Single dosage forms containing elraglusib and at least one other active ingredient

Abstract

Disclosed herein are dosage forms comprising a combination of a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of: (a) at least one KRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) any combination of (a)-(d). The dosage forms of the present disclosure can be used to treat subjects suffering from one or more cancers.

Description

SINGLE DOSAGE FORMS CONTAINING ELRAGLUSIB AND AT LEAST ONE OTHER ACTIVE INGREDIENTRELATED APPLICATION INFORMATION

[0001] This application claims priority to U.S. Application No. 63 / 721,614 filed on November 18, 2024, the contents of which are herein incorporated by reference.FIELD

[0002] The present disclosure relates to single dosage forms comprising: a combination of a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of: (a) at least one KRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) any combination of (a)-(d). In some embodiments, the single dosage forms described are suitable for oral administration or intravenous administration for use in treating subjects suffering from one or more cancers.BACKGROUND

[0001] Difficult-to-treat cancers, such as pancreatic cancer, malignant bone tumors, soft tissue malignant tumors, brain cancer, and acute myeloid leukemia (AML), remain some of the most challenging diseases in oncology due to their aggressive progression, resistance to conventional therapies, and often poor prognosis. Together, these cancers impact hundreds of thousands of individuals worldwide each year, substantially reducing life expectancy and quality of life for patients and their families. For instance, pancreatic cancer alone affects over 60,000 people annually in the United States, with a five-year survival rate of less than 10% due to late-stage diagnoses and limited treatment effectiveness. Similarly, brain cancers, including aggressive forms like glioblastoma, present a five-year survival rate of only 5-10% and claim thousands of lives each year, hindered by limited therapeutic options and a high tendency to recur despite treatment.

[0002] Malignant bone and soft tissue tumors affect both children and adults, posing unique challenges as they often resist chemotherapy and radiotherapy, leaving surgical resection as the primary treatment option. AML, which predominantly affects older adults, exhibits survival ratesthat decline with age; while the five-year survival rate for patients under twenty years of age may reach around 65%, and drops significantly in older populations due to the disease’s aggressive nature and patients' reduced tolerance for intensive chemotherapy.

[0003] The high incidence, low survival rates, and limited effectiveness of existing treatments for these cancers underscore the need for innovative approaches targeting their unique biological mechanisms. Standard treatment approaches — surgery, radiation, and chemotherapy — remain essential in managing these cancers; however, they frequently prove inadequate, especially in advanced or recurrent cases. Pancreatic cancer, for instance, is known for evading early detection and quickly developing resistance to chemotherapy. Malignant bone and soft tissue tumors often recur despite aggressive surgical and radiation interventions, while brain cancers face the additional obstacle of the blood-brain barrier, which restricts drug delivery. Additionally, AML progresses rapidly and frequently relapses following initial chemotherapy.

[0004] These challenges are largely driven by the cancers’ capacity for genetic mutations, altered signaling pathways, and immune evasion, which allow them to survive and adapt despite conventional treatments. Consequently, there is an urgent need for innovative therapies that can precisely target the molecular drivers of these cancers while working synergistically with existing treatments and with each other to enhance efficacy. For example, patients may develop resistance to targeted anti-cancer agents by up-regulating or switching to compensatory pathways that circumvent the inhibition of the targeted agents. For example, resistance to BRAF inhibitors often occurs through activating or up-regulating MEK and thus MEK inhibitors given after BRAF or at the same time as BRAF inhibitors have shown superior clinical outcomes to BRAF inhibition alone (REF) (See, for example, Toye E., et al., “Targeting the multifaceted BRAF in cancer: New Directions”, Oncotarget, 15: 486-492 (July 16, 2024)). Advanced therapeutic approaches designed to counteract resistance mechanisms, when used in combination with current anticancer agents, offer promising potential to significantly improve patient outcomes for these hard-to-treat cancers.SUMMARY

[0003] In one embodiment, the present disclosure relates to a single dosage form. The single dosage form comprises: a combination of a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of: (a) at least oneKRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) any combination of (a)-(d), wherein the dosage form is suitable for oral administration or intravenous administration to a subject.

[0004] In some aspects, the dosage form is suitable for oral administration.

[0005] In further aspects, the dosage form is a solid dosage form. In yet further aspects, the solid dosage form is a capsule or tablet.

[0006] In yet further aspects, the dosage form is suitable for intravenous injection.

[0007] In still further aspects, the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one KRAS inhibitor. In yet still further aspects, the dosage form further comprises at least one mTOR inhibitor. In yet still further aspects, the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one BRAF inhibitor. In yet still yet further aspects, the dosage form further comprises at least one mTOR inhibitor. In yet still other aspects, the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one MEK inhibitor. In yet still further aspects, the dosage form further comprises at least one mTOR inhibitor. In still further aspects, the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one mTOR inhibitor.

[0008] In yet still further aspects, the therapeutically effective amount of elraglusib in the dosage form is from about from 0.1 mg / kg to about 100 mg / kg.

[0009] In yet still further aspects, the therapeutically effective amount of at least one KRAS inhibitor in the dosage form is from about 0.1 mg to about 2000 mg. Moreover, in still other aspects, the KRAS inhibitor is Sotorasib (LUMAKRAS), Adagrasib (KRAZATI), ASP2453, MRTX1133, Divarasib (GDC-6036; RG6330); MK-1084, RMC-6236, RMC-6291, RMC-9805, Olomorasib (LY3537982), Garsorasib (D-1553), Glecirasib (JAB-21822), Opnurasib (JDQ-443), HB 1-2438, HG-10370, IBI-351 (GFH925), BI-1823911, BI-3706674, JNJ-74699157, YL- 17231, YL-15293, BBO-8520, BEBT-607, D3S-001, FMC-376, GED255, GH35, HYP-2090PTSA, ZG19018, ASP3082, HRS-4642, INCB161734, TSN1611, QTX3034, MRTX1133, PF-07934040, or any combination thereof.

[0010] In yet still further aspects, the therapeutically effective amount of at least one BRAF inhibitor is from about 50 mg to about 2000 mg. In still yet further aspects, the BRAF inhibitor is dabrafenib, vemurafenib, encorafenib or any combination thereof.

[0011] In yet still further aspects, the therapeutically effective amount of at least one MEK inhibitor in the dosage form is from about 0.5 mg to about 500 mg. In still further aspects, the MEK inhibitor is trametinib, binimetinib, cobimetinib, or any combination thereof.

[0012] In still yet further aspects, the therapeutically effective amount of at least one mTOR inhibitor in the dosage form is from about 0.1 mg / kg to about 15 mg / kg. In yet still further aspects, the mTOR inhibitor is sirolimus, everolimus, temsirolimus, or any combination thereof.

[0013] In yet still further aspects, the dosage form further comprises one or more pharmaceutically acceptable excipients.

