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WO2025049962A1 - Polythérapies anticancéreuses faisant appel à une composition comprenant un inhibiteur de la voie mtor - Google Patents

Polythérapies anticancéreuses faisant appel à une composition comprenant un inhibiteur de la voie mtor Download PDF

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Publication number
WO2025049962A1
WO2025049962A1 PCT/US2024/044748 US2024044748W WO2025049962A1 WO 2025049962 A1 WO2025049962 A1 WO 2025049962A1 US 2024044748 W US2024044748 W US 2024044748W WO 2025049962 A1 WO2025049962 A1 WO 2025049962A1
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Prior art keywords
albumin
inhibitor
sirolimus
administered
nanoparticles
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PCT/US2024/044748
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English (en)
Inventor
Shihe HOU
Andrew Kwon
Brian James MCMORRAN
Igor Vivanco
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Aadi Bioscience, Inc.
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Publication of WO2025049962A1 publication Critical patent/WO2025049962A1/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
    • 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
    • A61K31/437—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 five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 a breast cancer or a gynecological cancer using a composition comprising nanoparticles comprising an mTOR inhibitor (such as an allosteric mTOR inhibitor, e.g., sirolimus) and an albumin in combination with a second therapeutic agent, such as a PI3K inhibitor (e.g., gedatolisib or alpelisib), an AKT inhibitor (e.g., miransertib or capivasertib), or an mTOR ATP competitive inhibitor (e.g., sapanisertib).
  • an mTOR inhibitor such as an allosteric mTOR inhibitor, e.g., sirolimus
  • a second therapeutic agent such as a PI3K inhibitor (e.g., gedatolisib or alpelisib), an AKT inhibitor (e.g., miransertib or capivasertib), or
  • sirolimus (INN/USAN), also known as rapamycin – an immunosuppressant drug used to prevent rejection in organ transplantation.
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 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 United States for treatment of advanced breast cancer, pancreatic neuroendocrine tumors, advanced renal cell carcinoma, and subependymal giant cell astrocytoma (SEGA) associated with Tuberous Sclerosis.
  • SEGA subependymal giant cell astrocytoma
  • 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 (mTORC1).
  • FKBP12 cytosolic protein FK-binding protein 12
  • mTORC1 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
  • 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., nab-sirolimus or Fyarro®, are known, e.g., US. Pat. No.8,911,786 and US Pat. No.11,497,737. [0006] There remains a continuing need in the art for advanced treatments of certain cancers including breast and gynecological cancers.
  • FIGS.1A and 1B show histograms of viable cells numbers (FIG.1A) and cell death (FIG.1B) for MDA-MB-453 cells receiving single-agent treatments of gedatolisib or nab- sirolimus, or combination treatments of gedatolisib and nab-sirolimus.
  • FIGS.2A and 2B show histograms of viable cells numbers (FIG.2A) and cell death (FIG.2B) for MDA-MB-361 cells receiving single-agent treatments of gedatolisib, alpelisib, or sf-6102887 Attorney Reference: 63877-20229.40 nab-sirolimus, or combination treatments of gedatolisib and nab-sirolimus or alpelisib and nab- sirolimus.
  • FIGS.3A and 3B show histograms of viable cells numbers (FIG.3A) and cell death (FIG.3B) for MDA-MB-453 cells receiving single-agent treatments of alpelisib or nab- sirolimus, or combination treatments of alpelisib and nab-sirolimus.
  • FIGS.4A and 4B show histograms of viable cells numbers (FIG.4A) and cell death (FIG.4B) for MDA-MB-453 cells receiving single-agent treatments comprising capivasertib or nab-sirolimus, or combination treatments of capivasertib and nab-sirolimus.
  • FIGS.5A and 5B show histograms of viable cells numbers (FIG.5A) and cell death (FIG.5B) for MDA-MB-361 cells receiving single-agent treatments of capivasertib or nab- sirolimus, or combination treatments of capivasertib and nab-sirolimus.
  • FIGS.6A and 6B show histograms of viable cells numbers (FIG.6A) and cell death (FIG.6B) for MDA-MB-361 cells receiving single-agent treatments of miransertib or nab- sirolimus, or combination treatments of miransertib and nab-sirolimus after 6 hours.
  • FIGS.7A-7C show Western blot analyses for various markers (including p4EBP1 and AKT) from MDA-MB-453 cells receiving single-agent treatments of gedatolisib, alpelisib, or nab-sirolimus, or combination treatments of gedatolisib and nab-sirolimus or alpelisib and nab-sirolimus after 6 hours (FIG.7A) and 5 days (FIGS.7B-7C).
  • markers including p4EBP1 and AKT
  • FIG.8 shows Western blot analyses for various markers (including p4EBP1 and AKT) from MCF7 cells receiving single-agent treatments of capivasertib or nab-sirolimus, or combination treatments of capivasertib and nab-sirolimus after 6 hours.
  • the present application provides is a method of treating a cancer in an individual in need thereof, the method comprising administering to the individual: (a) a composition comprising nanoparticles comprising sirolimus and an albumin; and (b) a second therapeutic agent, wherein the second therapeutic agent is a PI3K inhibitor, wherein the PI3K inhibitor specifically binds to and inhibits the activity of a PI3K protein.
  • a composition comprising nanoparticles comprising sirolimus and an albumin
  • a second therapeutic agent is a PI3K inhibitor
  • the PI3K inhibitor specifically binds to and inhibits the activity of a PI3K protein.
  • sf-6102887 Attorney Reference: 63877-20229.40
  • the PI3K inhibitor is an isoform-specific PI3K inhibitor.
  • the PI3K inhibitor is a dual PI3K/mTOR inhibitor. In some embodiments, the PI3K inhibitor is gedatolisib. In some embodiments, the isoform-specific PI3K inhibitor is a class I PI3K inhibitor. In some embodiments, the class I PI3K inhibitor is gedatolisib or alpelisib. [0017] In some embodiments, the PI3K inhibitor is selected from the group consisting of gedatolisib, alpelisib, copanlisib, idelalisib, umbralisib, and duvelisib.
  • a method of treating a cancer in an individual in need thereof comprising administering to the individual: (a) a composition comprising nanoparticles comprising sirolimus and an albumin; and (b) a second therapeutic agent, wherein the second therapeutic agent is an AKT inhibitor, wherein the AKT inhibitor specifically binds to and inhibits an AKT serine/threonine kinase.
  • the AKT inhibitor is a pan-AKT inhibitor.
  • the AKT inhibitor is an allosteric AKT inhibitor.
  • the AKT inhibitor is an ATP-competitive AKT inhibitor.
  • the AKT inhibitor is miransertib.
  • the AKT inhibitor is capivasertib. In some embodiments, the pan-AKT inhibitor is miransertib or capivasertib. [0020] In some embodiments, the AKT inhibitor is selected from the group consisting of miransertib, capivasertib, AY1125976, MK-2206, and TAS-117, ipatasertib, and afuresertib.
  • the second therapeutic agent is administered to the individual orally, intramuscularly, intravenously, intraarterially, intraperitoneally, intravesicularly, subcutaneously, intrathecally, intrapulmonarily, intratracheally, intraocularly, transdermally, or by inhalation.
  • the second therapeutic agent is alpelisib.
  • alpelisib is administered to the individual orally.
  • alpelisib is administered to the individual at an amount of about 150 mg to about 350 mg orally.
  • alpelisib is administered to the individual daily.
  • the second therapeutic agent is gedatolisib.
  • gedatolisib is administered to the individual intravenously. In some embodiments, sf-6102887 Attorney Reference: 63877-20229.40 gedatolisib is administered to the individual at an amount of about 90 mg to about 310 mg intravenously. In some embodiments, gedatolisib is administered to the individual weekly. In some embodiments, gedatolisib is administered to the individual on day 1, 8, and 15 of a 21-day cycle. [0024] In some embodiments, the second therapeutic agent is miransertib. In some embodiments, miransertib is administered to the individual orally.
  • the miransertib is administered to the individual at an amount of about 5 mg to about 60 mg orally. In some embodiments, miransertib is administered to the individual daily.
  • the second therapeutic agent is capivasertib. In some embodiments, capivasertib is administered to the individual orally. In some embodiments, the capivasertib is administered to the individual at an amount of about 150 mg to about 500 mg orally. In some embodiments, capivasertib is administered to the individual twice daily.
  • the cancer is a hormone receptor positive cancer. In some embodiments, the cancer is a hormone receptor negative cancer. In some embodiments, the cancer is triple-negative cancer.
  • the cancer is the breast cancer.
  • the breast cancer is a ductal carcinoma in situ (DCIS) breast cancer, invasive ductal carcinoma (IDC) breast cancer, lobular carcinoma in situ (LCIS) breast cancer, invasive lobular carcinoma (ILC) breast cancer, or inflammatory breast cancer (IBC).
  • the cancer is the gynecological cancer.
  • the gynecological cancer is a cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, or vulvar cancer.
  • the cancer comprises PI3K-AKT mutational activation.
  • the cancer comprises mutations in one or more of genes of the PI3K-AKT pathway. In some embodiments, the cancer is PI3K-mutated cancer. In some embodiments, the cancer is locally advanced, advanced, malignant, advanced malignant, or metastatic. In some embodiments, the cancer is refractory, relapsed, recurrent, or resistant to a prior treatment. In some embodiments, the prior treatment comprises an mTOR inhibitor and/ or a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin. In some embodiments, sf-6102887 Attorney Reference: 63877-20229.40 the prior treatment comprises a PI3K inhibitor. In some embodiments, the prior treatment comprises an AKT inhibitor.
  • the individual has not been treated with an mTOR inhibitor and/ or a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin.
  • the individual is human.
  • sirolimus in the sirolimus nanoparticle composition is administered at an amount of about 10 mg/m 2 to about 150 mg/m 2 . In some embodiments, sirolimus in the sirolimus nanoparticle composition is administered at an amount of about 100 mg/m 2 . In some embodiments, sirolimus in the sirolimus nanoparticle composition is administered at an amount of about 75 mg/m 2 .
  • sirolimus in the sirolimus nanoparticle composition is administered at an amount of about 56 mg/m 2 . In some embodiments, sirolimus in the sirolimus nanoparticle composition is administered at an amount of about 45 mg/m 2 . In some embodiments, sirolimus in the sirolimus nanoparticle composition is administered at an amount of about 30 mg/m 2 . [0032] In some embodiments, the sirolimus nanoparticle composition is administered twice out of every 3 weeks. In some embodiments, the sirolimus nanoparticle composition is administered on days 1 and 8 of a 21-day cycle. [0033] In some embodiments, the average diameter of the nanoparticles in the composition is no greater than about 150 nm.
