Dispersion of Etrumadenant

Abstract

A solid dispersion comprising 20-40% by weight of etrumadenant and 60-80% by weight of a polymer selected from HPMCAS, PVPPA, CAP, HPMC E3, HPMCP, PVP, and polyvinyl caprolactam-polyvinyl acetate-PEG graft copolymer. A process for preparing the composition by spray drying. The composition for use in treating cancer. Dosage forms, granules, compositions, pharmaceutical compositions, and tablets thereof; methods of use; and methods for making the solid dispersion are also provided.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 375,574, filed September 14, 2022, and U.S. Provisional Patent Application No. 63 / 387,672, filed December 15, 2022, the contents of each of which are incorporated herein by reference in their entirety.

[0002] Provided herein are solid and semi-solid dispersions of etrumadenant and compositions thereof. [Background technology]

[0003] Adenosine is a purine nucleoside compound containing a complex of adenine and a ribose sugar molecule (ribofuranose). Adenosine occurs naturally in mammals and plays an important role in several biochemical processes, including energy transfer (as adenosine triphosphate and adenosine monophosphate) and signal transduction (as cyclic adenosine monophosphate). Adenosine also aids in processes related to vasodilation, including cardiac vasodilation, and acts as a neuromodulator (i.e., is thought to be involved in promoting sleep). In addition to its involvement in these biochemical processes, adenosine is used as a therapeutic antiarrhythmic drug, for example, to treat supraventricular tachycardia. Tumors evade host responses by inhibiting immune function and promoting tolerance, and adenosine has been shown to play an important role in mediating tumor evasion of the immune system. Adenosine, expressed on various immune cell subsets and endothelial cells, is a key regulator of adenosine-mediated immune response. 2A R and A 2B Adenosine signaling through R has been established as having an important role in protecting tissues during inflammatory responses. Thus, under certain conditions, adenosine protects tumors from immune destruction (see, e.g., Fishman, P. et al. (2009) HandbExpPharmacol 193:399-441).

[0004] Adenosine receptors are a type of purinergic G protein-coupled receptor that has adenosine as its endogenous ligand. The four types of adenosine receptors in humans are A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, A14, A15, A16, A17, A18, A19, A19, A20, A21, A22, A23, A24, A25, A26, A27, A28, A29, A30, A31, A32, A33, A34, A35, A36, A37, A38, A39, A40, A41, A42, A43, A44, A45, A46, A47, A48, A49, A50, A51, A52, A53, A5 2A , A 2B Modulation of A1 has been proposed for the management and treatment of, for example, neurological disorders, asthma, and heart and kidney failure. 2A Antagonists have been proposed, for example, for the management and treatment of Parkinson's disease. 2B Modulation of A3 has been proposed for the management and treatment of, for example, asthma and chronic lung diseases, including glaucoma, cancer, and stroke.

[0005] Historically, adenosine receptor modulators have been non-selective.This is acceptable in some indications, such as when the endogenous agonist adenosine, which acts on all four adenosine receptors in cardiac tissue, is administered parenterally to treat severe tachycardia.However, the use of subtype-selective adenosine receptor agonists and antagonists offers the possibility of achieving desired results while minimizing or eliminating adverse effects. Etrumadenant (also known as AB928) has been reported to be a subtype-selective adenosine receptor antagonist. 2A R and A 2B R, with potencies at both receptors of less than 10 nM. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Fishman, P et al. (2009) HandbExpPharmacol193:399-441 Summary of the Invention

[0007] Provided herein is a solid dispersion comprising about 20% to about 40% (w / w) etrumadenant and about 60% to about 80% (w / w) of a polymer (w / w) selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone (PVP-VA).

[0008] Dosage forms, granules, compositions, pharmaceutical compositions, and tablets thereof; methods of use thereof; and methods of making the solid dispersions are also provided.

[0009] Other aspects and iterations of the present disclosure are provided in more detail below. [Brief explanation of the drawings]

[0010] [Figure 1] 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline etrumadenant.

[0011] [Figure 2A]

[0033] Figure 1 shows a diagram of a solvent shift dissolution experiment. The API (i.e., starting drug substance) is dissolved in DMSO and then administered to a solution of FaSSIF (fasted state simulated intestinal fluid) and polymer. Sampler aliquots are taken at various time points and analyzed by HPLC.

[0012] [Figure 2B] Figure 1 is a graph showing the results of a solvent-shift dissolution experiment at 25% drug loading. Etrumadenant solubility (μg / mL) is shown on the y-axis and time (min) is shown on the x-axis. As summarized in the figure legend, the polymers tested included CAP, HPMCE3LV, HPMCAS-H, HPMCAS-L, HPMCAS-M, HPMCP, PVP, PVP-VA, and Soluplus. A control sample without polymer is also shown on the graph.

[0013] [Figure 2C]Figure 1 is a graph showing the results of a solvent-shift dissolution experiment at 50% drug loading. Etrumadenant solubility (μg / mL) is shown on the y-axis and time (min) is shown on the x-axis. As summarized in the figure legend, the polymers tested included CAP, HPMCE3LV, HPMCAS-H, HPMCAS-L, HPMCAS-M, HPMCP, PVP, PVP-VA, and Soluplus. A control sample without polymer is also shown on the graph.

[0014] [Figure 3A] Modulated differential scanning calorimetry (MDSC) plots of SDI particles in inverted (FIG. 3A) or non-inverted (FIG. 3B) mode are shown. [Figure 3B] Modulated differential scanning calorimetry (MDSC) plots of SDI particles in inverted (FIG. 3A) or non-inverted (FIG. 3B) mode are shown.

[0015] [Figure 4] 1 shows the XRPD patterns of SDI particles and the starting drug substance (i.e., AB928).

[0016] [Figure 5] 1 is a graph showing the non-settling dissolution of SDI particles (see figure legend) and starting drug substance ("AB928API"). The vertical line (shown in the figure legend as "Gastric Transit (0.1NHCl → FaSSIF)") indicates the time of gastric transit, i.e., the change from 0.1NHCl to FaSSIF.

[0017] [Figure 6] 1 shows the XRPD patterns of 25:75AB928:HPMCAS-M SDI and 40:60AB928:HPMCAS-M SDI after 12 weeks of stability at 25° C. / 60% RH (“25 / 60”) or 40° C. / 75% RH (“40 / 75”) in open or closed containers.

[0018] [Figure 7]Figure 1 shows the XRPD patterns of 25:75 AB928:PVP-VA SDI and 40:60 AB928:PVP-VA SDI after 12 weeks of stability at 25°C / 60% RH ("25 / 60") or 40°C / 75% RH ("40 / 75") in open or sealed containers.

[0019] [Figure 8] 1 shows the XRPD patterns of 25:75 AB928:HPMCAS-M SDIs, 30:70 AB928:HPMCAS-M SDIs, 35:65 AB928:HPMCAS-M SDI, and 40:60 AB928:HPMCAS-M SDI after 6 months of stability at 25° C. / 60% RH (“25 / 60”) or 40° C. / 75% RH (“40 / 75”) in sealed containers.

[0020] [Figure 9A] MDSC plots of 25:75 AB928:HPMCAS-M SDIs, 30:70 AB928:HPMCAS-M SDIs, 35:65 AB928:HPMCAS-M SDI, and 40:60 AB928:HPMCAS-M SDI after 6 months of stability at 25° C. / 60% RH (“25 / 60”) or 40° C. / 75% RH (“40 / 75”) in open containers (FIG. 9A) or sealed containers (FIG. 9B). [Figure 9B] MDSC plots of 25:75 AB928:HPMCAS-M SDIs, 30:70 AB928:HPMCAS-M SDIs, 35:65 AB928:HPMCAS-M SDI, and 40:60 AB928:HPMCAS-M SDI after 6 months of stability at 25° C. / 60% RH (“25 / 60”) or 40° C. / 75% RH (“40 / 75”) in open containers (FIG. 9A) or sealed containers (FIG. 9B).

[0021] [Figure 10]1 is a graph showing the non-precipitating dissolution of 25:75 AB928:HPMCAS-M SDIs, 30:70 AB928:HPMCAS-M SDIs, 35:65 AB928:HPMCAS-M SDI, and 40:60 AB928:HPMCAS-M SDI at t=0d (time of manufacture). The vertical line (shown in the figure legend as "Gastric Transit (0.1NHCl → FaSSIF)") indicates the time of gastric transit, i.e., the change from 0.1NHCl to FaSSIF.

[0022] [Figure 11] 1 is a graph showing non-precipitating dissolution of 25:75 AB928:HPMCAS-M SDIs, 30:70 AB928:HPMCAS-M SDIs, 35:65 AB928:HPMCAS-M SDIs, and 40:60 AB928:HPMCAS-M SDs after 6 months of stability at 25° C. / 60% RH or 40° C. / 75% RH in sealed containers. The vertical line (shown in the figure legend as "Gastric Transit (0.1 NHCl → FaSSIF)") indicates the time of gastric transit, i.e., the change from 0.1 NHCl to FaSSIF.

[0023] [Figure 12A] 1 shows a graph illustrating the tabletability of 25:75 AB928:HPMCAS-M SDI tablets (“25% HPMCAS-M SDI tablets”) and 40:60 AB928:HPMCAS-M SDI tablets (“40% HPMCAS-M SDI tablets”). [Figure 12B] 2 shows a graph showing the compressibility of the same tablet. [Figure 12C] Graph showing the compactibility of the same tablet is shown. [Figure 12D] Graph showing the disintegration time of the same tablet is shown.

[0024] [Figure 13A] 1 shows a graph illustrating the tabletability of 25:75 AB928:PVP-VA SDI tablets (“25% PVP-VA SDI tablets”) and 40:60 AB928:PVP-VA SDI tablets (“40% PVP-VA SDI tablets”). [Figure 13B]2 shows a graph showing the compressibility of the same tablet. [Figure 13C] Graph showing the compactibility of the same tablet is shown. [Figure 13D] Graph showing the disintegration time of the same tablet is shown.

[0025] [Figure 14] 1 is a graph showing non-precipitation dissolution of tablets containing 25:75AB928:HPMCAS-M SDI or 25:75AB928:PVP-VA at t=0 or 3 months for stability at 25° C. / 60% RH (“25 / 60”) or 40° C. / 75% RH (“40 / 75”) in a sealed container.

[0026] [Figure 15] 1 is a graph showing non-precipitation dissolution of tablets containing 40:60 AB928:HPMCAS-M SDI or 40:60 AB928:PVP-VA after 0 or 3 months of stability at 25° C. / 60% RH (“25 / 60”) or 40° C. / 75% RH (“40 / 75”) in sealed containers.

[0027] [Figure 16] 1 is a graph showing non-precipitation dissolution of tablets containing 25:75 AB928:HPMCAS-M SDI or 40:60 AB928:HPMCAS-M SDI after 0 or 12 months of stability at 25° C. / 60% RH (“25 / 60”) or 40° C. / 75% RH (“40 / 75”) in a sealed container.

[0028] [Figure 17A] 1 is a graph showing the plasma concentration of AB928 (y-axis) versus time (x-axis) following oral administration of an AB928 capsule ("Capsule Control") or one of three AB928 tablet formulations with HPMCAS SDI (see figure legend).

[0029] [Figure 17B]1 is a graph showing the plasma concentration of AB928 (y-axis) versus time (x-axis) following oral administration of an AB928 capsule with a PVP-VA SDI ("capsule control") or one of three AB928 tablet formulations (see figure legend).

[0030] [Figure 18] 1 shows a boxplot, median, and Cmax of plasma etrumadenant after a single dose of 150 mg etrumadenant with and without multiple doses of 200 mg itraconazole. In the graph, the upper and lower limits of the box represent the third and first quartiles, respectively, and the midline represents the median. The black circle represents the mean value. The upper and lower whiskers of the boxplot represent the maximum and minimum observed values ​​within the 1.5 x interquartile range, respectively. The open circles represent individual parameter values.

[0031] [Figure 19] 1 shows the X-ray powder diffraction (XRPD) pattern of a crystalline form of the phosphate salt of etrumadenant ("Phosphate Form I").

[0032] [Figure 20] 1 shows the X-ray powder diffraction (XRPD) pattern of a crystalline form of the phosphate salt of etrumadenant ("Phosphate Form II").

[0033] [Figure 21] 1 shows the X-ray powder diffraction (XRPD) pattern of crystalline etruma denantho fumarate. DETAILED DESCRIPTION OF THE INVENTION

[0034] The present disclosure provides dispersions comprising etremadenant, pharmaceutically acceptable salts thereof, compositions thereof, and pharmaceutical compositions thereof (such as tablets). It is contemplated that the dispersions, compositions, and pharmaceutical compositions provided herein may exhibit one or more of improved drug solubility, improved bioavailability, and / or elimination or reduction of the food effect (e.g., compared to crystalline forms of etremadenant or its pharmaceutically acceptable salts). Methods for producing and using the dispersions are also provided herein. The etremadenant dispersions disclosed herein can be formulated to have a high drug load, for example, up to 50% (w / w) etremadenant.

[0035] I. Definition Unless otherwise defined, all technical terms, notations, and other scientific or technical terms used herein are intended to have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains. It is understood that embodiments of the invention described herein include "consisting of" and / or "consisting essentially of" embodiments. The terms "comprising," "including," and "having" are intended to be non-exclusive and mean that there may be more elements than the listed elements. The term "essentially consisting of" means that certain additional components may be present, i.e., components that do not materially affect the essential characteristics of the compound or composition.

[0036] Furthermore, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to an "aparticle" includes a reference to one or more particles and equivalents thereof known to those skilled in the art.

[0037] The term "about" is used herein with its inherent meaning of approximation and to provide literal support for the exact number it precedes, as well as numbers that are near or approximate the number it precedes. In general, the term "about" refers to the normal error range for the respective value, readily known to those skilled in the art. If the degree of approximation is not clear from the context, "about" means either within ±10% of the provided value, or rounded to the nearest significant figure, and in all cases includes the provided value. When ranges are provided, they include the boundaries.

[0038] Also, as used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in alternatives ("or"). Similarly, a phrase in the form "A / B" or "A and / or B" means (A), (B), or (A and B). A phrase in the form "at least one of A, B, and C" means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).

[0039] As used herein, the term "% w / w" refers to the weight of a component based on the total weight of the composition including the component. For example, if component A is present in an amount of 50% w / w in 100 mg of a composition, then component A is present in an amount of 50 mg.

[0040] The "Dv50" value refers to the size of 50% of the total volume of material in the sample. The "Dv90" value refers to the size of 90% of the total volume of material in the sample.

[0041] The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and may exhibit the physical properties of a solid or a liquid, depending on temperature. Typically, such materials do not produce distinctive X-ray diffraction patterns and exhibit the properties of a solid, but are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs, which is characterized by a change of state, typically second-order (glass transition).

[0042] As used herein, the term "polymer matrix" is defined to mean a composition comprising one or more polymers in which an active agent is dispersed or entrapped within the matrix.

[0043] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired base. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, maleic acid, oxalic acid, and cinnamic acid.Also included are salts of amino acids, such as arginate, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0044] The term "disintegrant" refers to a substance that, when added to a solid preparation, facilitates its disintegration or breakdown after administration and allows the release of the active ingredient as efficiently as possible to enable its rapid dissolution. Non-limiting examples of disintegrants include corn starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid.

[0045] The term "bulking agent" (also known as diluent) refers to a chemical compound used to dilute the compound of interest before delivery. Diluents can also help stabilize the compound. Non-limiting examples of diluents include starch, saccharides, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressible sugar, dibasic calcium phosphate dehydrate, mannitol, microcrystalline cellulose, and tribasic calcium phosphate.

[0046] As used herein, the term "glidant" is intended to mean an agent used in tablet and capsule formulations to improve flow properties during tablet compression and to provide an anti-caking effect. Non-limiting examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.

[0047] The term "lubricant" refers to an excipient added to a powder blend to prevent the compressed powder mass from sticking to the equipment during the tableting or encapsulation process. Lubricants can aid in the ejection of the tablet from the die and improve powder flow. Non-limiting examples of lubricants include magnesium stearate, stearic acid, silica, fat, or talc; and lauric acid, oleic acid, and C8 / C 10 Solubilizers such as fatty acids, including fatty acids, are included.

[0048] The term "coating" or "film coating" refers to a thin, uniform film on the surface of a substrate (e.g., a tablet). Film coatings are particularly useful for protecting active ingredients from photodegradation. Non-limiting examples of film coatings include polyvinyl alcohol-based, hydroxyethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate film coatings.

[0049] The term "non-functional coating" refers to a coating that can improve the product appearance, handling, and / or stability of a substrate (e.g., a tablet), but does not measurably affect the biopharmaceutical properties of the substrate.

[0050] The terms "patient" and "subject" are used interchangeably herein to refer to a human or non-human animal (e.g., a mammal).

[0051] The terms "administration," "administering," and the like, when applied to, e.g., a subject, cell, tissue, organ, or biological fluid, refer to contacting the subject, cell, tissue, organ, or biological fluid with, e.g., a dispersion, composition, or pharmaceutical composition described herein. In the context of a cell, administration includes contacting a reagent with the cell (e.g., in vitro or ex vivo), as well as contacting a reagent with a fluid in contact with the cell.

[0052] Terms such as "treat," "treatment," or "treating" refer to a course of action that eliminates, reduces, inhibits, alleviates, improves, or prevents the worsening of the disease, disorder, or condition to which the term applies, or at least one symptom associated therewith, either temporarily or permanently. Treatment includes, by way of example, inhibiting active disease (e.g., preventing the onset or further development of the disease, disorder, or condition or its associated clinical symptoms), improving quality of life, and / or prolonging survival of a subject.

[0053] The terms "prevent," "preventing," "prevention," "prevention," and the like generally refer to a course of action initiated in a manner that prevents, suppresses, inhibits, or reduces the risk of a subject developing a disease, disorder, condition, etc. (e.g., as determined by the absence of clinical symptoms) or delays its onset (e.g., prior to the onset of the disease, disorder, condition, or its symptoms), either temporarily or permanently, in situations where the subject is predisposed to having a particular disease, disorder, or condition. In certain instances, these terms also refer to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or otherwise undesirable state. Prevention also refers to a course of action initiated in a subject after the subject has been treated for a disease, disorder, condition, or symptom thereof, in order to prevent the recurrence of the disease, disorder, condition, or symptom.

[0054] II. Etremadès d'Antique Etrumadenant (also known as AB928) binds to the adenosine 2a receptor (A 2a R) and adenosine 2b receptor (A2b Its chemical name is 3-[2-amino-6-(1-{[6-(2-hydroxypropan-2-yl)pyridin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl]-2-methylbenzonitrile, and its structural formula is shown below. [ka]

[0055] Etrumadenant and its pharmaceutically acceptable salts can be in various forms, including, but not limited to, amorphous forms, crystalline forms, mixtures of crystalline forms, and mixtures of amorphous and crystalline forms. In various embodiments of the present disclosure (e.g., compositions, dispersions, granules, tablets, etc.), etrumadenant or its pharmaceutically acceptable salts can be in amorphous form, crystalline form, or any mixture thereof. Crystalline forms of etrumadenant include those described in WO 2020 / 018680, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the crystalline etrumadenant can be Form I of WO 2020 / 018680. In some embodiments, the crystalline etrumadenant can be Form II of WO 2020 / 018680. In some embodiments, the crystalline etrumadenant can be Form III of WO 2020 / 018680.

[0056] Methods for the preparation of etremadenant are known in the art, see, for example, WO 2018 / 136700, WO 2020 / 018680, and WO 2020 / 247789, the disclosures of which are incorporated herein by reference in their entireties.

[0057] III. Dispersion of Etrumadenant and Method for Producing the Same dispersion Disclosed herein is a dispersion of etremadenant or a pharmaceutically acceptable salt thereof that is in a solid or semi-solid state at temperatures below 40°C.

[0058] As used herein, a dispersion of etremadenant or a pharmaceutically acceptable salt thereof refers to a dispersion (i.e., distribution) of an active agent, e.g., etremadenant or a pharmaceutically acceptable salt thereof, in a matrix. As used herein, a "solid dispersion" refers to a dispersion that is in a solid state at temperatures below 40°C, and a "semi-solid dispersion" refers to a dispersion that is in a semi-solid state at temperatures below 40°C. In some embodiments, the solid dispersions described herein are in a solid state at 25°C. In some embodiments, the semi-solid dispersions described herein are in a semi-solid state at 25°C.

[0059] For the avoidance of doubt, a semi-solid state is a state that is between a solid and a liquid. Although similar to solids in some respects, such as having the ability to support their own weight and retain their shape, semi-solids also share some properties of liquids, such as the ability to conform to the shape of something that applies pressure to it and to flow under pressure. The dispersions of the present disclosure can also be characterized by, for example, MDSC, XRPD, scanning electron microscopy (SEM), non-settling dissolution, Karl Fischer titration, assay, impurities, and non-settling dissolution.

[0060] The matrix of the dispersion comprises at least one hydrophilic polymer (e.g., 1, 2, 3, 4, or more polymers; or 1 to 4 polymers; or 1 to 3 polymers). In some embodiments, the matrix comprises or consists essentially of a single polymer. In some embodiments, the matrix comprises or consists essentially of a mixture of polymers. The polymers may be synthetic or natural. Non-limiting examples of suitable polymers can include polyethylene glycol polymers (e.g., PEG400, PEG1500, PEG4000, etc.), cellulosic polymers (e.g., HPMC, HPMCAS, HPMCP, CAP, etc.), and vinylpyrrolidone-based polymers (e.g., povidone ("PVP"), copovidone ("PVP-VA"), Soluplus®, etc.).

[0061] The matrix may further comprise one or more additional components, including, but not limited to, one or more antioxidants, one or more surfactants, one or more solubilizing agents, or any combination thereof. Non-limiting examples of suitable antioxidants include ascorbic acid, BHT, tocophersolan, and vitamin E. Non-limiting examples of suitable surfactants include inulin, inutec, poloxamer, tocophersolan, Compritol® surfactants (e.g., Compritol® 888ATO, etc.), Gelucire® surfactants (e.g., Gelucire® 44 / 14, etc.), and Kolliphor® surfactants (e.g., Kolliphor® HS15, Kolliphor® RH40, etc.), polysorbates (e.g., polysorbate 20, polysorbate 80, etc.), egg lecithin, and soy lecithin. The solvent(s) and / or water used to prepare the dispersion may also be present in the dispersion, but typically these are present in small amounts (e.g., preferably less than 5% by weight, less than 4% by weight, less than 3% by weight, or less than 2% by weight).

[0062] Thus, the dispersions of the present disclosure comprise etrumadenant or a pharmaceutically acceptable salt thereof and a polymer. Further, in some embodiments, the dispersions of the present disclosure may consist essentially of (i) etrumadenant or a pharmaceutically acceptable salt thereof, and (ii) a polymer, a mixture of polymers, or a mixture of polymer(s) and surfactant(s). For the avoidance of doubt, a dispersion consisting essentially of (A) and (B) allows for the presence of materials that do not affect the essential properties of the dispersion, such as minor amounts of impurities, related substances of A and / or B, residual solvent, and water.

[0063] In some embodiments, the present disclosure provides a solid dispersion comprising etremadenant or a pharmaceutically acceptable salt thereof and a polymer. In some embodiments, the solid dispersion comprises (i) etremadenant or a pharmaceutically acceptable salt thereof, and (ii) a polymer, a mixture of polymers, or a mixture of polymer(s) and surfactant(s). In some embodiments, the solid dispersion consists essentially of (i) etremadenant or a pharmaceutically acceptable salt thereof, and (ii) a polymer, a mixture of polymers, or a mixture of polymer(s) and surfactant(s). Non-limiting examples of suitable polymers include cellulose-based polymers (e.g., HPMC, HPMCAS, HPMCP, CAP, etc.) and vinylpyrrolidone-based polymers (e.g., povidone, copovidone, Soluplus, etc.). In some embodiments, the solid dispersion of the present disclosure comprises or consists essentially of etremadenant or a pharmaceutically acceptable salt thereof and a polymer selected from HPMCAS and copovidone.

[0064] In another aspect, the present disclosure provides a semi-solid dispersion comprising etremadenant or a pharmaceutically acceptable salt thereof and a polymer. In some embodiments, the semi-solid dispersion comprises (i) etremadenant or a pharmaceutically acceptable salt thereof, and (ii) a polymer, a mixture of polymers, or a mixture of polymer(s) and surfactant(s). In some embodiments, the semi-solid dispersion consists essentially of (i) etremadenant or a pharmaceutically acceptable salt thereof, and (ii) a polymer, a mixture of polymers, or a mixture of polymer(s) and surfactant(s). Non-limiting examples of suitable polymers include cellulose-based polymers (e.g., HPMC, HPMCAS, HPMCP, CAP, etc.) and vinylpyrrolidone-based polymers (e.g., povidone, copovidone, Soluplus, etc.). In a specific example, the solid dispersion of the present disclosure comprises or consists essentially of etremadenant or a pharmaceutically acceptable salt thereof and one or more polyethylene glycol polymers.

