a multityrosine kinase inhibitor (such as pazopanib) is started and terminated almost simultaneously. In some embodiments, the administration of an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and a multityrosine kinase inhibitor (e.g., pazopanib) is started almost simultaneously, and after the termination of administration of the mTOR inhibitor nanoparticle composition, the administration of the multityrosine kinase inhibitor (e.g., pazopanib) 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 a multityrosine kinase inhibitor (e.g., pazopanib) are stopped almost simultaneously, and the administration of the multityrosine kinase inhibitor (e.g., pazopanib) is started after the initiation of the administration of the mTOR inhibitor nanoparticle composition (e.g., one month after approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months).

[0057] In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered daily. In some embodiments, the dose of the multityrosine kinase inhibitor (e.g., pazopanib) is reduced due to considerations for the patient, such as adverse events. In some embodiments, the dose of the multityrosine kinase inhibitor (e.g., pazopanib) is reduced to every other day. In some embodiments, the reduction in the dose of the multityrosine kinase inhibitor (e.g., pazopanib) is performed only for part of the treatment, for example, until the individual recovers (at least partially) from an adverse event.

[0058] In some embodiments, administration of a composition comprising an mTOR inhibitor and albumin, as well as a multityrosine kinase inhibitor (e.g., pazopanib), 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.

[0059] In some embodiments, the administration of an mTOR inhibitor nanoparticle composition (e.g., a sirolimus / albumin nanoparticle composition) and a multityrosine kinase inhibitor (e.g., pazopanib) is not simultaneous. For example, in some embodiments, the administration of the mTOR inhibitor nanoparticle composition (e.g., a sirolimus / albumin nanoparticle composition) is completed before the administration of the multityrosine kinase inhibitor (e.g., pazopanib). In some embodiments, the administration of the multityrosine kinase inhibitor (e.g., pazopanib) is completed before the administration of the mTOR inhibitor nanoparticle composition (e.g., 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.

[0060] The frequency of administration of mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and multityrosine kinase inhibitors (such as pazopanib) 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 multityrosine kinase inhibitors (such as pazopanib) 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 a multityrosine kinase inhibitor (such as pazopanib) may be administered more frequently or less frequently, for example, daily. In some embodiments, sustained-release formulations of nanoparticles and / or multityrosine kinase inhibitors (e.g., pazopanib) 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.

[0061] mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and multityrosine kinase inhibitors (such as pazopanib) 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 multityrosine kinase inhibitor (e.g., pazopanib) in the mTOR inhibitor nanoparticle composition are administered in a predetermined ratio.

[0062] The required dose of an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) and / or a multityrosine kinase inhibitor (e.g., pazopanib) 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., a limus drug, e.g., sirolimus or its derivatives) and / or multityrosine kinase inhibitor (e.g., pazopanib) 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 multityrosine kinase inhibitor (e.g., pazopanib) 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). 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 2This method includes administering the drug in any of the following doses. In some embodiments, this method includes administering a multityrosine kinase inhibitor (e.g., pazopanib) in a dose of less than about 800 mg, for example, about 700 mg, 600 mg, 500 mg, 400 mg, 300 mg, 200 mg, or 100 mg.

[0063] In some embodiments, a sufficient amount of a multityrosine kinase inhibitor (e.g., pazopanib) is administered so as to reduce the usual dose of the mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) in the mTOR inhibitor nanoparticle composition required to produce the same level of therapeutic effect by at least about 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% or more.

[0064] In some embodiments, the doses of both the mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) and the multityrosine kinase inhibitor (e.g., pazopanib) in the mTOR inhibitor nanoparticle composition are reduced compared to the corresponding usual doses when each is administered alone. In some embodiments, both the mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) and the multityrosine kinase inhibitor (e.g., pazopanib) in the mTOR inhibitor nanoparticle composition are administered at sub-thermal levels, i.e., reduced levels. In some embodiments, the doses of the mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or its derivatives) and / or the multityrosine kinase inhibitor (e.g., pazopanib) 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 multityrosine kinase inhibitors (e.g., pazopanib) are approximately 50%, 40%, 30%, 20%, or less than 10% of the MTD.

[0065] 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 soft tissue sarcoma may receive treatments to suppress and / or delay disease progression.

[0066] As those skilled in the art will understand, in some embodiments, an appropriate dose of the second agent is approximately equivalent to doses already used in clinical treatment where a multityrosine kinase inhibitor (e.g., pazopanib) 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.

[0067] In some embodiments, the amounts of the mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) and the multityrosine kinase inhibitor (e.g., pazopanib) are below the level at which the mTOR inhibitor nanoparticle composition and the multityrosine kinase inhibitor (e.g., pazopanib) 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.

[0068] 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 a multityrosine kinase inhibitor (such as pazopanib) according to the same dosing schedule. 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 a multityrosine kinase inhibitor (e.g., pazopanib).

[0069] 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 / m²2 , 250 mg / m 2 , 260 mg / m 2 , 300 mg / m 2 , 350 mg / m 2 , 400 mg / m 2 , 500 mg / m 2 , 540 mg / m 2 , 750 mg / m 2 , 1000 mg / m 2 , or 1080 mg / m 2 of any of the TOR inhibitors. In some embodiments, the mTOR inhibitor nanoparticle composition is about 350 mg / mm 2 , 300 mg / m 2 , 250 mg / m 2 , 200 mg / m 2 , 150 mg / m 2 , 120 mg / m 2 , 100 mg / m 2 , 90 mg / m 2 , 50 mg / m 2 , or 30 mg / m 2 less than any of the mTOR inhibitors (such as rapamycin drugs such as sirolimus). In some embodiments, the amount of mTOR inhibitor (such as a rapamycin drug, such as 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 2 , 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 / m2 , 18 mg / m² 2 , 17 mg / m² 2 , 16 mg / m² 2 , 15 mg / m² 2 , 14 mg / m² 2 , 13 mg / m² 2 , 12 mg / m² 2 , 11 mg / m² 2 , 10 mg / m² 2 , 9 mg / m² 2 , 8 mg / m² 2 , 7 mg / m² 2 , 6 mg / m² 2 , 5 mg / m² 2 , 4 mg / m² 2 , 3 mg / m² 2 , 2 mg / m² 2 , or 1 mg / m² 2 It is less than any of the following. In some embodiments, the mTOR inhibitor (e.g., limus 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 , 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 / m²2 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.

[0070] In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered in doses ranging from approximately 1 mg to approximately 2,500 mg, which includes any of the following: approximately 100 mg to approximately 900 mg, approximately 200 mg to approximately 800 mg, approximately 200 mg to approximately 700 mg, approximately 200 mg to approximately 600 mg, or approximately 200 mg to approximately 400 mg. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered in doses of 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, or 100 mg or less. In some embodiments, a multityrosine kinase inhibitor (e.g., pazopanib) is administered 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, 500 mg, 450 mg, 400 mg, 350 mg, 300 mg, 250 mg, 200 mg, 150 mg, or 100 mg. In some embodiments, a multityrosine kinase inhibitor (e.g., pazopanib) is administered at approximately 400 mg.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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 )

[0075] 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.