  • the average diameter of the nanoparticles in the composition is no greater than about 120 nm. In some embodiments, the weight ratio of the albumin to sirolimus in the nanoparticle composition is no greater than about 9:1. In some embodiments, the nanoparticles comprise sirolimus associated with the albumin. In some embodiments, the nanoparticles comprise sirolimus coated with the albumin. In some embodiments, the sirolimus nanoparticle composition is administered intravenously. [0034] In some embodiments, the sirolimus nanoparticle composition is administered concurrently with the secondary therapeutic agent. In some embodiments, the sirolimus nanoparticle composition is administered sequentially with the secondary therapeutic agent.
  • the sirolimus nanoparticle composition is administered prior to the secondary therapeutic agent. In some embodiments, the secondary therapeutic agent is administered prior to the sirolimus nanoparticle composition. In some embodiments, the sf-6102887 Attorney Reference: 63877-20229.40 sirolimus nanoparticle composition is administered simultaneously with the secondary therapeutic agent.
  • the present application provides, in certain aspects, treatments for a cancer (such as a breast cancer or a gynecological cancer) in an individual in need thereof, the methods comprising administering to the individual: (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., sirolimus) and an albumin; and (b) a second therapeutic agent selected from the group consisting of a PI3K inhibitor, an AKT inhibitor, and/ or an mTOR ATP competitive inhibitor.
  • a cancer such as a breast cancer or a gynecological cancer
  • a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., sirolimus) and an albumin
  • a second therapeutic agent selected from the group consisting of a PI3K inhibitor, an AKT inhibitor, and/ or an mTOR ATP competitive inhibitor.
  • certain second therapeutic agents encompassed herein have two more or functions, e.g., a dual inhibitor, and reference to a single characteristic does not exclude such second therapeutic agents having two or more functions (e.g., in certain aspects gedatolisib can be referred to as a PI3K inhibitor and in other aspects gedatolisib can be referred to as an mTOR ATP competitive inhibitor).
  • the PI3K inhibitor is an agent that specifically binds to and inhibits the activity of a PI3K protein.
  • the PI3K inhibitor is a dual PI3K/mTOR inhibitor, e.g., gedatolisib.
  • the PI3K inhibitor is an isoform-specific PI3K inhibitor, e.g., gedatolisib or alpelisib.
  • the AKT inhibitor is an agent that specifically binds to and inhibits an Akt serine/threonine kinase.
  • the AKT inhibitor is an allosteric AKT inhibitor, e.g., miransertib.
  • the AKT inhibitor is an ATP-competitive AKT inhibitor, e.g., capivasertib.
  • the AKT inhibitor is a pan-AKT inhibitor, e.g., miransertib or capivasertib.
  • the subject matter of the present application is based, at least in part, on the inventors’ unique perspectives and findings that vertical pathway inhibition (including hitting the same target) with a combination of nab-sirolimus and a PI3K inhibitor (including dual inhibitors that are both a PI3K inhibitor and an ATP competitive mTOR inhibitor, such as gedatolisib) or an AKT inhibitor is useful for treating a breast cancer or gynecological cancer.
  • sf-6102887 Attorney Reference: 63877-20229.40
  • the inventors found that the combinations taught here overcome a drug-resistance mechanism.
  • p4EBP1 phosphorylated 4E-binding protein 1
  • p4EBP1 phosphorylated 4E-binding protein 1
  • the inventors demonstrated that treatment with nab-sirolimus and a PI3K inhibitor, namely, gedatolisib or alpelisib, or an AKT inhibitor, namely miransertib or capivasertib, resulted in a synergistic decrease of p4EBP1 compared to single-agent treatments.
  • a method of treating a cancer in an individual in need thereof, wherein the cancer is a breast cancer or a gynecological cancer comprising administering to the individual: (a) a composition comprising nanoparticles comprising sirolimus and an albumin; and (b) a second therapeutic agent, wherein the second therapeutic agent is a PI3K inhibitor, wherein the PI3K inhibitor specifically binds to and inhibits the activity of a PI3K protein.
  • the PI3K inhibitor is gedatolisib, or alpelisib.
  • a method of treating a cancer in an individual in need thereof, wherein the cancer is a breast cancer or a gynecological cancer comprising administering to the individual: (a) a composition comprising nanoparticles comprising sirolimus and an albumin; and (b) a second therapeutic agent, wherein the second therapeutic agent is an AKT inhibitor, wherein the AKT inhibitor specifically binds to and inhibits an Akt serine/threonine kinase.
  • the AKT inhibitor is miransertib or capivasertib.
  • nab stands for nanoparticle albumin-bound
  • nab-sirolimus is an albumin stabilized nanoparticle formulation of sirolimus.
  • nab-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 or “treating” is an approach for obtaining beneficial or desired results including clinical results.
  • beneficial or desired sf-6102887 Attorney Reference: 63877-20229.40 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.
  • 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.
  • CAT scan computerized axial tomography
  • MRI Magnetic Resonance Imaging
  • ultrasound ultrasound
  • clotting tests arteriography
  • biopsy biopsy
  • urine cytology and cystoscopy.
  • sf-6102887 Attorney Reference: 63877-20229.40 Development may also refer to cancer progression that may be initially undetectable and includes occurrence, recurrence, and onset.
  • the term “effective amount” used herein 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. In some embodiments, an effective amount is an amount sufficient to delay development of cancer. In some embodiments, an effective amount is an amount sufficient to prevent or delay recurrence. In some embodiments, 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 (i.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” or “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 sf-6102887 Attorney Reference: 63877-20229.40 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.
  • 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. sf-6102887 Attorney Reference: 63877-20229.40 [0053]
  • the terms “comprising,” “having,” “containing,” and “including,” and other similar forms, and grammatical equivalents thereof, as used herein, are intended to be equivalent in meaning and to be open ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items.
  • an article “comprising” components A, B, and C can consist of (i.e., contain only) components A, B, and C, or can contain not only components A, B, and C but also one or more other components.
  • “comprises” and similar forms thereof, and grammatical equivalents thereof, include disclosure of embodiments of “consisting essentially of” or “consisting of.” [0054] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictate otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure, subject to any specifically excluded limit in the stated range.
  • Methods of treatment are methods for the treatment of a breast cancer or a gynecological cancer in an individual in need thereof, the method comprising administering to the individual: (a) a composition comprising nanoparticles comprising an mTOR inhibitor, including an sf-6102887 Attorney Reference: 63877-20229.40 allosteric mTOR inhibitor such as sirolimus, and an albumin; and (b) a second therapeutic agent.
  • a composition comprising nanoparticles comprising an mTOR inhibitor, including an sf-6102887 Attorney Reference: 63877-20229.40 allosteric mTOR inhibitor such as sirolimus, and an albumin.
  • a composition comprising nanoparticles comprising an mTOR inhibitor, including an allosteric mTOR inhibitor such as sirolimus, and an albumin; and (b) a second therapeutic agent, wherein the second therapeutic agent is an mTOR inhibitor, such as an ATP competitive mTOR inhibitor, a PI3K inhibitor, or an AKT inhibitor, or an agent that provides two or more of such mechanisms including a dual ATP competitive mTOR inhibitor and a PI3K inhibitor such as gedatolisib.
  • an mTOR inhibitor such as an ATP competitive mTOR inhibitor, a PI3K inhibitor, or an AKT inhibitor, or an agent that provides two or more of such mechanisms including a dual ATP competitive mTOR inhibitor and a PI3K inhibitor such as gedatolisib.
  • the second therapeutic agent is gedatolisib. In some embodiments, the second therapeutic agent is sapanisertib. In some embodiments, the second therapeutic agent is alpelisib. In some embodiments, the second therapeutic agent is miransertib. In some embodiments, the second therapeutic agent is capivasertib.
  • the PI3K inhibitor specifically binds to and inhibits the activity of a PI3K protein. In some embodiments, the PI3K inhibitor is a dual inhibitor that inhibits the activity of a PI3K protein and mTOR, such as gedatolisib.
  • the AKT inhibitor specifically binds to and inhibits an AKT serine/threonine kinase.
  • a method of treating a cancer in an individual in need thereof, wherein the cancer is a breast cancer or a gynecological cancer comprising administering to the individual: (a) a composition comprising nanoparticles comprising an mTOR inhibitor, such as sirolimus, and an albumin; and (b) a second therapeutic agent, wherein the second therapeutic agent is a PI3K inhibitor, wherein the PI3K inhibitor specifically binds to and inhibits the activity of a PI3K protein.
  • the PI3K inhibitor is alpelisib. In some embodiments, when the PI3K inhibitor is alpelisib, alpelisib is administered to the individual orally. In some embodiments, when the PI3K inhibitor is alpelisib, alpelisib is administered to the individual at an amount of about 150 mg to about 350 mg orally. In some embodiments, when the PI3K inhibitor is alpelisib, alpelisib is administered to the individual daily. [0061] In some embodiments, the PI3K inhibitor is gedatolisib. In some embodiments, when the PI3K inhibitor is gedatolisib, gedatolisib is administered to the individual intravenously.
  • gedatolisib when the PI3K inhibitor is gedatolisib, gedatolisib is administered to the sf-6102887 Attorney Reference: 63877-20229.40 individual at an amount of about 90 mg to about 310 mg intravenously. In some embodiments, when the PI3K inhibitor is gedatolisib, gedatolisib is administered to the individual weekly. In some embodiments, when the PI3K inhibitor is gedatolisib, gedatolisib is administered to the individual on day 1, 8, and 15 of a 21-day cycle.
  • a method of treating a cancer in an individual in need thereof, wherein the cancer is a breast cancer or a gynecological cancer comprising administering to the individual: (a) a composition comprising nanoparticles comprising an mTOR inhibitor, such as sirolimus, and an albumin; and (b) a second therapeutic agent, wherein the second therapeutic agent is an AKT inhibitor, wherein the AKT inhibitor specifically binds to and inhibits an AKT serine/threonine kinase.
  • the AKT inhibitor is miransertib.
  • the AKT inhibitor when the AKT inhibitor is miransertib, miransertib is administered to the individual orally. In some embodiments, when the AKT inhibitor is miransertib, miransertib is administered to the individual at an amount of about 5 mg to about 60 mg orally. In some embodiments, when the AKT inhibitor is miransertib, miransertib is administered to the individual daily. [0064] In some embodiments, the AKT inhibitor is capivasertib. In some embodiments, when the AKT inhibitor is capivasertib, capivasertib is administered to the individual orally.
  • the second therapeutic agent acts, at least in part, as an mTOR ATP competitive inhibitor.
  • the second therapeutic agent is gedatolisib.
  • the second therapeutic agent is sapanisertib.
  • the composition comprising nanoparticles comprising sirolimus and the albumin, e.g., nab-sirolimus is administered to the individual at an amount of about 70 mg/m 2 to about 110 mg/m 2 , such as about 100 mg/m 2 .
