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WO2024228964A1 - Traitements comprenant une composition de nanoparticules d'inhibiteur de mtor - Google Patents

Traitements comprenant une composition de nanoparticules d'inhibiteur de mtor Download PDF

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Publication number
WO2024228964A1
WO2024228964A1 PCT/US2024/026882 US2024026882W WO2024228964A1 WO 2024228964 A1 WO2024228964 A1 WO 2024228964A1 US 2024026882 W US2024026882 W US 2024026882W WO 2024228964 A1 WO2024228964 A1 WO 2024228964A1
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Prior art keywords
albumin
mtor inhibitor
nanoparticles
composition
nanoparticle composition
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PCT/US2024/026882
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English (en)
Inventor
Erlinda M. Gordon
Neil P. Desai
Anita N. SCHMID
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Aadi Bioscience, Inc.
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Application filed by Aadi Bioscience, Inc. filed Critical Aadi Bioscience, Inc.
Publication of WO2024228964A1 publication Critical patent/WO2024228964A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5169—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present application in certain aspects, pertains to methods and compositions for the treatment of undifferentiated pleomorphic sarcoma or leiomyosarcoma, using a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • rapamycin is a conserved serine/threonine kinase that serves as a central hub of signaling in the cell to integrate intracellular and extracellular signals and to regulate cellular growth and homeostasis.
  • Activation of the mTOR pathway is associated with cell proliferation and survival, while inhibition of mTOR signaling leads to inflammation and cell death.
  • Dysregulation of the mTOR signaling pathway has been implicated in an increasing number of human diseases, including cancer such as advanced solid malignancies and autoimmune disorders. Consequently, mTOR inhibitors have found wide applications in treating diverse pathological conditions such as solid tumors, hematological malignancies, organ transplantation, restenosis, and rheumatoid arthritis.
  • Sirolimus also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants.
  • Sirolimus-eluting stents were approved in the United States to treat coronary restenosis. Additionally, sirolimus has been demonstrated as an effective inhibitor of tumor growth in various cell lines and animal models.
  • Other limus drugs, such as analogs of sirolimus have been designed to improve the pharmacokinetic and pharmacodynamic properties of sirolimus. For example, Temsirolimus was approved in the United States and Europe for the treatment of renal cell carcinoma. Everolimus was approved in the U. S.
  • sirolimus for treatment of advanced breast cancer, pancreatic neuroendocrine tumors, advanced renal cell carcinoma, and subependymal giant cell astrocytoma (SEGA) associated with Tuberous Sclerosis.
  • the mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12), and the sirolimus-FKBP12 complex in turn inhibits the mTOR pathway by directly binding to the mTOR Complex 1 (mTORCl).
  • FKBP12 cytosolic protein FK-binding protein 12
  • mTORCl mTOR Complex 1
  • Albumin-based nanoparticle compositions have been developed as a drug delivery system for delivering substantially water insoluble drugs. See, for example, U. S. Pat.
  • Abraxane® an albumin stabilized nanoparticle formulation of paclitaxel
  • Abraxane® an albumin stabilized nanoparticle formulation of paclitaxel
  • Albumin derived from human blood has been used for the manufacture of Abraxane® as well as various other albumin-based nanoparticle compositions.
  • Albumin-based nanoparticle composition comprising sirolimus, e.g, «a6-sirolimus or Fyarrao®, are known, e.g, US. Pat. No. 8,911,786 and US Pat. No. 11,497,737.
  • the present application provides a method of treating undifferentiated pleomorphic sarcoma in an individual in need thereof, the method comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin; and optionally (b) an effective amount of a second therapeutic agent (such as an anti-PD-1 antibody).
  • a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin
  • a second therapeutic agent such as an anti-PD-1 antibody
  • the undifferentiated pleomorphic sarcoma has phosphatase and tensin homolog (PTEN) loss.
  • PTEN loss is a loss-of-function mutation or epigenetic silencing.
  • the individual is selected for the treatment on the basis of having the PTEN loss.
  • the method further comprises selecting the individual on the basis of having the PTEN loss.
  • the undifferentiated pleomorphic sarcoma has a tuberous sclerosis complex 2 (TSC2) mutation.
  • TSC2 tuberous sclerosis complex 2
  • the TSC2 mutation is a missense mutation, nonsense mutation, deletion, splicing site mutation, insertion, substation, rearrangement, or frameshift, or a combination thereof.
  • the individual is selected for the treatment on the basis of the TSC2 mutation.
  • the method further comprises selecting the individual on the basis of having the TSC2 mutation.
  • the present application provides a method of treating leiomyosarcoma in an individual in need thereof, the method comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin; and optionally (b) an effective amount of a second therapeutic agent (e.g., an anti-PD-1 antibody).
  • a second therapeutic agent e.g., an anti-PD-1 antibody
  • the leiomyosarcoma is estrogen receptor-positive leiomyosarcoma.
  • the individual is selected for the treatment on the basis of having the estrogen receptor-positive leiomyosarcoma.
  • the method further comprises selecting the individual on the basis of having the estrogen receptor-positive leiomyosarcoma.
  • the undifferentiated pleomorphic sarcoma or the leiomyosarcoma is locally advanced, advanced, malignant, advanced malignant, or metastatic.
  • the undifferentiated pleomorphic sarcoma or the leiomyosarcoma is relapsed or refractory to a prior treatment.
  • the prior treatment comprises a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin.
  • the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is from about 10 mg/m 2 to about 150 mg/m 2 In some embodiments, the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 100 mg/m 2 . In some embodiments, the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 75 mg/m 2 . In some embodiments, the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 56 mg/m 2 . In some embodiments, the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 45 mg/m 2 .
  • the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 30 mg/m 2 .
  • the mTOR inhibitor nanoparticle composition is administered weekly. In some embodiments, the mTOR inhibitor nanoparticle composition is administered 2 out of every 3 weeks. In some embodiments, the mTOR inhibitor nanoparticle composition is administered on days 8 and 15 of a 21 -day cycle.
  • the mTOR inhibitor nanoparticle composition and the anti- PD-1 antibody are administered concurrently to the individual. In some embodiments, the mTOR inhibitor nanoparticle composition and the anti-PD-1 antibody are administered sequentially to the individual. In some embodiments, the mTOR inhibitor nanoparticle composition and the anti-PD-1 antibody are administered simultaneously to the individual.
  • the second therapeutic agent e.g., anti-PD-1 antibody
  • the second therapeutic agent is administered at an amount of about 1 mg/kg to about 10 mg/kg.
  • the second therapeutic agent e.g., anti-PD-1 antibody
  • the second therapeutic agent e.g., anti-PD-1 antibody
  • the second therapeutic agent e.g., anti-PD-1 antibody
  • the second therapeutic agent e.g., anti-PD-1 antibody
  • the second therapeutic agent is administered for at least one cycle prior to administration of the mTOR inhibitor nanoparticle composition.
  • the mTOR inhibitor is a limus drug.
  • the limus drug is sirolimus.
  • the average diameter of the nanoparticles in the composition is no greater than about 150 nm. In some embodiments, the average diameter of the nanoparticles in the composition is no greater than about 120 nm.
  • the weight ratio of the albumin to the mTOR inhibitor in the nanoparticle composition is no greater than about 9:1.
  • the nanoparticles comprise the mTOR inhibitor associated with the albumin. In some embodiments, the nanoparticles comprise the mTOR inhibitor coated with the albumin.
  • the mTOR inhibitor nanoparticle composition is administered intravenously, intraarterially, intraperitoneally, intravesicularly, subcutaneously, intrathecally, intrapulmonarily, intramuscularly, intratracheally, intraocularly, transdermally, orally, or by inhalation. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously.
  • the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, atezolizumab, dostarlimab, durvalumab, and avelumab. In some embodiments, the anti-PD-1 antibody is nivolumab.
  • the individual is human.
  • the present application provides, in certain aspects, treatments for cancer, such as undifferentiated pleomorphic sarcoma (including undifferentiated pleomorphic sarcoma having a PTEN loss and/or a TSC2 mutation) or leiomyosarcoma (including estrogen receptor-positive leiomyosarcoma), comprising (a) a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin (e.g, nab- sirolimus); and optionally (b) a second therapeutic agent (e.g., an anti-PD-1 antibody (e.g, nivolumab)).
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • albumin e.g, nab- sirolimus
  • a second therapeutic agent e.g., an anti-PD-1 antibody
  • the method is for the treatment of undifferentiated pleomorphic sarcoma having a PTEN loss and a TSC2 mutation in an individual in need thereof. In some embodiments, the method is for the treatment of estrogen receptor-positive leiomyosarcoma in an individual in need thereof.
  • the present application is based, at least in part, on the finding that individuals with undifferentiated pleomorphic sarcoma (including undifferentiated pleomorphic sarcoma having a PTEN loss and/or a TSC2 mutation) or leiomyosarcoma (including estrogen receptor-positive leiomyosarcoma) unexpectedly showed improved response to treatment with «a/>-sirolimus and an anti-PD-1 antibody, nivolumab, as compared to individuals receiving the combination treatment and having other cancer subtypes.
  • a method of treating undifferentiated pleomorphic sarcoma having a PTEN loss and/ or a TSC2 mutation comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin, e.g, /706-sirolimus: and optionally (b) a second therapeutic agent (e.g., an effective amount of an anti-PD-1 antibody, e.g, nivolumab).
  • a method of treating estrogen receptor-positive leiomyosarcoma in an individual in need thereof comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin, e.g, /706-sirolimus: and optionally (b) an effective amount of a second therapeutic agent (e.g., an anti-PD-1 antibody, e.g, nivolumab).
  • a second therapeutic agent e.g., an anti-PD-1 antibody, e.g, nivolumab
  • nab stands for nanoparticle albumin-bound
  • «a6-sirolimus” is an albumin stabilized nanoparticle formulation of sirolimus. «a6-sirolimus is also known as nab- rapamycin, which has been previously described. See, for example, U.S. Patent Nos. 8,911,786 and 11,497,737, each of which is incorporated herein by reference in their entirety.
  • treatment is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g, preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g, metastasis) of the disease, preventing or delaying the recurrence of the disease, reducing recurrence rate of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • the treatment reduces the severity of one or more symptoms associated with cancer by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding symptom in the same subject prior to treatment or compared to the corresponding symptom in other subjects not receiving the treatment.
  • treatment is a reduction of pathological consequence of cancer.
  • the methods of the invention contemplate any one or more of these aspects of treatment.
  • the term “refractory” or “resistant” refers to a cancer or disease that has not responded to treatment.
  • “delaying” the development of cancer means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a method that “delays” development of cancer is a method that reduces probability of disease development in a given time frame and/or reduces the extent of the disease in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
  • Cancer development can be detectable using standard methods, including, but not limited to, computerized axial tomography (CAT scan), Magnetic Resonance Imaging (MRI), ultrasound, clotting tests, arteriography, biopsy, urine cytology, and cystoscopy. Development may also refer to cancer progression that may be initially undetectable and includes occurrence, recurrence, and onset.
  • CAT scan computerized axial tomography
  • MRI Magnetic Resonance Imaging
  • ultrasound ultrasound
  • clotting tests arteriography
  • biopsy biopsy
  • urine cytology urine cytology
  • cystoscopy cystoscopy
  • an effective amount refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease such as ameliorate, palliate, lessen, and/or delay one or more of its symptoms.
  • an effective amount comprises an amount sufficient to cause a tumor to shrink and/or to decrease the growth rate of the tumor (such as to suppress tumor growth) or to prevent or delay other unwanted cell proliferation in cancer.
  • an effective amount is an amount sufficient to delay development of cancer.
  • an effective amount is an amount sufficient to prevent or delay recurrence.
  • an effective amount is an amount sufficient to reduce recurrence rate in the individual.
  • An effective amount can be administered in one or more administrations.
  • the effective amount of the drug or composition may: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, retard, slow to some extent and preferably stop cancer cell infiltration into peripheral organs; (iv) inhibit (z.e., slow to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and/or recurrence of tumor; (vii) reduce recurrence rate of tumor, and/or (viii) relieve to some extent one or more of the symptoms associated with the cancer.
  • an “effective amount” may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • An effective amount may be considered in the context of administering one or more therapeutic agents, and a nanoparticle composition (e.g, a composition including sirolimus and an albumin) may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved.
  • the components (e.g, the first and second therapies) in a combination therapy of the invention may be administered sequentially, simultaneously, or concurrently using the same or different routes of administration for each component.
  • an effective amount of a combination therapy includes an amount of the first therapy and an amount of the second therapy that when administered sequentially, simultaneously, or concurrently produces a desired outcome.
  • ‘In conjunction with” or “in combination with” refers to administration of one treatment modality in addition to another treatment modality, such as administration of a nanoparticle composition described herein in addition to administration of the other agent to the same individual under the same treatment plan.
  • “in conjunction with” or “in combination with” refers to administration of one treatment modality before, during or after delivery of the other treatment modality to the individual.
  • the term “simultaneous administration,” as used herein, means that a first therapy and second therapy in a combination therapy are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes.
  • the first and second therapies may be contained in the same composition (e.g, a composition comprising both a first and second therapy) or in separate compositions (e.g., a first therapy is contained in one composition and a second therapy is contained in another composition).
  • the term “sequential administration” means that the first therapy and second therapy in a combination therapy are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60, or more minutes. Either the first therapy or the 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 packages or kits.
  • the term “concurrent administration” means that the administration of the first therapy and that of a second therapy in a combination therapy overlap with each other.
  • antibody includes full-length antibodies and antigen-binding fragments thereof.
  • a full-length antibody comprises two heavy chains and two light chains.
  • the variable regions of the light and heavy chains are responsible for antigen binding.
  • the variable region in both chains generally contain three highly variable loops called the complementarity determining regions (CDRs) (light chain (LC) CDRs including LC-CDR1, LC-CDR2, and LC- CDR3, heavy chain (HC) CDRs including HC-CDR1, HC-CDR2, and HC-CDR3).
  • CDRs complementarity determining regions
  • CDR boundaries for the antibodies and antigen-binding fragments disclosed herein may be defined or identified by the conventions of Kabat, Chothia, or Al-Lazikani (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991).
  • the three CDRs of the heavy or light chains are interposed between flanking stretches known as framework regions (FRs), which are more highly conserved than the CDRs and form a scaffold to support the hypervariable loops.
  • FRs framework regions
  • the constant regions of the heavy and light chains are not involved in antigen binding, but exhibit various effector functions.
  • Antibodies are assigned to classes based on the amino acid sequence of the constant region of their heavy chain.
  • the five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, which are characterized by the presence of a, 6, e, y, and p heavy chains, respectively.
  • Several of the major antibody classes are divided into subclasses such as IgGl (y 1 heavy chain), lgG2 (y2 heavy chain), lgG3 (y3 heavy chain), lgG4 (y4 heavy chain), IgAl (al heavy chain), or lgA2 (a2 heavy chain).
  • antigen-binding fragment refers to an antibody fragment including, for example, a diabody, a Fab, a Fab', a F(ab')2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv-dsFv 1 ), a disulfide stabilized diabody (ds diabody), a single-chain antibody molecule (scFv), an scFv dimer (bivalent diabody), a multispecific antibody formed from a portion of an antibody comprising one or more CDRs, a camelized single domain antibody, a nanobody, a domain antibody, a bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not comprise a complete antibody structure.