[0065] Provided herein are solid dispersions comprising about 25% to about 50% (w / w) etrumadenant and about 50% to about 75% (w / w) of a polymer. In some embodiments, the polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), copovidone, cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose E3 (HPMC E3), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinylpyrrolidone (PVP), and polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®).

[0066] Provided herein is a solid dispersion comprising about 20% to about 40% (w / w) etrumadenant and about 60% to about 80% (w / w) of a polymer selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), copovidone (PVP-VA), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose E3 (HPMC E3), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinylpyrrolidone (PVP), and polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®).

[0067] Provided herein is a solid dispersion comprising about 25% to about 50% (w / w) etrumadenant and about 50% to about 75% (w / w) of a polymer (w / w) selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone.

[0068] Provided herein is a solid dispersion comprising about 25% to about 40% (w / w) etrumadenant and about 60% to about 75% (w / w) of a polymer (w / w) selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone.

[0069] Provided herein is a solid dispersion comprising about 20% to about 40% (w / w) etrumadenant and about 60% to about 80% (w / w) of a polymer (w / w) selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone.

[0070] Provided herein is a solid dispersion comprising about 35% to about 50% (w / w) etrumedenant, or a pharmaceutically acceptable salt thereof, and about 65% to about 50% (w / w) of a polymer selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone.

[0071] In some embodiments, such solid dispersions contain about 25% to about 40% (w / w) etremadenant.

[0072] In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) etremadenant; or about 25% to about 30% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 25% to about 30% (w / w) etremadenant.

[0073] In some embodiments, the solid dispersion comprises about 22.5% to about 27.5% (w / w) etremadenant; or about 27% to about 33% (w / w) etremadenant; or about 31.5% to about 38.5% (w / w) etremadenant; or about 36% to about 44% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 22.5% to about 27.5% (w / w) etremadenant; or about 27% to about 33% (w / w) etremadenant; or about 31.5% to about 38.5% (w / w) etremadenant.

[0074] In some embodiments, the solid dispersion comprises about 22.5% to about 27.5% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 27% to about 33% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 31.5% to about 38.5% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 36% to about 44% (w / w) etremadenant.

[0075] In some embodiments, the solid dispersion comprises about 20% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 22.5% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 25% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 27% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 27.5% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 30% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 31.5% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 33% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 32.5% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 35% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 36% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 37.5% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 38.5% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 40% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 42.5% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 44% (w / w) etremadenant. In some embodiments, the solid dispersion comprises about 45% (w / w) etremadenant.

[0076] In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) etremadenant and about 65% to about 75% (w / w) polymer; or about 25% to about 30% (w / w) etremadenant and about 70% to about 75% (w / w) polymer. In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) etremadenant and about 65% to about 75% (w / w) polymer. In some embodiments, the solid dispersion comprises about 25% to about 30% (w / w) etremadenant and about 70% to about 75% (w / w) polymer.

[0077] In some embodiments, the solid dispersion comprises about 25% etremadenant and about 75% (w / w) polymer. In some embodiments, the solid dispersion comprises about 30% etremadenant and about 70% (w / w) polymer. In some embodiments, the solid dispersion comprises about 35% etremadenant and about 65% (w / w) polymer. In some embodiments, the solid dispersion comprises about 40% etremadenant and about 60% (w / w) polymer.

[0078] In some embodiments, the solid dispersion has a single glass transition temperature (T g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T) of about 75° C. to about 100° C. g ); and / or characterized by a crystallinity of 5% or less, or 1% or less.

[0079] In some embodiments, the solid dispersion has a glass transition temperature (T g or a crystallinity of 5% or less. In some embodiments, the solid dispersion has a glass transition temperature (T g or a crystallinity of 3% or less. In some embodiments, the solid dispersion has a glass transition temperature (T g ); or characterized by a crystallinity of 1% or less.

[0080] In some embodiments, the solid dispersion has a glass transition temperature (T g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T) of about 60° C. to about 125° C. g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T) of about 75° C. to about 125° C. g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T) of about 65° C. to about 115° C. g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T) of about 70° C. to about 100° C. g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T) of about 75° C. to about 90° C. g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T) of about 75° C. to about 85° C. g In some embodiments, the solid dispersion is characterized by a glass transition temperature (T) of about 72° C. to about 83° C. g ) is characterized by T g can be determined by modulated differential scanning calorimetry (MDSC).

[0081] In some embodiments, the solid dispersion is characterized by a crystallinity of 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In some embodiments, the solid dispersion is characterized by a crystallinity of 5% or less. In some embodiments, the solid dispersion is characterized by a crystallinity of 3% or less. In some embodiments, the solid dispersion is characterized by a crystallinity of 1% or less. In some embodiments, crystallinity refers to the amount of crystalline ethlomadenant relative to the total SDI.

[0082] Crystallinity can be determined, for example, by X-ray powder diffraction (XRPD). In some embodiments, the solid dispersion is characterized by a crystallinity that is less than the limit of quantitation (LOQ) by XRPD. In some embodiments, the solid dispersion is characterized by a crystallinity that is less than the limit of detection (LOD) by XRPD. In some embodiments where crystallinity is determined by XRPD, crystallinity refers to the amount of crystalline ethlomadenant relative to the total API.

[0083] In some embodiments, the solid dispersion has a single melting temperature (T m and / or a diffraction pattern by X-ray powder diffraction (XRPD) that is free of discrete peaks. In some embodiments, the solid dispersion has a single melting temperature (T m ); or characterized by a diffraction pattern by X-ray powder diffraction (XRPD) in which no discrete peaks are present.

[0084] In some embodiments, the polymer is HPMCAS. In some embodiments, the polymer is copovidone.

[0085] In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) etremadenant and about 65% to about 75% copovidone; or about 25% to about 30% (w / w) etremadenant and about 70% to about 75% (w / w) copovidone. In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) etremadenant and about 65% to about 75% copovidone. In some embodiments, the solid dispersion comprises about 25% to about 30% (w / w) etremadenant and about 70% to about 75% (w / w) copovidone.

[0086] Some embodiments provide a solid dispersion comprising about 25% to about 40% (w / w) etrumedenant and about 60% to about 75% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0087] Some embodiments provide a solid dispersion comprising about 25% to about 35% (w / w) etrumedenant and about 65% to about 75% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0088] Some embodiments provide a solid dispersion comprising about 25% to about 40% (w / w) etrumadenant and about 60% to about 75% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS), The solid dispersion has a single glass transition temperature (T g ); or characterized by a crystallinity of 5% or less, or 1% or less.

[0089] Some embodiments provide a solid dispersion comprising about 25% to about 40% (w / w) etrumadenant and about 60% to about 75% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS), The solid dispersion has a single glass transition temperature (T g ); or characterized by a crystallinity of 5% or less.

[0090] Some embodiments provide a solid dispersion comprising about 25% to about 40% (w / w) etrumadenant and about 60% to about 75% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS), The solid dispersion has a single glass transition temperature (T g ); or characterized by a crystallinity of 3% or less.

[0091] Some embodiments provide a solid dispersion comprising about 25% to about 40% (w / w) etrumadenant and about 60% to about 75% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS), The solid dispersion has a single glass transition temperature (T g ); or characterized by a crystallinity of 1% or less.

[0092] Some embodiments provide a solid dispersion comprising about 25% to about 35% (w / w) etrumadenant and about 65% to about 75% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS), The solid dispersion has a single glass transition temperature (T g ); or characterized by a crystallinity of 5% or less, or 1% or less.

[0093] Some embodiments provide a solid dispersion comprising about 25% to about 35% (w / w) etrumadenant and about 65% to about 75% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS), The solid dispersion has a single glass transition temperature (T g ); or characterized by a crystallinity of 5% or less.

[0094] Some embodiments provide a solid dispersion comprising about 25% to about 35% (w / w) etrumadenant and about 65% to about 75% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS), The solid dispersion has a single glass transition temperature (T g ); or characterized by a crystallinity of 3% or less.

[0095] Some embodiments provide a solid dispersion comprising about 25% to about 35% (w / w) etrumadenant and about 65% to about 75% (w / w) hydroxypropyl methylcellulose acetate succinate (HPMCAS), The solid dispersion has a single glass transition temperature (T g ); or has a crystallinity of 1% or less.

[0096] In some aspects, the solid dispersion comprises about 25% to about 35% (w / w) etremadenant and about 65% to about 75% HPMCAS; or about 25% to about 30% (w / w) etremadenant and about 70% to about 75% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 25% to about 35% (w / w) etremadenant and about 65% to about 75% HPMCAS. In some embodiments, the solid dispersion comprises about 25% to about 30% (w / w) etremadenant and about 70% to about 75% (w / w) HPMCAS.

[0097] In some embodiments, the solid dispersion comprises about 22.5% to about 27.5% (w / w) etremadenant and about 65% to about 75% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 27% to about 33% (w / w) etremadenant and about 65% to about 75% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 31.5% to about 38.5% (w / w) etremadenant and about 65% to about 75% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 36% to about 44% (w / w) etremadenant and about 65% to about 75% (w / w) HPMCAS.

[0098] In some embodiments, the solid dispersion comprises about 22.5% to about 27.5% (w / w) etremadenant and about 70% to about 75% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 27% to about 33% (w / w) etremadenant and about 70% to about 75% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 31.5% to about 38.5% (w / w) etremadenant and about 70% to about 75% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 36% to about 44% (w / w) etremadenant and about 70% to about 75% (w / w) HPMCAS.

[0099] In some embodiments, the solid dispersion comprises about 25% (w / w) etremadenant and about 75% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 30% (w / w) etremadenant and about 70% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 35% (w / w) etremadenant and about 65% (w / w) HPMCAS. In some embodiments, the solid dispersion comprises about 40% (w / w) etremadenant and about 60% (w / w) HPMCAS.

[0100] In some embodiments, the HPMCAS may be any commercially available grade of HPMCAS. In some embodiments, the HPMCAS comprises an acetyl content of about 5% to about 14%, a succinyl content of about 4% to about 18%, a methoxyl content of about 20% to about 26%, and a hydroxypropoxy content of about 5% to about 10%. In some embodiments, the HPMCAS comprises an acetyl content of about 7% to about 11%, a succinyl content of about 10% to about 14%, a methoxyl content of about 21% to about 25%, and a hydroxypropoxy content of about 5% to about 9%.

[0101] In some embodiments, the solid dispersion comprises a single T g In some embodiments, the solid dispersion comprising ethlomadenant and HPMCAS has a single glass transition temperature of about 75° C. to about 85° C. Tg and / or a crystallinity of 5% or less, or 1% or less. In some embodiments, the solid dispersion comprising etremadenant and HPMCAS has a single glass transition temperature of about 75° C. to about 85° C. Tg or characterized by a crystallinity of 5% or less. In some embodiments, the solid dispersion comprising etremadenant and HPMCAS has a single glass transition temperature of about 75° C. to about 85° C. Tg or characterized by a crystallinity of 3% or less. In some embodiments, the solid dispersion comprising etremadenant and HPMCAS has a single glass transition temperature of about 75° C. to about 85° C. Tgor a crystallinity of 1% or less. In some embodiments, the solid dispersion is characterized by the absence of other melting or crystallization events; and / or an XRPD diffraction pattern lacking discrete peaks. In some embodiments, the solid dispersion is characterized by the absence of other melting or crystallization events; or an XRPD diffraction pattern lacking discrete peaks.

[0102] In some embodiments, the solid dispersions described herein have a lower AUC than crystalline etrumadenant in a non-sedimentation dissolution test. 35~210 FaSSIF(min * The non-sedimentation dissolution test can be performed as described herein. In some embodiments, the solid dispersions described herein exhibit a non-sedimentation dissolution test that results in an AUC of 0.01 μgA / mL or greater than 0.01 μgA / mL, compared to crystalline etrumadenant. 35~210 FaSSIF(min * μgA / mL) is increased by approximately 4-fold, 5-fold, 6-fold, or 7-fold.

[0103] In some embodiments, the solid dispersions described herein have a total impurity level of less than 2% (area %) as measured by HPLC. In some embodiments, the solid dispersions described herein have a total impurity level of less than 1% (area %) as measured by HPLC. Analysis of impurities by HPLC can be performed as described herein. In some embodiments, the solid dispersions or tablets have a total impurity level of about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% (area %) as measured by HPLC. In some embodiments, the tablets have a total impurity level of less than 1% (area %) as measured by HPLC. In some embodiments, the solid dispersion or tablet has a total impurity content of less than 0.5% (area %) as measured by HPLC.

[0104] Some embodiments provide solid dispersions that are physically stable, chemically stable, and / or have stable in vitro dissolution properties when stored in sealed or open packaging for 3 months or more (e.g., 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 months) at 25°C and 60% relative humidity (long-term stability studies) or 40°C and 75% relative humidity (accelerated stability studies). Stability can be assessed by various analytical methods, including XRPD, MDSC, assays for ethlomadenant and impurities by HPLC, and non-precipitation dissolution tests.

[0105] In some embodiments, the solid dispersion, upon storage in a sealed or open package at 25° C. and 60% relative humidity and / or 40° C. and 75% relative humidity for 3 months or more, exhibits: (i) a single glass transition temperature (T) of about 75° C. to about 85° C., as measured by MDSC; g ) or another T described herein g (ii) the absence of other melting or crystallization events as measured by MDSC; (iii) a diffraction pattern by XRPD that is free of discrete peaks; (iv) a crystallinity of 5% or less, or 1% or less, or less than the LOQ or LOD by XRPD; or (v) any combination of (i)-(iv).

[0106] In some embodiments, storage in sealed or open packaging at 25° C. and 60% relative humidity and / or 40° C. and 75% relative humidity for 3 months or more reduces the amount of etrumadenant as measured by the no-precipitation dissolution test at 210 minutes (C 210 (μgA / mL) differs by no more than about 25% from the value measured at 0 months. In some embodiments, storage in sealed or open packaging at 25° C. and 60% relative humidity and / or 40° C. and 75% relative humidity for 3 months or more results in the amount of etrumadenant (C ) measured by the non-precipitation dissolution test at 210 minutes. 210(μgA / mL) differs by no more than about 15% from the value measured at 0 months. In some embodiments, storage in sealed or open packaging at 25° C. and 60% relative humidity and / or 40° C. and 75% relative humidity for 3 months or more results in a decrease in the amount of etrumadenant (C) as measured by the non-sedimentation dissolution test at 210 minutes. 210 (μgA / mL) differs by no more than about 12% from the value measured at 0 months. In some embodiments, storage in sealed or open packaging at 25° C. and 60% relative humidity and / or 40° C. and 75% relative humidity for 3 months or longer results in a decrease in the amount of etrumadenant (C) as measured by the non-precipitation dissolution test at 210 minutes. 210 (μgA / mL) differs by no more than about 10% from the value measured at 0 months. In some embodiments, storage in sealed or open packaging at 25° C. and 60% relative humidity and / or 40° C. and 75% relative humidity for 3 months or longer results in a decrease in the amount of etrumadenant (C) as measured by the non-precipitation dissolution test at 210 minutes. 210 (μgA / mL) differs by approximately 5% or less from the value measured at 0 months.

[0107] In some embodiments, storage in sealed or open packaging at 25° C. and 60% relative humidity and / or 40° C. and 75% relative humidity for 3 months or more reduces the AUC 35-210FaSSIF (min * The amount of etrumadenant in FaSSIF, as measured by AUC (μgA / mL), differs by no more than about 25% from the value measured at 0 months. In some embodiments, the AUC (AUC) of etrumadenant is increased after storage in sealed or open packaging at 25° C. and 60% relative humidity and / or 40° C. and 75% relative humidity for 3 months or more. 35-210FaSSIF (min * The amount of etrumadenant in FaSSIF, as measured by AUC (μgA / mL), differs by no more than about 15% from the value measured at 0 months. In some embodiments, the AUC (μgA / mL) of etrumadenant varies by no more than about 15% from the value measured at 0 months after storage in sealed or open packages at 25° C. and 60% relative humidity and / or 40° C. and 75% relative humidity for 3 months or more. 35-210FaSSIF (min *The amount of etrumadenant in FaSSIF, as measured by AUC (μgA / mL), differs by no more than about 10% from the value measured at 0 months. In some embodiments, the AUC (AUC) of etrumadenant is increased after storage in sealed or open packages at 25° C. and 60% relative humidity and / or 40° C. and 75% relative humidity for 3 months or more. 35-210FaSSIF (min * When measured by α-tocopherol / mL (μgA / mL), the amount of etremadenant in FaSSIF differs by approximately 5% or less from the value measured at 0 months.

[0108] In some embodiments, storage of the solid dispersion in a sealed package at 25° C. and 60% relative humidity for 6 months, 12 months, 18 months, 24 months, or 36 months results in: (i) the amount of etrumadenant in the solid dispersion is about 90% to about 110% of the value measured at 0 months; (ii) the solid dispersion has a total impurity amount (area %) of 2% or less, or 1% or less, as measured by high performance liquid chromatography (HPLC); (iii) The solid dispersion exhibits a single T g , and optionally a single melting temperature (T m ) characterized by; (iv) the solid dispersion is characterized by a diffraction pattern by XRPD that is free of discrete peaks; (v) The amount of etremadenant measured at 210 min by the non-settling dissolution test (C 210 (μgA / mL) or AUC 35-210FaSSIF (min * μgA / mL) differs by 15% or less from the value measured at 0 months; or (vi) Any combination of (i) to (v).

[0109] In some embodiments, the solid dispersion is stored in a sealed package at 25° C. and 60% relative humidity for 6 months, 12 months, 18 months, 24 months, or 36 months. (i) the amount of etrumadenant in the solid dispersion is about 90% to about 110% of the value measured at 0 months; (ii) the solid dispersion has a total impurity amount (area %) of 2% or less, or 1% or less, as measured by high performance liquid chromatography (HPLC); (iii) The solid dispersion exhibits a single T g , and optionally a single melting temperature (T m ) characterized by; (iv) the solid dispersion is characterized by a diffraction pattern by XRPD that is free of discrete peaks; or (v) Any combination of (i) to (iv).

[0110] In some embodiments, provided herein are samples comprising one or more of the dispersions described herein. In some embodiments, provided herein are samples comprising one or more of the solid dispersions described herein. Such samples may exhibit one or more properties, such as those described herein for the solid dispersions / dispersions described herein.

[0111] Some embodiments provide particles, such particles comprising the solid dispersion(s) described herein. Such particles may exhibit one or more properties, such as those described herein for the solid dispersions / dispersions described herein.

[0112] The solid dispersions described herein can be made according to the methods described herein. In some embodiments, the solid dispersions described herein are formed by spray drying.

[0113] Some embodiments provide spray-dried particles, such particles formed by spray drying and comprising a solid dispersion described herein. Such spray-dried particles may exhibit one or more properties, such as those described herein for the solid dispersions / solid dispersions described herein.

[0114] In some embodiments, the spray-dried particles comprise a solid dispersion described herein, wherein the spray-dried particles are characterized by a Dv90 of less than 150 μm or a Dv50 of less than 50 μm. In some embodiments, the spray-dried particles are characterized by a Dv90 of less than 150 μm. In some embodiments, the spray-dried particles are characterized by a Dv50 of less than 50 μm. In some embodiments, the spray-dried particles are characterized by a Dv90 of about 80 μm to about 130 μm; and / or a Dv50 of about 25 μm to about 40 μm. In some embodiments, the spray-dried particles are characterized by a Dv90 of about 80 μm to about 130 μm. In some embodiments, the spray-dried particles are characterized by a Dv50 of about 25 μm to about 40 μm.

[0115] In some embodiments, provided herein are samples comprising one or more particles described herein. Such samples may exhibit one or more properties, such as those described herein for the solid dispersions / dispersions described herein and / or the particles described herein.

[0116] Dispersion manufacturing method Provided herein are methods for making the dispersions described herein.

[0117] In some embodiments, the dispersions described herein can be prepared according to methods known in the art. Non-limiting examples of methods known in the art for preparing solid dispersions include, but are not limited to, spray drying, melt extrusion, freeze drying, and solution evaporation. In some embodiments, the present invention provides a process for preparing a solid dispersion comprising etrumadenant, the process comprising: mixing etrumadenant, a polymer described herein, and a solvent to form a spray solution; and spray-drying the spray solution to form a solid dispersion. The term "spray solution" as used herein can also be referred to as "solution" or "feed solution."

[0118] Some embodiments provide a process for preparing a solid dispersion comprising etremadenant, comprising: mixing etremadenant, a polymer selected from HPMCAS and copovidone, and a solvent to form a spray solution; and spray drying the spray solution to produce a solid dispersion.

[0119] Some embodiments further undergo further drying of the solid dispersion to produce a dry powder having a moisture content of less than about 1% (w / w).

[0120] Some embodiments provide a process for preparing spray-dried particles comprising a solid dispersion described herein, comprising: mixing etremadenant, a polymer selected from HPMCAS and copovidone, and a solvent to form a spray solution; and spray drying the spray solution to produce spray-dried particles.

[0121] In some embodiments, the weight ratio of etrumadenant to polymer is from 25:75 to 40:60.

[0122] Some embodiments provide a process for preparing spray-dried particles comprising a solid dispersion described herein, comprising: mixing ethlomadenant, HPMCAS, and a solvent to form a spray solution; and spray drying the spray solution to produce spray-dried particles.

[0123] In some embodiments, the weight ratio of etremadenant to HPMCAS is from 25:75 to 40:60.

[0124] In some embodiments, the spray solution is prepared at a solids loading of 8% to 13%.

[0125] In some embodiments, the spray-dried particles are further dried to produce a dry powder having a moisture content of less than about 1% (w / w).

[0126] In some embodiments, the spray drying process comprises spraying the spray solution into a drying chamber having an outlet temperature of about 38°C to about 46°C, a gas to liquid ratio of about 0.5 to about 0.7, and a relative saturation (total) of about 15% to about 23%.

[0127] IV. Compositions and Pharmaceutical Compositions Provided herein are compositions comprising a semi-solid or solid dispersion described herein, a particle described herein, a spray-dried particle described herein, or a sample thereof.

[0128] The dispersions of etremadenant described herein may be in the form of compositions suitable for administration to a subject.

[0129] Some embodiments provide pharmaceutical compositions comprising a dispersion of etrumadenant described herein and one or more pharmaceutically or physiologically acceptable diluents, carriers, or excipients.

[0130] In some embodiments, etrumadenant or a pharmaceutically acceptable salt thereof is present in a therapeutically acceptable amount. Pharmaceutical compositions can be used in the methods of the present disclosure, such as by administering to a subject to practice the therapeutic and prophylactic methods and uses described herein.

[0131] The pharmaceutical compositions of the present disclosure can be formulated to be compatible with the intended method or route of administration, exemplary routes of administration being described herein. Additionally, the pharmaceutical compositions can be used in combination with other therapeutically active agents or compounds, such as those described herein, to treat or prevent diseases, disorders, and conditions, such as those contemplated by the present disclosure.

[0132] Pharmaceutical compositions containing the dispersions described herein may be in a form suitable for oral use, such as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically elegant and palatable preparation. Tablets, capsules, etc. contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc.

[0133] Tablets, capsules, and the like suitable for oral administration may be uncoated, or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used. They may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or polymeric materials, such as polyesters, polyamic acids, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or lactide / glycolide copolymers, polylactide / glycolide copolymers, or ethylene-vinyl acetate copolymers, to control delivery of the administered composition. For example, oral agents can be encapsulated in microcapsules prepared by coacervation techniques or interfacial polymerization, using hydroxymethylcellulose or gelatin-microcapsules or poly(methyl methchlorate) microcapsules, respectively, or in colloidal drug delivery systems. Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing the above-mentioned formulations will be apparent to those skilled in the art.

[0134] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0135] Aqueous suspensions contain the active ingredient in admixture with excipients suitable for their manufacture. Such excipients can be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and axia gum; dispersing or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), or condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), or ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecanoethyleneoxycetanol), or ethylene oxide and partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions can also contain one or more preservatives.

[0136] Oily suspensions can be formulated by suspending the active ingredient in vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil, such as liquid paraffin.Oily suspensions can contain thickening agents, such as beeswax, hard paraffin or cetyl alcohol.Sweeteners and flavoring agents, such as those mentioned above, can be added to provide a palatable oral preparation.