  • the composition comprising nanoparticles comprising sirolimus and the albumin, e.g., nab- sirolimus is administered intravenously.
  • the composition comprising nanoparticles comprising sirolimus and the albumin, e.g., nab-sirolimus is administered to the sf-6102887 Attorney Reference: 63877-20229.40 individual weekly, such as two out of every three weeks, e.g., on days 1 and 8 of a 21-day cycle.
  • the individual is human.
  • the cancer such as a breast cancer or a gynecological cancer
  • the cancer is a hormone receptor positive cancer.
  • the cancer is a hormone receptor positive breast cancer.
  • the cancer is an estrogen receptor positive breast cancer.
  • the cancer is a progesterone receptor positive breast cancer.
  • the cancer is an estrogen receptor and progesterone receptor positive breast cancer.
  • the cancer is a hormone receptor positive gynecological cancer.
  • the cancer is a hormone receptor positive gynecological cancer.
  • the cancer is an estrogen receptor positive gynecological cancer. In some embodiments, the cancer is a progesterone receptor positive gynecological cancer. In some embodiments, the cancer is an estrogen receptor and progesterone receptor positive gynecological cancer. In some embodiments, the methods are useful for breast cancer regardless of hormone receptor status. [0070] In some embodiments, the cancer is hormone dependent (e.g., relies on hormone- driven development and/ or growth), such as estrogen dependent, progesterone dependent, or estrogen and progesterone dependent.
  • hormone dependent e.g., relies on hormone- driven development and/ or growth
  • the cancer is a hormone receptor negative cancer.
  • the cancer is hormone receptor negative breast cancer.
  • the cancer is hormone receptor negative gynecological cancer.
  • the cancer such as a breast cancer or a gynecological cancer, is a triple-negative cancer.
  • the breast cancer is a ductal carcinoma in situ (DCIS) breast cancer, invasive ductal carcinoma (IDC) breast cancer, lobular carcinoma in situ (LCIS) breast cancer, invasive lobular carcinoma (ILC) breast cancer, or inflammatory breast cancer (IBC).
  • the gynecological cancer is a cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, or vulvar cancer.
  • the gynecological cancer is a fallopian tube cancer.
  • the cancer comprises a PI3K-AKT mutational activation.
  • the mutational activation comprises a genetic mutation that results in an activation in PI3K and/ or AKT.
  • PI3K-AKT mutational activation comprises a loss-of-function mutation in PTEN. Mutations that result in PI3K and/ or AKT activation can be detected by next generation sequencing or other methods for detecting a genetic mutation known in the art.
  • the mutational activation comprises an epigenetic modification that results in an activation in PI3K and/or AKT.
  • the mutational activation comprises a post-translational modification that results in an activation in PI3K and/or AKT.
  • PI3K-AKT mutational activation comprises increased PI3K activity within the mutant cell compared to healthy cells. In some embodiments, PI3K-AKT mutational activation comprises increased AKT kinase activity within the mutant cell compared to healthy cells. In some embodiments, PI3K-AKT mutational activation is measured by an increased amount of phosphorylation of T308 and/or S473 of AKT1. In some embodiments, PI3K-AKT mutational activation is measured by an increased amount of phosphorylation of T309 and/or S474 of AKT2. Increased amount of phosphorylated AKT may be measured by Western blotting or other methods known in the art for protein quantification.
  • the cancer such as a breast cancer or a gynecological cancer, comprises one or more mutations in one or more of genes of the PI3K-AKT pathway.
  • the cancer is PI3K-mutated cancer (i.e., the cancer comprises a PI3K mutation).
  • the cancer is AKT-mutated cancer (i.e., the cancer comprises an AKT mutation).
  • sf-6102887 Attorney Reference: 63877-20229.40 [0075]
  • the cancer is locally advanced, advanced, malignant, advanced malignant, or metastatic.
  • the cancer is refractory, relapsed, recurrent, or resistant to a prior treatment.
  • the prior treatment comprises an mTOR inhibitor (e.g., a non-nanoparticle formulation of sirolimus) and/ or a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., sirolimus) and an albumin (e.g., nab-sirolimus).
  • the prior treatment comprises a PI3K inhibitor (such as alpelisib or gedatolisib).
  • the prior treatment comprises an AKT inhibitor (such as miransertib or capivasertib).
  • the prior treatment does not comprise a combination treatment comprising (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., sirolimus) and an albumin (e.g., nab-sirolimus); and (b) a PI3K inhibitor (such as alpelisib or gedatolisib).
  • the prior treatment does not comprise a combination treatment comprising (a) a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., sirolimus) and an albumin (e.g., nab-sirolimus); and (b) an AKT inhibitor (such as miransertib or capivasertib).
  • the individual has not been treated with an mTOR inhibitor (e.g., a non-nanoparticle formulation of sirolimus) and/ or a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., sirolimus) and an albumin (e.g., nab- sirolimus).
  • an mTOR inhibitor e.g., a non-nanoparticle formulation of sirolimus
  • a composition comprising nanoparticles comprising an mTOR inhibitor (e.g., sirolimus) and an albumin (e.g., nab- sirolimus).
  • the cancer such as a breast cancer or a gynecological cancer, is any classification stage, such as stage I, II, III, or IV, e.g., according to the International Federation of Gynecology and Obstetrics (FIGO) staging.
  • stage I, II, III, or IV e.g., according to the International Federation of Gyne
  • 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, the breast or gynecological cancer being treated, 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., sf-6102887 Attorney Reference: 63877-20229.40 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., sf-6102887 Attorney Reference: 63877-20229.40 an effect above a clinically acceptable level of toxicity
  • the mTOR inhibitor nanoparticle composition when the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered, the mTOR inhibitor nanoparticle composition is administered to the individual simultaneously with a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) for at least one administration (e.g., due cycle differences of different agents it may be certain administration can be performed simultaneously while other cannot be).
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miranserti
  • the mTOR inhibitor nanoparticle compositions and a second therapeutic agent described herein 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.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • simultaneous administration can be achieved by administering a solution containing the combination of compounds.
  • simultaneous administration of separate solutions or compositions one of which contains the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and the other of which contains a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib), can be employed.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • 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 administered intravenously) and the other comprising a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib).
  • a PI3K inhibitor such as alpelisib or gedatolisib
  • an AKT inhibitor such as miransertib or capivasertib
  • simultaneous administration of the mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) in the nanoparticle composition and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) can be combined with supplemental doses of the mTOR inhibitor and/or the second therapeutic agent.
  • a PI3K inhibitor such as alpelisib or gedatolisib
  • an AKT inhibitor such as miransertib or capivasertib
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) are not administered simultaneously for at least one administration.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered before a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib).
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • 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.
  • 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 a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) are concurrent for at least one administration, i.e., the administration period of the mTOR inhibitor nanoparticle composition and that of the second therapeutic agent overlap with each other.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • 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, 1415, 16, 17, 18, 19, or 20 cycles) prior to the administration of a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib).
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib.
  • the second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a PI3K inhibitor such as alpelisib or gedatolisib
  • an AKT inhibitor such as miransertib or capivasertib
  • the administration of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) are initiated at about the same time (for example, within any one of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, or 3 weeks).
  • a PI3K inhibitor such as alpelisib or gedatolisib
  • an AKT inhibitor such as miransertib or capivasertib
  • the administration of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) are terminated at about the same time (for example, within any one of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, or 3 weeks).
  • a PI3K inhibitor such as alpelisib or gedatolisib
  • an AKT inhibitor such as miransertib or capivasertib
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a second therapeutic agent described herein 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 a second therapeutic agent described herein 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).
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • 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 a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) are initiated and terminated at about the same time.
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the administrations of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) are initiated at about the same time and the administration of the second therapeutic agent ⁇ 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.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the administration of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein sf-6102887 Attorney Reference: 63877-20229.40 (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) stop at about the same time and the administration of the second therapeutic agent 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.
  • a second therapeutic agent described herein sf-6102887 Attorney Reference: 63877-20229.40 (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) stop at about the same time and the administration of the second therapeutic
  • the second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the administration of a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a patient consideration such as an adverse event.
  • the reduction in administration of a second therapeutic agent described herein is for only a portion of the treatment, e.g., until the individual recovers (at least partially) from the adverse event.
  • the second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a sub-therapeutic dose for single-agent use of the second therapeutic agent e.g., the combination treatments taught herein enable use of lower doses of one or both therapeutic agents to provide efficacious treatment.
  • the administration of the composition comprising an mTOR inhibitor and an albumin and a second therapeutic agent described herein continues for at least any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 1415, 16, 17, 18, 19, or 20 cycles.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the administration of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) are non-concurrent.
  • a PI3K inhibitor such as alpelisib or gedatolisib
  • an AKT inhibitor such as miransertib or capivasertib
  • the administration of the mTOR inhibitor nanoparticle composition is terminated before a second therapeutic agent sf-6102887 Attorney Reference: 63877-20229.40 described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) is administered.
  • a second therapeutic agent sf-6102887 Attorney Reference: 63877-20229.40 described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) is administered.
  • the administration of a second therapeutic agent described herein is terminated before the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) is administered.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • mTOR inhibitor nanoparticle composition such as sirolimus/albumin nanoparticle composition
  • the dosing frequency of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) can be administered at different dosing frequency or intervals.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the mTOR inhibitor nanoparticle composition can be administered once every three weeks, while the second therapeutic agent can be administered more or less frequently, e.g., daily.
  • the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) can be administered using the same route of administration or different routes of administration.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as sf-6102887 Attorney Reference: 63877-20229.40 alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a PI3K inhibitor such as sf-6102887 Attorney Reference: 63877-20229.40 alpelisib or gedatolisib
  • an AKT inhibitor such as miransertib or capivasertib
  • the doses required for the mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) in the mTOR inhibitor nanoparticle composition and/or a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) may (but not necessarily) be the same or lower than what is normally required when each agent is administered alone.
  • a PI3K inhibitor such as alpelisib or gedatolisib
  • an AKT inhibitor such as miransertib or capivasertib
  • a subtherapeutic amount of the mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib.
  • “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 a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) are administered alone.
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • 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).
  • the method comprises administering a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin at a dosage of less than about 100 mg/m 2 , such as about any of 90 mg/m 2 , 80 mg/m 2 , 70 mg/m 2 , 60 mg/m 2 , 50 mg/m 2 , 40 mg/m 2 , 30 mg/m 2 , 20 mg/m 2 , or 10 mg/m 2 .
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • enough of the mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) in the mTOR inhibitor nanoparticle composition is administered so as to allow reduction of the normal dose of the a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, sf-6102887 Attorney Reference: 63877-20229.40 or an AKT inhibitor such as miransertib or capivasertib) required to affect the same degree of treatment by at least about any of 5%, 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or more.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, sf-6102887 Attorney Reference: 63877-20229.40 or an AKT inhibitor such as miransertib or capivasertib
  • the dose of both the mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) in the mTOR inhibitor nanoparticle composition and a second therapeutic agent described herein are reduced as compared to the corresponding normal dose of each when administered alone.