  • an antigen-binding fragment is capable of binding to the same antigen to which the parent antibody or a parent antibody fragment (e.g, a parent scFv) binds.
  • an antigen-binding fragment may comprise one or more CDRs from a particular human antibody grafted to a framework region from one or more different human antibodies.
  • the term “specifically binds” or “is specific for” refers to measurable and reproducible interactions, such as binding between a target and an antibody or antibody moiety that is determinative of the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules.
  • an antibody or antibody moiety that specifically binds to a target is an antibody or antibody moiety that binds this target with greater affinity, avidity, more readily, and/or with greater duration than its bindings to other targets.
  • an antibody or antibody moiety that specifically binds to an antigen reacts with one or more antigenic determinants of the antigen (for example PD-1 or a portion thereol) with a binding affinity that is at least about 10 times its binding affinity for other targets.
  • pharmaceutically acceptable or “pharmacologically compatible” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and/or are included on the Inactive Ingredient Guide prepared by the U. S. Food and Drug administration.
  • the term “individual” refers to a mammal and includes, but is not limited to, human, bovine, horse, feline, canine, rodent, rat, mouse, dog, or primate. In some embodiments, the individual is a human individual.
  • Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”
  • a cancer including undifferentiated pleomorphic sarcoma (including undifferentiated pleomorphic sarcoma having a PTEN loss and/or a TSC2 mutation) or leiomyosarcoma (including estrogen receptor-positive leiomyosarcoma), in an individual in need thereof, the treatments comprising administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereol) and an albumin; and optionally (b) a second therapeutic agent (e.g., an anti-PD-1 antibody).
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereol
  • a second therapeutic agent e.g., an anti-PD-1 antibody
  • a method of treating undifferentiated pleomorphic sarcoma having a PTEN loss and/or a TSC2 mutation in an individual in need thereof comprising administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin (e.g, m6-sirolimus); and optionally (b) a second therapeutic agent (e.g., an anti-PD-1 antibody (e.g, nivolumab)).
  • the PTEN loss is a loss-of-function mutation or epigenetic silencing.
  • the individual is selected for the treatment on the basis of having the PTEN loss.
  • the TSC2 mutation is a missense mutation, nonsense mutation, deletion, splicing site mutation, insertion, substation, rearrangement, or frameshift, or a combination thereof.
  • the individual is selected for the treatment on the basis of the TSC2 mutation.
  • the method further comprises selecting the individual on the basis of having the PTEN loss and/ or the TSC2 mutation.
  • a method of treating estrogen receptor-positive leiomyosarcoma in an individual in need thereof comprising administering to the individual (a) a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin (e.g, na6-sirolimus); and optionally (b) a second therapeutic agent (e.g., an anti-PD-1 antibody (e.g, nivolumab)).
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • albumin e.g, na6-sirolimus
  • a second therapeutic agent e.g., an anti-PD-1 antibody (e.g, nivolumab)
  • the cancer such as the undifferentiated pleomorphic sarcoma or the leiomyosarcoma
  • the cancer is locally advanced, advanced, malignant, advanced malignant, or metastatic.
  • the cancer such as the undifferentiated pleomorphic sarcoma or the leiomyosarcoma
  • the prior treatment comprises a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin, e.g, m/j-sirolimus.
  • prior treatment comprises a non-nanoparticle formulation of an mTOR inhibitor, such as sirolimus.
  • the methods provided herein are applicable to all stages of cancer, such as the undifferentiated pleomorphic sarcoma or leiomyosarcoma, including stages, I, II, III, and IV, according to the American Joint Committee on Cancer (AJCC) staging groups.
  • the cancer such as the undifferentiated pleomorphic sarcoma or leiomyosarcoma
  • the cancer is an early stage cancer, non-metastatic cancer, primary cancer, advanced cancer, locally advanced cancer, metastatic cancer, cancer in remission, cancer in an adjuvant setting, or cancer in a neoadjuvant setting.
  • the solid tumor is localized resectable, localized unresectable, or unresectable.
  • the cancer such as the undifferentiated pleomorphic sarcoma or leiomyosarcoma
  • the dose of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) administered to an individual (e.g, a human) may vary with the particular composition, the method of administration, and the particular stage of tumor being treated. The amount should be sufficient to produce a desirable response, such as a therapeutic or prophylactic response against the tumor.
  • the amount of mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) in the composition is below the level that induces a toxicological effect (e.g, an effect above a clinically acceptable level of toxicity) or is at a level where a potential side effect can be controlled or tolerated when the mTOR inhibitor nanoparticle composition is administered to the individual.
  • a toxicological effect e.g, an effect above a clinically acceptable level of toxicity
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered to the individual simultaneously with the second therapeutic agent such as an anti-PD-1 antibody.
  • the mTOR inhibitor nanoparticle compositions and the anti-PD-1 antibody are administered with a time separation of no more than about 15 minutes, such as no more than about any of 10, 5, or 1 minutes.
  • simultaneous administration can be achieved by administering a solution containing the combination of compounds.
  • simultaneous administration of separate solutions one of which contains the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the other of which contains the anti-PD-1 antibody, can be employed.
  • simultaneous administration can be achieved by administering a composition containing the combination of compounds.
  • simultaneous administration can be achieved by administering two separate compositions, one comprising the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the other comprising the anti-PD-1 antibody.
  • simultaneous administration of the mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • the mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • the anti-PD-1 antibody can be combined with supplemental doses of the mTOR inhibitor and/or the anti-PD-1 antibody.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the second therapeutic agent such as anti-PD-1 antibody are not administered simultaneously.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered before the anti-PD-1 antibody.
  • the anti-PD-1 antibody is administered before the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition).
  • the time difference in non-simultaneous administrations can be greater than 1 minute, five minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, two hours, three hours, six hours, nine hours, 12 hours, 24 hours, 36 hours, or 48 hours.
  • the first administered compound is provided time to take effect on the patient before the second administered compound is administered. In some embodiments, the difference in time does not extend beyond the time for the first administered compound to complete its effect in the patient, or beyond the time the first administered compound is completely or substantially eliminated or deactivated in the patient.
  • the administration of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the second therapeutic agent such as anti-PD-1 antibody are concurrent, /.£., the administration period of the mTOR inhibitor nanoparticle composition and that of the anti-PD-1 antibody overlap with each other.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered for at least one cycle (for example, at least any 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 anti-PD-1 antibody.
  • the anti-PD-1 antibody is administered for at least any of one, two, three, or four weeks.
  • the administrations of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the anti-PD-1 antibody are initiated at about the same time (for example, within any one of 1, 2, 3, 4, 5, 6, or 7 days). In some embodiments, the administrations of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the anti-PD- 1 antibody are terminated at about the same time (for example, within any one of 1, 2, 3, 4, 5, 6, or 7 days).
  • the administration of the anti-PD-1 antibody continues (for example for about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) after the termination of the administration of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition).
  • the administration of the anti-PD-1 antibody is initiated after (for example after about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) the initiation of the administration of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition).
  • the administrations of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the anti-PD-1 antibody are initiated and terminated at about the same time.
  • the administrations of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the anti-PD-1 antibody are initiated at about the same time and the administration of the anti-PD-1 antibody continues (for example for about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) after the termination of the administration of the mTOR inhibitor nanoparticle composition.
  • the administration of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the anti-PD-1 antibody stop at about the same time and the administration of the anti-PD-1 antibody is initiated after (for example after about any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months) the initiation of the administration of the mTOR inhibitor nanoparticle composition.
  • the second therapeutic agent such as anti-PD-1 antibody is administered on day 1 of a 21 -day cycle, and the mTOR inhibitor nanoparticle composition is administered on days 8 and 15 of the 21 -day cycle.
  • the first cycle only includes administration of the anti-PD-1 antibody, e.g, on day 1.
  • the administration of the composition comprising an mTOR inhibitor and an albumin and an anti- PD-1 antibody continues for at least any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 15, 16, 17, 18, 19, or 20 cycles.
  • the administration of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the second therapeutic agent such as anti-PD-1 antibody are non-concurrent.
  • the administration of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is terminated before the anti-PD-1 antibody is administered.
  • the administration of the anti-PD-1 antibody is terminated before the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered.
  • the time period between these two non-concurrent administrations can range from about two to eight weeks, such as about four weeks.
  • the dosing frequency of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the second therapeutic agent such as anti-PD-1 antibody may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the second therapeutic agent such as anti-PD-1 antibody can be administered at different dosing frequency or intervals.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) can be administered weekly, while the anti-PD-1 antibody can be administered more or less frequently.
  • a sustained continuous release formulation of the nanoparticle and/or anti-PD-1 antibody may be used.
  • Various formulations and devices for achieving sustained release are known in the art. A combination of the administration configurations described herein can also be used.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the second therapeutic agent such as anti-PD-1 antibody can be administered using the same route of administration or different routes of administration.
  • the mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereol
  • the anti-PD-1 antibody are administered at a predetermined ratio.
  • the doses required for the mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereol) in the mTOR inhibitor nanoparticle composition and/or the second therapeutic agent such as anti-PD-1 antibody may (but not necessarily) be the same or lower than what is normally required when each agent is administered alone.
  • a subtherapeutic amount of the mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) in the mTOR inhibitor nanoparticle composition and/or the anti-PD-1 antibody is administered.
  • “Subtherapeutic amount” or “subtherapeutic level” refer to an amount that is less than the therapeutic amount, that is, less than the amount normally used when the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and/or the anti-PD-1 antibody are administered alone. The reduction may be reflected in terms of the amount administered at a given administration and/or the amount administered over a given period of time (reduced frequency).
  • enough second therapeutic agent e.g., anti-PD-1 antibody
  • the mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • enough mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • the second therapeutic agent e.g. anti-PD-1 antibody
  • both the mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • the anti-PD-1 antibody are reduced as compared to the corresponding normal dose of each when administered alone.
  • both the mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) in the mTOR inhibitor nanoparticle composition and the anti- PD-1 antibody are administered at a subtherapeutic, i.e., reduced, level.
  • the dose of the mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) in the mTOR inhibitor nanoparticle composition and/or the anti-PD-1 antibody is substantially less than the established maximum toxic dose (MTD).
  • the dose of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and/or the anti- PD-1 antibody is less than about 50%, 40%, 30%, 20%, or 10% of the MTD.
  • a combination of the administration configurations described herein can be used.
  • the combination therapy methods described herein may be performed alone or in conjunction with another therapy, such as surgery, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and/or chemotherapy and the like. Additionally, a person having a greater risk of developing the solid tumor may receive treatments to inhibit and/or delay the development of the disease.
  • the appropriate doses of second agents will be approximately those already employed in clinical therapies wherein the anti-PD-1 antibody is administered alone or in combination with other chemotherapeutic agents. Variation in dosage will likely occur depending on the condition being treated. As described above, in some embodiments, the second chemotherapeutic agent may be administered at a reduced level.
  • the amounts of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the anti-PD-1 antibody are below the levels that induce a toxicological effect (i.e., an effect above a clinically acceptable level of toxicity) or are at a level where a potential side effect can be controlled or tolerated when the mTOR inhibitor nanoparticle composition and the anti-PD-1 antibody are administered to the individual.
  • the amount of the mTOR inhibitor nanoparticle composition is not limited to, the amount of the mTOR inhibitor nanoparticle composition
  • the amount of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is more than about any of 80%, 90%, 95%, or 98% of the MTD when administered with the anti-PD-1 antibody.
  • the amount of an mTOR inhibitor (such as a limus drug, e.g, sirolimus) in the mTOR inhibitor nanoparticle composition is about any of 25 mg/m 2 , 30 mg/m 2 , 45 mg/m 2 , 50 mg/m 2 , 56 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 90 mg/m 2 , 100 mg/m 2 , 120 mg/m 2 , 160 mg/m 2 , 175 mg/m 2 , 180 mg/m 2 , 200 mg/m 2 , 210 mg/m 2 , 220 mg/m 2 , 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 mTOR inhibitor.
  • an mTOR inhibitor such as a
  • the mTOR inhibitor nanoparticle composition includes less than about any of 350 mg/m 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 mTOR inhibitor (such as a limus drug, e.g, sirolimus).
  • a limus drug e.g, sirolimus
  • the amount of the mTOR inhibitor (such as a limus drug, e.g, sirolimus) per administration is less than about any of 25 mg/m 2 , 22 mg/m 2 , 20 mg/m 2 , 18 mg/m 2 , 15 mg/m 2 , 14 mg/m 2 , 13 mg/m 2 , 12 mg/m 2 , 11 mg/m 2 , 10 mg/m 2 , 9 mg/m 2 , 8 mg/m 2 , 7 mg/m 2 , 6 mg/m 2 , 5 mg/m 2 , 4 mg/m 2 , 3 mg/m 2 , 2 mg/m 2 , or 1 mg/m 2 .
  • the mTOR inhibitor such as a limus drug, e.g, sirolimus
  • the effective amount of mTOR inhibitor (such as a limus drug, e.g, sirolimus) in the mTOR inhibitor nanoparticle composition is included in any of the following ranges: about 1 to about 5 mg/m 2 , about 5 to aboutlO mg/m 2 , about 10 to about 25 mg/m 2 , about 25 to about 50 mg/m 2 , about 50 to about 75 mg/m 2 , about 75 to about 100 mg/m 2 , about 100 to about 125 mg/m 2 , about 125 to aboutl50 mg/m 2 , aboutl50 to about 175 mg/m 2 , aboutl75 to about 200 mg/m 2 , about 200 to about 225 mg/m 2 , about 225 to about 250 mg/m 2 , about 250 to about 300 mg/m 2 , about 300 to about 350 mg/m 2 , or about 350 to about 400 mg/m 2 .
  • mTOR inhibitor such as a limus drug, e.g, sirolimus
  • the effective amount of mTOR inhibitor (such as a limus drug, e.g, sirolimus) in the mTOR inhibitor nanoparticle composition is about 30 to about 300 mg/m 2 , such as about 100 to about 150 mg/m 2 , about 120 mg/m2, about 130 mg/m 2 , or aboutl40 mg/m 2 .
  • 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 2 out of 3 weeks.
  • the amount of the mTOR inhibitor nanoparticle composition is on days 8 and 15 of a 21-day cycle, days 1 or 8 of a 21-day cycle, days 15 and 21 or a 21-day cycle, days 1 and 15 of a 21-day cycle, or days 1 and 21 of a 21-day cycle.
  • the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, atezolizumab, dostarlimab, durvalumab, and avelumab.
  • the amount of an anti-PD-1 antibody (such as nivolumab) is about 1 mg/kg to about 10 mg/kg.
  • the amount of an anti-PD-1 antibody is at least about 1 mg/kg, such as at least about any of 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, or 10 mg/kg. In some embodiments, the amount of an anti-PD-1 antibody (such as nivolumab) 1 mg/kg or less, such as any of 2 mg/kg or less, 3 mg/kg or less, 4 mg/kg or less, 5 mg/kg or less, 6 mg/kg or less, 7 mg/kg or less, 8 mg/kg or less, 9 mg/kg or less, or 10 mg/kg or less.