[0137] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0138] The pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion.The oil phase can be vegetable oil, such as olive oil or peanut oil, or mineral oil, such as liquid paraffin, or their mixture.Suitable emulsifiers can be naturally occurring gums, such as gum acacia or gum tragacanth; naturally occurring phosphatides, such as esters or partial esters derived from soybeans, lecithin, and fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of partial esters and ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0139] In some embodiments, the pharmaceutical composition comprises a dispersion containing a therapeutically effective amount of etrumadenant or a pharmaceutically acceptable salt thereof and one or more pharmaceutically and physiologically acceptable formulating agents. Suitable pharmaceutically or physiologically acceptable diluents, carriers, or excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethyl, or n-propyl, p-hydroxybenzoic acid), emulsifiers, suspending agents, dispersing agents, solvents, fillers, extenders, surfactants, buffers, vehicles, diluents, and / or adjuvants. For example, a suitable vehicle may be saline or citrate-buffered saline, optionally supplemented with other materials common in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize various buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, buffer components may be water-soluble materials such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0140] After the pharmaceutical composition has been formulated, it may be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored either in a ready-to-use form, a lyophilized form requiring reconstitution before use, a liquid form requiring dilution before use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, an ampoule, a syringe, or an auto-injector (e.g., similar to an EpiPen®)), while a multi-use container (e.g., a multi-use vial) is provided in other embodiments.

[0141] The formulations may also include carriers to protect the compositions against rapid degradation or elimination from the body, such as controlled-release formulations, including liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, time-delay materials such as glyceryl monostearate or glyceryl stearate may be used alone or with a wax. A variety of drug delivery devices can be used to deliver the dispersions or compositions described herein, including implants (e.g., implantable pumps) and catheter systems, slow-injection pumps and devices, all of which are well known to those skilled in the art.

[0142] Depot injections, generally administered subcutaneously or intramuscularly, can also be used to release the dispersion or composition disclosed herein over a period of time.Depot injections are usually based on either solid or oil, and generally contain at least one of the formulation components described herein.Those skilled in the art are familiar with the possible formulations and use of depot injections.

[0143] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents described herein. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol. Acceptable diluents, solvents, and dispersion media that may be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any solvent-free fixed oil, including synthetic mono- or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables. Prolonged absorption of certain injectable formulations can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0144] The present disclosure contemplates the administration of the dispersions or compositions described herein in the form of suppositories for rectal administration.Suppositories can be prepared by mixing a drug with a suitable non-irritating excipient that is solid at normal temperatures but liquid at rectal temperatures, and therefore melts in the rectum to release the drug.Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0145] The dispersions or compositions described herein may be in the form of any other suitable pharmaceutical composition now known or hereafter developed (e.g., a spray for nasal or inhalation use).

[0146] Some embodiments provide a dosage form comprising a semi-solid dispersion described herein. In some embodiments, the dosage form is a tablet or a capsule. In some embodiments, the dosage form is a tablet. In some embodiments, the dosage form is a capsule. Some embodiments provide a capsule comprising a semi-solid dispersion described herein.

[0147] Some embodiments provide dosage forms comprising the solid dispersions described herein. Some embodiments provide tablets comprising the solid dispersions described herein.

[0148] Some embodiments provide a dosage form comprising the spray-dried particles described herein.

[0149] In some embodiments, the dosage form is a tablet or a capsule. In some embodiments, the dosage form is a tablet. In some embodiments, the dosage form is a capsule. Exemplary tablets and capsules are as described herein. Exemplary Compositions

[0150] Some embodiments provide compositions comprising a solid dispersion described herein, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants.

[0151] In some embodiments, the composition comprises about 40% to about 60% (w / w) solid dispersion, hi some embodiments, the composition comprises about 45% to about 50% (w / w) solid dispersion.

[0152] In some embodiments, the composition comprises about 47% (w / w) solid dispersion, about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of one or more disintegrants, about 0.5 to about 1% (w / w) of one or more glidants, and less than 1% (w / w) of one or more lubricants.

[0153] In some embodiments, the composition comprises about 47.3% (w / w) solid dispersion, about 47.3% (w / w) of one or more fillers, about 4.1% (w / w) of one or more disintegrants, about 0.6% (w / w) of one or more glidants, and about 0.6% (w / w) of one or more lubricants.

[0154] In some embodiments, the composition comprises about 50% (w / w) solid dispersion, about 17.5% (w / w) of one or more fillers, about 31.8% (w / w) of one or more disintegrants, and about 0.6% (w / w) of one or more lubricants.

[0155] In some embodiments, the composition comprises about 35% to about 45% (w / w) solid dispersion, about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants.

[0156] In some embodiments, the composition comprises about 40% (w / w) solid dispersion, about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants.

[0157] In some embodiments, the composition comprises about 40% (w / w) solid dispersion, about 44% (w / w) of one or more fillers, about 5% (w / w) of one or more disintegrants, and about 0.5% (w / w) of one or more lubricants.

[0158] In some embodiments, the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; The one or more glidants, when present, is colloidal silica.

[0159] In some embodiments, the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; or The one or more disintegrants is croscarmellose sodium; or The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; or The one or more glidants, when present, is colloidal silica.

[0160] In some embodiments, the co-processed MCC comprises MCC co-processed with alginate, chitosan, DCP, guar gum, mannitol, silicon dioxide, sorbitol, or the like.

[0161] In some embodiments, the one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; The one or more glidants, when present, is colloidal silica.

[0162] In some embodiments, the one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica; or The one or more disintegrants is croscarmellose sodium; or The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; or The one or more glidants, when present, is colloidal silica.

[0163] In some embodiments, the one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants is magnesium stearate;

[0164] In some embodiments, the one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica; or The one or more disintegrants is croscarmellose sodium; or The one or more lubricants is magnesium stearate.

[0165] In some embodiments, the compositions described herein comprise a first filler and a second filler, wherein the solid dispersion, the first filler, and the second filler have a weight ratio of 2:1:1. In some embodiments, the compositions described herein comprise a first filler and a second filler, wherein the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1.

[0166] In some embodiments, the first filler and the second filler are each independently selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0167] In some embodiments, the first filler and the second filler are each independently selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0168] In some embodiments, the first filler is MCC and the second filler is mannitol.

[0169] In some embodiments, one or more disintegrants is croscarmellose sodium; one or more lubricants is sodium stearyl fumarate, and one or more glidants is colloidal silica.

[0170] In some embodiments, one or more disintegrants is croscarmellose sodium; alternatively, one or more lubricants is sodium stearyl fumarate; alternatively, one or more glidants is colloidal silica.

[0171] In some embodiments, one or more disintegrants is croscarmellose sodium; alternatively, one or more lubricants is magnesium stearate.

[0172] In some embodiments, the composition comprises about 40% to about 60% (w / w) of a solid dispersion, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; wherein the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; The one or more glidants, when present, is colloidal silica.

[0173] In some embodiments, the composition comprises about 40% to about 50% (w / w) of a solid dispersion, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; wherein the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; The one or more glidants, when present, is colloidal silica.

[0174] In some embodiments, the composition comprises about 40% to about 60% (w / w) of a solid dispersion, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; wherein The solid dispersion comprises about 25% to about 40% (w / w) etremadenant and about 60% to about 75% (w / w) HPMCAS; the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; The one or more glidants, when present, is colloidal silica.

[0175] In some embodiments, the composition comprises about 40% to about 50% (w / w) of a solid dispersion, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; wherein The solid dispersion comprises about 25% to about 40% (w / w) etremadenant and about 60% to about 75% (w / w) HPMCAS; the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; The one or more glidants, when present, is colloidal silica.

[0176] In some embodiments, the composition comprises about 47% (w / w) solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) croscarmellose sodium, about 0.5 to about 1% (w / w) colloidal silica, and less than 1% (w / w) sodium stearyl fumarate; wherein The one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0177] In some embodiments, the composition comprises about 47.3% (w / w) solid dispersion, about 47.3% (w / w) of one or more fillers, about 4.1% (w / w) croscarmellose sodium, about 0.6% (w / w) colloidal silica, and about 0.6% (w / w) sodium stearyl fumarate; wherein The one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0178] In some embodiments, the composition comprises about 40% (w / w) solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) croscarmellose sodium, and about 0.25% to about 0.75% (w / w) magnesium stearate; wherein: The one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0179] In some embodiments, the composition comprises about 40% (w / w) solid dispersion, about 44% (w / w) one or more fillers, about 5% (w / w) croscarmellose sodium, and about 0.5% (w / w) magnesium stearate; wherein: The one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0180] In some embodiments, the composition comprises about 45% to about 50% (w / w) solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) croscarmellose sodium, about 0.5 to about 1% (w / w) colloidal silica, and less than 1% (w / w) sodium stearyl fumarate; wherein The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0181] In some embodiments, the composition comprises about 47% (w / w) solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) croscarmellose sodium, about 0.5 to about 1% (w / w) colloidal silica, and less than 1% (w / w) sodium stearyl fumarate; wherein The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0182] In some embodiments, the composition comprises about 47.3% (w / w) solid dispersion, about 47.3% (w / w) of one or more fillers, about 4.1% (w / w) croscarmellose sodium, about 0.6% (w / w) colloidal silica, and about 0.6% (w / w) sodium stearyl fumarate; wherein The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0183] In some embodiments, the composition comprises about 35% to about 45% (w / w) solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) croscarmellose sodium, and about 0.25% to about 0.75% (w / w) magnesium stearate; wherein: The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0184] In some embodiments, the composition comprises about 40% (w / w) solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) croscarmellose sodium, and about 0.25 to about 0.75% (w / w) magnesium stearate; wherein: The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0185] In some embodiments, the composition comprises about 40% (w / w) solid dispersion; about 44% (w / w) of one or more fillers, about 5% (w / w) croscarmellose sodium, and about 0.5% (w / w) magnesium stearate; wherein: The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0186] In some embodiments, the composition comprises about 45% to about 50% (w / w) solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) croscarmellose sodium, about 0.5 to about 1% (w / w) colloidal silica, and less than 1% (w / w) sodium stearyl fumarate; wherein The solid dispersion comprises about 25% to about 40% (w / w) etremadenant and about 60% to about 75% (w / w) HPMCAS; The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0187] In some embodiments, the composition comprises about 47% (w / w) solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) croscarmellose sodium, about 0.5 to about 1% (w / w) colloidal silica, and less than 1% (w / w) sodium stearyl fumarate; wherein The solid dispersion comprises about 25% to about 40% (w / w) etremadenant and about 60% to about 75% (w / w) HPMCAS; The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0188] In some embodiments, the composition comprises about 47.3% (w / w) solid dispersion, about 47.3% (w / w) of one or more fillers, about 4.1% (w / w) croscarmellose sodium, about 0.6% (w / w) colloidal silica, and about 0.6% (w / w) sodium stearyl fumarate; wherein The solid dispersion comprises about 25% to about 40% (w / w) etremadenant and about 60% to about 75% (w / w) HPMCAS; The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0189] In some embodiments, the composition comprises about 35% to about 45% (w / w) solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) croscarmellose sodium, and about 0.25% to about 0.75% (w / w) magnesium stearate; wherein: The solid dispersion comprises about 20% to about 40% (w / w) etremadenant and about 60% to about 80% (w / w) HPMCAS; The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0190] In some embodiments, the composition comprises about 40% (w / w) solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) croscarmellose sodium, and about 0.25 to about 0.75% (w / w) magnesium stearate; wherein: The solid dispersion comprises about 20% to about 40% (w / w) etremadenant and about 60% to about 80% (w / w) HPMCAS; The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0191] In some embodiments, the composition comprises about 40% (w / w) solid dispersion; about 44% (w / w) of one or more fillers, about 5% (w / w) croscarmellose sodium, and about 0.5% (w / w) magnesium stearate; wherein: The solid dispersion comprises about 20% to about 40% (w / w) etremadenant and about 60% to about 80% (w / w) HPMCAS; The one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0192] In some embodiments, the composition comprises about 47% (w / w) solid dispersion, about 30% to about 50% (w / w) of a first filler and a second filler, about 4% to about 6% (w / w) of one or more disintegrants, about 0.5 to about 1% (w / w) of one or more glidants, and less than 1% (w / w) of one or more lubricants, wherein the solid dispersion, the first filler, and the second filler have a weight ratio of 2:1:1.

[0193] In some embodiments, the composition comprises about 40% (w / w) solid dispersion, about 40% to about 50% (w / w) of a first filler and a second filler, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants, wherein the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1.

[0194] In some embodiments, the composition comprises about 47% (w / w) solid dispersion, about 30% to about 50% (w / w) of a first filler and a second filler, about 4% to about 6% (w / w) of one or more disintegrants, about 0.5 to about 1% (w / w) of one or more glidants, and less than 1% (w / w) of one or more lubricants; The solid dispersion, the first filler, and the second filler have a weight ratio of 2:1:1, and the first filler and the second filler are each independently selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0195] In some embodiments, the composition comprises about 40% (w / w) solid dispersion, about 40% to about 50% (w / w) of a first filler and a second filler, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants; the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1; and the first filler and the second filler are each independently selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0196] In some embodiments, the composition comprises about 47% (w / w) solid dispersion, about 30% to about 50% (w / w) of a first filler and a second filler, about 4% to about 6% (w / w) of one or more disintegrants, about 0.5 to about 1% (w / w) of one or more glidants, and less than 1% (w / w) of one or more lubricants; The solid dispersion, the first filler, and the second filler have a weight ratio of 2:1:1, and the first filler and the second filler are each independently selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0197] In some embodiments, the composition comprises about 40% (w / w) solid dispersion, about 40% to about 50% (w / w) of a first filler and a second filler, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants; the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1; and the first filler and the second filler are each independently selected from MCC, mannitol, silicified MCC, and mesoporous silica.

[0198] In some embodiments, the composition comprises about 47% (w / w) solid dispersion, about 30% to about 50% (w / w) of a first filler and a second filler, about 4% to about 6% (w / w) of one or more disintegrants, about 0.5 to about 1% (w / w) of one or more glidants, and less than 1% (w / w) of one or more lubricants; The solid dispersion, the first filler, and the second filler have a weight ratio of 2:1:1, the first filler being MCC and the second filler being mannitol.

[0199] In some embodiments, the composition comprises about 40% (w / w) solid dispersion, about 40% to about 50% (w / w) of a first filler and a second filler, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants; the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1; the first filler is MCC and the second filler is mannitol.

[0200] In some embodiments, the composition comprises about 47% (w / w) solid dispersion, about 30% to about 50% (w / w) of a first filler and a second filler, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5% to about 1% (w / w) of colloidal silica, and less than 1% (w / w) of sodium stearyl fumarate; The solid dispersion, the first filler, and the second filler have a weight ratio of 2:1:1, where the first filler is MCC and the second filler is mannitol.

[0201] In some embodiments, the composition comprises about 40% (w / w) solid dispersion, about 40% to about 50% (w / w) of a first filler and a second filler, about 2% to about 7% (w / w) croscarmellose sodium, and about 0.25% to about 0.75% (w / w) magnesium stearate; the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1; and the first filler is MCC and the second filler is mannitol.

[0202] Some embodiments provide an intragranular component comprising a composition described herein.

[0203] In some embodiments, the intragranular component comprises a solid dispersion described herein, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants.

[0204] granules Some embodiments provide granules comprising a solid dispersion described herein, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants.

[0205] Some embodiments provide granules comprising the spray-dried particles described herein, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants.

[0206] In some embodiments, the granules comprise about 40% to about 60% (w / w) of the solid dispersion or spray-dried particles, hi some embodiments, the granules comprise about 45% to about 50% (w / w) of the solid dispersion or spray-dried particles.

[0207] In some embodiments, the granules comprise about 47% (w / w) solid dispersion or spray-dried particles, about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of one or more disintegrants, about 0.5 to about 1% (w / w) of one or more glidants, and less than 1% (w / w) of one or more lubricants.

[0208] In some embodiments, the granules comprise about 47.3% (w / w) of the solid dispersion or spray-dried particles, about 47.3% (w / w) of one or more fillers, about 4.1% (w / w) of one or more disintegrants, about 0.6% (w / w) of one or more glidants, and about 0.6% (w / w) of one or more lubricants.

[0209] In some embodiments, the granules comprise about 35% to about 45% (w / w) of the solid dispersion or spray-dried particles, about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of one or more disintegrants, and about 0.25% to about 0.75% (w / w) of one or more lubricants.

[0210] In some embodiments, the granules comprise about 40% (w / w) of the solid dispersion or spray-dried particles, about 44% (w / w) of one or more fillers, about 5% (w / w) of one or more disintegrants, and about 0.5% (w / w) of one or more lubricants.

[0211] In some embodiments, the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; and / or one or more disintegrants is croscarmellose sodium; and / or The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; and / or The one or more glidants, when present, is colloidal silica.

[0212] In some embodiments, the one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica; and / or one or more disintegrants is croscarmellose sodium; and / or The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; and / or The one or more glidants, when present, is colloidal silica.

[0213] In some embodiments, the granules described herein comprise a first filler and a second filler, wherein the solid dispersion, the first filler, and the second filler have a weight ratio of 2:1:1. In some embodiments, the granules described herein comprise a first filler and a second filler, wherein the solid dispersion, the first filler, and the second filler have a weight ratio of about 2.2:1.4:1.

[0214] In some embodiments, the first filler is MCC and the second filler is mannitol.

[0215] In some embodiments, the one or more disintegrants is croscarmellose sodium; and / or the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and / or The one or more glidants, when present, is colloidal silica.

[0216] In some embodiments, the one or more disintegrants is croscarmellose sodium; and / or the one or more lubricants are sodium stearyl fumarate or magnesium stearate; and / or The one or more glidants, when present, are selected from colloidal silica.

[0217] Pharmaceutical Composition Some embodiments provide pharmaceutical compositions comprising an intragranular component comprising a composition described herein and an extragranular component comprising one or more fillers, optionally one or more disintegrants, optionally one or more glidants, and one or more lubricants.

[0218] Some embodiments provide pharmaceutical compositions comprising an intragranular component as described herein and an extragranular component comprising one or more fillers, optionally one or more disintegrants, optionally one or more glidants, and one or more lubricants.

[0219] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular component, or about 85% (w / w) intragranular component. In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular component. In some embodiments, the pharmaceutical composition comprises about 87% to about 93% (w / w) intragranular component. In some embodiments, the pharmaceutical composition comprises about 85% (w / w) intragranular component. In some embodiments, the pharmaceutical composition comprises about 90% (w / w) intragranular component.

[0220] In some embodiments, the extragranular component comprises about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of one or more disintegrants, about 0.5% to about 1.0% (w / w) of one or more glidants, and about 0.5% to about 1.0% (w / w) of one or more lubricants. In some embodiments, the extragranular component comprises about 5% to about 15% (w / w) of one or more fillers and about 0.25% to about 0.75% (w / w) of one or more lubricants.

[0221] In some embodiments, the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, co-processed microcrystalline cellulose, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants, when present, is croscarmellose sodium; the one or more lubricants being sodium stearyl fumarate or magnesium stearate; The one or more glidants, when present, is colloidal silica.

[0222] In some embodiments, the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, co-processed microcrystalline cellulose, silicified microcrystalline cellulose, and mesoporous silica; or The one or more disintegrants, when present, is croscarmellose sodium; or The one or more lubricants are sodium stearyl fumarate or magnesium stearate; or The one or more glidants, when present, is colloidal silica.

[0223] In some embodiments, the one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants is sodium stearyl fumarate; The one or more glidants is colloidal silica.

[0224] In some embodiments, the one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose, and mesoporous silica; or The one or more disintegrants is croscarmellose sodium; or one or more lubricants is sodium stearyl fumarate; or The one or more glidants is colloidal silica.

[0225] In some embodiments, the one or more fillers are selected from microcrystalline cellulose and mannitol, and the one or more lubricants is magnesium stearate.

[0226] In some embodiments, the pharmaceutical composition comprises two fillers, optionally in a ratio of 1:1 to 2:1.

[0227] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components; wherein: The intragranular components are about 35% to about 50% (w / w) solid dispersion, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; The extragranular components are about 5% to about 15% (w / w) of one or more fillers, optionally about 1% to about 2% (w / w) of one or more disintegrants, optionally about 0.5% to about 1.0% (w / w) of one or more glidants, and about 0.25% to about 1.0% (w / w) of one or more lubricants; During the ceremony, the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; The one or more glidants, when present, is colloidal silica.

[0228] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components; wherein: The intragranular components are about 35% to about 50% (w / w) solid dispersion, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; The extragranular components are about 5% to about 15% (w / w) of one or more fillers, optionally about 1% to about 2% (w / w) of one or more disintegrants, optionally about 0.5% to about 1.0% (w / w) of one or more glidants, and about 0.25% to about 1.0% (w / w) of one or more lubricants; During the ceremony, the one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; The one or more glidants, when present, is colloidal silica.

[0229] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components; wherein: The intragranular components are about 35% to about 50% (w / w) solid dispersion, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; The solid dispersion comprises about 20% to about 40% (w / w) etremadenant and about 60% to about 80% (w / w) HPMCAS; The extragranular components are about 5% to about 15% (w / w) of one or more fillers, optionally about 1% to about 2% (w / w) of one or more disintegrants, optionally about 0.5% to about 1.0% (w / w) of one or more glidants, and about 0.25% to about 1.0% (w / w) of one or more lubricants; During the ceremony, the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants, if present, are sodium stearyl fumarate or magnesium stearate; The one or more glidants, when present, is colloidal silica.

[0230] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components, wherein: The intragranular components are about 45% to about 50% (w / w) of a solid dispersion, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; The solid dispersion comprises about 25% to about 40% (w / w) etremadenant and about 60% to about 75% (w / w) HPMCAS; The extragranular components are about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of one or more disintegrants, about 0.5% to about 1.0% (w / w) of one or more glidants, species or species of glidants, and about 0.5% to about 1.0% (w / w) of one or more lubricants; During the ceremony, the one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose, and mesoporous silica; The one or more disintegrants is croscarmellose sodium; The one or more lubricants, if present, is sodium stearyl fumarate; The one or more glidants, when present, is colloidal silica.

[0231] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components, wherein: The intragranular components are about 35% to about 45% (w / w) of a solid dispersion, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants; The solid dispersion comprises about 20% to about 40% (w / w) etremadenant and about 60% to about 80% (w / w) HPMCAS; The extragranular components are comprising about 5% to about 15% (w / w) of one or more fillers and about 0.25% to about 0.75% (w / w) of one or more lubricants; The one or more fillers are selected from microcrystalline cellulose and mannitol; the one or more disintegrants are croscarmellose sodium, and the one or more lubricants are magnesium stearate.

[0232] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components, wherein: The intragranular component comprises about 47% (w / w) of the solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5 to about 1% (w / w) of colloidal silica, and less than 1% (w / w) of sodium stearyl fumarate; the extragranular components comprising about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of croscarmellose sodium, about 0.5% to about 1.0% (w / w) of colloidal silica, and about 0.5% to about 1.0% (w / w) of sodium stearyl fumarate; The one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0233] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components; wherein: The intragranular component comprises about 35% to about 45% (w / w) of the solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of croscarmellose sodium, and about 0.25% to about 0.75% (w / w) of magnesium stearate; the extragranular components include about 5% to about 15% (w / w) of one or more fillers and about 0.25% to about 0.75% (w / w) of one or more lubricants; The one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0234] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components; wherein: the intragranular component comprising about 47.3% (w / w) solid dispersion, about 47.3% (w / w) one or more fillers, about 4.1% (w / w) croscarmellose sodium, about 0.6% (w / w) colloidal silica, and about 0.6% (w / w) sodium stearyl fumarate; the extragranular components comprising about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of croscarmellose sodium, about 0.5% to about 1.0% (w / w) of colloidal silica, and about 0.5% to about 1.0% (w / w) of sodium stearyl fumarate; The one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica.

[0235] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components; wherein: Intragranular Component The intragranular component comprises about 47% (w / w) of the solid dispersion; about 43% to about 47% (w / w) of one or more fillers, about 4% to about 6% (w / w) of croscarmellose sodium, about 0.5 to about 1% (w / w) of colloidal silica, and less than 1% (w / w) of sodium stearyl fumarate; the extragranular components comprising about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of croscarmellose sodium, about 0.5% to about 1.0% (w / w) of colloidal silica, and about 0.5% to about 1.0% (w / w) of sodium stearyl fumarate; The one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose, and mesoporous silica.

[0236] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components; wherein: the intragranular component comprising about 47.3% (w / w) solid dispersion, about 47.3% (w / w) one or more fillers, about 4.1% (w / w) croscarmellose sodium, about 0.6% (w / w) colloidal silica, and about 0.6% (w / w) sodium stearyl fumarate; the extragranular components comprising about 10% to about 15% (w / w) of one or more fillers, about 1% to about 2% (w / w) of croscarmellose sodium, about 0.5% to about 1.0% (w / w) of colloidal silica, and about 0.5% to about 1.0% (w / w) of sodium stearyl fumarate; The one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose, and mesoporous silica.