[0014] In yet another embodiment, the present disclosure relates to a method of treating a subject suffering from cancer. The method comprises the step of administering to a subject suffering from cancer a therapeutically effective amount of a dosage form described above. In the method, the cancer is brain cancer, lung cancer, breast cancer, head and neck cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, testicular cancer, bladder cancer, colorectal cancer, anal cancer, neuroblastoma, renal cancer, pancreatic cancer, bile duct cancer, liver cancer, gastric cancer, esophageal cancer, thyroid cancer, skin cancer, sarcomas, a malignant B-cell lymphoproliferative disorder, a malignant T-cell lymphoproliferative disorder, a myeloid malignancy, a histiocytic neoplasm, or any combination thereof. In yet other aspects, the cancer is a solid tumor.DETAILED DESCRIPTION

[0015] Provided herein are dosage forms that comprise a combination of a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of: (a) at least one KRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) any combination of (a)-(d). In some embodiments, the dosage forms described are suitable for oral administration or intravenous or subcutaneous administration to treat subjects suffering from one or more cancers.DEFINITIONS

[0016] The following terms are used to describe the invention of the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are well known and commonly used in the art. In case of conflict, the present disclosure, including definitions, will control. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the embodiments and aspects described herein.

[0018] Compounds and materials are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. The following terms are used to describe the invention of the present disclosure. In instances where a term is not specifically defined herein, that term is given an art-recognized meaning by those of ordinary skill applying that term in context to its use in describing the present disclosure.

[0019] The use of the terms “a” and “an” and “the” and similar referents (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. By way of example, "an element" means one element or more than one element.

[0020] As used herein, the term “substantially” means to a great or significant extent, but not completely.

[0021] It should also be understood that, in certain methods described herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited unless the context indicates otherwise. Furthermore, the terms first, second, etc., as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality of, for example, layers.

[0022] The terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms "a," "and", and "the" include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments "comprising," "consisting of," and "consisting essentially of," the embodiments or elements presented herein, whether explicitly set forth or not.

[0023] The terms “about” or “approximately,” as used herein, is inclusive of the stated value and means within an acceptable range of deviation for the particular value as determined by one of ordinary skill in the art, considering the measurement in question and the error associated with measurement of the particular quantity (i.e., the limitations of the measurement system). For example, “about” can mean within one or more standard deviations, or within ± 10% or 5% of the stated value. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All ranges disclosed herein include both end points as discrete values as well as all integers and fractions specified within the range. For example, a range of 0.1-2.0 includes 0.1, 0.2, 0.3, 0.4 . . . 2.0. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any nonclaimed element as essential to the practice of the invention as used herein.

[0024] The phrase "and / or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with "and / or" should be construed in the same fashion, i.e., "one or more" of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the "and / or" clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to "A and / or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to Aonly (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0025] As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of a number or list of elements. In general, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."

[0026] As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and / or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0027] The phrase "one or more," as used herein, means at least one, and thus includes individual components as well as mixtures / combinations of the listed components in any combination.

[0028] Other than in the examples, or where otherwise indicated, all numbers expressing quantities of ingredients and / or reaction conditions are to be understood as being modified in allinstances by the term "about," meaning within 10% of the indicated number (eg., "about 10%" means 9%-l 1% and "about 2%" means 1.8%-2.2%).

[0029] All percentages and ratios are calculated by weight unless otherwise indicated. All percentages are calculated based on the total composition unless otherwise indicated. Generally, unless otherwise expressly stated herein, "weight" or "amount" as used herein with respect to the percent amount of an ingredient refers to the amount of the raw material comprising the ingredient, wherein the raw material may be described herein to comprise less than and up to 100% activity of the ingredient. Therefore, weight percent of an active in a composition is represented as the amount of raw material containing the active that is used and may or may not reflect the final percentage of the active, wherein the final percentage of the active is dependent on the weight percent of active in the raw material.

[0030] All ranges and amounts given herein are intended to include subranges and amounts using any disclosed point as an end point. Thus, a range of "1% to 10%, such as 2% to 8%, such as 3% to 5%," is intended to encompass ranges of "1% to 8%," " 1% to 5%," "2% to 10%, " and so on. All numbers, amounts, ranges, etc., are intended to be modified by the term "about," whether or not so expressly stated. Similarly, a range given of "about 1% to 10%" is intended to have the term "about" modifying both the 1% and the 10% endpoints. Further, it is understood that when an amount of a component is given, it is intended to signify the amount of the active material unless otherwise specifically stated.

[0031] As used herein, the term "administering" means either directly administering a compound, composition, or dosage form of the present disclosure or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound(s), active ingredient(s), or substance(s) within the body of a subject or patient.

[0032] As used herein the term “B-cell lymphoproliferative disorder” refers to a disorder resulting from abnormal B lymphocytes in a subject or patient. These disorders are characterized by the uncontrolled growth and proliferation of B cells, which play a crucial role in producing antibodies and fighting infection. In malignant B-cell lymphoproliferative disorders, the affected B cells no longer function properly in defending the body against pathogens. Instead, the B-cells multiply excessively, crowding out healthy cells and potentially spreading to various parts of the body. Examples of malignant B-cell lymphoproliferative disorders include, but are not limited to, B-lymphoblastic leukemias / lymphomas (B-ALL / LBL), diffuse large B-cell lymphoma, acutelymphocytic leukemia, lymphoid blast phase chronic myeloid leukemia, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphomas, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL), nodal marginal zone lymphoma (NMZL), follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, hairy cell leukemia, splenic marginal zone lymphoma, primary central nervous system lymphoma, Waldenstrom’s macroglobulinemia / lymphoplasmacytic lymphoma, multiple myeloma, plasma cells dyscrasias, plasma cell neoplasms, primary mediastinal B-cell lymphoma, Hodgkin lymphoma, or any combination thereof.

[0033] As used herein, the term “BRAF inhibitor” refers to a therapeutic agent or drug designed to inhibit the activity of the BRAF protein, which is part of the mitogen-activated protein kinase (MAPK) signaling pathway. Mutations in the BRAF gene, particularly the V600E and V6000K mutations, lead to continuous activation of this pathway, promoting cell proliferation and survival, which can result in cancer. BRAF inhibitors work by selectively binding to and inhibiting the mutated BRAF kinase, thereby disrupting this signaling pathway and slowing tumor growth. Examples of BRAF inhibitors include, but are not limited to, vemurafenib (ZELBORAF), dabrafenib (TAFINLAR), or encorafenib (BRAFTOVI), or any combination thereof. Table A below provides information on the route of administration, the BRAF mutations targeted by each of these inhibitors, and dosage. Methods for making BRAF inhibitors, such as vemurafenib (ZELBORAF), dabrafenib (TAFINLAR), or encorafenib (BRAFTOVI), are well known in the art.Table AxThe dosage of any BRAF inhibitor recited in this table are merely exemplary and a person skilled in the art would understand that these dosages might need to be adjusted based on the pharmacokinetic and pharmacodynamic interactions between the combination of elraglusib or apharmaceutically acceptable salt thereof and at least one BRAF inhibitor contained in a single dosage form of the present disclosure. Additionally, potential synergistic or antagonistic effects may necessitate dose reductions or increases, respectively, to maintain optimal therapeutic efficacy while mitigating adverse events. Furthermore, the combined toxicity profile and potential for overlapping side effects might mandate dose reductions to ensure patient safety.