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • both the mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) in the mTOR inhibitor nanoparticle composition and a second therapeutic agent described herein 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 a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) is substantially less than the established maximum toxic dose (MTD).
  • a PI3K inhibitor such as alpelisib or gedatolisib
  • an AKT inhibitor such as miransertib or capivasertib
  • the dose of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and/or a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) is less than about 50%, 40%, 30%, 20%, or 10% of the MTD.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a combination of the administration configurations described herein can be used.
  • 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 hormone-dependent cancer 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 a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) is administered sf-6102887 Attorney Reference: 63877-20229.40 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.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • 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 a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) 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 a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) are administered to the individual.
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT
  • the amount of the mTOR inhibitor nanoparticle composition is close to a maximum tolerated dose (MTD) of the composition following the same dosing regimen when administered with a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib).
  • MTD maximum tolerated dose
  • the amount of the mTOR inhibitor nanoparticle composition is more than about any of 80%, 90%, 95%, or 98% of the MTD when administered with a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib).
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib.
  • reference to amounts of a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin are based on the amount of the mTOR inhibitor therein.
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 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 40 mg/m 2 , 39 mg/m 2 , 38 mg/m 2 , 37 mg/m 2 , 36 mg/m 2 , 35 mg/m 2 , 34 mg/m 2 , 33 mg/m 2 , 32 mg/m 2 , 31 mg/m 2 , 30 mg/m 2 , 29 mg/m 2 , 28 mg/m 2 , 27 mg/m 2 , 26 mg/m 2 , 25 mg/m 2 , 24 mg/m 2 , 23 mg/m 2 , 22 mg/m 2 , 21 mg/m 2 , 20 mg/m 2 , 19 mg/m 2 , 18 mg/m 2 , 17 mg/m 2 , 16 mg/m 2 , 15 mg/m 2 , 14 mg/m 2 , 13 mg/m 2 , 12 mg/m 2 , 11 mg/m 2 , 10 mg/
  • the 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 about 10 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 about150 mg/m 2 , about150 to about 175 mg/m 2 , about175 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 .
  • the 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/m 2 , about 130 mg/m 2 , or about 140 mg/m 2 .
  • the amount of the mTOR inhibitor nanoparticle composition is administered every four weeks (e.g., day 1 of a 28-day cycle). In some embodiments, the amount of the mTOR inhibitor nanoparticle composition is administered every three weeks (e.g., day 1 of a 21-day cycle).
  • the amount of the mTOR inhibitor nanoparticle composition is administered every two weeks (e.g., day 1 of a 14-day cycle). In some embodiments, the amount of the mTOR inhibitor nanoparticle composition is administered weekly. In some embodiments, the amount of the mTOR inhibitor nanoparticle composition is administered weekly every 2 out of 3 weeks. In some embodiments, 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 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, sf-6102887 Attorney Reference: 63877-20229.40 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 1x, 2x, 3x, 4x, 5x, 6x, or 7x (i.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 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 sf-6102887 Attorney Reference: 63877-20229.40 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.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • 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.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • 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 dosing frequency of the mTOR inhibitor nanoparticle composition may be adjusted over the course of the treatment based on the judgment of the administering physician.
  • 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. In some embodiments, 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 sf-6102887 Attorney Reference: 63877-20229.40 includes, but is not limited to, about any of 10 mg/m 2 , 20 mg/m 2 , 30 mg/m 2 , 40 mg/m 2 , 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 thereof) in a nanoparticle composition can be in the range of about 20-400 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).
  • 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
  • the dosage of an mTOR inhibitor 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 second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an sf-6102887 Attorney Reference: 63877-20229.40 AKT inhibitor such as miransertib or capivasertib
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an sf-6102887 Attorney Reference: 63877-20229.40 AKT inhibitor such as miransertib or capivasertib
  • the second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • PI3K inhibitors such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • PI3K inhibitors are provided below.
  • the PI3K inhibitor is alpelisib.
  • the PI3K inhibitor is alpelisib, wherein alpelisib is administered to the individual orally.
  • alpelisib is administered to the individual at an amount of about 150 mg to about 350 mg, such as about any of 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 325 mg, 330 mg, 340 mg, or 350 mg.
  • alpelisib is administered to the individual daily.
  • alpelisib is administered to the individual daily at an amount of 300 mg.
  • sf-6102887 Attorney Reference: 63877-20229.40
  • second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • PI3K inhibitors are provided below.
  • the PI3K inhibitor is gedatolisib.
  • the PI3K inhibitor is gedatolisib, wherein gedatolisib is administered to the individual intravenously.
  • gedatolisib is administered to the individual at an amount of about 90 mg to about 310 mg, such as about any of 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, or 310 mg.
  • gedatolisib is administered to the individual weekly.
  • gedatolisib is administered to the individual weekly at an amount of 180 mg weekly. In some embodiments, gedatolisib is administered to the individual on day 1, 8, and 15 of a 21-day cycle. In some embodiments, gedatolisib is administered to the individual weekly at an amount of 180 mg on day 1, 8, and 15 of a 21-day cycle.
  • second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the AKT inhibitor is miransertib.
  • the AKT inhibitor is miransertib, wherein miransertib is administered to the individual orally.
  • miransertib is administered to the individual at an amount of about 5 mg to about 60 mg, such as about any of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg.
  • miransertib is administered to the individual daily.
  • miransertib is administered to the individual daily at an amount of 50 mg.
  • second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • PI3K inhibitor such as alpelisib or gedatolisib
  • AKT inhibitor such as miransertib or capivasertib
  • the AKT inhibitor is capivasertib.
  • the AKT inhibitor is capivasertib, wherein capivasertib is administered to the individual orally.
  • capivasertib is administered to the individual at an amount of about 150 mg to about 500 mg, such as about any of 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 325 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 375 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 425 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 475 mg, 480 mg, 490 mg, or 500mg.
  • capivasertib is administered to the individual twice daily. In some embodiments, capivasertib is administered to the individual at an amount of about 400 mg twice daily. In some embodiments, capivasertib is administered to the individual twice daily according to an intermittent dosing schedule of four days on and three days off. In some embodiments, capivasertib is administered to the individual on days 1-4 of a 7-day cycle. In some embodiments, the capivasertib is administered to the individual twice daily on days 1-4 of a 7-day cycle. In some embodiments, capivasertib is administered to the individual at an amount of about 400 mg twice daily on days 1-4 of a 7-day cycle.
  • capivasertib is administered to the individual at an amount of about 480 mg twice daily. In some embodiments, capivasertib is administered to the individual at an amount of about 480 mg twice daily on days 1-4 of a 7-day cycle.
  • An mTOR inhibitor nanoparticle composition such as sirolimus/albumin nanoparticle composition
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • 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.
  • compositions and/or agents can be administered, for example, parenterally (such as intravenous).
  • 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) and a second therapeutic agent described herein sf-6102887 Attorney Reference: 63877-20229.40 (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) can be administered in a single unit dose or separate dosage forms.
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • 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 described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) in a single unit dose, as well as individually combined with an mTOR inhibitor nanoparticle composition and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) when these compounds are administered separately.
  • an mTOR inhibitor nanoparticle composition such as sirolimus/albumin nanoparticle composition
  • 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 hydroxytoluene, 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 second therapeutic agent described herein (e.g., sf-6102887 Attorney Reference: 63877-20229.40 a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) 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, e
  • 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.
  • Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art. Reference is made, for example, to Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990).
  • 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, via intravenous administration or subcutaneous administration. In some embodiments, sustained continuous release formulation of the composition may be used. In some embodiments, the mTOR inhibitor nanoparticle composition is administered intravenously. In some embodiments, the mTOR inhibitor nanoparticle composition is administered subcutaneously.
  • the mTOR inhibitor nanoparticle composition is administered to the individual orally, intramuscularly, intravenously, intraarterially, intraperitoneally, intravesicularly, subcutaneously, intrathecally, intrapulmonarily, intratracheally, intraocularly, transdermally, or by inhalation.
  • the second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • an individual such as a human
  • routes including, for example, oral, intramuscular, intravenous, intra-arterial, intraperitoneal, intrapulmonary, inhalation, intravesicular, intra- tracheal, subcutaneous, intraocular, intrathecal, transmucosal, and transdermal.
  • the PI3K inhibitor is alpelisib and is administered to the individual orally.
  • the PI3K inhibitor is gedatolisib and is administered to the individual intravenously.
  • the AKT inhibitor is miransertib or capivasertib and is administered to the individual orally.
  • Breast cancer is a common cancer type that develops in the breast tissue of females and males. Breast cancers can present as cancerous lumps, with other changes in anatomy including a change in breast shape, dimpling of the skin, milk rejection, fluid excretion, and/ or other changes to the skin and/ or nipples.
  • breast cancers There are a number of types of breast cancer, including a ductal carcinoma in situ (DCIS) breast cancer, invasive ductal carcinoma (IDC) breast cancer, lobular carcinoma in situ (LCIS) breast cancer, invasive lobular carcinoma (ILC) breast cancer, or inflammatory breast cancer (IBC).
  • DCIS ductal carcinoma in situ
  • IHC invasive ductal carcinoma in situ
  • LCIS lobular carcinoma in situ
  • IBC invasive lobular carcinoma
  • IBC inflammatory breast cancer
  • Breast cancers can be diagnosed by cell analysis, such as by a microscope analysis or marker analysis (such as IHC) of a tissue sample, such as a biopsy, from the affected area.
  • Breast cancers can be hormone receptor-positive (HR+), or hormone- receptor-negative (HR-).
  • the hormone receptor status of breast cancer can be determined e.g., by obtaining a biopsy to test for, e.g., the presence of estrogen or progesterone receptor using techniques such as immunohistochemistry (IHC).
  • Breast cancers can be hormone-dependent (e.g., relies on hormone-driven development and/ or growth), such as estrogen dependent, progesterone dependent, or estrogen and progesterone dependent, or hormone-independent (e.g., does not rely on hormone-driven development and/ or growth).
  • Gynecological cancers comprise 10-15% of women’s cancers and are more prevalent in woman that are past reproductive age. Gynecological cancer may present in various forms based on origin.
  • Gynecological cancers include ovarian cancer, endometrial cancer, vulvar cancer, vaginal cancer, uterine cancer, cervical cancer, and, more rarely, fallopian tube cancer. Gynecological cancers are often diagnosed using a tissue biopsy to identify cell types and for certain subtypes can be diagnosed using visual inspection (such as using an endoscope). sf-6102887 Attorney Reference: 63877-20229.40 Gynecological cancers can be hormone receptor-positive (HR+), or hormone-receptor-negative (HR-).