[0237] In some embodiments, the pharmaceutical composition comprises about 85% to about 95% (w / w) intragranular and extragranular components; wherein: The intragranular component comprises about 35% to about 45% (w / w) of the solid dispersion; about 40% to about 50% (w / w) of one or more fillers, about 2% to about 7% (w / w) of croscarmellose sodium, and about 0.25% to about 0.75% (w / w) of magnesium stearate; the extragranular components include about 5% to about 15% (w / w) of one or more fillers and about 0.25% to about 0.75% (w / w) of magnesium stearate; The one or more fillers are selected from microcrystalline cellulose and mannitol

[0238] In some embodiments, the one or more fillers of the intragranular component and the one or more fillers of the extragranular component are each independently selected from the fillers described above. In some embodiments, the one or more fillers of the intragranular component are the same as the one or more fillers of the extragranular component. In some embodiments, the one or more fillers of the intragranular component are different from the one or more fillers of the extragranular component.

[0239] In some embodiments, the pharmaceutical composition or compositions is a formulation of Table 16, Table 19, Table 20, or Table 24.

[0240] Exemplary tablets Some embodiments provide the compositions described herein formulated as pharmaceutical compositions or tablets. In some embodiments, the tablets described herein may be made according to methods known in the art.

[0241] Some embodiments provide tablets that are physically stable, chemically stable, have stable in vitro dissolution properties, and / or have stable in vivo properties when stored in sealed or open packaging at 25°C and 60% relative humidity (long-term stability studies) or 40°C and 75% relative humidity (accelerated stability studies) for 3 months or more (e.g., 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 months). Stability can be assessed by various analytical methods, including assays for etrumadenant and impurities by high-performance liquid chromatography (HPLC), non-precipitating dissolution tests, precipitating dissolution tests, and pharmacokinetic analysis under fed and / or fasted conditions. Some embodiments provide tablets that are physically stable, chemically stable, have stable in vitro dissolution properties, and / or have stable in vivo properties when stored in sealed or open packaging for 6, 9, or 12 months at 25°C and 60% relative humidity (long-term stability studies) or 40°C and 75% relative humidity (accelerated stability studies).

[0242] Some embodiments provide a tablet comprising microcrystalline cellulose (MCC), mannitol, croscarmellose sodium, colloidal silica, sodium stearyl fumarate, and a solid dispersion described herein.Some embodiments provide a tablet comprising microcrystalline cellulose (MCC), mannitol, croscarmellose sodium, magnesium stearate, and a solid dispersion described herein.

[0243] In some embodiments, the tablet comprises about 25% to about 60% (w / w) solid dispersion. In some embodiments, the tablet comprises about 35% to about 55% (w / w) solid dispersion. In some embodiments, the tablet comprises about 30% to about 55% (w / w) solid dispersion. In some embodiments, the tablet comprises about 35% to about 45% (w / w) solid dispersion. In some embodiments, the tablet comprises about 40% to about 50% (w / w) solid dispersion.

[0244] In some embodiments, the tablet contains about 40% to about 50% (w / w) of a solid dispersion described herein, about 10% to about 25% (w / w) of MCC, about 20% to about 25% (w / w) of mannitol, about 5% to about 6% (w / w) of croscarmellose sodium, about 1% (w / w) of colloidal silica, and about 1% (w / w) of sodium stearyl fumarate. In some embodiments, the tablet contains about 35% to about 45% (w / w) of a solid dispersion described herein, about 30% to about 42% (w / w) of MCC, about 13% to about 23% (w / w) of mannitol, about 2% to about 8% (w / w) of croscarmellose sodium, and about 0.5% to about 1.5% (w / w) of magnesium stearate.

[0245] In some embodiments, the tablet is a tablet of Table 16, Table 19, Table 20, or Table 24.

[0246] In some embodiments, the tablet has a weight of about 100 mg to about 1 g. In some embodiments, the tablet has a weight of about 100 mg, about 250 mg, about 500 mg, or about 750 mg. In some embodiments, the tablet has a weight of 750 mg to 800 mg, 760 mg to 790 mg, 770 mg to 780 mg, 775 mg to 785 mg, or 780 mg to 790 mg.

[0247] In some embodiments, the tablet has a weight of 1 g. In some embodiments, the tablet has a weight of about 100 mg. In some embodiments, the tablet has a weight of about 250 mg. In some embodiments, the tablet has a weight of about 500 mg. In some embodiments, the tablet has a weight of about 750 mg.

[0248] In some embodiments, the tablets described herein further comprise a coating. In some embodiments, the coating is a non-functional coating.

[0249] Some embodiments provide a tablet as described herein, wherein the tablet is an immediate release tablet.Some embodiments provide a tablet as described herein, wherein the percent of etremadenant released in 45 minutes is 85% or greater, as measured by the dissolution method of Table 21.

[0250] Some embodiments provide a tablet described herein, wherein the tablet has a total impurity content of less than 2% (area %) as measured by HPLC. Analysis of impurities by HPLC can be performed as described herein. In some embodiments, the tablet has a total impurity content of about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1.0%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1% (area %) as measured by HPLC. In some embodiments, the tablet has a total impurity content of less than 1% (area %) as measured by HPLC. In some embodiments, the tablet has a total impurity content of less than 0.5% (area %) as measured by HPLC.

[0251] Some embodiments provide a tablet as described herein, which upon storage in a sealed package at 25° C. and 60% relative humidity for 6 months, 12 months, 18 months, 24 months, or 36 months: (i) the amount of etrumadenant in the tablet is about 90 to about 110% of the value measured at 0 months; (ii) total impurities of 2% or less, 1% or less, or 0.5% or less (area %) as measured by HPLC; (iii) The amount of etremadenant measured at 210 min by the non-settling dissolution test (C 210 (μgA / mL) or AUC 35-210FaSSIF (min * μgA / mL) differs by 15% or less from the value measured at 0 months; or (iv) Any combination of (i) to (iii).

[0252] In some embodiments, storage in a sealed package at 25° C. and 60% relative humidity for 6 months, 12 months, 18 months, 24 months, or 36 months results in: (i) the amount of etrumadenant in the tablet is about 90 to about 110% of the value measured at 0 months; (ii) less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5% (area %) total impurities as measured by HPLC; or (iii) Any combination of (i) to (ii).

[0253] In some embodiments, the amount of total impurities and etremadenant at 210 minutes due to non-settling dissolution are as described herein.

[0254] The tablets described herein can be administered to humans in a fed or fasted state. In some embodiments, when the tablets are administered to humans in a fed or fasted state, the overall exposure of the human to etremadenant is equivalent. The overall exposure is measured by the AUC last (Fasting) vs. AUC last (fed) ratio or AUC inf In some embodiments, equivalence can be measured by the ratio of AUC (fasted) to AUC (fed). 0-inf This refers to achieving an equivalence limit of 80 to 125 percent.

[0255] The tablets described herein are contemplated to exhibit desirable properties including, but not limited to, advantageous levels of weight, thickness, breaking force, flowability, tabletability, and / or compressibility, as well as a robust disintegration profile as further described herein.

[0256] Some embodiments provide methods of making the tablets described herein. In some embodiments, the tablets described herein can be made according to the methods described in the examples provided herein. In some embodiments, certain components of the tablet can be blended, lubricated, de-lumped, roller-compacted, milled, and / or compressed. The order of such steps can be varied as needed. In some embodiments, a film coating can be applied. In some embodiments, the resulting tablets and / or film-coated tablets can be packaged as appropriate, for example, to form a kit as described herein.

[0257] Some embodiments provide a process for making a tablet described herein, comprising: (i) blending a dispersion described herein with one or more excipients described herein, where blending is optionally performed in one or more steps to provide a mixture; (ii) adding a lubricant; (iii) de-lumping; (iv) roller compacting and milling to form granules; (v) adding one or more additional excipients to the granules to form a second mixture; (vi) compressing the second mixture to form a tablet; and optionally (vii) adding a film coating to form a film-coated tablet. In some embodiments, the order of step (ii) (adding the lubricant) and step (iii) may be reversed, such that de-lumping occurs before adding the lubricant.

[0258] Some embodiments provide a process for making a tablet described herein, comprising: (i) blending a dispersion described herein with one or more excipients described herein; (ii) milling / dispersing the mixture; (iii) adding a lubricant and blending to form a second mixture; (iv) compressing; (v) milling; (vi) adding one or more additional excipients and blending to form a third mixture; (vi) compressing the third mixture to form a tablet; and, optionally, (vii) adding a film coating to form a film-coated tablet.

[0259] V. Therapeutic and Prophylactic Uses The present disclosure provides adenosine A 2A Receptor (A 2A R), adenosine A 2B Receptor (A 2B R), or adenosine A 2A Receptor (A 2B R) and adenosine A 2B Receptor (A 2B The present invention provides a method for using a dispersion described herein, a composition described herein, a granule described herein, a pharmaceutical composition described herein, a dosage form described herein, or a tablet described herein to inhibit R.

[0260] As used herein, the terms "inhibit," "inhibition," and the like refer to the inhibition of a particular target, e.g., A 2A R.A. 2B R or A 2A R and A 2B This refers to the ability of an antagonist to decrease both the function or activity of R. The decrease is preferably at least 50%, and can be, for example, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%.

[0261] The present disclosure contemplates the administration of the dispersions, compositions, or pharmaceutical compositions described herein in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, intracisternal, intraarticular, intracerebral (intraparenchymal), and intracerebroventricular), nasal, intravaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal, and inhalation. Depot injections, generally administered subcutaneously or intramuscularly, can also be used to release the solid form of the etremadenant disclosed herein over a predetermined period of time. Some embodiments of the present disclosure contemplate oral administration.

[0262] The present disclosure also provides 2A R.A. 2B R or A 2A R and A 2B The present invention encompasses the use of the dispersions described herein, the compositions described herein, and the pharmaceutical compositions described herein for the treatment or prevention of diseases, disorders, and / or conditions that would benefit from the inhibition of both R and R. Specific uses are described in detail below, but it should be understood that the disclosure is not limited thereto. Additionally, while general classifications of certain diseases, disorders, and conditions are described below, some of the diseases, disorders, and conditions may be members of more than one classification, or may not be members of any of the disclosed classifications.

[0263] Some embodiments include adenosine A 2A Receptor (A 2A R) and / or adenosine A 2B Receptor (A 2B The present invention provides a method of treating a disease, disorder, or condition mediated at least in part by R, comprising administering to a subject in need thereof a dosage form described herein, a pharmaceutical composition described herein, or a tablet described herein.

[0264] In some embodiments, the diseases, disorders, and / or conditions described herein are at least in part attributable to A 2AIn some embodiments, the diseases, disorders, and / or conditions described herein are mediated, at least in part, by A. 2B In some embodiments, the diseases, disorders, and / or conditions described herein are mediated, at least in part, by A. 2A R and A 2B In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be administered in an amount effective to treat or prevent cardiovascular diseases, CNS-related and neurological disorders, immune-related disorders, metabolic diseases, microbial-related disorders, or oncology and oncology-related disorders. 2A R.A. 2B R or A 2A R and A 2B Cardiovascular diseases, CNS-related and neurological disorders, immune-related disorders, metabolic disorders, microbial-related disorders, or oncology and oncology-related diseases that may benefit from treatment with both R inhibitors are described in WO 2018136700 and WO 2020018680 A1, the disclosures of which are incorporated herein by reference.

[0265] In some embodiments, the dispersion, composition, or pharmaceutical composition described herein comprises A 2A R or A 2B R or A 2A R and A 2B The compound is administered in an amount effective to reduce or reverse immunosuppression mediated by both R and R.

[0266] In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are administered in an amount to increase or enhance an immune response, improve immunization, including increasing vaccine efficacy, or increase inflammation.

[0267] In some embodiments of the aforementioned methods, the dispersions described herein, compositions described herein, or pharmaceutical compositions described herein are used in combination with at least one additional therapy. Each additional therapy can be a therapeutic agent or another treatment modality. Contemplated additional therapies include those described in International Publication Nos. 2018136700 and 2020018680A1, as well as those described below. In embodiments including one or more additional therapeutic agents, each agent can target a different but complementary mechanism of action. The additional therapeutic agent can be a small chemical molecule; a macromolecule, e.g., a protein, antibody, peptibody, peptide, DNA, RNA, or fragments of such macromolecules; or cell therapy or gene therapy. Non-limiting examples of additional treatment modalities include surgical removal of the tumor, bone marrow transplant, radiation therapy, and photodynamic therapy. The use of the dispersions, compositions, or pharmaceutical compositions described herein in combination with one or more additional therapies can have a synergistic therapeutic or preventative effect against the underlying disease, disorder, or condition. Additionally, or alternatively, combination therapy may allow for a reduced dosage of one or more of the therapies, thereby ameliorating, reducing, or eliminating adverse effects associated with one or more of the agents.

[0268] In embodiments including one or more additional therapeutic modalities, the dispersions, compositions, or pharmaceutical compositions described herein can be administered before, after, or during treatment with the additional therapeutic modality. In embodiments including one or more additional therapeutic agents, the therapeutic agents used in such combination therapy can be formulated as a single composition or as separate compositions. When administered separately, each therapeutic agent in the combination can be administered simultaneously or near simultaneously, or at different times. Furthermore, therapeutic agents are "administered in combination" even if they have different dosage forms (e.g., oral capsules and intravenous), are given at different dosing intervals, one therapeutic agent is given on a fixed dosing regimen while another is titrated, tapered, or discontinued, or each therapeutic agent in the combination is independently titrated, tapered, or dose-up or -down, or discontinued and / or resumed during the course of a patient's treatment. When the therapeutic agents in the combination are formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0269] Oncology and Oncology-Related Disorders According to the present disclosure, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent cancer (e.g., carcinoma, sarcoma, leukemia, lymphoma, myeloma, etc.).

[0270] Provided herein are methods of treating cancer, comprising administering to a subject in need thereof a dosage form described herein, a pharmaceutical composition described herein, or a tablet described herein.

[0271] In some embodiments, the cancer may be locally advanced and / or unresectable, metastatic, or at risk of becoming metastatic. Alternatively, or in addition, the cancer may be recurrent or no longer responding to treatment, such as standard treatments known to those of skill in the art. In various embodiments, the dispersions, compositions, or pharmaceutical compositions described herein may be used in an adjuvant or neoadjuvant setting. Alternatively, or in addition, the dispersions, compositions, or pharmaceutical compositions described herein may be used as a first-line treatment, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein may be used to treat or prevent cancer, and may be used as a second, third, or higher line of treatment, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. When indicated as a second or higher line of treatment, in some embodiments, the earlier line of therapy included a checkpoint inhibitor.

[0272] In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent malignant hematological disorders. Exemplary types affecting the hematopoietic system include acute myeloid leukemia, adult T-cell leukemia, T-cell large granular lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute monocytic leukemia, Hodgkin's and non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, and multiple myeloma.

[0273] In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent solid tumors. Solid tumors can be, for example, ovarian cancer, endometrial cancer, breast cancer, lung cancer (small cell or non-small cell), colorectal cancer, prostate cancer, cervical cancer, biliary tract cancer, pancreatic cancer, gastric cancer, esophageal cancer, liver cancer (hepatocellular carcinoma), kidney cancer (renal cell carcinoma), head and neck tumors, mesothelioma, melanoma, sarcoma, central nervous system (CNS) hemangioblastoma, and brain tumors (e.g., gliomas such as astrocytoma, oligodendroglioma, and glioblastoma). In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent lung cancer, genitourinary cancer, gastrointestinal cancer, or a combination thereof.

[0274] In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, lung cancer, gastrointestinal cancer, genitourinary cancer, or gynecological cancer. In some embodiments, the cancer is bladder cancer, breast cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is castration-resistant prostate cancer, esophageal adenocarcinoma, non-small cell lung cancer, pancreatic ductal adenocarcinoma, prostate adenocarcinoma, or urothelial cancer.

[0275] In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent breast cancer. In further embodiments, the breast cancer is hormone receptor-positive (e.g., ERα-positive breast cancer, PR-positive breast cancer, ERα-positive and PR-positive breast cancer), HER2-positive breast cancer, HER2-overexpressing breast cancer, or any combination thereof. In yet further embodiments, the breast cancer is triple-negative breast cancer. In yet another embodiment, the breast cancer is locally advanced or metastatic triple-negative breast cancer, optionally with disease progression on previous treatment.

[0276] In some embodiments, compounds according to the present disclosure are useful for treating genitourinary cancer. In further embodiments, the genitourinary cancer is gynecological cancer. In still further embodiments, the gynecological cancer is endometrial cancer, cervical cancer, ovarian cancer, or fallopian tube cancer. In yet another embodiment, the gynecological cancer is locally advanced or metastatic ovarian cancer, optionally with disease progression on previous treatment. In still further embodiments, the genitourinary cancer is urothelial cancer, optionally with advanced or metastatic urothelial cancer. In some embodiments, the genitourinary cancer is advanced or metastatic MTAP-deficient urothelial cancer. In still further embodiments, the genitourinary cancer is prostate cancer. In still further embodiments, the genitourinary cancer is adenocarcinoma of the prostate, optionally eligible for radical prostatectomy. In further embodiments, the genitourinary cancer is castration-resistant prostate cancer, optionally with metastatic castration-resistant prostate cancer. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent kidney cancer. In a further embodiment, the kidney cancer is renal cell carcinoma. In a further embodiment, the renal cell carcinoma is clear cell renal cell carcinoma.

[0277] In some embodiments, compounds according to the present disclosure are useful for treating and / or preventing kidney cancer. In further embodiments, the kidney cancer is renal cell carcinoma. In further embodiments, the renal cell carcinoma is clear cell renal cell carcinoma.

[0278] In some embodiments, compounds according to the present disclosure are useful in treating liver cancer. In further embodiments, the liver cancer is hepatocellular carcinoma.

[0279] In some embodiments, compounds according to the present disclosure are useful for the treatment and / or prevention of head and neck cancer, hi further embodiments, the head and neck cancer is head and neck squamous cell carcinoma, and optionally the cancer has not been previously treated.

[0280] In some embodiments, compounds according to the present disclosure are useful in the treatment of skin cancer, hi further embodiments, the skin cancer is melanoma.

[0281] In some embodiments, compounds according to the present disclosure are useful for treating lung cancer. In further embodiments, the lung cancer is mesothelioma, small cell lung cancer (SCLC), or non-small cell lung cancer (NSCLC). In still further embodiments, the NSCLC can be lung squamous cell carcinoma or lung adenocarcinoma. In still further embodiments, the NSCLC is metastatic, locally advanced, or non-squamous NSCLC that recurs with progression.

[0282] In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent pancreatic cancer, hi further embodiments, the pancreatic cancer is pancreatic neuroendocrine tumor or pancreatic adenocarcinoma.

[0283] In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent neuroendocrine tumors, hi further embodiments, the neuroendocrine tumor is a pancreatic neuroendocrine tumor, a pheochromocytoma, a paraganglioma, or a tumor of the adrenal gland.

[0284] In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent brain cancer. In further embodiments, the brain cancer is glioma. In yet other embodiments, the glioma is astrocytoma, oligodendroglioma, or glioblastoma.

[0285] In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein can be used to treat or prevent gastrointestinal (GI) cancer. In some embodiments, the GI cancer is a lower GI cancer, such as colon cancer or rectal cancer. In some embodiments, the lower GI cancer is rectal adenocarcinoma, optionally non-metastatic rectal adenocarcinoma. In some embodiments, the lower GI cancer is colorectal adenocarcinoma that is metastatic, advanced, or recurrent with progression. In some embodiments, the GI cancer is an upper GI cancer, such as esophageal cancer or gastric cancer. In further embodiments, the upper GI cancer is adenocarcinoma, squamous cell carcinoma, or any combination thereof. In further embodiments, the upper GI cancer is esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastroesophageal junction adenocarcinoma (GEJ), gastric adenocarcinoma (also referred to herein as "gastric cancer"), or any combination thereof, optionally, the upper GI cancer is metastatic, advanced, or recurrent with progression.

[0286] The present disclosure also provides methods for treating or preventing other cancer-related diseases, disorders, or conditions. The use of the terms cancer-related diseases, disorders, and conditions is meant to refer broadly to conditions directly or indirectly related to cancer, including cancer or non-cancerous proliferative diseases, including, for example, angiogenesis and pre-cancerous conditions, such as dysplasia, as well as non-cancerous proliferative diseases, disorders, or conditions, such as benign proliferative breast disease and papilloma. For clarity, the terms cancer-related diseases, disorders, and conditions do not include cancer itself.

[0287] Generally, the disclosed methods for treating or preventing cancer or a cancer-related disease, disorder, or condition in a subject in need thereof include administering to the subject a dispersion, composition, or pharmaceutical composition described herein. In some embodiments, the present disclosure provides methods for treating or preventing cancer or a cancer-related disease, disorder, or condition using a dispersion, composition, or pharmaceutical composition described herein and at least one additional therapeutic agent (examples of which are described elsewhere herein).

[0288] Patient selection In some cases, methods according to the present disclosure may be provided to selected patients, e.g., subjects identified as having detectable PD-L1 expression, microsatellite instability (MSI), deficient mismatch repair (dMMR), high tumor mutation burden, or any combination thereof, in a relevant tissue or sample. In some cases, the subject is identified as having an oncogene-driven cancer having a mutation in at least one gene associated with the cancer.

[0289] In some embodiments, patients are selected by assessing expression of relevant biomarkers, e.g., PD-L1 expression, microsatellite instability markers, etc., in relevant samples, such as peripheral blood samples or tumor biopsies, using immunohistochemistry, immunophenotyping, PCR-based amplification, RNA sequencing, or other clinically validated assays. In one embodiment, the present disclosure provides a method of treating cancer in a patient with (i) detectable PD-L1 expression, (ii) elevated PD-L1 expression, (iii) low MSI, (iv) high MSI, or (v) any combination of (i)-(iv), by administering a compound, dispersion, composition, or pharmaceutical composition described herein. In another embodiment, the present disclosure provides a method of treating cancer in a patient with (i) detectable PD-L1 expression, (ii) elevated PD-L1 expression, (iii) low MSI, (iv) high MSI, or (v) any combination of (i)-(iv), by administering a therapeutically effective amount of a compound, dispersion, composition, or pharmaceutical composition described herein. In yet another embodiment, the present disclosure provides a method of administering a therapeutically effective amount of a compound, dispersion, composition, or pharmaceutical composition described herein to an individual for the treatment of cancer based on a determination of the relative amount of PD-L1 expression. In yet another embodiment, the present disclosure provides a method of administering a therapeutically effective amount of a compound, dispersion, composition, or pharmaceutical composition described herein to an individual for the treatment of cancer, the method comprising measuring PD-L1 expression and / or microsatellite instability (e.g., low MSI or high MSI) in a sample obtained from the individual, for example, by immunohistochemistry, immunophenotyping, PCR-based amplification, or other clinically validated test, and administering a therapeutically effective amount of the compound, dispersion, composition, or pharmaceutical composition to the individual whose sample contained detectable PD-L1 expression and / or microsatellite instability. In various embodiments of the present disclosure, detectable PD-L1 expression can be a tumor proportion (TPS) score of ≧50%, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test. In various embodiments of the present disclosure, detectable PD-L1 expression can be a TPS score of less than 50% as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test. Combination therapy

[0290] The present disclosure contemplates the use of a dispersion described herein, a composition described herein, a granule described herein, a pharmaceutical composition described herein, a dosage form described herein, or a tablet described herein in combination with one or more additional therapies useful in the treatment of cancer. Some embodiments provide a method of treating cancer in a subject, comprising administering to the subject a dosage form described herein, a pharmaceutical composition described herein, or a tablet described herein and at least one additional therapeutic agent to the subject in need thereof. Exemplary therapies are further described below and in WO 2018 / 136700 (PCT Application No. PCT / US2018 / 014352) and WO 2020 / 018680 (PCT Application No. PCT / US2019 / 042226), the disclosures of which are incorporated herein by reference.

[0291] In some embodiments, one or more of the additional therapies is an additional therapeutic modality. Exemplary therapeutic modalities include, but are not limited to, surgical resection of the tumor, bone marrow transplantation, radiation therapy, and photodynamic therapy.

[0292] In some embodiments, one or more of the additional therapies is a therapeutic agent. Exemplary therapeutic agents include chemotherapeutic agents, radiopharmaceuticals, hormone therapy, epigenetic modulators, ATP-adenosine axis targeting agents, targeted therapy, signal transduction inhibitors, RAS signaling inhibitors, PI3K inhibitors, arginase inhibitors, HIF inhibitors, AXL inhibitors, PAK4 inhibitors, immunotherapeutic agents, cell therapy, gene therapy, immune checkpoint inhibitors, and agonists of stimulatory or costimulatory immune checkpoints.