  • the amount of an anti-PD-1 antibody (such as nivolumab) is about any of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, or 10 mg/kg.
  • the amount of an anti-PD-1 antibody is administered weekly, every two weeks, every three weeks, or monthly.
  • the amount of an anti-PD-1 antibody is administered every three weeks.
  • the amount of an anti-PD-1 antibody is administered every 21 days.
  • the dosing frequencies for the administration of the mTOR inhibitor nanoparticle composition include, but are not limited to, daily, every two days, every three days, every four days, every five days, every six days, weekly without break, three out of four weeks (such as on days 1, 8, and 15 of a 28-day cycle), once every three weeks, once every two weeks, or two out of three weeks.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered about once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered at least about any of lx, 2x, 3x, 4x, 5x, 6x, or 7x (z.e., daily) a week.
  • the intervals between each administration are less than about any of 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.
  • the intervals between each administration are more than about any of 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, or 12 months.
  • the interval between each administration is no more than about a week.
  • the dosing frequency is once every two days for one time, two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, or eleven times. In some embodiments, the dosing frequency is once every two days for five times.
  • the mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) is administered over a period of at least ten days, wherein the interval between each administration is no more than about two days, and wherein the dose of the mTOR inhibitor at each administration is about 0.25 mg/m 2 to about 250 mg/m 2 , about 0.25 mg/m 2 to about 150 mg/m 2 , about 0.25 mg/m 2 to about 75 mg/m 2 , such as about 0.25 mg/m 2 to about 25 mg/m 2 , or about 25 mg/m 2 to about 50 mg/m 2 .
  • a limus drug e.g, sirolimus or a derivative thereof
  • the administration of the mTOR inhibitor nanoparticle composition can be extended over an extended period of time, such as from about a month up to about seven years.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered over a period of at least about any of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 48, 60, 72, or 84 months.
  • the dosage of an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) in a nanoparticle composition can be in the range of 5-400 mg/m 2 when given on a 3-week schedule, or 5-250 mg/m 2 (such as 80-150 mg/m 2 , for example 100-120 mg/m 2 ) when given on a weekly schedule.
  • the amount of an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) is about 60 to about 300 mg/m 2 (e.g, about 260 mg/m 2 ) on a 3-week schedule.
  • the exemplary dosing schedules for the administration of the mTOR inhibitor nanoparticle composition include, but are not limited to, 100 mg/m 2 , weekly, without break; 10 mg/m 2 weekly, 3 out of four weeks (such as on days 1, 8, and 15 of a 28-day cycle); 45 mg/m 2 weekly, 3 out of four weeks (such as on days 1, 8, and 15 of a 28-day cycle); 75 mg/m 2 weekly, 3 out of four weeks (such as on days 1, 8, and 15 of a 28-day cycle); 100 mg/m 2 , weekly, 3 out of 4 weeks; 125 mg/m 2 , weekly, 3 out of 4 weeks; 125 mg/m 2 , weekly, 2 out of 3 weeks; 130 mg/m 2 , weekly, without break; 175 mg/m 2 , once every 2 weeks; 260 mg/m 2 , once every 2 weeks; 260 mg/m 2 , once every 3 weeks; 180-300 mg/
  • the individual is treated for at least about any of one, two, three, four, five, six, seven, eight, nine, or ten treatment cycles.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) described herein allow infusion of the mTOR inhibitor nanoparticle composition to an individual over an infusion time that is shorter than about 24 hours.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered over an infusion period of less than about any of 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or 10 minutes.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered over an infusion period of about 30 minutes.
  • the exemplary dose of the mTOR inhibitor (in some embodiments a limus drug, e.g, sirolimus) in the mTOR inhibitor nanoparticle composition includes, but is not limited to, about any of 50 mg/m 2 , 60 mg/m 2 , 75 mg/m 2 , 80 mg/m 2 , 90 mg/m 2 , 100 mg/m 2 , 120 mg/m 2 , 160 mg/m 2 , 175 mg/m 2 , 200 mg/m 2 , 210 mg/m 2 , 220 mg/m 2 , 260 mg/m 2 , and 300 mg/m 2 .
  • the dosage of an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereol) in a nanoparticle composition can be in the range of about 100-400 mg/m 2 when given on a 3-week schedule, or about 10-250 mg/m 2 when given on a weekly schedule.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereol
  • a nanoparticle composition can be in the range of about 100-400 mg/m 2 when given on a 3-week schedule, or about 10-250 mg/m 2 when given on a weekly schedule.
  • the dosage of an mTOR inhibitor (such as a limus drug, 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.
  • the limus drug is administered at about 100 mg weekly, about 200 mg weekly, about 300 mg weekly, about 100 mg twice weekly, or about 200 mg twice weekly.
  • the administration is further followed by a monthly maintenance dose (which can be the same or different from the weekly doses).
  • the dosage of an mTOR inhibitor (such as a limus drug, e.g, sirolimus) in a nanoparticle composition can be in the range of about 30 mg to about 400 mg.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) described herein allow infusion of the mTOR inhibitor nanoparticle composition to an individual over an infusion time that is shorter than about 24 hours.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered over an infusion period of less than about any of 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or 10 minutes. In some embodiments, the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered over an infusion period of about 30 minutes to about 40 minutes.
  • the anti-PD-1 antibody (such as nivolumab) described herein can be infused to an individual over an infusion time that is shorter than about 24 hours.
  • the anti-PD-1 antibody (such as nivolumab) is administered over an infusion period of less than about any of 24 hours, 12 hours, 8 hours, 5 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or 10 minutes.
  • the anti-PD-1 antibody (such as nivolumab) is administered over an infusion period of about 30 minutes.
  • each dosage contains both an mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and an anti-PD-1 antibody to be delivered as a single dosage, while in other embodiments, each dosage contains either the mTOR inhibitor nanoparticle composition or the anti-PD-1 antibody to be delivered as separate dosages.
  • an mTOR inhibitor nanoparticle composition such as sirolimus/albumin nanoparticle composition
  • an anti-PD-1 antibody to be delivered as a single dosage
  • each dosage contains either the mTOR inhibitor nanoparticle composition or the anti-PD-1 antibody to be delivered as separate dosages.
  • An mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and an anti-PD-1 antibody, in pure form or in an appropriate pharmaceutical composition, can be administered via any of the accepted modes of administration or agents known in the art.
  • the compositions and/or agents can be administered, for example, orally, nasally, parenterally (such as intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally.
  • the dosage form can be, for example, a solid, semi-solid, lyophilized powder, or liquid dosage form, such as tablets, pills, soft elastic or hard gelatin capsules, powders, solutions, suspensions, suppositories, aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • the mTOR inhibitor nanoparticle composition such as sirolimus/albumin nanoparticle composition
  • the second therapeutic agent e.g., anti-PD-1 antibody
  • the phrase “pharmaceutical combination” includes a combination of two drugs in either a single dosage form or a separate dosage forms, i.e., the pharmaceutically acceptable carriers and excipients described throughout the application can be combined with an mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent (e.g., anti-PD-1 antibody) in a single unit dose, as well as individually combined with an mTOR inhibitor nanoparticle composition and a second therapeutic agent (e.g., an anti-PD-1 antibody) when these compounds are administered separately.
  • an mTOR inhibitor nanoparticle composition such as sirolimus/albumin nanoparticle composition
  • a second therapeutic agent e.g., an anti-PD-1 antibody
  • Auxiliary and adjuvant agents may include, for example, preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms is generally provided by various antibacterial and antifungal agents, such as, parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, such as sugars, sodium chloride, and the like, may also be included. Prolonged absorption of an injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the auxiliary agents also can include wetting agents, emulsifying agents, pH buffering agents, and antioxidants, such as citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxy toluene, and the like.
  • Solid dosage forms can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They can contain pacifying agents and can be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds also can be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • Such dosage forms are prepared, for example, by dissolving, or dispersing, the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) or anti-PD-1 antibody described herein, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethyl formamide; oils, in particular, cottonseed oil, groundnut oil, com germ oil, olive oil, castor oil and ses
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of the compounds described herein, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a pharmaceutically acceptable excipient.
  • the composition will be between about 5% and about 75% by weight of a compound described herein, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) can be administered to an individual (such as a human) via various routes, including, for example, intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, intraocular, intrathecal, transmucosal, and transdermal.
  • sustained continuous release formulation of the composition may be used.
  • the composition is administered intravenously.
  • the composition is administered intraportally.
  • the composition is administered intraarterially.
  • the composition is administered intraperitoneally.
  • the anti-PD-1 antibody (such nivolumab) can be administered to an individual (such as a human) via various routes, including, for example, intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, inhalation, intravesicular, intramuscular, intra-tracheal, subcutaneous, intraocular, intrathecal, transmucosal, and transdermal.
  • the anti-PD-1 antibody is administered intravenously.
  • a method of treating undifferentiated pleomorphic sarcoma in an individual in need thereof comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin; and optionally (b) an effective amount of a second therapeutic agent (e.g., an anti-PD-1 antibody).
  • a second therapeutic agent e.g., an anti-PD-1 antibody
  • Undifferentiated pleomorphic sarcoma is a high-grade, and often aggressive, soft-tissue sarcoma. Undifferentiated pleomorphic sarcoma usually appear as asymptomatic, unremarkable, rapidly growing cutaneous or subcutaneous nodule without superficial skin abnormalities. It is likely that the origin of undifferentiated pleomorphic sarcoma is mesenchymal stem cells. Undifferentiated pleomorphic sarcoma has been found to affect, amongst other areas, bones, soft tissues, and the retroperitoneum, and can also metastasize to other organs.
  • Undifferentiated pleomorphic sarcoma can be diagnosed via histopathology of tumor samples, such as from a core needle technique or biopsy. Markers can be used to diagnose undifferentiated pleomorphic sarcoma, and include keratins, S100 protein, and/or SOXIO, smooth muscle actin (SMA), and desmin. MDM2 and CDK4 may also be helpful to distinguish undifferentiated pleomorphic sarcoma from dedifferentiated liposarcoma. Undifferentiated pleomorphic sarcoma exhibits atypical, pleomorphic spindle cells with abundant mitotic figures, and the tumor may display storiform, fascicular, or sheet-like configuration within a fibrous stroma. Robles-Tenorio & Solis-Ledesma, Slat Pear Is. Undifferentiated Pleomorphic Sarcoma, 2022.
  • the undifferentiated pleomorphic sarcoma has phosphatase and tensin homolog (PTEN) loss.
  • PTEN loss is a loss-of-function mutation or epigenetic silencing. PTEN loss is described in, e.g., Chang et al. , Biomolecules , 9, 2019; Vidotto et al., BrJ Cancer, 122, 2020, the contents of each of which are incorporated herein by reference in their entirety.
  • the undifferentiated pleomorphic sarcoma has a tuberous sclerosis complex 2 (TSC2) mutation.
  • TSC2 mutation is a missense mutation, nonsense mutation, deletion, splicing site mutation, insertion, substation, rearrangement, or frameshift, or a combination thereof.
  • the TSC2 mutation is an mTOR-activating aberration of TSC2.
  • the TSC2 mutation comprises a single-nucleotide variant (SNV).
  • the SNV comprises a mutation selected from the group consisting of C1503T, C2743G, C5383T, C3755G, G760T, C3442T, G880A, T707C, A4949G, or a deletion of any one or more of the amino acids at the position of 1405-1409, 1960-1970, 4999, 5002, 3521, 5208, 5238-5255.
  • the TSC2 mutation is a copy number variation of TSC2.
  • the TSC2 mutation is a loss of function mutation.
  • the TSC2 mutation results in an aberrant expression level of TSC2.
  • the TSC2 mutation results in an aberrant activity level of a protein encoded by TSC2.
  • the TSC2 mutation results in a loss of heterozygosity of TSC2.
  • Mutation analysis of TSC2 genes is known, e.g, Avgeris et al., Sci Rep, 7, 2017, the contents of which are incorporated herein by reference in their entirety.
  • the individual is selected for the treatment on the basis of having a PTEN loss. In some embodiments, the individual is selected for the treatment on the basis of a TSC2 mutation. In some embodiments, the individual is selected for the treatment on the basis of having a PTEN loss and a TSC2 mutation. In some embodiments, the method further comprises selecting the individual on the basis of having a PTEN loss. In some embodiments, the method further comprises selecting the individual on the basis of having a TSC2 mutation. In some embodiments, the method further comprises selecting the individual on the basis of having a PTEN loss and a TSC2 mutation.
  • a method of treating undifferentiated pleomorphic sarcoma having a PTEN loss in an individual comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) and an albumin; and optionally (b) an effective amount of a second therapeutic agent (e.g., an anti-PD-1 antibody).
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) and an albumin, wherein the mTOR inhibitor in the nanoparticles is associated (e.g, coated) with the albumin; and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • albumin such as a limus drug, e.g, sirolimus or a derivative thereof
  • the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm)
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with the albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm, for example about 100 nm), wherein the weight ratio of albumin and the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 9: 1 or less (such as about 9:1 or about 8:1); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • an albumin such as a limus drug, e.g, sirolimus or a derivative thereof
  • the nanoparticles comprise
  • 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 «a6-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is «a6-sirolimus. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, atezolizumab, dostarlimab, durvalumab, and avelumab. In some embodiments, the anti-PD-1 antibody is nivolumab.
  • the nanoparticle composition and anti-PD-1 antibody are administered sequentially. In some embodiments, the nanoparticle composition and anti-PD-1 antibody are administered simultaneously. In some embodiments, the nanoparticle composition and anti-PD-1 antibody are administered concurrently. In some embodiments, the mTOR inhibitor nanoparticle composition is administered 2 out of every 3 weeks, such as on days 8 and 15 of a 21 -day cycle. In some embodiments, the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is from about 10 mg/m 2 to about 150 mg/m 2 , such as about 100 mg/m 2 . In some embodiments, the anti-PD-1 antibody is administered every three weeks, such as on day 1 of a 21-day cycle.
  • the anti-PD-1 antibody is administered for at least one cycle prior to administration of the mTOR inhibitor nanoparticle composition. In some embodiments, the anti-PD-1 antibody is administered at an amount of about 1 mg/kg to about 10 mg/kg, such as about 3 mg/kg.
  • a method of treating undifferentiated pleomorphic sarcoma having a TSC2 mutation in an individual comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin; and optionally (b) an effective amount of a second therapeutic agent (e.g., an anti-PD-1 antibody).
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • a second therapeutic agent e.g., an anti-PD-1 antibody
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the mTOR inhibitor in the nanoparticles is associated (e.g, coated) with the albumin; and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • albumin such as a limus drug, e.g, sirolimus or a derivative thereof
  • the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm)
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with the albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm, for example about 100 nm), wherein the weight ratio of albumin and the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 9: 1 or less (such as about 9:1 or about 8:1); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • an albumin such as a limus drug, e.g, sirolimus or a derivative thereof
  • the nanoparticles comprise
  • 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 «a6-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is «a6-sirolimus. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, atezolizumab, dostarlimab, durvalumab, and avelumab. In some embodiments, the anti-PD-1 antibody is nivolumab.
