Method for treating cancer with an mTOR inhibitor

Abstract

The present disclosure relates to methods for the treatment of a disease or disorder (e.g., cancer) with an mTOR inhibitor. Specifically, the present disclosure relates to methods of treating a subject having cancer by administering a specific dosage of an mTOR inhibitor. In some embodiments, the present disclosure includes methods for delaying, preventing, or treating acquired resistance to a RAS inhibitor using a dosage of an mTOR inhibitor. In some embodiments, the present disclosure relates to methods of treating or preventing adverse events associated with the administration of an mTOR inhibitor using tacrolimus.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 348,263, filed on June 2, 2022, and U.S. Provisional Patent Application No. 63 / 345,809, filed on May 25, 2022, which are hereby incorporated by reference in their entirety for all purposes.

[0002] Reference to Sequence Listing The content of the electronic sequence listing (Name: REME_032_02WO_SeqList_ST26.xml; Size: 17,326 bytes; Date of creation: May 22, 2023) is hereby incorporated by reference in its entirety into this specification.

[0003] Field of the Disclosure The present disclosure relates to methods for the treatment of a disease or disorder (e.g., cancer) with an mTOR inhibitor. Specifically, in some embodiments, the present disclosure relates to a method of treating a subject having cancer by administering a dose of an mTOR inhibitor. In some embodiments, the present disclosure includes methods for delaying, preventing, or treating acquired resistance to a RAS inhibitor using a dose of an mTOR inhibitor. In some embodiments, the present disclosure relates to a method of treating or preventing adverse events associated with the administration of an mTOR inhibitor using tacrolimus.

Background Art

[0004] The mammalian target of rapamycin (mTOR), a serine - threonine kinase, is associated with lipid kinases of the phosphoinositide 3 - kinase (PI3K) family. mTOR exists within two complexes, mTORC1 and mTORC2, which are differentially regulated, have significantly different substrate specificities, and are differentially sensitive to rapamycin. mTORC1 integrates signals derived from growth factor receptors with the cell's nutrient status and controls the level of cap - dependent mRNA translation by modulating the activity of key translational components such as eIF4E, a cap - binding protein and an oncogene.

[0005] For the treatment of cancers that depend on the activation of PI3K / mTOR signaling, in addition to first - generation mTOR inhibitors, pan - PI3K inhibitors and isoform - selective PI3K inhibitors are being evaluated. Rapalogs and pan - mTOR active - site inhibitors do not completely inhibit the mTORC1 - mediated phosphorylation of 4EBP1 at clinically achievable exposures and are thus considered "incomplete" pathway inhibitors. This is at least partially consistent with the minimal clinical success of these agents. In addition, pan - mTOR active - site inhibitors exhibit a lack of selectivity and are likely to inhibit lipid kinases. There are important cancer groups that are associated with deregulation of PI3K / mTOR signaling and are currently not addressed by existing inhibitor treatment strategies, leaving a medical need unmet. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0006] Currently, the majority of subjects with mutations / rearrangements conferring activation of the mTOR pathway do not have approved targeted treatment options. This potentially represents a population of subjects who could benefit from treatment. Additionally, resistance to currently approved and new targeted therapies presents another potential population of subjects. Treatment options for either population mainly include chemotherapy regimens that have marginal benefit and are often associated with adverse side effects. Accordingly, new treatment options are needed for these subjects.

Means for Solving the Problems

[0007] The present disclosure relates to methods for treating a disease or disorder (e.g., cancer) with an mTOR inhibitor (e.g., RMC-5552). In particular, the present disclosure provides methods that include administering a specific dosage of an mTOR inhibitor (e.g., RMC-5552). Such methods have surprisingly been found to be effective and tolerable in subjects.

[0008] The present disclosure provides a method for treating a subject having cancer, the method comprising administering to the subject a compound at a dosage of from about 3 mg per week to about 25 mg per week; the compound is RMC-5552:

Chemical formula

[0009] The present disclosure also provides a method for treating a subject having salivary gland cancer, the method comprising administering to the subject a compound at a dosage of from about 3 mg per week to about 25 mg per week; the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0010] The present disclosure also provides a method for delaying or preventing the acquisition of resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject a compound in an amount of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is to receive administration of a RAS inhibitor; The present disclosure also provides a method, wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0011] The present disclosure also provides a method for treating acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject a compound in an amount of from about 3 mg per week to about 25 mg per week; The present disclosure also provides a method, wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0012] The present disclosure also provides the use of a compound in the treatment of cancer, the treatment comprising administering to a subject in need thereof a compound at a dosage of from about 3 mg per week to about 25 mg per week; The present disclosure also provides the use, wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0013] The present disclosure also provides the use of a compound in the manufacture of a medicament for the treatment of cancer, the treatment comprising administering the medicament to a subject in need thereof to deliver a compound at a dosage of from about 3 mg per week to about 25 mg per week; The present disclosure also provides the use, wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0014] The present disclosure also provides a compound for use in a method of treating cancer, the method comprising administering to a subject in need thereof a compound at a dosage of from about 3 mg per week to about 25 mg per week; The compound for use is also provided, wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0015] The present disclosure also provides a medicament for treating cancer, comprising a compound, the treatment comprising administering the medicament to deliver to a subject in need thereof a compound at a dosage of from about 3 mg per week to about 25 mg per week; The medicament is also provided, wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0016] The present disclosure also provides a compound for use in a method of treating cancer in a subject having acquired resistance to a RAS inhibitor, the method comprising administering to the subject a compound at a dosage of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is to receive administration of a RAS inhibitor; The compound for use is also provided, wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0017] The present disclosure also provides a combination of a compound and a RAS inhibitor for simultaneous, separate, or sequential use in a method of treating cancer in a subject having acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a compound at a dosage of from about 3 mg per week to about 25 mg per week; The combination of the compound and the RAS inhibitor is also provided, wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0018] The present disclosure also provides the use of a compound in a treatment for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the treatment comprising administering to the subject a compound at a dosage of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is going to receive administration of a RAS inhibitor; The compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Use is also provided.

[0019] The present disclosure also provides the use of a compound in the manufacture of a medicament for a treatment for delaying or preventing acquired resistance to a RAS inhibitor, the treatment comprising administering the medicament to a subject in need thereof to deliver a compound at a dosage of from about 3 mg per week to about 25 mg per week; wherein the subject has already received or is going to receive administration of a RAS inhibitor; The compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Use is also provided.

[0020] The present disclosure also provides a compound for use in a method for delaying or preventing acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a compound at a dosage of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is going to receive administration of a RAS inhibitor; The compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. A compound for use is also provided.

[0021] The present disclosure also relates to a medicament for a treatment for delaying or preventing acquired resistance to a RAS inhibitor, the medicament comprising a compound, the treatment comprising administering the medicament to a subject in need thereof to deliver a dosage of the compound from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is to receive administration of a RAS inhibitor; The present disclosure also provides a medicament wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0022] The present disclosure also relates to the use of a compound in the treatment of acquired resistance to a RAS inhibitor, the treatment comprising administering a dosage of the compound from about 3 mg per week to about 25 mg per week to a subject in need thereof; The present disclosure also provides a use wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0023] The present disclosure also relates to the use of a compound in the manufacture of a medicament for the treatment of acquired resistance to a RAS inhibitor, the treatment comprising administering the medicament to a subject in need thereof to deliver a dosage of the compound from about 3 mg per week to about 25 mg per week; The present disclosure also provides a use wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0024] The present disclosure also relates to a compound for use in a method of treating acquired resistance to a RAS inhibitor, the method comprising administering a dosage of the compound from about 3 mg per week to about 25 mg per week to a subject in need thereof; The present disclosure also provides a compound for use wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0025] The present disclosure also provides a medicament for treating acquired resistance to a RAS inhibitor, the medicament comprising a compound, and the treatment comprising administering the medicament to deliver a dosage of the compound of from about 3 mg per week to about 25 mg per week to a subject in need thereof; The present disclosure also provides a medicament, wherein the compound is RMC-5552 or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0026] The present disclosure also provides a method for treating or preventing mucositis in a subject in need thereof who has been treated with, is being treated with, or will be treated with an mTOR inhibitor, the method comprising administering tacrolimus solution to the subject.

[0027] The present disclosure also provides the use of tacrolimus solution in a method for treating or preventing mucositis, the treatment comprising administering tacrolimus solution to a subject in need thereof who has been treated with, is being treated with, or will be treated with an mTOR inhibitor.

[0028] The present disclosure also provides the use of tacrolimus solution in the manufacture of a medicament for treating or preventing mucositis, the treatment comprising administering the medicament to a subject in need thereof who has been treated with, is being treated with, or will be treated with an mTOR inhibitor.

[0029] The present disclosure also provides a tacrolimus solution for use in a method for treating or preventing mucositis, the method comprising administering the tacrolimus solution to a subject in need thereof who has been treated with, is being treated with, or will be treated with an mTOR inhibitor.

[0030] The present disclosure also provides a medicament for the treatment or prevention of mucositis, comprising a tacrolimus solution, wherein the treatment comprises administering the medicament to a subject in need thereof who has been, is being, or is to be treated with an mTOR inhibitor.

Brief Description of the Drawings

[0031]

Figure 1

Figure 2-1

Figure 2-2

Figure 3

Figure 4-1

Figure 4-2

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Mode for Carrying Out the Invention

[0032] The present disclosure relates to methods of treating a disease or disorder (e.g., cancer) with a compound (e.g., RMC-5552). In some embodiments, the present disclosure provides methods for delaying, preventing, or treating acquired resistance to a RAS inhibitor (e.g., a KRAS G12C inhibitor) by administering a compound (e.g., RMC-5552).

[0033] The methods include administering the compound (e.g., RMC-5552) at a specific dosage. For example, in some embodiments, the compound (e.g., RMC-5552) is administered at a dosage of about 3 mg per week to about 25 mg per week.

[0034] The dosages of the compounds described herein (i.e., RMC-5552) have surprisingly been found to be effective in treating the disease or disorder of the subject while maintaining tolerability for the subject. A common point of inefficacy for drug therapies is that the subject cannot tolerate the side effects of the drug while continuing to use the drug in an amount effective for treating the disease. Low drug dosages may reduce or eliminate side effects but can result in inefficacy in treating the disease. For example, side effects associated with various cancer treatments include stomatitis / mucositis, anorexia and fatigue, anemia, dehydration, hyponatremia, nausea, and vomiting. The dosages of the compounds of the present disclosure (i.e., RMC-5552) have surprisingly been found not to cause such side effects at severities that require a reduction below the therapeutically effective amount of drug use.

[0035] As used above and throughout the present disclosure, unless indicated otherwise, the following terms are to be understood to have the following meanings. When terms are not indicated, conventional terms known to those skilled in the art are followed.

[0036] The terms "comprising," "containing," and "including" as used herein are used in their open, non-limiting sense.

[0037] In the present disclosure, the articles "a" and "an" are used to refer to one or more than one grammatical object of the article (i.e., at least one grammatical object). By way of example, "an element" means one element or more than one element.

[0038] As used herein, the term "and / or" refers to one or both of "and" or "or".

[0039] To provide a more concise description, some of the quantitative expressions given herein do not have the term "about" as a qualifier. Whether or not the term "about" is explicitly used, any quantity given herein is intended to refer to the given measured value, but also to refer to an approximation to the given such value that is reasonably inferred based on the skill in the art and includes equivalent and approximate values resulting from the experimental and / or measurement conditions for the given such value. When the yield is given as a percentage, such yield always refers to the mass of the entity for which the yield is given with respect to the maximum amount of the same entity obtained under specific stoichiometric conditions. Unless otherwise indicated, the concentration given as a percentage refers to a mass ratio.

[0040] As used in the present disclosure, the term "disorder" is used to mean and is used interchangeably with the terms disease, condition, or illness, unless otherwise indicated.

[0041] The term "inhibitor" means a compound that prevents a biomolecule (e.g., a protein, nucleic acid) from completing or initiating a reaction. An inhibitor may inhibit a reaction by competitive means, non-competitive means, or uncompetitive means. Exemplary inhibitors include, but are not limited to, nucleic acids, DNA, RNA, shRNA, siRNA, proteins, protein mimetics, peptides, peptide mimetics, antibodies, small molecules, chemicals, enzymes, receptors, or analogs that mimic the binding sites of other proteins, such as those involved in signal transduction, therapeutic agents, pharmaceutical compositions, drugs, and combinations thereof. In some embodiments, the inhibitor can be a nucleic acid molecule, including but not limited to siRNA, that reduces the amount of a functional protein in a cell. Thus, a compound that is said to be "capable of inhibiting" a particular protein, e.g., mTOR or RAS, includes any such inhibitor.

[0042] As used herein, the term "therapeutic agent" refers to any substance, e.g., a compound or composition, that is capable of treating a disease or disorder. In some embodiments, therapeutic agents useful in the context of the present disclosure include, without limitation, mTOR inhibitors, such as RAS inhibitors, e.g., KRAS G12C inhibitors, and certain cancer chemotherapeutic agents.

[0043] As used herein with respect to a subject, the term "treating" or "treatment of" refers to ameliorating at least one symptom, pathology, or marker of a disease or disorder of the subject, either directly or by enhancing the effect of another treatment. Treatment includes curing, ameliorating, or at least partially ameliorating the disorder, and may include even a minimal change or improvement in one or more measurable markers of the disease or condition being treated. "Treating" or "treatment of" does not necessarily indicate complete eradication or cure of the disease or condition, or of its associated symptoms. The subject to be treated is any subject in need thereof. Those of skill in the art will be aware of exemplary markers of clinical improvement.

[0044] mTOR inhibitor As used herein, the term "mTOR inhibitor" refers to a compound that inhibits the activity of mTOR (e.g., kinase activity). Examples of mTOR inhibitors include, but are not limited to, RMC-5552, everolimus, sirolimus, nab-sirolimus, ΓΝΚ128, PP242, PP121, MLN0128, AZD8055, AZD2014, NVP-BEZ235, BGT226, SF1126, torin 1, torin 2, WYE687, salts of WYE687 (e.g., hydrochloride), PF04691502, PI-103, CC-223, OSI-027, XL388, KU-0063794, GDC-0349, and PKI-587. In some embodiments, the mTOR inhibitor is a more selective inhibitor of mTORC1 as compared to mTORC2. In some embodiments, the mTOR inhibitor is a more selective inhibitor of mTORC2 as compared to mTORC1. In multiple embodiments, the mTOR inhibitor is an active site mTOR inhibitor. As used herein, an "active site mTOR inhibitor" refers to a compound that inhibits the activity of mTOR (e.g., kinase activity) and binds to the active site of mTOR (e.g., an ATP binding site that overlaps with the ATP binding site of mTOR and blocks access of ATP to the ATP binding site of mTOR).

[0045] In some embodiments of the present specification, the compounds (e.g., RMC-5552) employed in the embodiments of the present disclosure are sometimes referred to as "mTOR dual-site inhibitors" or "dual-site inhibitors of mTOR". In the present disclosure, the terms "mTOR dual-site inhibitor" and "dual-site inhibitor of mTOR" are used interchangeably to refer to two pharmacophores in a single compound. One pharmacophore binds to the well-known FRB (FKBP12-rapamycin binding) site on mTORC1, and the other pharmacophore binds to the mTOR kinase active site. As a result of these two binding interactions, such compounds have two biologically useful functions: (1) selectivity for mTORC1 over mTORC2, characteristic of the natural compound rapamycin; and (2) profound inhibition of mTORC1, characteristic of known active site inhibitors. These properties enable the selective inhibition of the phosphorylation of mTORC1 substrates, including 4EBP1. Non-limiting examples of mTOR dual-site inhibitors are found in WO2019212991, WO2019212990, and WO2018204416, which are incorporated herein by reference in their entirety. In some embodiments, the mTOR dual-site inhibitor has a molecular weight between 1600 and 2100 Da, including the endpoints, and exhibits selective (greater than 10-fold) inhibition of mTORC1 over mTORC2. In some embodiments, the two pharmacophores are connected by a linker. The linker can be any suitable linker, such as a PEG linker, or a linker described in Hoang Thi, Thai Thanh et al., "The Importance of Poly(ethylene glycol) Alternatives for Overcoming PEG Immunogenicity in Drug Delivery and Bioconjugation", Polymers, Vol. 12, No. 2, p. 298, February 2, 2020.

[0046] In some embodiments, the mTOR inhibitor has the formula Ic:

Chemical Structure

[0047] A 1 and A 2 are independently absent or independently,

Chemical formula

[0048] Each L 1 is independently

Chemical formula

[0049] L 2 and L 3 are independently either absent or independently

Chemical formula

[0050] Each B is independently, [Chem.] selected from; each B 1 is independently, -[wavy line]-NR 3 -(C(R 3 )2) n -[wavy line]-NR 3 -(C(R 3 )2) n -(C6~C 10 )arylene-(C(R 3 )2) n - -[wavy line]-NR 3 -(C(R 3 )2) n -heteroarylene-, -[wavy line]-NR 3 -(C(R 3 )2) n -heteroarylene-(C(R 3 )2) n - -[wavy line]-(C6~C 10 )arylene-, -[wavy line]-NR 3 -(C(R 3 )2) n -NR 3 C(O)-, -[wavy line]-NR 3 -(C(R 3 )2) n -heteroarylene-heterocyclylene-(C6~C 10 )arylene-, -[wavy line]-heteroarylene-heterocyclylene-(C6~C 10 )arylene-

[0051] [Chem.] -[wavy line]-NR 3 -(C(R 3 )2) n -S(O)2-arylene-C(O)-, and -[wavy line]-NR 3 -(C(R 3 )2) n -S(O)2-arylene-(C(R 3 )2)n -[wherein, B 1 's left - hand side - [wavy line] - bond is, as depicted, A 2 , L 3 , or L 1 and is bonded to; heteroarylene, heterocyclylene, and arylene are each independently, optionally, selected from being substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, or hydroxyl]; each R 3 is independently H or (C1 - C6) alkyl; each R 4 is independently H, (C1 - C6) alkyl, halogen, 5 - to 12 - membered heteroaryl, 5 - to 12 - membered heterocyclyl(C6 - C 10 ) aryl [wherein, heteroaryl, heterocyclyl, and aryl are optionally substituted with -N(R 3 )2, -OR 3 , halogen (C1 - C6) alkyl, -(C1 - C6) alkylene - heteroaryl, -(C1 - C6) alkylene - CN, -C(O)NR 3 - heteroaryl, or -C(O)NR 3 - heterocyclyl]; each R 5 is independently H, (C1 - C6) alkyl, -C(O)OR 3 , or -N(R 3 )2 [wherein the alkyl of (C1 - C6) alkyl is optionally substituted with -N(R 3 )2 or -OR 3 ; each R 6 is independently H, (C1 - C6) alkyl, -C(O)OR 3 , or -N(R 3 )2 [wherein the alkyl of (C1 - C6) alkyl is optionally substituted with -N(R 3 )2 or -OR 3 ; each R 7 is independently H, (C1 - C6) alkyl, -C(O)OR 3 , or -N(R 3)2[wherein the alkyl of (C1-C6) alkyl may optionally be -N(R 3 )2 or -OR 3 and is substituted]; each R 8 is independently H, (C1-C6) alkyl, -C(O)OR 3 , or -N(R 3 )2[wherein the alkyl of (C1-C6) alkyl may optionally be -N(R 3 )2 or -OR 3 and is substituted]; each Y is independently C(R 3 )2 or a bond; each n is independently an integer from 1 to 12; each o is independently an integer from 0 to 30; each p is independently an integer from 0 to 12; each q is independently an integer from 0 to 30; each r is independently an integer from 1 to 6] . See, for example, WO2019212990, which is incorporated herein by reference in its entirety.

[0052] In some embodiments, the two pharmacophores described in formula Ic are connected by a linker such as one of the linkers described in Hoang Thi, Thai Thanh et al., "The Importance of Poly(ethylene glycol) Alternatives for Overcoming PEG Immunogenicity in Drug Delivery and Bioconjugation", Polymers, Vol. 12, No. 2, p. 298, February 2, 2020.

[0053] In another embodiment of the present disclosure, the mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552) is an enantiomer. In some embodiments, the compound is the (S)-enantiomer. In other embodiments, the compound is the (R)-enantiomer. In still other embodiments, the compound is the (+) enantiomer or the (-) enantiomer.

[0054] It should be understood that all isomers, including mixtures thereof, are included within the present disclosure. When a compound contains a double bond, the substituents may be in the E configuration or the Z configuration. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituents may have the cis configuration or the trans configuration. All tautomers are also intended to be included.

[0055] mTOR inhibitors (e.g., mTOR dual stereoisomer inhibitors, e.g., RMC-5552) may contain asymmetric or chiral centers and thus may exist as different stereoisomers. The methods of the present disclosure are intended to take into account these mixtures, including racemic mixtures, as well as all stereoisomers of mTOR inhibitors (e.g., mTOR dual stereoisomer inhibitors, e.g., RMC-5552). In addition, the present disclosure encompasses methods that include all geometric and positional isomers. For example, when an mTOR inhibitor (e.g., mTOR dual stereoisomer inhibitor, e.g., RMC-5552) incorporates a double bond or fused ring, both the cis and trans forms, as well as mixtures, are encompassed within the scope of the present disclosure. Each compound disclosed herein includes all enantiomers that conform to the general structure of the compound. The compound may be in racemic form, enantiomerically pure form, or any other form from a stereochemical perspective. The assay results may reflect data collected for the compound in racemic form, enantiomerically pure form, or any other form from a stereochemical perspective.

[0056] As used herein, the term "tautomer" may refer to a set of compounds that have the same number and types of atoms, but different bonding properties and are in equilibrium with each other. A "tautomer" is a single member of this set of compounds. Typically, a single tautomer is depicted, but it can be understood that this single structure can represent all possible tautomers that may exist. Examples can include enol-ketone tautomerism. When a ketone is depicted, it can be understood that both the enol form and the ketone form are part of the present disclosure. The mTOR inhibitors of the present disclosure (e.g., mTOR dual stereoisomer inhibitors, e.g., RMC-5552) can exist within their tautomers (e.g., as amides or imino ethers). In this specification, all such tautomers are contemplated as part of the methods of the present disclosure.

[0057] In addition to the tautomers that can exist in all amide groups, carbonyl groups, and oxime groups within the mTOR inhibitors of the present disclosure, the compounds within this family readily interconvert via ring-opening molecular species between two major isomers known as pyran isomers and oxepane isomers (shown below). This interconversion is promoted by magnesium ions, weakly acidic conditions, or alkylamine salts as described in the following references: i) Hughes, P.F., Musser, J., Conklin, M., Russo, R., 1992, Tetrahedron Lett., 33(33):4739 - 32; ii) Zhu, T., 2007, U.S. Patent No. 7,241,771, Wyeth; iii) Hughes, P.F., 1994, U.S. Patent No. 5,344,833, American Home Products Corp. The following scheme shows the interconversion between the pyran isomer and the oxepane isomer in a compound containing a compound according to

Chemical formula

[0058] This interconversion occurs under mild conditions and the thermodynamic equilibrium position can vary among different members of the compounds of formula Ic, so any isomers are contemplated for the compounds of formula Ic. For simplicity of description, all intermediates and the pyran isomers of the compounds of formula Ic are shown, but it is understood that mTOR inhibitors (e.g., mTOR dual stereoisomer inhibitors, e.g., RMC-5552) can exist in their oxepane forms. All such oxepane forms are contemplated as part of the methods of the present disclosure herein.

[0059] The term "solvate" refers to a complex formed by a solute and a solvent with a variable stoichiometric ratio. Such solvents for the purposes of the present disclosure can be capable of not interfering with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing a stoichiometric amount of water as well as compositions containing a variable amount of water.

[0060] As used herein, the term "salt" refers to acidic salts formed by inorganic and / or organic acids, as well as basic salts formed by inorganic and / or organic bases. In addition, when a compound contains both a basic moiety such as, but not limited to, pyridine or imidazole, and an acidic moiety such as, but not limited to, a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt" as used herein. Pharmaceutically acceptable salts (i.e., non-toxic salts, physiologically acceptable salts) are preferred, but other salts may also be useful. Salts of mTOR inhibitors (e.g., mTOR dual stereoisomer inhibitors, e.g., RMC-5552) are formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent, in a medium such as a medium in which the salt precipitates, or in an aqueous medium, followed by lyophilization. The compounds of the present disclosure may include pharmaceutically acceptable salts of the compounds disclosed herein.Representative "pharmaceutically acceptable salts" include, for example, acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium salt, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylic acid salt, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycosylarsanilate, hexafluorophosphate, hexylresorcinol, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium salt, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, 1,1-methene-bis-2-hydroxy-3-naphthoate, embonate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, slamate, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate, etc., and may include water-soluble salts and water-insoluble salts.

[0061] "Pharmaceutically acceptable salts" may also include both acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to salts formed by inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc., which retain the biological effectiveness and the properties of the free base.

[0062] "Pharmaceutically acceptable basic addition salts" may refer to salts that are not biologically or otherwise harmful and retain the biological effectiveness and properties of the free acid. These salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases can include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. For example, inorganic salts can include, but are not limited to, ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts. Salts derived from organic bases can include salts of primary amines, secondary amines, and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines, and basic ion exchange resins such as ammonia resins, isopropylamine resins, trimethylamine resins, diethylamine resins, triethylamine resins, tripropylamine resins, diethanolamine resins, ethanolamine resins, deanol resins, 2-dimethylaminoethanol resins, 2-diethylaminoethanol resins, dicyclohexylamine resins, lysine resins, arginine resins, histidine resins, caffeine resins, procaine resins, hydrabamine resins, choline resins, betaine resins, benethamine resins, benzathine resins, ethylenediamine resins, glucosamine resins, methylglutamine resins, theobromine resins, triethanolamine resins, tromethamine resins, purine resins, piperazine resins, piperidine resins, N-ethylpiperidine resins, polyamine resins, etc., but are not limited to these.

[0063] Unless stated otherwise, the structures depicted herein may also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of a hydrogen atom with deuterium or tritium, or 13 C or 14 replacement of a carbon atom with 15 C, or replacement of a nitrogen atom with 17 N, or 18Compounds having this structure, with the exception of the replacement of oxygen atoms by O, are within the scope of the present disclosure. Such isotopically labeled compounds are useful as research tools or diagnostic tools.

[0064] The term RMC-6272 refers to an mTOR dual stereoisomer inhibitor having the following structure:

Chemical formula

[0065] The term RMC-5552 refers to an mTOR dual stereoisomer inhibitor having the following structure:

Chemical formula

[0066] In some embodiments, the mTOR dual stereoisomer inhibitor is

Chemical formula

[0067] In some embodiments, the mTOR dual stereoisomer inhibitor is

Chemical formula

[0068] The mechanistic target of rapamycin (mTOR) The term "mTOR" refers to the protein "mechanistic target of rapamycin (serine / threonine kinase)" or "mammalian target of rapamycin". The term "mTOR" may refer to the nucleotide sequence or protein sequence of human mTOR (e.g., Entrez 2475, Uniprot P42345, RefSeq NM_004958, or RefSeq NP_004949) (SEQ ID NO: 1). The term "mTOR" can include any mutants of these, in addition to both the wild-type forms of the nucleotide sequence or protein. In some embodiments, "mTOR" is wild-type mTOR. In some embodiments, "mTOR" is one or more mutant forms. The term "mTOR" XYZ may refer to the nucleotide sequence or protein of mutant mTOR, in which case, typically, in the wild-type, the numbered Y amino acid of mTOR having the X amino acid has the Z amino acid in the mutant. In some embodiments, mTOR is human mTOR. In some embodiments, mTOR has a nucleotide sequence corresponding to reference number: GL206725550 (SEQ ID NO: 2). In some embodiments, mTOR has a nucleotide sequence corresponding to RefSeq NM_004958.3 (SEQ ID NO: 2). In some embodiments, mTOR has a protein sequence corresponding to reference number: GL4826730 (SEQ ID NO: 1). In some embodiments, mTOR has a protein sequence corresponding to RefSeq NP_004949.1 (SEQ ID NO: 1). In some embodiments, mTOR has the following amino acid sequence: (SEQ ID NO: 1) has

[0069] In some embodiments, mTOR is mutant mTOR. In some embodiments, mutant mTOR is associated with diseases not associated with wild-type mTOR. In some embodiments, mTOR comprises at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any derivable range of mutations thereof) compared to the above sequence.

[0070] The term "mTORC1" refers to a protein complex comprising mTOR and Raptor (regulatory-associated protein of mTOR). mTORC1 may also include MLST8 (mammalian lethal with SEC 13 protein 8), PRAS40, and / or DEPTOR. mTORC1 can function as a nutrient / energy / redox sensor and a regulator of protein synthesis. The term "mTORC1 pathway" or "mTORC1 signaling pathway" may refer to a cellular pathway that includes mTORC1. The mTORC1 pathway includes pathway components upstream and downstream of mTORC1. The mTORC1 pathway is a signaling pathway that is modulated by modulation of mTORC1 activity. In some embodiments, the mTORC1 pathway is a signaling pathway that is modulated by modulation of mTORC1 activity but not by modulation of mTORC2 activity. In some embodiments, the mTORC1 pathway is a signaling pathway that is modulated to a greater extent by modulation of mTORC1 activity than by modulation of mTORC2 activity.

[0071] The term "mTORC2" refers to a protein complex that includes mTOR and RICTOR (rapamycin-insensitive companion of mTOR). mTORC2 may also include GβL, mSIN1 (mammalian stress-activated protein kinase interacting protein 1), Protor1 / 2, DEPTOR, TTI1, and / or TEL2. mTORC2 can regulate cell metabolism and the cytoskeleton. The term "mTORC2 pathway" or "mTORC2 signaling pathway" may refer to a cellular pathway that includes mTORC2. The mTORC2 pathway includes pathway components upstream and downstream of mTORC2. The mTORC2 pathway is a signaling pathway that is modulated by the modulation of mTORC2 activity. In some embodiments, the mTORC2 pathway is a signaling pathway that is modulated by the modulation of mTORC2 activity but not by the modulation of mTORC1 activity. In some embodiments, the mTORC2 pathway is a signaling pathway that is modulated by the modulation of mTORC2 activity to a greater extent than by the modulation of mTORC1 activity.