  • HR+ hormone receptor-positive
  • HR- hormone-receptor-negative
  • the hormone receptor status of gynecological cancer can be determined e.g., by obtaining a biopsy to test for, e.g., the presence of estrogen or progesterone receptor using techniques such as immunohistochemistry (IHC).
  • Gynecological cancers can be hormone- dependent (e.g., relies on hormone-driven development and/ or growth), such as estrogen dependent, progesterone dependent, or estrogen and progesterone dependent, or hormone- independent (e.g., does not rely on hormone-driven development and/ or growth).
  • a method of treating a breast or gynecological cancer in an individual in need thereof comprising administering to the individual: (a) a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin; and (b) a PI3K inhibitor, such as a class I PI3K inhibitor (e.g., gedatolisib or alpelisib).
  • a PI3K inhibitor such as a class I PI3K inhibitor (e.g., gedatolisib or alpelisib).
  • a method of treating a breast cancer 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., nab-sirolimus); and (b) gedatolisib.
  • a breast cancer such as a HR+ breast cancer, a HR- breast cancer, a hormone-dependent breast cancer, a hormone- independent breast cancer, a ductal carcinoma in situ (DCIS) breast cancer, invasive ductal carcinoma (IDC) breast cancer, lobular carcinoma in situ (LCIS) breast cancer, invasive lobular carcinoma (ILC) breast cancer, or inflammatory breast cancer (IBC)
  • the method comprises 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., nab-sirolimus), wherein the mTOR inhibitor in the nanoparticles is associated (e.g., coated) with the albumin; and (b) gedatolisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) gedatolisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), wherein the nanoparticles comprise sf-6102887 Attorney Reference: 63877-20229.40 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) gedatolisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) gedatolisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • an albumin e.g., nab-sirolimus
  • the mTOR inhibitor is a limus drug. In some embodiments, the mTOR inhibitor is sirolimus or a derivative thereof. In some embodiments, the mTOR inhibitor nanoparticle composition comprises nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is administered weekly, such as twice out of every 3 weeks, such as on days 1 and 8, 1 and 15, 1 and 21, or 8 and 15 of a 21-day cycle.
  • the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg/m 2 to about 150 mg/m 2 , such as about any of 100 mg/m 2 , 75 mg/m 2 , 56 mg/m 2 , 45 mg/m 2 , or 30 mg/m 2 .
  • the mTOR inhibitor nanoparticle composition is administered intravenously.
  • the mTOR inhibitor 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.
  • gedatolisib is administered to the individual intravenously.
  • gedatolisib is administered to the individual weekly.
  • gedatolisib is administered to the individual on days 1, 8, and 15 of a 21-day cycle.
  • the amount of gedatolisib is about 90 mg to about 310 mg, such as about 180 mg.
  • gedatolisib is administered to the individual on days 1, 8, and 15 of a 21-day cycle, at an amount of about 90 mg to about 310 mg, such as about 180 mg.
  • the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • the amount of gedatolisib is about 90 mg to about 310 mg, such as about 180 mg.
  • gedatolisib is administered to the individual on days 1, 8, and 15 of a 21- day cycle, at an amount of about 90 mg to about 310 mg, such as about 180 mg, wherein the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • a method of treating a gynecological cancer such as a HR+ gynecological cancer, a HR- gynecological cancer, a hormone-dependent gynecological cancer, a hormone-independent gynecological cancer, a cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, or vulvar cancer
  • an individual such as a human
  • administering comprising 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., nab-sirolimus); and (b) gedatolisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), wherein the mTOR inhibitor in the nanoparticles is associated (e.g., coated) with the albumin; and (b) gedatolisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) gedatolisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) gedatolisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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 sf-6102887 Attorney Reference: 63877-20229.40 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) gedatolisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • an albumin
  • the mTOR inhibitor is a limus drug. In some embodiments, the mTOR inhibitor is sirolimus or a derivative thereof. In some embodiments, the mTOR inhibitor nanoparticle composition comprises nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is administered weekly, such as twice out of every 3 weeks, such as on days 1 and 8, 1 and 15, 1 and 21, or 8 and 15 of a 21-day cycle.
  • the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg/m 2 to about 150 mg/m 2 , such as about any of 100 mg/m 2 , 75 mg/m 2 , 56 mg/m 2 , 45 mg/m 2 , or 30 mg/m 2 .
  • the mTOR inhibitor nanoparticle composition is administered intravenously.
  • the mTOR inhibitor 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.
  • gedatolisib is administered to the individual intravenously.
  • gedatolisib is administered to the individual weekly.
  • gedatolisib is administered to the individual on days 1, 8, and 15 of a 21-day cycle.
  • the amount of gedatolisib is about 90 mg to about 310 mg, such as about 180 mg.
  • gedatolisib is administered to the individual on days 1, 8, and 15 of a 21-day cycle, at an amount of about 90 mg to about 310 mg, such as about 180 mg.
  • the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • gedatolisib is administered to the individual on days 1, 8, and 15 of a 21-day cycle, at an amount of about 90 mg to about 310 mg, such as about 180 mg, wherein the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • a method of treating a breast cancer 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., nab-sirolimus); and (b) alpelisib.
  • a breast cancer such as a HR+ breast cancer, a HR- breast cancer, a hormone-dependent breast cancer, a hormone- independent breast cancer, a ductal carcinoma in situ (DCIS) breast cancer, invasive ductal carcinoma (IDC) breast cancer, lobular carcinoma in situ (LCIS) breast cancer, invasive lobular sf-6102887 Attorney Reference: 63877-20229.40 carcinoma (ILC) breast cancer, or inflammatory breast cancer (IBC)) in an individual (such as a human) comprising administering to the individual: (a) a composition comprising nanoparticles comprising an mTOR inhibitor (such as
  • the method comprises 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., nab-sirolimus), wherein the mTOR inhibitor in the nanoparticles is associated (e.g., coated) with the albumin; and (b) alpelisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) alpelisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) alpelisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) alpelisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • an albumin e.g., nab-sirolimus
  • the mTOR inhibitor is a limus drug. In some embodiments, the mTOR inhibitor is sirolimus or a derivative thereof. In some embodiments, the mTOR inhibitor nanoparticle composition comprises nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is administered weekly, such as twice out of every 3 weeks, such as on days 1 and 8, 1 and 15, 1 and 21, or 8 and 15 of a 21-day cycle.
  • the amount of the mTOR inhibitor in the mTOR inhibitor sf-6102887 Attorney Reference: 63877-20229.40 nanoparticle composition is about 10 mg/m 2 to about 150 mg/m 2 , such as about any of 100 mg/m 2 , 75 mg/m 2 , 56 mg/m 2 , 45 mg/m 2 , or 30 mg/m 2 .
  • the mTOR inhibitor nanoparticle composition is administered intravenously.
  • the mTOR inhibitor 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.
  • alpelisib is administered to the individual orally.
  • alpelisib is administered to the individual daily.
  • the amount of alpelisib is about 150 mg to about 350 mg, such as about 300 mg.
  • alpelisib is administered to the individual daily, at an amount of about 150 mg to about 350 mg, such as about 300 mg.
  • the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • alpelisib is administered to the individual daily, at an amount of about 150 mg to about 350 mg, such as about 300 mg, wherein the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • a method of treating a gynecological cancer such as a HR+ gynecological cancer, a HR- gynecological cancer, a hormone-dependent gynecological cancer, a hormone-independent gynecological cancer, a cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, or vulvar cancer
  • an individual such as a human
  • administering comprising 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., nab-sirolimus); and (b) alpelisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), wherein the mTOR inhibitor in the nanoparticles is associated (e.g., coated) with the albumin; and (b) alpelisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), wherein the nanoparticles have an average particle size of no greater than sf-6102887 Attorney Reference: 63877-20229.40 about 150 nm (such as no greater than about 120 nm); and (b) alpelisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) alpelisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) alpelisib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • an albumin e.g., nab-sirolimus
  • the mTOR inhibitor is a limus drug. In some embodiments, the mTOR inhibitor is sirolimus or a derivative thereof. In some embodiments, the mTOR inhibitor nanoparticle composition comprises nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is administered weekly, such as twice out of every 3 weeks, such as on days 1 and 8, 1 and 15, 1 and 21, or 8 and 15 of a 21-day cycle.
  • the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg/m 2 to about 150 mg/m 2 , such as about any of 100 mg/m 2 , 75 mg/m 2 , 56 mg/m 2 , 45 mg/m 2 , or 30 mg/m 2 .
  • the mTOR inhibitor nanoparticle composition is administered intravenously.
  • the mTOR inhibitor 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.
  • alpelisib is administered to the individual orally.
  • alpelisib is administered to the individual daily.
  • the amount of alpelisib is about 150 mg to about 350 mg, such as about 300 mg.
  • alpelisib is administered to the individual daily, at an amount of about 150 mg to sf-6102887 Attorney Reference: 63877-20229.40 about 350 mg, such as about 300 mg.
  • the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • alpelisib is administered to the individual daily, at an amount of about 150 mg to about 350 mg, such as about 300 mg, wherein the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • a method of treating a breast cancer or a gynecological cancer in an individual in need thereof comprising administering to the individual: (a) a composition comprising nanoparticles comprising an mTOR inhibitor and an albumin; and (b) an AKT inhibitor, such as a pan-AKT inhibitor (e.g., miransertib or capivasertib).
  • a pan-AKT inhibitor e.g., miransertib or capivasertib.
  • a method of treating a breast cancer 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., nab-sirolimus); and (b) miransertib.
  • a breast cancer such as a HR+ breast cancer, a HR- breast cancer, a hormone-dependent breast cancer, a hormone- independent breast cancer, a ductal carcinoma in situ (DCIS) breast cancer, invasive ductal carcinoma (IDC) breast cancer, lobular carcinoma in situ (LCIS) breast cancer, invasive lobular carcinoma (ILC) breast cancer, or inflammatory breast cancer (IBC)
  • the method comprises 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., nab-sirolimus), wherein the mTOR inhibitor in the nanoparticles is associated (e.g., coated) with the albumin; and (b) miransertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) miransertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), wherein the nanoparticles comprise sf-6102887 Attorney Reference: 63877-20229.40 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) miransertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) miransertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • an albumin e.g., nab-sirolimus
  • the mTOR inhibitor is a limus drug. In some embodiments, the mTOR inhibitor is sirolimus or a derivative thereof. In some embodiments, the mTOR inhibitor nanoparticle composition comprises nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is administered weekly, such as twice out of every 3 weeks, such as on days 1 and 8, 1 and 15, 1 and 21, or 8 and 15 of a 21-day cycle.
  • the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg/m 2 to about 150 mg/m 2 , such as about any of 100 mg/m 2 , 75 mg/m 2 , 56 mg/m 2 , 45 mg/m 2 , or 30 mg/m 2 .