  • the nanoparticle composition and anti-PD-1 antibody are administered sequentially. In some embodiments, th the nanoparticle composition and anti-PD-1 antibody are administered simultaneously. In some embodiments, the nanoparticle composition and anti-PD-1 antibody are administered concurrently. In some embodiments, the mTOR inhibitor nanoparticle composition is administered 2 out of every 3 weeks, such as on days 8 and 15 of a 21 -day cycle. In some embodiments, the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is from about 10 mg/m 2 to about 150 mg/m 2 , such as about 100 mg/m 2 . In some embodiments, the anti-PD-1 antibody is administered every three weeks, such as on day 1 of a 21-day cycle.
  • the anti-PD-1 antibody is administered for at least one cycle prior to administration of the mTOR inhibitor nanoparticle composition. In some embodiments, the anti-PD-1 antibody is administered at an amount of about 1 mg/kg to about 10 mg/kg, such as about 3 mg/kg.
  • a method of treating undifferentiated pleomorphic sarcoma having a PTEN loss and a TSC2 mutation in an individual comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin; and optionally (b) an effective amount of a second therapeutic agent (e.g., an anti-PD-1 antibody).
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • a second therapeutic agent e.g., an anti-PD-1 antibody
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the mTOR inhibitor in the nanoparticles is associated (e.g, coated) with the albumin; and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • albumin such as a limus drug, e.g, sirolimus or a derivative thereof
  • the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm)
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with the albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm, for example about 100 nm), wherein the weight ratio of albumin and the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 9: 1 or less (such as about 9:1 or about 8:1); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • an albumin such as a limus drug, e.g, sirolimus or a derivative thereof
  • the nanoparticles comprise
  • 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 na6-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is na6-sirolimus. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, atezolizumab, dostarlimab, durvalumab, and avelumab. In some embodiments, the anti-PD-1 antibody is nivolumab.
  • the nanoparticle composition and anti-PD-1 antibody are administered sequentially. In some embodiments, the nanoparticle composition and anti-PD-1 antibody are administered simultaneously. In some embodiments, the nanoparticle composition and anti-PD-1 antibody are administered concurrently. In some embodiments, the mTOR inhibitor nanoparticle composition is administered 2 out of every 3 weeks, such as on days 8 and 15 of a 21 -day cycle. In some embodiments, the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is from about 10 mg/m 2 to about 150 mg/m 2 , such as about 100 mg/m 2 . In some embodiments, the anti-PD-1 antibody is administered every three weeks, such as on day 1 of a 21-day cycle.
  • the anti-PD-1 antibody is administered for at least one cycle prior to administration of the mTOR inhibitor nanoparticle composition. In some embodiments, the anti-PD-1 antibody is administered at an amount of about 1 mg/kg to about 10 mg/kg, such as about 3 mg/kg.
  • a method of treating leiomyosarcoma in an individual in need thereof comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin; and optionally (b) an effective amount of a second therapeutic agent (e.g. an anti- PD-1 antibody).
  • a second therapeutic agent e.g. an anti- PD-1 antibody
  • Leiomyosarcoma is a subtype of soft tissue sarcoma, presented in most parts of the human body, with common locations including the abdomen, retroperitoneum, larger blood vessels, and the uterus.
  • Leiomyosarcoma is a malignant mesenchymal tumor composed of cells that show distinct features of the smooth muscle lineage, and can be categorized as somatic soft tissue leiomyosarcoma, cutaneous leiomyosarcoma, or vascular leiomyosarcoma. Diagnosis can be performed on a tumor sample, such as obtained from a core needle biopsy.
  • Leiomyosarcoma exhibit areas of high cellularity, commonly arranged in fascicles, and malignant cells are characterized by abundant pink to deep red cytoplasm on hematoxylin and eosin (H&E) staining, with cigar-shaped, centrally located nuclei. Such distinguishing features are lost in dedifferentiated tumors.
  • H&E hematoxylin and eosin
  • the leiomyosarcoma is estrogen receptor-positive leiomyosarcoma.
  • the individual is selected for the treatment on the basis of having the estrogen receptor-positive leiomyosarcoma. In some embodiments, the method further comprises selecting the individual on the basis of having the estrogen receptor-positive leiomyosarcoma.
  • a method of treating estrogen receptorposition leiomyosarcoma in an individual comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereol) and an albumin; and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereol
  • an albumin such as a limus drug, e.g., sirolimus or a derivative thereol
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereol) and an albumin, wherein the mTOR inhibitor in the nanoparticles is associated (e.g, coated) with the albumin; and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereol
  • albumin an albumin
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • albumin such as a limus drug, e.g, sirolimus or a derivative thereof
  • the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm)
  • the method comprises administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) and an albumin, wherein the nanoparticles comprise the mTOR inhibitor associated (e.g, coated) with the albumin, wherein the nanoparticles have an average particle size of no greater than about 150 nm (such as no greater than about 120 nm, for example about 100 nm), wherein the weight ratio of albumin and the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 9: 1 or less (such as about 9:1 or about 8:1); and (b) an effective amount of an anti-PD-1 antibody.
  • an mTOR inhibitor such as a limus drug, e.g, sirolimus or a derivative thereof
  • an albumin such as a limus drug, e.g, sirolimus or a derivative thereof
  • the nanoparticles comprise
  • 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 «a6-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is «a6-sirolimus. In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, atezolizumab, dostarlimab, durvalumab, and avelumab. In some embodiments, the anti-PD-1 antibody is nivolumab.
  • the nanoparticle composition and anti-PD-1 antibody are administered sequentially. In some embodiments, the nanoparticle composition and anti-PD-1 antibody are administered simultaneously. In some embodiments, the nanoparticle composition and anti-PD-1 antibody are administered concurrently. In some embodiments, the mTOR inhibitor nanoparticle composition is administered 2 out of every 3 weeks, such as on days 8 and 15 of a 21 -day cycle. In some embodiments, the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is from about 10 mg/m 2 to about 150 mg/m 2 , such as about 100 mg/m 2 . In some embodiments, the anti-PD-1 antibody is administered every three weeks, such as on day 1 of a 21-day cycle.
  • the anti-PD-1 antibody is administered for at least one cycle prior to administration of the mTOR inhibitor nanoparticle composition. In some embodiments, the anti-PD-1 antibody is administered at an amount of about 1 mg/kg to about 10 mg/kg, such as about 3 mg/kg.
  • a method of treating a cancer in an individual in need thereof wherein the cancer is selected from the group consisting of adenocarcinoma of ascending colon, cervical adenosquamous cell carcinoma, chondrosarcoma, chordoma, clear cell sarcoma, colorectal cancer, such as metastatic colorectal cancer, desmoplastic round cell tumor, desmoplastic small cell tumor, Ewing Sarcoma, myxoid liposarcoma, osteosarcoma, including osteogenic osteosarcoma, pleomorphic spindle cell sarcoma, serous carcinoma of endometrium, or synovial sarcoma, the method comprising administering to the individual: (a) an effective amount of a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin; and optionally (b) an effective amount of a second therapeutic agent (e.g., an anti-PD-1 antibody).
  • a second therapeutic agent e.g., an anti-PD
  • the cancer is chondrosacoma, and the individual has an aberration at one or more (e.g., two or more, e.g., three or more) of the genes selected from the group consisting of TP53 p.Y220C, TUBB3, AXL.
  • the cancer is chondrosacoma, and the individual has an aberration at one or more (e.g., two or more, e.g., three or more) of the genes selected from the group consisting of BRCA2 truncation intron 7, EZH2 truncation intron 19, MLL2 R5048H, loss of RBI exons 3-9, and TP53 RllOdel.
  • the cancer is chondrosacoma, and the individual has an aberration at IDH1. In some embodiments, the cancer is chondrosacoma, and the individual has an aberration at IDH1. In some embodiments, the cancer is chondrosacoma, and the individual has an aberration at IDH1. In some embodiments, the cancer is chondrosacoma, and the individual has an aberration at one or more (e.g., two or more, e.g., three or more) of statuses selected from the group consisting of tumor mutational burden (TMB-low), mismatch repair (MMR)-proficient, PD-L1 -negative, MLH1 -positive, MLH2-positive, MLH6-positive, and PMS2-positive.
  • TMB-low tumor mutational burden
  • MMR mismatch repair
  • the cancer is osteosarcoma, and the individual has a C17orf39 mutation and is MUTYH-positive. In some embodiments, the cancer is osteosarcoma, and the individual has an aberration at DPBl*04:01 and/or DPBI*04:02; and/or is DPw4-positive.
  • the cancer is chondrosacoma, and the individual has an aberration at one or more (e.g., two or more, e.g., three or more) of the genes selected from the group consisting of BRCA2, FGFR1, KDM5A, MAF, MY018A, PCLO, RELN, and SF3B1; and/or the individual is RBI -positive and TP53-positive.
  • the cancer is osteosarcoma, and the individual is microsatellite (MSI)-stable, MMR-proficient, TMB-intermediate, and/or TP53- positive.
  • MSI microsatellite
  • the cancer is osteosarcoma
  • the individual is TMB- intermediate, PD-L1 -negative, MLH1 -positive, MLH2 -positive, MLH6-positive, PMS2-positive and/or has an aberration in TP53.
  • the cancer is Ewing Sarcoma
  • the individual has an aberration in EWSR1 (e.g., a gene fusion comprising at least a portion of the EWSR1 gene) and/or is KMT2D-proficient.
  • the cancer is Ewing Sarcoma
  • the individual has an aberration in EWSR1 (e.g., a gene fusion comprising at least a portion of the EWSR1 gene, e.g., a EWSRl-FLIl fusion), and/or is tumor exonic mutational burden-high, MLH1 -positive, MLH2-positive, MLH6-positive, and/or PMS2-positive.
  • the cancer is Ewing Sarcoma
  • the individual has an aberration in EWSR1 (e.g., a gene fusion comprising at least a portion of the EWSR1 gene) and/or EZH2 (e.g. a pathogenic variant of EZH2), and/or is MLH1 -positive, MLH2-positive, MLH6-positive, and/or PMS2-positive.
  • EWSR1 e.g., a gene fusion comprising at least a portion of the EWSR1 gene
  • EZH2 e.g. a pathogenic variant of EZH2
  • MLH1 -positive MLH2-positive
  • MLH6-positive MLH6-positive
  • PMS2-positive e.g., PMS2-positive
  • the cancer is synovial sarcoma
  • the individual is NY- ESO-1 -positive (e.g., NY-ESO-1 -positive in 99% of tumor cells).
  • the cancer is desmoplastic round cell tumor, and the individual has an aberration in EWSR1 (e.g., a gene fusion comprising at least a portion of the EWSR1 gene, e.g., EWSR1-WT1 fusion) and/or is TMB-low.
  • EWSR1 e.g., a gene fusion comprising at least a portion of the EWSR1 gene, e.g., EWSR1-WT1 fusion
  • the cancer is clear cell sarcoma, and the individual is EWSR- positive.
  • the cancer is chordoma, and the individual has an aberration at one or more (e.g., two or more, e.g., three or more) of the genes selected from the group consisting of ARAF, ARID 1 A, ASXL1, BAP1, DNMT3A, FANCE, FGFR4, FLT3, FLT4, JAK3, KDM5C, NF1, PTCH, TERT, and TP53; and/or is MSI-stable, TMB-low, TSC2-positive, and/or INI-1 positive.
  • the cancer is serous carcinoma of endometrium, and the individual has an aberration at PIK3CA and/or is TP53-positive.
  • the cancer is metastatic colorectal cancer
  • the individual has an aberration in CRKL (e.g., amplification of the CRKL locus) and/or TP53 (e.g., a pathogenic variant of TP53, e.g., p.T253P); and/or is MSI-high, MMR-deficient (dMMR), PTEN-positive, MLH1 -positive, MLH2 -positive, MLH6-positive, and/or PMS2-positive.
  • CRKL e.g., amplification of the CRKL locus
  • TP53 e.g., a pathogenic variant of TP53, e.g., p.T253P
  • MSI-high, MMR-deficient (dMMR) PTEN-positive
  • MLH1 -positive MLH2 -positive
  • MLH6-positive MLH6-positive
  • the cancer is cervical adenosquamous cell carcinoma, and the individual has an aberration in ERBB2 and/or AKT2 (e.g., amplification of the AKT2 locus); and/or is PD-L1 -positive and/or TMB-intermediate.
  • AKT2 e.g., amplification of the AKT2 locus
  • the cancer is osteogenic osteosarcoma
  • the individual has an aberration at one or more (e.g., two or more, e.g., three or more) of the genes selected from the group consisting of BRCA2, FGFR1, KDM5A, MAF, MYO 18 A, PCLO, RELN, and SF3B1; and/or is RBI-positive and/or TP53 -positive.
  • the cancer is adenocarcinoma of ascending colon, and the individual has an aberration at one or more (e.g., two or more, e.g., three or more) of the genes selected from the group consisting of KRAS, NRAS, APC, BRCA, PIK3CA, SMAD4, and TP53; and/or is TMB-intermediate.
  • the genes selected from the group consisting of KRAS, NRAS, APC, BRCA, PIK3CA, SMAD4, and TP53; and/or is TMB-intermediate.
  • the cancer is pleomorphic Spindle cell sarcoma
  • the individual has an aberration at one or more (e.g., two or more, e.g., three or more) of the genes selected from the group consisting of APC, ATRX, BRCA2, FBXW7, FLT1, GNA13, IRS2, JAK3, KMT2A, MED12, MLL2, PRKAR1 A, and SOX9; and/or is microsatellite stable (MSS), TMB-low, CCND3-positive, RBI-positive, VEGFA-positive, PDL-1 -positive, and/or TSC2- positive.
  • MSS microsatellite stable
  • an individual being “-positive” for a biomarker means the individual has detectable expression of a biomarker, such as detectable via standard biomarker measurement techniques including immunohistochemistry, mass spectrometry, PCR, or sequencing.
  • the expression of a biomarker is detectable when normalized reads per kilobase million (RPKM), normalized fragments per kilobase million (FPKM) or normalized transcripts per kilobase million (TPM) of the biomarker is greater than or equal to 1.
  • an individual being “- negative” for a biomarker means the individual has no detectable expression of a biomarker, such as detectable via standard biomarker measurement techniques including immunohistochemistry, mass spectrometry, PCR, or sequencing.
  • the individual is selected for a treatment described herein on a basis of having an aberration at one or more (e.g., two or more, e.g., three or more) of the genes selected from AKT1, AKT2, APC, ARAF, ARID1A, ASXL1, ATRX, AXL, BAP1, BRCA, BRCA2, C17orf39, CCND3, CRKL, DNMT3A, ERBB2, EWSR1, EZH2, FANCE, FBXW7, FGFR1, FGFR4, FLU, FLT1, FLT3, FLT4, GNA13, HLA-A2, HLA- DPB1, IDH1, INI-1, IRS2, JAK3, KDM5A, KDM5C, KMT2A, KMT2D, KRAS, MAF, MED12, MLL2, MUTYH, MY018A, NF1, NRAS, NTRK1/2/3, NY-ESO-1, PC
  • the individual is selected for treatment on a basis of an aberration at PTEN and/or TSC2.
  • the aberration at PTEN is a PTEN loss.
  • the aberration at TSC2 is a TSC2 mutation.
  • the aberration at BRCA2 is a truncation in BRCA2 intron 7.