[0034] As used herein, the term “combination” is used in its broadest sense and means that a subject or patient is administered at least two active ingredients, active agents, or therapeutic agents, more particularly elraglusib or a pharmaceutically acceptable salt thereof (as a first active ingredient or agent) and at least one other active ingredient or agent (e.g., such as at least one KRAS inhibitor, at least one BRAF inhibitor, at least one MEK inhibitor, at least one mTOR inhibitor, or any combination thereof as the second active ingredient or agent). More particularly, the term “in combination” refers to the concomitant administration of two (or more) active ingredients or agents for the treatment of a, e.g., single disease state (e.g., the single disease state can be cancer). As used herein, the active ingredients or agents may be combined and administered in a single dosage form, may be administered as separate dosage forms at the same time, or may be administered as separate dosage forms that are administered alternately or sequentially on the same or separate days. In one embodiment, the active ingredients or agents are combined and administered in a single dosage form (e.g., a fixed dose combination). In another embodiment, the active ingredients or agents are administered in separate dosage forms (e g., wherein it is desirable to vary the amount of one but not the other). The single dosage form may include additional active ingredients or agents for the treatment of the same disease state (e.g. cancer). Alternatively, the single dosage form may include additional active ingredients or agents for the treatment of two different disease states.

[0035] Additionally, the active ingredients or agents disclosed herein can be administered alone or in combination with adjuvants or pharmaceutically acceptable excipients that enhance stability of the active ingredients or agents, alone or in combination with one or more other active ingredients or agents that facilitate administration of the dosage forms containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those active ingredients or agents are used as monotherapies.

[0036] As used herein, the term “elraglusib” or “9-TNG-41” as used interchangeably herein, refers to a Glycogen Synthase Kinase-3 (GSK-3) inhibitor having the chemical name 3-(5-Fluoro-benzofuran-3-yl)-4-(5-methyl-5H-[l,3]dioxolo[4,5f]indol-7-yl)-pyrrole-2, 5-dione and the molecular formula C22H13N2O5F. The chemical structure of elraglusib is shown below in Formula I.Formula I

[0037] In the dosage forms of the present disclosure, the elraglusib or pharmaceutically acceptable salt thereof can be used in amorphous form, crystalline form, or a combination of amorphous and crystalline forms.

[0038] Crystalline or solids forms of elraglusib are described in U.S. Patent No. 11,136,334 and U.S. Patent Publication No. 2022 / 0348591, the contents of each of which are herein incorporated by reference. Additionally, methods for making elraglusib or the crystalline (solid) forms thereof are described in U.S. Patent Nos. 8,207,216 and 11,136,334 and U.S. Patent Publication No. 2022 / 0348591, the contents of which are herein incorporated by reference.

[0039] The elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure can be in the form of amorphous solid dispersions (“ASDs”), tablets, liquid solutions, and liquid suspensions of elraglusib that are suitable for oral administration as described in WO 2024 / 006750.

[0040] As used herein, the phrase “KRAS inhibitor” refers to a therapeutic agent or drug designed to target and inhibit the activity of the KRAS protein, which is frequently mutated in a variety of cancers. KRAS is part of the RAS / MAPK signaling pathway, which regulates cell division, and mutations in KRAS are known to lead to uncontrolled cell growth and cancer. Examples of KRAS inhibitors include, but are not limited to, sotorasib (LUMAKRAS), adagrasib (KRAZATI), MRTX1133, divarasib (GDC-6036; RG6330); MK-1084, RMC-6236,RMC-6291, RMC-9805, olomorasib (LY3537982), garsorasib (D-1553), glecirasib (JAB-21822), opnurasib (JDQ-443), HBL2438, HG-10370, IBI-351 (GFH925), BI-1823911, BI-3706674, JNJ-74699157, YL-17231, YL-15293, BBO-8520, BEBT-607, D3S-001, FMC-376, GED255, GH35, HYP-2090PTSA, ZG19018, ASP3082, HRS-4642, INCB161734, TSN1611, QTX3034, MRTX1133, PF-07934040, and any combination thereof. Table B below provides information on the route of administration, the KRAS mutation targeted by each of these inhibitors, and dosage. Methods for making KRAS inhibitors, such as, sotorasib (LUMAKRAS), adagrasib (KRAZATI), MRTX1133, divarasib (GDC-6036; RG6330); MK-1084, RMC-6236, RMC-6291, RMC-9805, olomorasib (LY3537982), garsorasib (D-1553), glecirasib (JAB-21822), opnurasib (JDQ-443), HBI-2438, HG-10370, IBI-351 (GFH925), BI-1823911, BI-3706674, JNJ-74699157, YL-17231, YL-15293, BBO-8520, BEBT-607, D3S-001, FMC-376, GED255, GH35, HYP-2090PTSA, ZG19018, ASP3082, HRS-4642, INCB161734, TSN1611, QTX3034, MRTX1133, and PF-07934040 are well known in the art.Table Bskilled in the art would understand that these dosages might need to be adjusted based on the pharmacokinetic and pharmacodynamic interactions resulting from the combination of elraglusib or a pharmaceutically acceptable salt thereof and at least one KRAS inhibitor contained in a single dosage form of the present disclosure. Additionally, potential synergistic or antagonistic effects may necessitate dose reductions or increases, respectively, to maintain optimal therapeutic efficacy while mitigating adverse events. Furthermore, the combined toxicity profile and potential for overlapping side effects might mandate dose reductions to ensure patient safety.

[0041] As used herein, a “MEK inhibitor” refers to a therapeutic agent or drug designed to target and inhibit mitogen-activated protein kinase enzymes MEK1 and / or MEK2. These inhibitors target the Ras / Raf / MEK / ERK signaling pathway, which plays a critical role in regulating cellular activities such as proliferation, survival, differentiation, and motility. MEK inhibitors work by: (1) blocking the activity of MEK 1 and MEK2 enzymes in the MAPK / ERK pathway; (2) inhibiting cell proliferation; and / or (3) inducing apoptosis (programmed cell death) in cancer cells. MEK inhibitors have shown potential in treating various cancers, particularly those with dysregulation of the MAPK pathway. Approximately 80% of tumors develop BRAF inhibitor resistance via reactivation of MAPK signaling. To prevent or overcome this resistance, combination of MEK and BRAF inhibitors were approved by the FDA for the treatment of cancer. Examples of MEK inhibitors include trametinib, binimetinib, cobimetinib, or any combination thereof. Table C below provides information on the route of administration and dosage. Methods for making MEK inhibitors such as trametinib, binimetinib, and cobimetinib, are well known in the art.TABLE Cin the art would understand that these dosages might need to be adjusted based on the pharmacokinetic and pharmacodynamic interactions between the combination of elraglusib or a pharmaceutically acceptable salt thereof and at least one MEK inhibitor contained in a single dosage form of the present disclosure. Additionally, potential synergistic or antagonistic effects may necessitate dose reductions or increases, respectively, to maintain optimal therapeutic efficacy while mitigating adverse events. Furthermore, the combined toxicity profile and potential for overlapping side effects might mandate dose reductions to ensure patient safety.