[0293] In some embodiments, one or more of the additional therapeutic agents is a chemotherapeutic agent. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metredopa, and uredopa; ethylenimines and methylameramines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil, chlornaphthoate, and thiazolinone; azine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabimycin cin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detrevicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, pomalidomide, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pemetrexed, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiplatin, and thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and 5-FU;Androgens such as calsterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as furoic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; elformitine, elliptinium acetate; e Toglucide; Gallium nitrate; Hydroxyurea, Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid, 2-ethylhydrazide; Procarbazine; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triazicone; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Mannomustine; Mitobronitrol; Mitolactone Tol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, such as paclitaxel, nab-paclitaxel, and docetaxel; chlorambucil; gemcitabine, 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, such as cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C, mitoxan thoron; vincristine, vinorelbine, navelbine, novantrone; teniposide; daunomycin; aminopterin; xeloda, ibandronate; proteasome inhibitors such as CPT11, bortezomib, carfilzomib, and ixazomib; topoisomerase inhibitors such as irinotecan, topotecan, etoposide, mitoxantrone, and teniposide; difluoromethylornithine (DMFO); retinoic acid; esperamycin, capecitabine; anthracyclines;and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy comprises a chemotherapy regimen comprising one or more chemotherapeutic agents. In one embodiment, the combination therapy comprises a chemotherapy regimen comprising one or more of FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), platinum and platinum coordination complexes (e.g., cisplatin, carboplatin, oxaliplatin, etc.), taxoids (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), and / or gemcitabine.

[0294] In some embodiments, one or more of the additional therapeutic agents is a radiopharmaceutical. A radiopharmaceutical is a form of internal radiation therapy in which a radiation source (i.e., one or more radionuclides) is placed inside the subject's body. The radiation source can be in solid or liquid form. Non-limiting examples of radiopharmaceuticals include sodium iodide I-131, radium-223 dichloride, lobenguane iodine-131, radioiodinated vesicles (e.g., saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles), various forms of brachytherapy, and various forms of targeted radionuclides. Targeted radionuclides include radionuclides associated (e.g., by covalent or ionic interactions) with a molecule (a "targeting agent") that specifically binds to a target on a cell, typically a cancer cell or immune cell. The targeting agent may be a small molecule, a sugar (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a saccharide (including oligosaccharides and polysaccharides), lipid, protein, or peptide, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neo-antigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody, and the target is a tumor-associated antigen (i.e., an antigen enriched but not specific to cancer cells), a tumor-specific antigen (i.e., an antigen minimal or no expression in normal tissues), or a neo-antigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). Non-limiting examples of targeted radionuclides include somatostatin or its peptide analogs (e.g., 177Lu-Dotatate, etc.); prostate-specific membrane antigen or its peptide analogs (e.g., 177Lu-PSMA-617, 225Ac-PSMA-617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); cognate ligands of the receptors, peptides derived from the ligands, or variants thereof (e.g., 188-relabeled VEGF 125-136or variants thereof with higher affinity for the VEGF receptor; or antibodies targeting tumor antigens (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-omburtamab, etc.), including radionuclides bound to antibodies targeting tumor antigens (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-omburtamab, etc.).

[0295] In some embodiments, one or more of the additional therapeutic agents is a hormone therapy. Hormonal therapy acts to regulate or inhibit hormone action on tumors. Examples of hormone therapy include, but are not limited to, selective estrogen receptor degraders such as fulvestrant, gildestrant, SAR439859, RG6171, AZD9833, lindestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, selective estrogen receptor modulators such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, and toremifene, aromatase inhibitors such as anaphylaxis inhibitors, anaphylaxis inhibitors, and anaphylaxis inhibitors. Other aromatase inhibiting agents include strozole, exemestane, letrozole, and 4(5)-imidazoles; gonadotropin-releasing hormone agonists such as nafarelin, triptorelin, and goserelin; gonadotropin-releasing hormone antagonists such as degarelix; antiandrogens such as abiraterone, enzalutamide, apalutamide, dalotamide, flutamide, nilutamide, bicalutamide, and leuprolide; 5α-reductase inhibitors such as finasteride and dutasteride. In certain embodiments, the combination therapy includes the administration of a hormone or related hormone agent. In one embodiment, the combination therapy includes the administration of enzalutamide.

[0296] In some embodiments, one or more of the additional therapeutic agents is an epigenetic modulator. Epigenetic modulators alter the epigenetic mechanisms that control gene expression and may be, for example, inhibitors or activators of epigenetic enzymes. Non-limiting examples of epigenetic modulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HDAC) inhibitors. In one or more embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with DNA methyltransferase (DNMT) inhibitors or hypomethylating agents. Exemplary DNMT inhibitors include decitabine, zebularine, and azacitadine. In one or more embodiments, combinations of the dispersions, compositions, or pharmaceutical compositions described herein with histone deacetylase (HDAC) inhibitors are also contemplated. Exemplary HDAC inhibitors include vorinostat, gibinostat, abexinostat, panobinostat, belinostat, and trichostatin A.

[0297] In some embodiments, one or more of the additional therapeutic agents is an ATP-adenosine axis targeting agent. ATP-adenosine axis targeting agents alter signal transduction mediated by adenine nucleosides and nucleotides (e.g., adenosine, AMP, ADP, ATP), for example, by regulating adenosine levels or targeting adenosine receptors. In certain embodiments, the ATP-adenosine axis targeting agent is an inhibitor of an ectonucleotidase involved in the conversion of ATP to adenosine or an antagonist of an adenosine receptor. Ectonucleotidases involved in the conversion of ATP to adenosine include ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, ​​also known as CD39 or cluster of differentiation 39) and ecto-5'-nucleotidase (NT5E or 5NT, also known as CD73 or cluster of differentiation 73). Exemplary small molecule CD73 inhibitors include CB-708, ORIC-533, LY3475070, and quemliclustat (AB680). Exemplary anti-CD39 and anti-CD73 antibodies include ES002023, TTX-030, IPH-5201, SRF-617, CPI-006, oleculab (MEDI9447), NZV930, IPH5301, GS-1423, uriledolimab (TJD5, TJ004309), AB598, and BMS-986179. In one embodiment, the present disclosure contemplates the combination of a dispersion, composition, or pharmaceutical composition described herein with a CD73 inhibitor, such as those described in WO 2017 / 120508, WO 2018 / 067424, WO 2018 / 094148, and WO 2020 / 046813. In a further embodiment, the CD73 inhibitor is quemlicustat.

[0298] In some embodiments, one or more of the additional therapeutic agents is a targeted therapy. In one aspect, the targeted therapy may include a chemotherapeutic agent, a radionuclide, a hormone therapy, or another small molecule drug conjugated to the targeting agent. The targeting agent may be a small molecule, a sugar (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a sugar (including oligosaccharides and polysaccharides), a lipid, a protein, or a peptide, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neoantigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neoantigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody-drug conjugate comprising an antibody and a drug, wherein the antibody specifically binds to Trop-2, HER2, HER3, Nectin-4, or Trop-2. Specific examples of targeted therapies include, but are not limited to, patritumab deruxtecan, sacituzumab govitecan-hziy, telisotuzumab vedotin, and trastuzumab deruxtecan. In other aspects, the targeted therapy may inhibit or interfere with specific proteins that aid in tumor growth and / or spread. Non-limiting examples of such targeted therapies include signal transduction inhibitors, RAS signaling inhibitors, inhibitors of oncogenic transcription factors, activators of oncogenic transcription factor repressors, angiogenesis inhibitors, immunotherapeutic agents, ATP-adenosine axis targeting agents, AXL inhibitors, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, 2α inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists, and PD-1 antagonists. ATP-adenosine axis targeting agents are described above, while other agents are described in more detail below.

[0299] In some embodiments, one or more of the additional therapeutic agents is a signal transduction inhibitor. A signal transduction inhibitor is an agent that selectively inhibits one or more steps in a signal transduction pathway. Signal transduction inhibitors (STIs) contemplated by the present disclosure include, but are not limited to, (i) BCR-ABL kinase inhibitors (e.g., imatinib), (ii) epidermal growth factor receptor tyrosine kinase inhibitors (EGFRTKIs), including small molecule inhibitors (e.g., CLN-081, gefitinib, erlotinib, afatinib, icotinib, and osimertinib) and anti-EGFR antibodies, (iii) human epidermal growth factor receptor tyrosine kinase inhibitors (HERIs), including transmembrane tyrosine kinase inhibitors (TKIs), and (iv) human epidermal growth factor receptor tyrosine kinase inhibitors (HEGFR-TKIs). R) family inhibitors, such as HER-2 / neu receptor inhibitors (e.g., trastuzumab) and HER-3 receptor inhibitors, (iv) vascular endothelial growth factor receptor (VEGFR) inhibitors, such as small molecule inhibitors (e.g., axitinib, regorafenib, sunitinib, and sorafenib), VEGF kinase inhibitors (e.g., lenvatinib, cabozantinib, pazopanib, tivozanib, XL092, etc.), and anti-VEGF antibodies (e.g., bevacizumab);(v) inhibitors of AKT family kinases or the AKT pathway (e.g., rapamycin), (vi) inhibitors of serine / threonine-protein kinase B-Raf (BRAF), such as vemurafenib, dabrafenib, and encorafenib, (vii) inhibitors of rearrangements during transfection (RET), including, for example, selpacatinib and pralsetonib, (viii) inhibitors of tyrosine-protein kinase Met (MET) (e.g., tepotinib, tivantinib, cabozantinib, and crizotinib), (ix) inhibitors of anaplastic lymphoma kinase (ADL) (e.g., anaplastic lymphoma kinase (ALK)), (x) inhibitors of anaplastic lymphoma kinase (ADL ... kinase, ALK) inhibitors (e.g., ensartinib, ceritinib, loratinib, crizotinib, and brigatinib), (x) inhibitors of the RAS signaling pathway described elsewhere herein (e.g., inhibitors of KRAS, HRAS, RAF, MEK, ERK), (xi) FLT-3 inhibitors (e.g., gilteritinib), (xii) inhibitors of Trop-2, (xiii) inhibitors of the JAK / STAT pathway, e.g., JAK inhibitors including tofacitinib and ruxolitinib, or STAT inhibitors such as napabucasin, (xiv) inhibitors of NF-kB, (xv) cell cycle kinase inhibitors (e.g., (e.g., flavopiridol), (xvi) phosphatidylinositol kinase (PI3K) inhibitors, (xix) protein kinase B (AKT) inhibitors (e.g., capivasertib, miransertib), (xx) platelet-derived growth factor receptor (PDGFR) inhibitors (e.g., imatinib, sunitinib, regorafenib, avapritinib, lenvatinib, nintedanib, famitinib, ponatinib, axitinib, lepretinib, etc.), (xxi) insulin-like growth factor receptor (IGFR) inhibitors (e.g., erlotinib, afatinib, gefitinib, osimertinib, dacomitinib). In some embodiments, the additional therapeutic agent comprises an inhibitor of EGFR, VEGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-kB, PI3K, AKT, or any combination thereof. In some embodiments, the additional therapeutic agent comprises an inhibitor of EGFR and / or VEGFR;

[0300] In some embodiments, one or more of the additional therapeutic agents is a RAS signaling inhibitor. Oncogenic mutations in RAS family genes, such as HRAS, KRAS, and NRAS, are associated with various cancers. For example, in KRAS family genes, mutations such as G12C, G12D, G12V, G12A, G13D, Q61H, G13C, and G12S, among others, have been observed in multiple tumor types. Direct and indirect inhibitory strategies have been investigated to inhibit mutant RAS signaling. Indirect inhibitors target effectors other than RAS in the RAS signaling pathway, including, but not limited to, inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g., SOS1), mTORC1, SHP2 (PTPN11), and AKT. Non-limiting examples of indirect inhibitors under development include RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, and BI1701963. Direct inhibitors of RAS mutants are also being explored, generally targeting the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors under development include, but are not limited to, sotorasib, adagrasib, mRNA-5671, and ARS1620. In some embodiments, the one or more RAS signaling inhibitors are selected from the group consisting of a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an SOS1 inhibitor, an mTORC1 inhibitor, an SHP2 inhibitor, and an AKT inhibitor. In other embodiments, the one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0301] In some embodiments, one or more of the additional therapeutic agents are inhibitors of phosphatidylinositol 3-kinase (PI3K), particularly inhibitors of the PI3Kγ isoform. PI3Kγ inhibitors can stimulate anti-cancer immune responses through modulation of myeloid cells, for example, by inhibiting suppressive myeloid cells and attenuating immunosuppressive tumor-infiltrating macrophages, or by stimulating macrophages and dendritic cells to produce cytokines that contribute to effective T-cell responses, resulting in reduced cancer development and spread. Exemplary PI3Kγ inhibitors include copanlisib, duvelisib, AT-104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458, and pictilisib. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with one or more PI3Kγ inhibitor(s) described in WO 2020 / 0247496 A1.

[0302] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of arginase. Arginase has been shown to be either responsible for or involved in inflammation-induced immune dysfunction, tumor immune escape, immunosuppression, and the immunopathology of infectious diseases. Exemplary arginase compounds include CB-1158 and OAT-1746. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with one or more arginase inhibitor(s) described in WO 2019 / 173188 and WO 2020 / 102646.

[0303] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of an oncogenic transcription factor or an activator of an oncogenic transcription factor repressor. Suitable agents may act at the expression level (e.g., RNAi, siRNA, etc.), via physical degradation, at the protein / protein level, at the protein / DNA level, or by binding to an activation / inhibition pocket. Non-limiting examples include inhibitors of one or more subunits of the MLL complex (e.g., HDAC, DOT1L, BRD4, menin, LEDGF, WDR5, KDM4C (JMJD2C), and PRMT1), inhibitors of hypoxia-inducible factor (HIF) transcription factors, etc.

[0304] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of hypoxia-inducible factor (HIF) transcription factors, particularly HIF-2α. Exemplary HIF-2α inhibitors include velzutifan, ARO-HIF2, PT-2385, and those described in WO2021113436 and WO2021188769. In some embodiments, a dispersion, composition, or pharmaceutical composition described herein is combined with one or more HIF-2α inhibitors described in WO2021188769.

[0305] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of Anexselect (AXL). The AXL signaling pathway is associated with tumor growth and metastasis and is thought to mediate resistance to various cancer therapies. There are various AXL inhibitors under development that also inhibit other kinases within the TAM family (i.e., TYRO3, MERTK), as well as other receptor tyrosine kinases, including MET, FLT3, RON, and AURORA, among others. Exemplary multikinase inhibitors include sitravatinib, rebastinib, glesatinib, gilteritinib, merestinib, cabozantinib, foretinib, BMS777607, LY2801653, S49076, and RXDX-106. AXL-specific inhibitors have also been developed, including, for example, small molecule inhibitors including DS-1205, SGI-7079, SLC-391, duvelmatinib, bemcentinib, and DP3975; anti-AXL antibodies, such as ADCT-601; and antibody-drug conjugates (ADCs), such as BA3011. Another strategy for inhibiting AXL signaling involves targeting GAS6, an AXL ligand. For example, batiracept is being developed as an Fc-fusion protein that binds to the GAS6 ligand and thereby inhibits AXL signaling. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with one or more AXL inhibitors described in International Publication No. 2022 / 246177 (PCT / US2022 / 030227) or International Publication No. 2022 / 246179 (PCT / US2022 / 030230).

[0306] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of p21-activated kinase 4 (PAK4). PAK4 overexpression has been demonstrated across a variety of cancer types, including those that are particularly resistant to PD-1 therapy. While there are no approved PAK4 inhibitors, several are in development and exhibit dual PAK4 / NAMPT inhibitor activity, e.g., ATG-019 and KPT-9274. In some embodiments, the pharmaceutical compositions described herein are combined with a PAK4-selective inhibitor. In some embodiments, the dispersions, compositions, or pharmaceutical compositions described herein are combined with a PAK4 / NAMPT dual inhibitor, e.g., ATG-019 or KPT-9274.

[0307] In some embodiments, one or more of the additional therapeutic agents is (i) an agent that inhibits the enzyme poly(ADP-ribose) polymerase (e.g., olaparib, niraparib, and rucaparib); (ii) an inhibitor of the Bcl-2 family of proteins (e.g., venetoclax, navitoclax, etc.); (iii) an inhibitor of MCL-1; (iv) an inhibitor of the CD47-SIRPα pathway (e.g., anti-CD47 antibodies, magrolimus, etc.); or (v) an isocitrate dehydrogenase (IDH) inhibitor, e.g., an IDH-1 or IDH-2 inhibitor (e.g., ivosidenib, enazidenib, etc.).

[0308] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent. Immunotherapeutic agents treat diseases by stimulating or suppressing the immune system. Immunotherapeutic agents useful in treating cancer typically induce or amplify an immune response against cancer cells. Non-limiting examples of suitable immunotherapeutic agents include immunomodulators; cellular immunotherapies; vaccines; gene therapies; ATP-adenosine axis targeting agents; immune checkpoint modulators; and certain signal transduction inhibitors. ATP-adenosine axis targeting agents and signal transduction inhibitors are described above. Immunomodulators, cellular immunotherapies, vaccines, gene therapies, and immune checkpoint modulators are further described below.

[0309] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically, a cytokine or chemokine, such as IL1, IL-2, IL-12, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharide (LPS); organic or inorganic adjuvants that activate antigen-presenting cells and promote presentation of antigen epitopes on major histocompatibility complex molecule agonists, including, but not limited to, major histocompatibility receptor (TLR) agonists, antagonists of the mevalonate pathway, agonists of STING; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and immunostimulatory oligonucleotides, and other T cell adjuvants.

[0310] In some embodiments, one or more of the additional therapeutic agents are immunotherapeutic agents, more specifically cell therapy. Cell therapy is a form of treatment in which viable cells are administered to a subject. In certain embodiments, one or more of the additional therapeutic agents are cellular immunotherapies that activate or suppress the immune system. Cellular immunotherapies useful for treating cancer typically induce or amplify an immune response. The cells can be autologous or allogeneic immune cells (e.g., monocytes, macrophages, dendritic cells, NK cells, T cells, etc.) collected from one or more subjects. Alternatively, the cells can be "(re)programmed" allogeneic immune cells produced from immune progenitor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell progenitor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells may be expanded subsets of cells with distinct effector functions and / or maturation markers (e.g., adaptive memory NK cells, tumor-infiltrating lymphocytes, immature dendritic cells, monocyte-derived dendritic cells, plasmacytoid dendritic cells, conventional dendritic cells (sometimes referred to as classical dendritic cells), M1 macrophages, M2 macrophages, etc.), may be genetically modified to target the cells to specific antigens and / or to enhance the anti-tumor effect of the cells (e.g., engineered T cell receptor (TCR) cell therapy, chimeric antigen receptor (CAR) cell therapy, lymph node homing of antigen-loaded dendritic cells, etc.), may be engineered to increase expression of tumor-associated antigens, or any combination thereof. Non-limiting types of cell therapy include CAR-T cell therapy, CAR-NK cell therapy, TCR therapy, and dendritic cell vaccines. Exemplary cellular immunotherapies include sipuleucel-T, tifagen-lecleucel, lysocabtagene-malaleucel, idecabtagene-villeucel, brexacabtagene-autoleucel, and axicabtagene-ciloleucel, as well as CTX110, JCAR015, JCAR017, MB-CART19.1, MB-CART20.1, MB-CART2019.1, UniCAR02-T-CD123, BMCA-CAR-T, JNJ-68284528, BNT211, and NK-92 / 5.28.z.

[0311] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically, a gene therapy. Gene therapy includes recombinant nucleic acids administered ex vivo to a subject or a subject's cells to modify the expression of an endogenous gene or to effect heterologous expression of a protein (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, microRNA (miRNA) agents, viral or bacterial gene delivery, etc.), as well as gene editing therapies that may or may not include nucleic acid components (e.g., meganucleases, zinc finger nucleases, TAL nucleases, CRISPR / Cas nucleases, etc.), oncolytic viruses, etc. Non-limiting examples of gene therapies that may be useful in cancer treatment include Gendicine® (rAd-p53), Oncorine® (rAD5-H101), talimogine laherparepvec, Mx-dnG1, ARO-HIF2 (Arrowhead), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics), and CTX130 (CRISPR Therapeutics).

[0312] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically, an agent that modulates an immune checkpoint. Immune checkpoints are a series of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells, etc.). Immune checkpoints are engaged when proteins on the surface of immune cells recognize and bind to their cognate ligands. The present invention contemplates the use of the dispersions, compositions, or pharmaceutical compositions described herein in combination with agonists of stimulatory or costimulatory pathways and / or antagonists of inhibitory pathways. Agonists of stimulatory or costimulatory pathways and antagonists of inhibitory pathways may have utility as agents to overcome distinct immunosuppressive pathways within the tumor microenvironment, inhibit regulatory T cells, reverse / prevent T cell anergy or exhaustion, induce innate immune activation and / or inflammation at the tumor site, or any combination thereof.

[0313] In some embodiments, one or more of the additional therapeutic agents is an immune checkpoint inhibitor. As used herein, the term "immune checkpoint inhibitor" refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. The terms "immune checkpoint inhibitor," "checkpoint inhibitor," and "CPI" may be used interchangeably herein. Immune checkpoint inhibitors may antagonize inhibitory or co-inhibitory immune checkpoints by interfering with receptor-ligand binding and / or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated and can be blocked in various types of cancer cells, include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuating factor); CTLA-4 (cytotoxic T lymphocyte-associated antigen 4); TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T with Ig and ITIM domains) These include cellular immune receptors; CD276 (B7-H3), PD-L2, galectin-9, CEACAM-1, CD69, galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, as well as killer inhibitory receptors, which can be divided into two classes based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs) and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints are also contemplated and have been described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands, such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)).

[0314] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 antagonist. In further embodiments, the CTLA-4 antagonist may be an antagonist CTLA-4 antibody. Suitable antagonist CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab or tremelimumab, and bispecific antibodies such as MEDI5752 and KN046.

[0315] In some embodiments, the immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonist PD-1 antibody small molecule or peptide. Suitable antagonist PD-1 antibodies include monospecific antibodies such as balstilimab, budigalimab, camrelizumab, cosibelimab, dostarimab, cemiplimab, ezabenlimab (BI-754091), MEDI-0680 (AMP-514; WO 2012 / 145493), nivolumab, pembrolizumab, pidilizumab (CT-011), retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimberelimab; and bispecific antibodies such as LY3434172. In yet a further embodiment, the PD-1 antagonist may be a recombinant protein (AMP-224) composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1. In a particular embodiment, the immune checkpoint inhibitor is zimberelimab.

[0316] In some embodiments, the immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-L1 antagonist may be an antagonist PD-L1 antibody. Suitable antagonist PD-L1 antibodies include monospecific antibodies such as avelumab, atezolizumab, durvalumab, BMS-936559, and embafolimab, and bispecific antibodies such as LY3434172 and KN046.

[0317] In some embodiments, the immune checkpoint inhibitor is a TIGIT antagonist. In further embodiments, the TIGIT antagonist may be an antagonist TIGIT antibody. Suitable antagonist anti-TIGIT antibodies include monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS986207, COM902, domvanalimab, EOS-448, etidilimab, IBI-929, JS006, M6223, osipellimab, SEA-TGT, tiragolumab, and vibostolimab; and bispecific antibodies such as AGEN1777 and AZD2936. In certain embodiments, the immune checkpoint inhibitor is an antagonist anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In certain embodiments, the immune checkpoint inhibitor is domvanalimab or AB308.

[0318] In some embodiments, the immune checkpoint inhibitor is a LAG-3 antagonist. In further embodiments, the LAG-3 antagonist can be an antagonist LAG-3 antibody. Suitable antagonist LAG-3 antibodies include, for example, BMS-986016 (WO 10 / 19570, WO 14 / 08218), or IMP-731 or IMP-321 (WO 8 / 132601, WO 9 / 44273).

[0319] In certain embodiments, the immune checkpoint inhibitor is a B7-H3 antagonist. In further embodiments, the B7-H3 antagonist is an antagonist B7-H3 antibody. Suitable antagonist B7-H3 antibodies include, for example, enoblitutumab, omburtamab, enoblitutumab, DS-7300a, ABBV-155, and SHR-A1811.

[0320] In some embodiments, one or more of the additional therapeutic agents activates a stimulatory or costimulatory immune checkpoint. Examples of stimulatory or costimulatory immune checkpoints (ligands and receptors) include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2.

[0321] In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be an agonist CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and utomilumab. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist can be an agonist GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO 06 / 105021, WO 09 / 009116), and MK-4166 (WO 11 / 028683). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is an OX40 agonist. In further embodiments, the OX40 agonist can be an agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383, MEDI-6469, MEDI-0562, PF-04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonist CD40 antibody. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD27 agonist. In further embodiments, the CD27 agonist can be an agonist CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0322] In some embodiments, one or more of the additional therapeutic agents is an agent that inhibits or depletes immunosuppressive immune cells. For example, to inhibit or deplete immunosuppressive macrophages or monocytes, the agent may be a CSF-1R antagonist, e.g., a CSF-1R antagonist antibody, including ematuzumab or cabilalizumab.