  • the aberration at EZH2 is a truncation in intron 19.
  • the aberration at EWSR1 is a EWSR1 fusion.
  • the EWSR1 fusion is a EWSR1-FLI1 fusion.
  • the aberration at EWSR1 is a EWSR1 gene rearrangement.
  • the aberration at FLU is a FLU fusion. In some embodiments, the FLU fusion is a EWSRl-FLIl fusion. In some embodiments, the aberration at MLL2 is a R5048H mutation. In some embodiments, the aberration at RBI is loss of RBI exons 3-9. In some embodiments, the aberration at TP53 is TP53 p.Y220C. In some embodiments, the aberration at TP53 is TP53 p.T253P. In some embodiments, the aberration at TP53 is TP53 RllOdel. In some embodiments, the aberration at AKT2 is a genetic amplification of AKT2.
  • the aberration at CRKL is a genetic amplification of CRKL.
  • the aberration in HLA-DPB1 is DPBl*04:01 and/or DPBI*04:02.
  • the individual is selected for treatment on a basis of not having a fusion in NTRK1/2/3.
  • the individual is selected for treatment on a basis of having detectable expression of a biomarker, such as detectable via standard biomarker measurement techniques including immunohistochemistry, mass spectrometry, PCR, or sequencing.
  • the expression of a biomarker is detectable when normalized reads per kilobase million (RPKM), normalized fragments per kilobase million (FPKM) or normalized transcripts per kilobase million (TPM) of the biomarker is greater than or equal to 1.
  • RPKM normalized reads per kilobase million
  • FPKM normalized fragments per kilobase million
  • TPM normalized transcripts per kilobase million
  • the individual is selected for treatment on a basis of being DPw4-positive.
  • the individual is selected for treatment on a basis of being INI-1 positive.
  • the individual is selected for treatment on a basis of being NYESO positive and HLA-A2 positive. In some embodiments, the individual is selected for treatment on a basis of being PTEN-positive. In some embodiments, the individual is selected for treatment on a basis of not having detectable expression of a biomarker. In some embodiments, the individual is selected for treatment on a basis of being PD-L1 -negative. In some embodiments, the individual is selected for treatment on a basis of having a mutational status or genotype. In some embodiments, the individual is selected for treatment on a basis of being tumor mutational burden (TMB)-low. In some embodiments, the individual is selected for treatment on a basis of being TMB-intermediate.
  • TMB tumor mutational burden
  • the individual is selected for treatment on a basis of being tumor exonic mutational burden high. In some embodiments, the individual is selected for treatment on a basis of being microsatellite stable (MSS). In some embodiments, the individual is selected for treatment on a basis of having high microsatellite instability and/or mismatch repair (MMR)-deficient.
  • MSS microsatellite stable
  • MMR mismatch repair
  • tumor mutational burden is the number of somatic (non-inherited) mutations per megabase (Mb) of genome.
  • TMB can be used as a metric for predicting outcomes such as cancer treatment success and survival probability.
  • TMB can be measured using high throughput sequencing techniques such as NGS.
  • Different cancers may have variations in TMB levels.
  • TMB levels can be categorized as high, intermediate and low, based on the number of mutations/Mb. For example, in some embodiments, TMB levels can be set as follows: (i) low - 1-5 mutations/Mb; (ii) intermediate - 6-15 mutations/Mb; and (iii) high - 16 or more mutations/Mb.
  • MMR Mismatch repair
  • pMMR MMR proficient
  • dMMR MMR deficient
  • Microsatellite instability is a phenotype that results when DNA mismatch repair is defective.
  • MSI is a marker for cancer MMR status. MSI results in the insertion or deletion of repetitive sequences in the genome. MSI status is tested using PCR-based assays to determine the instability using five markers: BAT-25, BAT-26, D2S123, D5S346 and D17S250.
  • MSI status can be subdivided into high microsatellite instability (MSI-H: two or more markers are unstable), low microsatellite instability (MSI-L: one marker is unstable), and microsatellite stable (MSS: no markers show instability).
  • based upon includes assessing, determining, or measuring the individual’s characteristics as described herein (and preferably selecting an individual suitable for receiving treatment).
  • the status of an aberration is “used as a basis” for selection, assessing, measuring, or determining method of treatment as described herein, the aberration at one or more genes is determined before and/or during treatment, and the status (including presence, absence, expression level, activity level and/or phosphorylation level of the aberration) obtained is used by a clinician in assessing any of the following: (a) probable or likely suitability of an individual to initially receive treatment(s); (b) probable or likely unsuitability of an individual to initially receive treatment(s); (c) responsiveness to treatment; (d) probable or likely suitability of an individual to continue to receive treatment(s); (e) probable or likely unsuitability of an individual to continue to receive treatment(s); (I) adjusting dosage; or (g) predicting likelihood of clinical benefits.
  • an individual when selected for treatment “on a basis” of having an aberration (including presence, absence, expression level, activity level and/or phosphorylation level of the aberration) at one or more genetic aberrations, individual may be selected for treatment on more than one basis, and the selection basis for treatment may comprise further criteria.
  • aberration including presence, absence, expression level, activity level and/or phosphorylation level of the aberration
  • the undifferentiated pleomorphic sarcoma is characterized as having a PTEN loss and/ or a TSC2 mutation.
  • the leiomyosarcoma is characterized as being estrogen receptorpositive leiomyosarcoma.
  • steps for assessing and/ or determining the status of a cancer, such as undifferentiated pleomorphic sarcoma and/ or leiomyosarcoma, in an individual are examples of a cancer, such as undifferentiated pleomorphic sarcoma and/ or leiomyosarcoma, in an individual.
  • the method comprises obtaining a sample of the cancer, such as undifferentiated pleomorphic sarcoma and/ or leiomyosarcoma, from an individual.
  • the method comprises determining the presence, absence, or level of a biomarker, e.g, presence of a PTEN loss, such as via protein expression, sequencing, or an activity assay.
  • the method comprises determining the presence of a TSC2 mutation, such as via protein expression, sequencing, or an activity assay.
  • the method comprises determining the presence, absence, or level of an estrogen receptor, such as via protein expression, sequencing, or an activity assay.
  • the status of a cancer and/or an individual can be assessed or determined by analyzing a sample from the individual.
  • the assessment may be based on fresh tissue samples or archived tissue samples. Suitable samples include, but are not limited to, tumor tissue, normal tissue adjacent to the tumor tissue, normal tissue distal to the tumor tissue, or peripheral blood lymphocytes.
  • the sample is a tumor tissue.
  • the sample is a biopsy containing tumor cells, such as fine needle aspiration of solid tumor cells or laparoscopy obtained tumor cells.
  • the biopsied cells are centrifuged into a pellet, fixed, and embedded in paraffin prior to the analysis. In some embodiments, the biopsied cells are flash frozen prior to the analysis. In some embodiments, the sample is a plasma sample.
  • the sample comprises a circulating metastatic cancer cell.
  • the sample is obtained by sorting circulating tumor cells (CTCs) from blood.
  • CTCs circulating tumor cells
  • the CTCs have detached from a primary tumor and circulate in a bodily fluid.
  • the CTCs have detached from a primary tumor and circulate in the bloodstream.
  • the CTCs are an indication of metastasis.
  • the sample is mixed with an antibody that recognizes a molecule (such as a protein) or fragment thereof.
  • the sample is mixed with a nucleic acid that recognizes nucleic acids (such as DNA or RNA) or fragment thereof.
  • the sample is used for sequencing analysis, such as next-generation DNA, RNA and/or exome sequencing analysis.
  • Samples may be assessed before the start of the treatment, at any time during the treatment, and/or at the end of the treatment.
  • compositions comprising nanoparticles comprising an mTOR inhibitor
  • the mTOR inhibitor nanoparticle compositions described herein comprise nanoparticles comprising (in various embodiments consisting essentially of or consisting of) an mTOR inhibitor (such as a limus drug, e.g, rapamycin or a derivative thereof) and an albumin (such as human serum albumin).
  • an mTOR inhibitor such as a limus drug, e.g, rapamycin or a derivative thereof
  • an albumin such as human serum albumin.
  • Nanoparticles of poorly water soluble drugs have been disclosed in, for example, U. S. Pat. Nos.5, 916, 596; 6,506,405; 6,749,868, 6,537,579, 7,820,788, and 8,911,786, 11,497,737, and also in U. S. Pat. Pub. Nos. 2006/0263434, and 2007/0082838; PCT Patent Application W008/137148, U.S. Patent Application No.: 62/927,047, each of which is
  • the composition comprises nanoparticles with an average or mean diameter of no greater than about 1000 nanometers (nm), such as no greater than about any of 900, 800, 700, 600, 500, 400, 300, 200, and 100 nm.
  • the average or mean diameters of the nanoparticles is no greater than about 200 nm.
  • the average or mean diameters of the nanoparticles is no greater than about 150 nm.
  • the average or mean diameters of the nanoparticles is no greater than about 100 nm.
  • the average or mean diameter of the nanoparticles is about 10 to about 400 nm.
  • the average or mean diameter of the nanoparticles is about 10 to about 150 nm. In some embodiments, the average or mean diameter of the nanoparticles is about 40 to about 120 nm. In some embodiments, the average or mean diameter of the nanoparticles are no less than about 50 nm. In some embodiments, the nanoparticles are sterile- filterable.
  • the particle size is measured as the volume-weighted mean particle size (Dv50) of the nanoparticles in the composition.
  • the nanoparticles comprise the mTOR inhibitor associated with the albumin. In some embodiments, the nanoparticles comprise the mTOR inhibitor coated with the albumin.
  • the albumin has sulfhydryl groups that can form disulfide bonds.
  • at least about 5% including for example at least about any one of 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%) of the albumin in the nanoparticle portion of the composition are crosslinked (for example crosslinked through one or more disulfide bonds).
  • the nanoparticles comprising the mTOR inhibitor (such as a limus drug, e.g, rapamycin or a derivative thereof) are associated (e.g, coated) with an albumin (such as human albumin or human serum albumin).
  • a limus drug e.g, rapamycin or a derivative thereof
  • an albumin such as human albumin or human serum albumin
  • the composition comprises an mTOR inhibitor (such as a limus drug, e.g, rapamycin or a derivative thereof) in both nanoparticle and non-nanoparticle forms (e.g, in the form of solutions or in the form of soluble albumin/nanoparticle complexes), wherein at least about any one of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the mTOR inhibitor in the composition are in nanoparticle form.
  • an mTOR inhibitor such as a limus drug, e.g, rapamycin or a derivative thereof
  • the mTOR inhibitor (such as a limus drug, e.g, rapamycin or a derivative thereof) in the nanoparticles constitutes more than about any one of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the nanoparticles by weight.
  • the nanoparticles have a non-polymeric matrix.
  • the nanoparticles comprise a core of an mTOR inhibitor (such as a limus drug, e.g, rapamycin or a derivative thereof) that is substantially free of polymeric materials (such as polymeric matrix).
  • the composition comprises an albumin in both nanoparticle and non-nanoparticle portions of the composition, wherein at least about any one of 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the albumin in the composition are in non-nanoparticle portion of the composition.
  • the weight ratio of the albumin to the mTOR inhibitor (such as a limus drug, e.g, rapamycin or a derivative thereof) in the mTOR inhibitor nanoparticle composition is such that a sufficient amount of mTOR inhibitor binds to, or is transported by, the cell.
  • the weight ratio of an albumin to an mTOR inhibitor (such as a limus drug, e.g, rapamycin or a derivative thereof) will have to be optimized for different albumin and mTOR inhibitor combinations
  • the weight ratio of an albumin to an mTOR inhibitor (such as a limus drug, e.g., rapamycin or a derivative thereof) (w/w) 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.
  • the albumin to mTOR inhibitor (such as a limus drug, e.g., rapamycin or a derivative thereof) weight ratio is about any of 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.
  • a limus drug e.g., rapamycin or a derivative thereof
  • the weight ratio of the albumin (such as human albumin or human serum albumin) to the mTOR inhibitor (such as a limus drug, e.g, rapamycin or a derivative thereof) in the composition is any 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, about 1 : 1 to about 1:1.
  • the composition comprises nanoparticles comprising an mTOR inhibitor and an albumin, wherein the weight ratio of the albumin to the mTOR inhibitor in the composition is about 0.01:1 to about 100:1.
  • the composition comprises nanoparticles comprising an mTOR inhibitor (such as rapamycin) and an albumin, wherein the weight ratio of the albumin to the mTOR inhibitor (such as rapamycin) in the composition is about 18:1 or less (including for example 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).
  • the composition comprises nanoparticles comprising rapamycin, or a derivative thereof, and an albumin, wherein the weight ratio of the albumin to the rapamycin or derivative thereof in the composition is about 18:1 or less (including for example 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).
  • the mTOR inhibitor (such as rapamycin) is coated with albumin.
  • the mTOR inhibitor nanoparticle composition (such as rapamycin/albumin nanoparticle composition) comprises one or more of the above characteristics.
  • the nanoparticles described herein may be present in a dry formulation (such as lyophilized composition) or suspended in a biocompatible medium.
  • Suitable biocompatible media include, but are not limited to, water, buffered aqueous media, saline, buffered saline, optionally buffered solutions of amino acids, optionally buffered solutions of proteins, optionally buffered solutions of sugars, optionally buffered solutions of vitamins, optionally buffered solutions of synthetic polymers, lipid-containing emulsions, and the like.
  • the pharmaceutically acceptable carrier comprises an albumin (such as human albumin or human serum albumin).
  • the albumin may either be natural in origin or synthetically prepared.
  • the albumin is human albumin or human serum albumin.
  • the albumin is a recombinant albumin.
  • HSA Human serum albumin
  • HSA solution Intravenous use of HSA solution has been 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 in conjunction with exchange transfusion in the treatment of neonatal hyperbilirubinemia (see, e.g., Finlayson, Seminars in Thrombosis and Hemostasis, 6, 85-120, (1980)).
  • Other albumins are contemplated, such as bovine serum albumin.
  • HSA Human serum albumin
  • HSA has multiple hydrophobic binding sites (a total of eight for fatty acids, an endogenous ligand of HSA) and binds a diverse set of drugs, especially neutral and negatively charged hydrophobic compounds (Goodman et al., The Pharmacological Basis of Therapeutics, 9 th ed, McGraw-Hill New York (1996)).
  • Rapamycin and propofol have been shown to bind HSA (see, e.g., Paal et al., Eur. J. Biochem., 268(7), 2187-91 (200a), Purcell et al., Biochem. Biophys. Acta, 1478(a), 61-8 (2000), AAXmayex et al., Arzneistoffforschung, 45, 1053-6 (1995), and Garrido et al., Rev. Esp. Anestestiol.
  • An mTOR inhibitor (such as a limus drug, e.g. , rapamycin or a derivative thereol) is “stabilized” in an aqueous suspension if it remains suspended in an aqueous medium (such as without visible precipitation or sedimentation) for an extended period of time, such as for at least about any of 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.
  • the suspension is generally, but not necessarily, suitable for administration to an individual (such as a human). Stability of the suspension is generally (but not necessarily) evaluated at a storage temperature (such as room temperature (such as 20-25 °C) or refrigerated conditions (such as 4 °C)).