[0042] As used herein, a “mTOR inhibitor” refers to a therapeutic agent or drug designed to target and inhibit the mammalian target of rapamycin (mTOR), a serine / threonine protein kinase that plays a crucial role in cell growth, proliferation, and survival. mTOR is a key component of two distinct protein complexes: mTORCl and mT0RC2, which regulate various cellular processes including protein synthesis, lipid metabolism, autophagy, and cell cycle progression. mTOR inhibitors work by binding to the FKBP12 protein, forming a complex that inhibits mTOR kinase activity. This inhibition leads to decreased protein synthesis, cell cycle arrest, and potentially increased autophagy. There are two types of mTOR inhibitors, first generation and second generation. The first generation mTOR inhibitors inhibit mTORCl (e.g., sirolimus, everolimus, temsirolimus, or any combinatios thereof). The second generation mTOR inhibitors target both mTORCl and mT0RC2 complexes (e.g., AZD8055, OSI-027). The present disclosure focuses on first generation mTOR inhibitors. Table D below provides information on the route of administration, and dosage for the first generation mTOR inhibitors, sirolimus, everolimus, and temsirolimus. Methods for making mTOR inhibitors, such as sirolimus, everolimus, and temsirolimus are well known in the art.TABLE D1The dosage of any mTOR inhibitor recited in this table is merely exemplary and a personskilled in the art would understand that these dosages might need to be adjusted based on the pharmacokinetic and pharmacodynamic interactions between the combination of elraglusib or a pharmaceutically acceptable salt thereof and at least one mTOR inhibitor contained in a single dosage form of the present disclosure. Additionally, potential synergistic or antagonistic effects may necessitate dose reductions or increases, respectively, to maintain optimal therapeutic efficacy while mitigating adverse events. Furthermore, the combined toxicity profile and potential for overlapping side effects might mandate dose reductions to ensure patient safety.

[0043] As used herein, the term “myeloid malignancy” refers to a clonal disorder that originates in hematopoietic stem or progenitor cells within the bone marrow of a subject or patient. These diseases are characterized by abnormal proliferation, impaired self-renewal, and / or defective differentiation of myeloid lineage cells. Examples of myeloid malignancies include, but are not limited to: (a) acute myeloid leukemia (AML); (b) myelodysplastic syndromes (MDS); (c) myeloproliferative neoplasms (MPN), such as, chronic myeloid leukemia (CML), primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia, chronic neutrophilic leukemia, and / or chronic eosinophilic leukemia; (d) mastocytosis; or (e) any combination of (a)-(d).

[0044] The term “subject” or “patient” is used herein to refer to an animal, such as a mammal, including a primate (such as a human, a non-human primate, e.g., a monkey, and a chimpanzee), a non-primate (such as a cow, a pig, a camel, a llama, a horse, a goat, a rabbit, a sheep, a hamster, a guinea pig, a cat, a dog, a rat, a mouse, and a whale), a bird (e.g., a duck or a goose), and a shark. In an embodiment, the subject or patient is a human subject or a human patient, such as a humanbeing treated or assessed for a disease, disorder or condition, a human at risk for a disease, disorder or condition, a human having a disease, disorder or condition, and / or human being treated for a disease, disorder or condition as described herein. In one embodiment, the subject is about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years of age. In another embodiment, the subject is about 5-10, 10-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50, 50-55, 55-60, 60-65, 65-70, 70-75, 75-80, 80-85, 85-90, 90-95, 95-100 years of age. Values and ranges intermediate to the above recited ranges are also intended to be part of this invention. In addition, ranges of values using a combination of any of the above-recited values as upper and / or lower limits are intended to be included. As used herein, a subject is “in need of treatment” if such subject would benefit biologically, medically, or in quality of life from such treatment. A subject in need of treatment does not necessarily present symptoms, particular in the case of preventative or prophylaxis treatments.

[0045] The phrase, “pharmaceutically acceptable”, whether by itself or in conjunction with another term or terms, indicates that the designated entity such as, for example, a pharmaceutically acceptable excipient, is generally chemically and / or physically compatible with other ingredients in a composition, and / or is generally physiologically compatible with the recipient thereof.

[0046] The phrase, “pharmaceutically acceptable salt” as used herein refers to a salt of a compound (e.g., active ingredient or agent) described herein that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyljbenzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-di sulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid,and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0047] As used herein, the phrase, “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an active ingredient or agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. Pharmaceutically acceptable excipients will be known to those of skill in the art, and include, for example, excipients described in treatises such as, for example, Paul J. Sheskey, et al. (eds), Handbook of Pharmaceutical Excipients, Pharmaceutical Press,' 9th Revised edition (October 20, 2020).

[0048] As used herein, the term “solid dispersion” refers to a solid material in which an active ingredient or agent is dispersed in another material, such as one more polymers.

[0049] As used herein, whether by itself or in conjunction with another term or terms, it should be understood that the phrases "method of treating" and "method of treatment" may be used interchangeably with the phrase "for use in the treatment of a particular disorder or disease”.

[0050] As used herein the term “T-cell lymphoproliferative disorder” refers to a disorder resulting from abnormal T lymphocytes in a subject or patient. These disorders are characterized by the uncontrolled growth and proliferation of T cells, which are responsible for destroying cells infected by pathogens or that have become cancerous. Examples of malignant T-cell lymphoproliferative disorders include, but are not limited to, T-lymphoblastic leukemia / lymphoma (T-ALL / LBL), T-cell leukemia / lymphoma, extranodal natural killer / T-cell lymphoma, cutaneous T-cell lymphoma, intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, peripheralT-cell lymphoma, T-cell acute lymphocytic leukemia, mature T-cell leukemias, lymphoid blast phase chronic myeloid leukemia, post-transplantation lymphoproliferative disorder, EBV-positive T-cell lymphomas, unspecified T-cell lymphoma, or any combination thereof.

[0051] As used herein, whether used alone or in conjunction with another term or terms, "therapeutic" and "therapeutically effective amount" refer to an amount of a compound or composition that (a) treats a particular condition, symptom, disorder, or disease described herein; (b) attenuates, ameliorates, or eliminates one or more symptoms of a particular condition, disorder, or disease described herein; (c) delays the onset or relapse (reoccurrence) of a particular condition, symptom, disorder, or disease described herein; (d) prevents the onset of a particular condition, symptom, disorder, or disease described herein. It should be understood that the terms "therapeutic" and "therapeutically effective" encompass any one of the aforementioned effects (a)-(d), either alone or in combination with any of the others (a)-(d).

[0052] As used herein, whether by themselves or in conjunction with another term or terms, "treats," "treating," "treated," and "treatment," refer to and include ameliorative, palliative, and / or curative uses and results, or any combination thereof. In other embodiments, the methods described herein can be used prophylactically, that is, preventatively. It should be understood that "prophylaxis" or a prophylactic use or result do not refer to nor require absolute or total prevention (i.e., a 100% preventative or protective use or result). As used herein, prophylaxis or a prophylactic (preventative) use or result refers to uses and results in which administration of a compound or composition diminishes or reduces the severity of a particular condition, symptom, disorder, or disease described herein; diminishes or reduces the likelihood of experiencing a particular condition, symptom, disorder, or disease described herein; or delays the onset or relapse (reoccurrence) of a particular condition, symptom, disorder, or disease described herein; or any combination of the foregoing.I. Dosage Forms

[0053] In one embodiment, the present disclosure relates to a dosage form comprising at least two active ingredients. In still other embodiments, the present disclosure relates to a dosage form that comprises at least three active ingredients. In still other embodiments, the present disclosure relates to a dosage form that comprises at least four active ingredients. The dosage forms of the present disclosure comprise a therapeutically effective amount of elraglusib or a pharmaceuticallyacceptable salt thereof and at least one, two, or three other active ingredients. More specifically, the one, two, or three other active ingredients can be at least one KRAS inhibitor, at least one BRAF inhibitor, at least one MEK inhibitor, at least one mTOR inhibitor or any combination thereof.