[0323] In some embodiments, each additional therapeutic agent may independently be a chemotherapeutic agent, a radiopharmaceutical, a hormone therapy, an epigenetic modulator, a targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. For example, in one embodiment, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition described herein in combination with one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition described herein in combination with one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeting agent, an immunotherapeutic agent, or a cell therapy. In another embodiment, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition described herein in combination with one or more immunotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeting agent, a chemotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition described herein in combination with one or more immunotherapeutic agents and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, or a cell therapy. In another embodiment, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition described herein in combination with one or more immune checkpoint inhibitors and / or one or more ATP-adenosine axis targeting agents, and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, an immunotherapeutic agent, or a cell therapy.In further embodiments of the above, (a) the targeting agent is a PI3K inhibitor, an arginase inhibitor, a HIF2α inhibitor, an AXL inhibitor, a PAK4 inhibitor, a VEGFR inhibitor, a VEGF kinase inhibitor, an anti-VEGF antibody, or an antibody-drug conjugate; (b) the immunotherapeutic agent is an ATP-adenosine axis targeting agent or an immune checkpoint inhibitor; (c) the ATP-adenosine axis targeting agent is a CD73 inhibitor or a CD39 inhibitor; (d) the ATP-adenosine axis targeting agent is quemlicustat or AB598; (e) the immunotherapeutic agent is an anti-PD-1 antagonist antibody, an anti-PD-L1 antagonist antibody, or an anti-TIGIT antagonist antibody; (f) the immunotherapeutic agent is zimberelimab, domvanalimab, or AB308; or (g) any combination thereof. In still further embodiments of the above, the present disclosure contemplates the use of a dispersion, composition, or pharmaceutical composition described herein in combination with domvanalimab, etrumadenant, quemliculstat, zimberelimab, AB308, AB521, AB598, AB610, or any combination thereof.

[0324] The choice of additional therapeutic agents may be informed by the current standard of care for the particular cancer and / or the mutational status and / or disease stage of the target cancer. Detailed standard of care guidelines are published, for example, by the National Comprehensive Cancer Network (NCCN). See, for example, NCCN Colon Cancer v3.2021, NCCN Hepatobiliary Cancer v5.2021, NCCN Kidney Cancer v3.2022, NCCN NSCLC v7.2021, NCCN Pancreatic Adenocarcinoma v2.2021, NCCN Esophageal and Esophagogastric Junction Cancers v4.2021, NCCN Gastric Cancer v5.2021, Cervical Cancer v1.2022, and Ovarian Cancer / Fallopian Tube Cancer / Primary Peritoneal Cancer v3.2021.

[0325] VI. Administration The conjugates, compositions, or pharmaceutical compositions described herein can be administered to a subject in an amount that depends, for example, on the goal of administration (e.g., the desired degree of degradation); the age, weight, sex, and health and physical condition of the subject to whom the formulation is administered; the route of administration; and the nature of the disease, disorder, condition, or symptoms thereof. The dosing regimen can also take into account the existence, nature, and extent of any adverse effects associated with the agent being administered. Effective dosages and dosing regimens can be readily determined, for example, from safety and dose escalation studies, in vivo studies (e.g., animal models), and other methods known to those skilled in the art.

[0326] In general, dosing parameters indicate that the dosage is below that which would be irreversibly toxic to the subject (maximum tolerated dose (MTD)) and not less than that required to produce a measurable effect in the subject, as determined, for example, by pharmacokinetic and pharmacodynamic parameters relevant to ADME, taking into account the route of administration and other factors.

[0327] An effective dose (ED) or therapeutically effective amount is a dose or amount of a drug that produces a therapeutic response or desired effect in some percentage of subjects who take it. The "median effective dose" or ED50 of a drug is a dose or amount of a drug that produces a therapeutic response or desired effect in 50% of the population to which it is administered. The ED50 is commonly used as a measure of the reasonable expected effect of a drug, but is not necessarily the dose that a clinician would deem appropriate taking all relevant factors into account. Thus, in some situations, the effective amount will exceed the calculated ED50, in other situations, the effective amount will be below the calculated ED50, and in still other situations, the effective amount will be the same as the calculated ED50.

[0328] Additionally, an effective dose of etrumadenant of the complexes, compositions, or pharmaceutical compositions described herein can be an amount that, when administered to a subject in one or more doses, produces the desired result relative to a healthy subject. For example, for a subject experiencing a particular disorder, an effective dose can be one that improves a diagnostic parameter, measure, marker, etc. of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or greater than 90%, where 100% is defined as the diagnostic parameter, measure, marker, etc. exhibited by a normal subject.

[0329] In some embodiments, etrumadenant dispersions, compositions, and pharmaceutical compositions contemplated by the present disclosure may be administered (e.g., orally) at dosage levels of about 0.01 mg / kg to about 50 mg / kg, or about 1 mg / kg to about 25 mg / kg of subject body weight per day to achieve the desired therapeutic effect. In some embodiments, etrumadenant dispersions, compositions, and pharmaceutical compositions contemplated by the present disclosure may be administered (e.g., orally) at dosage levels of about 50 mg to about 250 mg, one or more times per day to achieve the desired therapeutic effect.

[0330] As used herein, "total daily dosage" or "total daily dose" refers to the total amount of active agent (e.g., etrumadenant) administered within a 24-hour period. The total daily dose can be administered in any manner (e.g., orally) or frequency. For example, a total daily dose of 100 mg of active agent can be administered as 50 mg twice daily or 100 mg once daily.

[0331] In some embodiments, etremadenant dispersions, compositions, and pharmaceutical compositions contemplated by the present disclosure can be orally administered to a subject in need thereof to provide a total daily dose of about 50 mg to about 250 mg of etremadenant, or about 50 mg to about 150 mg of etremadenant. In some embodiments, the subject is administered a total daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

[0332] In some embodiments, etrumadenant dispersions, compositions, and pharmaceutical compositions contemplated by the present disclosure can be administered (e.g., orally) at the above-described dosage levels without dose adjustment or interruption due to concomitant use of cytochrome P450 (CYP) inhibitors or inducers, P-glycoprotein (P-gp) inhibitors or inducers, or breast cancer resistance protein (BCRP) inhibitors or inducers. P-gp and BCRP are efflux transporters expressed in the gastrointestinal tract and can affect the oral bioavailability of drugs. CYP enzymes are catalytic enzymes, and their inhibition or induction can affect drug bioavailability by altering the rate of drug metabolism. The most common CYP enzymes involved in drug metabolism include CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A enzyme isoforms. CYP inhibitors can be classified as strong, moderate, or weak based on the inhibitor's effect on the target substrate. Index CYP substrates are known in the art. See, for example, the International Council for Harmonization (ICH) M12 Guideline on Drug Interaction Studies, published July 21, 2022. A subject's genotype can also affect CYP activity. According to the U.S. Food and Drug Administration, a normal metabolizer is a subject who does not have a genetic variant that is expected to affect metabolism, an ultrarapid metabolizer is a subject who generally has two or more copies of a genetic variant that increases metabolic function, an intermediate metabolizer is a subject who generally has one or two copies of a genetic variant that reduces the ability to metabolize a drug, and a poor metabolizer is a subject who generally has two copies of a genetic variant that results in little or no ability to metabolize a drug (www.fda.gov / medical-devices / precision-medicine / table-pharmacogenetic-associations).

[0333] In vitro data suggest that etrumadenant metabolism is mediated by CYP3A4, CYP2C8, and uridine 5'-diphosphoglucuronosyltransferase (UGT) enzyme isoforms, and that etrumadenant is a substrate of P-gp and breast cancer resistance protein (BCRP). However, as further described herein, in humans, co-administration of etrumadenant with a potent CYP3A4 inhibitor has limited effect on the pharmacokinetics of etrumadenant, and co-administration of etrumadenant with a P-gp inhibitor may not affect the oral absorption of etrumadenant. Thus, in some embodiments, etrumadenant dispersions, compositions, and pharmaceutical compositions contemplated by the present disclosure can be administered (e.g., orally) at the above-described dosage levels without dose adjustment or discontinuation due to concomitant use of a CYP3A4 inhibitor or P-gp inhibitor, or without dose adjustment or discontinuation due to the subject being a CYP3A4 poor metabolizer.

[0334] Some embodiments provide a method of treating cancer in a subject who is concurrently receiving a CYP3A4 inhibitor or a P-gp inhibitor, or who is a CYP3A4 poor metabolizer, comprising administering to a subject in need thereof a dosage form described herein, a pharmaceutical composition described herein, or a tablet described herein. 2A Receptor (A 2A R) or adenosine A 2B Receptor (A 2B R), wherein the subject is concurrently receiving a CYP3A4 inhibitor or a P-gp inhibitor, or the subject is a CYP3A4 poor metabolizer, comprising administering a therapeutically effective amount of etormadenant. In some embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor. In some embodiments, the CYP3A4 inhibitor is a moderate CYP3A4 inhibitor. In some embodiments, the CYP3A4 inhibitor is a weak CYP3A4 inhibitor.

[0335] For oral administration, the compositions may be provided in the form of tablets, capsules, etc., containing 1.0 to 1000.0 milligrams of active ingredient, specifically 1.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of active ingredient. In some embodiments, the tablets or capsules described herein contain 10 mg to 100 mg of etremadenant or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets or capsules described herein contain 50 mg to 100 mg of etremadenant or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets or capsules described herein contain 75 mg of etremadenant or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets or capsules described herein are administered once daily to achieve the desired therapeutic effect.

[0336] In some embodiments, the tablets described herein contain 50 mg of etremadenant. In some embodiments, the tablets described herein contain 75 mg of etremadenant. In some embodiments, the tablets described herein contain 100 mg of etremadenant. In some embodiments, the tablets described herein contain 150 mg of etremadenant.

[0337] In some embodiments, the dosage of the dispersion or composition of etremadenant or a pharmaceutically acceptable salt thereof is contained in a "unit dosage form." The phrase "unit dosage form" refers to physically discrete units, each unit containing a predetermined amount of etremadenant, alone or in combination with one or more additional agents, sufficient to produce a desired effect. It will be understood that the parameters of the unit dosage form depend on the particular agent and the effect to be achieved.

[0338] Exemplary Dosages Some embodiments include adenosine A 2A Receptor (A 2AR) at least in part by adenosine A 2B Receptor (A 2B R) at least in part by A 2A R and A 2A

[0013] Also provided is a method for treating a disease, disorder, or condition mediated at least in part by both R and R receptors, comprising administering to a subject in need thereof a dosage form, pharmaceutical composition, or tablet of the present disclosure.

[0339] Some embodiments provide a method of treating cancer, comprising administering to a subject in need thereof a dosage form, pharmaceutical composition, or tablet of the present disclosure. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is breast cancer, lung cancer, gastrointestinal cancer, genitourinary cancer, or gynecological cancer. In some embodiments, the cancer is bladder cancer, breast cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is castration-resistant prostate cancer, esophageal adenocarcinoma, non-small cell lung cancer, pancreatic ductal adenocarcinoma, prostate adenocarcinoma, or urothelial cancer. In some embodiments, the cancer is locally advanced, unresectable, or metastatic cancer.

[0340] In some embodiments, the pharmaceutical composition is a formulation of Table 16, Table 19, Table 20, or Table 24. In some embodiments, the tablet is a tablet of Table 16, Table 19, Table 20, or Table 24.

[0341] In some embodiments, the subject is administered a total daily dose of about 50 mg etremadenant to about 250 mg etremadenant, or about 50 mg etremadenant to about 150 mg etremadenant, optionally, the total daily dose being administered once daily.

[0342] In some embodiments, the subject is administered a total daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg.

[0343] In some embodiments, the total daily dose of etrumadenant is not adjusted for subjects who are CYP3A4 poor metabolizers or who are concurrently taking a CYP3A4 inhibitor (e.g., a weak, moderate, or strong CYP3A4 inhibitor) or a P-gp inhibitor.

[0344] In some forms, the subject is further administered one or more additional therapies (e.g., one, two, three, etc.) optionally selected from radiation therapy, a chemotherapeutic agent, a checkpoint inhibitor, an ATP-adenosine axis targeting agent, a PI3K inhibitor, an arginase inhibitor, a HIF2α inhibitor, an AXL inhibitor, a PAK4 inhibitor, a VEGFR inhibitor, a VEGF kinase inhibitor, an anti-VEGF antibody, and an antibody-drug conjugate.

[0345] In some embodiments, the subject further receives one or more (e.g., one, two, three, etc.) additional treatments optionally selected from radiation therapy, chemotherapy, AB308, AB521, AB598, AB801, domvanalimab, quemliculstat, and sacituzumab govitecan.

[0346] In embodiments in which the subject is administered one or more chemotherapeutic agents, the one or more chemotherapeutic agents may be FOLFOX, FOLFIRI, CAPOX, platinum or platinum coordination complexes (e.g., cisplatin, carboplatin, oxaliplatin, etc.), taxoids (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), gemcitabine, folate analogs (e.g., pemetrexed, etc.), or antiandrogens (e.g., enzalutamide, etc.).

[0347] VII. Kit The present disclosure also contemplates kits comprising the dispersions, compositions, or pharmaceutical compositions described herein. Kits are generally in the form of physical structures housing various components, as described below, that can be utilized, for example, in practicing the methods described above.

[0348] The kit may include one or more of the dispersions, compositions, or pharmaceutical compositions described herein (e.g., provided in a sterile container). The dispersions, compositions, or pharmaceutical compositions described herein may be provided in a ready-to-use form (e.g., tablet or capsule) or in a form that requires reconstitution or dilution, for example, before administration (e.g., powder). If the dispersions, compositions, or pharmaceutical compositions described herein are in a form that requires reconstitution or dilution by the user, the kit may also include a diluent (e.g., sterile water), buffer, pharmaceutically acceptable excipient, etc., packaged together or separately from the dispersions, compositions, or pharmaceutical compositions described herein. If combination therapy is intended, the kit may include several agents separately or already combined in the kit. Each component of the kit may be enclosed in an individual container, or all of the various containers may be in a single package. The kits of the present disclosure may be designed for the conditions (e.g., refrigeration or freezing) necessary to properly maintain the components contained therein.

[0349] The kit may include a label or package insert containing information identifying the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredients, including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.). The label or package insert may include manufacturer information such as lot number and expiration date. The label or package insert may, for example, be incorporated into the physical structure that houses the component, be included separately within the physical structure, or be attached to a component of the kit (e.g., an ampoule, tube, or vial).

[0350] The label or insert may further comprise or be incorporated into a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), an optical disk, such as a CD or DVD-ROM / RAM, a DVD, an MP3, a magnetic tape, or an electronic storage medium, such as RAM and ROM or a hybrid thereof, such as a magnetic / optical storage medium, FLASH® media, or a memory-type card. In some embodiments, the actual instructions are not present in the kit, but means are provided for obtaining the instructions from a remote source, for example, via the internet. [Example]

[0351] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of what the inventors regard as the present disclosure. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for.

[0352] Unless otherwise indicated, temperatures are in degrees Celsius (°C) and pressures are at or near atmospheric. Standard abbreviations are used, including: rt or rt = room temperature; min = minute; h or hr = hour; ng = nanogram; μg = microgram; mg = milligram; g = gram; kg = kilogram; μl or μL = microliter; ml or mL = milliliter; l or L = liter; μM = micromole; mM = millimole; M = mole; mol = mole; mmol = millimole; nM = nanomole; gA = grams of active substance; mgA = milligrams of active substance; μgA = micrograms of active substance; HPMCAS = hydroxypropyl methylcellulose acetate succinate or hypromellose acetate succinate; CAP = cellulose acetate phthalate; PVP-VA = polyvinylpyrrolidone / vinyl acetate copolymer (copovidone); FaSSIF = fasted state simulated intestinal fluid.

[0353] Example 1 The thermal properties and X-ray diffraction patterns of the starting drug substances used in the following examples were characterized by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD).

[0354] Thermal Properties. Thermal properties were measured using a TA Instruments Discovery DSC2500 DSC equipped with a TA instruments Refrigerated Cooling System 90 operated in modulated mode. Briefly, bulk drug substance was analyzed by standard DSC at a heating rate of 10°C / min up to 220°C. Amorphous etrumadenant was prepared from the starting drug substance by rapid melt quenching using liquid N2 and then analyzed by modified DSC (MDSC). Events monitored included the glass transition temperature (T g ), cold crystallization (T c ), and melting temperature (T m In one experiment, the thermal properties were as follows: T g = 69°C;T c = No crystallization occurs up to 220°C; T m = 192°C. Slight lot-to-lot variation may occur.

[0355] XRPD. Diffraction patterns of the starting drug substance were obtained by XRPD. XRPD was performed using a Rigaku Miniflex 6G X-ray diffractometer. Samples were irradiated with monochromated CuKα radiation and analyzed from 5° to 40° in continuous scan mode. Samples were rotated during analysis to minimize preferred orientation effects. A summary of XRPD analytical parameters can be found in Table 1. The diffraction pattern of the starting drug substance indicates that it is a crystalline material (Figure 1), consistent with the thermal analysis. [Table 1]

[0356] Example 2: Comparative Etrumadenant Tablets Containing Crystalline API Etrumadenant tablets were manufactured containing 50 mg of etrumadenant crystalline free base. The tablets were prepared as follows: The API was blended with the intragranular ingredients in a suitable blender. The blend was de-lumped, then compressed and milled into granules. The extragranular ingredients were then blended with the granules, and the mixture was subjected to tableting. The tablet composition is shown in Table 2. [Table 2]

[0357] Example 3: Etrumadenant Capsules The chemical stability of etrumadenant in multiple semi-solid fill formulations was tested at 5% drug loading. Briefly, the vehicle composition was prepared by melting selected excipients while mixing. The starting drug substance was then added, and the formulation was mixed with continued heating until a clear solution was formed. The solution was then filled into capsules, which were subsequently sealed with gelatin bands. The gelatin band solution was prepared by mixing gelatin with a solution of polysorbate 80 and water until the mixture was homogeneous.

[0358] The vehicle compositions included PEG 400, PEG 1500, or PEG 4000 with Solutol HS15, Kolliphor RH40S, or Gelucire 44 / 14 in ratios ranging from 1:1 to 3:1. All semi-solid fill formulations tested achieved improved solubility compared to the starting drug substance in water and were chemically stable when stored in sealed containers for various lengths of time (e.g., 1 day, 7 days, 1 month, 2 months) at 2-8°C, 25°C, and 40°C / 75% relative humidity (RH). Based on in vitro dissolution and nonclinical pharmacokinetic (PK) studies, capsules containing 25 mg of etrumadenant were prepared, and PEG 1500:Kolliphor RH40 (3:1) was selected as the clinical formulation. Exemplary formulations are provided in Table 3. [Table 3]

[0359] Example 4: Exemplary solid dispersions of ethremadenant First, the dynamic solubility and supersaturation maintenance of etrumadenant were measured in the presence of selected cellulosic and vinylpyrrolidone-based polymer excipients. Solvent-shift dissolution experiments were performed as follows: The starting drug substance was dissolved in dimethyl sulfoxide (DMSO) at 200 mg / mL to generate a drug stock solution. Each polymer was dissolved at 1 mg / mL and 3 mg / mL in FaSSIF (2 mg / mL simulated intestinal fluid (SIF) in 100 mM phosphate buffer solution (PBS), pH 6.8), prepared according to the manufacturer's instructions. The polymers tested included cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose E3 (HPMC E3LV), hydroxypropyl methylcellulose acetate succinate, grade H (HPMCAS-H), HPMCAS, grade L (HPMCAS-L), HPMCAS, grade M (HPMCAS-M), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone / vinyl acetate copolymer (copovidone) (PVP-VA), and Soluplus®. Then, 25 μL of drug stock solution was introduced into 10 mL of polymer FaSSIF solution or, as a control, into 10 mL of FaSSIF without polymer, with stirring at 300 rpm using a magnetic stir bar (etremadenant was diluted to 1 mg / mL). 0.5 mL aliquots were taken at the following time points without medium change: 5, 15, 30, 45, and 60 min. Aliquots were transferred to 1.5 mL centrifuge tubes and spun down at 13,000 rpm for 3 min. 100 μL of the supernatant was sampled and diluted with 900 μL of 3:1 ACN:ACN HO for HPLC analysis using the parameters listed in Table 4. [Table 4]

[0360] The etrumadenant concentrations measured in the presence of polymer were compared to those measured in the absence of polymer in FaSSIF. At a 25% drug loading, i.e., a 1:3 drug-to-polymer ratio (w / w), all polymers resulted in prolonged supersaturation of etrumadenant throughout 60 minutes, compared to the control, which began to precipitate after the 45-minute time point. At a 50% drug loading, i.e., a 1:1 drug-to-polymer ratio (w / w), all polymers, except for PVP and HPMCP, showed improved persistence of supersaturation. The 25% drug loading showed a higher degree of supersaturation than amorphous etrumadenant when compared to the 50% drug loading. The data are shown in Figures 2B and 2C.

[0361] Eight solid dispersions prepared using different ratios of starting drug substance to polymer (25:75 w / w or 40:60 w / w) and different polymers (HPMCAS-L, HPMCAS-M, CAP, or PVP-VA) were then characterized. In this example, and throughout the following examples, solid dispersions (also referred to as SDIs) are identified using a nomenclature in which the drug-to-polymer(s) weight ratio is specified, followed by the drug and polymer(s). As an example, "25:75 AB928:HPMCAS-M SDI" refers to a solid dispersion prepared using 25% by weight AB928 (etremadenant) and 75% by weight HPMCAS-M. Stated another way, 100% of the weight of the solids used to make the dispersion can be attributed to etremadenant and HMPCAS-M, which are in a 1:3 weight ratio. The resulting dispersion does not contain exactly 25% by weight of ethlomadenant and 75% by weight of HPMCAS-M, but as residual solvent, water and impurities may account for a portion of the weight of the dispersion.

[0362] Each of the eight formulations was spray-dried from pure acetone. Briefly, the starting drug substance and one of the four polymers from the previous paragraph were added to the spray solvent (acetone) at a 10% (w / w) solids loading and mixed at 20-25°C until complete dissolution was achieved to produce the spray solution. The spray solution was then spray-dried by spraying into a drying chamber, and the solvent was removed in a carrier gas to produce the SDI powder. Spray-drying parameters are provided in Table 5. The SDI powder was then subjected to secondary drying to remove residual solvent. [Table 5]

[0363] The obtained SDI powders were characterized by various analytical methods including X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), modulated differential scanning calorimetry (MDSC), residual solvents by gas chromatography headspace sampling (GC-HS), assay and related substances by high performance liquid chromatography (HPLC), water content by Karl Fischer titration (KF), and non-sedimentation dissolution.

[0364] Residual acetone remaining after secondary drying was measured using GC-HS. Measurements were performed using an HP6890 Series GC equipped with an Agilent 7697A headspace sampler. A 30 m x 0.32 mm x 1.8 μm capillary column with a 6% cyanopropylphenyl 94% dimethylpolysiloxane GC column was used for the test. GC samples were prepared by dissolving approximately 100 mg of sample in 4 mL of dimethyl sulfoxide (DMSO). Residual solvents in all formulations were well below the acetone limit (5000 ppm) set by the International Conference on Harmonization (ICH).

[0365] Thermal analysis by MDSC, performed as described in Example 1, showed that all dispersions (see legend to Figure 3 for dispersions) had a single, relatively high glass transition temperature (T) ranging from about 76°C to about 123°C. g) (Figure 3). g The presence of α-tocopherol indicates a thoroughly mixed amorphous solid dispersion with good homogeneity, while a high T g showed good physical stability of the dispersion, e.g., there was a low tendency for the etremadenant to recrystallize during long-term storage.

[0366] To further assess the crystallinity of the spray-dried particles, samples of the SDI powder were analyzed by XRPD as described in Example 1. Amorphous material produces an "amorphous halo" diffraction pattern, absent the discrete peaks seen in crystalline material. XRPD characterization showed that the eight dispersions were amorphous, with no crystalline peaks observed in the diffractograms (Figure 4).

[0367] The surface morphology of the spray-dried particles was characterized using SEM. SEM samples were prepared by dispersing the SDI powder onto an adhesive carbon-coated sample stub and coating it with a thin conductive layer of gold using a Cressington 108 Auto. Samples were analyzed using an FEI Quanta 200 SEM equipped with an Everhart-Thornley (secondary electron beam) detector operated in high vacuum mode. Micrographs were captured at various magnifications for qualitative particle morphology analysis. Experimental parameters, including spot size, working distance, and accelerating voltage, were varied for each sample to obtain the best imaging conditions. For each dispersion, the observed morphology consisted of whole and collapsed spheres with smooth surfaces. No crystalline material was observed in any of the samples.

[0368] The SDI powder collected after secondary drying was analyzed for moisture content using a Metrohm 831 Karl Fischer Coulometric Titrator equipped with a Metrohm 874 oven processor. Approximately 100 mg of sample was sealed in a 6 mL crimp vial and then the moisture content was measured using the following parameters: reagent Hydranal Coulomat AG-Oven, oven temperature 130°C, and sample extraction time 300 seconds. The moisture content was typically less than 1% by weight.