[0076] In some embodiments, the individual receives treatment for at least one, two, three, four, five, six, seven, eight, nine, or ten treatment cycles.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] In some embodiments, exemplary dosing schedules for administering a multityrosine kinase inhibitor include daily or every other day. In some embodiments, exemplary dosing schedules for administering a multityrosine kinase inhibitor are daily. In some embodiments, exemplary dosing schedules for administering a multityrosine kinase inhibitor are once, two, three, four, five, six, or seven times per week. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is suitable for oral administration.

[0082] mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and multityrosine kinase inhibitors (such as pazopanib) 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.

[0083] As discussed above, mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and multityrosine kinase inhibitors (such as pazopanib) can be administered in a single unit dose or in separate dosage forms. Therefore, the term “pharmaceutical combination” includes a combination 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 multityrosine kinase inhibitors (e.g., pazopanib) in a single unit dose, as well as individually with mTOR inhibitor nanoparticle compositions and multityrosine kinase inhibitors (e.g., pazopanib) when these compounds are administered separately.

[0084] 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.

[0085] 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.

[0086] 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 a multityrosine kinase inhibitor (e.g., pazopanib), 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.

[0087] 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.

[0088] 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).

[0089] 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.

[0090] Multityrosine kinase inhibitors (e.g., pazopanib) can be administered to an individual (e.g., a human) via various routes, including, for example, oral, intravenous, intra-arterial, intraperitoneal, intrapulmonary, inhalation, intravesicular, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal, transmucosal, and transdermal. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered orally.

[0091] B. Treatment of soft tissue sarcoma and its subtypes In some embodiments, a method for treating soft tissue sarcoma in an individual (e.g., human) is provided, 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib).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 contains nab-sirolimus. In some embodiments, the composition of the mTOR inhibitor nanoparticles is nab-sirolimus. In some embodiments, the multityrosine kinase inhibitor is pazopanib (e.g., pazopanib hydrochloride). In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, such as on day 1, day 8, or day 15 of a 21-day cycle. In some embodiments, the mTOR inhibitor nanoparticle composition is administered twice every three weeks, such as on day 1 and day 8 of a 21-day cycle. In some embodiments, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg / m³. 2 ~about 150mg / m 2 For example, about 1 mg / m² 2 ~about 60mg / m 2 , about 30mg / m 2 This includes. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, for example, on day 1 of a 21-day cycle, at a dose of approximately 1 mg / m². 2 ~about 60mg / m 2 (about 30mg / m 2It is administered intravenously (including). In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered daily. In some embodiments, the amount of the multityrosine kinase inhibitor (e.g., pazopanib) is about 10 mg to about 800 mg, for example, about 400 mg. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered orally. In some embodiments, the multityrosine kinase inhibitor is administered orally daily in amounts of about 10 mg to about 800 mg (including about 400 mg). In some embodiments, a method for treating soft tissue sarcoma in an individual (such as a human) is provided, the method comprising (a) administering to the individual a composition comprising nanoparticles containing an mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and albumin, at a dose of about 10 mg / m³ every three weeks (e.g., day 1 of a 21-day cycle). 2 ~about 60mg / m 2 For example, approximately 30 mg / m² 2 (b) administering the drug intravenously in the specified amount, and (b) orally administering pazopanib to the individual in an amount of approximately 200 mg to approximately 600 mg (e.g., approximately 400 mg).

[0092] In some embodiments, a method is provided for treating soft tissue sarcoma in an individual requiring treatment for soft tissue sarcoma, the soft tissue sarcoma being selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melanin schwannoma, and pleomorphic rhabdomyosarcoma, and the method comprises administering to the individual (a) a composition comprising nanoparticles containing an mTOR inhibitor and albumin, and (b) a multityrosine kinase inhibitor.

[0093] Spindle cell sarcoma is an undifferentiated soft tissue sarcoma that occurs in the bone and can appear in most parts of the human body, as well as common areas including the arms, legs, and pelvis. Spindle cell sarcoma is a malignant tumor composed of cells characterized by their elongated or “spindle cell” shape and can be classified into pleomorphic anaplastic sarcoma, fibrosarcoma, angiosarcoma, and leiomyosarcoma. Diagnosis can be made by one or more of the following: X-ray, ultrasound, magnetic resonance imaging, or histological examination by tumor biopsy. Stradling, “Spindle Cell Sarcoma: Information for Patients,” 2015. Diagnosis of spindle cell sarcoma can be made by “diagnosis by exclusion” because there are no distinguishing features other than the shape of the tumor cells. Diagnosis of spindle cell sarcoma may be based on its elongated cell morphology, which, unlike the most common type of anaplastic sarcoma known as anaplastic pleomorphic sarcoma, often consists of a mixture of cells of different sizes and shapes. Sarcoma UK, “What is Sarcoma:Types of Sarcoma:Spindle Cell Sarcoma,2023;<https: / / sarcoma.org.uk / about-sarcoma / what-is-sarcoma / types-of-sarcoma / spindle-cell-sarcoma / > Accessible via [platform name].

[0094] In some embodiments, a method for treating spindle cell sarcoma in an individual (e.g., human) is provided, 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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 have an average particle size of about 150 nm or less (e.g., about 120 nm or less), and (b) a multityrosine kinase inhibitor (e.g., pazopanib). 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 an 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). The method comprises administering to an individual (a) a composition, and (b) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib).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 contains nab-sirolimus. In some embodiments, the composition of the mTOR inhibitor nanoparticles is nab-sirolimus. In some embodiments, the multityrosine kinase inhibitor is pazopanib (e.g., pazopanib hydrochloride). In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, such as on day 1, day 8, or day 15 of a 21-day cycle. In some embodiments, the mTOR inhibitor nanoparticle composition is administered twice every three weeks, such as on day 1 and day 8 of a 21-day cycle. In some embodiments, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg / m³. 2 ~about 150mg / m 2 For example, about 1 mg / m² 2 ~about 60mg / m 2 , about 30mg / m 2 This includes. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, for example, on day 1 of a 21-day cycle, at a dose of approximately 1 mg / m². 2 ~about 60mg / m 2 (about 30mg / m 2It is administered intravenously (including). In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered daily. In some embodiments, the amount of the multityrosine kinase inhibitor (e.g., pazopanib) is about 10 mg to about 800 mg, for example, about 400 mg. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered orally. In some embodiments, the multityrosine kinase inhibitor is administered orally daily in amounts of about 10 mg to about 800 mg (including about 400 mg). In some embodiments, a method for treating spindle cell sarcoma in an individual (e.g., human) is provided, the method comprising (a) administering to the individual a composition comprising nanoparticles containing an mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and albumin, at a dose of about 10 mg / m³ every three weeks (e.g., day 1 of a 21-day cycle). 2 ~about 60mg / m 2 For example, approximately 30 mg / m² 2 (b) administering the drug intravenously in the specified amount, and (b) orally administering pazopanib to the individual in an amount of approximately 200 mg to approximately 600 mg (e.g., approximately 400 mg).