[0072] The term "rapamycin" or "sirolimus" refers to a macrolide produced by the bacterium Streptomyces hygroscopicus. Rapamycin can prevent the activation of T cells and B cells. Rapamycin has the IUPAC name (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadehydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-oxaazacyclotriacontine-1,5,11,28,29(4H,6H,31H)-pentone. Rapamycin has the CAS number: 53123-88-9. Rapamycin may be made synthetically (e.g., by chemical synthesis) or by means of a production method that does not involve the use of Streptomyces hygroscopicus.

[0073] The term "analogue" is used in accordance with its simple ordinary meaning in chemistry and biology and refers to a chemical compound that is structurally similar to another compound (i.e., the so-called "reference" compound), but whose composition is different, for example, by replacement of one atom by an atom of a different element, or by the presence of a particular functional group, or by replacement of one functional group by another functional group, or by the absolute stereochemistry at one or more chiral centers of the reference compound, including its isomers.

[0074] The term "rapamycin analogue" or "rapalog" refers to an analogue or derivative (e.g., prodrug) of rapamycin.

[0075] The term "FKBP" refers to the protein peptidyl-prolyl cis-trans isomerase A. For non-limiting examples of FKBP, see Cell Mol Life Sci., September 2013, 70(18):3243-3275. In some embodiments, "FKBP" may refer to "FKBP-12" or "FKBP 12" or "FKBP1A". In some embodiments, "FKBP" may refer to a human protein. The term "FKBP" includes wild-type and mutant forms of the protein. In some embodiments, "FKBP" may refer to a wild-type human protein. In some embodiments, "FKBP" may refer to a wild-type human nucleic acid. In some embodiments, FKBP is a mutant FKBP. In some embodiments, the mutant FKBP is associated with a disease not associated with wild-type FKBP. In some embodiments, FKBP contains at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any derivable range of mutations thereof) compared to wild-type FKBP.

[0076] The terms "FKBP-12" or "FKBP 12" or "FKBP1A" may refer to the protein "peptidyl-prolyl cis-trans isomerase FKBP1A". In some embodiments, "FKBP-12" or "FKBP 12" or "FKBP1A" may refer to a human protein. The terms "FKBP-12" or "FKBP 12" or "FKBP1A" include wild-type and mutant forms of the protein. In some embodiments, "FKBP-12" or "FKBP 12" or "FKBP1A" may refer to a protein associated with Entrez Gene 2280, OMIM 186945, UniProt P62942, and / or RefSeq (Protein) NP_000792 (SEQ ID NO: 3). In some embodiments, the above references may refer to proteins and related nucleic acids that are known as of the filing date of the present application. In some embodiments, "FKBP-12" or "FKBP 12" or "FKBP1A" may refer to a wild-type human protein. In some embodiments, "FKBP-12" or "FKBP 12" or "FKBP1A" may refer to a wild-type human nucleic acid. In some embodiments, FKBP-12 is a mutant FKBP-12. In some embodiments, mutant FKBP-12 is associated with diseases not associated with wild-type FKBP-12. In some embodiments, FKBP-12 may include at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any derivable range of mutations thereof) compared to wild-type FKBP-12. In some embodiments, FKBP-12 has a protein sequence corresponding to Ref. No.: GI206725550. In some embodiments, FKBP-12 has a protein sequence corresponding to RefSeq NP_000792.1 (SEQ ID NO: 3).

[0077] The terms "4E-BP1" or "4EBP1" or "EIF4EBP1" refer to the protein "eukaryotic translation initiation factor 4E-binding protein 1". In some embodiments, "4E-BP1" or "4EBP1" or "EIF4EBP1" may refer to a human protein. The terms "4E-BP1" or "4EBP1" or "EIF4EBP1" include wild-type and mutant forms of the protein. In some embodiments, "4E-BP1" or "4EBP1" or "EIF4EBP1" may refer to a protein associated with Entrez Gene 1978, OMIM 602223, UniProt Q13541, and / or RefSeq(protein)NP_004086 (SEQ ID NO: 4). In some embodiments, the above references may refer to proteins and related nucleic acids that are known as of the filing date of the present application. In some embodiments, "4E-BP1" or "4EBP1" or "EIF4EBP1" may refer to a wild-type human protein. In some embodiments, "4E-BP1" or "4EBP1" or "EIF4EBP1" may refer to a wild-type human nucleic acid. In some embodiments, 4EBP1 is a mutant 4EBP1. In some embodiments, the mutant 4EBP1 is associated with a disease not associated with wild-type 4EBP1. In some embodiments, 4EBP1 may include at least one amino acid mutation (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, or thirty mutations, or any derivable range of mutations thereof) compared to wild-type 4EBP1. In some embodiments, 4EBP1 has a protein sequence corresponding to reference number: GL4758258. In some embodiments, 4EBP1 has a protein sequence corresponding to RefSeq NP_004086.1 (SEQ ID NO: 4).

[0078] The term "Akt" refers to a serine / threonine-specific protein kinase that is also known as "protein kinase B" (PKB) or "Akt1" and is involved in cellular processes such as glucose metabolism, apoptosis, proliferation, and other functions. In some embodiments, "Akt" or "AM" or "PKB" may refer to a human protein. The terms "Akt" or "Akt1" or "PKB" include the wild-type and mutant forms of the protein. In some embodiments, "Akt" or "Akt1" or "PKB" may refer to a protein associated with Entrez Gene 207, OMIM 164730, UniProt P31749, and / or RefSeq (protein) NP_005154 (SEQ ID NO: 5). In some embodiments, the above references may refer to proteins and related nucleic acids that are known as of the filing date of the present application. In some embodiments, "Akt" or "Akt1" or "PKB" may refer to a wild-type human protein. In some embodiments, "Akt" or "Akt1" or "PKB" may refer to a wild-type human nucleic acid. In some embodiments, Akt is a mutant Akt. In some embodiments, mutant Akt is associated with diseases that are not associated with wild-type Akt. In some embodiments, Akt may include at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations, or any derivable range of mutations among these) compared to wild-type Akt. In some embodiments, Akt has a protein sequence corresponding to GI:62241011, which is a reference number. In some embodiments, Akt has a protein sequence corresponding to RefSeq NP_005154.2 (SEQ ID NO: 5).

[0079] As used herein, the term "mutation" refers to any modification of a nucleic acid and / or polypeptide that results in an alteration of the nucleic acid or polypeptide. The term "mutation" includes, for example, point mutations, deletions, or insertions of single or multiple residues within a polynucleotide, including alterations that occur within the protein-coding region of a gene, as well as alterations within regions external to the protein-coding sequence, such as regulatory or promoter sequences, and may also include amplifications and / or chromosomal breaks or translocations.

[0080] Reference to a "subtype" of a cell (e.g., KRAS G12C subtype, KRAS G12S subtype, KRAS G12D subtype, KRAS G12V subtype) means that the cell contains a gene mutation that encodes a change in the protein of the indicated type. For example, a cell classified as a "KRAS G12C subtype" contains at least one KRAS allele that encodes an amino acid substitution of cysteine to glycine at position 12 ( G12C ); similarly, other cells of a particular subtype (e.g., KRAS G12D , KRAS G12S , and KRAS G12V subtype) contain at least one allele with the indicated mutation (e.g., a KRAS G12D mutation, a KRAS G12S mutation, or a KRAS G12V mutation), respectively. Unless otherwise noted, all substitutions at all amino acid positions referred to herein (e.g., those in KRAS G12C such as 「G12C」 ) correspond to substitutions in the human version of the indicated protein; that is, KRAS G12C refers to a G→C substitution at position 12 of human KRAS.

[0081] Treatment methods The present disclosure provides a method for treating an mTOR-mediated disease or disorder by administering a dose of an mTOR inhibitor (e.g., an mTOR dual inhibitor such as RMC-5552) to a subject suffering from or prone to developing an mTOR-mediated disease or disorder.

[0082] In some embodiments, the method includes administering an mTOR inhibitor (e.g., an mTOR dual inhibitor, such as RMC-5552) (e.g., an mTOR dual inhibitor, such as RMC-5552) as monotherapy. The term "monotherapy" refers to a treatment method that includes administering to a subject, optionally as a pharmaceutical composition, a single therapeutic agent.

[0083] Some embodiments are directed to a method of treating a subject having cancer by administering to the subject an mTOR dual inhibitor at a dose of about 3 mg per week to about 25 mg per week;

[0084] wherein the mTOR dual inhibitor is

Chemical formula

[0085] In some embodiments, the cancer is salivary gland cancer, and the method includes administering to the subject an mTOR dual inhibitor at a dose of about 3 mg per week to about 25 mg per week;

[0086] wherein the mTOR dual inhibitor is

Chemical formula

[0087] In some embodiments, the dosage is from about 4 mg per week to about 25 mg per week, from about 4 mg per week to about 20 mg per week, from about 4 mg per week to about 16 mg per week, from about 4 mg per week to about 14 mg per week, from about 4 mg per week to about 12 mg per week, from about 4 mg per week to about 10 mg per week, from about 4 mg per week to about 9 mg per week, from about 4 mg per week to about 8 mg per week, from about 4 mg per week to about 7 mg per week, from about 4 mg per week to about 6 mg per week, from about 5 mg per week to about 25 mg per week, from about 5 mg per week to about 20 mg per week, from about 5 mg per week to about 16 mg per week, from about 5 mg per week to about 14 mg per week, from about 5 mg per week to about 12 mg per week, from about 5 mg per week to about 10 mg per week, from about 5 mg per week to about 9 mg per week, from about 5 mg per week to about 8 mg per week, from about 5 mg per week to about 7 mg per week, from about 5 mg per week to about 6 mg per week, from about 6 mg per week to about 25 mg per week, from about 6 mg per week to about 20 mg per week, from about 6 mg per week to about 16 mg per week, from about 6 mg per week to about 14 mg per week, from about 6 mg per week to about 12 mg per week, from about 6 mg per week to about 10 mg per week, from about 6 mg per week to about 9 mg per week, from about 6 mg per week to about 8 mg per week, from about 6 mg per week to about 7 mg per week, from about 7 mg per week to about 25 mg per week, from about 7 mg per week to about 20 mg per week, from about 7 mg per week to about 16 mg per week, from about 7 mg per week to about 14 mg per week, from about 7 mg per week to about 12 mg per week, from about 6 mg per week to about 10 mg per week, from about 7 mg per week to about 9 mg per week, from about 7 mg per week to about 8 mg per week, from about 8 mg per week to about 25 mg per week, from about 8 mg per week to about 20 mg per week, from about 8 mg per week to about 16 mg per week, from about 8 mg per week to about 14 mg per week, from about 8 mg per week to about 12 mg per week, from about 8 mg per week to about 10 mg per week,About 9 mg per week to about 25 mg per week, about 9 mg per week to about 20 mg per week, about 9 mg per week to about 16 mg per week, about 9 mg per week to about 14 mg per week, about 9 mg per week to about 12 mg per week, about 9 mg per week to about 10 mg per week, about 10 mg per week to about 25 mg per week, about 10 mg per week to about 20 mg per week, about 10 mg per week to about 16 mg per week, about 10 mg per week to about 14 mg per week, about 10 mg per week to about 12 mg per week, about 11 mg per week to about 25 mg per week, about 11 mg per week to about 20 mg per week, about 11 mg per week to about 16 mg per week, about 11 mg per week to about 14 mg per week, or about 11 mg per week to about 12 mg per week.

[0088] In some embodiments, the dosage is about 4 mg per week, about 4.5 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, about 10 mg per week, about 10.5 mg per week, about 11 mg per week, about 11.5 mg per week, about 12 mg per week, about 12.5 mg per week, about 13 mg per week, about 13.5 mg per week, about 14 mg per week, about 14.5 mg per week, about 15 mg per week, about 16 mg per week, about 18 mg per week, about 20 mg per week, about 22 mg per week, or about 25 mg per week.

[0089] Surprisingly, doses of the mTOR dual inhibitor (i.e., RMC-5552) from 1.6 mg per week to 6 mg per week exhibit a dose-proportional increase in exposure, whereas doses above 6 mg per week were observed to exhibit an increase that exceeds dose-proportional increase. In dosing regimens, dose-proportional increase is generally preferred as it generally increases control over target exposure and is often associated with the desired drug clearance. These concerns are often addressed in light of the need for higher doses to provide efficacy in treating the disease. Thus, in some embodiments, the dose is 6 mg per week, which is the inflection point of the dose-proportional curve (e.g., about 5 mg per week to about 9 mg per week, about 6 mg per week to about 9 mg per week, about 6 mg per week to about 8 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, or about 9 mg per week), or a dose in the vicinity thereof.

[0090] Surprisingly, it was also observed that above a dose of about 6 mg per week (e.g., between 6 mg per week and 12 mg per week), there is a steep dose-response relationship. Thus, in some embodiments, doses above about 6 mg per week are used. Doses in these ranges may be intolerable due to side effects (e.g., mucositis). As described herein, tacrolimus (e.g., tacrolimus oral rinse; see the extensive discussion of tacrolimus below) can, surprisingly, mitigate side effects, thereby enabling higher doses. Thus, in some embodiments, doses above about 6 mg per week are used in combination with tacrolimus.

[0091] In some embodiments, a high dosage (e.g., a dosage exceeding about 6 mg per week) is initially used before reducing the dosage. For example, in some embodiments, a dosage exceeding about 6 mg per week (i.e., a dosage exceeding the dose-proportional increase threshold) is administered over one week or several weeks, followed by a dosage less than about 6 mg per week (i.e., a dosage near or below the dose-proportional increase threshold). In some embodiments, a drug holiday (e.g., a drug holiday lasting 1, 2, 3, 4, or 5 weeks) is taken between the high dosage and the low dosage. In some embodiments, the dosage in the first 1, 2, 3, 4, or 5 weeks is higher than the dosage in subsequent weeks. In some embodiments, the dosage in the first week is higher than the dosage in subsequent weeks.

[0092] In some embodiments, the dosage in the first 1, 2, 3, 4, or 5 weeks is about 6 mg per week to about 25 mg per week, about 6 mg per week to about 20 mg per week, about 6 mg per week to about 16 mg per week, about 6 mg per week to about 14 mg per week, about 6 mg per week to about 12 mg per week, about 6 mg per week to about 10 mg per week, about 8 mg per week to about 25 mg per week, about 8 mg per week to about 20 mg per week, about 8 mg per week to about 16 mg per week, about 8 mg per week to about 14 mg per week, about 8 mg per week to about 12 mg per week, about 8 mg per week to about 10 mg per week, about 10 mg per week to about 25 mg per week, about 10 mg per week to about 20 mg per week, about 10 mg per week to about 16 mg per week, about 10 mg per week to about 14 mg per week, or about 10 mg per week to about 12 mg per week. In some embodiments, the dosage in the first 1, 2, 3, 4, or 5 weeks is about 10 mg per week to about 12 mg per week. In some embodiments, the dosage in the first week is about 10 mg per week to about 12 mg per week.

[0093] In some embodiments, the dosage in the first 1, 2, 3, 4, or 5 weeks is about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, about 10 mg per week, about 10.5 mg per week, about 11 mg per week, about 11.5 mg per week, about 12 mg per week, about 12.5 mg per week, about 13 mg per week, about 13.5 mg per week, about 14 mg per week, about 14.5 mg per week, about 15 mg per week, about 16 mg per week, about 18 mg per week, about 20 mg per week, about 22 mg per week, or about 25 mg per week. In some embodiments, the dosage in the first 1, 2, 3, 4, or 5 weeks is about 10 mg per week. In some embodiments, the dosage in the first 1, 2, 3, 4, or 5 weeks is about 11 mg per week. In some embodiments, the dosage in the first 1, 2, 3, 4, or 5 weeks is about 12 mg per week. In some embodiments, the dosage in the first week is about 10 mg per week. In some embodiments, the dosage in the first week is about 11 mg per week. In some embodiments, the dosage in the first week is about 12 mg per week.

[0094] In some embodiments, the dosage in the first 1, 2, 3, 4, or 5 weeks is followed by a dosage of 1, 2, 3, 4, or 5 weeks without administration. In some embodiments, the dosage in the first week is followed by a dosage of 1, 2, 3, 4, or 5 weeks without administration.

[0095] In some embodiments, the dosage after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks is from about 3 mg per week to about 12 mg per week, from about 3 mg per week to about 10 mg per week, from about 3 mg per week to about 8 mg per week, from about 3 mg per week to about 6 mg per week, from about 4 mg per week to about 12 mg per week, from about 4 mg per week to about 10 mg per week, from about 4 mg per week to about 8 mg per week, from about 4 mg per week to about 6 mg per week, from about 5 mg per week to about 12 mg per week, from about 5 mg per week to about 10 mg per week, from about 5 mg per week to about 8 mg per week, from about 5 mg per week to about 6 mg per week, from about 6 mg per week to about 12 mg per week, from about 6 mg per week to about 10 mg per week, from about 6 mg per week to about 8 mg per week, from about 6 mg per week to about 7 mg per week, from about 7 mg per week to about 12 mg per week, from about 7 mg per week to about 10 mg per week, from about 7 mg per week to about 8 mg per week, from about 8 mg per week to about 12 mg per week, or from about 8 mg per week to about 10 mg per week. In some embodiments, the dosage after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks is from about 3 mg per week to about 12 mg per week.

[0096] In some embodiments, the dosage after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks is about 3 mg per week, about 3.5 mg per week, about 4 mg per week, about 4.5 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, or about 10 mg per week. In some embodiments, the dosage after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks is about 6 mg per week.

[0097] For example, in some embodiments, the dosage in the first 1, 2, 3, 4, or 5 weeks is about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, about 10 mg per week, about 10.5 mg per week, about 11 mg per week, about 11.5 mg per week, about 12 mg per week, about 12.5 mg per week, about 13 mg per week, about 13.5 mg per week, about 14 mg per week, about 14.5 mg per week, about 15 mg per week, about 16 mg per week, about 18 mg per week, about 20 mg per week, about 22 mg per week, or about 25 mg per week; This is followed by 0, 1, 2, 3, 4, or 5 weeks without administration; This is followed by a dosage of about 3 mg to about 12 mg per week, about 3 mg to about 10 mg per week, about 3 mg to about 8 mg per week, about 3 mg to about 6 mg per week, about 4 mg to about 12 mg per week, about 4 mg to about 10 mg per week, about 4 mg to about 8 mg per week, about 4 mg to about 6 mg per week, about 5 mg to about 12 mg per week, about 5 mg to about 10 mg per week, about 5 mg to about 8 mg per week, about 5 mg to about 6 mg per week, about 6 mg to about 12 mg per week, about 6 mg to about 10 mg per week, about 6 mg to about 8 mg per week, about 6 mg to about 7 mg per week, about 7 mg to about 12 mg per week, about 7 mg to about 10 mg per week, about 7 mg to about 8 mg per week, about 8 mg to about 12 mg per week, or about 8 mg to about 10 mg per week.

[0098] For example, in some embodiments, the dosage in the first 1, 2, 3, 4, or 5 weeks is also about 6 mg per week to about 25 mg per week, about 6 mg per week to about 20 mg per week, about 6 mg per week to about 16 mg per week, about 6 mg per week to about 14 mg per week, about 6 mg per week to about 12 mg per week, about 6 mg per week to about 10 mg per week, about 8 mg per week to about 25 mg per week, about 8 mg per week to about 20 mg per week, about 8 mg per week to about 16 mg per week, about 8 mg per week to about 14 mg per week, about 8 mg per week to about 12 mg per week, about 8 mg per week to about 10 mg per week, about 10 mg per week to about 25 mg per week, about 10 mg per week to about 20 mg per week, about 10 mg per week to about 16 mg per week, about 10 mg per week to about 14 mg per week, or about 10 mg per week to about 12 mg per week; This is followed by 0, 1, 2, 3, 4, or 5 weeks without administration; This is followed by a dosage of about 3 mg per week, about 3.5 mg per week, about 4 mg per week, about 4.5 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, or about 10 mg per week.

[0099] In some embodiments, after several weeks (e.g., 1, 2, 3, 4, or 5 weeks) of low-dose administration, further dosing interruptions (e.g., 0, 1, 2, 3, 4, or 5 weeks without dosing), and / or further dose reductions are made. In some embodiments, this is followed by further dosing interruptions and / or dose reductions. In some embodiments, the dose is tapered over the course of treatment. In some embodiments, the dose is reduced by about 1 mg per week, about 2 mg per week, about 3 mg per week, about 4 mg per week, about 5 mg per week, or about 6 mg per week every 1, 2, 3, 4, or 5 weeks. In some embodiments, a dosing interruption is made between each dose reduction.

[0100] Administration of the disclosed compounds or compositions can be achieved via any mode of administration for a therapeutic agent. These modes can include systemic or topical administration such as oral administration, nasal administration, parenteral administration, transdermal administration, subcutaneous administration, intravaginal administration, intraoral administration, rectal administration, topical administration, intrathecal administration, or intracranial administration.

[0101] In some embodiments, administration can include oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, or subcutaneous administration, or implantation of a sustained release device, such as a small osmotic pump, into a subject. Administration can be by any route, including parenteral and transmucosal administration (e.g., buccal, sublingual, intranasal, gingival, intranasal, vaginal, rectal, or transdermal administration). Parental administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administrations. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusions, transdermal patches, and the like. The compositions of the present disclosure may be delivered transdermally, may be delivered by a topical route, and may be delivered as an applicator stick, solution, suspension, emulsion, gel, cream, ointment, paste, jelly, paint, powder, and aerosol formulations. Oral formulations include tablets, pills, powders, dragees, capsules, solutions, lozenges, sachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by a patient. Solid formulations include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. Liquid formulations include solutions, suspensions, and emulsions, such as aqueous solutions or aqueous / propylene glycol solutions. The compositions of the present disclosure may additionally include components that provide sustained release and / or comfort. Such components include high molecular weight, anionic, mucoadhesive polymers, gelling polysaccharides, and micronized drug carrier matrices. These components are discussed in more detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are hereby incorporated by reference in their entirety for all purposes. The compositions of the present disclosure may also be delivered as microspheres for sustained release in the body.For example, the microspheres may be administered via intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J. Biomater Set Polym. Ed., 7: 623-645, 1995); they may be administered as biodegradable / injectable gel formulations (see, for example, Gao, Pharm. Res., 12: 857-863, 1995); they may be administered as oral microspheres (see, for example, Eyles, J. Pharm. Pharmacol., 49: 669-674, 1997). In another embodiment, the formulations of the compositions of the present disclosure are delivered by the use of liposomes that fuse with cell membranes or are endocytosed, i.e., by employing receptor ligands conjugated to liposomes that bind to cell surface membrane protein receptors resulting in endocytosis. In particular, the delivery of the mTOR inhibitor to target cells in vivo can be focused by using liposomes whose surface bears receptor ligands that are specific for the target cells or are otherwise preferentially directed to specific organs (see, for example, Al-Muhammed, J. Microencapsul., 13: 293-306, 1996; Chonn, Curr. Opin. Biotechnol., 6: 698-708, 1995; Ostro, Am. J. Hosp. Pharm., 46: 1576-1587, 1989). In some embodiments, the mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552) is delivered by nanoparticles.

[0102] Depending on the intended mode of administration, the mTOR inhibitor (e.g., mTOR dual stereoisomer inhibitor, e.g., RMC-5552) may be in solid dosage forms, such as, for example, injections, tablets, suppositories, pills, delayed release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions and other semi-solid or liquid dosage forms, and in some cases, unit dosage forms, in accordance with conventional medical practice. Similarly, the mTOR inhibitor (e.g., mTOR dual stereoisomer inhibitor, e.g., RMC-5552) is administered in intravenous (both bolus and infusion) forms, intraperitoneal forms, intrathecal forms, subcutaneous forms, and intramuscular forms, and in all forms using forms well known to those skilled in the pharmaceutical art.

[0103] Exemplary pharmaceutical compositions include an mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552), and a) a diluent, such as purified water, hydrogenated vegetable oil or partially hydrogenated vegetable oil or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil such as EPA or DHA, etc., triglyceride oils, or esters or triglycerides thereof, or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, such as silica, talc, stearic acid, its magnesium or calcium salts, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; for tablets, also, if desired, c) a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, acacia, tragacanth, or natural / synthetic gums such as sodium alginate, wax and / or polyvinylpyrrolidone; d) a disintegrant, such as starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or a foaming mixture; e) an absorbent, a coloring agent, a flavoring agent, and a sweetening agent; f) an emulsifier or dispersant, such as Tween 80, Labrasol, HPMC, DOSS, Caproyl 909, Labrafac, Labrafil, Peceol, Transcutol, Capmul MCM, Capmul PG-12, Captex 355, Gelucire, vitamin E TGPS, or other acceptable emulsifiers; and / or g) a pharmaceutically acceptable carrier, such as cyclodextrin, hydroxypropyl cyclodextrin, PEG400, PEG200, etc., agents that enhance the absorption of the compound, in the form of tablets and gelatin capsules.

[0104] As used herein, the term "carrier" encompasses carriers, excipients, and diluents, and refers to a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, composition, or medium that is involved in the retention or transport of a pharmaceutical agent from one organ or body part of a subject to another organ or body part. The excipient shall be selected based on the suitability of the desired dosage form and the release profile characteristics. Exemplary carrier materials include, for example, binders, suspending agents, disintegrating agents, filling agents, surfactants, solubilizing agents, stabilizing agents, lubricants, humectants, diluents, spray-dried dispersants, and the like.

[0105] The term "pharmaceutically compatible carrier material" may include, for example, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, alpha starch, and the like. See, for example, Hoover, John E., "Remington’s Pharmaceutical Sciences", Mack Publishing Co., Easton, Pa., 1975.

[0106] Liquid compositions, particularly injectable compositions, are prepared, for example, by dissolution, dispersion, and the like. For example, an mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552) is dissolved or mixed with a pharmaceutically acceptable solvent such as water, physiological saline, aqueous dextrose, glycerol, ethanol, etc., thereby forming an injectable isotonic solution or an injectable isotonic suspension. Proteins such as albumin, chylomicron particles, or serum proteins are used to solubilize the mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552).

[0107] mTOR inhibitors (e.g., mTOR dual stereoscopic inhibitors, e.g., RMC-5552) can also be manufactured as suppositories prepared from fatty acid emulsion agents or suspension agents using polyalkylene glycols such as propylene glycol as carriers.

[0108] mTOR inhibitors (e.g., mTOR dual stereoscopic inhibitors, e.g., RMC-5552) can also be administered in the form of liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes are formed from various phospholipids containing cholesterol, stearylamine, or phosphatidylcholine. In some embodiments, for example, as described in U.S. Patent No. 5,262,564, the contents of which are incorporated herein by reference, the thin film of the lipid component hydrates with an aqueous solution of the drug to form a lipid layer encapsulating the drug.

[0109] mTOR inhibitors (e.g., mTOR dual stereoscopic inhibitors, e.g., RMC-5552) can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds couple. The disclosed compounds can also couple with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylasparagineamide-phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Further, the disclosed compounds couple to biodegradable polymers useful in achieving controlled release of the drug, such as classes of poly(lactic acid), poly(epsilon-caprolactone), poly(hydroxybutyric acid), polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked block copolymers or amphiphilic block copolymers of hydrogels. In one embodiment, the disclosed compounds do not covalently bind to polymers, such as polycarboxylic acid polymers, or polyacrylates.

[0110] Parenteral administration is generally used for subcutaneous injection and subcutaneous infusion, intramuscular injection and intramuscular infusion, or intravenous injection and intravenous infusion. Injectables are manufactured in the conventional form of a solution or suspension, or a solid form suitable for dissolution in a liquid prior to injection.

[0111] In some embodiments, the dosage is administered via intravenous ("IV") infusion. In some embodiments, the dosage is administered over about 0.5 hour to about 2 hours, over about 0.5 hour to about 1.5 hours, over about 0.5 hour to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours. In some embodiments, the dosage is administered over about 0.5 hour, about 1 hour, about 1.5 hours, or about 2 hours. In some embodiments, the dosage is administered over about 1 hour.

[0112] In some embodiments, the dosage is from about 4 mg per week to about 25 mg per week, from about 4 mg per week to about 14 mg per week, from about 4 mg per week to about 12 mg per week, from about 5 mg per week to about 25 mg per week, from about 5 mg per week to about 14 mg per week, from about 5 mg per week to about 12 mg per week, from about 5 mg per week to about 10 mg per week, from about 6 mg per week to about 25 mg per week, from about 6 mg per week to about 14 mg per week, from about 6 mg per week to about 12 mg per week, from about 6 mg per week to about 9 mg per week, from about 6 mg per week to about 8 mg per week, from about 7 mg per week to about 25 mg per week, from about 7 mg per week to about 14 mg per week, from about 7 mg per week to about 12 mg per week, from about 7 mg per week to about 8 mg per week, from about 8 mg per week to about 25 mg per week, from about 8 mg per week to about 14 mg per week, from about 8 mg per week to about 12 mg per week, or from about 8 mg per week to about 10 mg per week, and the dosage is administered over about 0.5 hours to about 2 hours, over about 0.5 hours to about 1.5 hours, over about 0.5 hours to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours. In some embodiments, the dosage is from about 3 mg per week to about 25 mg per week and is administered over about 0.5 hours to about 2 hours.

[0113] In some embodiments, the dosage is from about 4 mg per week to about 25 mg per week, from about 4 mg per week to about 14 mg per week, from about 4 mg per week to about 12 mg per week, from about 5 mg per week to about 25 mg per week, from about 5 mg per week to about 14 mg per week, from about 5 mg per week to about 12 mg per week, from about 5 mg per week to about 10 mg per week, from about 6 mg per week to about 25 mg per week, from about 6 mg per week to about 14 mg per week, from about 6 mg per week to about 12 mg per week, from about 6 mg per week to about 9 mg per week, from about 6 mg per week to about 8 mg per week, from about 7 mg per week to about 25 mg per week, from about 7 mg per week to about 14 mg per week, from about 7 mg per week to about 12 mg per week, from about 7 mg per week to about 8 mg per week, from about 8 mg per week to about 25 mg per week, from about 8 mg per week to about 14 mg per week, from about 8 mg per week to about 12 mg per week, or from about 8 mg per week to about 10 mg per week, and the dosage is administered over about 0.5 hours, about 1 hour, about 1.5 hours, or about 2 hours. In some embodiments, the dosage is from about 3 mg per week to about 25 mg per week and is administered over about 1 hour.