[0369] In vitro drug dissolution performance for each dispersion was evaluated under non-settling conditions in a two-stage process that simulated the pH and bile salt concentrations for both gastric and intestinal exposure. In vitro dissolution testing under non-settling conditions allowed for direct assessment of each dispersion's ability to generate and maintain supersaturation over the solubility of crystalline ethlomadenant, and is used as a predictive surrogate to ensure product quality and in vivo performance, and is a valid test for differentiating formulations at given stability conditions.

[0370] To initiate dissolution (t=0), a sample of SDI powder was briefly suspended in 4 mL of FaSSIF (2 mg / mL SIF in 100 mM PBS) and then transferred to 50 mL of SGF (0.1 N HCl (aq)) preheated to 37°C in a USP Type 2 container (100 mL total container volume) while stirring (paddle) at 100 rpm. A gastric transfer step was performed in 30 minutes, in which the volume in each dissolution container was approximately doubled using 2× FaSSIF (4.48 mg / mL SIF powder (BioRelevant)) to yield a final pH of 6.8 in a total volume of 100 mL. Samples taken before and after this transfer at the indicated times were evaluated for drug concentration by HPLC. The drug concentrations measured in this study represent SDI-free drug, drug in micelles, and drug complexes suspended in solution. A summary of the dissolution and HPLC parameters is provided in Tables 6 and 7, respectively. [Table 6] [Table 7]

[0371] All dispersions demonstrate improved in vitro non-settling dissolution performance compared to crystalline etrumadenant (Figure 5 and Table 8). Predicted gastric dissolution in this model varied between formulations, and correlation between gastric dissolution levels and subsequent predicted intestinal dissolution levels was poor. All formulations maintained their intestinal dissolution levels throughout the experiment, and no precipitation was observed. Overall, the non-settling dissolution studies suggest that the dispersions should enhance the bioavailability of etrumadenant compared to the starting drug substance. [Table 8]

[0372] To screen the physical and chemical stability of the etremadenant dispersions, SDI powders were stressed for 4 and 12 weeks at 25°C and 60% relative humidity (RH) (25°C / 60%RH) in open high-density polyethylene (HDPE) bottles without purified cotton in the caps and bottle necks ("open packaging"), 40°C / 75%RH in open packaging, and 40°C / 75%RH in sealed packaging (i.e., double low-density polyethylene (LDPE) bags, each gooseneck closed with a cable tie). 0.5 g of silica gel desiccant was added between the LDPE bags, and the bags were placed in the HDPE bottles. The SDI powders were evaluated for physical and chemical stability by appearance, amorphous character by XRPD, assay and related substances by HPLC, particle morphology by SEM, and the presence of crystals by polarized light microscopy (PLM) (for 12 weeks only).

[0373] Table 9 summarizes the changes in appearance over stability. Notably, all SDIs exhibited stability up to 12 weeks under open dish accelerated stability conditions. The PVP-VA formulations exhibited greater particle coalescence under high humidity conditions. [Table 9]

[0374] XRPD analysis of the SDI stability samples showed that all of the SDI remained amorphous, with no detectable crystalline material after 12 weeks (Figures 6 and 7). The 4-week diffractogram also showed an amorphous halo.

[0375] The surface morphology of SDI particles was characterized using SEM. At 4 weeks, a small amount of particle fusion was observed for the 40:60 AB928:HPMCAS-M SDI at 40°C / 75%RH open and closed conditions. By 12 weeks, this fusion had occurred to a greater extent. For the remaining AB928:HPMCAS-M SDI samples, typical SDI morphology was evident at t=0. The HPMCAS-M SDI sample consisted of whole and collapsed spheres with smooth surfaces. No crystalline material was observed in any of the samples.

[0376] Coalescence was also observed for AB928. PVP-VA SDI samples were analyzed by SEM at 12 weeks. SDI particles fused into large blocks in the 25:75 AB928:PVP-VA SDI samples at 40°C / 75% RH open and sealed, and the 40:60 AB928:PVP-VA SDI sample at 40°C / 75% RH open. Slight fusion was evident among individual SDI particles in the 40:60 AB928:PVP-VA SDI samples at 25°C / 60% RH open and 40°C / 75% RH sealed. At 25°C / 60% RH, the 25:75 AB928:PVP-VA SDI sample showed typical SDI morphology evident at t = 0. No crystalline material was observed in either sample.

[0377] Purity analysis of SDI stability samples showed no change in related impurities compared to the crystalline API in all SDI samples when stored at 2-8°C for 4 weeks, 25°C / 60% RH, and 40°C / 75% RH open and sealed for 4 and 12 weeks.

[0378] Example 5: Exemplary solid dispersions of ethremadenant Four dispersions prepared with different ratios of starting drug substance to HPMCAS-M (25:75, 30:70, 35:65, and 40:60) were prepared for stability testing. Each formulation was spray-dried from acetone:water (95:05), as generally described in Table 10. Samples of the dispersions were obtained at the time of manufacture (t=0) and after storage in open and sealed packaging at 25±2°C / 60±5% RH and at 40±2°C / 75±5% RH in open and sealed packaging (t=1 month, 3 months, and 6 months). Samples were characterized by various analytical methods, including X-ray powder diffraction (XRPD), modulated differential scanning calorimetry (MDSC), high-performance liquid chromatography (HPLC) assays and impurities / related substances, and non-precipitable dissolution. Samples obtained after 6 months in open packaging for stability were analyzed only for appearance and by MDSC. A description of the analytical methods is provided in Example 4. [Table 10]

[0379] All samples remained off-white powders after 6 months on stability and appeared amorphous by XRPD (Figure 8). Impurity analysis by assay and HPLC showed that after 6 months on the stability assay, etrumadenant values ​​were close to target (±10%), the impurity profile matched that of the starting drug substance, and there was no significant impurity growth after 6 months.

[0380] Samples analyzed by MDSC consisted of a single T gAn additional thermal event at approximately 180°C was detected on stability for 40:60 AB928:HPMCAS-M SDI by MDSC non-inversion after 3 weeks (open packaging) or 1 month (sealed packaging). This event appeared to increase in magnitude during storage. No change in appearance was observed between 3 and 6 months. An additional thermal event at approximately 180°C was also observed for 35:75 AB928:HPMCAS-M SDI by MDSC non-inversion after 6 months of stability in both open and sealed packaging. The additional endothermic event observed at approximately 180°C suggested a low level of crystallization. g The values ​​are summarized in Tables 11 and 12 (+ indicates temperatures between about 70°C and about 90°C; * ND, not determined); representative MDSC curves are shown in Figure 9. [Table 11] [Table 12]

[0381] A non-sedimentation dissolution test at t=0 confirmed that formulating etrumadenant as a solid dispersion with HMPCAS-M improved the solubility of etrumadenant in FaSSIF. AUC 35~210FaSSIF decreased with increasing drug loading. Samples were placed for stability at 25°C / 60% RH and 40°C / 75% RH in sealed or open containers and the non-sediment dissolution test was evaluated again. The non-sediment dissolution data are summarized in Tables 13 and 14. Representative dissolution curves are shown in Figures 10 and 11. [Table 13] [Table 14]

[0382] Example 6: Exemplary tablets containing a solid dispersion of etremadenant Four dispersions prepared with different starting drug substance to polymer ratios were prepared for tableting: 25:75 AB928:HPMCAS-M, 40:60 AB928:HPMCAS-M, 25:7.5:67.5 AB928:TPGS:PVP-VA, and 40:7.5:52.5 AB928:TPGS:PVP-VA. TPGS (tocophersolan) was incorporated into the two PVP-VA SDIs at 7.5% (w / w) to evaluate the effect of the surfactant on dissolution performance. Each formulation was spray dried from pure acetone according to the parameters summarized in Table 15. The resulting SDI powders were then characterized by various methods, including XRPD, SEM, MDSC, and in vitro non-settling dissolution. A description of the analytical methods is provided in Example 4. [Table 15]

[0383] Thermal analysis performed by MDSC showed that all four dispersions exhibited a single T g The SDI particles were shown to have a Tg of approximately 72°C to approximately 83°C, indicating an intimately mixed amorphous solid dispersion with good uniformity. XRPD characterization revealed that the SDI was an amorphous dispersion, with no crystalline peaks observed in the SDI diffractogram. The surface morphology of the SDI particles characterized by SEM showed typical SDI morphology consisting of smooth-surfaced whole and collapsed spheres. No crystalline material was observed in any of the samples. The dissolution performance of the SDI was tested using a non-settling dissolution test. All SDIs demonstrated similar dissolution performance compared to the SDI described in Example 4, with the 25% AB928:HPMCAS-M formulation performing best. The incorporation of TPGS at 7.5 wt% into the PVP-VA SDI did not result in a significant increase in dissolution in vitro.

[0384] Immediate release tablets containing the four dispersions were then developed. Due to the poor flowability of the dispersions, efforts were made to develop dry granules containing SDI.

[0385] For HPMCAS SDI, a 1:1 microcrystalline cellulose (MCC):mannitol ratio was used because it was believed that a mixture of brittle and plastic fillers could help improve the tablet's mechanical properties. Croscarmellose sodium (Ac-Di-Sol) was selected as a superdisintegrant because its use could achieve acceptable disintegration times. Colloidal silica (Cab-O-Sil) was used as a glidant because it was believed to improve flowability, which may be useful for scale-up work. Sodium stearyl fumarate (SSF) was selected as a lubricant because it was believed to help reduce the formulation's sticking to process equipment.

[0386] For the PVP-VA SDI, crospovidone (Kollidon CL) was added as a superdisintegrant, and mesoporous silica (Parteck SLC and Syloid XDP3150) was added as a disintegration aid. These ingredients are believed to be able to shorten the disintegration time. Furthermore, silicified microcrystalline cellulose (Prosolv SMCC 90) was used instead of microcrystalline cellulose and colloidal silica. Additional excipients were added after dry granulation and before tableting. Extragranular excipients were chosen because they are intended to reduce the risk of over-compacting the formulation during tableting. [Table 16]

[0387] Tablets were prepared as follows: SDI was blended with intragranular ingredients in a suitable blender. The blend was de-lumped using a suitable conical mill and then subjected to roller compaction and milling. Using a roller compactor with a vibratory mill equipped with a suitable sieve (25 mesh), the blend was first compressed into ribbons (targeting a solids fraction of approximately 0.7), which were then milled into granules. The extragranular ingredients were then blended with the granules, and the mixture was subjected to tableting. Tablets were compressed to a target weight using a rotary tablet press. Individual tablet weights, average weights of 10 tablets, tablet hardness, and thickness were monitored at predetermined manufacturing process intervals throughout the compression operation.

[0388] Tabletability, compressibility, compactibility, and disintegration profiles were generated for all formulations using 0.4062" and 0.5000" standard circular concave (SRC) tooling for 50 mgA and 100 mgA tablets, respectively. Compression profiles were generated over the range of 100-200 MPa.

[0389] Disintegration was performed using a Varian VK-100 disintegration apparatus according to USP <701> The tablet disintegration was evaluated according to the "disintegration" method. The apparatus consisted of a 1000 mL low-form beaker and a basket rack assembly with six open-ended transparent tubes. The beaker was filled with 750 mL of ROI water and maintained at a temperature of 37°C (±2°C). The basket was fully submerged at a frequency of 29 to 32 cycles per minute, and the tablet disintegration time was recorded when the last visible tablet material passed through the basket.

[0390] Tablet tensile strength was calculated based on the following formula applied to standard round concave (SRC) tablets: where P = breaking load, D = tablet width, t = tablet thickness, and W = band thickness.

number

[0391] Tablet hardness was measured using a Natoli Hardness Tester (S / N 1403029) according to USP <1217> The tablet was tested according to the "Tablet Breaking Force". After measuring the thickness and weight of the tablet, the tablet breaking force was evaluated as it is a breaking process. The tablet was placed in an automatic breaking device and the tablet hardness was measured in kiloponds (kP) or kilogram force.

[0392] The HPMCAS-M SDI tablets exhibited increased tabletability compared to the PVP-VA SDI tablets, achieving higher tensile strength at a given compression pressure. The PVP-VA SDI tablets also exhibited a longer disintegration time than the HPMCAS-M SDI tablets. See Figures 12 and 13.

[0393] The four tablet formulations were also characterized for assay and related substances / impurities by HPLC and non-sediment dissolution as described in Example 4, and for water content by Karl Fischer coulometric titration using the oven-drying method. The water content values ​​for the tablets were consistent across both drug loads for each polymer formulation. It is contemplated that the PVP-VA SDI tablets contained higher water content due to the increased hygroscopicity of the PVP-VA polymer compared to HPMCAS-M. Assay and related substances / impurity analysis of the tablets by HPLC showed similar total related substances compared to the parent SDI or the as-received crystalline ethlomadenant, indicating that no chemical degradation occurred during the spray-drying or tablet manufacturing process.

[0394] The dissolution performance of the tablets was tested in a non-settling dissolution test. The dissolution performance of the tablets was also evaluated under accelerated stability conditions, 25°C / 60% RH and 40°C / 75% RH, after 1 and 3 months of storage in sealed packaging. Release test results (described above) were used for the t=0 time point. Representative data are shown in Figures 14 and 15. Non-settling dissolution tests of the AB928:HPMCAS-M SDI tablets were also conducted after the tablets had been stable for 6, 9, and 12 months. See Table 16.

[0395] The pharmacokinetics (PK) of the SDI tablets compared to the capsule control was evaluated in male beagle dogs that were fasted overnight prior to study drug administration. Whole blood samples were collected pre-dose and 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration of a single dose of study drug (PO). The PK of the crystalline AB928 tablets listed in Table 2 was also evaluated under similar conditions. The formulations and PK data tested are summarized in Tables 17 and 18 (Terminal_T = terminal elimination half-life; MRTINF = mean residence time from time 0 to infinity; other parameters are as described herein). Additional data are shown in Table 17. [Table 17] [Table 18]

[0396] Example 7: Exemplary tablets containing a solid dispersion of etremadenant 25:75 AB928:HPMCAS-M SDI tablets were prepared as generally described in Example 6 using different intragranular excipients (Avicel PH-105, Partek M100, FlowLac 90, Emcompress, Avicel DG, Nisso HPC SSL SFP) according to Table 19. During dry granulation, the target solid ribbon fraction was 0.6-0.7. For tableting, compression profiles were generated over the range of 50-200 MPa. The weight, thickness, hardness, and disintegration of the resulting tablets were evaluated as described in Example 6. [Table 19]

[0397] The first batch of tablets, F1-F5, was developed first. All formulations showed good weight, thickness, breaking force, tabletability, and compressibility. The disintegration times of F1-F5 increased dramatically at pressures >150 MPa, indicating that achieving a robust disintegration profile was a significant technical hurdle.

[0398] Secondary tablets F1.1, F1.2, and F4.1 were then developed to implement various approaches to shorten the disintegration time (e.g., decreasing the SDI content, increasing the disintegrant, increasing the extragranular filler (e.g., Avicel PH-200, Partek M200)). All formulations again showed good weight, thickness, breaking force, tabletability, and compressibility. Notably, all formulations also achieved robust disintegration profiles.

[0399] Example 8: Exemplary tablets containing a solid dispersion of etremadenant Etrumadenant film-coated tablets were manufactured containing 75 mg of etrumadenant. The tablets were prepared as follows: SDI was blended with the intragranular ingredients in a suitable blender. The blend was de-lumped using a suitable conical mill and then subjected to roller compaction and milling. Using a roller compactor with a vibratory mill equipped with a suitable sieve, the blend was first compressed into ribbons, which were then milled into granules. The extragranular ingredients were then blended with the granules, and the mixture was subjected to tableting. Tablets were compressed to a target weight using a rotary tablet press and then film-coated. Individual tablet weights, average weights of 10 tablets, tablet hardness, and thickness were monitored at predetermined intervals throughout the compression process. The tablet composition is shown in Table 20. [Table 20]

[0400] The tablets were packaged in high density polyethylene (HDPE) bottles containing desiccant, sealed with a foil heat induction seal and a polypropylene (PP) child-resistant enclosure, and then stabilized at 25°C / 60% relative humidity and 40°C / 75% relative humidity.

[0401] Tablets were sampled over time and tested for appearance, HPLC assay and impurities, water content, and dissolution. Assays were determined by reversed-phase gradient HPLC. Impurities (and degradation products of etremadenant) were determined by reversed-phase gradient HPLC. Impurities were identified solely by HPLC relative retention time (RRT), and these RRTs were approximate due to occasional HPLC analysis. Water content in etremadenant was determined according to USP <921> The same HPLC method was used for identification, assay and related substances, and the parameters are summarized in Table 21 and the dissolution method in Table 22. [Table 21] [Table 22]

[0402] There were no significant changes in appearance, assay, impurities, or dissolution after 12 months at long-term storage conditions of 25°C ± 2°C / 60% ± 5% RH and after 6 months at accelerated storage conditions of 40°C ± 2°C / 75% ± 5% RH. Under both conditions, the moisture content gradually increased over time.

[0403] T=0 data corresponds to lot release results. [Table 23]

[0404] Example 9: Exemplary tablets containing a solid dispersion of etremadenant Etrumadenant tablets were manufactured to contain 50 mg or 75 mg of etrumadenant. Tablets were prepared as follows: SDI was blended with the intragranular ingredients in a suitable blender. The blend was de-lumped using a suitable conical mill and then subjected to roller compaction and milling. Using a roller compactor with a vibratory mill equipped with a suitable sieve, the blend was first compressed into ribbons, which were then milled into granules. The extragranular ingredients were then blended with the granules, and the mixture was subjected to tableting. Tablets were compressed to the target weight using either a manual or rotary tablet press. The tablet composition is shown in Table 24. [Table 24]

[0405] Example 10: Comparison of Etrumadenant Tablets Tablets containing salts of etremadenant were also prepared.

[0406] A crystalline form of the phosphate salt of etremadenant ("Phosphate Form I") was prepared as follows: Approximately 176 mg of etremadenant was suspended in approximately 4 mL of water:acetone. Approximately 140 μL of 85% H3PO4 was then added, and the sample was allowed to stand at room temperature.

[0407] A crystalline form of the phosphate salt of etrumadenant ("Phosphate Form I") can also be prepared as follows: Approximately 5 g of etrumadenant was suspended in approximately 20 mL of tetrahydrofuran. Approximately 1.5 mL of 85% H3PO4 diluted with approximately 2 mL of water was then added to the suspension. A solution was formed, and the sample was seeded with Phosphate Form I (prepared as described above). A suspension was formed and stirred overnight. The sample was filtered, washed with approximately 10 mL of water, and the solid was dried at room temperature under vacuum with a nitrogen sweep to obtain Phosphate Form I.

[0408] A crystalline form of the phosphate salt of etrumedenant ("Phosphate Form I") is characterized by the XRPD shown in FIG.

[0409] Another sample of the crystalline form of the phosphate salt of etremadenant ("Phosphate Form II") was prepared as follows: Approximately 120 mL of ethanol:water (9:1 by volume) was added to a 250 mL container. To this, approximately 2 molar equivalents of phosphoric acid were added with a magnetic stirrer. Next, approximately 6 grams of crystalline etremadenant (Form I described in WO 2020 / 018680) was added, and the mixture was stirred at room temperature. Approximately 2 more equivalents of phosphoric acid were added to the mixture, which was further stirred at room temperature. The resulting solid was filtered and washed twice with approximately 15 mL of excess phosphoric acid in ethanol:water (9:1 by volume). The sample was dried overnight in a funnel filter to obtain the crystalline form of the phosphate salt of etremadenant ("Phosphate Form II"), characterized by XRPD shown in Figure 20.

[0410] Etrumadenant fumarate was isolated by charging a 4 mL glass vial with approximately 213 mg of crystalline etrumadenant (Form I, prepared as described in WO 2020 / 018680), approximately 70 mg of fumaric acid, and several mL of tetrahydrofuran to form a solution. The solution was allowed to evaporate at ambient temperature, resulting in a brown oil the next day. Approximately 1 mL of methanol was added to the oil to obtain a suspension. The solid was isolated and analyzed after approximately one week. The XRPD pattern of etrumadenant fumarate is shown in Figure 21.

[0411] Etrumadenant tablets were manually prepared to contain 50 mg of etrumadenant equivalent, delivered as the phosphate salt or the fumarate salt. The tablets were prepared as follows: The API was blended with the intragranular ingredients in a suitable blender. The blend was de-lumped, then compressed and milled into granules. The extragranular ingredients were then blended with the granules, and the mixture was subjected to tableting. The tablet composition for the phosphate salt is provided in Table 25, and the tablet composition for the fumarate salt is provided in Table 26. [Table 25] a Equivalent to 10.0% w / w étremadenne with a theoretical salt correction factor of 0.813 [Table 26] a Equivalent to 10.0% w / w Etrumadenant with a theoretical salinity correction factor of 0.787

[0412] Fasted, Pentagastrin-Pretreated Beagle Dog Study: The pharmacokinetics (PK) of etremadenant tablets was evaluated in male beagle dogs that were fasted overnight prior to study drug administration. Each animal received a single 6 μg / kg intramuscular injection of pentagastrin approximately 30 minutes prior to test substance administration. Whole blood samples were collected pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration (PO) of a single dose of study drug. The data are shown in Table 27. The crystalline form of the phosphate salt of etremadenant ("Phosphate Form I") could not be reproduced and was therefore undesirable. Tablets containing a solid dispersion of etremadenant provided the highest oral bioavailability. [Table 27] a The % bioavailability was 25100 h in beagle dogs after IV administration of 5 mg / kg. * Estimated based on AUClast in ng / mL.

[0413] Fasted, Famotidine-Pretreated Beagle Dog Study (Informed of Potential Drug-Drug Interactions with Acid Suppressants): The pharmacokinetics (PK) of etremadenant tablets was evaluated in male beagle dogs that were fasted overnight prior to study drug administration. Each animal received a single 20 mg tablet of famotidine approximately 1 hour prior to test substance administration. Whole blood samples were collected pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration of a single dose of study drug (PO). Data are shown in Table 28. The crystalline form of the phosphate salt of etremadenant ("Phosphate Form I") could not be reproduced and was therefore undesirable, while the crystalline fumarate salt exhibited the lowest oral bioavailability. Tablets with the solid dispersion of etremadenant provided the highest oral bioavailability. [Table 28] a The % bioavailability was 25100 h in beagle dogs after IV administration of 5 mg / kg. * Estimated based on AUClast in ng / mL.

[0414] Example 11: Pharmacokinetic study This example describes a Phase 1 study to compare the single-dose PK of etremadenant tablets versus etremadenant capsules in healthy adult participants (19-55 years of age) and to evaluate the effect of food on the single-dose PK of etremadenant tablets in healthy adult participants.

[0415] The study was an open-label, randomized, three-treatment, three-period crossover study to evaluate the relative bioavailability (BA) of etremadenant tablet and capsule formulations and the effect of food on the tablet formulation. A single dose of etremadenant was administered in a three-period crossover fashion on day 1 of each period. Participants (n=24) received etremadenant capsules under fasted (Treatment A) conditions and etremadenant tablets under fasted (Treatment B) and fed (high-fat meal; Treatment C) conditions. PK samples for etremadenant and its metabolites were collected pre-dose and up to 120 hours post-dose. There was a washout period of at least 7 days between etremadenant doses. All participants who received at least one dose of etrumadenant (including those who terminated the study early) were asked to return to the Clinical Research Unit (CRU) 14 (± 2) days after their last dose for a follow-up procedure to determine whether any adverse events (AEs) had occurred since their last study visit.

[0416] The study treatments are described below. Treatment A = 150 mg of etremadenant (6 x 25 mg capsules) at Time 0 on Day 1; participants fasted for at least 10 hours before and at least 4 hours after etremadenant administration. Treatment B = 150 mg of etremadenant (2 x 75 mg tablets) at Time 0 on Day 1; participants fasted for at least 10 hours before and at least 4 hours after etremadenant administration. Treatment C = 150 mg of etremadenant (2 x 75 mg tablets) at Time 0 on Day 1, 30 minutes after the start of a high-fat meal; participants fasted for at least 10 hours until 30 minutes before etremadenant administration if given a high-fat breakfast that was consumed entirely within 30 minutes; participants then fasted for at least 4 hours after administration. The compositions of the etremadenant capsules and etremadenant tablets are shown in Tables 3 and 20, respectively.

[0417] All etrumedenant capsules or tablets were administered orally with approximately 240 mL of water. If participants were unable to swallow all capsules and tablets at the same time, they were given additional water up to 50 mL as needed. Administration was completed within 10 minutes.

[0418] Study objectives included pharmacokinetics (PK) and safety. The following plasma PK parameters were calculated for etrumadenant and its metabolites, as appropriate: [Table 32]

[0419] Further PK parameters were calculated when deemed appropriate. Test / reference least squares mean (LSM) ratios for log-transformed PK parameters (AUClast, AUCinf, and Cmax) were calculated with two-sided 90% confidence intervals (CI). Comparisons of interest included: - Relative BA of tablet vs. capsule: LSM ratio of fasted tablet formulation (Treatment B - Test) compared to fasted capsule formulation (Treatment A - Reference). - Effect of food: LSM ratio of fed tablet formulation (Treatment C - Test) compared to fasted tablet formulation (Treatment B - Reference).