[0095] Solitary fibrous tumors are a subtype of soft tissue sarcoma found in most parts of the human body, with common presentations including intrathoracic and intraperitoneal locations. Spindle cell sarcomas are malignant mesenchymal tumors composed of cells with oval to spindle-shaped nuclei, minimal cytoplasm, and interstitial collagen bands arranged in an unpatterned distribution, with some areas being very rich in tumor cells while others are sparse in cells and have a high percentage of stromal collagen. Because the macroscopic and histological features of solitary fibrous tumors overlap with many other soft tissue tumors, they have historically been given various names, including benign mesothelioma, focal mesothelioma, solitary fibrous mesothelioma, and focal fibrous tumor. Like many other soft tissue masses, solitary fibrous tumors are often diagnosed incidentally on imaging. Plain chest radiography can show a clearly distinguishable mass of variable size originating from the pleura, with or without pedicles. Contrast-enhanced computed tomography can reveal often stenotic, often lobular, high-vascular tumors, especially when large, often with areas of necrosis. T2-weighted magnetic resonance imaging can reveal well-defined mass with broad areas of bright signaling reflecting extensive areas of necrosis. Furthermore, solitary fibrous tumors can be diagnosed by histopathology of tumor samples, such as core needle techniques or biopsies. Molecular markers can be used to diagnose solitary fibrous tumors, including the NAB2-STAT6 gene fusion product. However, the differentiation of soft tissue masses with STAT6 expression may also include dedifferentiated liposarcoma, and further analysis and confirmation of positivity of MDM2 and CKD4 may differentiate these two and confirm the diagnosis of dedifferentiated liposarcoma rather than solitary fibrous tumor. Davanzo, et al., Transl Gastroenterol Hepatol, 3, 2018.

[0096] In some embodiments, a method for treating solitary fibrous tumors in an individual (e.g., human) is provided, 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib).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 contains nab-sirolimus. In some embodiments, the composition of the mTOR inhibitor nanoparticles is nab-sirolimus. In some embodiments, the multityrosine kinase inhibitor is pazopanib (e.g., pazopanib hydrochloride). In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, such as on day 1, day 8, or day 15 of a 21-day cycle. In some embodiments, the mTOR inhibitor nanoparticle composition is administered twice every three weeks, such as on day 1 and day 8 of a 21-day cycle. In some embodiments, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg / m³. 2 ~about 150mg / m 2 For example, about 1 mg / m² 2 ~about 60mg / m 2 , about 30mg / m 2 This includes. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, for example, on day 1 of a 21-day cycle, at a dose of approximately 1 mg / m². 2 ~about 60mg / m 2 (about 30mg / m 2It is administered intravenously (including). In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered daily. In some embodiments, the amount of the multityrosine kinase inhibitor (e.g., pazopanib) is about 10 mg to about 800 mg, for example, about 400 mg. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered orally. In some embodiments, the multityrosine kinase inhibitor is administered orally daily in amounts of about 10 mg to about 800 mg (including about 400 mg). In some embodiments, a method is provided for treating solitary fibrous tumors in an individual (e.g., human), the method comprising (a) administering to the individual a composition comprising nanoparticles containing an mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and albumin, at a dose of about 10 mg / m³ every three weeks (e.g., day 1 of a 21-day cycle). 2 ~about 60mg / m 2 For example, approximately 30 mg / m² 2 (b) administering the drug intravenously in the specified amount, and (b) orally administering pazopanib to the individual in an amount of approximately 200 mg to approximately 600 mg (e.g., approximately 400 mg).

[0097] Leiomyosarcoma is a subtype of soft tissue sarcoma that can occur in most parts of the human body, as well as in common sites including the abdomen, retroperitoneum, major blood vessels, and uterus. Leiomyosarcoma is a malignant mesenchymal tumor composed of cells exhibiting distinct smooth muscle characteristics and can be classified into somatic soft tissue leiomyosarcoma, cutaneous leiomyosarcoma, or vascular leiomyosarcoma. Diagnosis can be made based on tumor samples obtained from core needle biopsy or other methods. Leiomyosarcoma exhibits densely cell-rich areas, usually arranged in bundles, and malignant cells are characterized by abundant cytoplasm that stains pink to dark red with hematoxylin and eosin (H&E) staining, and a centrally located cigar-shaped nucleus. These distinctive features are lost in dedifferentiated tumors. EL-Naggar et al., Cancer Genomics, Chapter 22, 2014. In some embodiments, leiomyosarcoma is uterine leiomyosarcoma. In some embodiments, leiomyosarcoma is non-uterine leiomyosarcoma.

[0098] In some embodiments, a method is provided for treating leiomyosarcoma (such as uterine leiomyosarcoma or non-uterine leiomyosarcoma) 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib).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) a multityrosine kinase inhibitor (e.g., pazopanib). 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 multityrosine kinase inhibitor is pazopanib (e.g., pazopanib hydrochloride). In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, such as on day 1, day 8, or day 15 of a 21-day cycle. In some embodiments, the mTOR inhibitor nanoparticle composition is administered twice every three weeks, such as on day 1 and day 8 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, about 1 mg / m² 2 ~about 60mg / m 2 , about 30mg / m 2 This includes. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, for example, on day 1 of a 21-day cycle, at a dose of approximately 1 mg / m². 2 ~about 60mg / m 2 (about 30mg / m 2It is administered intravenously (including). In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered daily. In some embodiments, the amount of the multityrosine kinase inhibitor (e.g., pazopanib) is about 10 mg to about 800 mg, for example, about 400 mg. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered orally. In some embodiments, the multityrosine kinase inhibitor is administered orally daily in amounts of about 10 mg to about 800 mg (including about 400 mg). In some embodiments, a method is provided for the treatment of leiomyosarcoma in an individual (e.g., human), the method comprising (a) administering to the individual a composition comprising nanoparticles containing an mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and albumin, at a dose of about 10 mg / m³ every three weeks (e.g., day 1 of a 21-day cycle). 2 ~about 60mg / m 2 For example, approximately 30 mg / m² 2 (b) administering the drug intravenously in the specified amount, and (b) orally administering pazopanib to the individual in an amount of approximately 200 mg to approximately 600 mg (e.g., approximately 400 mg).