  • a suspension is stable at a storage temperature if it exhibits no flocculation or particle agglomeration visible to the naked eye or when viewed using an optical microscope at 1000 times, at about fifteen minutes after preparation of the suspension. Stability can also be evaluated under accelerated testing conditions, such as at a temperature that is about 40 °C or higher.
  • compositions described herein may be a stable aqueous suspension of the mTOR inhibitor, such as a stable aqueous suspension of the mTOR inhibitor at a concentration of any of about 0.1 to about 200 mg/ml, about 0.1 to about 150 mg/ml, about 0.1 to about 100 mg/ml, 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, and about 5 mg/ml.
  • the concentration of the mTOR inhibitor is at least about any of 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.
  • the albumin is present in an amount that is sufficient to stabilize the mTOR inhibitor (such as a limus drug, e.g., rapamycin or a derivative thereol) in an aqueous suspension at a certain concentration.
  • the concentration of the mTOR inhibitor (such as a limus drug, e.g., rapamycin or a derivative thereof) in the composition is about 0.1 to about 100 mg/ml, including for example about any of 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.
  • the concentration of the mTOR inhibitor (such as a limus drug, e.g., rapamycin or a derivative thereof) is at least about any of 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.
  • the albumin is present in an amount that avoids use of surfactants (such as Cremophor), so that the composition is free or substantially free of surfactant (such as Cremophor).
  • the composition, in liquid form comprises from about 0.1% to about 50% (w/v) (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)) of an albumin.
  • the composition, in liquid form comprises about 0.5% to about 5% (w/v) of albumin.
  • the albumin allows the composition to be administered to an individual (such as a human) without significant side effects.
  • the albumin (such as human serum albumin or human albumin) is in an amount that is effective to reduce one or more side effects of administration of the mTOR inhibitor (such as a limus drug, e.g, rapamycin or a derivative thereof) to a human.
  • the mTOR inhibitor such as a limus drug, e.g, rapamycin or a derivative thereof
  • reducing one or more side effects of administration of the mTOR inhibitor refers to reduction, alleviation, elimination, or avoidance of one or more undesirable effects caused by the mTOR inhibitor, as well as side effects caused by delivery vehicles (such as solvents that render the limus drugs suitable for injection) used to deliver the mTOR inhibitor.
  • Such side effects include, for example, myelosuppression, neurotoxicity, hypersensitivity, inflammation, venous irritation, phlebitis, pain, skin irritation, peripheral neuropathy, neutropenic fever, anaphylactic reaction, venous thrombosis, extravasation, and combinations thereof.
  • side effects are merely exemplary and other side effects, or combination of side effects, associated with limus drugs (such as a limus drug, e.g, rapamycin or a derivative thereof) can be reduced.
  • the composition is a dry (such as lyophilized) composition that can be reconstituted, resuspended, or rehydrated to form generally a stable aqueous suspension of the nanoparticles comprising an mTOR inhibitor and an albumin.
  • the composition is a liquid (such as aqueous) composition obtained by reconstituting or resuspending a dry composition.
  • the composition is an intermediate liquid (such as aqueous) composition that can be dried (such as lyophilized).
  • mTOR inhibitor used herein refers to an inhibitor of mTOR.
  • mTOR is a serine/threonine-specific protein kinase downstream of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) pathway, and a key regulator of cell survival, proliferation, stress, and metabolism.
  • PI3K phosphatidylinositol 3-kinase
  • Akt protein kinase B pathway
  • mTOR The mammalian target of rapamycin (mTOR) (also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 (FRAP1)) is an atypical serine/threonine protein kinase that is present in two distinct complexes, mTOR Complex 1 (mTORCl) and mTOR Complex 2 (mT0RC2).
  • mTORCl is composed of mTOR, regulatory- associated protein of mTOR (Raptor), mammalian lethal with SEC 13 protein 8 (MLST8), PRAS40 and DEPTOR (Kim et al. (2002). Cell 110: 163-75; Fang et al. (2001). Science 294 (5548): 1942-5).
  • mTORCl integrates four major signal inputs: nutrients (such as amino acids and phosphatidic acid), growth factors (insulin), energy and stress (such as hypoxia and DNA damage).
  • nutrients such as amino acids and phosphatidic acid
  • growth factors such as growth factors and phosphatidic acid
  • energy and stress such as hypoxia and DNA damage.
  • Amino acid availability is signaled to mTORCl via a pathway involving the Rag and Ragulator (LAMTOR1-3)
  • Growth factors and hormones e.g, insulin
  • Akt which inactivates TSC2 to prevent inhibition of mTORCl.
  • low ATP levels lead to the AMPK-dependent activation of TSC2 and phosphorylation of raptor to reduce mTORCl signaling proteins.
  • mTORCl has a number of downstream biological effects including translation of mRNA via the phosphorylation of downstream targets (4E-BP1 and p70 S6 Kinase), suppression of autophagy (Atgl3, ULK1), ribosome biogenesis, and activation of transcription leading to mitochondrial metabolism or adipogenesis. Accordingly, mTORCl activity promotes either cellular growth when conditions are favorable or catabolic processes during stress or when conditions are unfavorable.
  • mTORC2 is composed of mTOR, rapamycin-insensitive companion of mTOR (RICTOR), G[3L, and mammalian stress-activated protein kinase interacting protein 1 (mSINl).
  • mTORC2 In contrast to mTORCl, for which many upstream signals and cellular functions have been defined (see above), relatively little is known about mTORC2 biology.
  • mT0RC2 regulates cytoskeletal organization through its stimulation of F-actin stress fibers, paxillin, RhoA, Rael, Cdc42, and protein kinase C a (PKCa). It had been observed that knocking down mT0RC2 components affects actin polymerization and perturbs cell morphology (Jacinto et al. (2004). Nat. Cell Biol. 6, 1122-1128; Sarbassov et al. (2004). Curr. Biol. 14, 1296-1302).
  • mTORC2 controls the actin cytoskeleton by promoting protein kinase Ca (PKCa) phosphorylation, phosphorylation of paxillin and its relocalization to focal adhesions, and the GTP loading of RhoA and Rael.
  • PKCa protein kinase Ca
  • the mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) is an inhibitor of mTORCl. In some embodiments, the mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) is an inhibitor of mT0RC2. In some embodiments, the mTOR inhibitor (such as a limus drug, e.g, sirolimus or a derivative thereof) is an inhibitor of both mTORCf and mT0RC2.
  • the mTOR inhibitor is a limus drug, which includes sirolimus and its analogs.
  • limus drugs include, but are not limited to, temsirolimus (CCI- 779), everolimus (RAD001), ridaforolimus (AP-23573), deforolimus ( MK-8669), zotarolimus (ABT-578), pimecrolimus, and tacrolimus (FK-506).
  • the limus drug is selected from the group consisting of temsirolimus (CCI-779), everolimus (RAD001), ridaforolimus (AP-23573), deforolimus (MK-8669), zotarolimus (ABT-578), pimecrolimus, and tacrolimus (FK-506).
  • the mTOR inhibitor is an mTOR kinase inhibitor, such as CC-115 or CC-223.
  • the mTOR inhibitor is sirolimus.
  • Sirolimus is macrolide antibiotic that complexes with FKBP-12 and inhibits the mTOR pathway by binding mTORCl.
  • the mTOR inhibitor is selected from the group consisting of sirolimus (rapamycin), BEZ235 (NVP-BEZ235), everolimus (also known as RAD001, Zortress, Certican, and Afinitor), AZD 8055, temsirolimus (also known as CCI-779 and Torisel), CC-115, CC-223, PI-103, Ku-0063794, INK 128, AZD2014, NVP-BGT226, PF-04691502, CH5132799, GDC-0980 (RG7422), Torin 1, WAY-600, WYE-125132, WYE-687, GSK2126458, PF- 05212384 (PKI-587), PP-121, OSI-027, Palomid 529, PP242, XL765, GSK1059615, WYE-354, and ridaforolimus (also known as deforolimus).
  • BEZ235 is an imidazoquilonine derivative that is an mTORCl catalytic inhibitor (Roper J, et al. PLoS One, 2011, 6(9), e25132).
  • Everolimus is the 40-O-(2- hydroxy ethyl) derivative of sirolimus and binds the cyclophilin FKBP-12, and this complex also mTORCl.
  • AZD8055 is a small molecule that inhibits the phosphorylation of mTORCl (p70S6K and 4E-BP1).
  • Temsirolimus is a small molecule that forms a complex with the FK506-binding protein and prohibits the activation of mTOR when it resides in the mTORCl complex.
  • PI-103 is a small molecule that inhibits the activation of the rapamycin-sensitive (mTORCl) complex (Knight et al. (2006) Cell. 125: 733-47).
  • KU-0063794 is a small molecule that inhibits the phosphorylation of mTORCl at Ser2448 in a dose-dependent and time-dependent manner.
  • GDC-0980 is an orally bioavailable small molecule that inhibits Class I PI3 Kinase and TORC1.
  • Torin 1 is a potent small molecule inhibitor of mTOR.
  • WAY-600 is a potent, ATP-competitive and selective inhibitor of mTOR.
  • WYE-125132 is an ATP-competitive small molecule inhibitor of mTORCl.
  • GSK2126458 is an inhibitor of mTORCl.
  • PKI-587 is a highly potent dual inhibitor of PI3Ka, PI3Ky 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 mTORCl and mTORC2 with IC50 of 22 nM and 65 nM, respectively.
  • Palomid 529 is a small molecule inhibitor of mTORCl that lacks affinity for ABCB1/ABCG2 and has good brain penetration (Lin et al. (2013) Int J Cancer DOI:
  • PP242 is a selective mTOR inhibitor.
  • XL765 is a dual inhibitor of mTOR/PI3k for mTOR, pl 10a, pl 10[3, pl lOy and pl 106.
  • GSK1059615 is a novel and dual inhibitor of PI3Ka, PI3KJ3, PI3K8, PI3Ky and mTOR.
  • WYE-354 inhibits mTORCl in HEK293 cells (0.2 pM-5 pM) and in HUVEC cells (10 nM-lpM).
  • WYE-354 is a potent, specific and ATP-competitive inhibitor of mTOR.
  • Deforolimus (Ridaforolimus, AP23573, MK-8669) is a selective mTOR inhibitor.
  • C Other components in the Nanoparticle Composition
  • the composition is suitable for administration to a human.
  • the composition is suitable for administration to a mammal such as, in the veterinary context, domestic pets and agricultural animals.
  • the following formulations and methods are merely exemplary and are in no way limiting.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions.
  • Tablet forms can include one or more of lactose, mannitol, com starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • Suitable carriers, excipients, and diluents include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, saline solution, syrup, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation compatible with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. Injectable formulations are preferred.
  • the composition is formulated to have a pH range of about 4.5 to about 9.0, including for example pH ranges of about any of 5.0 to about 8.0, about 6.5 to about 7.5, and about 6.5 to about 7.0.
  • the pH of the composition is formulated to no less than about 6, including for example no less than about any of 6.5, 7, or 8 (such as about 8).
  • the composition can also be made to be isotonic with blood by the addition of a suitable tonicity modifier, such as glycerol.
  • the methods described herein are particularly suitable for albumin-based nanoparticle compositions described herein in more details.
  • the nanoparticle composition in some embodiments includes (a) nanoparticles that include rapamycin and albumin, and (b) a non-nanoparticle portion that includes rapamycin and albumin.
  • the rapamycin and the albumin of the nanoparticles are associated with each other in the nanoparticles.
  • the nanoparticles may include a coating having the albumin, which surrounds a core comprising the rapamycin.
  • the rapamycin and the albumin may or may not associated with each other (z.e., the rapamycin may be in a reversible binding equilibrium with the albumin), but do not associate with each other in a manner that forms nanoparticles. That is, the nanoparticle composition may include 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.
  • the albumin of the nanoparticles may be further distinguishable from the albumin in the non-nanoparticle portion of the composition; for example, the oligomeric profile of the albumin in the nanoparticles may differ from the oligomeric profile of the albumin in the non-nanoparticle portion of the composition.
  • the oligomer profile means the percentage of various albumin species compared with the total albumin in the composition.
  • the types of albumin species includes albumin monomers, dimers, trimers, oligomers, and polymers.
  • albumin monomers or “monomeric albumin” refers to an albumin species having one, and only one, albumin unit
  • albumin dimers or “dimeric albumin” refers to an albumin species having two, and only two, albumin units
  • albumin trimers or “trimeric albumin” refers to albumin species having three, and only three, albumin units
  • albumin polymers refers to albumin species having a higher molecular weight than albumin monomers and albumin dimers
  • albumin oligomers or “oligomeric albumin” refers to lower molecular weight polymeric albumin species associated with a UV-based size-exclusion chromatography peak observed between a peak associated with albumin dimers and higher molecular weight polymeric albumin species.
  • the albumin of the nanoparticles associates with the rapamycin of the nanoparticles so that a nanoparticle suspension has a high concentration of rapamycin, which allows the composition to be used as a pharmaceutical composition for treating certain diseases, such as cancer.
  • Manufactured nanoparticles (which may be made, for example, using the methods described herein) may be formulated, filtered, or otherwise processed to obtain the pharmaceutical composition, which may be suitable for medical use in a human individual.
  • rapamycin is dissolved in an organic solvent.
  • organic solvents include, for example, ketones, esters, ethers, chlorinated solvents, and other solvents known in the art.
  • the organic solvent can be a mixture of methylene chloride/ethanol, chloroform/ethanol, or chloroform//c/7-butanol (for example with a ratio of about any one of 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 with a ratio of about any one of 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).
  • the organic solvent comprises between about 10% and about 50% tert-butanol by volume.
  • the organic solvent comprises about any of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% tert-butanol by volume. In some embodiments, the organic solvent comprises about any of 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, or 45-50%, or any combination of such ranges, of tert-butanol by volume. In some embodiments, the organic solvent comprises between about 50% and about 90% chloroform by volume. In some embodiments, the organic solvent comprises about any of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% chloroform by volume.
  • the organic solvent comprises about any of 50- 55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, or 85-90%, or any combination of such ranges, of chloroform by volume. In some embodiments, the organic solvent comprises between about 10% and about 50% tert-butanol by volume and between about 50% and about 90% chloroform by volume. In some embodiments, the organic solvent comprises chloroform and tert-butanol at a volumetric ratio of about 1:1 to about 1:9, such as about any of 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, and 9:1.
  • Albumin such as recombinant albumin, for example NOVOZYMETM recombinant albumin or INTRIVIATM recombinant albumin disclosed herein
  • an aqueous solution such as water
  • the mixture is subjected to high pressure homogenization (e.g, using an Avestin, APV Gaulin, MICROFLUIDIZERTM such as a MICROFLUIDIZERTM Processor M-l 10EH from Microfluidics, Stansted, or Ultra Turrax homogenizer).
  • the emulsion may be cycled through the high pressure homogenizer for between about 2 to about 100 cycles, such as about 5 to about 50 cycles or about 6 to about 20 cycles (e.g, about any one of 6, 8, 10, 12, 14, 16, 18 or 20 cycles).
  • the organic solvent can then be removed by evaporation utilizing suitable equipment known for this purpose, including, but not limited to, rotary evaporators, falling film evaporators, wiped film evaporators, spray driers, and the like that can be operated in batch mode or in continuous operation.