  • the mTOR inhibitor nanoparticle composition is administered intravenously.
  • the mTOR inhibitor 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.
  • miransertib is administered to the individual orally.
  • miransertib is administered to the individual daily.
  • the amount of miransertib is about 5 mg to about 60 mg, such as about 50 mg.
  • miransertib is administered to the individual daily, at an amount of about 5 mg to about 60 mg, such as about 50 mg.
  • the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • miransertib is administered to the individual daily, at an amount of about 5 mg to about 60 mg, such as about 50 mg, and the individual has sf-6102887 Attorney Reference: 63877-20229.40 been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • a method of treating a gynecological cancer such as a HR+ gynecological cancer, a HR- gynecological cancer, a hormone-dependent gynecological cancer, a hormone-independent gynecological cancer, a cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, or vulvar cancer
  • an individual such as a human
  • administering comprising 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., nab-sirolimus); and (b) miransertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), wherein the mTOR inhibitor in the nanoparticles is associated (e.g., coated) with the albumin; and (b) miransertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) miransertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) miransertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) miransertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • an albumin e.g., nab-sirolimus
  • the mTOR inhibitor is a limus drug. In some embodiments, the mTOR inhibitor is sirolimus or a derivative thereof. sf-6102887 Attorney Reference: 63877-20229.40
  • the mTOR inhibitor nanoparticle composition comprises nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is administered weekly, such as twice out of every 3 weeks, such as on days 1 and 8, 1 and 15, 1 and 21, or 8 and 15 of a 21-day cycle.
  • the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg/m 2 to about 150 mg/m 2 , such as about any of 100 mg/m 2 , 75 mg/m 2 , 56 mg/m 2 , 45 mg/m 2 , or 30 mg/m 2 .
  • the mTOR inhibitor nanoparticle composition is administered intravenously.
  • the mTOR inhibitor 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.
  • miransertib is administered to the individual orally.
  • miransertib is administered to the individual daily.
  • the amount of miransertib is about 5 mg to about 60 mg, such as about 50 mg.
  • miransertib is administered to the individual daily, at an amount of about 5 mg to about 60 mg, such as about 50 mg.
  • the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • miransertib is administered to the individual daily, at an amount of about 5 mg to about 60 mg, such as about 50 mg, and the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • a method of treating a breast cancer 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., nab-sirolimus); and (b) capivasertib.
  • a breast cancer such as a HR+ breast cancer, a HR- breast cancer, a hormone-dependent breast cancer, a hormone- independent breast cancer, a ductal carcinoma in situ (DCIS) breast cancer, invasive ductal carcinoma (IDC) breast cancer, lobular carcinoma in situ (LCIS) breast cancer, invasive lobular carcinoma (ILC) breast cancer, or inflammatory breast cancer (IBC)
  • the method comprises administering to the individual: (a) a composition comprising nanoparticles sf-6102887 Attorney Reference: 63877-20229.40 comprising an mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) and an albumin (e.g., nab-sirolimus), wherein the mTOR inhibitor in the nanoparticles is associated (e.g., coated) with the albumin; and (b) capivasertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) capivasertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) capivasertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) capivasertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • an albumin e.g., nab-sirolimus
  • the mTOR inhibitor is a limus drug. In some embodiments, the mTOR inhibitor is sirolimus or a derivative thereof. In some embodiments, the mTOR inhibitor nanoparticle composition comprises nab- sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is administered weekly, such as twice out of every 3 weeks, such as on days 1 and 8, 1 and 15, 1 and 21, or 8 and 15 of a 21-day cycle.
  • the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg/m2 to about 150 mg/m 2 , such as about any of 100 mg/m 2 , 75 mg/m 2 , 56 mg/m 2 , 45 mg/m 2 , or 30 mg/m 2 .
  • the mTOR inhibitor nanoparticle composition is administered intravenously.
  • the mTOR inhibitor 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 sf-6102887 Attorney Reference: 63877-20229.40 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.
  • capivasertib is administered to the individual orally.
  • capivasertib is administered to the individual twice daily (including intermittent dosing schedules, such as four days on and three days off).
  • the amount of capivasertib is about 150 mg to about 500 mg, such as about 400 mg or about 480 mg.
  • capivasertib is administered to the individual twice daily (including intermittent dosing schedules, such as four days on and three days off), at an amount of about 150 mg to about 500 mg, such as about 400 mg or about 480 mg.
  • the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • capivasertib is administered to the individual twice daily (including intermittent dosing schedules, such as four days on and three days off), at an amount of about 150 mg to about 500 mg, such as about 400 mg or about 480 mg, wherein the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • a method of treating a gynecological cancer such as a HR+ gynecological cancer, a HR- gynecological cancer, a hormone-dependent gynecological cancer, a hormone-independent gynecological cancer, a cervical cancer, ovarian cancer, uterine cancer, vaginal cancer, or vulvar cancer
  • an individual such as a human
  • administering comprising 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., nab-sirolimus); and (b) capivasertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), wherein the mTOR inhibitor in the nanoparticles is associated (e.g., coated) with the albumin; and (b) capivasertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the method comprises 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., nab-sirolimus), 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) capivasertib.
  • an mTOR inhibitor such as a limus drug, e.g., sirolimus or a derivative thereof
  • albumin e.g., nab-sirolimus
  • the mTOR inhibitor is a limus drug. In some embodiments, the mTOR inhibitor is sirolimus or a derivative thereof. In some embodiments, the mTOR inhibitor nanoparticle composition comprises nab- sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is nab-sirolimus. In some embodiments, the mTOR inhibitor nanoparticle composition is administered weekly, such as twice out of every 3 weeks, such as on days 1 and 8, 1 and 15, 1 and 21, or 8 and 15 of a 21-day cycle.
  • the amount of the mTOR inhibitor in the mTOR inhibitor nanoparticle composition is about 10 mg/m 2 to about 150 mg/m 2 , such as about any of 100 mg/m 2 , 75 mg/m 2 , 56 mg/m 2 , 45 mg/m 2 , or 30 mg/m 2 .
  • the mTOR inhibitor nanoparticle composition is administered intravenously.
  • the mTOR inhibitor 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.
  • capivasertib is administered to the individual orally.
  • capivasertib is administered to the individual twice daily (including intermittent dosing schedules, such as four days on and three days off).
  • the amount of capivasertib is about 150 mg to about 500 mg, such as about 400 mg or about 480 mg.
  • capivasertib is administered to the individual twice daily (including intermittent dosing schedules, such as four days on and three days off), at an amount of about sf-6102887 Attorney Reference: 63877-20229.40 150 mg to about 500 mg, such as about 400 mg or about 480 mg.
  • the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • capivasertib is administered to the individual twice daily (including intermittent dosing schedules, such as four days on and three days off), at an amount of about 150 mg to about 500 mg, such as about 400 mg or about 480 mg, wherein the individual has been previously treated with (and, optionally, is resistant to) mTOR inhibitor therapy, PI3K inhibitor therapy, or AKT inhibitor therapy.
  • 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. In some embodiments, the average or mean diameters of the nanoparticles is no greater than about 150 nm. In some embodiments, the average or mean diameters of the nanoparticles is no greater than about 100 nm. In some embodiments, the average or mean diameter of the nanoparticles is about 10 to about 400 nm. In some embodiments, 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.
  • the nanoparticles are sterile- filterable.
  • sf-6102887 Attorney Reference: 63877-20229.40
  • Methods of determining average particle sizes are known in the art, for example, dynamic light scattering (DLS) has been routinely used in determining the size of submicrometre-sized particles based.
  • DLS dynamic light scattering
  • ISO22412 Particle Size Analysis Dynamic Light Scattering, International Organisation for Standardisation (ISO) 2008 and Dynamic Light Scattering Common Terms Defined, Malvern Instruments Limited, 2011.
  • 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. [0135] In some embodiments, the albumin has sulfhydryl groups that can form disulfide bonds. In some embodiments, 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., sirolimus 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., sirolimus 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%, sf-6102887 Attorney Reference: 63877-20229.40 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 sf-6102887 Attorney Reference: 63877-20229.40 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. In some embodiments, the albumin is a recombinant albumin.
  • Human serum albumin (HSA) is a highly soluble globular protein of Mr 65K and consists of 585 amino acids. HSA is the most abundant protein in the plasma and accounts for 70-80 % of the colloid osmotic pressure of human plasma. The amino acid sequence of HSA contains a total of 17 disulfide bridges, one free thiol (Cys 34), and a single tryptophan (Trp 214).
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 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), Altmayer 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 thereof) 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 oC) or refrigerated conditions (such as 4 oC)). For example, 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 oC or higher.
  • a storage temperature such as room temperature (such as 20-25 oC) or refrigerated conditions (such as 4 oC)
  • 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
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 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 thereof) 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.
  • a limus drug e.g., rapamycin or a derivative thereof
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 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.
  • limus drugs such as a limus drug, e.g., rapamycin or a derivative thereof
  • 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).
  • the methods described herein in some embodiments comprise administration of nanoparticle compositions of mTOR inhibitors.
  • 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 (mTORC1) and mTOR Complex 2 (mTORC2).
  • mTORC1 is composed of mTOR, regulatory- associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8), PRAS40 and DEPTOR (Kim et al. (2002). Cell 110: 163–75; Fang et al. (2001). Science 294 (5548): 1942–5).
  • mTORC1 integrates four major signal inputs: nutrients (such as amino acids sf-6102887 Attorney Reference: 63877-20229.40 and phosphatidic acid), growth factors (insulin), energy and stress (such as hypoxia and DNA damage).
  • Amino acid availability is signaled to mTORC1 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 mTORC1.
  • low ATP levels lead to the AMPK-dependent activation of TSC2 and phosphorylation of raptor to reduce mTORC1 signaling proteins.
  • Active mTORC1 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 (Atg13, ULK1), ribosome biogenesis, and activation of transcription leading to mitochondrial metabolism or adipogenesis. Accordingly, mTORC1 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 ⁇ L, and mammalian stress-activated protein kinase interacting protein 1 (mSIN1).
  • mTORC2 regulates cytoskeletal organization through its stimulation of F-actin stress fibers, paxillin, RhoA, Rac1, Cdc42, and protein kinase C ⁇ (PKC ⁇ ). It had been observed that knocking down mTORC2 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).
  • the mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) is an inhibitor of mTORC1. In some embodiments, the mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) is an inhibitor of mTORC2.
  • the mTOR inhibitor (such as a limus drug, e.g., sirolimus or a derivative thereof) is an inhibitor of both mTORC1 and mTORC2.
  • sf-6102887 Attorney Reference: 63877-20229.40
  • the mTOR inhibitor is a limus drug, which includes sirolimus and its analogs. Examples of 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 mTORC1. Sirolimus is known to act as an allosteric mTOR inhibitor.