[0099] Myxofibrosarcoma is a malignant soft tissue sarcoma commonly found in the extremities of elderly patients. It is classified as a type of fibroblastic / myofibroblastic tumor. Clinically, primary lesions can appear primarily as deep or subcutaneous multinodular tumors, or they can affect the stratum corneum and appear as skin lesions. Macroscopically, myxofibrosarcoma consists of nodules ranging in size from a few millimeters to 1-2 cm, usually less than 5 cm. The tumor nodules are separated by thin fibrous septa and abundant dendritic blood vessels. The tumor is soft, has a grayish-white, mucous appearance, and contains areas of necrosis and hemorrhage. (Waters et al., American Journal of Roentgenology, 188:W193-W198, 2007). Myxofibrosarcoma can be diagnosed based on the analysis of its cytomorphological features. Macroscopically, myxofibrosarcoma is characterized by numerous nodules of varying shapes, either gelatinous or firmer, located on the surface of the lesion, while deeper lesions often exhibit invasive margins. From a molecular perspective, myxofibrosarcoma exhibits a highly complex karyotype with many different genomic abnormalities. Currently, there are no specific molecular pathological markers available for standard differential diagnosis. (Vanni et al., Ther Adv Med Oncol, 14, 2002)

[0100] In some embodiments, a method for treating myxofibrosarcoma in an individual (e.g., human) is provided, the method comprising administering to the individual (a) a composition comprising nanoparticles containing an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, and (b) a multityrosine kinase inhibitor (e.g., pazopanib). In some embodiments, the method comprises administering to the individual (a) a composition comprising nanoparticles containing 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib).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 contains nab-sirolimus. In some embodiments, the composition of the mTOR inhibitor nanoparticles is nab-sirolimus. In some embodiments, the multityrosine kinase inhibitor is pazopanib (e.g., pazopanib hydrochloride). In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, such as on day 1, day 8, or day 15 of a 21-day cycle. In some embodiments, the mTOR inhibitor nanoparticle composition is administered twice every three weeks, such as on day 1 and day 8 of a 21-day cycle. In some embodiments, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg / m³. 2 ~about 150mg / m 2 For example, about 1 mg / m² 2 ~about 60mg / m 2 , about 30mg / m 2 This includes. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, for example, on day 1 of a 21-day cycle, at a dose of approximately 1 mg / m². 2 ~about 60mg / m 2 (about 30mg / m 2It is administered intravenously (including). In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered daily. In some embodiments, the amount of the multityrosine kinase inhibitor (e.g., pazopanib) is about 10 mg to about 800 mg, for example, about 400 mg. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered orally. In some embodiments, the multityrosine kinase inhibitor is administered orally daily at about 10 mg to about 800 mg (including about 400 mg). In some embodiments, a method for treating myxofibrosarcoma in an individual (e.g., human) is provided, the method comprising (a) administering to the individual a composition comprising nanoparticles containing an mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and albumin, at a dose of about 10 mg / m³ every three weeks (e.g., day 1 of a 21-day cycle). 2 ~about 60mg / m 2 For example, approximately 30 mg / m² 2 (b) administering the drug intravenously in the specified amount, and (b) orally administering pazopanib to the individual in an amount of approximately 200 mg to approximately 600 mg (e.g., approximately 400 mg).

[0101] Undifferentiated pleomorphic sarcoma (UPS) is a highly malignant, often aggressive soft tissue sarcoma. It typically presents as an asymptomatic, inconspicuous, rapidly growing cutaneous or subcutaneous nodule without any visible abnormalities on the skin surface. The origin of UPS is likely mesenchymal stem cells. It is known to affect sites such as bone, soft tissue, and retroperitoneum, and may metastasize to other organs. UPS can be diagnosed by histopathology of tumor samples, such as core needle techniques or biopsies. Markers can be used to diagnose UPS, and include keratin, S100 protein, SOX10, smooth muscle actin (SMA), and desmin. MDM2 and CDK4 may also be helpful in differentiating UPS from dedifferentiated liposarcoma. Undifferentiated pleomorphic sarcomas exhibit atypical, pleomorphic spindle cells and abundant mitotic figures, and the tumor may present with a fibrous stroma with a floral, fascicular, or sheet-like structure. Robles-Tenorio & Solis-Ledesma, StatPearls, Undifferentiated Pleomorphic Sarcoma, 2022.

[0102] In some embodiments, a method for treating undifferentiated pleomorphic sarcoma in an individual (e.g., human) is provided, 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib).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 contains nab-sirolimus. In some embodiments, the composition of the mTOR inhibitor nanoparticles is nab-sirolimus. In some embodiments, the multityrosine kinase inhibitor is pazopanib (e.g., pazopanib hydrochloride). In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, such as on day 1, day 8, or day 15 of a 21-day cycle. In some embodiments, the mTOR inhibitor nanoparticle composition is administered twice every three weeks, such as on day 1 and day 8 of a 21-day cycle. In some embodiments, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg / m³. 2 ~about 150mg / m 2 For example, about 1 mg / m² 2 ~about 60mg / m 2 , about 30mg / m 2 This includes. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, for example, on day 1 of a 21-day cycle, at a dose of approximately 1 mg / m². 2 ~about 60mg / m 2 (about 30mg / m 2It is administered intravenously (including). In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered daily. In some embodiments, the amount of the multityrosine kinase inhibitor (e.g., pazopanib) is about 10 mg to about 800 mg, for example, about 400 mg. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered orally. In some embodiments, the multityrosine kinase inhibitor is administered orally daily in amounts of about 10 mg to about 800 mg (including about 400 mg). In some embodiments, a method is provided for treating undifferentiated pleomorphic sarcoma in an individual (e.g., human), the method comprising (a) administering to the individual a composition comprising nanoparticles containing an mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and albumin, at a dose of about 10 mg / m³ every three weeks (e.g., day 1 of a 21-day cycle). 2 ~about 60mg / m 2 For example, approximately 30 mg / m² 2 (b) administering the drug intravenously in the specified amount, and (b) orally administering pazopanib to the individual in an amount of approximately 200 mg to approximately 600 mg (e.g., approximately 400 mg).

[0103] Melanin schwannomas are rare soft tissue sarcomas that most commonly occur in the paravertebral sympathetic nerve chain. Histologically, melanin schwannomas are characterized by typical spindle-shaped neoplastic Schwann cells and melanosomes at various stages of maturation. These tumors are macroscopically pigmented, and immunophenotypically, both Schwann cell markers and melanocyte differentiation markers are present. (Scheithauer, et al., WHO Classification of Tumors of the Central Nervous System, pp. 152-5, 2007). Melanin schwannomas can be diagnosed based on imaging techniques. When originating from spinal nerves, melanin schwannomas can be diagnosed by radiographs and computed tomography scans, revealing foramen enlargement, bone erosion, sclerosis, and a "dumbbell" morphology. Furthermore, bone marrow images can depict obstruction of contrast agent flow without spinal cord displacement, and tumors in contact with bone may show cortical erosion, sclerosis, and localized destruction. Microscopically, melanin schwannomas are well-defined but unencapsulated, containing tangled bundles or foci of plump spindle cells and epithelioid cells. Melanin schwannomas are characterized by the accumulation of melanin in tumor cells and associated melanophages. Alexiev, et al., Arch Pathol Lab Med (2018) 142 (12):1517-1523.