[0114] In some embodiments, the dosage is about 4 mg per week, about 4.5 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, about 10 mg per week, about 10.5 mg per week, about 11 mg per week, about 11.5 mg per week, about 12 mg per week, about 12.5 mg per week, about 13 mg per week, about 13.5 mg per week, about 14 mg per week, about 14.5 mg per week, about 15 mg per week, about 16 mg per week, about 18 mg per week, about 20 mg per week, about 22 mg per week, or about 25 mg per week, and is administered over about 0.5 hours to about 2 hours, over about 0.5 hours to about 1.5 hours, over about 0.5 hours to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours. In some embodiments, the dosage is about 6 mg per week or about 8 mg per week and is administered over about 0.5 hours to about 2 hours.

[0115] In some embodiments, the dosage is about 4 mg per week, about 4.5 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, about 10 mg per week, about 10.5 mg per week, about 11 mg per week, about 11.5 mg per week, about 12 mg per week, about 12.5 mg per week, about 13 mg per week, about 13.5 mg per week, about 14 mg per week, about 14.5 mg per week, about 15 mg per week, about 16 mg per week, about 18 mg per week, about 20 mg per week, about 22 mg per week, or about 25 mg per week, and is administered over about 0.5 hours, about 1 hour, about 1.5 hours, or about 2 hours. In some embodiments, the dosage is about 6 mg per week or about 8 mg per week and is administered over about 1 hour.

[0116] In some embodiments, the dosage is administered once a week. For example, in some embodiments, a dosage of about 3 mg to about 25 mg per week is administered via an IV infusion once a week. In some embodiments, a dosage of about 6 mg per week or about 8 mg per week is administered via an IV infusion once a week. In some embodiments, the dosage is administered once a week over about 0.5 hours to about 2 hours. In some embodiments, the dosage is administered once a week over about 1 hour.

[0117] In some embodiments, the dosage is administered over multiple weekly administrations (e.g., multiple IV infusions over a period of time). The total amount of mTOR inhibitor (e.g., mTOR dual inhibitor, e.g., RMC-5552) administered over multiple weekly administrations is the dosage. In some embodiments, the dosage is administered twice weekly, three times weekly, or four times weekly. For example, in some embodiments, a dosage of from about 3 mg per week to about 25 mg per week is administered by IV infusion twice weekly or three times weekly. In some embodiments, a dosage of about 6 mg per week or about 8 mg per week is administered by IV infusion twice weekly or three times weekly. In some embodiments, the dosage is administered over a period of from about 0.5 hours to about 2 hours, twice weekly or three times weekly. In some embodiments, the dosage is administered by IV infusion, twice weekly or three times weekly, for about 0.5 hours to about 1 hour each time.

[0118] As used herein, the term "subject" encompasses mammals and non-mammals. Examples of mammals include any member of the class Mammalia: humans, chimpanzees, and other non-human primates such as other apes and monkey species; farm animals such as cows, horses, sheep, goats, pigs; companion animals such as rabbits, dogs, and cats; laboratory animals such as rodents including rats, mice, and guinea pigs, etc., but are not limited thereto. Examples of non-mammals include, but are not limited to, birds, fish, etc. In some embodiments, the subject is a human.

[0119] A "patient" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or macaque. "Patient" includes both humans and animals.

[0120] Adverse event Many of the challenges associated with cancer drug treatment are the administration of sufficient amounts of drug to a subject without inducing intolerable side effects. Surprisingly, the steps of administering and / or applying an oral rinse (e.g., a tacrolimus oral rinse) and / or ice to a subject, in combination with an mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor (e.g., RMC-5552), and an allosteric mTOR inhibitor (e.g., everolimus, sirolimus, and nab-sirolimus)), have been found to result in the ability to administer high doses and / or to result in a reduction in side effects.

[0121] In some embodiments, the methods of the disclosure treat and / or prevent one or more side effects associated with the administration of an mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and nab-sirolimus). Such side effects include, but are not limited to, anemia, nausea, mucositis (e.g., stomatitis), vomiting, diarrhea, fatigue, anorexia, hyponatremia, hyperglycemia, headache, dyspnea, and rash.

[0122] For example, using the solutions (e.g., oral rinses) and / or ice chips described below, the dosage of an mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and nab-sirolimus) is administered without inducing intolerable stomatitis and / or mucositis.

[0123] As used herein, mucositis generally refers to the inflammation and / or ulceration of the inner lining of the digestive tract, which is usually painful. Mucositis is often seen as an adverse effect of chemotherapy and radiotherapy treatments for cancer. Mucositis can occur anywhere along the digestive tract, but oral mucositis is particularly common and refers to the inflammation and ulceration that occur in the oral cavity. Given the prevalence of oral mucositis, in some cases, the term "mucositis" is used to refer to "oral mucositis". Oral mucositis is also known as stomatitis.

[0124] In some embodiments, the method further comprises administering and / or applying a solution (e.g., an oral rinse) and / or ice to the subject and / or the subject's oral cavity. In some embodiments that employ a solution (e.g., an oral rinse) and / or ice, the subject can tolerate a higher dosage of an mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and nab-sirolimus) than when not employing the solution and / or ice.

[0125] In some embodiments, the step of employing a solution (e.g., an oral rinse) and / or ice is done prior to the administration of an mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552). In some embodiments, the dosage of the mTOR dual inhibitor (e.g., RMC-5552) is from about 6 mg per week to about 25 mg per week, from about 6 mg per week to about 20 mg per week, from about 6 mg per week to about 16 mg per week, from about 6 mg per week to about 14 mg per week, from about 6 mg per week to about 12 mg per week, from about 6 mg per week to about 10 mg per week, from about 8 mg per week to about 25 mg per week, from about 8 mg per week to about 20 mg per week, from about 8 mg per week to about 16 mg per week, from about 8 mg per week to about 14 mg per week, from about 8 mg per week to about 12 mg per week, from about 8 mg per week to about 10 mg per week, from about 10 mg per week to about 25 mg per week, from about 10 mg per week to about 20 mg per week, from about 10 mg per week to about 16 mg per week, from about 10 mg per week to about 14 mg per week, or from about 10 mg per week to about 12 mg per week. In some embodiments, the dosage is from about 10 mg per week to about 12 mg per week. In some embodiments, the dosage is from about 10 mg per week to about 12 mg per week. In some embodiments, the dosage is about 10.5 mg per week, about 11 mg per week, about 11.5 mg per week, about 12 mg per week, about 12.5 mg per week, about 13 mg per week, about 13.5 mg per week, about 14 mg per week, about 14.5 mg per week, about 15 mg per week, about 16 mg per week, about 18 mg per week, about 20 mg per week, about 22 mg per week, or about 25 mg per week. In some embodiments, the dosage is about 10 mg per week. In some embodiments, the dosage is about 11 mg per week. In some embodiments, the dosage is about 12 mg per week. In some embodiments, the dosage is about 10 mg per week. In some embodiments, the dosage is about 11 mg per week.In some embodiments, the dosage is about 12 mg per week.

[0126] In some embodiments, the method of the present disclosure further comprises administering a dexamethasone solution (e.g., an oral rinse) to a subject.

[0127] In some embodiments, the dexamethasone solution (e.g., an oral rinse) comprises from about 0.1 mg to about 1 mg per 5 mL, from about 0.5 mg to about 5 mg per 5 mL, or from about 0.5 mg to about 20 mg per 5 mL of dexamethasone. In some embodiments, the dexamethasone solution (e.g., an oral rinse) comprises about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, or about 20 mg of dexamethasone per 5 mL. In some embodiments, the dexamethasone solution (e.g., an oral rinse) comprises about 0.5 mg of dexamethasone per 5 mL.

[0128] In some embodiments, the subject is administered about 2.5 mL, about 5 mL, or about 10 mL of the dexamethasone solution (e.g., an oral rinse). In some embodiments, the subject is administered about 2.5 mL of the dexamethasone solution (e.g., an oral rinse). In some embodiments, the dexamethasone solution (e.g., an oral rinse) is administered 1, 2, 3, or 4 times per day.

[0129] In some embodiments, the method of the present disclosure further comprises administering tacrolimus to a subject. For example, in some embodiments, tacrolimus is administered as a gel, or as an ointment (e.g., as a 0.1% ointment, or as a 0.03% ointment), as a solution (e.g., an oral rinse), or as a tablet, pill, or capsule. Without being bound by any theory, it is thought that tacrolimus binds directly to the mTORC1 complex at the same binding site as the mTOR dual stereoisomer inhibitors (e.g., RMC-5552) disclosed herein, adding the benefit of blocking one of the two binding sites, or, in the case of allosteric mTOR inhibitors (e.g., everolimus, sirolimus, and nab-sirolimus), tacrolimus beneficially competes with the allosteric mTOR inhibitor for binding to the presenting protein (e.g., FKBP12), thereby selectively reducing the efficacy of the mTOR inhibitor and inhibiting mTOR signaling in the tissue of the subject in contact with tacrolimus, and as a result, mitigating the adverse events induced by the mTOR inhibitor in said tissue.

[0130] In some embodiments, the method further comprises administering a tacrolimus solution (e.g., an oral rinse) to a subject. In some embodiments, the tacrolimus solution (e.g., an oral rinse) comprises from about 0.1 mg to about 1 mg of tacrolimus per mL. In some embodiments, the tacrolimus solution (e.g., an oral rinse) comprises a solution (e.g., an oral rinse) of about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, or about 20 mg of tacrolimus per mL. In some embodiments, the tacrolimus solution (e.g., an oral rinse) comprises about 0.5 mg of tacrolimus per mL. In some embodiments, the tacrolimus solution (e.g., an oral rinse) comprises about 0.1 mg of tacrolimus per mL.

[0131] In some embodiments, the subject is administered about 2.5 mL, about 5 mL, or about 10 mL of a tacrolimus solution (e.g., an oral rinse). In some embodiments, the subject is administered about 2.5 mL of a tacrolimus solution (e.g., an oral rinse). In some embodiments, the tacrolimus solution (e.g., an oral rinse) is administered 1, 2, 3, or 4 times per day. In some embodiments, the tacrolimus solution (e.g., an oral rinse) is administered on the day of administration of an mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor such as RMC-5552) or immediately prior to administration of an mTOR inhibitor (e.g., RMC-5552). In some embodiments, the tacrolimus solution (e.g., an oral rinse) is administered on the day of IV infusion or immediately prior to IV infusion. In some embodiments, the tacrolimus solution (e.g., an oral rinse) is administered only on the day of administration of an mTOR inhibitor (e.g., RMC-5552) or only immediately prior to administration of an mTOR inhibitor (e.g., RMC-5552). In some embodiments, the tacrolimus solution (e.g., an oral rinse) is administered only on the day of IV infusion or only immediately prior to IV infusion.

[0132] In some embodiments, the method further comprises administering a combination solution (e.g., an oral rinse) to the subject, wherein the combination solution (e.g., an oral rinse) comprises dexamethasone and tacrolimus.

[0133] In some embodiments, the combination solution (e.g., an oral rinse) comprises from about 0.1 mg per 5 mL to about 1 mg per 5 mL, from about 0.5 mg per 5 mL to about 5 mg per 5 mL, or from about 0.5 mg per 5 mL to about 20 mg per 5 mL of dexamethasone. In some embodiments, the dexamethasone solution (e.g., an oral rinse) comprises about 0.5 mg per 5 mL, about 1 mg per 5 mL, about 5 mg per 5 mL, about 10 mg per 5 mL, or about 20 mg per 5 mL of dexamethasone. In some embodiments, the combination solution (e.g., an oral rinse) comprises about 0.5 mg per 5 mL of dexamethasone.

[0134] In some embodiments, the combination solution (e.g., oral rinse) contains tacrolimus at about 0.1 mg per mL to about 1 mg per mL. In some embodiments, the combination solution (e.g., oral rinse) contains tacrolimus at about 0.1 mg per mL, about 0.5 mg per mL, about 1 mg per mL, about 5 mg per mL, about 10 mg per mL, or about 20 mg per mL. In some embodiments, the combination solution (e.g., oral rinse) contains tacrolimus at about 0.5 mg per mL. In some embodiments, the combination solution (e.g., oral rinse) contains tacrolimus at about 0.1 mg per mL.

[0135] In some embodiments, the subject is administered about 2.5 mL of the combination solution (e.g., oral rinse). In some embodiments, the combination solution (e.g., oral rinse) is administered 1, 2, 3, or 4 times daily. In some embodiments, the combination solution (e.g., oral rinse) is administered on the day of administration of an mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552), or immediately prior to administration of an mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552). In some embodiments, the combination solution (e.g., oral rinse) is administered on the day of IV infusion, or immediately prior to IV infusion. In some embodiments, the combination solution (e.g., oral rinse) is administered only on the day of administration of an mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552), or only immediately prior to administration of an mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552). In some embodiments, the combination solution (e.g., oral rinse) is administered only on the day of IV infusion, or only immediately prior to IV infusion of an mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552).

[0136] In some embodiments, a method of treating a subject having cancer further comprises applying and / or administering ice to the subject's oral cavity. The ice may be applied before administering an mTOR inhibitor (e.g., an mTOR dual inhibitor such as RMC-5552), during the administration of an mTOR inhibitor (e.g., RMC-5552), after administering an mTOR inhibitor (e.g., RMC-5552), or any combination of the foregoing. In some embodiments, the ice is applied for about 1 to about 60 minutes, about 1 to about 30 minutes, or about 1 to about 10 minutes before administering an mTOR inhibitor (e.g., RMC-5552), or for about 1, about 5, about 10, about 15, about 20, about 30, or about 60 minutes before administering an mTOR inhibitor (e.g., RMC-5552). In some embodiments, the ice is applied during the administration of an mTOR inhibitor (e.g., RMC-5552). In some embodiments, the ice is applied for about 1 to about 60 minutes, about 1 to about 30 minutes, or about 1 to about 10 minutes after administering an mTOR inhibitor (e.g., RMC-5552), or for about 1, about 5, about 10, about 15, about 20, about 30, or about 60 minutes after administering an mTOR inhibitor (e.g., RMC-5552). In some embodiments, the ice is applied for about 10 minutes before administering an mTOR inhibitor (e.g., RMC-5552), during the administration of an mTOR inhibitor (e.g., RMC-5552), and for about 10 minutes after administering an mTOR inhibitor (e.g., RMC-5552). In some embodiments, the ice is applied for about 1 to about 60 minutes, about 1 to about 30 minutes, or about 1 to about 10 minutes before intravenous (IV) infusion, or for about 1, about 5, about 10, about 15, about 20, about 30, or about 60 minutes before IV infusion. In some embodiments, the ice is applied during IV infusion. In some embodiments, the ice is applied for about 1 to about 60 minutes, about 1 to about 30 minutes, or about 1 to about 10 minutes after IV infusion, or for about 1, about 5, about 10, about 15, about 20, about 30, or about 60 minutes after IV infusion. In some embodiments, the ice is applied for about 10 minutes before IV infusion, during IV infusion, and for about 10 minutes after IV infusion.

[0137] In some embodiments, the present disclosure is directed to a method of treating or preventing mucositis (e.g., stomatitis) in a subject in need thereof, the method comprising administering an effective amount of tacrolimus (e.g., a tacrolimus solution such as a tacrolimus oral rinse). In some embodiments, the mucositis (e.g., stomatitis) is associated with the administration of an mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and nab-sirolimus). In some embodiments, the subject in need thereof is undergoing, has undergone, or will undergo treatment with an mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and nab-sirolimus). In some embodiments, the tacrolimus is administered as a gel, or as an ointment (e.g., as a 0.1% ointment, or as a 0.03% ointment), as a solution (e.g., an oral rinse), or as a tablet, pill, or capsule. In some embodiments, the tacrolimus is administered to the subject as a tacrolimus solution (e.g., an oral rinse). In some embodiments, the tacrolimus solution (e.g., an oral rinse) comprises from about 0.1 mg to about 1 mg of tacrolimus per mL. In some embodiments, the tacrolimus solution (e.g., an oral rinse) comprises a solution (e.g., an oral rinse) of about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, or about 20 mg of tacrolimus per mL. In some embodiments, the tacrolimus solution (e.g., an oral rinse) comprises about 0.5 mg of tacrolimus per mL. In some embodiments, the tacrolimus solution (e.g., an oral rinse) comprises about 0.1 mg of tacrolimus per mL. In some embodiments, the subject is administered about 2.5 mL, about 5 mL, or about 10 mL of the tacrolimus solution (e.g., an oral rinse). In some embodiments, the subject is administered about 2.5 mL of the tacrolimus solution (e.g., an oral rinse). In some embodiments, the tacrolimus solution (e.g., an oral rinse) is administered 1, 2, 3, or 4 times per day.In some embodiments, the tacrolimus solution (e.g., oral rinse) is administered on the day of administration of the mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and nab-sirolimus), or immediately prior to the administration of the mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and nab-sirolimus). In some embodiments, the tacrolimus solution (e.g., oral rinse) is administered on the day of IV infusion, or immediately prior to IV infusion. In some embodiments, the tacrolimus solution (e.g., oral rinse) is administered only on the day of administration of the mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and nab-sirolimus), or only immediately prior to the administration of the mTOR inhibitor (e.g., RMC-5552, everolimus, sirolimus, and nab-sirolimus). In some embodiments, the tacrolimus solution (e.g., oral rinse) is administered only on the day of IV infusion, or only immediately prior to IV infusion.

[0138] Combination therapy In some methods, the mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor such as RMC-5552) is used in combination with one or more additional therapeutic agents. In these embodiments, the dosage of one or more additional therapeutic agents is reduced from their standard dosage (i.e., the dosage when they are administered alone).

[0139] The term "combination therapy" refers to a treatment method that involves administering to a subject, optionally, at least two therapeutic agents as one or more pharmaceutical compositions. When used in combination therapy, an mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552) may be administered simultaneously with one or more therapeutic agents or administered separately. Administration in this combination may include co-administration in the same dosage form of the mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552) and one or more therapeutic agents, co-administration in their individual dosage forms, and separate administration. That is, the mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552) and any one of the one or more therapeutic agents described herein are formulated together and co-administered in the same dosage form. Alternatively, the mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552) and one or more therapeutic agents may be agents in individual formulations that are co-administered. In another alternative, one or more therapeutic agents may be administered following the administration of the mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552), and vice versa. In some embodiments of the separate administration protocol, the mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552) and one or more therapeutic agents are administered at intervals of minutes, or hours, or days.

[0140] In some embodiments, the mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552) and one or more additional therapeutic agents are administered in any order, simultaneously, or sequentially. The mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552) is administered before or after, promptly, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, up to 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1 - 7, 1 - 14, 1 - 21, or 1 - 30 days before or after one or more additional therapeutic agents.

[0141] The additional therapeutic agent(s) is / are administered in an effective amount. The additional therapeutic agent(s) is / are administered in a therapeutically effective amount. In some embodiments, the effective amount of one or more of the additional therapeutic agents, when used in combination therapy, may be lower than the therapeutic amount of the same therapeutic agent when used as monotherapy, for example, due to an additive or synergistic effect of combining two or more therapeutic agents.

[0142] The term "effective amount" or "therapeutically effective amount" when used in connection with a compound refers to an amount of the compound sufficient to produce the desired biological result. This result may be, in some cases, a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration to a biological system. For example, the "effective amount" for the therapeutic use of one or more additional therapeutic agents is the amount of the one or more additional therapeutic agents required to produce a clinically significant attenuation of the disease.

[0143] In some embodiments, the method includes administration of one or more additional therapeutic agents. In some embodiments, the method includes administration of an additional therapeutic agent in a therapeutically effective amount. In some embodiments, the additional therapeutic agent is an anti-cancer agent. In some embodiments, the additional therapeutic agent is an immunotherapy agent. In some embodiments, the additional therapeutic agent is an immuno-oncology agent. In some embodiments, the additional therapeutic agent is an anti-autoimmune disease agent. In some embodiments, the additional therapeutic agent is an anti-inflammatory disease agent. In some embodiments, the additional therapeutic agent is an anti-neurodegenerative disease agent. In some embodiments, the additional therapeutic agent is an anti-metabolic disease agent. In some embodiments, the additional therapeutic agent is an anti-cardiovascular disease agent. In some embodiments, the additional therapeutic agent is an anti-aging agent. In some embodiments, the additional therapeutic agent is an anti-senescence agent. In some embodiments, the additional therapeutic agent is an agent for treating or preventing transplant rejection. In some embodiments, the additional therapeutic agent is an agent for treating or preventing fungal infection. In some embodiments, the additional therapeutic agent is an immunosuppressant. In some embodiments, the additional therapeutic agent is an mTOR modulator. In some embodiments, the additional therapeutic agent is an mTOR inhibitor. In some embodiments, the additional therapeutic agent is an active site mTOR inhibitor. In some embodiments, the additional therapeutic agent is rapamycin. In some embodiments, the additional therapeutic agent is a rapamycin analog. In some embodiments, the additional therapeutic agent is an mTOR pathway inhibitor. In some embodiments, the additional therapeutic agent is a CDK4 / 6 inhibitor, or an anti-PD1 / PD-L1, PI3K inhibitor. In some embodiments, the additional therapeutic agent is a RAS inhibitor.

[0144] In some embodiments, one or more additional therapeutic agents in the combination therapy include steroids. Suitable steroids include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoxymethasone, dexamethasone, diflorasone, diflucortolone, difluprednate, enoxolone, fluazacort, flucoronide, flumethasone, flunisolide, fluocinonide acetonide, fluocinonide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halomethasone, hydrocortisone, loteprednol etabonate, majipredone, medrysone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone phosphate sodium, prednisone, prednybarl, prednylidene, remexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0145] Further examples of therapeutic agents used in combination therapies with mTOR inhibitors (e.g., RMC-5552) include the compounds described in the following patents: U.S. Patent Nos. 6,258,812, 6,630,500, 6,515,004, 6,713,485, 5,521,184, 5,770,599, 5,747,498, 5,990,141, 6,235,764, and 8,623,885, and International Patent Applications WO01 / 37820, WO01 / 32651, WO02 / 68406, WO02 / 66470, WO02 / 55501, WO04 / 05279, WO04 / 07481, WO04 / 07458, WO04 / 09784, WO02 / 59110, WO99 / 45009, WO00 / 59509, WO99 / 61422, WO00 / 12089, and WO00 / 02871.

[0146] The therapeutic agent can be a biopharmaceutical (e.g., a cytokine (e.g., an interleukin such as interferon or IL-2)) used in the treatment of cancer or a symptom associated therewith. In some embodiments, the biopharmaceutical is an immunoglobulin-based biopharmaceutical that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof). Antibody-drug conjugates are also included.

[0147] The therapeutic agent can be a T cell checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is an inhibitory antibody (e.g., a single specific antibody such as a monoclonal antibody). The antibody can be, for example, a humanized antibody or a fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent such as an antibody that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4 (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PD-1 (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PDL-1 (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of PDL-2 (e.g., a PDL-2 / Ig fusion protein) (e.g., an inhibitory antibody or an Fc fusion or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or a combination thereof (e.g., an inhibitory antibody or a small molecule inhibitor).In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), for example, PD-L1 antibodies such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or without limitation, ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDI4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002, which are checkpoint inhibitors disclosed in Preusser, M. et al. (2015), Nat. Rev. Neurol.

[0148] The therapeutic agent can be an anti-TIGIT antibody such as MBSA43, BMS-986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0149] The therapeutic agent can be an agent for treating cancer or a symptom associated therewith (e.g., a cytotoxic agent, a small molecule other than a peptide, or other compounds useful in treating cancer or a symptom associated therewith, collectively referred to as an "anticancer agent"). The anticancer agent can be, for example, a chemotherapeutic agent or a targeted therapeutic agent.

[0150] Anticancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs, and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthraquinone-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, adrenocortical steroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Further anticancer agents include leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. In some embodiments, one or more additional therapeutic agents include two or more anticancer agents. The two or more anticancer agents are administered in combination or used in cocktails administered individually. Appropriate dosing regimens for combination anticancer agents are known in the art and are described, for example, in Saltz et al., Proc. Am. Soc. Clin. Oncol., 18:233a (1999); and Douillard et al., Lancet, 355(9209):1041-1047 (2000).

[0151] Other non-limiting examples of anti-cancer agents used in the combination therapies described herein include Gleevec® (imatinib mesylate); Kyprolis® (carfilzomib); Velcade® (bortezomib); Casodex (bicalutamide); Iressa® (gefitinib); alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocone, meturedopa, and uredopa; ethyleneimines and methylmelamines including altretamine, triethylenemelamine, triethylenethiophosphoramide, triethylenephosphoramide, and trimethylolmelamine; acetogenins (notably, bullatacin and bullatacinone); camptothecin (including topotecan, a synthetic analogue); bryostatin; calistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogues); cryptophycins (particularly, cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin A; spongistatin; nitrogen mustards such as chlorambucil, chloronaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbiquine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; enediyne antibiotics (e.g., calicheamicin gamma II and calicheamicin omega II such as calicheamicin (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33:183-186 (1994)); dynemicin A such as dynemicin; bisphosphonates such as clodronate; esperamicin;Neo-carcinostatin chromophore and related chromoprotein, including engomycin antibiotic chromophore, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, caminomycin, calminomycin, cardinophilin, chromomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, adriamycin (doxorubicin), morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, keramycin, rhodomycin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin and other antibiotics; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, drostanolone propionate, epitioestanol, mepitiostane, testolactone; anti-adrenal cortex antibodies such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatrexate; defofamine; dexamethasone; diaziquone; eflornithine; elliptinium acetate; epothilones such as epothilone B; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine;PSK (Registered Trademark) polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; lysoxine; schizophyllan; spirigermanium; tenuazonic acid; triaziquone; 2,2’,2’’-trichloroethylamine; trichothecenes such as T-2 toxin, verrucarin A, lolitrem A, and anguidine; urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, for example, Taxol (Registered Trademark) (paclitaxel), Abraxane (Trademark) (Cremophor-free albumin-engineered nanoparticle formulation of paclitaxel), and Taxotere (Registered Trademark) (docetaxel); chlorambucil; tamoxifen (Nolvadex (Registered Trademark)); raloxifene; aromatase inhibitory 4(5)-imidazole; 4-hydroxytamoxifen; trioxifene; keoxifene; LY117018; onapristone; toremifene (Fareston (Registered Trademark)); flutamide, nilutamide, bicalutamide, leuprorelin, goserelin; chlorambucil; Gemzar (Registered Trademark) which is gemcitabine; 6-thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine (Registered Trademark) (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; ibandronate; irinotecan (for example, CPT-11); RFS 2000 which is a topoisomerase inhibitor; difluoromethylornithine (DMFO); retinoids such as retinoic acid; esperamicin; capecitabine (for example, Xeloda (Registered Trademark)); and pharmaceutically acceptable salts of any of the above.;

[0152] Further non-limiting examples of anti-cancer agents for use in the combination therapy disclosed herein include trastuzumab (Herceptin®), bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Rituxan®), Taxol®, Arimidex®, ABVD, avicin, abagovomab, acridine carboxamide, adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, alpharazine, alvocidib, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, amonafide, anthracenedione, anti-CD22 immunotoxins, antineoplastic agents (e.g., cell cycle non-specific antineoplastic agents, and other antineoplastic agents described herein), antitumor herbs, apaziquone, atiprimod, azathioprine, belotecan, bendamustine, BIBW 2992, biricoder, brostallicin, bryostatin, buthionine sulfoximine, CBV (chemotherapy), calyculin, dichloroacetic acid, discodermolide, elsamitrucin, enocitabine, eribulin, exatecan, exisulind, ferdinol, forodesin, fosfestrol, ICE chemotherapy regimen, IT-101, imexon, imiquimod, indolocarbazole, irofulven, laniquidar, larotaxel, lenalidomide, lucantone, lurtotecan, mafosfamide, mitozolomide, nafoxidine, nedaplatin, olaparib, ortataxel, PAC-1, pawpaw, pixantrone, proteasome inhibitor, rebeccamycin, resiquimod, rubitecan, SN-38, salinosporamide A, sapacitamine, Stanford V, swainsonine, talaporfin, tariquidar, tegafur-uracil, temodar, tesetaxel, triplatin tetranitrate, tris(2-chloroethyl)amine, troxacitabine, uramustine, vadimezan, vinflunine, ZD6126, and zosquidar.