[0420] A non-parametric Wilcoxon signed rank test will be performed on the variable Tmax for the test-reference difference and the results will be tabulated.

[0421] The relative bioavailability of capsules versus tablets is shown in Table 29. Etrumadenant Cmax, AUC, and Tmax in capsules and tablets are statistically equivalent. Administration of etrumadenant under fed conditions did not affect its overall exposure (AUClast and AUCINF) compared to fasted conditions (Table 30). [Table 29] [Table 30]

[0422] Example 12: Drug-drug interaction studies An open-label, fixed-sequence, two-period drug-drug interaction (DDI) study was designed to evaluate the effect of multiple doses of a potent inhibitor of CYP3A4 and P-gp on the single-dose PK of etrumadenant in humans. Etrumadenant was supplied as a 25 mg capsule. The composition of the etrumadenant capsule is provided in Table 3. Itraconazole was used as a representative potent inhibitor of CYP3A4 and P-gp. It was supplied as a 10 mg / mL oral solution, Sporanox® (or generic equivalent) by Janssen Pharmaceuticals. Twenty healthy adult male and female participants (not of childbearing potential) were enrolled. Participants were screened within 28 days prior to their first dose.

[0423] A single 150 mg dose of etremadenant was administered orally under fasting conditions (i.e., fasted for at least 10 hours before dosing and at least 4 hours after dosing) on ​​Day 1 of Period 1. PK sampling for etremadenant and its metabolites was performed pre-dose and up to 120 hours post-dose. There was a 5-day washout between etremadenant administration in Period 1 and the first itraconazole dose in Period 2.

[0424] In Period 2, 200 mg of itraconazole was administered orally twice daily (BID) on Day 1 and once daily (QD) for 9 consecutive days (Days 2 through 10), and a single 150 mg dose of etrumadenant was administered orally 1 hour after the itraconazole dose on Day 6. Itraconazole was administered under fasting conditions. On Day 6, participants fasted for at least 10 hours before and at least 4 hours after etrumadenant administration. PK sampling of etrumadenant and its metabolites was performed pre-dose and up to 120 hours after etrumadenant administration. PK sampling for itraconazole and 1-hydroxy-itraconazole was collected on Days 5, 6, 7, 9, and 11.

[0425] Itraconazole was administered twice on the first day of period 2 as a loading dose to accelerate CYP3A inhibition, and then inhibition was maintained by administering 200 mg itraconazole QD for 9 consecutive days. A 200 mg BID dose level is expected to provide similar inhibition to a 400 mg QD dose. While itraconazole reaches steady state within approximately 15 days, it has been established that 200 mg QD itraconazole for 3–5 days provides maximal CYP3A inhibition sufficient to detect DDIs. Itraconazole is also a P-gp inhibitor, and literature reports have shown that 5 days of 200 mg QD itraconazole increased oral digoxin AUC by approximately 1.7-fold. Therefore, administration of itraconazole for at least 4 days is considered sufficient as a CYP3A4 and P-gp inhibitor in DDI studies. To maintain the level of inhibition, itraconazole was administered throughout the PK sampling of etrumadenant (i.e., through Day 10 of Period 2). Additionally, itraconazole oral solution was administered under fasting conditions to maximize bioavailability.

[0426] Participants were admitted to the Clinical Research Unit (CRU) on Day -1 of Period 1 at the time indicated by the CRU until after the 120-hour blood draw and completion of study procedures in Period 2. Safety was monitored throughout the study by repeated clinical and laboratory assessments. No participants discontinued from the study. All participants who received at least one dose of study drug (including those who terminated the study early) were asked to return to the CRU approximately 14 days after their last dose for follow-up procedures to determine whether any adverse events (AEs) had occurred since their last study visit. All adverse events reported in the study were mild and resolved without treatment.

[0427] Summary of plasma etormadenant PK parameters and C with and without itraconazole max , AUC last , and AUC infBox plots of the data are shown in Table 27 and Figure 18. Multiple doses of itraconazole resulted in approximately 63%, 62%, and 18% increases in etrumadenant AUClast, AUCinf, and Cmax, respectively, compared with etrumadenant given alone. The increase in etrumadenant AUC after coadministration of etrumadenant and itraconazole indicates that etrumadenant metabolism is inhibited by itraconazole via CYP3A4 in humans. The magnitude of the increase (62-63%) suggests that etrumadenant is neither a moderately sensitive nor a sensitive substrate of CYP3A4, according to the U.S. Food and Drug Administration (FDA) Drug Interaction Guidance (2020). Etrumadenant C max The minimal increase in (18%) suggests that coadministration of a P-gp inhibitor (itraconazole) with etrumadenant does not result in significant exposure changes in etrumadenant peak concentrations.

[0428] Multiple doses of a strong CYP3A4 and P-gp inhibitor (itraconazole) resulted in increased metabolite-to-parent ratios of MPAUC0-24 and MPCmax for the etrumadenant glucuronide metabolite compared with etrumadenant given alone. MP AUC0-24 and MP Cmax values ​​increased by approximately 8% and 6%, respectively, with coadministration of itraconazole. The limited change in metabolite-to-parent ratios is consistent with etrumadenant glucuronide being the primary metabolite formed by direct glucuronidation of etrumadenant. As a result, coadministration of a CYP3A4 or P-gp inhibitor has little effect on the fraction of etrumadenant eliminated via the glucuronidation pathway.

[0429] Multiple doses of a strong CYP3A4 and P-gp inhibitor (itraconazole) resulted in a decrease in the metabolite-to-parent ratio of MPAUC0-24 and MPCmax for N-dealkylated etrumadenant compared with etrumadenant given alone. MP AUC0-24 and MP Cmax values ​​were reduced by approximately 87% and 90%, respectively, with coadministration of itraconazole. The decrease in the formation of N-dealkylated etrumadenant is consistent with an inhibitory effect of itraconazole on the CYP3A4 elimination pathway, suggesting that etrumadenant is eliminated by the CYP3A4 pathway via the formation of N-dealkylated etrumadenant.

[0430] The total percent change in plasma exposure of drug-related materials is less than 26% and 7% for AUC and C in the presence and absence of itraconazole, respectively. This change is clinically insignificant. Therefore, the absorption of etrumadenant is not affected by coadministration of a P-gp inhibitor (itraconazole) with etrumadenant.

[0431] In summary, the effect of strong CYP3A4 inhibitors on the PK of etremadenant is limited, and P-gp may not affect the oral absorption of etremadenant. Physiologically based pharmacokinetic modeling suggested that the fraction of etremadenant metabolized via CYP3A4 was approximately 0.4. [Table 31]

Claims

1. 1. A solid dispersion comprising about 20% to about 40% (w / w) etrumadenant and about 60% to about 80% (w / w) of a polymer selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS), copovidone (PVP-VA), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose E3 (HPMC E3), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinylpyrrolidone (PVP), and polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®).

2. A solid dispersion comprising about 20% to about 40% (w / w) etrumadenant and about 60% to about 80% (w / w) of a polymer (w / w) selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS) and copovidone (PVP-VA).

3. The solid dispersion is about 25% to about 35% (w / w) étrumadenant; or 3. The solid dispersion of claim 1 or 2, comprising about 25% to about 30% (w / w) etremadenant.

4. The solid dispersion is about 25% to about 35% (w / w) etremadenant and about 65% to about 75% of said polymer; or 3. The solid dispersion of claim 1 or 2, comprising about 25% to about 30% (w / w) etrumedenant and about 70% to about 75% (w / w) of said polymer.

5. The solid dispersion is about 22.5% to about 27.5% (w / w) étrumadenant; or about 27% to about 33% (w / w) étrumadenant; or 3. The solid dispersion of claim 1 or claim 2, comprising about 31.5% to about 38.5% (w / w) etremadenant.

6. The solid dispersion has a single glass transition temperature (T ｇ 6. The solid dispersion of claim 5, characterized by:

7. The solid dispersion is A glass transition temperature (T) of about 75°C to about 100°C ｇ );or, 7. The solid dispersion of claim 6, characterized by a crystallinity of 5% or less.

8. The solid dispersion is A glass transition temperature (T) of about 75°C to about 100°C ｇ );or, 7. The solid dispersion of claim 6, characterized by a crystallinity of 1% or less.

9. The solid dispersion is A single melting temperature (T ｍ );or, 7. The solid dispersion of claim 6, characterized by a diffraction pattern by X-ray powder diffraction (XRPD) in which no discrete peaks are present or no discrete peaks are present.

10. 3. The solid dispersion according to claim 1, wherein the polymer is HPMCAS.

11. 11. The solid dispersion of claim 10, wherein the HPMCAS comprises an acetyl content of about 5% to about 14%, a succinyl content of about 4% to about 18%, a methoxyl content of about 20% to about 26%, and a hydroxypropoxy content of about 5% to about 10%.

12. 11. The solid dispersion of claim 10, wherein the HPMCAS comprises an acetyl content of about 7% to about 11%, a succinyl content of about 10% to about 14%, a methoxyl content of about 21% to about 25%, and a hydroxypropoxy content of about 5% to about 9%.

13. The solid dispersion is about 22.5% to about 27.5% (w / w) étrumadenant; or about 27% to about 33% (w / w) étrumadenant; or 13. The solid dispersion of any one of claims 10 to 12, comprising about 31.5% to about 38.5% (w / w) etremadenant.

14. The solid dispersion is a single T ｇ The solid dispersion according to any one of claims 10 to 13, characterized by:

15. The solid dispersion is A single glass transition temperature (T ｇ );or, 15. The solid dispersion of claim 14, characterized by a crystallinity of 5% or less.

16. The solid dispersion is There is no other melting or crystallization event; or 15. The solid dispersion of claim 14, characterized by a diffraction pattern by XRPD that is free of discrete peaks.

17. 17. The solid dispersion of any one of claims 10 to 16, wherein the solid dispersion is formed by spray drying.

18. The solid dispersion exhibited a higher AUC than crystalline ethlomadenant by a non-precipitation dissolution test. ３５～２１０ FaSSIF(min ＊ 10. The solid dispersion of any one of the preceding claims, having at least a 3-fold increase in saturation (μgA / mL).

19. The solid dispersion was compared to crystalline etrumadenant by non-precipitation dissolution testing, with an AUC ３５～２１０ FaSSIF(min ＊ 20. The solid dispersion of claim 18, having about a 4-fold, 5-fold, 6-fold, or 7-fold increase in ATP (µgA / mL).

20. 10. The solid dispersion of any one of the preceding claims, wherein the solid dispersion has a total impurity content of less than 1% (area %) as measured by HPLC.

21. When the solid dispersion is stored in a sealed package at 25° C. and 60% relative humidity for 6 months, 12 months, 18 months, 24 months, or 36 months, (i) the amount of etrumadenant in the solid dispersion is from about 90% to about 110% of the value measured at 0 months; (ii) the solid dispersion has a total impurity amount (area %) of 2% or less, or 1% or less, as measured by high performance liquid chromatography (HPLC); (iii) the solid dispersion has a single T ｇ , and optionally a single melting temperature (T ｍ ) characterized by; (iv) the solid dispersion is characterized by a diffraction pattern by XRPD that is free of discrete peaks; or (v) The solid dispersion of any one of the preceding claims, which is any combination of (i) to (iv).

22. 22. Spray-dried particles comprising the solid dispersion of any one of claims 1 to 21, wherein the spray-dried particles are characterized by a Dv90 of less than 150 μm or a Dv50 of less than 50 μm.

23. Dv90 of about 80 μm to about 130 μm; or 23. The spray-dried particles of claim 22, characterized by a Dv50 of about 25 μm to about 40 μm.

24. A dosage form comprising the solid dispersion of any one of claims 1 to 21 or the spray-dried particles of any one of claims 22 to 23.

25. 25. The dosage form of claim 24, wherein the dosage form is a tablet or a capsule.

26. 22. A granule comprising the solid dispersion of any one of claims 1 to 21, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants.

27. 22. A composition comprising the solid dispersion of any one of claims 1 to 21, one or more fillers, one or more disintegrants, optionally one or more glidants, and optionally one or more lubricants.

28. 28. The composition of claim 27, wherein the composition comprises about 40% to about 60% (w / w) of the solid dispersion.

29. 28. The composition of claim 27, wherein the composition comprises about 45% to about 50% (w / w) of the solid dispersion.

30. 28. The composition of claim 27, wherein the composition comprises about 35% to about 45% (w / w) of the solid dispersion, about 40% to about 50% (w / w) of the one or more fillers, about 2% to about 7% (w / w) of the one or more disintegrants, and about 0.25% to about 0.75% (w / w) of the one or more lubricants.

31. 28. The composition of claim 27, wherein the composition comprises about 47% (w / w) of the solid dispersion, about 43% to about 47% (w / w) of the one or more fillers, about 4% to about 6% (w / w) of the one or more disintegrants, about 0.5 to about 1% (w / w) of the one or more glidants, and less than 1% (w / w) of the one or more lubricants.

32. 28. The composition of claim 27, wherein the composition comprises about 47.3% (w / w) of the solid dispersion, about 47.3% (w / w) of the one or more fillers, about 4.1% (w / w) of the one or more disintegrants, about 0.6% (w / w) of the one or more glidants, and about 0.6% (w / w) of the one or more lubricants.

33. 28. The composition of claim 27, wherein the composition comprises about 50% (w / w) of the solid dispersion, about 17.5% (w / w) of the one or more fillers, about 31.8% (w / w) of the one or more disintegrants, and about 0.6% (w / w) of the one or more lubricants.

34. the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose (MCC), co-processed MCC, silicified microcrystalline cellulose, and mesoporous silica; or the one or more disintegrants is croscarmellose sodium; or the one or more lubricants, when present, are sodium stearyl fumarate or magnesium stearate; or 34. The composition of any one of claims 27 to 33, wherein the one or more glidants, if present, is colloidal silica.

35. the one or more fillers are selected from MCC, mannitol, silicified MCC, and mesoporous silica; or the one or more disintegrants is croscarmellose sodium; or the one or more lubricants, when present, are sodium stearyl fumarate or magnesium stearate; or 35. The composition of claim 34, wherein the one or more glidants, when present, is colloidal silica.

36. 33. The composition of claim 32, comprising a first filler and a second filler, wherein the solid dispersion, the first filler, and the second filler have a weight ratio of 2:1:

1.

37. 36. The composition of claim 30 or claim 35, wherein the first filler is MCC and the second filler is mannitol.

38. the one or more disintegrants is croscarmellose sodium; or the one or more lubricants is sodium stearyl fumarate; or 38. The composition of claim 36 or 37, wherein the one or more glidants, when present, is colloidal silica.

39. the one or more disintegrants is croscarmellose sodium; the one or more lubricants is sodium stearyl fumarate; 38. The composition of claim 36 or 37, wherein the one or more glidants is colloidal silica.

40. 38. The composition of claim 37, wherein the one or more disintegrants is croscarmellose sodium; or the one or more lubricants is magnesium stearate.

41. 41. A pharmaceutical composition comprising an intragranular component comprising the composition of any one of claims 27 to 40, and an extragranular component comprising one or more fillers, optionally one or more disintegrants, optionally one or more glidants, and one or more lubricants.

42. 42. The pharmaceutical composition of claim 41, wherein the pharmaceutical composition comprises about 85% to about 95% (w / w) of the intragranular component, or about 85% (w / w) of the intragranular component.

43. 43. The pharmaceutical composition of claim 41 or 42, wherein the extragranular component comprises from about 10% to about 15% (w / w) of the one or more fillers, from about 1% to about 2% (w / w) of the one or more disintegrants, from about 0.5% to about 1.0% (w / w) of the one or more glidants, and from about 0.5% to about 1.0% (w / w) of the one or more lubricants.

44. 43. The pharmaceutical composition of claim 41 or 42, wherein the extragranular component comprises from about 5% to about 15% (w / w) of the one or more fillers and from about 0.25% to about 0.75% (w / w) of the one or more lubricants.

45. the one or more fillers are selected from anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tribasic calcium phosphate, guar gum, lactose monohydrate, mannitol, sorbitol, microcrystalline cellulose, co-processed microcrystalline cellulose, silicified microcrystalline cellulose, and mesoporous silica; or the one or more disintegrants, when present, is croscarmellose sodium; or the one or more lubricants are sodium stearyl fumarate or magnesium stearate; or 43. The pharmaceutical composition of claim 42, wherein the one or more glidants, when present, is colloidal silica.

46. the one or more fillers are selected from microcrystalline cellulose, mannitol, silicified microcrystalline cellulose, and mesoporous silica; or the one or more disintegrants is croscarmellose sodium; or the one or more lubricants is sodium stearyl fumarate; or 44. The pharmaceutical composition of claim 43, wherein the one or more glidants is colloidal silica.

47. 45. The pharmaceutical composition of claim 44, wherein the one or more fillers are selected from microcrystalline cellulose and mannitol, and the one or more lubricants is magnesium stearate.

48. 48. The pharmaceutical composition according to any one of claims 41 to 47, wherein the pharmaceutical composition comprises two fillers, optionally in a ratio of 1:1 to 2:

1.

49. 42. The pharmaceutical composition of claim 41, wherein the composition is a formulation of Table 16, Table 19, Table 20, or Table 24.

50. 22. A tablet comprising microcrystalline cellulose (MCC), mannitol, croscarmellose sodium, colloidal silica, sodium stearyl fumarate, and the solid dispersion of any one of claims 1 to 21.

51. 51. The tablet of claim 50, wherein the tablet comprises about 25% to about 60% (w / w) of the solid dispersion.

52. 51. The tablet of claim 50, wherein the tablet comprises about 35% to about 55% (w / w) of the solid dispersion.

53. The tablet according to any one of claims 50 to 52, wherein the solid dispersion is according to any one of claims 10 to 21.

54. 54. The tablet of claim 53, wherein the solid dispersion is as defined in claim 17.

55. 55. The tablet of any one of claims 50 to 54, wherein the tablet comprises about 40% to about 50% (w / w) of the solid dispersion, about 10% to 25% (w / w) MCC, about 20% to about 25% (w / w) mannitol, about 5% to about 6% (w / w) croscarmellose sodium, about 1% (w / w) colloidal silica, and about 1% (w / w) sodium stearyl fumarate.

56. A tablet comprising microcrystalline cellulose (MCC), mannitol, croscarmellose sodium, magnesium stearate, and the solid dispersion of any one of claims 1 to 21.

57. 57. The tablet of claim 56, wherein the tablet comprises about 35% to about 45% (w / w) of the solid dispersion, about 30% to about 42% (w / w) MCC, about 13% to about 23% (w / w) mannitol, about 2% to about 8% (w / w) croscarmellose sodium, and about 0.5% to about 1.5% (w / w) magnesium stearate.

58. 51. The tablet of claim 50, wherein the tablet is a tablet of Table 16, Table 19, Table 20, or Table 24.

59. 59. The tablet of any one of claims 50 to 58, wherein the tablet has a weight of from about 100 mg to about 1 g.

60. 60. The tablet of claim 59, wherein the tablet has a weight of about 100 mg, about 250 mg, about 500 mg, or about 750 mg.

61. 60. The tablet of claim 59, wherein the tablet has a weight of 750 mg to 800 mg, 760 mg to 790 mg, 770 mg to 780 mg, 775 mg to 785 mg, or 780 mg to 790 mg.

62. 62. The tablet of any one of claims 50 to 61, further comprising a coating.

63. 63. The tablet of claim 62, wherein the coating is a non-functional coating.

64. 64. A tablet according to any one of claims 50 to 63, wherein the percent of etremadenant released in 45 minutes is 85% or greater as measured by the dissolution method of Table 21.

65. When stored in sealed packages at 25°C and 60% relative humidity for 6, 12, 18, 24, or 36 months: (i) the amount of etremadenant in the tablet is about 90 to about 110% of the value measured at 0 months; (ii) less than or equal to 2%, less than or equal to 1%, or less than or equal to 0.5% (area %) total impurities as measured by HPLC; or (iii) The tablet according to any one of claims 50 to 64, which is any combination of (i) to (ii).

66. 66. The tablet of any one of claims 50 to 65, wherein upon administration of the tablet to a human in a fed or fasted state, the overall exposure of the human to etremadenant is equivalent.

67. 1. A process for preparing a solid dispersion comprising etremadenant, comprising: mixing etremadenant, a polymer selected from HPMCAS and copovidone, and a solvent to form a spray solution; spray drying the spray solution to produce the solid dispersion.

68. 68. The process of claim 67, wherein the weight ratio of etremadenant to polymer is from 25:75 to 40:

60.

69. 69. The process of claim 67 or 68, wherein the spray solution is prepared at a solids loading of 8% to 13%.

70. 70. The process of any one of claims 67 to 69, wherein the spray drying step comprises spraying the spray solution into a drying chamber having an outlet temperature of from about 38°C to about 46°C, a gas to liquid ratio of from about 0.5 to about 0.7, and a relative saturation (total) of from about 15% to about 23%.

71. 71. The process of any one of claims 67 to 70, wherein the solid dispersion is further dried to produce a dry powder having a moisture content of less than about 1% (w / w).

72. Adenosine A ２Ａ Receptor (A ２Ａ R) and / or adenosine A ２Ｂ Receptor (A ２Ｂ 67. A method of treating a disease, disorder, or condition mediated at least in part by a compound selected from the group consisting of benzodiazepines (B1), benzodiazepines (B2), benzodiazepines (B3), benzodiazepines (B4), benzodiazepines (B5), benzodiazepines (B6), benzodiazepines (B7), benzodiazepines (B8), benzodiazepines (B9), benzodiazepines (B10), benzodiazepines (B11), benzodiazepines (B12), benzodiazepines (B13), benzodiazepines (B14), benzodiazepines (B15), benzodiazepines (B16), benzodiazepines (B17), benzodiazepines (B18), benzodiazepines (B19), benzodiazepines (B21), benzodiazepines (B22), benzodiazepines (B23), benzodiazepines (B24), benzodiazepines (B25), benzodiazepines (B26), benzodiazepines (B27), benzodiazepines (B28), benzodiazepines (B29 ...30), benzodiazepines (B31), benzodiazepines (B31), benzodiazepines (B32), benzodiazepines (B32), benzodiazepines (B33), benzodiazepines (B34), benzodiazepines

73. The disease, disorder, or condition is ２Ａ 73. The method of claim 72, wherein the method is at least partially mediated by R.

74. The disease, disorder, or condition is ２Ｂ 73. The method of claim 72, wherein the method is at least partially mediated by R.

75. The disease, disorder, or condition is ２Ａ R and A ２Ｂ 73. The method of claim 72, wherein the vasopressin-releasing hormone (vasopressin) is at least partially mediated by both R and R receptors.

76. 67. A method of treating cancer, comprising administering to a subject in need thereof a dosage form according to claim 24 or claim 25, a pharmaceutical composition according to any one of claims 41 to 49, or a tablet according to any one of claims 50 to 66.

77. 67. A method of treating cancer in a subject, said method comprising administering to a subject in need thereof an effective amount of the dosage form of claim 24 or claim 25, the pharmaceutical composition of any one of claims 41-49, or the tablet of any one of claims 50-66; and at least one additional therapeutic agent.

78. 78. The method of claim 77, wherein the cancer is a solid tumor.

79. 78. The method of claim 77, wherein the cancer is breast cancer, lung cancer, gastrointestinal cancer, genitourinary cancer, or gynecological cancer.

80. 78. The method of claim 77, wherein the cancer is bladder cancer, breast cancer, colorectal cancer, gastric cancer, gastroesophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

81. 78. The method of claim 77, wherein the cancer is castration-resistant prostate cancer, esophageal adenocarcinoma, non-small cell lung cancer, pancreatic ductal adenocarcinoma, prostate adenocarcinoma, or urothelial carcinoma.

82. 82. The method of any one of claims 72-81, wherein the subject is administered a total daily dose of about 50 mg etremadenant to about 250 mg etremadenant, or about 50 mg etremadenant to about 150 mg etremadenant.

83. 83. The method of claim 82, wherein the subject is administered a total daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg.

84. 67. A method of treating cancer in a subject who is concomitantly receiving a CYP3A4 inhibitor or a P-gp inhibitor, or who is a CYP3A4 poor metabolizer, comprising administering to a subject in need thereof a dosage form according to claim 24 or claim 25, a pharmaceutical composition according to any one of claims 41 to 49, or a tablet according to any one of claims 50 to 66.

85. At least in part adenosine A ２Ａ Receptor (A ２Ａ R) or adenosine A ２Ｂ Receptor (A ２Ｂ 1. A method for treating a disease, disorder, or condition mediated by CYP3A4, wherein the patient is concurrently receiving a CYP3A4 inhibitor or a P-gp inhibitor, or the subject is a CYP3A4 poor metabolizer, the method comprising administering a therapeutically effective amount of etormadenant.

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