[0104] In some embodiments, a method for treating melanin schwannomas in an individual (e.g., human) is provided, 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib).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 contains nab-sirolimus. In some embodiments, the composition of the mTOR inhibitor nanoparticles is nab-sirolimus. In some embodiments, the multityrosine kinase inhibitor is pazopanib (e.g., pazopanib hydrochloride). In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, such as on day 1, day 8, or day 15 of a 21-day cycle. In some embodiments, the mTOR inhibitor nanoparticle composition is administered twice every three weeks, such as on day 1 and day 8 of a 21-day cycle. In some embodiments, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg / m³. 2 ~about 150mg / m 2 For example, about 1 mg / m² 2 ~about 60mg / m 2 , about 30mg / m 2 This includes. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, for example, on day 1 of a 21-day cycle, at a dose of approximately 1 mg / m². 2 ~about 60mg / m 2 (about 30mg / m 2It is administered intravenously (including). In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered daily. In some embodiments, the amount of the multityrosine kinase inhibitor (e.g., pazopanib) is about 10 mg to about 800 mg, for example, about 400 mg. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered orally. In some embodiments, the multityrosine kinase inhibitor is administered orally daily in amounts of about 10 mg to about 800 mg (including about 400 mg). In some embodiments, a method is provided for treating melanin schwannoma in an individual (e.g., human), the method comprising (a) administering to the individual a composition comprising nanoparticles containing an mTOR inhibitor (e.g., limus drugs, e.g., sirolimus or its derivatives) and albumin, at a dose of about 10 mg / m³ every three weeks (e.g., day 1 of a 21-day cycle). 2 ~about 60mg / m 2 For example, approximately 30 mg / m² 2 (b) administering the drug intravenously in the specified amount, and (b) orally administering pazopanib to the individual in an amount of approximately 200 mg to approximately 600 mg (e.g., approximately 400 mg).

[0105] Rhabdomyosarcoma pleomorphis is a rare, high-grade soft tissue sarcoma composed of undifferentiated round and spindle-shaped cells that differentiate into skeletal muscle without fetal or alveolar components. Typically, it is an aggressive, metastatic lesion that occurs in the deep soft tissues of the extremities. Rhabdomyosarcoma pleomorphis is most commonly found in the deep soft tissues of the extremities, as well as in less common locations including the pelvis, abdomen, chest, and head and neck. Diagnosis of rhabdomyosarcoma pleomorphis may be by exclusion, combining morphological features, immunoprofiling, and molecular profiling to rule out alternative diagnoses. Noujaim et al., Anticancer Research, 2015;35(11) 6213-6217. Diagnostic criteria for rhabdomyosarcoma pleomorphis remain a subject of debate. Thorough histopathological and immunohistochemical analysis reveals a skeletal muscle phenotype, and immunohistochemical analysis shows expression of vimentin, desmin, SMA, myogenin, and MyoD1, while S100 and CD117 are not expressed. This may be used to confirm the diagnosis of rhabdomyosarcoma pleomorphism. Xi et al., Medicine, 97(51):p e13648, 2018.

[0106] In some embodiments, a method for treating rhabdomyosarcoma pleomorphis in an individual (e.g., human) is provided, the method comprising administering to the individual (a) a composition comprising nanoparticles containing an mTOR inhibitor (e.g., a limus drug, e.g., sirolimus or a derivative thereof) and albumin, and (b) a multityrosine kinase inhibitor (e.g., pazopanib). In some embodiments, the method comprises administering to the individual (a) a composition comprising nanoparticles containing 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib). 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) a multityrosine kinase inhibitor (e.g., pazopanib).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 contains nab-sirolimus. In some embodiments, the composition of the mTOR inhibitor nanoparticles is nab-sirolimus. In some embodiments, the multityrosine kinase inhibitor is pazopanib (e.g., pazopanib hydrochloride). In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, such as on day 1, day 8, or day 15 of a 21-day cycle. In some embodiments, the mTOR inhibitor nanoparticle composition is administered twice every three weeks, such as on day 1 and day 8 of a 21-day cycle. In some embodiments, the amount of mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg / m³. 2 ~about 150mg / m 2 For example, about 1 mg / m² 2 ~about 60mg / m 2 , about 30mg / m 2 This includes. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition is administered once every three weeks, for example, on day 1 of a 21-day cycle, at a dose of approximately 1 mg / m². 2 ~about 60mg / m 2 (about 30mg / m 2It is administered intravenously (including). In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered daily. In some embodiments, the amount of the multityrosine kinase inhibitor (e.g., pazopanib) is about 10 mg to about 800 mg, for example, about 400 mg. In some embodiments, the multityrosine kinase inhibitor (e.g., pazopanib) is administered orally. In some embodiments, the multityrosine kinase inhibitor is administered orally daily in amounts of about 10 mg to about 800 mg (including about 400 mg). In some embodiments, a method is provided for the treatment of rhabdomyosarcoma pleomorphis in an individual (e.g., human), the method comprising (a) administering to the individual a composition comprising an mTOR inhibitor (e.g., limus drug, e.g., sirolimus or its derivatives) and albumin nanoparticles, at a dose of about 10 mg / m³ every three weeks (e.g., day 1 of a 21-day cycle). 2 ~about 60mg / m 2 For example, approximately 30 mg / m² 2 (b) administering the drug intravenously in the specified amount, and (b) orally administering pazopanib to the individual in an amount of approximately 200 mg to approximately 600 mg (e.g., approximately 400 mg).

[0107] III. Composition containing nanoparticles containing an mTOR inhibitor The mTOR inhibitor nanoparticle compositions described herein include nanoparticles comprising (in various embodiments substantially comprising, or comprising) an mTOR inhibitor (e.g., a limus drug, e.g., rapamycin or its derivatives) and albumin (e.g., human serum albumin). Nanoparticles of poorly water-soluble drugs (e.g., macrolides) are disclosed, for example, in U.S. Patents 5,916,596, 6,506,405, 6,749,868, 6,537,579, 7,820,788, and 8,911,786, 11,497,737, as well as U.S. Patent Publications 2006 / 0263434 and 2007 / 0082838, PCT Patent Application W008 / 137148, and U.S. Patent Application 62 / 927,047, each of these documents in their entirety incorporated herein by reference.

[0108] 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.

[0109] 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.

[0110] In some embodiments, the nanoparticles contain an mTOR inhibitor associated with albumin. In some embodiments, the nanoparticles contain an mTOR inhibitor coated with albumin.

[0111] 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).

[0112] In some embodiments, nanoparticles containing an mTOR inhibitor (e.g., a limus drug, e.g., rapamycin or its derivatives) are associated with (e.g., coated with) albumin (e.g., human albumin or human serum albumin). In some embodiments, the composition comprises an mTOR inhibitor (e.g., a limus drug, e.g., rapamycin or its derivatives) 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 its derivatives) 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).

[0113] 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.

[0114] 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.

[0115] 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.

[0116] In some embodiments, the mTOR inhibitor nanoparticle composition (such as a rapamycin / albumin nanoparticle composition) includes one or more of the above-described properties.