[0153] Further non-limiting examples of anti-cancer agents used in the combination therapies disclosed herein include vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine), natural products such as epipodophyllotoxins (e.g., etoposide and teniposide), antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin, and idarubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), mitomycin, enzymes (e.g., L-asparaginase, which metabolizes L-asparagine systemically and eliminates cells that do not have the ability to synthesize their own asparagine), antiplatelet agents, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide and analogs, melphalan, and chlorambucil), ethyleneimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), CDK inhibitors (e.g., CDK4 / 6 inhibitors such as abemaciclib, ribociclib, palbociclib;Seliciclib, UCN-01, P1446A-05, PD-0332991, Dinaciclib, P27-00, AT-7519, RGB286638, and SCH727965), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine (BCNU) and analogs, and streptozocin), and other anti-proliferative alkylating / anti-mitotic alkylating agents, dacarbazine (DTIC), folic acid analogs, pyrimidine analogs (e.g., fluorouracil, floxuridine, and cytarabine), purine analogs and related inhibitors (e.g., mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine), and other anti-proliferative antimetabolites / anti-mitotic antimetabolites, aromatase inhibitors (e.g., anastrozole, exemestane, and letrozole), and platinum coordination complexes (e.g., cisplatin and carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide, histone deacetylase (HDAC) inhibitors (e.g., trichostatin, sodium butyrate, apicidin, suberoylanilide hydroxamic acid, vorinostat, LBH589, romidepsin, ACY-1215, and panobinostat), KSP (Eg5) inhibitors (e.g., Array520), DNA binders (e.g., Zalypsis (registered trademark)), PI3K delta inhibitors (e.g., GS-1101 and TGR-1202), PI3K delta / PI3K gamma inhibitors (e.g., CAL-130), and PI3K inhibitors such as copanlisib, alpelisib, and idelalisib;Multi-target kinase inhibitors (e.g., TG02 and sorafenib), hormones (e.g., estrogen), and hormone agonists such as luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin, leuprolide, and triptorelin), BAFF neutralizing antibodies (e.g., LY2127399), IKK inhibitors, p38MAPK inhibitors, anti-IL-6 (e.g., CNT0328), telomerase inhibitors (e.g., GRN163L), aurora kinase inhibitors (e.g., MLN8237), cell surface monoclonal antibodies (e.g., anti-CD38 (HUMAX-CD38), anti-CSl (e.g., elotuzumab), HSP90 inhibitors (e.g., 17AAG and KOS953), PI3K / Akt inhibitors (e.g., perifosine), Akt inhibitors (e.g., GSK-2141795), PKC inhibitors (e.g., enzastaurin), FTIs (e.g., Zarnestra (trademark)), anti-CD138 (e.g., BT062), Torc1 / 2 specific kinase inhibitors (e.g., INK128), ER / UPR targeting agents (e.g., MKC-3946), cFMS inhibitors (e.g., ARRY-382), JAK1 / 2 inhibitors (e.g., CYT387), PARP inhibitors (e.g., olaparib and veliparib (ABT-888)), and BCL-2 antagonists.;

[0154] In some embodiments, the anti-cancer agent is selected from mechlorethamine, camptothecin, ifosfamide, tamoxifen, raloxifene, gemcitabine, Navelbine (registered trademark), sorafenib, or any of the foregoing similar variants or derivative variants.

[0155] In some embodiments, the anti-cancer agent is a HER2 inhibitor. Non-limiting examples of HER2 inhibitors include monoclonal antibodies such as trastuzumab (Herceptin®) and pertuzumab (Perjeta®); small molecule tyrosine kinase inhibitors such as gefitinib (Iressa®), erlotinib (Tarceva®), pyrimethamine, CP-654577, CP-724714, canertinib (CI 1033), HKI-272, lapatinib (GW-572016; Tykerb®), PKI-166, AEE788, BMS-599626, HKI-357, BIBW 2992, ARRY-334543, and JNJ-26483327.

[0156] In some embodiments, the anti-cancer agent is an ALK inhibitor. Non-limiting examples of ALK inhibitors include ceritinib, TAE-684 (NVP-TAE694), PF02341066 (crizotinib or 1066), alectinib; brigatinib; entrectinib; ensartinib (X-396); lorlatinib; ASP3026; CEP-37440; 4SC-203; TL-398; PLB1003; TSR-011; CT-707; TPX-0005, and AP26113. Further examples of ALK kinase inhibitors are described in Examples 3-39 of WO05016894.

[0157] In some embodiments, the anti-cancer agent is an inhibitor of a member downstream of receptor tyrosine kinase (RTK) / growth factor receptor (e.g., an SHP2 inhibitor (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, JAB-3312, RLY-1971, ERAS-601, or BBP-398), an SOS1 inhibitor (e.g., BI-1701963, BI-3406, or RMC-5845), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, or an AKT inhibitor). In some embodiments, the anti-cancer agent is JAB-3312.

[0158] In some embodiments, the therapeutic agent combined with an mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552) is an inhibitor of the MAP kinase (MAPK) pathway (or a "MAPK inhibitor"). The MAPK inhibitor includes, but is not limited to, one or more MAPK inhibitors as described in Cancers (Basel), September 2015, 7(3):1758-1784. For example, the MAPK inhibitor is selected from one or more of trametinib, binimetinib, selumetinib, cobimetinib, LErafAON (NeoPharm), ISIS5132; vemurafenib, pimasertib, TAK733, RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; AZD6244; refametinib (RDEA119 / BAY86-9766); GDC-0973 / XL581; AZD8330 (ARRY-424704 / ARRY-704); RO5126766 (Roche; described in PLoS One, November 25, 2014, 9(11)); and GSK1120212 (or JTP-74057; described in Clin Cancer Res., March 1, 2011, 17(5):989-1000). The MAPK inhibitor can be PLX8394, LXH254, GDC-5573, or LY3009120.

[0159] In some embodiments, the anti-cancer agent is a disruptor or inhibitor of the RAS-RAF-ERK signaling pathway or the PI3K-AKT-TOR signaling pathway or the PI3K-AKT signaling pathway. The PI3K / AKT inhibitor can include, but is not limited to, one or more PI3K / AKT inhibitors as described in Cancers (Basel), September 2015, 7(3):1758-1784. For example, the PI3K / AKT inhibitor is selected from one or more of NVP-BEZ235; BGT226; XL765 / SAR245409; SF1126; GDC-0980; PI-103; PF-04691502; PKI-587; GSK2126458.

[0160] In some embodiments, the anti-cancer agent is a PD-1 antagonist or a PD-L1 antagonist.

[0161] In some embodiments, the additional therapeutic agent includes an ALK inhibitor, a HER2 inhibitor, an EGFR inhibitor, an IGF-1R inhibitor, a MEK inhibitor, a PI3K inhibitor, an AKT inhibitor, a TOR inhibitor, an MCL-1 inhibitor, a BCL-2 inhibitor, an SHP2 inhibitor, a proteasome inhibitor, and immunotherapy. In some embodiments, the therapeutic agent can be a pan-RTK inhibitor such as afatinib.

[0162] The IGF-1R inhibitor includes linsitinib or a pharmaceutically acceptable salt thereof.

[0163] The EGFR inhibitor includes, but is not limited to, a small molecule antagonist, an antibody inhibitor, or a specific antisense nucleotide or siRNA. Useful antibody inhibitors of EGFR include cetuximab (Erbitux®), panitumumab (Vectibix®), zalutumumab, nimotuzumab, and matuzumab. Further antibody-based EGFR inhibitors include any anti-EGFR antibody or antibody fragment that can partially or completely block the activation of EGFR by its natural ligand. Non-limiting examples of antibody-based EGFR inhibitors are described in Modjtahedi et al., Br. J. Cancer, 1993, 67:247-253; Teramoto et al., Cancer, 1996, 77:639-645; Goldstein et al., Clin. Cancer Res., 1995, 1:1311-1318; Huang et al., 1999, Cancer Res., 15:59(8):1935-40; and Yang et al., Cancer Res., 1999, 59:1236-1243. The EGFR inhibitor can be the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra), or Mab C225 (ATCC accession number: HB-8508), or an antibody or an antibody fragment having its binding specificity.

[0164] Small molecule antagonists of EGFR include gefitinib (Iressa®), erlotinib (Tarceva®), and lapatinib (TykerB®). See, for example, Yan et al., "Pharmacogenetics and Pharmacogenomics in Oncology Therapeutic Antibody Development", BioTechniques, 2005, 39(4):565-8; and Paez et al., "EGFR Mutations in Lung Cancer Correlation with Clinical Response to Gefitinib Therapy", Science, 2004, 304(5676):1497-500. In some embodiments, the EGFR inhibitor is osimertinib (Tagrisso®). Further non-limiting examples of small molecule EGFR inhibitors are the EGFR inhibitors described in the following patent publications: EP0520722; EP0566226; WO96 / 33980; U.S. Patent No. 5,747,498; WO96 / 30347; EP0787772; WO97 / 30034; WO97 / 30044; WO97 / 38994; WO97 / 49688; EP837063; WO98 / 02434; WO97 / 38983; WO95 / 19774; WO95 / 19970; WO97 / 13771; WO98 / 02437; WO98 / 02438; WO97 / 32881; DE19629652; WO98 / 33798; WO97 / 32880; WO97 / 32880; EP682027; WO97 / 02266; WO97 / 27199; WO98 / 07726; WO97 / 34895; WO96 / 31510; WO98 / 14449; WO98 / 14450; WO98 / 14451; WO95 / 09847; WO97 / 19065; WO98 / 17662; U.S. Patent No. 5,789,427; U.S. Patent No. 5,650,415; U.S. Patent No. 5,656,643; WO99 / 35146; WO99 / 35132; WO99 / 07701; and WO92 / 20642, and all pharmaceutically acceptable salts of such EGFR inhibitors.Further non-limiting examples of low molecular weight EGFR inhibitors include any of the EGFR inhibitors described in Traxler et al., Exp.Opin.Ther.Patents, 1998, 8(12):1599-1625.

[0165] MEK inhibitors include, but are not limited to, pimasertib, selumetinib, cobimetinib (Cotellic®), trametinib (Mekinist®), and binimetinib (Mektovi®). In some embodiments, the MEK inhibitor targets a MEK mutation that is a Class I MEK1 mutation selected from D67N; P124L; P124S; and L177V. In some embodiments, the MEK mutation is a Class II MEK1 mutation selected from ΔE51-Q58; ΔF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.

[0166] PI3K inhibitors include wortmannin; 17-hydroxywortmannin analogs described in WO06 / 044453; 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as pictilisib or GDC-0941 and described in WO09 / 036082 and WO09 / 055730); 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235 and described in WO06 / 122806); (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (described in WO08 / 070740); LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, commercially available from Axon Medchem); PI 103 hydrochloride (3-[4-(4-morpholinylpyrido-[3’,2’:4,5]furo[3,2-d]pyrimidin-2-yl]phenol hydrochloride, commercially available from Axon Medchem); PIK 75 (2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide-benzenesulfonic acid, monohydrochloride), commercially available from Axon Medchem); PIK 90 (N-(7,8-dimethoxy-2,3-dihydro-imidazo[1,2-c]quinazolin-5-yl)-nicotinamide, commercially available from Axon Medchem); AS-252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione, commercially available from Axon Medchem);TGX-221 (7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one, commercially available from Axon Medchem); XL-765; and XL-147, including but not limited to these. Other PI3K inhibitors include demethoxybiridin, perifosine, CAL101, PX-866, BEZ235, SF1126, INK1117, IPI-145, BKM120, XL147, XL765, Palomid529, GSK1059615, ZSTK474, PWT33597, IC87114, TGI00-115, CAL263, PI-103, GNE-477, CUDC-907, and AEZS-136.

[0167] AKT inhibitors include Akt-1-1 (inhibiting Akt1) (Barnett et al., Biochem. J. 2005, 385(2):399 - 408); Akt-1-1,2 (inhibiting Akt1 and 2) (Barnett et al., Biochem. J. 2005, 385(2):399 - 408); API-59CJ-Ome (e.g., Jin et al., Br. J. Cancer, 2004, 91:1808 - 12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO05 / 011700); indole-3-carbinol and its derivatives (e.g., U.S. Patent No. 6,656,963; Sarkar and Li, J Nutr., 2004, 134(Suppl 12):3493 - 3498); perifosine (e.g., interfering with the membrane localization of Akt; Dasmahapatra et al., Clin. Cancer Res., 2004, 10(15):5242 - 52); phosphatidylinositol ether lipid analogs (e.g., Gills and Dennis, Expert. Opin. Investig. Drug, 2004, 13:787 - 97); and triciribine (TCN or API-2 or NCI identification number: NSC154020; Yang et al., Cancer Res., 2004, 64:4394 - 9), including but not limited to these.

[0168] BRAF inhibitors used in combination with an mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552) include, for example, vemurafenib, dabrafenib, and encorafenib. BRAF can include class 3 BRAF mutations. In some embodiments, the class 3 BRAF mutation is one or more selected from the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R; and A762E.

[0169] MCL-1 inhibitors include, but are not limited to, AMG-176, MIK665, and S63845. Myeloid cell leukemia-1 (MCL-1) protein is one of the key anti-apoptotic members of the B-cell lymphoma-2 (BCL-2) protein family. Overexpression of MCL-1 is closely associated with tumor progression, as well as resistance to conventional chemotherapy and targeted therapeutic agents, including BCL-2 inhibitors such as ABT-263.

[0170] In some embodiments, the additional therapeutic agent is an SHP2 inhibitor. SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions, including proliferation, differentiation, maintenance of the cell cycle, and migration. SHP2 has two N-terminal Src homology 2 (SH2) domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the intracellular localization and functional regulation of SHP2. The molecule exists in an inactive, auto-inhibited conformation stabilized by a binding network involving residues from both the N-SH2 domain and the PTP domain. For example, stimulation by a cytokine or growth factor that activates via a receptor tyrosine kinase (RTK) results in exposure of the catalytic site, which results in enzymatic activation of SHP2.

[0171] SHP2 is involved in signal transduction via the RAS-mitogen-activated protein kinase (MAPK), JAK-STAT, or phosphatidylinositol 3-kinase-AKT pathways. Mutations within the PTPN11 gene, and subsequently within SHP2, have been identified in several human developmental disorders such as Noonan syndrome and Leopard syndrome, as well as in human cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung, and colon. Some of these mutations destabilize the autoinhibitory conformation of SHP2 and promote the autoactivation of SHP2 or the enhancement of growth factor-driven activation. Thus, SHP2 represents an attractive target for the development of novel therapeutics for the treatment of a variety of diseases, including cancer. SHP2 inhibitors (e.g., RMC-4550 or SHP099), in combination with RAS pathway inhibitors (e.g., MEK inhibitors), have been shown to inhibit the growth of multiple cancer (e.g., pancreatic cancer, lung cancer, ovarian cancer, and breast cancer) cell lines in vitro. Thus, SHP2 inhibitors, in combination therapies accompanied by RAS pathway inhibitors, could be a general strategy for preventing tumor resistance in a wide range of malignancies.

[0172] Non-limiting examples of such SHP2 inhibitors known in the art include: Chen et al., Mol Pharmacol., 2006, 70, 562; Sarver et al., J. Med. Chem., 2017, 62, 1793; Xie et al., J. Med. Chem., 2017, 60, 113734; and Igbe et al., Oncotarget, 2017, 8, 113734; as well as WO2023282702, WO2023280283, WO2023280237, WO2023018155, WO2023011513, WO2022271966, WO2022271964, WO2022271911, WO2022259157, WO2022242767, WO2022241975, WO2022237676, WO2022237367, WO2022237178, WO2022235822, WO2022234409, WO2022208408, WO2022207924, WO2022167682, WO2022166844, WO2022161222, WO2022156765, WO2022135568, WO2022089406, WO2022089389, WO2022063190, WO2022043685, WO2022042331, WO2022033430, WO2022033430, WO2022017444, WO2022007869, WO2021259077, WO2021249449, WO2021249057, WO2021244659, WO2021218755, WO2021281752, WO2021197542, WO2021176072, WO2021149817, WO2021148010, WO2021147879, WO2021143823, WO2021143701, WO2021143680, WO2021121397, WO2021119525, WO2021115286, WO2021110796, WO2021088945, WO2021073439, WO2021061706, WO2021061515, WO2021043077, WO2021033153, WO2021028362, WO2021033153, WO2021028362, WO2021018287, WO2020259679, WO2020249079, WO2020210384, WO2020201991,WO2020181283, WO2020177653, WO2020165734, WO2020165733, WO2020165732, WO2020156243, WO2020156242, WO2020108590, WO2020104635, WO2020094104, WO2020094018, WO2020081848, WO2020073949, WO2020073945, WO2020072656, WO2020065453, WO2020065452, WO2020063760, WO2020061103, WO2020061101, WO2020033828, WO2020033286, WO2020022323, WO2019233810, WO2019213318, WO2019183367, WO2019183364, WO2019182960, WO2019167000, WO2019165073, WO2019158019, WO2019152454, WO2019051469, WO2019051084, WO2018218133, WO2018172984, WO2018160731, WO2018136265, WO2018136264, WO2018130928, WO2018129402, WO2018081091, WO2018057884, WO2018013597, WO2017216706, WO2017211303, WO2017210134, WO2017156397, WO2017100279, WO2017079723, WO2017078499, WO2016203406, WO2016203405, WO2016203404, WO2016196591, WO2016191328, WO2015107495, WO2015107494, WO2015107493, WO2014176488, WO2014113584, US20210085677, US10858359, US10934302, US10954243, US10988466, US11001561, US11033547, US11034705, US11044675, US11179397, CN115677661, CN115677660, CN115611869, CN115521305, CN115490697, CN115466273, CN115394612,CN115304613, CN115304612, CN115300513, CN115197225, CN114957162, CN114920759, CN114716448, CN114671879, CN114539223, CN114524772, CN114213417, CN114163457, CN113896710, CN113248521, CN113248449, CN113135924, CN113024508, CN112920131, CN112823796, CN112402385, CN111848599, CN111704611, CN111265529, and CN108113848, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers thereof, each of which is incorporated herein by reference in its entirety.,

[0173] In some embodiments, the SHP2 inhibitor binds within the active site. In some embodiments, the SHP2 inhibitor is a mixed-type irreversible inhibitor. In some embodiments, the SHP2 inhibitor, e.g., a non-covalent allosteric inhibitor, binds to an allosteric site. In some embodiments, the SHP2 inhibitor is a covalent SHP2 inhibitor, such as an inhibitor that targets a cysteine residue (C333) outside the active site of the phosphatase. In some embodiments, the SHP2 inhibitor is a reversible inhibitor. In some embodiments, the SHP2 inhibitor is an irreversible inhibitor. In some embodiments, the SHP2 inhibitor is SHP099. In some embodiments, the SHP2 inhibitor is TNO155. In some embodiments, the SHP2 inhibitor is RMC-4550. In some embodiments, the SHP2 inhibitor has a structure as follows:

Chemical formula

[0174] In some embodiments, the SHP2 inhibitor is JAB-3068, JAB-3312, RLY-1971, ERAS-601, or BBP-398.

[0175] In some embodiments, the additional therapeutic agent is selected from the group consisting of a HER2 inhibitor, an SHP2 inhibitor, a CDK4 / 6 inhibitor, an SOS1 inhibitor, and a PD-L1 inhibitor. See, for example, Hallin et al., Cancer Discovery, DOI:10.1158 / 2159-8290 (October 28, 2019); and Canon et al., Nature, 575:217 (2019).

[0176] Proteasome inhibitors include, but are not limited to, carfilzomib (Kyprolis®), bortezomib (Velcade®), and oprozomib.

[0177] Immunotherapies include, but are not limited to, monoclonal antibodies, immunomodulatory imides (IMiDs), GITR agonists, genetically engineered T cells (e.g., CAR-T cells), bispecific antibodies (e.g., BiTE), and anti-PD-1 agents, anti-PDL-1 agents, anti-CTLA4 agents, anti-LAG1 agents, and anti-OX40 agents.

[0178] An immunomodulatory imide (IMiD) is a class of immunomodulatory drugs (drugs that regulate the immune response) that contain an imide group. The IMiD class includes thalidomide and its analogs (lenalidomide, pomalidomide, and apremilast).

[0179] Exemplary anti-PD-1 antibodies and methods for their use are described by Goldberg et al., Blood, 2007, 110(1):186-192; Thompson et al., Clin. Cancer Res. 2007, 13(6):1757-1761; and WO06 / 121168A1), and elsewhere in this specification.

[0180] GITR agonists include GITR fusion proteins such as GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies) described in U.S. Patent No. 6,111,090, U.S. Patent No. 8,586,023, WO2010 / 003118, and WO2011 / 090754; or, for example, anti-GITR antibodies described in U.S. Patent No. 7,025,962, EP1947183, U.S. Patent No. 7,812,135, U.S. Patent No. 8,388,967, U.S. Patent No. 8,591,886, U.S. Patent No. 7,618,632, EP1866339, and WO2011 / 028683, WO2013 / 039954, WO05 / 007190, WO07 / 133822, WO05 / 055808, WO99 / 40196, WO01 / 03720, WO99 / 20758, WO06 / 083289, WO05 / 115451, and WO2011 / 051726, but are not limited thereto.

[0181] Another example of a therapeutic agent used in a combination mTOR inhibitor (e.g., an mTOR dual inhibitor, e.g., RMC-5552) is an anti-angiogenic agent. Anti-angiogenic agents include, but are not limited to, chemically synthesized compositions, antibodies, antigen-binding regions, radionuclides, as well as combinations and conjugates thereof, manufactured in vitro. Anti-angiogenic agents can be agonists, antagonists, allosteric modulators, toxins, and more generally act to inhibit or stimulate their targets (e.g., activate or inhibit receptors or enzymes), thereby promoting cell death or arresting cell growth in some cases. In some embodiments, one or more additional therapeutic agents include anti-angiogenic agents.

[0182] The anti-angiogenic agent can be an MMP-2 (matrix metalloproteinase 2) inhibitor, an MMP-9 (matrix metalloproteinase 9) inhibitor, and a COX-II (cyclooxygenase 11) inhibitor. Non-limiting examples of the anti-angiogenic agent include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, and bevacizumab. Examples of useful COX-II inhibitors include celecoxib, valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO96 / 33172, WO96 / 27583, WO98 / 07697, WO98 / 03516, WO98 / 34918, WO98 / 34915, WO98 / 33768, WO98 / 30566, WO90 / 05719, WO99 / 52910, WO99 / 52889, WO99 / 29667, WO99007675, EP0606046, EP0780386, EP1786785, EP1181017, EP0818442, EP1004578, and US20090012085, as well as U.S. Patent Nos. 5,863,949 and 5,861,510. Preferred MMP-2 inhibitors and MMP-9 inhibitors are MMP-2 inhibitors and MMP-9 inhibitors that have little or no activity to inhibit MMP-1. Compared with other MMPs (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13), MMP-2 inhibitors and MMP-9 inhibitors that selectively inhibit MMP-2 or MMP-9 are more preferred. Some specific examples of MMP inhibitors are AG-3340, RO32-3555, and RS13-0830.

[0183] Additional exemplary anti-angiogenic agents include KDR (kinase domain receptor) inhibitors (e.g., antibodies and antigen-binding regions that specifically bind to the kinase domain receptor), anti-VEGF agents such as VEGF-TRAP™ (e.g., VEGF (e.g., bevacizumab), or antibodies or antigen-binding regions that specifically bind to soluble VEGF receptor or its ligand-binding region), and anti-VEGF receptor agents (e.g., antibodies or antigen-binding regions that specifically bind to the VEGF receptor), EGFR inhibitors such as Vectibix® (panitumumab), erlotinib (Tarceva®) (e.g., antibodies or antigen-binding regions that specifically bind to EGFR), anti-Ang1 agents and anti-Ang2 agents (e.g., antibodies or antigen-binding regions that specifically bind to Ang1 and Ang2, or their receptors, e.g., Tie2 / Tek), and anti-Tie2 kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind to Tie2 kinase). Other anti-angiogenic agents include Campath, IL-8, B-FGF, Tek antagonists (US2003 / 0162712; US6,413,932), anti-TWEAK agents (e.g., specific-binding antibodies or antigen-binding regions, or soluble TWEAK receptor antagonists; see US6,727,225), ADAM disintegrin domain that antagonizes the binding of integrin to its ligand (US2002 / 0042368), specific-binding anti-eph receptor or anti-ephrin antibodies or antigen-binding regions (U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; 6,057,124; and their patent family members), and anti-PDGF-BB antagonists (e.g., specific-binding antibodies or antigen-binding regions), antibodies or antigen-binding regions that specifically bind to the PDGF-BB ligand, and PDGFR kinase inhibitors (e.g., antibodies or antigen-binding regions that specifically bind thereto).Additional anti-angiogenic agents include SD-7784 (Pfizer, USA); Sirengetide (Merck KGaA, Germany, EPO0770622); pegaptanib octasodium (Gilead Sciences, USA); Alphastatin (BioActa, UK); M-PGA (Celgene, USA, US5712291); iromostat (Arriva, USA, US5892112); emaxanib (Pfizer, USA, US5792783); batranib (Novartis, Switzerland); 2-methoxyestradiol (EntreMed, USA); TLC ELL-12 (Elan, Ireland); anecortave acetate (Alcon, USA); alpha-D148 Mab (Amgen, USA); CEP-7055 (Cephalon, USA); anti-Vn Mab (Crucell, Netherlands); DAC antiangiogenic (ConjuChem, Canada); Angiocidin (InKine Pharmaceutical, USA); KM-2550 (Japan, Kyowa Hakko Bio Co., Ltd.); SU-0879 (Pfizer, USA); CGP-79787 (Novartis, Switzerland, EP0970070); ARGENT technology (Ariad, USA); YIGSR-Stealth (Johnson & Johnson, USA); fibrinogen E fragment (BioActa, UK); angiogenesis inhibitor (Trigen, UK); TBC-1635 (Encysive Pharmaceuticals, USA); SC-236 (Pfizer, USA); ABT-567 (Abbott, USA); Metastatin (EntreMed, USA); maspin (Japan, Sosei Co., Ltd.); 2-methoxyestradiol (Oncology Sciences Corporation, USA); ER-68203-00 (IV AX, USA); BeneFin (Lane Labs, USA); Tz-93 (Japan, Tsumura & Co.). TAN-1120 (Japan, Takeda Pharmaceutical Company Limited); FR-111142 (Japan, Fujisawa Pharmaceutical Co., Ltd., JP02233610); Platelet Factor 4 (RepliGen, USA, EP407122); Vascular Endothelial Growth Factor Antagonist (Borean, Denmark); Bevacizumab (pINN) (Genentech, USA); Angiogenesis Inhibitor (SUGEN, USA); XL784 (Exelixis, USA); XL647 (Exelixis, USA); Second Generation Alpha5 Beta3 Integrin MAb (Applied Molecular Evolution, USA; and MedImmune, USA); Enzastaurin Hydrochloride (Lilly, USA); CEP7055 (Cephalon, USA; and Sanofi-Synthelabo, France); BC 1 (Genoa Institute of Cancer Research, Italy); rBPI21 and BPI-derived Anti-angiogenic Agent (XOMA, USA); PI88 (Progen, Australia); Sirnaomics (Merck KGaA, German; Munich Technical University, Germany; Scripps Clinic and Research Foundation, USA); AVE 8062 (Japan, Ajinomoto Co., Inc.); AS 1404 (Cancer Research Laboratory, New Zealand); SG 292 (Telios, USA); Endostatin (Boston Children’s Hospital, USA); ATN 161 (Attenuon, USA); 2-Methoxyestradiol (Boston Children’s Hospital, USA); ZD 6474 (AstraZeneca, UK); ZD 6126 (Angiogene Pharmaceuticals, UK); PPI 2458 (Praecis, USA); AZD 9935 (AstraZeneca, UK); AZD 2171 (AstraZeneca, UK); Batirranib (pINN) (Novartis, Switzerland; and Schering AG, Germany); Tissue Factor Pathway Inhibitor (EntreMed, USA);Pegaptanib (Pinn) (Gilead Sciences, USA); Xanthriol (Yonsei University, South Korea); Gene-based VEGF-2 vaccine (Scripps Clinic and Research Foundation, USA); SPV5.2 (Supratek, Canada); SDX 103 (University of California at San Diego, USA); PX 478 (ProlX, USA); METASTATIN (EntreMed, USA); Troponin I (Harvard University, USA); SU 6668 (SUGEN, USA); OXI 4503 (OXiGENE, USA); o-Guanidine (Dimensional Pharmaceuticals, USA); Motuporamine C (British Columbia University, Canada); CDP 791 (Celltech Group, UK); Atiprimod (pINN) (GlaxoSmithKline, UK); E7820 (Eisai Co., Ltd., Japan); CYC 381 (Harvard University, USA); AE 941 (Aeterna, Canada); Angiogenesis vaccine (EntreMed, USA); Urokinase plasminogen activator inhibitor (Dendreon, USA); Oglufanide (pINN) (Melmotte, USA); HIF-lalfa inhibitor (Xenova, UK); CEP5214 (Cephalon, USA); BAY RES 2622 (Bayer, Germany); Angiocidin (InKine, USA); A6 (Angstrom, USA); KR 31372 (Korea Research Institute of Chemical Technology, South Korea); GW 2286 (GlaxoSmithKline, UK); EHT 0101 (ExonHit, France); CP 868596 (Pfizer, USA); CP 564959 (OSI, USA); CP 547632 (Pfizer, USA); 786034 (GlaxoSmithKline, UK); KRN 633 (Kirin Brewery, Japan);2-Methoxyestradiol Intraocular Drug Delivery System; anginex (Maastricht University, Netherlands; and Minnesota University, USA); ABT 510 (Abbott, USA); AAL 993 (Novartis, Switzerland); VEGI (ProteomTech, USA); Tumor Necrosis Factor Alpha Inhibitor; SU 11248 (Pfizer, USA and SUGEN USA); ABT 518 (Abbott, USA); YH16 (Yantai Rongchang, China); S-3APG (Boston Childrens Hospital, USA and EntreMed, USA); MAb, KDR (ImClone Systems, USA); Alpha5Beta MAb (Protein Design, USA); KDR Kinase Inhibitor (Celltech Group, UK; and Johnson & Johnson, USA); GFB 116 (South Florida University, USA; and Yale University, USA); CS 706 (Japan, Sankyo Co., Ltd.); Combretastatin A4 Prodrug (Arizona State University, USA); Chondroitinase AC (IBEX, Canada); BAY RES 2690 (Bayer, Germany); AGM 1470 (Harvard University, USA; Japan, Takeda Pharmaceutical Company Limited; and TAP, USA); AG 13925 (Agouron, USA); Tetrathiomolybdate (University of Michigan, USA); GCS 100 (Wayne State University, USA); CV 247 (Ivy Medical, UK); CKD 732 (Chong Kun Dang, South Korea); Ilsogladine (Japan, Nippon Shinyaku Co., Ltd.); RG 13577 (Aventis, France); WX 360 (Wilex, Germany); Squaramine (Genaera, USA); RPI 4610 (SiRNA, USA); Heparanase inhibitor (InSight, Israel); KL 3106 (Kolon, South Korea); Honokiol (Emory University, USA); ZK CDK (Schering AG, Germany); ZK Angio (Schering AG, Germany); ZK 229561 (Novartis, Switzerland; and Schering AG, Germany); XMP 300 (XOMA, USA); VGA 1102 (Japan, Taisho Pharmaceutical Co., Ltd.); VE-cadherin 2 antagonist (ImClone Systems, USA); Vasostatin (National Institutes of Health, USA); Flk-1 (ImClone Systems, USA); TZ 93 (Japan, Tsumura & Co.); TumStatin (Beth Israel Hospital, USA); Cleaved soluble FLT1 (vascular endothelial growth factor receptor 1) (Merck & Co., USA); Tie-2 ligand (Regeneron, USA); and thrombospondin 1 inhibitor (Allegheny Health, Education and Research Foundation, USA).