[0054] The dosages forms described herein can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others. The dosage forms may optionally contain one or more pharmaceutically acceptable excipients and / or solvents, diluents, and other liquid vehicles, dispersion or suspension aids, surface active agents, pH modifiers, isotonic agents, thickening or emulsifying agents, stabilizers and preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.

[0055] More specifically, in some embodiments, the dosage form is a single dosage form (e g., a single fixed dose dosage form) that comprises elraglusib or a pharmaceutically acceptable salt thereof and at least one KRAS inhibitor. In other embodiments, the dosage form is a single dosage form that comprises elraglusib or a pharmaceutically acceptable salt thereof and at least one BRAF inhibitor. In still other embodiments, the dosage form is a single dosage form that comprises elraglusib or a pharmaceutically acceptable salt thereof and at least one MEK inhibitor. In yet still other embodiments, the dosage form is a single dosage form that comprises elraglusib or a pharmaceutically acceptable salt thereof and at least one mTOR inhibitor. In yet still other embodiments, the dosage form is a single dosage form that comprises elraglusib or a pharmaceutically acceptable salt thereof, at least one KRAS inhibitor, and at least one BRAF inhibitor. In yet still other embodiments, the dosage form is a single dosage form that comprises elraglusib or a pharmaceutically acceptable salt thereof, at least one KRAS inhibitor and at least one MEK inhibitor. In yet still other embodiments, the dosage form is a single dosage form that comprises elraglusib or a pharmaceutically acceptable salt thereof, at least one KRAS inhibitor, and at least one mTOR inhibitor. In yet still other embodiments, the dosage form is a single dosage form that comprises elraglusib or a pharmaceutically acceptable salt thereof, at least one BRAF inhibitor, and at least one MEK inhibitor. In yet still other embodiments, the dosage form is a single dosage form that comprises elraglusib or a pharmaceutically acceptable salt thereof, at least one BRAF inhibitor, and at least one and at least one mTOR inhibitor. In yet still other embodiments, the dosage form is a single dosage form that comprises elraglusib or apharmaceutically acceptable salt thereof, at least one MEK inhibitor, and at least one mTOR inhibitor. In yet still other embodiments, the dosage form is a single dosage form that comprises elraglusib or a pharmaceutically acceptable salt thereof, at least one KRAS inhibitor, at least one BRAF inhibitor, and at least one MEK inhibitor. In yet still other embodiments, the dosage form is a single dosage form that comprises elraglusib or a pharmaceutically acceptable salt thereof, at least one KRAS inhibitor, at least one BRAF inhibitor, at least one MEK inhibitor, and at least one mTOR inhibitor.

[0056] In some embodiments, the dosage form is a solid dosage form. A solid dosage form is a pharmaceutical product that has a definite shape and volume. In the context of the present disclosure, a single solid dosage form contains at least two active ingredients, namely, at least elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of: (a) at least one KRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) any combination of (a)-(d), as well as one or more pharmaceutically acceptable excipients suitable for inclusion in a solid dosage form. In some embodiments, the solid dosage form is a tablet, such as an immediate-release tablet, a sustained-release tablet, a controlled-release tablet, a chewable tablet, and / or a buccal or sublingual tablet. Methods for making immediate-release tablets, sustained-release tablets, controlled-release tablets, chewable tablets, and / or buccal or sublingual tablets is well known in the art.

[0057] In some embodiments, the solid dosage form is in a tablet, such as an immediate-release tablet, a sustained-release tablet, a controlled-release tablet, a chewable tablet, and / or a buccal or sublingual tablet that contains at least elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of: (a) at least one KRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) any combination of (a)-(d), as active ingredients, and one or more pharmaceutically acceptable excipients. In further embodiments, the tablet is orally administered to a subject in need of treatment thereof, such as, for example, a subject suffering from at least one cancer.

[0058] Alternatively, the solid dosage form is a capsule, such as a hard-shelled capsule or a soft-shelled capsule. Thus, in some embodiments, the solid dosage form is a hard-shelled or soft-shelled capsule that contains at least elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of: (a) at least one KRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) anycombination of (a)-(d), as active ingredients, and one or more pharmaceutically acceptable excipients suitable for use in capsules. . In further embodiments, the capsule is orally administered to a subject in need of treatment thereof, such as, for example, a subject suffering from at least one cancer.

[0059] In still other embodiments, the solid dosage form is in the form of a powder, bead, beadlet, granule, microparticle, nanoparticle or any combination thereof. Methods for making powders, beads, beadlets, granules, microparticles, and nanoparticles are well known in the art. Thus, in some embodiments, the solid dosage form is a powder, bead, beadlet, granule, microparticle, nanoparticle or any combination thereof that contains at least elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of: (a) at least one KRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) any combination of (a)-(d), as active ingredients, and one or more pharmaceutically acceptable excipients suitable for use in powders, beads, beadlets, granules, microparticles and nanoparticles. In further embodiments, the powder, bead, beadlet, granule, microparticle, nanoparticle, or any combination thereof is orally administered to a subject in need of treatment thereof, such as, for example, a subject suffering from at least one cancer. Additionally, in some embodiments, the powder, bead, beadlet, granule, microparticle, nanoparticle, or any combination thereof is supplied to the subject or patient in the form of a sachet.

[0060] In addition to the one or more adjuvants and / or pharmaceutically acceptable excipients, the solid dosage form formulated for oral administration as described herein can also contain one or more flavoring agents and / or coloring agents.

[0005] In still other embodiments, the dosage form is a liquid dosage form. In some aspects, the dosage form is a single liquid dosage form. A liquid dosage form is a pharmaceutical product that is in a fluid state at room temperature. In the context of the present disclosure, a single liquid dosage form contains at least two active ingredients, namely, at least elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of: (a) at least one KRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) any combination of (a)-(d), dissolved or suspended in a liquid vehicle, such as water or a mixture of water and other pharmaceutically acceptable solvents. Additionally, theliquid dosage form may also contain other adjuvants and / or pharmaceutically acceptable excipients suitable for use in such dosage forms.

[0061] In some embodiments, the liquid dosage forms described herein are formulated or prepared for administration to a subject in need of treatment thereof parentally, such as by injection. For example, the liquid dosage forms described herein can be formulated or prepared for administration to a subject in need of treatment such as, intravenously, intramuscularly, subcutaneously, intradermally, epidermally, or any combination thereof. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable dosage form can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Dosage forms for parenteral administration may be injected by bolus injection or by timed push or may be administered by continuous infusion.