[0117] 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.

[0118] 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.

[0119] 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 (Cys34), and one tryptophan (Trp214). 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)).

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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)).

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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, INK The group is selected from 128, AZD2014, NVP-BGT226, PF-04691502, CH5132799, GDC-0980 (RG7422), Trin 1, WAY-600, WYE-125132, WYE-687, GSK2126458, PF-05212384 (PKI-587), PP-121, OSI-027, Palomid 529, PP242, XL765, GSK1059615, WYE-354, and ridafololimus (also known as defololimus).

[0134] 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 IPI3 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-competitive inhibitor of mTOR. Defololimus (ridafololimus, AP23573, MK-8669) is a selective mTOR inhibitor.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] C. rapamycin albumin-based nanoparticle composition 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.

[0140] 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.

[0141] 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.

[0142] Albumin (e.g., recombinant albumin, e.g., NOVOZYME® 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 a MICROFLUIDIZER® Processor M-110EH from Avestin, APV Gaulin, MICROFLUIDIZER®, e.g., Microfluidics, Stansted, or 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.

[0143] 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.

[0144] 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. ,

[0145] 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).

[0146] 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).

[0147] 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).

[0148] 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).

[0149] 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).

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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).

[0165] 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).

[0166] 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).

[0167] 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).

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[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 containing rapamycin and albumin (such as human albumin), and (b) a non-nanoparticle portion containing 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 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, 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 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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. 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.

[0185] 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.

[0186] 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.

[0187] 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).

[0188] 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).

[0189] 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.

[0190] 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%).

[0191] 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.

[0192] 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.

[0193] IV. Multityrosine kinase inhibitors In some embodiments, the multi-tyrosine kinase inhibitor inhibits two or more of the following (including any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12): vascular endothelial growth factor receptor (VEGFR)-1, -2, or -3; platelet-derived growth factor receptor (PDGFR)-α or -β; interleukin-2 receptor-induced T cell kinase (ITK); leukocyte-specific protein tyrosine kinase (LCK); colony-stimulating factor-1 receptor (c-fms); fibroblast growth factor receptor (FGFR)-1, -3, or -4; or stem cell factor receptor c-Kit. In some embodiments, multi-tyrosine kinase inhibitors inhibit vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3, platelet-derived growth factor receptor (PDGFR)-α and -β, interleukin-2 receptor-induced T cell kinase (ITK), leukocyte-specific protein tyrosine kinase (LCK), colony-stimulating factor-1 receptor (c-fms), fibroblast growth factor receptor (FGFR)-1, -3, and -4, and stem cell factor receptor c-Kit. Methods for determining inhibition, including inhibition of the above features, are understood in the art, and therefore the scope of multi-tyrosine kinase inhibitors described herein is also understood. For example, as described in Hamberg et al., Oncologist, 15, 2010 and Melichar et al., J Buon, 16, 2011, the contents of these documents are incorporated herein by reference in their entirety for all purposes.

[0194] In some embodiments, the multi-tyrosine kinase inhibitor competes with adenosine triphosphate for binding to the intracellular side of the tyrosine kinase receptor, thereby preventing ATP-induced activation of the receptor. In some embodiments, the multi-tyrosine kinase inhibitor is indazolylpyrimidine.

[0195] In some embodiments, the multityrosine kinase inhibitor is pazopanib or a pharmaceutical salt thereof. In some embodiments, the multityrosine kinase inhibitor is pazopanib hydrochloride (e.g., VOTRIENT®).

[0196] V. Manufactured Articles and Kits In some embodiments, there are provided manufactured articles containing materials useful in the treatment of soft tissue sarcomas (including spindle cell sarcomas, solitary fibrous tumors, or leiomyosarcomas), the manufactured articles, such as drugs or combinations of drugs, comprising an mTOR inhibitor nanoparticle composition (e.g., a sirolimus / albumin nanoparticle composition, e.g., nab-sirolimus) and a multi-tyrosine kinase inhibitor (e.g., pazopanib). The manufactured article can include a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, etc. The container can be formed from various materials such as glass or plastic. Generally, the container holds a composition effective to treat the diseases or disorders described herein and can have a sterile access port (e.g., the container can be an intravenous solution bag or a vial with a stopper pierceable by a subcutaneous injection needle). At least one active agent in the composition is (a) a nanoparticle formulation of an mTOR inhibitor (e.g., nab-sirolimus), or (b) a multi-tyrosine kinase inhibitor (e.g., pazopanib). The label or package insert indicates that the composition is to be used to treat a particular condition of an individual as described herein. The label or package insert further includes instructions for administering the composition to an individual according to the methods described herein. Manufactured articles and kits comprising the combination therapies described herein are also contemplated.

[0197] A package insert is the instructions customarily included in the commercial package of a therapeutic agent and contains information about the indications, usage, dosage, administration, contraindications, and / or warnings regarding the use of that therapeutic agent. In some embodiments, the package insert describes that this composition is used in the treatment of soft tissue sarcomas (e.g., spindle cell sarcomas, solitary fibrous tumors, or leiomyosarcomas).

[0198] 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.

[0199] Kits useful for a variety of purposes are also provided, such as the treatment of soft tissue sarcomas (e.g., spindle cell sarcomas, solitary fibrous tumors, or leiomyosarcomas). The kits of the present invention comprise one or more containers containing an mTOR inhibitor nanoparticle composition (such as a sirolimus / albumin nanoparticle composition) (or a unit dosage form and / or manufactured article), and in some embodiments further include instructions for use according to a multityrosine kinase inhibitor (e.g., pazopanib) and / or any of the methods described herein. The kits may further include 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.

[0200] 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.

[0201] Instructions for use of mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and multityrosine kinase inhibitors (e.g., pazopanib) 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 containing sufficient doses of mTOR inhibitor nanoparticle compositions (such as sirolimus / albumin nanoparticle compositions) and multityrosine kinase inhibitors (e.g., pazopanib), 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 multi-tyrosine kinase inhibitors (e.g., pazopanib), along with instructions for use, and is packaged in quantities sufficient for storage and use in pharmacies such as hospital pharmacies and dispensing pharmacies.

[0202] 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]

[0203] Example 1 This example demonstrates a Phase I trial of administering nabsilolimus and pazopanib to patients with soft tissue sarcoma (STS).

[0204] Patients and Methods research design This was a Phase I trial designed to confirm the safety and feasibility of the combination of oral pazopanib hydrochloride and intravenous nabsirolimus. To obtain preliminary efficacy information, this study limited enrollment to patients with advanced or unresectable STS who were candidates for pazopanib monotherapy.