[0184] Further examples of therapeutic agents used in combination with an mTOR inhibitor (e.g., RMC-5552) include agents that specifically bind to and inhibit the activity of growth factors, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding regions that specifically bind to its receptor, c-Met.

[0185] Another example of a therapeutic agent used in combination with an mTOR inhibitor (e.g., RMC-5552) is an autophagy inhibitor. Autophagy inhibitors include, but are not limited to, chloroquine, 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1, 5-amino-4-imidazolecarboxamide riboside (AICAR), okadaic acid, autophagy-suppressive algal toxins that inhibit type 2A or type 1 protein phosphatases, cAMP analogs, and drugs that increase cAMP levels such as adenosine, LY204002, N6-mercaptopurine riboside, and vinblastine. In addition, antisense RNAs or siRNAs that inhibit the expression of proteins, including but not limited to those involved in autophagy such as ATG5, are also used. In some embodiments, one or more additional therapeutic agents include an autophagy inhibitor.

[0186] Another example of a therapeutic agent used in combination with an mTOR inhibitor (e.g., RMC-5552) is an anti-neoplastic agent. In some embodiments, one or more additional therapeutic agents include an anti-neoplastic agent. Non-limiting examples of anti-neoplastic agents are acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ansell, ansethim, argrabin, arsenic trioxide, BAM-002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, cermolukin, cetrorelix, cladribine, clotrimazole, cytarabine ocfosfate, DA3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dirazep, docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumab ozogamicin, gimeracil / oteracil / tegafur formulation, glycopyrronium, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha-fetoprotein, ibandronic acid, idarubicin (imiquimod, interferon alpha, interferon alpha, natural, interferon alpha 2, interferon alpha 2a, interferon alpha 2b, interferon alpha-N1, interferon alpha n3, interferon alpha con1, interferon alpha, natural interferon beta, interferon beta 1a, interferon beta 1b, interferon gamma, natural interferon gamma 1a, interferon gamma 1b, interleukin 1 beta, iobenzguan, irinotecan, ilsogladine, lanreotide,LC9018 (Yakult Honsha Co., Ltd.), Leflunomide, Lenograstim, Lentinan Sulfate, Letrozole, Leukocyte Alpha Interferon, Leuprorelin, Levamisole + Fluorouracil, Rialozole, Lobaplatin, Lonidamine, Lovastatin, Masoprocol, Mercaptopurine, Metoclopramide, Mifepristone, Miltefosine, Muromonastim, Mismatch Double-Stranded RNA, Mitoguazone, Mitolactol, Mitoxantrone, Molgramostim, Nafarelin, Naloxone + Pentazocine, Nartograstim, Nedaplatin, Nilutamide, Noscapine, Novel Erythropoiesis-Stimulating Protein, NSC631570, Octreotide, Oprelvekin, Osaterone, Oxaliplatin, Paclitaxel, Pamidronic Acid, Pegaspargase, PEGylated Interferon Alpha 2b, Pentosan Polysulfate Sodium, Pentostatin, Picibanil, Pirarubicin, Rabbit Anti-Thymocyte Polyclonal Antibody, Polyethylene Glycol Interferon Alpha 2a, Porfimer Sodium, Raloxifene, Raltitrexed, Rasburicase, Etidronate Rhenium Re 186, RII Retinamid, Rituximab, Romurtide, Samarium (153Sm) Lexidronam, Sargramostim, Schizophyllan, Sobuzoxane, Sonermin, Strontium Chloride 89, Suramin, Tasonermin, Tazarotene, Tegafur, Temoporfin, Temozolomide, Teniposide, Tetrachlorodecaoxide, Thalidomide, Timalphasin, Thyrotropin Alpha, Topotecan, Toremifene, Tositumomab-Iodine 131, Trastuzumab, Treosulfan, Tretinoin, Trilostane, Trimethoprim, Triptorelin, Tumor Necrosis Factor Alpha, Natural, Ubenimex, Bladder Cancer Vaccine, Maruyama Vaccine, Melanoma Lysate Vaccine, Valrubicin, Verteporfin, Vinorelbine, Viridin, Dinostatin Stimalamer, or Zoledronic Acid; Abarelix; AE941 (Aeterna), Ambamustine, Antisense Oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), Decitabine, Dexaminoglutethimide, Diazouone, EL532 (Elan), EM800 (Endorecherche), Eniluracil, Ethanidazole,Fenretinide, Filgrastim SD01 (Amgen), Fluvestrant, Galactosamine, Gastrin 17 Immunogen, HLA - B7 Gene Therapy (Vical), Granulocyte Macrophage Colony Stimulating Factor, Histamine Dihydrochloride, Ibritumomab Tiuxetan, Irormostat, IM862 (Cytran), Interleukin 2, Iproxifene, LDI200 (Milkhaus), Relizumab, Rituximab, CA125 MAb (Biomira), Cancer MAb (New Japan Science Co., Ltd. PPD), HER - 2 / Fc MAb (Medarex), Idiotype 105AD7 MAb (CRC Technology), Idiotype CEA MAb (Trilex), LYM - 1 - iodine 131 MAb (Techni clone), Polymorphic Epithelial Mucin - Yttrium 90 MAb (Antisoma), Marimastat, Menogaril, Mitumomab, Motexafin Gadolinium, MX6 (Galderma), Nelarabine, Noratraxed, P30 protein, Pegvisomant, Pemetrexed, Porfiromycin, Prinomastat, RL0903 (Shire), Rubitecan, Satraplatin, Sodium Phenylacetate, Sparfloxacin, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe Mitsubishi Pharma Corporation), Tetrathiomolybdate, Taliblastine, Thrombopoietin, Tin Ethyl Ethiopurpurin, Tirapazamine, Cancer Vaccine (Biomira), Melanoma Vaccine (New York University), Melanoma Vaccine (Sloan Kettering Institute), Melanoma Tumor Lysate Vaccine (New York Medical College), Melanoma Cell Lysate Virus Vaccine (Royal Newcastle Hospital), or Balspondal.

[0187] Further examples of therapeutic agents used in combination with an mTOR inhibitor (e.g., RMC-5552) include ipilimumab (Yervoy®); tremelimumab; galiximab; nivolumab, also known as BMS-936558 (Opdivo®); pembrolizumab (Keytruda®); avelumab (Bavencio®); AMP224; BMS-936559; MPDL3280A, also known as RG7446; MEDI-570; AMG557; MGA271; IMP321; BMS-663513; PF-05082566; CDX-1127; anti-OX40 (Providence Health Services); huMAbOX40L; atacicept; CP-870893; lucatumumab; dacetuzumab; muromonab-CD3; ipilimumab; MEDI4736 (Imfinzi®); MSB0010718C; AMP224; adalimumab (Humira®); ado-trastuzumab emtansine (Kadcyla®); aflibercept (Eylea®); alemtuzumab (Campath®); basiliximab (Simulect®); belimumab (Benlysta®); basiliximab (Simulect®); belimumab (Benlysta®); brentuximab vedotin (Adcetris®); canakinumab (Ilaris®); certolizumab pegol (Cimzia®); daclizumab (Zenapax®); daratumumab (Darzalex®); denosumab (Prolia®); eculizumab (Soliris®); efalizumab (Raptiva®); gemtuzumab ozogamicin (Mylotarg®); golimumab (Simponi®); ibritumomab tiuxetan (Zevalin®); infliximab (Remicade®); motavizumab (Numax®); natalizumab (Tysabri®); obinutuzumab (Gazyva®); ofatumumab (Arzerra®); omalizumab (Xolair®);Palivizumab (Synagis®); Pertuzumab (Perjeta®); Pertuzumab (Perjeta®); Ranibizumab (Lucentis®); Racibacumab (Abthrax®); Tocilizumab (Actemra®); Tositumomab; Tositumomab-i-131; Tositumomab and Tositumomab-i-131 (Bexxar®); Ustekinumab (Stelara®); AMG102; AMG386; AMG479; AMG655; AMG706; AMG745; and AMG951;

[0188] When used for an adaptive effect, the effective dosage of the ALK inhibitor ranges from about 0.5 mg to about 5000 mg, which is required to treat the condition. Compositions for use in vivo or in vitro may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or may contain the disclosed compound in the range of one amount to another amount within the dosage list. In some embodiments, the composition is in the form of a split tablet.

[0189] When used for an adaptive effect, the effective dosage of the EGFR inhibitor ranges from about 0.5 mg to about 5000 mg, which is required to treat the condition. Compositions for use in vivo or in vitro may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or may contain the disclosed compound in the range of one amount to another amount within the dosage list. In some embodiments, the composition is in the form of a split tablet.

[0190] When used for an adaptive effect, the effective dosage of the MEK inhibitor ranges from about 0.05 mg to about 5000 mg, which is required to treat the condition. Compositions for use in vivo or in vitro may contain about 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or may contain the disclosed compound in the range of one amount to another amount within the dosage list. In some embodiments, the composition is in the form of a split tablet.

[0191] In some embodiments, at least one of the additional therapeutic agents is a RAS inhibitor. The terms "RAS inhibitor" and "inhibitor of RAS" are used interchangeably to refer to any inhibitor that targets the RAS protein. In various embodiments, these terms include RAS(off) inhibitors and RAS(on) inhibitors such as, for example, the KRAS(off) inhibitor and the KRAS(on) inhibitor disclosed herein. The term "RAS(off) inhibitor" refers to any inhibitor that binds to the RAS protein at its GDP-bound "off" position, as further defined herein. The term "RAS(on) inhibitor" refers to any inhibitor that binds to the RAS protein at its GDP-bound "on" position, as further defined herein. In some embodiments, the RAS inhibitor has a molecular weight of less than 700 Da. In some embodiments, the RAS inhibitor is selected from the group consisting of AMG510, MRTX1257, JNJ-74699157 (ARS-3248), LY3537982, LY3499446, ARS-853, ARS-1620, GDC-6036, BPI-421286, JDQ443, JAB-21000, JAB-22000, JAB-23000, RSC-1255, ERAS-3490, D-1553, JAB-21822, GH-35, ICP-915, IBI351, and BI1823911. The RAS inhibitor can be a RAS vaccine or another therapeutic modality designed to directly or indirectly reduce the oncogenic activity of RAS.

[0192] As used herein, the terms "RAS pathway" and "RAS / MAPK pathway" are used interchangeably to refer to a signaling cascade downstream of various cell surface growth factor receptors in which activation of RAS (and its various isoforms and allotypes) is a central event that drives various cell effector events that determine cell proliferation, activation, differentiation, mobilization, and other functional characteristics. SHP2 conveys a positive signal from a growth factor receptor to the RAS activation / inactivation cycle, which is modulated by guanine nucleotide exchange factors (GEFs; such as SOS1) that load GTP onto RAS to yield functionally active GTP-bound RAS as well as GTP activation proteins (GAPs; such as NF1) that facilitate signal termination by converting GTP to GDP. The GTP-bound RAS resulting from this cycle conveys an essential positive signal to a series of serine / threonine kinases that are a source of further signals for various cell effector functions, including RAF kinase and MAP kinase.

[0193] In some embodiments, the RAS inhibitor targets KRAS, NRAS, or HRAS. In some embodiments, the RAS inhibitor is a RAS mutant-specific inhibitor. In some embodiments, the RAS mutant is (a) the following K-Ras mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof; (b) the following H-Ras mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H, G13S, A18V, D119N, G13N, A146T, A66T, G12A, A146V, G12N, or G12R, and combinations thereof; and (c) The following N-Ras mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V, or A59T, and combinations thereof selected from

[0194] Mutations at these positions can result in RAS-driven tumors.

[0195] Methods for detecting mutations within the nucleotide sequences of KRAS, HRAS, or NRAS are known to those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan assays, SNP genotyping assays, high-resolution melting assays, and microarray analysis. In some embodiments, a sample is assayed for the G12C mutation of KRAS, HRAS, or NRAS by real-time PCR. In real-time PCR, a fluorescent probe specific for the G12C mutation of KRAS, HRAS, or NRAS is used. If the mutation is present, the probe binds and fluorescence is detected. In some embodiments, the G12C mutation of KRAS, HRAS, or NRAS is identified using a direct sequencing method for specific regions (e.g., exon 2 and / or exon 3) within the gene of KRAS, HRAS, or NRAS. This technique will identify all possible mutations within the region being sequenced.

[0196] Those skilled in the art are aware of methods for detecting mutations within the proteins of KRAS, HRAS, or NRAS. These methods include, but are not limited to, the detection of mutants of KRAS, HRAS, or NRAS using a binder specific to the mutant protein (e.g., an antibody), protein electrophoresis, and Western blotting, as well as direct peptide sequencing.

[0197] Methods for determining whether a tumor or cancer contains a G12C mutation or other KRAS, HRAS, or NRAS mutations can use a variety of samples. In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed into a cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0198] In some embodiments, at least one of the additional therapeutic agents is a RAS(off) inhibitor. In various embodiments, at least one of the additional therapeutic agents is a KRAS(off) inhibitor (e.g., any one or more of the KRAS(off) inhibitors disclosed herein or known in the art). In some embodiments, at least one of the additional therapeutic agents is a KRAS G12C (off) inhibitor (e.g., a KRAS G12C(One or more of the (OFF) inhibitors). In some embodiments, at least one of the additional therapeutic agents is AMG510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, at least one of the additional therapeutic agents is selected from AMG510 and MRTX849. In some embodiments, the therapeutic agent is AMG510. In some embodiments, the therapeutic agent is MRTX849. In various embodiments, at least one of the additional therapeutic agents is an mTOR inhibitor (e.g., an mTOR dual stereoisomer inhibitor, e.g., RMC-5552), and one of the additional therapeutic agents is a KRAS G12C inhibitor.

[0199] As used herein, the term "RAS(off) inhibitor" refers to an inhibitor that targets, i.e., selectively binds to or inhibits, the GDP-bound inactive state of RAS (e.g., selectively over the GTP-bound active state of RAS). Inhibition of the GDP-bound inactive state of RAS includes, for example, inhibiting the exchange of GDP for GTP, thereby blocking the inactive state by preventing RAS from adopting an active conformation. In some embodiments, the RAS(off) inhibitor may also bind to or inhibit the GTP-bound active state of RAS (e.g., with lower affinity or a smaller inhibition constant than the GDP-bound inactive state of RAS). In some embodiments, the RAS(off) inhibitor has a molecular weight of less than 700 Da. The term "KRAS(off) inhibitor" refers to any inhibitor that binds to KRAS at its GDP-bound "off" position. References to the term KRAS(off) inhibitor include, for example, AMG510, MRTX849, JDQ443, and MRTX1133. In some embodiments, the KRAS(off) inhibitor is selected from AMG510 and MRTX849. In some embodiments, the KRAS(off) inhibitor is AMG510. In some embodiments, the KRAS(off) inhibitor is MRTX849. In some embodiments, the RAS(off) inhibitor is selected from sotorasib (AMG510), adagrasib (MRTX849), MRTX1257, JNJ-74699157 (ARS-3248), LY3537982, LY3499446, ARS-853, ARS-1620, GDC-6036, JDQ443, BPI-421286, JAB-21000, RSC-1255, ERAS-3490, D-1553, JAB-21822, GH-35, ICP-915, IBI351, and BI1823911. In some embodiments, references to the term RAS(off) inhibitor include the following patent applications, each of which is incorporated herein by reference in its entirety: WO2023287896, WO2023287730, WO2023284881, WO2023284730, WO2023284537, WO2023283933, WO2023283213, WO2023280960,WO2023280280, WO2023280136, WO2023280026, WO2023278600, WO2023274383, WO2023274324, WO2023034290, WO2023020523, WO2023020521, WO2023020519, WO2023020518, WO2023018812, WO2023018810, WO2023018809, WO2023018699, WO2023015559, WO2023014979, WO2023014006, WO2023010121, WO2023009716, WO2023009572, WO2023004102, WO2023003417, WO2023001141, WO2023001123, WO2022271923, WO2022271823, WO2022271810, WO2022271658, WO2022269508, WO2022266167, WO2022266069, WO2022266015, WO2022265974, WO2022261154, WO2022261154, WO2022251576, WO2022251296, WO2022237815, WO2022232332, WO2022232331, WO2022232320, WO2022232318, WO2022223037, WO2022221739, WO2022221528, WO2022221386, WO2022216762, WO2022192794, WO2022192790, WO2022188729, WO2022187411, WO2022184178, WO2022173870, WO2022173678, WO2022135346, WO2022133731, WO2022133038, WO2022133345, WO2022132200, WO2022119748, WO2022109485, WO2022109487, WO2022098625, WO2022095960, WO2022093856, WO2022089219, WO2022087624, WO2022087375, WO2022087371, WO2022083616, WO2022083569, WO2022081655, WO2022076917, WO2022072783, WO2022066805, WO2022066646WO2022063297, WO2022061251, WO2022056307, WO2022052895, WO2022048545, WO2022047093, WO2022042630, WO2022040469, WO2022037631, WO2022037560, WO2022031678, WO2022028492, WO2022028346, WO2022026726, WO2022026723, WO2022015375, WO2022002102, WO2022002018, WO2021259331, WO2021257828, WO2021252339, WO2021248095, WO2021248090, WO2021248083, WO2021248082, WO2021248079, WO2021248055, WO2021245051, WO2021244603, WO2021239058, WO2021231526, WO2021228161, WO2021219090, WO2021219090, WO2021219072, WO2021218939, WO2021217019, WO2021216770, WO2021215545, WO2021215544, WO2021211864, WO2021190467, WO2021185233, WO2021180181, WO2021175199, WO2021173923, WO2021169990, WO2021169963, WO2021168193, WO2021158071, WO2021155716, WO2021152149, WO2021150613, WO2021147967, WO2021147965, WO2021143693, WO2021142252, WO2021141628, WO2021139748, WO2021139678, WO2021129824, WO2021129820, WO2021127404, WO2021126816, WO2021126799, WO2021124222, WO2021121371, WO2021121367, WO2021121330, WO2021088458, WO2021086833, WO2021085653, WO2021084765, WO2021081212, WO2021058018, WO2021057832, WO2021055728,WO2021031952, WO2021027911, WO2021023247, WO2020259513, WO2020259432, WO2020234103, WO2020233592, WO2020216190, WO2020178282, WO2020146613, WO2020118066, WO2020113071, WO2020106647, WO2020102730, WO2020101736, WO2020097537, WO2020086739, WO2020081282, WO2020050890, WO2020047192, WO2020035031, WO2020028706, WO2019241157, WO2019232419, WO2019217691, WO2019217307, WO2019215203, WO2019213526, WO2019213516, WO2019155399, WO2019150305, WO2019110751, WO2019099524, WO2019051291, WO2018218070, WO2018218071, WO2018218069, WO2018217651, WO2018206539, WO2018143315, WO2018140600, WO2018140599, WO2018140598, WO2018140514, WO2018140513, WO2018140512, WO2018119183, WO2018112420, WO2018068017, WO2018064510, WO2017201161, WO2017172979, WO2017100546, WO2017087528, WO2017058807, WO2017058805, WO2017058728, WO2017058902, WO2017058792, WO2017058768, WO2017058915, WO2017015562, WO2016168540, WO2016164675, WO2016049568, WO2016049524, WO2015054572, WO2014152588, WO2014143659, WO2013155223, CN114437084, CN114195788, CN114437107, CN114409653, CN114380827, CN114195804, CN114057776,CN114057744, CN114057743, CN113999226, CN113980032, CN113980014, CN113960193, CN113929676, CN113754653, CN113683616, CN113563323, CN113527299, CN113527294, CN113527293, CN113493440, CN113429405, CN113248521, CN113321654, CN113087700, CN113024544, CN113004269, CN112920183, CN112778284, CN112390818, CN112390788, CN112300196, CN112300194, CN112300173, CN112225734, CN112142735, CN112110918, CN112094269, CN112047937, and CN109574871, or any such RAS(off) inhibitor disclosed in any one of their pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers. As used herein, references to "AMG510" and "MRTX849" refer to the following compounds: [Chemical formula] mean.

[0200] In some embodiments, at least one of the additional therapeutic agents is a RAS(on) inhibitor. In various embodiments, at least one of the additional therapeutic agents is a KRAS(on) inhibitor (e.g., any one or more KRAS(on) inhibitors disclosed herein or known in the art). In some embodiments, at least one of the additional therapeutic agents is RMC-6236 (RAS MULTI (on) inhibitor), RMC-6291 (KRAS G12C (on) inhibitor), RMC-9805 (KRAS G12D (on) inhibitor), RMC-8839 (KRAS G13C (on) inhibitor), RMC-0708 (KRAS Q61H(On) inhibitor), or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, at least one of the additional therapeutic agents is KRAS G12C (On) inhibitor (e.g., any one or more of the KRAS G12C (On) inhibitors disclosed herein or known in the art). In some embodiments, KRAS G12C (On) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0201] As used herein, the term "RAS (on) inhibitor" refers to an inhibitor that targets, i.e., selectively binds to or inhibits, the GTP-bound active state of RAS, e.g., selectively overriding the GDP-bound inactive state of RAS. Inhibition of the GTP-bound active state of RAS includes, for example, inhibition of oncogenic signaling derived from the GTP-bound active state of RAS. In some embodiments, the RAS (on) inhibitor is an inhibitor that selectively binds to and inhibits the GTP-bound active state of RAS. In some embodiments, the RAS (on) inhibitor may also bind to or inhibit the GDP-bound inactive state of RAS (e.g., with lower affinity or a smaller inhibition constant than the GTP-bound active state of RAS). In some embodiments, the molecular weight of the RAS (on) inhibitor is between 800 and 1100 Da, inclusive of the endpoints. The term "KRAS (on) inhibitor" refers to any inhibitor that binds to KRAS at its GDP-bound "on" position. Reference to the term RAS (on) inhibitor includes, without limitation, any one or more RAS (on) inhibitors selected from the RAS (on) inhibitors disclosed in PCT / US2023 / 060288, 2023060253, WO2022235870, WO2022235864, WO2022060836, WO2021257736, WO2021091982, WO2021091967, or WO2021091956, or pharmaceutically acceptable salts, solvates, isomers (e.g., stereoisomers), prodrugs, or tautomers thereof, or any combination of such RAS (on) inhibitors.

[0202] Indication The present disclosure provides a method of treating an mTOR-mediated disease or disorder in a subject in need thereof. The present disclosure also provides a method of preventing an mTOR-mediated disease or disorder in a subject in need thereof. The present disclosure also provides a method of reducing the risk of an mTOR-mediated disease or disorder in a subject in need thereof.

[0203] In some embodiments, the disease is cancer or an immune-mediated disease. In some embodiments, the cancer is selected from gliovascular tumors, head and neck cancer, breast cancer, lung cancer, mesothelioma, lymphocyte cancer, stomach cancer, kidney cancer, renal carcinoma, liver cancer, ovarian cancer, ovarian endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, nerve cancer, spleen cancer, pancreatic cancer, proliferative blood disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulvar cancer, prostate cancer, penile cancer, bone cancer, muscle cancer, soft tissue cancer, intestinal cancer or rectal cancer, anal cancer, bladder cancer, bile duct cancer, eye cancer, gastrointestinal mesenchymal tumors, and neuroendocrine tumors. In some embodiments, the disorder is cirrhosis. In some embodiments, the immune-mediated disease is resistance to transplantation by the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limbs, muscle, nerve, duodenum, small intestine, or pancreatic islet cells; graft-versus-host disease caused by bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis. In certain embodiments, the disease is tuberous sclerosis (TSC). In certain embodiments, the disease is pancreatic neuroendocrine tumor (PNET), mantle cell lymphoma (MCL), colorectal cancer or colon cancer (CRC), uterine cancer, ovarian cancer, bladder cancer, urothelial cancer, or renal cell carcinoma (RCC).

[0204] In some embodiments, the cancer is selected from a cerebrovascular tumor, head and neck cancer, breast cancer, lung cancer, mesothelioma, lymphocyte cancer, stomach cancer, kidney cancer, renal carcinoma, liver cancer, ovarian cancer, ovarian endometriosis, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, nerve cancer, spleen cancer, pancreatic cancer, proliferative blood disorders, lymphoma, leukemia, endometrial cancer, cervical cancer, vulvar cancer, prostate cancer, penile cancer, bone cancer, muscle cancer, soft tissue cancer, intestinal cancer or rectal cancer, anal cancer, bladder cancer, bile duct cancer, eye cancer, gastrointestinal mesenchymal tumor, and neuroendocrine tumor. In some embodiments, the disorder is cirrhosis. In certain embodiments, the disease is tuberous sclerosis (TSC). In certain embodiments, the disease is pancreatic neuroendocrine tumor (PNET), mantle cell lymphoma (MCL), colorectal cancer or colon cancer (CRC), uterine cancer, ovarian cancer, bladder cancer, urogenital cancer, or renal cell carcinoma (RCC).

[0205] In some embodiments, the cancer includes solid cancers and lymphocyte cancers, kidney cancer, breast cancer, lung cancer, bladder cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, stomach cancer, brain cancer, head and neck cancer, skin cancer, uterine cancer, testicular cancer, glioblastoma, esophageal cancer, and liver cancer including hepatocellular carcinoma, acute lymphoblastic B cell lymphoma, non-Hodgkin lymphoma (e.g., Burkitt lymphoma, small cell lymphoma, and large cell lymphoma), lymphoma including Hodgkin lymphoma, leukemia (including AML, ALL, and CML), or multiple myeloma, including human cancers and carcinomas, human sarcomas, human adenocarcinomas, human lymphomas, human leukemias, etc. In certain embodiments, the disease is multiple myeloma. In certain embodiments, the disease is breast cancer. In certain embodiments, the disease is triple negative breast cancer.

[0206] In some embodiments, the cancer includes cancers, neoplasms, or malignancies found in mammals (e.g., humans), including leukemia, carcinomas, and sarcomas. Exemplary cancers treated by the compounds or methods provided herein include prostate cancer, thyroid cancer, endocrine cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, medulloblastoma, colorectal cancer, pancreatic cancer. Further examples can include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, Waldenström's macroglobulinemia, primary brain tumors, malignant insulinoma tumors, malignant carcinoids, bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urothelial cancer, hypercalcemia of malignancy, endometrial cancer, adrenocortical cancer, pancreatic endocrine or exocrine tumors, medullary thyroid cancer, medullary carcinoma of the thyroid, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.

[0207] In some embodiments, the disease is leukemia. The term "leukemia" broadly refers to a progressive malignant disease of the hematopoietic organs, and is generally characterized by abnormal proliferation and development of white blood cells and their progenitor cells in the blood and bone marrow. Leukemia is generally clinically classified based on (1) the duration and characteristics of the disease (acute or chronic disease); (2) the type of cells involved: myeloid (myelogenous) cells, lymphoid (lymphogenous) lymphocytes, or monocytes; and (3) the presence or absence of an increase in the number of abnormal cells in the blood (leukemic or non-leukemic (sub-leukemic)). Exemplary leukemias treated by the compounds or methods provided herein include, for example, acute non-leukemic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, fetal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia (hemocytoblastic leukemia), histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia (lymphogenous leukemia, lymphoid leukemia), lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, microgranuloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli-type leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, leader cell leukemia, Schilling leukemia, stem cell leukemia, sub-leukemic leukemia, or undifferentiated cell leukemia.

[0208] In some embodiments, the disease is melanoma. The term "melanoma" is understood to mean a tumor arising from the melanocyte lineage of the skin and other organs. Melanomas treated by the compounds or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, malignant lentigo melanoma, malignant melanoma, nodular melanoma, subungual melanoma, or superficial spreading melanoma.

[0209] In some embodiments, the immune-mediated disease is resistance to transplantation of the heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerve, duodenum, small intestine, or pancreatic islet cells; graft-versus-host disease caused by bone marrow transplantation; rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis.

[0210] In some embodiments, the disease is an autoimmune disease. As used herein, the term "autoimmune disease" refers to a disease or condition in which the subject's immune system exhibits an abnormal immune response against substances that normally do not induce an immune response in a healthy subject. Examples of autoimmune diseases treated by the compounds, pharmaceutical compositions, or methods described herein include acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic neuropathy, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Barlow disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid / benign mucous membrane pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture syndrome, granulomatosis with polyangiitis (GPA) (formerly known as Wegener's granulomatosis), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schönlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing diseases, immunoregulatory lipoprotein autoimmune disease, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes (type 1 diabetes), Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus,Sclerosing lichen, ligneous conjunctivitis, linear IgA disease (LAD), lupus (SLE), Lyme disease, chronic Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren ulcer, Mucosa - Barbera disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic's disease), neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry - Romberg syndrome, Personeage - Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivascular encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, type I polyglandular autoimmune syndrome, type II polyglandular autoimmune syndrome, and type III polyglandular autoimmune syndrome, rheumatoid polymyalgia, polymyositis, post - myocardial infarction syndrome, post - pericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, erythroleukemia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, episcleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff person syndrome, subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia, Takayasu arteritis, transient arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura (TTP), Tolosa - Hunt syndrome, transverse myelitis, type 1 diabetes, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vesiculobullous skin disease, vitiligo, or Wegener's granulomatosis (i.e., granulomatosis with polyangiitis (GPA)).