[0062] In yet other embodiments, the liquid dosage forms described herein are formulated or prepared for oral administration to a subject in need of treatment thereof in the form of a liquid, an emulsion, a microemulsion, a gel, a syrup, a slurry, a suspension, or any combination thereof. In addition to the active ingredients, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, cyclodextrins, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the dosage forms of the present disclosure can also includeadjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0063] In still even further embodiments, the dosage form is a single dosage form that is a single solid dosage form or a single liquid dosage form.

[0064] In some embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.01 mg / kg and about 100 mg / kg daily. In yet other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.05 mg / kg and about 100 mg / kg daily. In yet other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.05 mg / kg and about 90 mg / kg daily. In yet other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.05 mg / kg and about 80 mg / kg daily. In yet other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.05 mg / kg and about 70 mg / kg daily. In yet other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.05 mg / kg and about 60 mg / kg daily. In yet other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.05 mg / kg and about 50 mg / kg daily. In yet other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.05 mg / kg and about 40 mg / kg daily. In yet other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.05 mg / kg and about 30 mg / kg daily. In yet other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.05 mg / kg and about 20 mg / kg daily. In yet other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 0.05 mg / kg and about 10mg / kg daily. Tn still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about TOO mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about 90 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about 80 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about 70 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about 60 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about 50 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about 300 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about 40 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about 30 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about 20 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is from between about 1 mg / kg and about lOmg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 5 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 10 mg / kg daily. In still other embodiments, the therapeuticallyeffective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 15 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 20 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 25 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 35 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 45 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 50 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 60 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 70 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 75 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 80 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 90 mg / kg daily. In still other embodiments, the therapeutically effective amount of elraglusib or pharmaceutically acceptable salt thereof used in the dosage forms of the present disclosure is about 100 mg / kg daily. The exact dosage of elraglusib or pharmaceutically acceptable salt thereof in the dosage forms of the present disclosure will depend upon the other one, two, three or four active ingredients or agents administered, the disease state to be treated (e.g., cancer), the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.In some embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.01 mg to about 2000 mg daily. In still other embodiments, the therapeutically effective amount of at least one KRASinhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 2000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 2000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 1500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 1000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 900 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 800 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 600 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 200 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 100 mg daily. In still other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 2000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 2000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to1about 1500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 1000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 900 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 800 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 600 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 200 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 100 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 2000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 1500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 1000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 900 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 800 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor usedin the dosage forms of the present disclosure is from between about 50 mg to about 600 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 200 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 100 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 100 mg / kg to about 2000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 1000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 1000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 900 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 800 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 600 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 300 mg daily. In yet otherembodiments, the therapeutically effective amount of at least one KRAS inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 200 mg daily. The exact dosage of at least one KRAS inhibitor in the dosage forms of the present disclosure will depend upon the other one, two, three or four active ingredients or agents administered, the disease state to be treated (e.g., cancer), the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. In yet further embodiments, at least one KRAS inhibitor used in the dosage form at the above dosage is sotorasib (LUMAKRAS), adagrasib (KRAZATI), ASP2453, MRTX1133, divarasib (GDC-6036; RG6330); MK-1084, RMC-6236, RMC-6291, RMC-9805, olomorasib (LY3537982), garsorasib (D-1553), glecirasib (JAB-21822), opnurasib (JDQ-443), HBI-2438, HG-10370, IBI-351 (GFH925), BI-1823911, BI-3706674, JNJ-74699157, YL-17231, YL-15293, BBO-8520, BEBT-607, D3S-001, FMC-376, GED255, GH35, HYP-2090PTSA, ZG19018, ASP3082, HRS-4642, INCB161734, TSN1611, QTX3034, MRTX1133, PF-07934040, or any combination thereof. In still even further embodiments, the dosage form is a single dosage form that is a solid dosage form or a liquid dosage form.

[0065] In some embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.01 mg to about 2000 mg daily. In still other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 2000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg / kg to about 2000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg / kg to about 1500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 1000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 900 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 800 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in thedosage forms of the present disclosure is from between about 0.05 mg to about 600 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 200 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 100 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 2000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 1500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 1000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 900 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 800 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 600 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 200 mg daily.In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 100 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 2000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 1000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 1000 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 900 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 800 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 600 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one BRAF inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 200 mg daily. The exact dosage of at least one BRAF inhibitor in the dosage forms of the present disclosure will depend upon the other one, two, three or four active ingredients or agents administered, the disease state to be treated (e.g., cancer), the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. In yet further embodiments, at least one BRAF inhibitor in the dosage form used in the above dosage is dabrafenib, vemurafenib, encorafenib, or any combination thereof. In still even further embodiments, the dosage form is a single dosage form that is a solid dosage form or a liquid dosage form.

[0066] In some embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.01 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 200 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 100 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.5 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.5 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.5 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.5 mg to about 200 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 0.5 mg to about 100 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 50 mg to about 200 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitorused in the dosage forms of the present disclosure is from between about 50 mg to about 100 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one MEK inhibitor used in the dosage forms of the present disclosure is from between about 100 mg to about 200 mg daily. The exact dosage of at least one MEK inhibitor in the dosage forms of the present disclosure will depend upon the other one, two, three or four active ingredients or agents administered, the disease state to be treated (e.g., cancer), the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. In yet further embodiments, at least one MEK inhibitor used in the dosage form at the above dosage is trametinib, binimetinib, cobimetinib, or any combination thereof. In still even further embodiments, the dosage form is a single dosage form that is a solid dosage form or a liquid dosage form.

[0067] In some embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.01 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 200 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 100 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 75 mg daily. In yet other embodiments, the therapeuticallyeffective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 50 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 25 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.05 mg to about 15 mg daily. In still yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 500 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 400 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 300 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 200 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 100 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 75 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 50 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 25 mg daily. In yet other embodiments, the therapeutically effective amount of at least one mTOR inhibitor used in the dosage forms of the present disclosure is from between about 0.1 mg to about 15 mg daily. The exact dosage of at least one mTOR inhibitor in the dosage forms of the present disclosure will depend upon the other one, two, three or four active ingredients or agents administered, the disease state to be treated (e.g., cancer), the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician. In yet further embodiments, at least one mTOR inhibitor used in the dosage form at the above dosage is sirolimus, everolimus, temsirolimus, or any combination thereof. In still even furtherembodiments, the dosage form is a single dosage form that is a solid dosage form or a liquid dosage form.II. Methods of Treatment

[0068] In certain embodiments, the present disclosure relates to methods of treatment. More specifically, the method herein involves treating a subject or patient identified as suffering from cancer with a single dosage form (such as a single solid dosage form or a single liquid dosage form) as described in Section I.

[0069] In some embodiments, the methods involve treating a subject identified as suffering from cancer. A subject identified as having cancer is then administered a therapeutically effective amount of the single dosage form described in Section I. In some aspects, the cancer comprises a solid tumor.