[0205] The primary endpoint of this study was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose of nabsirolimus in combination with pazopanib. Secondary endpoints included characterization of adverse events of nabsirolimus / pazopanib combination therapy and descriptive characterization of the clinical benefit of nabsirolimus / pazopanib combination therapy (objective response rate, progression-free survival, and clinical benefit rates at 3 and 6 months). Correlated endpoints were included to assess the correlation between baseline mTOR pathway activation status, assessed by immunohistochemistry of phosphorylated S6 ribosomal protein, and clinical benefit; the correlation between baseline tumor expression of serum protein acidity and cysteine-rich (SPARC) / osteonectin, assessed by immunohistochemistry, and clinical benefit; and to evaluate the pharmacokinetics of nab-sirolimus in combination with pazopanib.

[0206] This study employed a standard "3-patient cohort" design (commonly known as 3+3), treating three patients at each dose level. If a dose-limiting toxicity (DLT) was observed in one of the three patients initially enrolled at each dose level, the cohort was expanded to six patients. If no DLT occurred after two doses, an increase to the next dose level was permitted. The MTD was defined as the highest dose that could be safely tolerated, where one or fewer patients experienced a DLT, and at least two patients experienced a DLT at the next higher dose level. Patients participating in the dose escalation trial were allowed to continue treatment at the designated dose level until significant disease progression or unacceptable toxicity occurred. Intra-patient dose escalation was not performed. Dose-limiting toxicity was defined as a grade 3–5 adverse event occurring during treatment cycle 1, according to the Common Terminology Criteria for Adverse Events version 5.0.

[0207] Pazopanib was administered orally, and nabsirolimus was administered intravenously. In the initial cohort, on days 1 and 8 of the 21-day cycle, patients received 800 mg or 400 mg of pazopanib daily, and 60, 45, or 30 mg / m² of nabsirolimus. 2 The drug was administered. Subsequently, based on a preliminary analysis of adverse events (AEs) and pharmacokinetics (PKs), nabsirolimus was administered only on day 1 of the 21-day cycle.

[0208] For evaluations completed during the study, cross-sectional imaging was performed every two cycles of treatment. For patients who completed the study treatment but did not start new treatment, disease evaluation was performed according to standard treatment practices.

[0209] The criteria for discontinuing treatment include any of the following: 1) Progressive disease according to RECIST version 1.1 criteria. 2) Unacceptable toxicity 3) The patient chooses to discontinue the treatment. 4) The doctor in charge recommends discontinuing the treatment.

[0210] Study group Eligible patients (18 years or older) had unresectable non-adipocyte STS that had progressed after 1–5 treatments, had adequate peripheral organ function, an ECOG performance status of 0–1, a measurable target lesion (RECIST v1.1), and had not received treatment with mTOR or angiogenesis inhibitors. Nineteen patients received treatment. The mean age of the patients was 59 years, they were predominantly Caucasian, and they were diagnosed with soft tissue sarcomas selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melanin schwannoma, and pleomorphic rhabdomyosarcoma (Table 1). [Table 1-1] [Table 1-2]

[0211] Main inclusion / exclusion criteria The main inclusion criteria include, but are not limited to, the following. 18 years of age or older Non-lipomatous soft tissue sarcoma If it is metastatic or locally advanced and curative therapy is not possible, surgery is not recommended and pazopanib is applicable. One or more measurable target lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Clinical / radiological progression or failure is recognized due to toxicity with at least one systemic therapy for progressive disease. Received up to 4 types of systemic therapy (received up to 2 types in combination with cytotoxic therapy). Neoadjuvant / adjuvant / maintenance therapy is not included. Appropriate end-organ function including normal left ventricular ejection fraction and QTc < 480 milliseconds Performance status 0 / 1.

[0212] The main exclusion criteria include, but are not limited to, the following. Histological findings for which pazopanib is not applicable (e.g., lipomatous STS, gastrointestinal stromal tumor, Kaposi sarcoma). Previous mTOR or angiogenesis inhibitor. Uncontrolled / symptomatic central nervous system metastasis. Clinically significant bleeding occurred within 6 months. Although there are exceptions, active secondary malignancies. Uncontrolled diabetes. Unstable coronary artery disease, myocardial infarction, or arterial thromboembolism occurred within 6 months. Interstitial lung disease, pneumonia, or pulmonary hypertension. Uncontrolled hypertension.

[0213] Results Nineteen patients received treatment. Initially, 13 patients were administered nabsirolimus on days 1 and 8. Table 2 shows treatment-related adverse events of any grade, and all grade 3–4 adverse events, experienced by ≥10% of the study population. DLTs included thrombocytopenia (TCP, n=7), decreased white blood cell / neutrophil count (n=2), increased lipase (n=1), and proteinuria (n=1). Due to the possibility of overlapping AEs or nabsirolimus / pazopanib interactions, an additional cohort received pazopanib 400 mg daily and nabsirolimus 30 or 45 mg / m². 2 The drug was administered (n=6). 30 mg / m² 2 No DLTs were observed in the cohort (n=3). 45 mg / m² 2 In the cohort, two out of three patients experienced TCP that met the DLT definition.

[0214] Grade 3-4 adverse events (AEs) occurring in more than 10% of patients included TCP (58%), neutropenia (11%), leukopenia (11%), lymphopenia (11%), and diarrhea (11%). Grade AEs occurring in more than 50% of patients included TCP (74%), mucositis (63%), fatigue (58%), and acneiform rash (53%). There were no grade 5 AEs. [Table 2-1] [Table 2-2]

[0215] Figure 1 shows swimmer plots of the total treatment duration for all patients participating in the study. Unless otherwise indicated (e.g., time of disease progression is marked with a circle), disease progression was observed at the end of treatment. Of the 19 patients who received treatment, 14 (74%) discontinued treatment due to disease progression, 2 (11%) due to adverse events (TCP-2, transaminase-1), and 1 (5%) due to disease-related death. As of May 10, 2023, 2 (11%) are still in the study.

[0216] Table 3 shows the treatment outcomes by dosing cohort, including the best objective response rate according to RECIST and progression-free survival. Although the evaluation of activity was not the primary objective of this Phase I study, the progression-free survival rates at 3 and 6 months in 18 evaluable patients were favorable, with 13 and 11 patients, respectively, having no disease progression at these two time points. For the leiomyosarcoma subset, 9 and 8 evaluable patients, respectively, had no disease progression at these time points.

[0217] As shown in the waterfall plot in Figure 2, among 18 evaluable patients with the best response rate, there were 3 partial response rates (leiomyosarcoma, solitary fibrous tumor, spindle cell sarcoma), 13 stable diseases, and 2 progressive diseases. These response rates indicate a significant improvement compared to the response rate of pazopanib monotherapy. Surprisingly, 2 of these 18 patients (11%) maintained stable disease for over 1 year.

[0218] The clinical benefit rates (CBR) at 3 and 6 months were 72% (13 / 18) and 59% (10 / 17), respectively. In the leiomyosarcoma subset, the CBR at 3 and 6 months was 90% (9 / 10) and 80% (8 / 10), respectively.