[0211] In some embodiments, the disclosed compositions or compounds can be used against immunosenescence. Immunosenescence may refer to, for example, a decline in immune function that results in, among other things, a depletion of the immune response to cancer, vaccination, and infectious agents. Immunosenescence is involved in both the host's ability to respond to infections and, in particular, the development of long-term immune memory by vaccination. This immunodeficiency is ubiquitous and is found as a function of the age of those species, compared to their life expectancy rather than chronological age, in both long-lived and short-lived species. Immunosenescence is thought to be a major contributing factor to the increased frequency of morbidity and mortality in the elderly. Immunosenescence is thought to repeat the evolutionary pattern in reverse, rather than being a random degradation phenomenon. Most of the parameters affected by immunosenescence are thought to be under genetic control. Immunosenescence is also sometimes thought to be the result of continuous induction of unavoidable exposure to various antigens such as viruses and bacteria. Immunosenescence is, for example, a multifactorial condition that causes many pathologically significant health problems in the elderly population. Age-dependent biological changes such as depletion of hematopoietic stem cells, increase in PD1+ lymphocytes, decrease in the total number of phagocytes and NK cells, and decline in humoral immunity contribute to the occurrence of immunosenescence. In one aspect, immunosenescence is measured in an individual by measuring the telomere length in immune cells (see, for example, U.S. Patent No. 5,741,677). Immunosenescence is also determined in an individual who is a subject 65 years of age or older by, for example, a number of naive CD4 and / or CD8 T cells less than a normal constant, a T cell repertoire, a number of PD1-expressing T cells, such as PD-1 negative T cells less than a normal constant, or by recording the response to vaccination. In certain embodiments, selective modulation of certain T cell populations by mTOR can improve vaccine efficacy and enhance the effectiveness of cancer immunotherapy in the aging population. The present disclosure provides a method of treating immunosenescence, the method comprising administering to a subject a therapeutically effective amount of one or more of the disclosed compositions or compounds.

[0212] In some embodiments, the disease is organ or tissue transplant rejection (e.g., transplantation of the heart, lung, liver, kidney, pancreas, skin, or cornea; graft-versus-host disease), restenosis, hamartoma syndromes (e.g., tuberous sclerosis or Cowden disease), lymphangioleiomyomatosis, retinitis pigmentosa, encephalomyelitis, insulin-dependent diabetes, lupus, dermatomyositis, arthritis, rheumatic diseases, steroid-resistant acute lymphoblastic leukemia, fibrosis, scleroderma, pulmonary fibrosis, renal fibrosis, cystic fibrosis, pulmonary hypertension, multiple sclerosis, VHL syndrome, Carney complex, familial adenomatous polyposis, juvenile polyposis syndrome, Birt-Hogg-Dubé syndrome, familial hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia caused by tau mutations, spinocerebellar ataxia type 3, motor neuron disease caused by SOD1 mutations, neuronal ceroid lipofuscinosis / Batten disease (pediatric neurodegenerative disease), wet age-related macular degeneration, dry age-related macular degeneration, muscle atrophy (atrophy, cachexia), myopathy (e.g., Danon disease), bacterial infection, viral infection, mycobacterial infection, group A streptococcal infection, type I HSV infection, HIV infection, neurofibromatosis (e.g., neurofibromatosis type 1), or Peutz-Jeghers syndrome.

[0213] In some embodiments, the disease is a neurodegenerative disease. As used herein, the term "neurodegenerative disease" refers to a disease or condition in which the function of the subject's nervous system is impaired. Examples of neurodegenerative diseases treatable by the compounds, pharmaceutical compositions, or methods described herein include Alexander disease, Alpers disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjögren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, kuru, Lewy body dementia, Machado-Joseph disease (spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion disease, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (multiple types with various features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, or tabes dorsalis.

[0214] In some embodiments, the disease is a metabolic disease. As used herein, the term "metabolic disease" refers to a disease or condition in which the subject's metabolism or metabolic system (e.g., the function of conserving or utilizing energy) is impaired. Metabolic diseases treatable by the compounds, pharmaceutical compositions, or methods described herein include diabetes (e.g., type I diabetes or type II diabetes), obesity, metabolic syndrome, or mitochondrial disease (e.g., mitochondrial dysfunction or abnormal mitochondrial function).

[0215] In some embodiments, the disease is an inflammatory disease. As used herein, the term "inflammatory disease" refers to a disease or condition characterized by an abnormal inflammation (e.g., an elevated level of inflammation compared to a control such as a healthy subject without the disease). Examples of inflammatory diseases include traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0216] In some embodiments, the disease is a cardiovascular disease. As used herein, the term "cardiovascular disease" refers to a disease or condition in which the function of the subject's cardiovascular system is impaired. Examples of cardiovascular diseases treated by the compounds, pharmaceutical compositions, or methods described herein include congestive heart failure; proarrhythmic syndromes (e.g., paroxysmal tachycardia, delayed afterdepolarization, ventricular tachycardia, supraventricular tachycardia, exercise-induced arrhythmia, QT prolongation syndrome, or bidirectional tachycardia); thromboembolic disorders (e.g., arterial cardiovascular thromboembolic disorder, venous cardiovascular thromboembolic disorder, or intracardiac thromboembolic disorder); atherosclerosis; restenosis; peripheral arterial disease; coronary artery bypass graft; carotid artery disease; arteritis; myocarditis; cardiovascular inflammation; vascular inflammation; coronary heart disease (CHD); unstable angina (UA); unstable refractory angina; stable angina (SA); chronic stable angina; acute coronary syndrome (ACS); myocardial infarction (primary or recurrent); acute myocardial infarction (AMI); myocardial infarction; non-Q wave myocardial infarction; non-STE myocardial infarction; coronary artery disease; ischemic heart disease; myocardial ischemia; ischemia; ischemic sudden death; transient ischemic attack; stroke; peripheral occlusive arterial disease; venous thrombosis; deep vein thrombosis; thrombophlebitis; arterial embolism; coronary artery thrombosis; cerebral artery thrombosis, cerebral embolism; renal embolism; pulmonary embolism; thrombosis (e.g., thrombosis associated with artificial valves or other implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis); thrombosis (e.g., thrombosis associated with atherosclerosis, surgery, prolonged immobilization, atrial fibrillation, congenital thrombotic predisposition, cancer, diabetes, hormones, or pregnancy); or arrhythmia (e.g., supraventricular arrhythmia, atrial arrhythmia, atrial flutter, or atrial fibrillation).

[0217] The present disclosure also provides a method of treating an age-related condition, the method comprising administering to a subject in need thereof. In certain embodiments, the age-related condition is selected from sarcopenia, skin atrophy, muscle atrophy, brain atrophy, atherosclerosis, arteriosclerosis, emphysema, osteoporosis, osteoarthritis, hypertension, erectile dysfunction, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, shortening of life expectancy, kidney dysfunction, and age-related hearing loss, age-related physical movement disorders (e.g., frailty), cognitive decline, age-related dementia, memory impairment, tendon rigidity, heart failure such as cardiac hypertrophy and systolic and diastolic dysfunction, immunosenescence, cancer, obesity, and diabetes.

[0218] In particular, various embodiments of the present disclosure involve methods, uses, and medicaments directed to the treatment of the following cancers.

[0219] In some embodiments, the cancer is a bulging cancer, appendiceal cancer, bile duct cancer, bladder cancer, proliferative blood disorder, bone cancer, cranial nerve angio-neuro tumor, breast cancer, cancer of unknown primary origin, cervical cancer, colorectal cancer, endometrial cancer, gastroesophageal cancer, gastrointestinal cancer, germ cell cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, mesothelioma, nerve-derived cancer, neuroendocrine tumor, eye cancer, ovarian cancer, ovarian endometriosis, pancreatic cancer, peritoneal cancer, penile cancer, prostate cancer, rhabdomyosarcoma, sarcoma, sex cord stromal tumor, skin cancer, soft tissue cancer, testicular cancer, uterine cancer, and vulvar cancer. In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, blood cancer, liver cancer, lung cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, kidney cancer, and rhabdomyosarcoma. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is triple-negative breast cancer.

[0220] In some embodiments, the cancer is a head and neck cancer. In some embodiments, the head and neck cancer is a head and neck squamous cell carcinoma, a salivary gland cancer, or a thyroid cancer. In some embodiments, the thyroid cancer is a thyroid carcinoma. In some embodiments, the head and neck cancer is a salivary gland cancer. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is surprisingly effective in the treatment of salivary gland cancer, with one subject showing a 63% reduction in tumor size.

[0221] In some embodiments, the cancer is a blood cancer. In some embodiments, the blood cancer is a leukemia, a lymphoma, a myeloproliferative disorder, a multiple myeloma, or a myelodysplastic syndrome. In some embodiments, the leukemia is an acute myeloid leukemia (AML), an acute lymphoblastic leukemia (ALL), or a chronic myeloid leukemia (CML). In some embodiments, the lymphoma is a mantle cell lymphoma (MCL), an acute lymphoblastic B cell lymphoma, a non-Hodgkin lymphoma (e.g., Burkitt lymphoma, small cell lymphoma, and large cell lymphoma), or a Hodgkin lymphoma.

[0222] In some embodiments, the cancer is a gastrointestinal cancer. In some embodiments, the gastrointestinal cancer is a GI neuroendocrine cancer, a gastrointestinal mesenchymal tumor, a gastric cancer, an anal cancer, a rectal cancer, a colorectal cancer (CRC), a colon cancer, or a small intestine cancer. In some embodiments, the gastrointestinal cancer is a colorectal cancer.

[0223] In some embodiments, the cancer is a renal cancer. In some embodiments, the renal cancer is a renal cell carcinoma (RCC).

[0224] In some embodiments, the cancer is a liver cancer. In some embodiments, the liver cancer is a hepatobiliary cancer, a hepatocellular carcinoma, a cholangiocarcinoma, a hepatoblastoma, an angiosarcoma, a hepatocellular adenoma, or a hemangioma. In some embodiments, the liver cancer is a hepatocellular carcinoma. In some embodiments, the liver cancer is a hepatoblastoma.

[0225] In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the lung cancer is squamous cell lung cancer.

[0226] In some embodiments, the cancer is ovarian cancer.

[0227] In some embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic neuroendocrine tumor (PNET).

[0228] In some embodiments, the cancer is prostate cancer.

[0229] In some embodiments, the cancer is skin cancer. In some embodiments, the skin cancer is melanoma. In some embodiments, the skin cancer is basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, or psoriasis.

[0230] In some embodiments, the cancer is uterine cancer.

[0231] In some embodiments, the cancer is sarcoma. The term "sarcoma" generally refers to a tumor composed of embryonal connective tissue-like substances and generally composed of tightly packed cells embedded in fibrous or homogeneous substances. Sarcomas treated by the compounds or methods provided herein include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanoma, myxosarcoma, osteosarcoma, ameloblastic fibrosarcoma, alveolar soft part sarcoma, enamel epithelial fibrosarcoma, cystosarcoma phyllodes, chloroma sarcoma, choriocarcinoma sarcoma, fetal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystadenosarcoma, synovial sarcoma, or angiectatic sarcoma.

[0232] In some embodiments, the cancer is a carcinoma. The term "carcinoma" refers to a new malignant growth composed of epithelial cells that tend to invade surrounding tissues and cause metastasis. Exemplary carcinomas treated by the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, adenocystic carcinoma, carcinoma in adenoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid carcinoma, basal cell squamous cell carcinoma, bronchioloalveolar carcinoma, bronchial carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocarcinoma, cholangiocellular carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, encrusted carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, hard carcinoma, fetal carcinoma, encephaloid carcinoma, epidermoid carcinoma, adenoid epithelioma, exophytic carcinoma, ulcerating carcinoma, fibrous carcinoma, gelatiniform mucinous carcinoma, giant cell carcinoma, adenocarcinoma, granular cell carcinoma, trichoblastoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, kidney-like carcinoma, infantile fetal carcinoma, intraepithelial carcinoma, intraepidermal carcinoma, intramucosal carcinoma, chromophobe carcinoma, Kultschitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous cell carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, mucosum carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, spinous cell carcinoma, pasty carcinoma, renal cell carcinoma, reserve cell carcinoma, sarcomatous carcinoma, Schnyder carcinoma, Skill's carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spherical cell carcinoma, spindle cell carcinoma, spongy carcinoma, squamousincluding carcinoma, squamous cell carcinoma, constricting carcinoma, angiogenic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, tuberosum carcinoma (carcinoma tuberosum, tuberous carcinoma), verrucous carcinoma, or choriocarcinoma.

[0233] In some embodiments, the cancer is a solid tumor.

[0234] In some embodiments, the cancer is characterized by a genotype abnormality that activates the mammalian target of rapamycin (mTOR) pathway. In some embodiments, the cancer includes a mutation within the mTOR pathway.

[0235] In some embodiments, the genotype abnormality or mutation is a genotype abnormality or mutation of mTOR, STK11, PIK3CA, PTEN, KEAP1, TSC1, or TSC2, or a combination thereof.

[0236] In some embodiments, the genotype abnormality or mutation is a genotype abnormality or mutation of PTEN. In some embodiments, the PTEN mutation is a dominant negative mutation. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating cancers with PTEN mutations, with 1 subject presenting a partial response (PR) and 2 subjects presenting a stable (SD) response.

[0237] In some embodiments, the gastric abnormality is a mutation of PIK3CA. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating cancers with PIK3CA mutations, with 3 subjects presenting a stable (SD) response.

[0238] In some embodiments, the gastric abnormality is a mutation of TSC2. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating cancers with TSC2 mutations, with 2 subjects presenting a stable (SD) response.

[0239] In some embodiments, the cancer comprises a KRAS G12C mutation. In some embodiments, the cancer comprises a co-occurrence of a KRAS G12C mutation and a STK11 mutation. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating cancers with mutations in STK11 and KRAS G12C mutations, and one subject exhibited a stable (SD) response. In some embodiments, the cancer comprises a KRAS G12C mutation and a co-occurrence of a PIK3CA E545K mutation.

[0240] In some embodiments, the cancer is characterized by an increase in mTORC1 activity. In some embodiments, the cancer is characterized by a decrease in 4EBP1 activity.

[0241] In some embodiments, the cancer comprises a mutation in the Myc family. In some embodiments, the cancer comprises an amplification of MYC, MYCL, MYCN, or combinations thereof, and / or a dependency on MYC, MYCL, MYCN, or combinations thereof. In some embodiments, the cancer comprises an amplification of MYC. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating cancers with an amplification of MYC, and one subject exhibited a stable (SD) response.

[0242] In some embodiments, the cancer comprises a mutation in NFE2L2 (also known as NRF2). As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating cancers with a mutation in NFE2L2, and one subject exhibited a stable (SD) response.

[0243] In some embodiments, the cancer comprises a BRAF fusion. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating cancers with a BRAF fusion, and one subject exhibited a stable (SD) response.

[0244] In some embodiments, the cancer is colorectal cancer and includes a mutation in PIK3CA. In some embodiments, the cancer is colorectal cancer and includes an amplification of MYC. In some embodiments, the cancer is colorectal cancer and includes a mutation in PIK3CA and an amplification of MYC. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating colorectal cancer including a mutation in PIK3CA and an amplification of MYC, and one subject exhibited a stable (SD) response.

[0245] In some embodiments, the cancer is head and neck cancer and includes a mutation in PIK3CA. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating head and neck cancer including a mutation in PIK3CA, and one subject exhibited a stable (SD) response. In some embodiments, the cancer is head and neck cancer and includes a mutation in PTEN. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating head and neck cancer including a mutation in PTEN, and one subject exhibited a partial response (PR). In some embodiments, the cancer is head and neck cancer and includes a mutation in PIK3CA and a mutation in PTEN.

[0246] In some embodiments, the cancer is liver cancer and includes a mutation in NFE2L2. In some embodiments, the cancer is hepatocellular carcinoma and includes a mutation in NFE2L2. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating hepatocellular carcinoma including a mutation in NFE2L2, and one subject exhibited a stable (SD) response.

[0247] In some embodiments, the cancer is ovarian cancer and includes a mutation in TSC2. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating ovarian cancer including a mutation in TSC2, and one subject exhibited a stable (SD) response.

[0248] In some embodiments, the cancer is pancreatic cancer and includes a mutation in STK11. In some embodiments, the cancer is pancreatic cancer and includes a KRAS G12C mutation. In some embodiments, the cancer is pancreatic cancer and includes a mutation in STK11 and a KRAS G12C mutation. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating pancreatic cancer that includes a mutation in STK11 and a KRAS G12C mutation, and one subject exhibited a stable (SD) response.

[0249] In some embodiments, the cancer is prostate cancer and includes a mutation in PTEN. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating prostate cancer that includes a mutation in PTEN, and one subject exhibited a stable (SD) response.

[0250] In some embodiments, the cancer is uterine cancer and includes a mutation in PIK3CA. In some embodiments, the cancer is uterine cancer and includes a mutation in PTEN. In some embodiments, the cancer is uterine cancer and includes a mutation in PIK3CA and a mutation in PTEN. In some embodiments, the cancer is uterine cancer and includes a mutation in TSC2. In some embodiments, the cancer is uterine cancer and includes a mutation in PIK3CA and a mutation in TSC2. In some embodiments, the cancer is uterine cancer and includes a mutation in PIK3CA, a mutation in PTEN, and a mutation in TSC2. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating uterine cancer that includes a mutation in PIK3CA, a mutation in PTEN, and a mutation in TSC2, and one subject exhibited a stable (SD) response.

[0251] In some embodiments, the cancer is lung cancer and includes a BRAF fusion. As described herein, the dosage of RMC-5552, an mTOR dual inhibitor, is effective in treating lung cancer, including a BRAF fusion, and one subject exhibited a stable (SD) response.

[0252] In some embodiments, the cancer includes a RAS mutation. In some embodiments, the cancer is colorectal cancer, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, appendiceal cancer, melanoma, acute myeloid leukemia, small intestine cancer, gastric cancer, germ cell cancer, cervical cancer, cancer of unknown primary, endometrial cancer, gastroesophageal cancer, GI neuroendocrine cancer, ovarian cancer, sex cord-stromal tumor cancer, hepatobiliary cancer, or bladder cancer.

[0253] In some embodiments, the cancer comprises clonality of pathogenic variants exceeding about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% in PIK3CA, PTEN, TSC1, or TSC2. In some embodiments, the cancer comprises clonality of pathogenic variants exceeding about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% in PTEN. In some embodiments, the cancer comprises clonality of pathogenic variants exceeding about 90% in PTEN. In some embodiments, the cancer comprises clonality of pathogenic variants exceeding about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% in TSC1. In some embodiments, the cancer comprises clonality of pathogenic variants exceeding about 90% in TSC1. In some embodiments, the cancer comprises clonality of pathogenic variants exceeding about 90% in PTEN. In some embodiments, the cancer comprises clonality of pathogenic variants exceeding about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% in TSC2. In some embodiments, the cancer comprises clonality of pathogenic variants exceeding about 90% in TSC2. In some embodiments, the cancer comprises clonality of pathogenic variants exceeding about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99% in PIK3CA. In some embodiments, the cancer comprises clonality of pathogenic variants exceeding about 90% in PIK3CA.

[0254] In some embodiments, the method results in tumor regression. In some embodiments, the method results in tumor apoptosis.

[0255] Prevention or treatment of acquired resistance to RAS inhibitors In some embodiments, the method comprises delaying, preventing, or treating acquired resistance (e.g., to a KRAS G12C inhibitor) to a RAS inhibitor by administering the RAS inhibitor (e.g., a KRAS G12C inhibitor) in combination with an mTOR inhibitor (e.g., an mTOR dual inhibitor, such as RMC-5552). In some embodiments, the present disclosure includes a method for inducing apoptosis in a cell (e.g., a tumor cell) by contacting the cell with a RAS inhibitor (e.g., a KRAS G12C (off) inhibitor such as a KRAS inhibitor) in combination with an mTOR inhibitor (e.g., an mTOR dual inhibitor, such as RMC-5552). In some embodiments, the present disclosure includes a method for inducing apoptosis in a cell (e.g., a tumor cell) by contacting the cell with a RAS inhibitor (e.g., a RAS G12C (on) inhibitor such as a RAS (on) inhibitor) in combination with an mTOR inhibitor (e.g., an mTOR dual inhibitor, such as RMC-5552).

[0256] As used herein, the term "preventing acquired resistance" means avoiding the development of acquired or adaptive resistance. Thus, for example, the use of an mTOR inhibitor (e.g., an mTOR dual inhibitor, such as RMC-5552) described herein in preventing acquired / adaptive resistance to a KRAS G12C inhibitor means that the mTOR inhibitor (e.g., an mTOR dual inhibitor, such as RMC-5552) is administered prior to any detectable presence of resistance to the KRAS G12C inhibitor, and the result of such administration of the mTOR inhibitor (e.g., an mTOR dual inhibitor, such as RMC-5552) is that resistance to the KRAS G12C inhibitor does not occur.

[0257] The present disclosure is a method for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject from about 3 mg of an mTOR dual inhibitor per week to about 25 mg of an mTOR dual inhibitor per week, wherein the subject has already been administered, or is to be administered, a RAS inhibitor;

[0258] The mTOR dual inhibitor is

Chemical formula

[0259] The present disclosure is a method for treating acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject from about 3 mg of an mTOR dual inhibitor per week to about 25 mg of an mTOR dual inhibitor per week;

[0260] The mTOR dual inhibitor is

Chemical formula

[0261] In some embodiments, a method for delaying, preventing, or treating acquired resistance to a RAS inhibitor comprises administering to the subject an effective amount of a RAS inhibitor. The RAS inhibitors are described in more detail in the "Combinations" section of the present disclosure, and all such RAS inhibitors are contemplated in the context of a method for delaying, preventing, or treating acquired resistance to a RAS inhibitor.

[0262] In some embodiments, the RAS inhibitor targets specific RAS mutations. In some embodiments, the RAS inhibitor targets KRAS mutations. In some embodiments, the RAS inhibitor targets KRAS G12C mutations.

[0263] In some embodiments, the RAS inhibitor is a KRAS(off) inhibitor. In some embodiments, the KRAS(off) inhibitor is AMG510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255, or a pharmaceutically acceptable salt of any of the foregoing.

[0264] In some embodiments, the RAS inhibitor is a RAS(on) inhibitor. In some embodiments, the RAS(on) inhibitor is a KRAS(on) inhibitor. In some embodiments, the KRAS(on) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, RMC-0708, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the KRAS(on) inhibitor is KRAS G12C (on) inhibitor. In some embodiments, KRAS G12C (on) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, a subject is administered a RAS inhibitor to treat or prevent cancer. In some embodiments, the cancer comprises a KRAS G12C mutation. In some embodiments, the cancer comprises the co-occurrence of a KRAS G12C mutation and a STK11 mutation. In some embodiments, the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer. In some embodiments, the cancer comprises the co-occurrence of a KRAS G12C mutation and a PIK3CA E545K mutation. In some embodiments, the cancer is colorectal cancer.

[0266] In some embodiments, the method results in tumor regression. In some embodiments, the method results in tumor apoptosis.

[0267] Exemplary embodiments Embodiment I-1: A method of treating a subject having cancer, comprising administering to the subject an mTOR dual inhibitor at a dosage of from about 3 mg per week to about 25 mg per week;

[0268] The mTOR dual inhibitor is

Chemical formula

[0269] Embodiment I-2: A method of treating a subject having salivary gland cancer, comprising administering to the subject an mTOR dual inhibitor at a dosage of from about 3 mg per week to about 25 mg per week;

[0270] The mTOR dual inhibitor is

Chemical formula

[0271] Embodiment I-3: The method according to Embodiment I-1 or I-2, wherein the dosage is from about 4 mg per week to about 12 mg per week, from about 5 mg per week to about 10 mg per week, from about 6 mg per week to about 9 mg per week, from about 6 mg per week to about 8 mg per week, or from about 7 mg per week to about 8 mg per week.

[0272] Embodiment I-4: The dosage is about 4 mg per week, about 4.5 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, or about 10 mg per week, and the method according to any one of Embodiments I-1 to I-3.

[0273] Embodiment I-5: The dosage is administered via IV infusion, and the method according to any one of Embodiments I-1 to I-4.

[0274] Embodiment I-6: The dosage is administered over about 0.5 hours to about 2 hours, over about 0.5 hours to about 1.5 hours, over about 0.5 hours to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours, and the method according to Embodiment I-5.

[0275] Embodiment I-7: The dosage is administered over about 1 hour, and the method according to Embodiment I-5 or I-6.

[0276] Embodiment I-8: The cancer is characterized by a genotype abnormality that activates the mammalian target of rapamycin (mTOR) pathway, and the method according to any one of Embodiments I-1 to I-7.

[0277] Embodiment I-9: The cancer contains a mutation within the mTOR pathway, and the method according to any one of Embodiments I-1 to I-8.

[0278] Embodiment I-10: The genotype abnormality or mutation is a genotype abnormality or mutation of mTOR, STK11, PIK3CA, PTEN, KEAP1, TSC1, or TSC2, or a combination thereof, and the method according to Embodiment I-8 or I-9.

[0279] Embodiment I-11: The method according to any one of Embodiments I-8 to I-10, wherein the genotype abnormality or mutation is a genotype abnormality or mutation of PTEN.

[0280] Embodiment I-12: The method according to Embodiment I-10 or I-11, wherein the PTEN mutation is a dominant negative mutation.

[0281] Embodiment I-13: The method according to any one of Embodiments I-1 to I-12, wherein the cancer is characterized by an increase in mTORC1 activity.

[0282] Embodiment I-14: The method according to any one of Embodiments I-1 to I-13, wherein the cancer is characterized by a decrease in 4EBP1 activity.

[0283] Embodiment I-15: The method according to any one of Embodiments I-1 to I-14, wherein the cancer comprises a mutation of the Myc family.

[0284] Embodiment I-16: The method according to Embodiment I-15, wherein the cancer comprises amplification of MYC, MYCL, MYCN, or a combination thereof, and / or dependence on MYC, MYCL, MYCN, or a combination thereof.

[0285] Embodiment I-17: The method according to any one of Embodiments I-1 to I-16, wherein the cancer comprises a mutation of NFE2L2.

[0286] Embodiment I-18: The method according to any one of Embodiments I-1 to I-17, wherein the cancer comprises a BRAF fusion.

[0287] Embodiment I-19: The method according to Embodiment I-1 or any one of Embodiments I-3 to I-18, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, blood cancer, liver cancer, lung cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, kidney cancer, and rhabdomyosarcoma.

[0288] Embodiment I-20: The method according to any one of Embodiments I-1 or I-3 to I-19, wherein the cancer is a solid tumor.

[0289] Embodiment I-21: The method according to any one of Embodiments I-1 or I-3 to I-20, wherein the cancer is a head and neck cancer.

[0290] Embodiment I-22: The method according to Embodiment I-21, wherein the cancer is a salivary gland cancer.

[0291] Embodiment I-23: The method according to any one of Embodiments I-1 to I-22, wherein the subject is a human.

[0292] Embodiment I-24: The method according to any one of Embodiments I-1 to I-23, further comprising the step of administering a dexamethasone oral rinse to the subject.

[0293] Embodiment I-25: The method according to Embodiment I-24, wherein the dexamethasone oral rinse contains about 0.5 mg of dexamethasone per 5 mL.

[0294] Embodiment I-26: The method according to Embodiment I-24 or I-25, wherein the subject is administered about 2.5 mL of the dexamethasone oral rinse.

[0295] Embodiment I-27: The method according to any one of Embodiments I-24 to I-26, wherein the dexamethasone oral rinse is administered once, twice, three times, or four times daily.

[0296] Embodiment I-28: The method according to any one of Embodiments I-1 to I-27, further comprising the step of administering a tacrolimus oral rinse to the subject.

[0297] Embodiment I-29: The method according to Embodiment I-28, wherein the tacrolimus oral rinse contains about 0.5 mg of tacrolimus per 1 mL.

[0298] Embodiment I-30: The method according to Embodiment I-28 or I-29, wherein the subject is administered with about 2.5 mL of tacrolimus oral rinse solution.

[0299] Embodiment I-31: The method according to any one of Embodiments I-28 to I-30, wherein the tacrolimus oral rinse solution is administered once, twice, three times, or four times a day.

[0300] Embodiment I-32: The method according to any one of Embodiments I-28 to I-31, wherein the tacrolimus oral rinse solution is administered on the day of administration of the mTOR dual inhibitor or immediately before the administration of the mTOR dual inhibitor.

[0301] Embodiment I-33: The method according to any one of Embodiments I-1 to I-23, further comprising the step of administering a combined oral rinse solution to the subject, the combined oral rinse solution comprising dexamethasone and tacrolimus.

[0302] Embodiment I-34: The method according to Embodiment I-33, wherein the combined oral rinse solution contains about 0.5 mg of dexamethasone per 5 mL.

[0303] Embodiment I-35: The method according to Embodiment I-33 or I-34, wherein the combined oral rinse solution contains about 0.5 mg of tacrolimus per 1 mL.

[0304] Embodiment I-36: The method according to any one of Embodiments I-33 to I-35, wherein the subject is administered with about 2.5 mL of the combined oral rinse solution.

[0305] Embodiment I-37: The method according to any one of Embodiments I-33 to I-36, wherein the combined oral rinse solution is administered once, twice, three times, or four times a day.

[0306] Embodiment I-38: The method according to any one of Embodiments I-33 to I-37, wherein the combined oral rinse solution is administered on the day of administration of the mTOR dual inhibitor or immediately before the administration of the mTOR dual inhibitor.

[0307] Embodiment I-39: The method according to any one of Embodiments I-1 to I-38, further comprising ice applied to the oral cavity of the subject.

[0308] Embodiment I-40: The method according to Embodiment I-39, wherein the ice is applied for about 10 minutes before administration of the mTOR dimer inhibitor, applied at the time of administration of the mTOR dimer inhibitor, and applied for about 10 minutes after administration of the mTOR dimer inhibitor.

[0309] Embodiment I-41: The method according to any one of Embodiments I-24 to I-40, wherein the dosage is about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, or about 9 mg per week.

[0310] Embodiment I-42: The method according to any one of Embodiments I-1 to I-41, further comprising the step of administering a RAS inhibitor to the subject.

[0311] Embodiment I-43: The method according to Embodiment I-42, wherein the RAS inhibitor targets a specific RAS mutation.

[0312] Embodiment I-44: The method according to Embodiment I-42 or I-43, wherein the RAS inhibitor targets a KRAS mutation.

[0313] Embodiment I-45: The RAS inhibitor targets a KRAS G12C mutation, and the method according to any one of Embodiments I-42 to I-44.

[0314] Embodiment I-46: The method according to any one of Embodiments I-42 to I-45, wherein the RAS inhibitor is a KRAS(off) inhibitor.