[0070] In yet other embodiments, the cancer identified in the subject is brain cancer, lung cancer, breast cancer, head and neck cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, testicular cancer, bladder cancer, colorectal cancer, anal cancer, neuroblastoma, renal cancer, pancreatic cancer, bile duct cancer, liver cancer, gastric cancer, esophageal cancer, thyroid cancer, skin cancer, sarcomas, a malignant B-cell lymphoproliferative disorder, a malignant T-cell lymphoproliferative disorder, a myeloid malignancy, a histiocytic neoplasm, or any combination thereof. A subject identified as having one or more of these cancers is administered a therapeutically effective amount of at least single dosage form as described in Section I.

[0071] In some aspects, the method involves treating a subject identified as having brain cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0072] In some aspects, the method involves treating a subject identified as having lung cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0073] In some aspects, the method involves treating a subject identified as having ovarian cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0074] In some aspects, the method involves treating a subject identified as having uterine cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0075] In some aspects, the method involves treating a subject identified as having cervical cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0076] In some aspects, the method involves treating a subject identified as having prostate cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0077] In some aspects, the method involves treating a subject identified as having testicular cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0078] In some aspects, the method involves treating a subject identified as having bladder cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0079] In some aspects, the method involves treating a subject identified as having colorectal cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0080] In some aspects, the method involves treating a subject identified as having anal cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0081] In some aspects, the method involves treating a subject identified as having neuroblastoma with a therapeutically effective amount of at least one single dosage form described in Section I.

[0082] In some aspects, the method involves treating a subject identified as having renal cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0083] In some aspects, the method involves treating a subject identified as having pancreatic cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0084] In some aspects, the method involves treating a subject identified as having bile duct cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0085] In some aspects, the method involves treating a subject identified as having liver cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0086] In some aspects, the method involves treating a subject identified as having gastric cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0087] In some aspects, the method involves treating a subject identified as having esophageal cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0088] In some aspects, the method involves treating a subject identified as having thyroid cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0089] In some aspects, the method involves treating a subject identified as having skin cancer with a therapeutically effective amount of at least one single dosage form described in Section I.

[0090] In some aspects, the method involves treating a subject identified as having a sarcoma with a therapeutically effective amount of at least one single dosage form described in Section I.

[0091] In some aspects, the method involves treating a subject identified as having a malignant B-cell lymphoproliferative disorder with a therapeutically effective amount of at least one single dosage form described in Section I. In some aspects, the malignant B-cell lymphoproliferative disorder is B-lymphoblastic leukemias / lymphomas (B-ALL / LBL), diffuse large B-cell lymphoma, acute lymphocytic leukemia, lymphoid blast phase chronic myeloid leukemia, chronic lymphocytic leukemia / small lymphocytic lymphoma, marginal zone lymphomas, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL), nodal marginal zone lymphoma (NMZL), follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, hairy cell leukemia, splenic marginal zone lymphoma, primary central nervous system lymphoma, Waldenstrom’s macroglobulinemia / lymphoplasmacytic lymphoma, multiple myeloma, plasma cells dyscrasias, plasma cell neoplasms, primary mediastinal B-cell lymphoma, Hodgkin lymphoma, or any combination thereof.

[0092] In some aspects, the method involves treating a subject identified as having a malignant T-cell lymphoproliferative disorder with a therapeutically effective amount of at least one single dosage form described in Section I. In some aspects, the malignant T-cell lymphoproliferative disorder is T-lymphoblastic leukemia / lymphoma (T-ALL / LBL), T-cell leukemia / lymphoma, extranodal natural killer / T-cell lymphoma, cutaneous T-cell lymphoma, intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, peripheral T-cell lymphoma, T-cell acute lymphocytic leukemia, mature T-cell leukemias, lymphoid blast phase chronic myeloid leukemia, post-transplantation lymphoproliferative disorder, EBV-positive T-cell lymphomas, unspecified T-cell lymphoma, or any combination thereof.

[0093] In some aspects, the method involves treating a subject identified as having a myeloid malignancy with a therapeutically effective amount of at least one single dosage form described in Section I. In some aspects, the myeloid malignance is: (a) acute myeloid leukemia (AML); (b) myelodysplastic syndromes (MDS); (c) myeloproliferative neoplasms (MPN), such as, chronic myeloid leukemia (CML), primary myelofibrosis (PMF), polycythemia vera (PV), essentialthrombocythemia, chronic neutrophilic leukemia, and / or chronic eosinophilic leukemia; (d) mastocytosis; or (e) any combination of (a)-(d).

[0094] In some aspects, the method involves treating a subject identified as having a histiocytic neoplasm with a therapeutically effective amount of at least one single dosage form described in Section I.

[0095] Certain aspects of the presently disclosed subject matter having been stated herein above, which are addressed in whole or in part by the presently disclosed subject matter, other aspects will become evident as the description proceeds when taken in connection with the accompanying examples.

[0096] EXAMPLESINCORPORATION BY REFERENCE

[0097] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. In case of conflict, the present application, including any definitions herein, will control.

[0098] The present disclosure has multiple aspects, illustrated by the non-limiting examples described herein.

[0099] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the disclosure, which is defined solely by the appended claims and their equivalents.

[0100] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the disclosure, may be made without departing from the spirit and scope thereof.

[0101] For reasons of completeness, various aspects of the disclosure are set out in the following numbered clauses:

[0102] Clause 1. A single dosage form comprising: a combination of a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeuticallyeffective amount of: (a) at least one KRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) any combination of (a)-(d), wherein the dosage form is suitable for oral administration or intravenous administration to a subject.

[0103] Clause 2. The dosage form of clause 1, wherein the dosage form is suitable for oral administration.

[0104] Clause 3. The dosage form of clause 2, wherein the dosage form is a solid dosage form.

[0105] Clause 4. The dosage form of clause 3, wherein the solid dosage form is a capsule or tablet.

[0106] Clause 5. The dosage form of clause 1, wherein the dosage form is suitable for intravenous injection.

[0107] Clause 6. The dosage form of any of clauses 1 to 5, wherein the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one KRAS inhibitor.

[0108] Clause 7. The dosage form of clause 6, wherein the dosage form further comprises at least one mTOR inhibitor.

[0109] Clause 8. The dosage form of any of clause 1 to 5, wherein the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one BRAF inhibitor.

[0110] Clause 9. The dosage form of clause 8, wherein the dosage form further comprises at least one mTOR inhibitor.

[0111] Clause 10. The dosage form of any of clauses 1 to 5, wherein the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one MEK inhibitor.

[0112] Clause 11. The dosage form of clause 10, wherein the dosage form further comprises at least one mTOR inhibitor.

[0113] Clause 12. The dosage form of any of clauses 1 to 5, wherein the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one mTOR inhibitor.

[0114] Clause 13. The dosage form of any of clauses 1 to 12, wherein the therapeutically effective amount of elraglusib is from about from 0.1 mg / kg to about 100 mg / kg.

[0115] Clause 14. The dosage form of any of clauses 1 to 13, wherein the therapeutically effective amount of at least one KRAS inhibitor is from about 0.1 mg to about 2000 mg.