  • the evaporator is a wiped film evaporator.
  • the solvent may be removed at reduced pressure (such as at about any one of 25 mm Hg, 30 mm Hg, 40 mm Hg, 50 mm Hg, 100 mm Hg, 200 mm Hg, or 300 mm Hg).
  • the amount of time used to remove the solvent under reduced pressure may be adjusted based on the volume of the formulation. For example, for a formulation produced on a 300 mL scale, the solvent can be removed at about 1 to about 300 mm Hg (e.g, about any one of 5-100 mm Hg, 10-50 mm Hg, 20-40 mm Hg, or 25 mm Hg) for about 5 to about 60 minutes (e.g, about any one of 7, 8, 9, 10, 11, 12, 13, 14, 15 16, 18, 20, 25, or 30 minutes).
  • the dispersion obtained can be further lyophilized.
  • the nanoparticle compositions described herein may have distinct characteristics for any one or more (in any combination) of the following: (1) the oligomeric status of the albumin associated with (such as in) the nanoparticles, such as the percentage of albumin monomers, dimers, and/or polymers (or trimers) of the albumin associated with (such as in) the nanoparticles; (2) the oligomeric status of the albumin associated with (such as in) the non-nanoparticle portion of the composition, such as the percentage of albumin monomers, dimers, and/or polymers (or trimers) of the albumin associated with (such as in) the non-nanoparticle portion of the composition; (3) the oligomeric status of the total albumin in the composition, such as the percentage of albumin monomers, dimers, and/or polymers (or trimers) of the total albumin in the composition; (4) the particle size profile of the nanoparticles, such as the average particle size, poly dispersity index, and
  • the oligomeric status (such as the percentage of albumin monomers, dimers, or polymers (or trimers)) of the nanoparticles, the non-nanoparticles portion, or the total composition is assessed by sizeexclusion chromatography using a saline mobile phase coupled with a multiple angle light scattering (MALS) detector).
  • MALS multiple angle light scattering
  • the nanoparticle compositions described herein may have distinct characteristics for any one or more (in any combination) of the following: (1) the oligomeric status of the albumin associated with (such as in) the nanoparticles, such as the percentage of albumin monomers, dimers, oligomers, and/or polymers (other than oligomers) of the albumin associated with (such as in) the nanoparticles; (2) the oligomeric status of the albumin associated with (such as in) the non-nanoparticle portion of the composition, such as the percentage of albumin monomers, dimers, oligomers, and/or polymers (other than oligomers) of the albumin associated with (such as in) the non-nanoparticle portion of the composition; (3) the oligomeric status of the total albumin in the composition, such as the percentage of albumin monomers, dimers, oligomers, and/or polymers (other than oligomers) of the total albumin in the composition; (4) the oligomeric status of the total albumin
  • albumin oligomers or “oligomeric albumin” refers to lower molecular weight polymeric albumin species associated with a UV-absorbance-based size-exclusion chromatography peak observed between a peak associated with albumin dimers and higher molecular weight polymeric albumin species.
  • the oligomeric status (such as the percentage of albumin monomers, dimers, oligomers, or polymers (other than oligomers)) of the nanoparticles, the non- nanoparticle portion, or the total composition is assessed by size-exclusion chromatography using a mobile phase containing an aqueous portion and a miscible organic portion (such as an aqueous buffer containing 7.5% methanol) coupled with a UV detector.
  • a mobile phase containing an aqueous portion and a miscible organic portion such as an aqueous buffer containing 7.5% methanol
  • the percentage of albumin in the nanoparticle portion that is in the form of monomeric, dimeric, oligomeric, or polymeric albumin (other than oligomeric albumin) is determined by separating the nanoparticles from the non-nanoparticle portion, dissolving the nanoparticles, and subjecting the dissolved nanoparticles to size-exclusion chromatography.
  • the sizeexclusion chromatography uses a mobile phase containing an aqueous portion and a miscible organic portion (such as an aqueous buffer containing 7.5% methanol) coupled with a UV detector.
  • the nanoparticle composition has one or more of the following 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 dimeric 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 trimeric albumin); (4) the weight ratio of the total albumin to the 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 the nanoparticles; (6) about 90% or more (or as further provided herein) of the total albumin in the composition is in the non-nanoparticle portion of the nanoparticles; (7) the composition comprises tert-butanol at a
  • 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 in alternative to any one of the previously described district characteristics): (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, such as about 1 mg/mL to about 7 mg/mL); (3) the osmolality of the composition is about 300 mOsm/kg to about 350 mOsm/kg (or as otherwise provided herein); (4) the viscosity of the composition is about 1.2 cP to about 1.5 cP (or as otherwise provided herein); and/or (5) the pH of the composition is about 6.0 to about 7.5 (or as otherwise provided herein).
  • the nanoparticles of the composition have one or more of the following distinct characteristics: (1) about 70% to about 85% (or as otherwise provided herein) of the albumin in the nanoparticles is in the form of albumin monomers; (2) about 9% to about 20% (or as otherwise provided herein) of the albumin in the nanoparticles is in the form of albumin dimers; (3) about 5% to about 15% (or as otherwise provided herein) of the albumin in the nanoparticles is in the form of albumin polymers (or albumin trimers); (4) the nanoparticles have a volume weighted mean particle size and/or Z-av erage particle size of about 200 nm or less (or as otherwise provided herein, such as between about 50 nm and about 200 nm); (5) the nanoparticles have a poly dispersity index of less than about 0.2 (or as otherwise provided herein, such as between about 0.03 and about 0.2); (6) the span of the particle size distribution ((Dv95- Dv
  • the nanoparticle composition may be a nanoparticle suspension, and in some embodiments the concentration of the albumin in the nanoparticle suspension that is in the nanoparticles is about 1.8 mg/mL to about 3 mg/mL (or as otherwise provided herein).
  • the nanoparticles of the composition have one or more of the following distinct characteristics: (1) about 25% to about 50% (or as otherwise provided herein) of the albumin in the nanoparticles is in the form of albumin monomers; (2) about 5% to about 16% (or as otherwise provided herein) of the albumin in the nanoparticles is in the form of albumin dimers; (3) about 1% to about 4.5% (or as otherwise provided herein) of the albumin in the nanoparticles is in the form of albumin oligomers; (4) about 42% to about 60% (or as otherwise provided herein) of the albumin in the nanoparticles is in the form of albumin polymers (other than oligomers); (5) the nanoparticles have a volume weighted mean particle size and/or Z-average particle size of about 200 nm or less (or as otherwise provided herein, such as between about 50 nm and about 200 nm); (6) the nanoparticles have a poly dispersity index of less than about 0.2
  • the nanoparticle composition may be a nanoparticle suspension, and in some embodiments the concentration of the albumin in the nanoparticle suspension that is in the nanoparticles is about 1.8 mg/mL to about 3 mg/mL (or as otherwise provided herein).
  • 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).
  • 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 in alternative to any one of the previously described district characteristics): (1) the concentration of albumin in the non-nanoparticle portion of the composition is between about 30 mg/mL and about 100 mg/mL (or as otherwise provided herein); and/or (2) the concentration of rapamycin in the non-nanoparticle portion is about 20 pg/mL to about 55 pg/mL (or as otherwise provided herein).
  • 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).
  • 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 in alternative to any one of the previously described district characteristics): (1) the concentration of albumin in the non-nanoparticle portion of the composition is between about 30 mg/mL and about 100 mg/mL (or as otherwise provided herein); and/or (2) the concentration of rapamycin in the non-nanoparticle portion is about 20 pg/mL to about 55 pg/mL (or as otherwise provided herein).
  • compositions can be in liquid (e.g, as a nanoparticle suspension) or powder forms.
  • the composition is a liquid nanoparticle suspension (for example prior to lyophilization).
  • the composition is a reconstituted suspension (e.g, in an aqueous solution such as a saline solution).
  • the composition is dried, such as lyophilized.
  • the composition is sterile.
  • the composition is contained in a sealed container, such as a sealed vial (e.g, a glass vial) or sealed bag.
  • the nanoparticle composition comprises (a) nanoparticles comprising rapamycin and albumin (such as human albumin), and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • 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 polymeric albumin (or trimeric albumin).
  • 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 dimeric albumin.
  • 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 monomeric albumin.
  • the weight ratio of the albumin to the rapamycin in the composition is about 1 : 1 to about 10:1.
  • about 90% or more of the albumin in the composition is in the non-nanoparticle portion.
  • about 90% or more of the rapamycin in the composition is in the nanoparticles.
  • the concentration of albumin in the nanoparticle composition that is in the non-nanoparticle portion or the concentration of total albumin in the nanoparticle composition is about 30 mg/mL to about 100 mg/mL.
  • the osmolality 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 morphology. In some embodiment, the nanoparticle composition is a nanoparticle suspension. In some embodiments, the nanoparticle composition is a dried composition. In some embodiments, the nanoparticle composition is sterile, for example by filtration.
  • the nanoparticle composition is contained within a sealed container, such as a sealed vial or a sealed bag. In some embodiments, the nanoparticle composition comprises less than 10 pg/mL tert-butanol and/or comprises less than 5 pg/mL chloroform.
  • 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.
  • albumin such as human albumin
  • 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.
  • albumin such as human albumin
  • 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 polymeric albumin (or trimeric albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • 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 polymeric albumin (other than oligomeric albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • 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 dimeric albumin; and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • 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 dimeric albumin; and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • 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 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.
  • albumin such as human albumin
  • 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, 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 comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as about 50 nm to about 200 nm), 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 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.
  • albumin such as human albumin
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as about 50 nm to about 200 nm), comprising a coating comprising albumin (such as human albumin) and a core comprising 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 comprising albumin (such as human albumin) and rapamycin.
  • a Z-average particle size of about 200 nm or less such as about 50 nm to about 200 nm
  • albumin such as human albumin
  • rapamycin a non-nanoparticle portion comprising albumin (such as human albumin
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as about 50 nm to about 200 nm), comprising about 55% to about 65% (by weight) rapamycin and about 25% to about 45% (by weight) 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 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.
  • a Z-average particle size of about 200 nm or less such as about 50 nm to about 200 nm
  • albumin such as human albumin
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as about 50 nm to about 200 nm), comprising a coating comprising albumin (such as human albumin) and a core comprising rapamycin, wherein the albumin comprises about 25% to about 45% of the nanoparticles by weight and the rapamycin comprises about 55% to about 75% of the nanoparticles by weight, 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.
  • albumin such as human albumin
  • rapamycin a non-nano
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as about 50 nm to about 200 nm), comprising about 55% to about 75% (by weight) rapamycin and about 25% to about 45% (by weight) 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 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; wherein the concentration of the rapamycin in the nanoparticle composition is about 1 mg/mL to about 100 mg/mL (such as about 1 mg/mL to about 15 mg/mL).
  • albumin such as human album
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as about 50 nm to about 200 nm), comprising a coating comprising albumin (such as human albumin) and a core comprising rapamycin, wherein the albumin comprises about 25% to about 45% of the nanoparticles by weight and the rapamycin comprises about 55% to about 75% of the nanoparticles by weight, 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; wherein the concentration of the rapamycin in the nanop
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as 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) rapamycin and about 25% to about 45% (by weight) 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 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; wherein the concentration of the rapamycin in the nanoparticle composition is about 1 mg/mL to
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as about 50 nm to about 200 nm) and a zeta potential of about -25 mV to about -50 mV, comprising a coating comprising albumin (such as human albumin) and a core comprising rapamycin, wherein the albumin comprises about 25% to about 45% of the nanoparticles by weight and the rapamycin comprises about 55% to about 75% of the nanoparticles by weight, 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 a non-
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as 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) rapamycin and about 25% to about 45% (by weight) 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 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; wherein the concentration of the rapamycin in the nanoparticle composition is about 1 mg/mL to
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as about 50 nm to about 200 nm) and a zeta potential of about -25 mV to about -50 mV, comprising a coating comprising albumin (such as human albumin) and a core comprising rapamycin, wherein the albumin comprises about 25% to about 45% of the nanoparticles by weight and the rapamycin comprises about 55% to about 75% of the nanoparticles by weight, 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 a non-
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as 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) rapamycin and about 25% to about 45% (by weight) 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 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; wherein the concentration of the rapamycin in the nanoparticle composition is about 1 mg/mL to
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 200 nm or less (such as about 50 nm to about 200 nm) and a zeta potential of about -25 mV to about -50 mV, comprising a coating comprising albumin (such as human albumin) and a core comprising rapamycin, wherein the albumin comprises about 25% to about 45% of the nanoparticles by weight and the rapamycin comprises about 55% to about 75% of the nanoparticles by weight, 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
  • 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; and (b) a non- nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • about 1.5% to about 3% of the albumin in the non-nanoparticle portion or the total albumin in the nanoparticle composition is in the form of polymeric albumin (or trimeric albumin).
  • about 7% to about 11% of the albumin in the non-nanoparticle portion in the nanoparticle composition is in the form of dimeric albumin.
  • about 7% to about 11% of the total albumin in the nanoparticle composition is in the form of dimeric albumin.
  • about 83% to about 92% of the albumin in the non-nanoparticle portion or the total albumin in the nanoparticle composition is in the form of monomeric albumin.
  • the weight ratio of the albumin to the rapamycin in the composition is about 7:1 to about 9:1.
  • about 95% or more of the albumin in the composition is in the non-nanoparticle portion.
  • about 98% to about 99.5% of the rapamycin in the composition is in the nanoparticles.
  • the concentration of albumin in the nanoparticle composition that is 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.
  • 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 polymeric albumin (or trimeric albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • 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 dimeric albumin; and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • 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 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 comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm, comprising rapamycin and albumin (such as human albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm, 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 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 comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm, comprising a coating comprising albumin (such as human albumin) and a core comprising 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 comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • the nanoparticle composition comprises (a) nanoparticles having a zeta potential of about -33 mV to about -39 mV, comprising rapamycin and albumin (such as human albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • the nanoparticle composition comprises (a) nanoparticles having a zeta potential of about -33 mV to about -39 mV, comprising a coating comprising albumin (such as human albumin) and a core comprising rapamycin; and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin
  • the nanoparticle composition comprises (a) nanoparticles having a zeta potential of about -33 mV to about -39 mV, 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 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 comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • the nanoparticle composition comprises (a) nanoparticles having a zeta potential of about -33 mV to about -39 mV, comprising a coating comprising albumin (such as human albumin) and a core comprising 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 comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • 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 rapamycin and albumin (such as human albumin); and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin.
  • 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 comprising albumin (such as human albumin) and a core comprising rapamycin; and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin
  • 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 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 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 comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • 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 comprising albumin (such as human albumin) and a core comprising 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 comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm, comprising about 62% to about 68% (by weight) rapamycin and about 32% to about 38% (by weight) 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 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 comprising albumin (such as human albumin) and rapamycin.
  • albumin such as human albumin
  • the nanoparticle composition comprises (a) nanoparticles having a Z-average particle size of about 85 nm to about 95 nm, comprising about 62% to about 68% (by weight) rapamycin and about 32% to about 38% (by weight) 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 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 comprising albumin (such as human albumin) and rapamycin; wherein the concentration of the rapamycin in the nanoparticle composition is about 1 mg/mL to about 100 mg/mL (such as about 1 mg/mL to about 15 mg/mL).