  • the mTOR inhibitor is selected from the group consisting of sirolimus (rapamycin), BEZ235 (NVP-BEZ235), everolimus (also known as RAD001, Zortress, Certican, and Afinitor), AZD8055, 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 mTORC1 catalytic inhibitor (Roper J, et al. PLoS One, 2011, 6(9), e25132).
  • Everolimus is the 40-O-(2- hydroxyethyl) derivative of sirolimus and binds the cyclophilin FKBP-12, and this complex also mTORC1.
  • AZD8055 is a small molecule that inhibits the phosphorylation of mTORC1 (p70S6K and 4E-BP1).
  • Temsirolimus is a small molecule that forms a complex with the FK506-binding protein and prohibits the activation of mTOR when it resides in the mTORC1complex.
  • PI-103 is a small molecule that inhibits the activation of the rapamycin-sensitive (mTORC1) complex (Knight et al. (2006) Cell.125: 733-47).
  • KU-0063794 is a small molecule that inhibits the phosphorylation of mTORC1 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 sf-6102887 Attorney Reference: 63877-20229.40 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 mTORC1.
  • GSK2126458 is an inhibitor of mTORC1.
  • PKI-587 is a highly potent dual inhibitor of PI3K ⁇ , PI3K ⁇ and mTOR.
  • PP-121 is a multi-target inhibitor of PDGFR, Hck, mTOR, VEGFR2, Src and Abl.
  • OSI-027 is a selective and potent dual inhibitor of mTORC1 and mTORC2 with IC50 of 22 nM and 65 nM, respectively.
  • Palomid 529 is a small molecule inhibitor of mTORC1 that lacks affinity for ABCB1/ABCG2 and has good brain penetration (Lin et al. (2013) Int J Cancer DOI: 10.1002/ijc.28126 (e-published ahead of print).
  • PP242 is a selective mTOR inhibitor.
  • XL765 is a dual inhibitor of mTOR/PI3k for mTOR, p110 ⁇ , p110 ⁇ , p110 ⁇ and p110 ⁇ .
  • GSK1059615 is a novel and dual inhibitor of PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K ⁇ and mTOR.
  • WYE-354 inhibits mTORC1 in HEK293 cells (0.2 ⁇ M–5 ⁇ M) and in HUVEC cells (10 nM-1 ⁇ M). WYE-354 is a potent, specific, and ATP-competitive inhibitor of mTOR.
  • Deforolimus (Ridaforolimus, AP23573, MK-8669) is a selective mTOR inhibitor.
  • 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, corn 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 sf-6102887 Attorney Reference: 63877-20229.40 acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • an inert base such as gelatin and glycerin
  • sucrose and sf-6102887 Attorney Reference: 63877-20229.40 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 non- aqueous, 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.
  • 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. In some embodiments, 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. C.
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 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 (i.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.
  • sf-6102887 Attorney Reference: 63877-20229.40
  • rapamycin is dissolved in an organic solvent.
  • Suitable organic solvents include, for example, ketones, esters, ethers, chlorinated solvents, and other solvents known in the art.
  • the organic solvent can be a mixture of methylene chloride/ethanol, chloroform/ethanol, or chloroform/tert-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. In some embodiments, 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.
  • the organic solvent comprises about any of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% chloroform by volume. In some embodiments, 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.
  • 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 NOVOZYME TM recombinant albumin or INTRIVIA TM 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-110EH 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 sf-6102887 Attorney Reference: 63877-20229.40 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, 1516, 18, 20, 25, or 30 minutes). The dispersion obtained can be further lyophilized.
  • 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, 1516, 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, polydispersity 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 size- exclusion 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 sf-610
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 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 size- exclusion 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-average 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 polydispersity 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- Dv5)/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 polydispersity 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 ⁇ g/mL to about 55 ⁇ g/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
  • the non-nanoparticle sf-6102887 Attorney Reference: 63877-20229.40 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 ⁇ g/mL to about 55 ⁇ g/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 sf-6102887 Attorney Reference: 63877-20229.40 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.
  • 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.
  • the nanoparticle composition comprises less than 10 ⁇ g/mL tert-butanol and/or comprises less than 5 ⁇ g/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.
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 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
  • a core comprising
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 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 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 sf-6102887 Attorney Reference: 63877-20229.40 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)
  • 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 seco-rapamycin is less than 3% (such as about 0.2% to about 3%) of the sum of seco-rapamycin and rapamycin in the composition.
  • 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.
  • 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. In some embodiments, about 95% or more of the albumin in the composition is in the non-nanoparticle portion. In some embodiments, about 98% to about 99.5% of the rapamycin in the composition is in the nanoparticles. In some embodiments, the concentration of albumin in the nanoparticle composition 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% sf-6102887 Attorney Reference: 63877-20229.40 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 sf-6102887 Attorney Reference: 63877-20229.40 albumin (such as human albumin) and a core comprising rapamycin; and (b) a non-nanoparticle portion comprising albumin (such as human albumin) and rapamycin [0205]
  • 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
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 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 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 sf-6102887 Attorney Reference: 63
  • seco- rapamycin is greater than about 0.2% (such as about 0.2% to about 3%) of the sum of seco- rapamycin and rapamycin in the composition.
  • “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).
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 composition, such as FYARROTM) is administered on Day 1, Day 8, or Day 15 of 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 to the individual twice 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 during Week 1 and Week 2 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 2 and Week 3 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 1 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 on Day 1 and Day 8 of 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 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).
  • 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).
  • 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).
  • Second therapeutic agent [0218]
  • the combination treatments provided herein comprise the use of a second therapeutic agent that is a PI3K inhibitor (such as alpelisib or gedatolisib) or an AKT inhibitor (such as miransertib or capivasertib).
  • the second therapeutic agent described herein may function via two or more mechanisms, e.g., as is the case with dual inhibitors.
  • the second agent is an agent that is both a PI3K inhibitor and an mTOR inhibitor (such as an ATP competitive mTOR inhibitor).
  • gedatolisib is known as a dual PI3K/ mTOR inhibitor (specifically, an ATP competitive mTOR inhibitor), and description of a second therapeutic agent that is a PI3K inhibitor and description of a second therapeutic agent that is an mTOR inhibitor, such as an ATP competitive mTOR inhibitor, will both encompass gedatolisib.
  • the second therapeutic agent acts, at least in part, as an mTOR ATP competitive inhibitor.
  • the second therapeutic agent is gedatolisib.
  • the second therapeutic agent is sapanisertib.
  • Additional description of certain second therapeutic agents is provided in the sections below.
  • A. PI3K inhibitors [0221] The methods of treatment described herein comprise administering a PI3K inhibitor, wherein the PI3K inhibitor specifically binds to and inhibits the activity of a PI3K protein.
  • the PI3K inhibitor may be an isoform-specific PI3K inhibitor, a pan-PI3K inhibitor, or a dual PI3K/mTOR inhibitor (such as a PI3K inhibitor and an ATP competitive mTOR inhibitor). Accordingly, one of ordinary skill in the art will readily recognize that the scope of the agents encompassed covers agents with specificity for some or all isoforms of PI3K sf-6102887 Attorney Reference: 63877-20229.40 protein as well as others with specificity for both a PI3K protein and one or both of mTORC1 and mTORC2.
  • Phosphoinositide 3-kinases are lipid kinases that regulate cellular processes such as proliferation, survival, adhesion, and motility through its function in the PI3K/AKT/mTOR pathway.
  • PI3K proteins can be classified into three main classes (I, II and III) based on the substrate specificities and structural characteristics. Class I PI3Ks can further be categorized into two subtypes (A and B) based on the mode of regulation.
  • Class IA PI3Ks form dimers containing a regulatory (p85 ⁇ , p85 ⁇ , p55 ⁇ , p55 ⁇ , p50 ⁇ isoforms) and a catalytic (p110 ⁇ , p110 ⁇ , p110 ⁇ isoforms) subunit.
  • Class I PI3Ks act downstream of both G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs).
  • GPCRs G protein-coupled receptors
  • RTKs receptor tyrosine kinases
  • the term “dual PI3K/mTOR inhibitor,” as used herein, may be used to describe an agent that targets some or all catalytic forms of PI3K, as well as of mTORC1 and mTORC2.
  • the dual PI3K/mTOR inhibitor is a PI3K and ATP competitive mTOR inhibitor, such as gedatolisib.
  • a dual PI3K/mTOR inhibitor is an isoform- specific class I PI3K inhibitor as well as an inhibitor of mTORC1 and mTORC2.
  • the dual PI3K/mTOR inhibitor is gedatolisib.
  • the term “isoform-specific PI3K inhibitor,” as used herein, may be used to describe an agent that is potent across some or all isoforms within a class of PI3K proteins.
  • the term “class I PI3K inhibitor” may be used to describe an agent that inhibits the activity of some or all isoforms of class I PI3K proteins.
  • the PI3K inhibitor is an isoform-specific PI3K inhibitor.
  • the isoform-specific PI3K inhibitor is a class I PI3K inhibitor. In some embodiments, the isoform-specific PI3K inhibitor inhibit all isoforms of class I PI3K proteins. In some embodiments, the class I PI3K inhibitor is gedatolisib. In some embodiments, the class I PI3K inhibitor is alpelisib. [0225] In some embodiments, the PI3K inhibitor is both a class I PI3K inhibitor and a dual PI3K/mTOR inhibitor, and the PI3K inhibitor is gedatolisib.
  • the PI3K inhibitor is selected from the group consisting of gedatolisib, alpelisib, copanlisib, idelalisib, umbralisib, and duvelisib. In some embodiments, the PI3K inhibitor is gedatolisib. In some embodiments, the PI3K inhibitor is alpelisib.
  • PI3K inhibitors such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • PI3K inhibitors are provided below.
  • the PI3K inhibitor is alpelisib.
  • the PI3K inhibitor is alpelisib, wherein alpelisib is administered to the individual orally.
  • alpelisib is administered to the individual at an amount of about 150 mg to about 350 mg, such as about any of 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 325 mg, 330 mg, 340 mg, or 350 mg.
  • alpelisib is administered to the individual daily.
  • alpelisib is administered to the individual daily at an amount of 300 mg.
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • the PI3K inhibitor is gedatolisib.
  • the PI3K inhibitor is gedatolisib, wherein gedatolisib is administered to the individual intravenously.
  • gedatolisib is administered to the individual at an amount of about 90 mg to about 310 mg, such as about any of 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, or 310 mg.
  • gedatolisib is administered to the individual weekly.
  • gedatolisib is administered to the individual weekly at an amount of 180 mg weekly.
  • gedatolisib is administered to the individual on day 1, 8, and 15 of a 21-day cycle. In some embodiments, gedatolisib is sf-6102887 Attorney Reference: 63877-20229.40 administered to the individual weekly at an amount of 180 mg on day 1, 8, and 15 of a 21-day cycle.