[0116] Clause 15. The dosage form of any of clauses 1 to 14, wherein the KRAS inhibitor is Sotorasib (LUMAKRAS), Adagrasib (KRAZATI), ASP2453, MRTX1133, Divarasib (GDC-6036; RG6330); MK-1084, RMC-6236, RMC-6291, RMC-9805, Olomorasib (LY3537982), Garsorasib (D-1553), Glecirasib (JAB-21822), Opnurasib (JDQ-443), HBI-2438, HG-10370, IBI-351 (GFH925), BI-1823911, BI-3706674, JNJ-74699157, YL-17231, YL-15293, BBO-8520, BEBT-607, D3S-001, FMC-376, GED255, GH35, HYP-2090PTSA, ZG19018, ASP3082, HRS-4642, INCB 161734, TSN1611, QTX3034, MRTX1133, PF-07934040, or any combination thereof.

[0117] Clause 16. The dosage form of any of clauses 1 to 15, wherein the therapeutically effective amount of at least one BRAF inhibitor is from about 50 mg to about 2000 mg.

[0118] Clause 17. The dosage form of any of clauses 1 to 16, wherein the BRAF inhibitor is dabrafenib, vemurafenib, encorafenib or any combination thereof.

[0119] Clause 18. The dosage form of any of clauses 1 to 17, wherein the therapeutically effective amount of at least one MEK inhibitor is from about 0.5 mg to about 500 mg.

[0120] Clause 19. The dosage form of any of clauses 1 to 18, wherein the MEK inhibitor is trametinib, binimetinib, cobimetinib, or any combination thereof.

[0121] Clause 20. The dosage form of any of clauses 1 to 19, wherein the therapeutically effective amount of at least one mTOR inhibitor is from about 0.1 mg / kg to about 15 mg / kg.

[0122] Clause 21. The dosage form of any of any of clauses 1 to 20, wherein the mTOR inhibitor is sirolimus, everolimus, temsirolimus, or any combination thereof.

[0123] Clause 22. The dosage form of any of clauses 1 to 21, wherein the dosage form further comprises one or more pharmaceutically acceptable excipients.

[0124] Clause 23. A method of treating a subject suffering from cancer, the method comprising the step of administering to a subject suffering from cancer a therapeutically effective amount of a dosage form of any of clauses 1-22.

[0125] Clause 24. The method of clause 23, wherein the cancer is brain cancer, lung cancer, breast cancer, head and neck cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, testicular cancer, bladder cancer, colorectal cancer, anal cancer, neuroblastoma, renal cancer, pancreatic cancer, bile duct cancer, liver cancer, gastric cancer, esophageal cancer,thyroid cancer, skin cancer, sarcomas, a malignant B-cell lymphoproliferative disorder, a malignant T-cell lymphoproliferative disorder, a myeloid malignancy, a histiocytic neoplasm, or any combination thereof.

[0126] Clause 25. The method of clause 23 or clause 24, wherein the cancer is a solid tumor.

Claims

WHAT IS CLAIMED IS:

1. A single dosage form comprising: a combination of a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of: (a) at least one KRAS inhibitor; (b) at least one BRAF inhibitor; (c) at least one MEK inhibitor; (d) at least one mTOR inhibitor; or (e) any combination of (a)-(d), wherein the dosage form is suitable for oral administration or intravenous administration to a subject.

2. The dosage form of claim 1, wherein the dosage form is suitable for oral administration.

3. The dosage form of claim 2, wherein the dosage form is a solid dosage form.

4. The dosage form of claim 3, wherein the solid dosage form is a capsule or tablet.

5. The dosage form of claim 1, wherein the dosage form is suitable for intravenous injection.

6. The dosage form of any of claims 1 to 5, wherein the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one KRAS inhibitor.

7. The dosage form of claim 6, wherein the dosage form further comprises at least one mTOR inhibitor.

8. The dosage form of any of claim 1 to 5, wherein the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one BRAF inhibitor.

9. The dosage form of claim 8, wherein the dosage form further comprises at least one mTOR inhibitor.

10. The dosage form of any of claims 1 to 5, wherein the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one MEK inhibitor.

11. The dosage form of claim 10, wherein the dosage form further comprises at least one mTOR inhibitor.

12. The dosage form of any of claims 1 to 5, wherein the dosage form comprises a therapeutically effective amount of elraglusib or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of at least one mTOR inhibitor.

13. The dosage form of any of claims 1 to 12, wherein the therapeutically effective amount of elraglusib is from about from 0.1 mg / kg to about 100 mg / kg.

14. The dosage form of any of claims 1 to 13, wherein the therapeutically effective amount of at least one KRAS inhibitor is from about 0.1 mg to about 2000 mg.

15. The dosage form of any of claims 1 to 14, wherein the KRAS inhibitor is Sotorasib (LUMAKRAS), Adagrasib (KRAZATI), ASP2453, MRTX1133, Divarasib (GDC-6036;RG6330); MK-1084, RMC-6236, RMC-6291, RMC-9805, Olomorasib (LY3537982), Garsorasib (D-1553), Glecirasib (JAB-21822), Opnurasib (JDQ-443), HBI-2438, HG-10370, IBI-351 (GFH925), BI-1823911, BI-3706674, JNJ-74699157, YL-17231, YL-15293, BBO-8520, BEBT-607, D3S-001, FMC-376, GED255, GH35, HYP-2090PTSA, ZG19018, ASP3082, HRS-4642, INCB161734, TSN1611, QTX3034, MRTX1133, PF-07934040, or any combination thereof.

16. The dosage form of any of claims 1 to 15, wherein the therapeutically effective amount of at least one BRAF inhibitor is from about 50 mg to about 2000 mg.

17. The dosage form of any of claims 1 to 16, wherein the BRAF inhibitor is dabrafenib, vemurafenib, encorafenib or any combination thereof.

18. The dosage form of any of claims 1 to 17, wherein the therapeutically effective amount of at least one MEK inhibitor is from about 0.5 mg to about 500 mg.

19. The dosage form of any of claims 1 to 18, wherein the MEK inhibitor is trametinib, binimetinib, cobimetinib, or any combination thereof.

20. The dosage form of any of claims 1 to 19, wherein the therapeutically effective amount of at least one mTOR inhibitor is from about 0.1 mg / kg to about 15 mg / kg.

21. The dosage form of any of any of claims 1 to 20, wherein the mTOR inhibitor is sirolimus, everolimus, temsirolimus, or any combination thereof.

22. The dosage form of any of claims 1 to 21, wherein the dosage form further comprises one or more pharmaceutically acceptable excipients.

23. A method of treating a subject suffering from cancer, the method comprising the step of administering to a subject suffering from cancer a therapeutically effective amount of a dosage form of any of claims 1-22.

24. The method of claim 23, wherein the cancer is brain cancer, lung cancer, breast cancer, head and neck cancer, ovarian cancer, uterine cancer, cervical cancer, prostate cancer, testicular cancer, bladder cancer, colorectal cancer, anal cancer, neuroblastoma, renal cancer, pancreatic cancer, bile duct cancer, liver cancer, gastric cancer, esophageal cancer, thyroid cancer, skin cancer, sarcomas, a malignant B-cell lymphoproliferative disorder, a malignant T-cell lymphoproliferative disorder, a myeloid malignancy, a histiocytic neoplasm, or any combination thereof.

25. The method of claim 23 or claim 24, wherein the cancer is a solid tumor.

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