Table 3-1

Table 3-2

[0219] Conclusion Parallel administration of pazopanib and nabsirolimus is feasible and tolerable. Preliminary evidence of the combination's activity was observed. Of the 18 patients for whom the best response could be evaluated, 3 achieved a partial response (leiomyosarcoma, solitary fibrous tumor, spindle cell sarcoma), 13 had stable disease, and 2 experienced disease progression. These results, including patients with stable disease, represent a significant improvement over existing therapies, where the response rate with pazopanib monotherapy is low at approximately 6%. Furthermore, patients who received the nabsirolimus and pazopanib combination therapy were confirmed to have maintained disease stability or partial response over a long period (Table 3).

[0220] As a result of dose adjustments, only two patients discontinued treatment due to adverse events. The main reason for discontinuation was disease progression. The recommended Phase 2 dose is 400 mg of pazopanib orally daily, accompanied by 30 mg / m² of nabsirolimus. 2 The drug is to be administered intravenously every 21 days. These doses are 800 mg per day, and 100 mg / m² on the 1st and 8th days every 21 days. 2 These drugs are less than [number missing] and are approved for the treatment of soft tissue sarcoma (pazopanib) and PEComa (nabsirolimus). Dose-limiting toxicities include thrombocytopenia, neutropenia, elevated lipase, and proteinuria. The most common DLT was thrombocytopenia.

Claims

1. A method for treating soft tissue sarcoma in an individual requiring treatment, wherein the method involves the individual, (a) A composition comprising nanoparticles containing an mTOR inhibitor and albumin, and (b) comprising administering a multityrosine kinase inhibitor, The method wherein the multi-tyrosine kinase inhibitor is administered in an amount of approximately 1 mg to approximately 2500 mg.

2. The method according to claim 1, wherein the soft tissue sarcoma is selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melanin schwannoma, and pleomorphic rhabdomyosarcoma.

3. A method for treating soft tissue sarcoma in individuals requiring treatment for soft tissue sarcoma, The aforementioned soft tissue sarcomas are selected from the group consisting of spindle cell sarcoma, solitary fibrous tumor, leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, melanin schwannoma, and pleomorphic rhabdomyosarcoma. The above method applies to the individual, (a) A composition comprising nanoparticles containing an mTOR inhibitor and albumin, and (b) The method comprising administering a multityrosine kinase inhibitor.

4. The method according to claim 2 or 3, wherein the leiomyosarcoma is a uterine leiomyosarcoma.

5. The method according to claim 2 or 3, wherein the leiomyosarcoma is a non-uterine leiomyosarcoma.

6. The method according to any one of claims 1 to 5, wherein the soft tissue sarcoma is locally progressive, progressive, malignant, progressive malignant, or metastatic.

7. The method according to any one of claims 1 to 6, wherein the soft tissue sarcoma is recurrent, refractory, or resistant to previous treatment.

8. The method according to claim 7, wherein the aforementioned prior treatment comprises a composition comprising an mTOR inhibitor and nanoparticles containing albumin.

9. The mTOR inhibitor in the mTOR inhibitor nanoparticle composition is approximately 10 mg / m ２ ~Approx. 150mg / m ２ The method according to any one of claims 1 to 8, administered in an amount.

10. The mTOR inhibitor in the mTOR inhibitor nanoparticle composition is approximately 10 mg / m ２ ~about 60mg / m ２ The method according to claim 9, administered in an amount.

11. The mTOR inhibitor in the aforementioned mTOR inhibitor nanoparticle composition is approximately 30 mg / m ２ , about 45mg / m ２ , or approximately 60 mg / m² ２ The method according to claim 9 or 10, administered in an amount.

12. The mTOR inhibitor in the aforementioned mTOR inhibitor nanoparticle composition is approximately 30 mg / m ２ The method according to any one of claims 1 to 11, administered in an amount.

13. The method according to any one of claims 1 to 12, wherein the mTOR inhibitor nanoparticle composition is administered once or twice every three weeks.

14. The method according to any one of claims 1 to 13, wherein the mTOR inhibitor nanoparticle composition is administered on day 1 of a 21-day cycle, or the mTOR inhibitor nanoparticle composition is administered on day 1 and day 8 of a 21-day cycle.

15. The method according to any one of claims 1 to 14, wherein the mTOR inhibitor is a limus drug.

16. The method according to claim 15, wherein the limus drug is sirolimus.

17. The method according to any one of claims 1 to 16, wherein the average diameter of the nanoparticles in the composition is about 150 nm or less.

18. The method according to claim 17, wherein the average diameter of the nanoparticles in the composition is about 120 nm or less.

19. The method according to any one of claims 1 to 18, wherein the weight ratio of albumin to the mTOR inhibitor in the nanoparticle composition is about 9:1 or less.

20. The method according to any one of claims 1 to 19, wherein the nanoparticles include the mTOR inhibitor associated with the albumin.

21. The method according to claim 20, wherein the nanoparticles include the mTOR inhibitor coated with the albumin.

22. The method according to any one of claims 1 to 21, wherein the mTOR inhibitor nanoparticle composition is administered intravenously.

23. The method according to any one of claims 1 to 22, wherein the multi-tyrosine kinase inhibitor inhibits two or more of the following: vascular endothelial growth factor receptor (VEGFR)-1, -2, or -3, platelet-derived growth factor receptor (PDGFR)-α or -β, interleukin-2 receptor-induced T cell kinase (ITK), leukocyte-specific protein tyrosine kinase (LCK), colony-stimulating factor-1 receptor (c-fms), fibroblast growth factor receptor (FGFR)-1, -3, or -4, or stem cell factor receptor c-Kit.

24. The method according to any one of claims 1 to 23, wherein the multityrosine kinase inhibitor is pazopanib or a pharmaceutically acceptable salt thereof.

25. The method according to any one of claims 1 to 24, wherein the multityrosine kinase inhibitor is pazopanib hydrochloride.

26. The method according to any one of claims 1 to 25, wherein the amount of the multityrosine kinase inhibitor administered to the individual is about 400 mg.

27. The method according to any one of claims 1 to 26, wherein the multityrosine kinase inhibitor is administered daily or every other day.

28. The method according to any one of claims 1 to 27, wherein the multityrosine kinase inhibitor is administered orally.

29. The method according to claim 28, wherein the multityrosine kinase inhibitor is administered without food.

30. The method according to any one of claims 1 to 29, wherein when the mTOR inhibitor nanoparticle composition is administered, the multityrosine kinase inhibitor is administered in parallel.

31. The method according to any one of claims 1 to 29, wherein when the mTOR inhibitor nanoparticle composition is administered, the multityrosine kinase inhibitor is administered consecutively.

32. The method according to any one of claims 1 to 29, wherein when the mTOR inhibitor nanoparticle composition is administered, the multityrosine kinase inhibitor is administered simultaneously.

33. The mTOR inhibitor in the mTOR inhibitor nanoparticle composition is intravenously administered at a dose of about 30 mg / m ２ on the first day of a 21-day cycle, and the multi-tyrosine kinase inhibitor is orally administered at a dose of about 400 mg per day. The method according to any one of claims 1 to 32.

34. The method according to any one of claims 1 to 33, wherein the individual is a human.

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