  • albumin such as human albumin
  • 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 about 62% to about 68% (by weight) rapamycin and about 32% to about 38% (by weight) 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 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 comprising albumin (such as human albumin) and rapamycin; wherein the concentration of the rapamycin in the nanoparticle composition is about 1 mg/mL to about 100 mg/m
  • 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 about 62% to about 68% (by weight) rapamycin and about 32% to about 38% (by weight) 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 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 comprising albumin (such as human albumin) and rapamycin; wherein the concentration of the rapamycin in the nanoparticle composition is about 1 mg/mL to about 100 mg/m
  • 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 of about -33 mV to about -39 mV, comprising about 62% to about 68% (by weight) rapamycin and about 32% to about 38% (by weight) 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 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 comprising albumin (such as human albumin) and rapamycin; wherein the concentration of the rapamycin in the nanoparticle composition is about 1 mg/mL to about 100 mg
  • “Commercial batch” as used herein refers to a batch size that is at least about 20 grams (by mass of rapamycin). Commercial batches are produced at a larger scale than experimental or bench- scale batches. The increased scale is associated with longer production times, including longer steps (such as evaporation steps) or longer hold times between steps.
  • the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered subcutaneously. In some embodiments, the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered at a dose between about 1 mg/m 2 and about 150 mg/m 2 , between about 5 mg/m 2 and about 75 mg/m 2 , e.g, via intravenous infusion.
  • a sirolimus/albumin nanoparticle composition such as FYARROTM
  • the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered at a dose of about any one of 5, 7.5, 10, 15, 30, 56, 75 or 100 mg/m 2 , e.g, via intravenous infusion.
  • the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered to the individual having cancer in one or more 21 -day cycles (e.g, three-week cycles).
  • the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered to the individual once during each 21-day cycle (e.g, three-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered during Week 1, Week 2, or Week 3 during each 21-day cycle (e.g, three-week cycle).
  • the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered on Day 1, Day 8, or Day 15 of each 21-day cycle (e.g, three-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered to the individual twice during each 21-day cycle (e.g, three-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered during Week 1 and Week 2 during each 21-day cycle (e.g, three-week cycle).
  • a sirolimus/albumin nanoparticle composition such as FYARROTM
  • the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered during Week 2 and Week 3 during each 21-day cycle (e.g, three- week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered during Week 1 and Week 3 during each 21 -day cycle (e.g, three-week cycle).
  • the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered on Day 1 and Day 8 of each 21-day cycle (e.g, three-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered on Day 1 and Day 15 of each 21-day cycle (e.g, three-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered on Day 8 and Day 15 of each 21-day cycle (e.g, three-week cycle).
  • a sirolimus/albumin nanoparticle composition such as FYARROTM
  • the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered to the individual three times during each 21-day cycle (e.g, three-week cycle). In some embodiments, the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered during Week 1, Week 2, and Week 3 during each 21-day cycle (e.g, three-week cycle).
  • the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is administered on Day 1, Day 8, and Day 15 of each 21-day cycle (e.g, three- week cycle).
  • the dosage of the mTOR inhibitor nanoparticle composition (e.g, a sirolimus/albumin nanoparticle composition, such as FYARROTM) is modified (e.g, if the individual experiences one or more adverse effects). Details regarding dosage modification for FYARROTM and circumstances under which dosage modifications are made are detailed at www(dot)accessdata(dot)fda(dot)gov/drugsatfda_docs/label/2021/2133121bl.pdf.
  • an article of manufacture containing materials useful for the treatment according to the methods provided herein, such as for undifferentiated pleomorphic sarcoma (including undifferentiated pleomorphic sarcoma having a PTEN loss and/ or a TSC2 mutation) or leiomyosarcoma (including estrogen receptor-positive leiomyosarcoma), the article of manufacture, such as a medicament or medicament combination, comprising an mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition, e.g, na/i-sirohmus) and an anti-PD-1 antibody (e.g, nivolumab).
  • an mTOR inhibitor nanoparticle composition such as sirolimus/albumin nanoparticle composition, e.g, na/i-sirohmus
  • an anti-PD-1 antibody e.g, nivolumab
  • the article of manufacture can comprise a container and a label or package insert on or associated with the container.
  • Suitable containers include, for example, bottles, vials, syringes, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds a composition which is effective for treating a disease or disorder described herein, and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
  • At least one active agent in the composition is a) a nanoparticle formulation of an mTOR inhibitor; or b) an anti-PD-1 antibody.
  • the label or package insert indicates that the composition is used for treating the particular condition in an individual.
  • the label or package insert will further comprise instructions for administering the composition to the individual.
  • Articles of manufacture and kits comprising combination therapies described herein are also contemplated.
  • Package insert refers to instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
  • the package insert indicates that the composition is used for treating a solid tumor (such as bladder cancer, renal cell carcinoma, or melanoma).
  • the article of manufacture may further comprise a second container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as phosphate-buffered saline, Ringer's solution and dextrose solution.
  • dextrose solution such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and de
  • Kits are also provided that are useful for various purposes, e.g., for treatment of an undifferentiated pleomorphic sarcoma (including undifferentiated pleomorphic sarcoma having a PTEN loss and/ or a TSC2 mutation) or leiomyosarcoma (including estrogen receptor-positive leiomyosarcoma).
  • Kits of the invention include one or more containers comprising an mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) (or unit dosage form and/or article of manufacture), and in some embodiments, further comprise an anti- PD-1 antibody (such as described herein) and/or instructions for use in accordance with any of the methods described herein.
  • an mTOR inhibitor nanoparticle composition such as sirolimus/albumin nanoparticle composition
  • an anti- PD-1 antibody such as described herein
  • kits of the invention may further comprise a description of selection of individuals suitable for treatment.
  • Instructions supplied in the kits of the invention are typically written instructions on a label or package insert (e.g, a paper sheet included in the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also acceptable.
  • the kits of the invention are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information.
  • the present application thus also provides articles of manufacture, which include vials (such as sealed vials), bottles, jars, flexible packaging, and the like.
  • the instructions relating to the use of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the anti-PD-1 antibody generally include information as to dosage, dosing schedule, and route of administration for the intended treatment.
  • the containers may be unit doses, bulk packages (e.g., multi-dose packages) or subunit doses.
  • kits may be provided that contain sufficient dosages of an mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and an anti-PD-1 antibody as disclosed herein to provide effective treatment of an individual for an extended period, such as any of a 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 more. Kits may also include multiple unit doses of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the anti-PD-1 antibody and instructions for use, packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
  • an mTOR inhibitor nanoparticle composition such as sirolimus/albumin nanoparticle composition
  • an anti-PD-1 antibody as disclosed herein
  • This example demonstrates a phase I/II investigation study administering nab- sirolimus and nivolumab to individual having a cancer. Patients and Methods
  • the primary endpoint was determination of the MTD of m/i-sirolimus when combined with nivolumab.
  • Secondary endpoints included the disease control rate [DCR: complete response (CR) plus partial response (PR) plus stable disease] as determined by local radiological assessment using Response Evaluation Criteria in Solid Tumors (RECIST) vl.l; the objective response rate (CR plus PR), and progression-free (PFS), and overall (OS) survival.
  • Secondary endpoints also included determination of the median PFS and median OS.
  • the exploratory endpoint evaluated the correlation between response based on immune-related response criteria (irRECIST) and that based on RECIST vl.l using Pearson’s coefficient of correlation.
  • the study employed the standard “cohort of three” design, wherein three patients were treated at each dose level with expansion to six patients per cohort when dose-limiting toxicity (DLT) was observed in one out of the three initially enrolled patients at each dose level. If no DLT occurred after two doses, escalation to the next dose level was permitted.
  • the MTD was defined as the highest safely tolerated dose at which no more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT.
  • Patients in the dose-escalation study were able to continue treatment at their designated dose levels for up to 18 3-week cycles or until significant disease progression or unacceptable toxicity occurred. No intra-patient dose escalation took place.
  • DLT included colitis, hepatitis, or pneumonitis of grade 3 or more; any grade 1-2 colitis, hepatitis or pneumonitis that recurred, worsened or persisted with oral steroids longer than 14 days; symptoms of adrenal crisis; any grade 4 hematological toxicity; or any non- hematological toxicity of grade 3 or more, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03 (14).
  • CCAE National Cancer Institute Common Terminology Criteria for Adverse Events
  • the study was designed to enroll up to 40-50 patients. Patients who failed to become evaluable for the secondary endpoint with a follow-up CT/MRI were replaced. Tumors with histology of Ewing sarcoma, PEComa, epithelioid sarcoma, desmoid tumor, chordoma, nonsmall-cell lung cancer, small-cell lung cancer, urothelial carcinoma, melanoma, renal cell carcinoma, squamous cell carcinoma of head and neck, hepatocellular carcinoma, classical Hodgkin’s lymphoma, microsatellite instability/mismatch repair deficiency (MSI-H/dMMR) metastatic colorectal cancer, and tumors with genetic mutations sensitive to mTOR inhibitors, were confirmed locally by the institution prior to enrollment.
  • MSI-H/dMMR microsatellite instability/mismatch repair deficiency
  • EOG Eastern Cooperative Oncology Group
  • Blood chemistry levels at screening obtained ⁇ 14 days prior to enrollment, local laboratory: Total bilirubin ⁇ 1.5*upper limit of normal (ULN) mg/dl, aspartate aminotransferase/alanine aminotransferase ⁇ 2.5*ULN ( ⁇ 5*ULN if attributable to liver metastases), alkaline phosphatase ⁇ 3 /ULN (or >3xULN when due to bone metastases), serum creatinine ⁇ 1.5xULN; f.
  • Blood counts at screening (obtained ⁇ 14 days prior to enrollment, local laboratory): Absolute neutrophil count >1 ,5x 10 9 /l, platelet count >100,000/mm3 (100*10 9 /l), hemoglobin >9 g/dl, serum triglyceride ⁇ 300 mg/dl, serum cholesterol ⁇ 350 mg/dl; g. Males and females of child-bearing age had to agree to use effective contraception 28 days before treatment with study drugs, while on study, and have a negative serum pregnancy test (human chorionic gonadotrophin) result at screening and to agree to have pregnancy testing during the study period, and after the end of treatment with study drugs. A second form of birth control was required even in the case of tubal ligation.
  • CNS metastases Known active uncontrolled or symptomatic central nervous system (CNS) metastases. For patients with controlled and asymptomatic CNS metastases, prior treatment for CNS metastases must have been completed >28 days (including radiotherapy/surgery) prior to the start of treatment in this study and should not be receiving chronic corticosteroid therapy for the CNS metastases; b. Active gastrointestinal bleeding; c. Uncontrolled pre-existing thyroid abnormality; d. Uncontrolled serious medical or psychiatric illness; e.
  • CNS central nervous system
  • cytochrome P450 3A4 cytochrome P450 3A4
  • any known CYP3A4 substrate with narrow therapeutic window such as fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, terfanide
  • Active hepatitis B or hepatitis C o.
  • Non-oncology vaccine therapy used for prevention of infectious disease within 4 weeks of trial enrollment;
  • Autoimmune disease including rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis and motor neuropathy considered to be of autoimmune origin (e.g. Guillain-Barre syndrome);
  • Systemic immunosuppression including human immunodeficiency virus positive status with or without acquired immune deficiency syndrome; r. Skin rash (psoriasis, eczema) affecting >25% body surface area; s. Inflammatory bowel disease (Crohn’s or ulcerative colitis); t.
  • the study was designed to take approximately 32 months from the first patient enrolled to last patient follow-up, including approximately 24 months of enrollment, an estimated 6 months of treatment (or until treatment was no longer tolerated) and an end of treatment visit at 4 weeks ( ⁇ 7 days) after the last treatment.
  • the study was designed to end at either the date of the last visit of the last patient, or the date of receipt of the last data point from the last patient that was required for primary, secondary, or exploratory analysis, as pre-specified in the protocol.
  • the study treatment was designed to end for a patient as of the date of the last dose of nivolumab or m6-sirolimus. End of treatment visit for a patient occurred when safety assessments and procedures were performed after the last treatment, which had to be at least 4 weeks ( ⁇ 7 days) after the last dose of nivolumab or m6-sirolimus.
  • Efficacy analyses' The disease control rate (CR, PR, SD), objective response rate (ORR), progression free survival (PFS) and overall survival (OS) were assessed by local radiological assessment using RECIST vl.l and irRECIST.
  • the focus of the study was to estimate the DCR in patients treated with nivolumab and m/j-sirolimus. Patients who disease progressed before receiving /7o6-sirolimus were replaced and were not included in the statistical analysis. The number and percentage of patients achieving response was summarized.
  • Table 1 shows the patients enrolled according to sex and race. There were 19 males and 15 females, of whom most (22/34) were White not of Hispanic origin.
  • Table 2 shows the patients enrolled according to age group and sex. The majority (56%) were young adults between 18 and 39 years of age.
  • Table 3 shows the histological tumor subtypes of patients enrolled in the study. Most patients (15/34) had osteosarcoma or Ewing sarcoma.
  • Table 4 shows AEs by body system observed in the phase I part and expanded phase IB part of the study, toxicity grade, and attribution to treatment regimen. 25 out of 31 (80.6%) patients who received at least one dose of /7o6-sirolimus had at least one treatment-related AE. The number of patients in the dose 3+ expanded phase IB category who had at least one treatment-related AE was 20 out of 25 (80%).
  • Grade 3 adverse events considered to be related to nivolumab included increased thyroid-stimulating hormone (3.2%), while grade 3 adverse events considered to be related to «a6-sirolimus included thrombocytopenia (9.7%), oral mucositis (3.2%), increased thyroid-stimulating hormone (3.2%), acute dehydration (3.2%), hypertriglyceridemia (3.2%) and hypophosphatemia (3.2%).
  • Table 5 shows the best overall response, PFS and OS data of patients enrolled in the study. sf-5924244
  • (ir)RECIST (Immune-related) Response Evaluation Criteria for Solid Tumors; PD: Progressive disease; PR: Partial response; SD: stable disease.
  • the best responders i.e. those with PR
  • PTEN phosphatase and tensin homolog
  • TSC2 tuberous sclerosis complex 2
  • Table 8 List of patients who were lost to follow-up.
  • Table 9 shows the sarcoma histology, mutation(s) if known, number of cycles treated, best overall response rate (BORR), progression free survival (PFS), and overall survival (OS) of each patient.
  • BORR overall response rate
  • PFS progression free survival
  • OS overall survival

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Abstract

La présente invention, selon certains aspects, concerne des procédés et des compositions pour le traitement de cancers, tels que le sarcome pléomorphe indifférencié ou le léiomyosarcome, à l'aide de : (a) une composition comprenant des nanoparticules comprenant un inhibiteur de mTOR (tel qu'un médicament limus, par exemple sirolimus ou un dérivé de celui-ci) et une albumine ; et, éventuellement, (b) un anticorps anti-PD-1.<i />
PCT/US2024/026882 2023-04-30 2024-04-29 Traitements comprenant une composition de nanoparticules d'inhibiteur de mtor WO2024228964A1 (fr)

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