[0315] Embodiment I-47: The method according to Embodiment I-46, wherein the KRAS (off) inhibitor is AMG510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255, or a pharmaceutically acceptable salt of any of the foregoing.

[0316] Embodiment I-48: The method according to any one of Embodiments I-42 to I-45, wherein the RAS inhibitor is a RAS (on) inhibitor.

[0317] Embodiment I-49: The method according to Embodiment I-48, wherein the RAS (on) inhibitor is a KRAS (on) inhibitor.

[0318] Embodiment I-50: The method according to Embodiment I-49, wherein the KRAS (on) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, or a pharmaceutically acceptable salt of any of the foregoing.

[0319] Embodiment I-51: The method according to Embodiment I-49 or I-50, wherein the KRAS (on) inhibitor is a KRAS G12C (on) inhibitor.

[0320] Embodiment I-52: The KRAS G12C (on) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof, according to the method of Embodiment I-51.

[0321] Embodiment I-53: The cancer is a KRAS G12C comprising a mutation, according to the method of any one of Embodiments I-1 to I-52.

[0322] Embodiment I-54: The cancer is a KRAS G12C comprising a co-occurrence of a mutation and a STK11 mutation, according to the method of any one of Embodiments I-1 to I-53.

[0323] Embodiment I-55: The cancer is KRAS G12C mutation and PIK3CA E545K mutation and the method according to any one of Embodiments I-1 to I-54 including co-occurrence thereof.

[0324] Embodiment I-56: The cancer is colorectal cancer, and the method according to any one of Embodiments I-1 to I-20 and I-23 to I-55 including a mutation of PIK3CA, an amplification of MYC, or a mutation of PIK3CA and an amplification of MYC.

[0325] Embodiment I-57: The cancer is head and neck cancer, and the method according to any one of Embodiments I-1 to I-21 and I-23 to I-55 including a mutation of PIK3CA, a mutation of PTEN, or a mutation of PIK3CA and a mutation of PTEN.

[0326] Embodiment I-58: The cancer is hepatocellular carcinoma, and the method according to any one of Embodiments I-1 to I-20 and I-23 to I-55 including a mutation of NFE2L2.

[0327] Embodiment I-59: The cancer is ovarian cancer, and the method according to any one of Embodiments I-1 to I-20 and I-23 to I-55 including a mutation of TSC2.

[0328] Embodiment I-60: The cancer is pancreatic cancer, and the method according to any one of Embodiments I-1 to I-20 and I-23 to I-55 including a mutation of STK11, KRAS G12C mutation, or a mutation of STK11 and KRAS G12C mutation.

[0329] Embodiment I-61: The cancer is prostate cancer, and the method according to any one of Embodiments I-1 to I-20 and I-23 to I-55 including a mutation of PTEN.

[0330] Embodiment I-62: The cancer is uterine cancer, and the method according to any one of Embodiments I-1 to I-20 and I-23 to I-55, which comprises a mutation in PIK3CA, a mutation in PIK3CA, a mutation in TSC2, or a combination thereof.

[0331] Embodiment I-63: The cancer is lung cancer, and the method according to any one of Embodiments I-1 to I-20 and I-23 to I-55, which comprises a BRAF fusion.

[0332] Embodiment I-64: The method according to any one of Embodiments I-1 to I-63, which results in tumor regression.

[0333] Embodiment I-65: The method according to any one of Embodiments I-1 to I-64, which results in tumor apoptosis.

[0334] Embodiment I-66: A method for delaying or preventing the acquisition of resistance to a RAS inhibitor in a subject in need thereof, which comprises administering to the subject from about 3 mg of an mTOR dual inhibitor per week to about 25 mg of an mTOR dual inhibitor per week, wherein the subject has already received or will receive administration of a RAS inhibitor;

[0335] The mTOR dual inhibitor is

Chemical formula

[0336] Embodiment I-67: A method for treating the acquisition of resistance to a RAS inhibitor in a subject in need thereof, which comprises administering to the subject from about 3 mg of an mTOR dual inhibitor per week to about 25 mg of an mTOR dual inhibitor per week;

[0337] The mTOR dual inhibitor is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, method.

[0338] Embodiment I-68: The method according to embodiment I-66 or I-67, further comprising the step of administering to a subject an effective amount of a RAS inhibitor.

[0339] Embodiment I-69: The method according to embodiment I-68, wherein the RAS inhibitor targets a specific RAS mutation.

[0340] Embodiment I-70: The method according to any one of embodiments I-66 to I-69, wherein the RAS inhibitor targets a KRAS mutation.

[0341] Embodiment I-71: The RAS inhibitor targets a KRAS G12C mutation, and the method according to any one of embodiments I-66 to I-70.

[0342] Embodiment I-72: The method according to any one of embodiments I-66 to I-71, wherein the RAS inhibitor is a KRAS(off) inhibitor.

[0343] Embodiment I-73: The method according to embodiment I-72, wherein the KRAS(off) inhibitor is AMG510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255, or a pharmaceutically acceptable salt of any of the foregoing.

[0344] Embodiment I-74: The method according to any one of embodiments I-66 to I-71, wherein the RAS inhibitor is a RAS(on) inhibitor.

[0345] Embodiment I-75: The method according to Embodiment I-74, wherein the RAS (on) inhibitor is a KRAS (on) inhibitor.

[0346] Embodiment I-76: The method according to Embodiment I-75, wherein the KRAS (on) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, or a pharmaceutically acceptable salt of any of the foregoing.

[0347] Embodiment I-77: The method according to Embodiment I-75 or I-76, wherein the KRAS (on) inhibitor is a KRAS G12C (on) inhibitor.

[0348] Embodiment I-78: The method according to Embodiment I-77, wherein the KRAS G12C (on) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0349] Embodiment I-79: The method according to any one of Embodiments I-66 to I-78, wherein a subject is administered an RAS inhibitor to treat or prevent cancer.

[0350] Embodiment I-80: The method according to Embodiment I-79, wherein the cancer comprises a KRAS G12C mutation.

[0351] Embodiment I-81: The method according to Embodiment I-79 or I-80, wherein the cancer comprises a co-occurrence of a KRAS G12C mutation and a STK11 mutation.

[0352] Embodiment I-82: The method according to any one of Embodiments I-79 to I-81, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer.

[0353] Embodiment I-83: The method according to any one of Embodiments I-79 to I-82, wherein the cancer comprises a co-occurrence of a KRAS G12C mutation and a PIK3CA E545K mutation.

[0354] Embodiment I-84: The method according to any one of Embodiments I-79 to I-81 and I-83, wherein the cancer is colorectal cancer.

[0355] Embodiment I-85: The method according to any one of Embodiments I-66 to I-84, which results in tumor regression.

[0356] Embodiment I-86: The method according to any one of Embodiments I-66 to I-84, which results in tumor apoptosis.

[0357] Embodiment I-87: Use of an mTOR dual inhibitor in the treatment of cancer, the treatment comprising administering to a subject in need thereof an mTOR dual inhibitor in a dosage of from about 3 mg per week to about 25 mg per week;

[0358] The mTOR dual inhibitor is

Chemical formula

[0359] Embodiment I-88: Use of an mTOR dual inhibitor in the manufacture of a medicament for the treatment of cancer, the treatment comprising administering the medicament to a subject in need thereof to deliver an mTOR dual inhibitor in a dosage of from about 3 mg per week to about 25 mg per week;

[0360] The mTOR dual inhibitor is

Chemical formula

[0361] Embodiment I-89: An mTOR dual inhibitor for use in a method of treating cancer, the method comprising administering to a subject in need thereof an mTOR dual inhibitor at a dosage of from about 3 mg per week to about 25 mg per week;

[0362] The mTOR dual inhibitor is

Chemical formula

[0363] Embodiment I-90: A medicament for treating cancer, comprising an mTOR dual inhibitor, the treatment comprising administering the medicament to deliver to a subject in need thereof an mTOR dual inhibitor at a dosage of from about 3 mg per week to about 25 mg per week;

[0364] The mTOR dual inhibitor is

Chemical formula

[0365] Embodiment I-91: The dosage is from about 4 mg per week to about 12 mg per week, from about 5 mg per week to about 10 mg per week, from about 6 mg per week to about 9 mg per week, from about 6 mg per week to about 8 mg per week, or from about 7 mg per week to about 8 mg per week, the use, the mTOR dual inhibitor for use, or the medicament for treatment according to any one of Embodiments I-87 to I-90.

[0366] Embodiment I-92: The dosage is about 4 mg per week, about 4.5 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, or about 10 mg per week, the use according to any one of Embodiments I-87 to I-91, the mTOR dual inhibitor for use, or the medicament for treatment.

[0367] Embodiment I-93: The dosage is administered via IV infusion, the use according to any one of Embodiments I-87 to I-92, the mTOR dual inhibitor for use, or the medicament for treatment.

[0368] Embodiment I-94: The dosage is administered over about 0.5 hour to about 2 hours, over about 0.5 hour to about 1.5 hours, over about 0.5 hour to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours, the use according to Embodiment I-93, the mTOR dual inhibitor for use, or the medicament for treatment.

[0369] Embodiment I-95: The dosage is administered over about 1 hour, the use according to Embodiment I-93 or I-94, the mTOR dual inhibitor for use, or the medicament for treatment.

[0370] Embodiment I-96: The cancer is characterized by a genotype abnormality that activates the mammalian target of rapamycin (mTOR) pathway, the use according to any one of Embodiments I-87 to I-95, the mTOR dual inhibitor for use, or the medicament for treatment.

[0371] Embodiment I-97: The cancer contains a mutation within the mTOR pathway, the use according to any one of Embodiments I-87 to I-96, the mTOR dual inhibitor for use, or the medicament for treatment.

[0372] Embodiment I-98: The genotype abnormality or mutation is a genotype abnormality or mutation of mTOR, STK11, PIK3CA, PTEN, KEAP1, TSC1, or TSC2, or a combination thereof, the use according to Embodiment I-96 or I-97, an mTOR dual inhibitor for use, or a medicament for treatment.

[0373] Embodiment I-99: The genotype abnormality or mutation is a genotype abnormality or mutation of PTEN, the use according to any one of Embodiments I-96 to I-98, an mTOR dual inhibitor for use, or a medicament for treatment.

[0374] Embodiment I-100: The PTEN mutation is a dominant negative mutation, the use according to Embodiment I-96 or I-99, an mTOR dual inhibitor for use, or a medicament for treatment.

[0375] Embodiment I-101: The cancer is characterized by an increase in mTORC1 activity, the use according to any one of Embodiments I-87 to I-100, an mTOR dual inhibitor for use, or a medicament for treatment.

[0376] Embodiment I-102: The cancer is characterized by a decrease in 4EBP1 activity, the use according to any one of Embodiments I-87 to I-101, an mTOR dual inhibitor for use, or a medicament for treatment.

[0377] Embodiment I-103: The cancer contains a mutation of the Myc family, the use according to any one of Embodiments I-87 to I-102, an mTOR dual inhibitor for use, or a medicament for treatment.

[0378] Embodiment I-104: The cancer includes amplification of MYC, MYCL, MYCN, or a combination thereof, and / or dependence on MYC, MYCL, MYCN, or a combination thereof, the use according to Embodiment I-103, an mTOR dual inhibitor for use, or a medicament for treatment.

[0379] Embodiment I-105: The cancer is the use according to any one of Embodiments I-87 to I-104, an mTOR dual inhibitor for use, or a medicament for treatment, comprising a mutation in NFE2L2.

[0380] Embodiment I-106: The cancer is the use according to any one of Embodiments I-87 to I-105, an mTOR dual inhibitor for use, or a medicament for treatment, comprising a BRAF fusion.

[0381] Embodiment I-107: The cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, blood cancer, liver cancer, lung cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, kidney cancer, and rhabdomyosarcoma, and is the use according to any one of Embodiments I-87 to I-106, an mTOR dual inhibitor for use, or a medicament for treatment.

[0382] Embodiment I-108: The cancer is a solid tumor, and is the use according to any one of Embodiments I-87 to I-107, an mTOR dual inhibitor for use, or a medicament for treatment.

[0383] Embodiment I-109: The cancer is head and neck cancer, and is the use according to any one of Embodiments I-87 to I-108, an mTOR dual inhibitor for use, or a medicament for treatment.

[0384] Embodiment I-110: The cancer is salivary gland cancer, and is the use according to Embodiment I-109, an mTOR dual inhibitor for use, or a medicament for treatment.

[0385] Embodiment I-111: The subject is human, and is the use according to any one of Embodiments I-87 to I-110, an mTOR dual inhibitor for use, or a medicament for treatment.

[0386] Embodiment I-112: The method or treatment further includes the step of administering an intraoral rinse solution of dexamethasone to a subject, the use according to any one of Embodiments I-87 to I-111, the mTOR dual inhibitor for use, or the medicament for treatment.

[0387] Embodiment I-113: The intraoral rinse solution of dexamethasone contains about 0.5 mg of dexamethasone per 5 mL, the use according to Embodiment I-112, the mTOR dual inhibitor for use, or the medicament for treatment.

[0388] Embodiment I-114: The subject is administered about 2.5 mL of the intraoral rinse solution of dexamethasone, the use according to Embodiment I-112 or I-113, the mTOR dual inhibitor for use, or the medicament for treatment.

[0389] Embodiment I-115: The intraoral rinse solution of dexamethasone is administered once, twice, three times, or four times a day, the use according to any one of Embodiments I-112 to I-114, the mTOR dual inhibitor for use, or the medicament for treatment.

[0390] Embodiment I-116: The method or treatment further includes the step of administering an intraoral rinse solution of tacrolimus to a subject, the use according to any one of Embodiments I-87 to I-115, the mTOR dual inhibitor for use, or the medicament for treatment.

[0391] Embodiment I-117: The intraoral rinse solution of tacrolimus contains about 0.5 mg of tacrolimus per 1 mL, the use according to Embodiment I-116, the mTOR dual inhibitor for use, or the medicament for treatment.

[0392] Embodiment I-118: The subject is administered about 2.5 mL of the intraoral rinse solution of tacrolimus, the use according to Embodiment I-116 or I-117, the mTOR dual inhibitor for use, or the medicament for treatment.

[0393] Embodiment I-119: The tacrolimus oral rinse is the use according to any one of Embodiments I-116 to I-118, the mTOR dual inhibitor for use, or the medicament for treatment, which is administered 1, 2, 3, or 4 times a day.

[0394] Embodiment I-120: The tacrolimus oral rinse is the use according to any one of Embodiments I-116 to I-119, the mTOR dual inhibitor for use, or the medicament for treatment, which is administered on the day of administering the mTOR dual inhibitor or immediately before administering the mTOR dual inhibitor.

[0395] Embodiment I-121: The method or treatment further includes the step of administering a combined oral rinse to a subject, and the combined oral rinse contains dexamethasone and tacrolimus, which is the use according to any one of Embodiments I-87 to I-111, the mTOR dual inhibitor for use, or the medicament for treatment.

[0396] Embodiment I-122: The combined oral rinse contains about 0.5 mg of dexamethasone per 5 mL, which is the use according to Embodiment I-121, the mTOR dual inhibitor for use, or the medicament for treatment.

[0397] Embodiment I-123: The combined oral rinse contains about 0.5 mg of tacrolimus per 1 mL, which is the use according to Embodiment I-121 or I-122, the mTOR dual inhibitor for use, or the medicament for treatment.

[0398] Embodiment I-124: The subject is administered about 2.5 mL of the combined oral rinse, which is the use according to any one of Embodiments I-121 to I-123, the mTOR dual inhibitor for use, or the medicament for treatment.

[0399] Embodiment I-125: The combined oral rinse is administered 1, 2, 3, or 4 times a day, which is the use according to any one of Embodiments I-121 to I-124, the mTOR dual inhibitor for use, or the medicament for treatment.

[0400] Embodiment I-126: The combination oral rinse is administered on the day of administration of the mTOR dual inhibitor or immediately prior to administration of the mTOR dual inhibitor, and is the use, mTOR dual inhibitor for use, or medicament for treatment according to any one of Embodiments I-121 to I-125.

[0401] Embodiment I-127: The method or treatment further includes ice applied to the subject's oral cavity, and is the use, mTOR dual inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-126.

[0402] Embodiment I-128: The ice is applied for about 10 minutes before administration of the mTOR dual inhibitor, applied at the time of administration of the mTOR dual inhibitor, and applied for about 10 minutes after administration of the mTOR dual inhibitor, and is the use, mTOR dual inhibitor for use, or medicament for treatment according to Embodiment I-127.

[0403] Embodiment I-129: The dosage is about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, or about 9 mg per week, and is the use, mTOR dual inhibitor for use, or medicament for treatment according to any one of Embodiments I-112 to I-128.

[0404] Embodiment I-130: The method or treatment further includes the step of administering a RAS inhibitor to the subject, and is the use, mTOR dual inhibitor for use, or medicament for treatment according to any one of Embodiments I-87 to I-129.

[0405] Embodiment I-131: The RAS inhibitor targets specific RAS mutations, and is the use, mTOR dual inhibitor for use, or medicament for treatment according to Embodiment I-130.

[0406] Embodiment I-132: The RAS inhibitor is the use according to Embodiment I-130 or I-131 that targets the KRAS mutation, the mTOR dual inhibitor for use, or the medicament for treatment.

[0407] Embodiment I-133: The RAS inhibitor targets the KRAS G12C mutation and is the use according to any one of Embodiments I-130 to I-132, the mTOR dual inhibitor for use, or the medicament for treatment.

[0408] Embodiment I-134: The RAS inhibitor is a KRAS(off) inhibitor and is the use according to any one of Embodiments I-130 to I-133, the mTOR dual inhibitor for use, or the medicament for treatment.

[0409] Embodiment I-135: The KRAS(off) inhibitor is AMG510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255, or a pharmaceutically acceptable salt of any of the foregoing, and is the use according to Embodiment I-134, the mTOR dual inhibitor for use, or the medicament for treatment.

[0410] Embodiment I-136: The RAS inhibitor is a RAS(on) inhibitor and is the use according to any one of Embodiments I-130 to I-133, the mTOR dual inhibitor for use, or the medicament for treatment.

[0411] Embodiment I-137: The RAS(on) inhibitor is a KRAS(on) inhibitor and is the use according to Embodiment I-136, the mTOR dual inhibitor for use, or the medicament for treatment.

[0412] Embodiment I-138: The use according to Embodiment I-137, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the KRAS (on) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, or a pharmaceutically acceptable salt of any of the foregoing.

[0413] Embodiment I-139: The use according to Embodiment I-137 or I-138, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the KRAS (on) inhibitor is a KRAS (on) inhibitor. G12C The use according to Embodiment I-137 or I-138, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the KRAS (on) inhibitor is a KRAS (on) inhibitor.

[0414] Embodiment I-140: The use according to Embodiment I-139, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the KRAS (on) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof. G12C The use according to Embodiment I-139, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the KRAS (on) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof.

[0415] Embodiment I-141: The use according to any one of Embodiments I-87 to I-140, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the cancer comprises a KRAS mutation. G12C The use according to any one of Embodiments I-87 to I-140, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the cancer comprises a KRAS mutation.

[0416] Embodiment I-142: The use according to any one of Embodiments I-87 to I-141, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the cancer comprises the co-occurrence of a KRAS mutation and a STK11 mutation. G12C The use according to any one of Embodiments I-87 to I-141, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the cancer comprises the co-occurrence of a KRAS mutation and a STK11 mutation.

[0417] Embodiment I-143: The use according to any one of Embodiments I-87 to I-142, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the cancer comprises the co-occurrence of a KRAS mutation and a PIK3CA mutation. G12C The use according to any one of Embodiments I-87 to I-142, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the cancer comprises the co-occurrence of a KRAS mutation and a PIK3CA mutation. E545K The use according to any one of Embodiments I-87 to I-142, the mTOR dual inhibitor for use, or the medicament for treatment, wherein the cancer comprises the co-occurrence of a KRAS mutation and a PIK3CA mutation.

[0418] Embodiment I-144: The cancer is colorectal cancer, and the method is any one of Embodiments I-87 to I-108 and I-111 to I-143, including a mutation in PIK3CA, an amplification of MYC, or a mutation in PIK3CA and an amplification of MYC.

[0419] Embodiment I-145: The cancer is head and neck cancer, and the method is any one of Embodiments I-87 to I-109 and I-111 to I-143, including a mutation in PIK3CA, a mutation in PTEN, or a mutation in PIK3CA and a mutation in PTEN.

[0420] Embodiment I-146: The cancer is hepatocellular carcinoma, and the method is any one of Embodiments I-87 to I-108 and I-111 to I-143, including a mutation in NFE2L2.

[0421] Embodiment I-147: The cancer is ovarian cancer, and the method is any one of Embodiments I-87 to I-108 and I-111 to I-143, including a mutation in TSC2.

[0422] Embodiment I-148: The cancer is pancreatic cancer, and the method is any one of Embodiments I-87 to I-108 and I-111 to I-143, including a mutation in STK11, a G12C mutation in KRAS, or a mutation in STK11 and a G12C mutation in KRAS.

[0423] Embodiment I-149: The cancer is prostate cancer, and the method is any one of Embodiments I-87 to I-108 and I-111 to I-143, including a mutation in PTEN.

[0424] Embodiment I-150: The cancer is uterine cancer, and the method is any one of Embodiments I-87 to I-108 and I-111 to I-143, including a mutation in PIK3CA, a mutation in PIK3CA, a mutation in TSC2, or a combination thereof.

[0425] Embodiment I-151: The cancer is lung cancer, and the method according to any one of Embodiments I-87 to I-108 and I-111 to I-143, which includes BRAF fusion.

[0426] Embodiment I-152: The method or treatment is the use according to any one of Embodiments I-87 to I-151, an mTOR dual inhibitor for use, or a medicament for treatment, which results in tumor regression.

[0427] Embodiment I-153: The method or treatment is the use according to any one of Embodiments I-87 to I-152, an mTOR dual inhibitor for use, or a medicament for treatment, which results in tumor apoptosis.

[0428] Embodiment I-154: An mTOR dual inhibitor for use in a method of treating cancer in a subject having acquired resistance to a RAS inhibitor, the method including the step of administering to the subject an mTOR dual inhibitor at a dosage of about 3 mg per week to about 25 mg per week, and the subject has already received or will receive administration of a RAS inhibitor;

[0429] The mTOR dual inhibitor is

Chemical formula

[0430] Embodiment I-155: A combination of an mTOR dual inhibitor and a RAS inhibitor for simultaneous use, separate use, or sequential use in a method of treating cancer in a subject having acquired resistance to a RAS inhibitor, the method including the step of administering to the subject in need thereof an mTOR dual inhibitor at a dosage of about 3 mg per week to about 25 mg per week;

[0431] The mTOR dual stereoisomer inhibitor is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, a combination of an mTOR dual stereoisomer inhibitor and a RAS inhibitor.

[0432] Embodiment I-156: Use of an mTOR dual stereoisomer inhibitor in a treatment for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the method comprising administering to the subject from about 3 mg of the mTOR dual stereoisomer inhibitor per week to about 25 mg of the mTOR dual stereoisomer inhibitor per week, wherein the subject has already received or will receive administration of the RAS inhibitor;

[0433] The mTOR dual stereoisomer inhibitor is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the use. Embodiment I-157: Use of an mTOR dual stereoisomer inhibitor in the manufacture of a medicament for a treatment for delaying or preventing acquired resistance to a RAS inhibitor, the treatment comprising administering the medicament to a subject in need thereof to deliver from about 3 mg to about 25 mg per week of the mTOR dual stereoisomer inhibitor; wherein the subject has already received or will receive administration of the RAS inhibitor;

[0434] The mTOR dual stereoisomer inhibitor is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, the use.

[0435] Embodiment I-158: An mTOR dual inhibitor for use in a method of delaying or preventing acquired resistance to a RAS inhibitor, the method comprising the step of administering to a subject in need thereof an mTOR dual inhibitor at a dosage of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is to receive administration of a RAS inhibitor;

[0436] The mTOR dual inhibitor is

Chemical formula

[0437] Embodiment I-159: A medicament for a treatment for delaying or preventing acquired resistance to a RAS inhibitor, comprising an mTOR dual inhibitor, the treatment comprising the step of administering the medicament to deliver to a subject in need thereof an mTOR dual inhibitor at a dosage of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is to receive administration of a RAS inhibitor;

[0438] The mTOR dual inhibitor is

Chemical formula

[0439] Embodiment I-160: Use of an mTOR dual inhibitor in the treatment of acquired resistance to a RAS inhibitor, the treatment comprising the step of administering to a subject in need thereof an mTOR dual inhibitor at a dosage of from about 3 mg per week to about 25 mg per week;

[0440] The mTOR dual inhibitor is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use.

[0441] Embodiment I-161: Use of an mTOR dual stereoisomer inhibitor in the manufacture of a medicament for the treatment of acquired resistance to a RAS inhibitor, the treatment comprising administering the medicament to a subject in need thereof to deliver an mTOR dual stereoisomer inhibitor at a dosage of from about 3 mg per week to about 25 mg per week;

[0442] The mTOR dual stereoisomer inhibitor is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use.

[0443] Embodiment I-162: An mTOR dual stereoisomer inhibitor for use in a method of treating acquired resistance to a RAS inhibitor, the method comprising administering an mTOR dual stereoisomer inhibitor at a dosage of from about 3 mg per week to about 25 mg per week to a subject in need thereof;

[0444] The mTOR dual stereoisomer inhibitor is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, for use as an mTOR dual stereoisomer inhibitor. Embodiment I-163: A medicament for the treatment of acquired resistance to a RAS inhibitor, comprising an mTOR dual stereoisomer inhibitor, the treatment comprising administering the medicament to deliver an mTOR dual stereoisomer inhibitor at a dosage of from about 3 mg per week to about 25 mg per week to a subject in need thereof;

[0445] The mTOR dual stereoisomer inhibitor is

Chemical formula

[0446] Embodiment I-164: The method or treatment further comprises administering to a subject an effective amount of a RAS inhibitor, the use according to any one of Embodiments I-154 to I-163, the mTOR dual stereoisomer inhibitor for use, or the medicament for treatment.

[0447] Embodiment I-165: The RAS inhibitor targets a specific RAS mutation, the use according to any one of Embodiments I-154 to I-164, the mTOR dual stereoisomer inhibitor for use, or the medicament for treatment.

[0448] Embodiment I-166: The RAS inhibitor targets a KRAS mutation, the use according to any one of Embodiments I-154 to I-165, the mTOR dual stereoisomer inhibitor for use, or the medicament for treatment.

[0449] Embodiment I-167: The RAS inhibitor targets a KRAS G12C Mutation, the use according to any one of Embodiments I-154 to I-166, the mTOR dual stereoisomer inhibitor for use, or the medicament for treatment.

[0450] Embodiment I-168: The RAS inhibitor is a KRAS(off) inhibitor, the use according to any one of Embodiments I-154 to I-167, the mTOR dual stereoisomer inhibitor for use, or the medicament for treatment.

[0451] Embodiment I-169: The KRAS (off) inhibitor is AMG510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255, or a pharmaceutically acceptable salt of any of the foregoing, the use according to Embodiment I-168, the mTOR dual inhibitor for use, or the medicament for treatment.

[0452] Embodiment I-170: The RAS inhibitor is a RAS (on) inhibitor, the use according to any one of Embodiments I-154 to I-167, the mTOR dual inhibitor for use, or the medicament for treatment.

[0453] Embodiment I-171: The RAS (on) inhibitor is a KRAS (on) inhibitor, the use according to Embodiment I-170, the mTOR dual inhibitor for use, or the medicament for treatment.

[0454] Embodiment I-172: The KRAS (on) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, or a pharmaceutically acceptable salt of any of the foregoing, the use according to Embodiment I-171, the mTOR dual inhibitor for use, or the medicament for treatment.

[0455] Embodiment I-173: The KRAS (on) inhibitor is a KRAS G12C (on) inhibitor, the use according to Embodiment I-171 or I-172, the mTOR dual inhibitor for use, or the medicament for treatment.

[0456] Embodiment I-174: The KRAS G12C (on) inhibitor is RMC-6291 or a pharmaceutically acceptable salt thereof, the use according to Embodiment I-173, the mTOR dual inhibitor for use, or the medicament for treatment.

[0457] Embodiment I-175: The use according to any one of Embodiments I-154 to I-174, the mTOR dual inhibitor for the use, or the medicament for treatment, wherein the subject is administered an RAS inhibitor so as to treat or prevent cancer.

[0458] Embodiment I-176: The use according to any one of Embodiments I-156 to I-175, the mTOR dual inhibitor for the use, or the medicament for treatment, wherein the subject has cancer.

[0459] Embodiment I-177: The use according to any one of Embodiments I-154, I-155, I-175, and I-176, the mTOR dual inhibitor for the use, or the medicament for treatment, wherein the cancer contains a KRAS G12C mutation.

[0460] Embodiment I-178: The use according to any one of Embodiments I-154, I-155, and I-175 to I-177, the mTOR dual inhibitor for the use, or the medicament for treatment, wherein the cancer contains a co-occurrence of a KRAS G12C mutation and a STK11 mutation.

[0461] Embodiment I-179: The use according to any one of Embodiments I-154, I-155, and I-175 to I-178, the mTOR dual inhibitor for the use, or the medicament for treatment, wherein the cancer is non-small cell lung cancer (NSCLC) or colorectal cancer.

[0462] Embodiment I-180: The use according to any one of Embodiments I-154, I-155, and I-175 to I-179, the mTOR dual inhibitor for the use, or the medicament for treatment, wherein the cancer contains a co-occurrence of a KRAS G12C mutation and a PIK3CA E545K mutation.

[0463] Embodiment I-181: The cancer is colorectal cancer, the use according to any one of Embodiments I-154, I-155, I-175 to I-178, and I-180, the mTOR dual inhibitor for use, or the medicament for treatment.

[0464] Embodiment I-182: The method or treatment results in tumor regression, the use according to any one of Embodiments I-154 to I-181, the mTOR dual inhibitor for use, or the medicament for treatment.

[0465] Embodiment I-183: The method or treatment results in tumor apoptosis, the use according to any one of Embodiments I-154 to I-182, the mTOR dual inhibitor for use, or the medicament for treatment.