  • AKT inhibitors [0229] The methods of treatment described herein comprise administering an AKT inhibitor, wherein the AKT inhibitor specifically binds to and inhibits the activity of an AKT serine/threonine kinase. As taught herein, the AKT inhibitor may be a pan-AKT inhibitor or isoform-specific AKT inhibitor.
  • AKT also known as protein kinase B (PKB)
  • PKA protein kinase B
  • AKT isoforms encoded by three separate genes, namely AKT1/PKB ⁇ , AKT2/PKB ⁇ and AKT3/PKB ⁇ . Enhanced activation of all the isoforms can be implicated in tumor development and progression, as shown in breast, ovarian, pancreatic, and prostate cancers among others (Song et al., Cancer Res, 79 (6): 1019-1031, 2019). In cancer cells, AKT1 is involved in proliferation and growth, promoting tumor initiation, and suppressing apoptosis.
  • All three AKT proteins have three functional domains: an N-terminal fragment with a pleckstrin-homology (PH) domain, a central kinase domain (KD) and a C-terminal fragment with a regulatory region (RR) containing a hydrophobic motif.
  • PH pleckstrin-homology
  • KD central kinase domain
  • RR regulatory region
  • the biology of AKT proteins and the mechanisms of action of AKT inhibitors is well known in the art, e.g., Martorana et al., Front sf-6102887 Attorney Reference: 63877-20229.40 Pharmacol, 12:662232, 2021 and Lazaro et al., Biochem Soc Trans, 48(3): 933-943, 2020, which are hereby incorporated herein by reference in its entirety.
  • the AKT inhibitor that specifically binds to and inhibits the activity of an AKT serine/threonine kinase is a pan-AKT inhibitor.
  • the pan-AKT inhibitor is miransertib.
  • the pan-AKT inhibitor is capivasertib.
  • the AKT inhibitor that specifically binds to and inhibits the activity of an AKT serine/threonine kinase is an isoform-specific AKT inhibitor.
  • the AKT inhibitor that specifically binds to and inhibits the activity of an AKT serine/threonine kinase is an allosteric AKT inhibitor.
  • the allosteric AKT inhibitor is miransertib.
  • the AKT inhibitor that specifically binds to and inhibits the activity of an AKT serine/threonine kinase is an ATP- competitive AKT inhibitor.
  • the AKT inhibitor is capivasertib.
  • the AKT inhibitor that specifically binds to and inhibits the activity of an AKT serine/threonine kinase is selected from the group consisting of miransertib, capivasertib, AY1125976, MK-2206, and TAS-117, ipatasertib, and afuresertib.
  • the AKT inhibitor that specifically binds to and inhibits the activity of a AKT protein is capivasertib.
  • the AKT inhibitor that specifically binds to and inhibits the activity of a AKT protein is miransertib.
  • Exemplary dosages, routes of administration, and dosing schedules for second therapeutic agent described herein are provided in other sections herein.
  • a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • AKT inhibitor such as miransertib or capivasertib
  • the AKT inhibitor is miransertib.
  • the AKT inhibitor is miransertib, wherein miransertib is administered to the individual orally.
  • miransertib is administered to the individual at an amount of about 5 mg to about 60 mg, such as about any of 5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg. In some embodiments, miransertib is administered to the individual daily. In some embodiments, miransertib is administered to the individual daily at an amount of 50 mg.
  • sf-6102887 Attorney Reference: 63877-20229.40
  • second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • AKT inhibitor such as miransertib or capivasertib
  • the AKT inhibitor is capivasertib.
  • the AKT inhibitor is capivasertib, wherein capivasertib is administered to the individual orally.
  • capivasertib is administered to the individual at an amount of about 150 mg to about 500 mg, such as about any of 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 325 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 375 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 425 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 475 mg, 480 mg, 490 mg, or 500mg.
  • capivasertib is administered to the individual twice daily. In some embodiments, capivasertib is administered to the individual at an amount of about 400 mg twice daily. In some embodiments, capivasertib is administered to the individual twice daily according to an intermittent dosing schedule of four days on and three days off. In some embodiments, capivasertib is administered to the individual on days 1-4 of a 7-day cycle. In some embodiments, the capivasertib is administered to the individual twice daily on days 1-4 of a 7-day cycle. In some embodiments, capivasertib is administered to the individual at an amount of about 400 mg twice daily on days 1-4 of a 7-day cycle.
  • capivasertib is administered to the individual at an amount of about 480 mg twice daily. In some embodiments, capivasertib is administered to the individual at an amount of about 480 mg twice daily on days 1-4 of a 7-day cycle.
  • C. mTOR ATP competitive inhibitors [0236] In some embodiments, the second therapeutic agent acts, at least in part, as an mTOR ATP competitive inhibitor. [0237] In some embodiments, the second therapeutic agent is gedatolisib, which is discussed in more detail above. [0238] In some embodiments, the second therapeutic agent is sapanisertib (also known as MLN0128, INK128, and TAK-228).
  • Sapanisertib acts, at least in part, as an mTOR ATP sf-6102887 Attorney Reference: 63877-20229.40 competitive inhibitor targeting both mTORC1 and mTORC2.
  • sapanisertib is administered to an individual orally.
  • sapanisertib is administered to an individual at a dose of about 0.5 mg to about 20 mg daily, including 3 mg once per day or 2 mg twice per day. V.
  • an article of manufacture containing materials useful for the taught treatments of a breast cancer or a gynecological cancer
  • the article of manufacture such as a medicament or medicament combination
  • an mTOR inhibitor nanoparticle composition such as sirolimus/albumin nanoparticle composition, e.g., nab-sirolimus
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib
  • 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 (e.g., nab-sirolimus); or (b) a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib).
  • mTOR inhibitor e.g., nab-sirolimus
  • a second therapeutic agent described herein e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib.
  • the label or package insert indicates that the composition is used for treating the particular condition in an individual, such as described herein.
  • the label or package insert will further comprise instructions for administering the composition to the individual according to the methods described herein. Articles of manufacture and kits comprising combination therapies described here
  • 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 sf-6102887 Attorney Reference: 63877-20229.40 treating a hormone-dependent cancer (e.g., an endometrial cancer (e.g., endometrioid endometrial cancer) or hormone-receptor positive breast cancer).
  • a hormone-dependent cancer e.g., an endometrial cancer (e.g., endometrioid endometrial cancer) or hormone-receptor positive breast cancer.
  • 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.
  • Kits are also provided that are useful for various purposes, e.g., for taught treatments of a breast cancer or a gynecological cancer.
  • 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 a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) and/or instructions for use in accordance with any of the methods described herein.
  • the kit may further comprise a description of selection of individuals suitable for treatment.
  • 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 a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) 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 sub-unit doses.
  • kits may be provided that contain sufficient dosages of an mTOR inhibitor nanoparticle composition (such as sf-6102887 Attorney Reference: 63877-20229.40 sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) 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.
  • an mTOR inhibitor nanoparticle composition such as sf-6102887 Attorney Reference: 63877-20229.40 sirolimus/albumin nanoparticle composition
  • a second therapeutic agent described herein e.g., a PI3K
  • Kits may also include multiple unit doses of the mTOR inhibitor nanoparticle composition (such as sirolimus/albumin nanoparticle composition) and a second therapeutic agent described herein (e.g., a PI3K inhibitor such as alpelisib or gedatolisib, or an AKT inhibitor such as miransertib or capivasertib) and instructions for use, packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
  • a PI3K inhibitor such as alpelisib or gedatolisib
  • an AKT inhibitor such as miransertib or capivasertib
  • nab-Sirolimus enhances the cytotoxic effects of PI3K/AKT pathway inhibitors in breast cancer cells
  • PI3K inhibitors alpelisibalpelisib or gedatolisib
  • AKT inhibitors capivasertib or miransertib
  • sf-6102887 Attorney Reference: 63877-20229.40
  • Another series of single-agent treatments of capivasertib, miransertib or nab- sirolimus and combination treatments of both capivasertib and nab-sirolimus or miransertib and nab-sirolimus were separately applied to aliquots of hormone receptor negative (MDA-MB-453) or hormone receptor positive breast cancer cell lines (either MCF7 or MDA-MB-361).
  • nab-sirolimus (20 nM or 80 nM), capivasertib (1 ⁇ M to 2 ⁇ M) and miransertib (25nM to 250nM).
  • FIGS.1A and 1B for MDA-MB-453 cells abi-009 is nab-sirolimus; bars are arranged in repeating saline, abi-00920 nM, and abi-00980 nM order;
  • FIGS.2A and 2B for MDA-MB-361 cells abi-009 is nab-sirolimus; bars are arranged in repeating saline, abi-00920 nM, and abi-00980 nM order).
  • FIGS.3A and 3B Similar results were observed with alpelisib (1 ⁇ M) plus nab-sirolimus (20 or 80 nM), as shown in FIGS.3A and 3B, as well as with capivasertib (1 ⁇ M; FIG.4A-4B for MDA-MB-453 cells: Sal is saline, AZD is capivasertib and abi is nab-sirolimus; FIGS.5A-5B for MDA-MB-361 cells: Sal is saline, AZD is capivasertib and Abi is nab-sirolimus) or miransertib (250 nM; FIGS.6A-6B for MDA-MB-361 cells: Sal is saline, and Abi is nab-sirolimus) combined with 80 nM nab-sirolimus.
  • phosphorylation of the key mTORC1 target 4EBP1 on threonine 70 was upregulated by alpelisib alone by 301% and upregulated by gedatolisib(a dual PI3K and ATP competitive mTOR inhibitor) by 128%-372%, however, the combination of gedatolisiband nab-sirolimus (allosteric mTOR inhibitor) decreased phosphorylation below even nab-sirolimus on its own.
  • the addition of nab-sirolimus to another agent targeting the same pathway, including additional mTOR pathway inhibitor may overcome mechanisms of drug resistance that lead to treatment failures. sf-6102887

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Abstract

Dans certains aspects, la présente demande concerne des méthodes et des compositions pour le traitement d'un cancer du sein ou d'un cancer gynécologique, faisant appel à une composition comprenant des nanoparticules contenant un inhibiteur de mTOR (tel qu'un inhibiteur de mTOR allostérique, par exemple, le sirolimus) et une albumine en association avec un second agent thérapeutique, par exemple, un inhibiteur de PI3K (tel que le gédatolisib ou l'alpelisib), un inhibiteur d'AKT (tel que le miransertib ou le capivasertib), ou un inhibiteur compétitif de l'ATP de mTOR (par exemple, le sapanisertib).
PCT/US2024/044748 2023-08-31 2024-08-30 Polythérapies anticancéreuses faisant appel à une composition comprenant un inhibiteur de la voie mtor WO2025049962A1 (fr)

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