[0466] Embodiment II-1: A method for treating a subject having cancer, comprising the step of administering to the subject a compound in a dosage of about 3 mg per week to about 25 mg per week;

[0467] The compound is

Chemical formula

[0468] Embodiment II-2: The use of a compound in the treatment of cancer, wherein the treatment comprises the step of administering to a subject in need thereof a compound in a dosage of about 3 mg per week to about 25 mg per week;

[0469] The compound is

Chemical formula

[0470] Embodiment II-3: Use of a compound in the manufacture of a medicament for the treatment of cancer, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a compound in an amount of from about 3 mg per week to about 25 mg per week;

[0471] The compound is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0472] Embodiment II-4: A compound for use in a method of treating cancer, the method comprising administering to a subject in need thereof a compound in an amount of from about 3 mg per week to about 25 mg per week;

[0473] The compound is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0474] Embodiment II-5: A medicament for the treatment of cancer, comprising a compound, wherein the treatment comprises administering the medicament to deliver a compound in an amount of from about 3 mg per week to about 25 mg per week to a subject in need thereof;

[0475] The compound is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0476] Embodiment II-6: A method of treating a subject having salivary gland cancer, comprising administering to the subject a compound in a dosage of from about 3 mg per week to about 25 mg per week;

[0477] The compound is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0478] Embodiment II-7: A method for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, comprising administering to the subject a compound in an amount of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or will receive administration of a RAS inhibitor;

[0479] The compound is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0480] Embodiment II-8: A method of treating acquired resistance to a RAS inhibitor in a subject in need thereof, comprising administering to the subject a compound in an amount of from about 3 mg per week to about 25 mg per week;

[0481] The compound is [Chemical formula] or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

[0482] Embodiment II-9: A compound for use in a method of treating cancer in a subject having acquired resistance to a RAS inhibitor, the method comprising administering to the subject a compound at a dosage of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is to receive administration of a RAS inhibitor;

[0483] The compound is

Chemical formula

[0484] Embodiment II-10: A combination of a compound and a RAS inhibitor for concurrent, separate, or sequential use in a method of treating cancer in a subject having acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a compound at a dosage of from about 3 mg per week to about 25 mg per week;

[0485] The compound is

Chemical formula

[0486] Embodiment II-11: Use of a compound in a treatment for delaying or preventing acquired resistance to a RAS inhibitor in a subject in need thereof, the treatment comprising administering to the subject a compound at a dosage of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is to receive administration of a RAS inhibitor;

[0487] The compound is

Chemical formula

[0488] Embodiment II-12: Use of a compound in the manufacture of a medicament for a treatment for delaying or preventing acquired resistance to a RAS inhibitor, the treatment comprising administering the medicament to a subject in need thereof to deliver a compound at a dosage of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is to receive administration of a RAS inhibitor;

[0489] The compound is

Chemical formula

[0490] Embodiment II-13: A compound for use in a method for delaying or preventing acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a compound at a dosage of from about 3 mg per week to about 25 mg per week, wherein the subject has already received or is to receive administration of a RAS inhibitor;

[0491] The compound is

Chemical formula

[0492] Embodiment II-14: A medicament for a treatment for delaying or preventing acquired resistance to a RAS inhibitor, comprising a compound, wherein the treatment comprises administering the medicament to deliver a dosage of the compound from about 3 mg per week to about 25 mg per week to a subject in need thereof, and the subject has already received or will receive administration of a RAS inhibitor;

[0493] The compound is

Chemical formula

[0494] Embodiment II-15: Use of a compound in the treatment of acquired resistance to a RAS inhibitor, wherein the treatment comprises administering a dosage of the compound from about 3 mg per week to about 25 mg per week to a subject in need thereof;

[0495] The compound is

Chemical formula

[0496] Embodiment II-16: Use of a compound in the manufacture of a medicament for the treatment of acquired resistance to a RAS inhibitor, wherein the treatment comprises administering the medicament to a subject in need thereof to deliver a dosage of the compound from about 3 mg per week to about 25 mg per week;

[0497] The compound is

Chemical formula

[0498] Embodiment II-17: A compound for use in a method of treating acquired resistance to a RAS inhibitor, the method comprising administering to a subject in need thereof a compound at a dosage of from about 3 mg per week to about 25 mg per week;

[0499] The compound is

Chemical formula

[0500] Embodiment II-18: A medicament for treating acquired resistance to a RAS inhibitor, comprising a compound, the treatment comprising administering the medicament to deliver to a subject in need thereof a compound at a dosage of from about 3 mg per week to about 25 mg per week;

[0501] The compound is

Chemical formula

[0502] Embodiment II-19: A method of treating or preventing mucositis in a subject in need thereof who has been treated with, is being treated with, or is to be treated with an mTOR inhibitor, the method comprising administering tacrolimus solution to the subject.

[0503] Embodiment II-20: Use of tacrolimus solution in a method of treating or preventing mucositis, the treatment comprising administering tacrolimus solution to a subject who has been treated with, is being treated with, or is to be treated with an mTOR inhibitor.

[0504] Embodiment II-21: Use of tacrolimus solution in the manufacture of a medicament for the treatment or prevention of mucositis, the treatment comprising administering the medicament to a subject who has been treated with, is being treated with, or is to be treated with an mTOR inhibitor.

[0505] Embodiment II-22: Tacrolimus solution for use in a method of treating or preventing mucositis, the method comprising administering the tacrolimus solution to a subject who has been treated with, is being treated with, or is to be treated with an mTOR inhibitor.

[0506] Embodiment II-23: A medicament for the treatment or prevention of mucositis, comprising a tacrolimus solution, the treatment comprising administering the medicament to a subject who has been treated with, is being treated with, or is to be treated with an mTOR inhibitor.

[0507] Embodiment II-24: The method, use, tacrolimus solution, and medicament according to Embodiment II-19 to II-23, wherein the mucositis is stomatitis.

[0508] Embodiment II-25: The method, use, tacrolimus solution, and medicament according to Embodiment II-19 to II-24, wherein the mTOR inhibitor is everolimus, sirolimus, and nab-sirolimus, or a combination thereof.

[0509] Embodiment II-26: The mTOR inhibitor has a structure

Chemical formula

[0510] Embodiment II-27: The subject is administered a compound at a dosage of about 3 mg per week to about 25 mg per week, or a stereoisomer, tautomer, or oxepane isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, in the method, use, tacrolimus solution, and pharmaceutical of Embodiment II-26.

[0511] Embodiment II-28: The dosage is about 4 mg per week to about 25 mg per week, about 4 mg per week to about 14 mg per week, about 4 mg per week to about 12 mg per week, about 5 mg per week to about 25 mg per week, about 5 mg per week to about 14 mg per week, about 5 mg per week to about 12 mg per week, about 5 mg per week to about 10 mg per week, about 6 mg per week to about 25 mg per week, about 6 mg per week to about 14 mg per week, about 6 mg per week to about 12 mg per week, about 6 mg per week to about 9 mg per week, about 6 mg per week to about 8 mg per week, about 7 mg per week to about 25 mg per week, about 7 mg per week to about 14 mg per week, about 7 mg per week to about 12 mg per week, about 7 mg per week to about 8 mg per week, about 8 mg per week to about 25 mg per week, about 8 mg per week to about 14 mg per week, about 8 mg per week to about 12 mg per week, or about 8 mg per week to about 10 mg per week, in the method, use, compound, pharmaceutical, combination, and tacrolimus solution of Embodiments II-1 to II-18 and II-27.

[0512] Embodiment II-29: The dosage is about 4 mg per week, about 4.5 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, about 10 mg per week, about 10.5 mg per week, about 11 mg per week, about 11.5 mg per week, about 12 mg per week, about 12.5 mg per week, about 13 mg per week, about 13.5 mg per week, about 14 mg per week, about 14.5 mg per week, about 15 mg per week, about 16 mg per week, about 18 mg per week, about 20 mg per week, about 22 mg per week, or about 25 mg per week, of the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-1 to II-18, II-27, and II-28.

[0513] Embodiment II-30: The dosage in the first 1, 2, 3, 4, or 5 weeks is higher than the dosage in subsequent weeks, of the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-1 to II-18 and II-27 to II-30.

[0514] Embodiment II-31: The dosage in the first 1, 2, 3, 4, or 5 weeks is about 6 mg per week to about 25 mg per week, about 6 mg per week to about 20 mg per week, about 6 mg per week to about 16 mg per week, about 6 mg per week to about 14 mg per week, about 6 mg per week to about 12 mg per week, about 6 mg per week to about 10 mg per week, about 8 mg per week to about 25 mg per week, about 8 mg per week to about 20 mg per week, about 8 mg per week to about 16 mg per week, about 8 mg per week to about 14 mg per week, about 8 mg per week to about 12 mg per week, about 8 mg per week to about 10 mg per week, about 10 mg per week to about 25 mg per week, about 10 mg per week to about 20 mg per week, about 10 mg per week to about 16 mg per week, about 10 mg per week to about 14 mg per week, or about 10 mg per week to about 12 mg per week, the method, use, compound, medicament, combination, and tacrolimus solution according to Embodiment II-30.

[0515] Embodiment II-32: The dosage in the first 1, 2, 3, 4, or 5 weeks is about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, about 10 mg per week, about 10.5 mg per week, about 11 mg per week, about 11.5 mg per week, about 12 mg per week, about 12.5 mg per week, about 13 mg per week, about 13.5 mg per week, about 14 mg per week, about 14.5 mg per week, about 15 mg per week, about 16 mg per week, about 18 mg per week, about 20 mg per week, about 22 mg per week, or about 25 mg per week, the method, use, compound, medicament, combination, and tacrolimus solution according to Embodiment II-30 or II-31.

[0516] Embodiment II-33: The dosage in the first week is higher than the dosage in subsequent weeks, the method, use, compound, medicament, combination, and tacrolimus solution according to Embodiments II-30 to II-32.

[0517] Embodiment II-34: The dosage in the first 1, 2, 3, 4, or 5 weeks is followed by 1, 2, 3, 4, or 5 weeks without administration, the method, use, compound, medicament, combination, and tacrolimus solution according to Embodiments II-30 to II-33.

[0518] Embodiment II-35: The dosage at 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks is from about 3 mg per week to about 12 mg per week, from about 3 mg per week to about 10 mg per week, from about 3 mg per week to about 8 mg per week, from about 3 mg per week to about 6 mg per week, from about 4 mg per week to about 12 mg per week, from about 4 mg per week to about 10 mg per week, from about 4 mg per week to about 8 mg per week, from about 4 mg per week to about 6 mg per week, from about 5 mg per week to about 12 mg per week, from about 5 mg per week to about 10 mg per week, from about 5 mg per week to about 8 mg per week, from about 5 mg per week to about 6 mg per week, from about 6 mg per week to about 12 mg per week, from about 6 mg per week to about 10 mg per week, from about 6 mg per week to about 8 mg per week, from about 6 mg per week to about 7 mg per week, from about 7 mg per week to about 12 mg per week, from about 7 mg per week to about 10 mg per week, from about 7 mg per week to about 8 mg per week, from about 8 mg per week to about 12 mg per week, or from about 8 mg per week to about 10 mg per week, the method, use, compound, medicament, combination, and tacrolimus solution according to Embodiments II-30 to II-34.

[0519] Embodiment II-36: The dosage after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks is about 3 mg per week, about 3.5 mg per week, about 4 mg per week, about 4.5 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, or about 10 mg per week, the method, use, compound, medicine, combination, and tacrolimus solution according to Embodiments II-30 to II-35.

[0520] Embodiment II-37: The dosage in the first 1, 2, 3, 4, or 5 weeks is about 6 mg per week to about 25 mg per week, about 6 mg per week to about 20 mg per week, about 6 mg per week to about 16 mg per week, about 6 mg per week to about 14 mg per week, about 6 mg per week to about 12 mg per week, about 6 mg per week to about 10 mg per week, about 8 mg per week to about 25 mg per week, about 8 mg per week to about 20 mg per week, about 8 mg per week to about 16 mg per week, about 8 mg per week to about 14 mg per week, about 8 mg per week to about 12 mg per week, about 8 mg per week to about 10 mg per week, about 10 mg per week to about 25 mg per week, about 10 mg per week to about 20 mg per week, about 10 mg per week to about 16 mg per week, about 10 mg per week to about 14 mg per week, or about 10 mg per week to about 12 mg per week; This is followed by 0, 1, 2, 3, 4, or 5 weeks without administration; To this, a dosage of about 3 mg per week to about 12 mg per week, about 3 mg per week to about 10 mg per week, about 3 mg per week to about 8 mg per week, about 3 mg per week to about 6 mg per week, about 4 mg per week to about 12 mg per week, about 4 mg per week to about 10 mg per week, about 4 mg per week to about 8 mg per week, about 4 mg per week to about 6 mg per week, about 5 mg per week to about 12 mg per week, about 5 mg per week to about 10 mg per week, about 5 mg per week to about 8 mg per week, about 5 mg per week to about 6 mg per week, about 6 mg per week to about 12 mg per week, about 6 mg per week to about 10 mg per week, about 6 mg per week to about 8 mg per week, about 6 mg per week to about 7 mg per week, about 7 mg per week to about 12 mg per week, about 7 mg per week to about 10 mg per week, about 7 mg per week to about 8 mg per week, about 8 mg per week to about 12 mg per week, or about 8 mg per week to about 10 mg per week continues, the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-30 to II-36.

[0521] Embodiment II-38: The dosage in the first 1, 2, 3, 4, or 5 weeks is about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, about 10 mg per week, about 10.5 mg per week, about 11 mg per week, about 11.5 mg per week, about 12 mg per week, about 12.5 mg per week, about 13 mg per week, about 13.5 mg per week, about 14 mg per week, about 14.5 mg per week, about 15 mg per week, about 16 mg per week, about 18 mg per week, about 20 mg per week, about 22 mg per week, or about 25 mg per week; To this, 0, 1, 2, 3, 4, or 5 weeks without administration follow; To this, there are the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-30 to II-37, wherein a dosage of about 3 mg per week, about 3.5 mg per week, about 4 mg per week, about 4.5 mg per week, about 5 mg per week, about 5.5 mg per week, about 6 mg per week, about 6.5 mg per week, about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, or about 10 mg per week continues.

[0522] Embodiment II-39: The dosage is for the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-1 to II-18 and II-27 to II-38, which are administered via IV infusion.

[0523] Embodiment II-40: The dosage is for the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiment II-39, which are administered over about 0.5 hours to about 2 hours, over about 0.5 hours to about 1.5 hours, over about 0.5 hours to about 1 hour, over about 1 hour to about 2 hours, or over about 1 hour to about 1.5 hours.

[0524] Embodiment II-41: The dosage is for the methods, uses, compounds, medicaments, combinations, or tacrolimus solutions described in Embodiment II-38 or II-40, which are administered over about 1 hour.

[0525] Embodiment II-42: The subject is human for the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-1 to II-41.

[0526] Embodiment II-43: The method further includes the step of administering a dexamethasone solution to the subject for the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-1 to II-42.

[0527] Embodiment II-44: The dexamethasone solution contains about 0.5 mg of dexamethasone per 5 mL, the method, use, compound, medicine, combination, and tacrolimus solution described in Embodiment II-43.

[0528] Embodiment II-45: The subject is administered about 2.5 mL of the dexamethasone solution, the method, use, compound, medicine, combination, and tacrolimus solution described in Embodiment II-43 or II-44.

[0529] Embodiment II-46: The dexamethasone solution is administered 1, 2, 3, or 4 times a day, the method, use, compound, medicine, combination, and tacrolimus solution described in Embodiments II-43 to II-45.

[0530] Embodiment II-47: The method further includes the step of administering the tacrolimus solution to the subject, the method, use, compound, medicine, and combination described in Embodiments II-1 to II-18 and II-28 to II-46.

[0531] Embodiment II-48: The tacrolimus solution contains about 0.1 mg of tacrolimus per 1 mL, the method, use, compound, medicine, combination, and tacrolimus solution described in Embodiments II-19 to II-27 and II-47.

[0532] Embodiment II-49: The tacrolimus solution contains about 0.1 mg of tacrolimus per 1 mL, the method, use, compound, medicine, combination, and tacrolimus solution described in Embodiments II-19 to II-27, II-47, and II-48.

[0533] Embodiment II-50: The subject is administered about 2.5 mL of the tacrolimus solution, the method, use, compound, medicine, combination, and tacrolimus solution described in Embodiments II-19 to II-27 and II-47 to II-49.

[0534] Embodiment II-51: The tacrolimus solution is administered once, twice, three times, or four times daily, and the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-19 to II-27 and II-47 to II-50.

[0535] Embodiment II-52: The tacrolimus solution is administered on the day the dose is administered or immediately before the dose is administered, and the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-19 to II-27 and II-47 to II-51.

[0536] Embodiment II-53: The method further includes the step of administering the combination solution to a subject, and the combination solution includes dexamethasone and tacrolimus, and the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-1 to II-52.

[0537] Embodiment II-54: The combination solution contains about 0.5 mg of dexamethasone per 5 mL, and the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiment II-53.

[0538] Embodiment II-55: The combination solution contains about 0.5 mg of tacrolimus per 1 mL, and the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiment II-53 or II-54.

[0539] Embodiment II-56: The subject is administered about 2.5 mL of the combination solution, and the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-53 to II-55.

[0540] Embodiment II-57: The combination solution is administered once, twice, three times, or four times daily, and the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-53 to II-56.

[0541] Embodiment II-58: The combined solution is administered on the day of administration of the dose or immediately before the dose is administered, according to the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-53 to II-57.

[0542] Embodiment II-59: The method further includes ice applied to the subject's oral cavity, according to the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-1 to II-58.

[0543] Embodiment II-60: The ice is applied for about 10 minutes before the dose is administered, applied at the time of administration of the dose, and applied for about 10 minutes after the dose is administered, according to the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiment II-59.

[0544] Embodiment II-61: The dose is about 6 mg per week to about 25 mg per week, about 6 mg per week to about 20 mg per week, about 6 mg per week to about 16 mg per week, about 6 mg per week to about 14 mg per week, about 6 mg per week to about 12 mg per week, about 6 mg per week to about 9 mg per week, about 6 mg per week to about 8 mg per week, or about 7 mg per week to about 8 mg per week, according to the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiments II-27, and II-43 to II-60.

[0545] Embodiment II-62: The dosage is about 7 mg per week, about 7.5 mg per week, about 8 mg per week, about 8.5 mg per week, about 9 mg per week, about 9.5 mg per week, about 10 mg per week, about 10.5 mg per week, about 11 mg per week, about 11.5 mg per week, about 12 mg per week, about 12.5 mg per week, about 13 mg per week, about 13.5 mg per week, about 14 mg per week, about 14.5 mg per week, about 15 mg per week, about 16 mg per week, about 18 mg per week, about 20 mg per week, about 22 mg per week, or about 25 mg per week, the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiment II-27, and II-43 to II-61.

[0546] Embodiment II-63: The method further comprises the step of administering a RAS inhibitor to a subject, the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiment II-1 to II-62.

[0547] Embodiment II-64: The method, use, compound, medicament, combination, and tacrolimus solution described in Embodiment II-63 further comprise the step of administering an effective amount of a RAS inhibitor to a subject.

[0548] Embodiment II-65: The RAS inhibitor targets a specific RAS mutation, the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiment II-63 or II-64.

[0549] Embodiment II-66: The RAS inhibitor targets a KRAS mutation, the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiment II-63 to II-65.

[0550] Embodiment II-67: The RAS inhibitor targets a KRAS G12C mutation, the methods, uses, compounds, medicaments, combinations, and tacrolimus solutions described in Embodiment II-65 or II-66.

[0551] Embodiment II-68: The method, use, compound, medicament, combination, and tacrolimus solution described in Embodiments II-63 to II-67, wherein the RAS inhibitor is a KRAS(off) inhibitor.

[0552] Embodiment II-69: The method, use, compound, medicament, combination, and tacrolimus solution described in Embodiment II-68, wherein the KRAS(off) inhibitor is AMG510, MRTX849, JDQ443, MRTX1133, ERAS-3490, ERAS-4, BPI-421286, D-1553, JAB-21822, GH-35, ICP-915, IBI351, LY3537982, GDC-6036, BI1823911, RSC-1255, or a pharmaceutically acceptable salt of any of the foregoing.

[0553] Embodiment II-70: The method, use, compound, medicament, combination, and tacrolimus solution described in Embodiments II-63 to II-67, wherein the RAS inhibitor is a RAS(on) inhibitor.

[0554] Embodiment II-71: The method, use, compound, medicament, combination, and tacrolimus solution described in Embodiment II-70, wherein the RAS(on) inhibitor is a KRAS(on) inhibitor.

[0555] Embodiment II-72: The method, use, compound, medicament, combination, and tacrolimus solution described in Embodiment II-71, wherein the KRAS(on) inhibitor is RMC-6236, RMC-6291, RMC-9805, RMC-8839, or a pharmaceutically acceptable salt of any of the foregoing.

[0556] Embodiment II-73: The method, use, compound, medicament, combination, and tacrolimus solution described in Embodiment II-71 or II-75, wherein the KRAS(on) inhibitor is a KRAS G12C (on) inhibitor.

[0557] Embodiment II-74: KRAS G12C(ON) inhibitor is the method, use, compound, medica...

Claims

1. A pharmaceutical product for use in a method of treating a subject with cancer, wherein the pharmaceutical product comprises a compound, and the method is as follows: A step of administering an initial dose of the compound to the subject, The compound is 【Chemistry 1】 or its stereoisomer, tautomutator, oxepang isomer, or any pharmaceutically acceptable salt of the foregoing, administered in amounts of approximately 6 mg to approximately 25 mg per week for 1 to 5 weeks; and A step of administering a subsequent dose of the compound, its stereoisomer, tautomutator, oxepang isomer, or any pharmaceutically acceptable salt thereof, at a dose of approximately 3 mg to approximately 12 mg per week; Pharmaceuticals, including

2. A pharmaceutical product for use in a method of treating a subject with cancer, wherein the pharmaceutical product comprises a compound, and the method is as follows: A step of administering an initial dose of the compound to the subject, The compound is 【Chemistry 2】 or its stereoisomer, tautomutator, oxepang isomer, or any pharmaceutically acceptable salt thereof, administered at a dose of approximately 6 mg to approximately 25 mg per week for 1 to 5 weeks; and A step of administering a subsequent dose of the compound, its stereoisomer, tautomutator, oxepang isomer, or any pharmaceutically acceptable salt thereof, at a dose of approximately 3 mg to approximately 12 mg per week; Includes, Cancer is a drug that includes PIK3CA mutations, PTEN mutations, TSC1 mutations, TSC2 mutations, or combinations thereof.

3. The pharmaceutical product according to claim 2, wherein the mutation is a PTEN mutation.

4. The pharmaceutical product according to claim 3, wherein the PTEN mutation is a dominant-negative mutation.

5. The pharmacopoeia according to claim 1 or 2, wherein the initial dose and subsequent dose are administered by intravenous infusion, respectively.

6. The pharmaceutical product according to claim 5, wherein the initial dose and subsequent dose are administered over periods of approximately 0.5 hours to approximately 2 hours, approximately 0.5 hours to approximately 1.5 hours, approximately 0.5 hours to approximately 1 hour, approximately 1 hour to approximately 2 hours, or approximately 1 hour to approximately 1.5 hours, respectively.

7. The pharmaceutical product according to claim 5, wherein the initial dose and subsequent dose are each administered over approximately one hour.

8. The pharmaceutical product according to claim 1 or 2, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, hematological cancer, liver cancer, lung cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, kidney cancer, and rhabdomyosarcoma.

9. The pharmaceutical product according to claim 1 or 2, wherein the initial dose is approximately 8 mg to approximately 16 mg per week.

10. The pharmaceutical product according to claim 1 or 2, wherein the subsequent dose is approximately 5 mg to approximately 10 mg per week.

11. The pharmaceutical product according to claim 1 or 2, wherein the initial dose is approximately 8 mg to approximately 16 mg per week, and the subsequent dose is approximately 5 mg to approximately 10 mg per week.

12. The method further comprises 1, 2, 3, 4, or 5 weeks without administration after the initial dose and before the subsequent dose, according to claim 1 or 2.

13. A pharmaceutical product for use in a method of treating a subject having cancer, wherein the pharmaceutical product comprises a compound, and the method comprises the step of administering to the subject a dose of the compound at a rate of approximately 6 mg to approximately 25 mg per week. The compound is 【Transformation 3】 or its stereoisomer, tautomutator, oxepang isomer, or any pharmaceutically acceptable salt of the above, Cancer is a medical treatment selected from the group consisting of breast cancer, colorectal cancer, endometrial cancer, head and neck cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, kidney cancer, thyroid cancer, vulvar cancer, and prostate cancer.

14. The pharmaceutical product according to claim 13, wherein the dosage is approximately 6 mg to approximately 14 mg per week.

15. The pharmaceutical product according to claim 13, wherein the liver cancer is hepatocellular carcinoma or cholangiocarcinoma.

16. The pharmaceutical product according to claim 15, wherein hepatocellular carcinoma includes a mutation in NFE2L2.

17. A pharmaceutical product for use in a method of treating a subject with cancer, wherein the pharmaceutical product comprises a compound, and the method comprises the step of administering to the subject a dose of the compound ranging from approximately 12.5 mg to approximately 25 mg per week. The compound is 【Chemistry 4】 or its stereoisomer, tautomutator, oxepang isomer, or any pharmaceutically acceptable salt of the above, Cancer is a medical treatment selected from the group consisting of breast cancer, colorectal cancer, endometrial cancer, head and neck cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, kidney cancer, thyroid cancer, vulvar cancer, and prostate cancer.

18. The pharmaceutical product according to claim 17, wherein the dosage is approximately 13 mg to approximately 20 mg per week.

19. The pharmaceutical product according to claim 17, wherein the cancer is hepatocellular carcinoma or cholangiocarcinoma.

20. The pharmaceutical product according to any one of claims 1, 13, and 17, wherein the cancer is a solid tumor.

21. The pharmaceutical product according to any one of claims 1, 13, and 17, wherein the cancer is head and neck cancer.

22. The pharmacopoeia according to any one of claims 1, 13, and 17, wherein the cancer is colorectal cancer, and comprises a mutation of PIK3CA, amplification of MYC, or a mutation of PIK3CA and amplification of MYC.

23. The pharmacopoeia according to any one of claims 1, 13, and 17, wherein the cancer is a head and neck cancer and comprises a mutation in PIK3CA, a mutation in PTEN, or a mutation in both PIK3CA and PTEN.

24. The pharmaceutical product according to claim 1 or 17, wherein the cancer is hepatocellular carcinoma and comprises an NFE2L2 mutation.

25. The pharmaceutical product according to any one of claims 1, 13, and 17, wherein the cancer is ovarian cancer and comprises a TSC2 mutation.

26. The cancer is pancreatic cancer, caused by an STK11 mutation and KRAS. G12C Mutation, or STK11 mutation and KRAS G12C A pharmaceutical product according to any one of claims 1, 13, and 17, including a mutation.

27. A pharmaceutical product for use in a method of treating a subject having cancer, wherein the pharmaceutical product comprises a compound, and the method comprises the step of administering to the subject a dose of the compound at a rate of approximately 6 mg to approximately 25 mg per week. The compound is 【Chemistry 4】 or its stereoisomer, tautomer, oxepang isomer, or any pharmaceutically acceptable salt of the above, Cancer is a drug that includes PIK3CA mutations, PTEN mutations, TSC1 mutations, TSC2 mutations, or combinations thereof.

28. A pharmaceutical product for use in a method of treating a subject with cancer, wherein the pharmaceutical product comprises a compound, and the method involves administering the compound to the subject in a dose of approximately 12.5 mg to approximately 25 mg per week. This includes the process of administering a substance. The compound is 【Transformation 5】 or its stereoisomer, tautomer, oxepang isomer, or any pharmaceutically acceptable salt of the above, Cancer is a drug that includes PIK3CA mutations, PTEN mutations, TSC1 mutations, TSC2 mutations, or combinations thereof.

29. The pharmacopoeia according to claim 27 or 28, wherein the cancer has a PTEN mutation.

30. The pharmaceutical product according to claim 29, wherein the PTEN mutation is a dominant-negative mutation.

31. The pharmacopoeia according to any one of claims 2, 27, and 28, wherein the cancer comprises clonal pathogenicity of more than 95% of the pathogenic mutations in one or more of PIK3CA, PTEN, TSC1, and TSC2, and the PTEN mutation is a dominant-negative mutation.

32. The pharmaceutical product according to claim 28, wherein the dosage is approximately 13 mg to approximately 20 mg per week.

33. The pharmacopoeia according to any one of claims 13, 17, 27, and 28, wherein the dosage is administered by intravenous infusion.

34. The pharmaceutical product according to claim 33, wherein the dose is administered over a period of approximately 0.5 hours to approximately 2 hours.

35. The pharmaceutical product according to claim 33, wherein the dose is administered over approximately one hour.

36. The method further comprises administering a tacrolimus solution to a subject, according to any one of claims 1, 2, 13, 17, 27, and 28.

37. The pharmaceutical product according to claim 36, wherein the tacrolimus solution contains approximately 0.1 mg to approximately 1 mg of tacrolimus per 1 mL.

38. The pharmacopoeia according to claim 36, wherein the tacrolimus solution is administered once, twice, three times, or four times daily.

39. The pharmaceutical product according to claim 36, wherein a tacrolimus solution is used to treat or prevent mucositis in a subject that has been, is being treated, or will be treated with a compound.

40. The pharmaceutical product according to claim 39, wherein mucositis is a canker sore.

41. The pharmacopoeia according to claim 36, wherein the tacrolimus solution is administered on the day the dose is administered, or immediately before the dose is administered.

42. The method further comprises administering a RAS inhibitor to a subject, according to any one of claims 1, 2, 13, 17, 27, and 28.

43. The pharmaceutical product according to claim 42, wherein the RAS inhibitor is a KRAS (off) inhibitor.

44. The pharmaceutical product according to claim 42, wherein the RAS inhibitor is an RAS(on) inhibitor.

45. The pharmaceutical product according to any one of claims 1, 2, 13, 17, 27, and 28, wherein the subject is a human.

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