WO2025265110A1

WO2025265110A1 - Oral pharmaceutical compositions comprising a naphthyridine compound

Info

Publication number: WO2025265110A1
Application number: PCT/US2025/034720
Authority: WO
Inventors: Fernando Antonio ALVAREZ-NUNEZ; John Inn CHUNG; Behnoush KHORSAND; Yuan-Hon Kiang; Yicong LIANG; Hwee Jing ONG
Original assignee: Amgen Inc
Current assignee: Amgen Inc
Priority date: 2024-06-21
Filing date: 2025-06-23
Publication date: 2025-12-26
Anticipated expiration: 2026-12-21

Abstract

Provided herein are pharmaceutical compositions comprising Compound A, such as 1-40 wt% Compound A, wherein the pharmaceutical compositions are suitable for oral administration. In some embodiments, the disclosed compositions are suitable for high drug loading. The disclosed compositions are suitable for treating diseases or disorders responsive to inhibiting protein arginine methyltransferase 5 (PRMT5) (e.g., cancer).

Description

ORAL PHARMACEUTICAL COMPOSITIONS COMPRISING A NAPHTHYRIDINE COMPOUND

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/662,893, filed June 21, 2024, which is hereby incorporated by reference in its entirety.

BACKGROUND

[002] Naphthyridine compounds have been shown to be important in a number of biological applications, including modulating processes mediated by the enzyme protein arginine methyltransferase 5 (PRMT5). It is known that PRMT5 plays a role in diseases such as proliferative disorders, metabolic disorders, and blood disorders. The compound ((S)-(4-amino-1 ,2-dihydrofur[3,4-c][1 ,7]naphthyridine-8-yl)-(3-

(4(trifluoromethy Ijpheny Ijmorphol inojmethanone) is a small molecule PMRT5 inhibitor currently being evaluated for the treatment of cancers with methylthioadenosine phosphorylase (MTAP) deletion occurring in about 15% of human cancers, including for example, non-small lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, gastric cancer, esophageal cancer, and cholangiocarcinoma in the second or third line of therapy. The compound (S)-(4-amino-1 ,3-dihydrofuro[3,4-c][1 ,7]naphthyridin-8-yl)(3-(4- (trifluoromethyl)phenyl)morpholino)methanone, disclosed in International Patent Application Publication No. WO 2022/132914 and referred to herein as "Compound A”, has the following structure,

[003] A goal in developing a drug is to provide dosage forms which make it possible to maintain a certain amount or concentration of drug in a subject's body that is clinically or therapeutically relevant, in a manner that provides suitable patient compliance. In some cases, this is complicated when the dosage forms comprise a high drug loading. Daily doses as high as 1600 mg/day or 1200 mg/day of Compound A currently being evaluated can pose a significant pill burden to a subject having to take many doses a day in order to achieve a recommended dosage. Another goal in developing a formulation of Compound A that is safe, effective, stable and convenient for patients.

[004] Thus, there is a need for oral dosage formulations of Compound A that can provide and maintain adequate therapeutic blood levels when administered to subjects, wherein the formulations have, for example, an acceptable size, are easy to swallow, reduce dosing frequency, and can easily be manufactured.

SUMMARY

[005] The disclosure provides pharmaceutical compositions comprising 1-40 wt% Compound A, a diluent, a disintegrant, and a lubricant, wherein the pharmaceutical compositions are suitable for oral administration. The disclosure further provides pharmaceutical compositions comprising Compound A, a diluent in an amount of 45- 75 wt%, a polyol in an amount of 3-25 wt%, a disintegrant in an amount of 1-10 wt%, and a lubricant in an amount of 0.5-7%, wherein the pharmaceutical compositions are free of a reducing sugar and suitable for oral administration. In some embodiments, the pharmaceutical compositions are in the form of a tablet. In some embodiments, the tablet comprises a coating, such as a film-coating.

[006] The disclosure also provides methods of using the disclosed pharmaceutical compositions, including methods of treating cancer (e.g., ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, esophageal, gastroesophageal junction (GEJ) cancer, biliary tract cancer (BTC), pancreatic, bladder cancer, glioma, solid tumor, head and neck squamous cell carcinoma (HNSCC), gallbladder cancer, and mesothelioma).

[007] The disclosure also provides a method of treating a disease or disorder responsive to inhibiting protein arginine methyltransferase 5 (PRMT5) comprising administering to the subject a therapeutically effective amount of the disclosed compositions.

BRIEF DESCRIPTION OF THE FIGURES

[008] Figure 1 shows a comparison of the dissolution profiles of tablets comprising 1 wt% Mg stearate and 1 .25 wt% Mg stearate.

[009] Figure 2 shows a flow diagram for the manufacturing process for 5 mg, 20 mg, and 100 mg tablets comprising Compound A as described in Example 1.

[0010] Figure 3 shows particle size distribution (PSD) of granules for 1% DL and 20% DL final blends as described in Example 1.

[0011] Figure 4 shows the impact of tablet hardness (kilopond) on the friability of 5 mg, 20 mg, and 100 mg tablets for three different hardnesses (main, low, and high) for each dosage strength. The tablets comprised Compound A and were prepared as described in Example 1 . For all tablet hardnesses evaluated, the quality target product profile (QTPP) criteria for friability (< 1%) was met.

[0012] Figure 5A shows impact of tablet hardness (kp) on the disintegration times of 5 mg tablets for three different hardnesses (low, target, and high). The tablets comprised Compound A and were prepared as described in Example 1 . For all tablet hardnesses evaluated, the quality target product profile (QTPP) criteria for disintegration (< 300 s) was met.

[0013] Figure 5B shows impact of tablet hardness (kp) on the disintegration times of 20 mg tablets for three different hardnesses (low, target, and high). The tablets comprised Compound A and were prepared as described in Example 1 . For all tablet hardnesses evaluated, the quality target product profile (QTPP) criteria for disintegration (< 300 s) was met.

[0014] Figure 5C shows impact of tablet hardness on the disintegration times of 100 mg tablets for three different hardnesses (low, target, and high). The tablets comprised Compound A and were prepared as described in Example 1 . For all tablet hardnesses evaluated, the quality target product profile (QTPP) criteria for disintegration (< 300 s) was met. [0015] Figure 6 shows the manufacturing process flow diagram for IR film-coated tablets comprising Compound A (200 mg and 300 mg), as described in Example 2.

[0016] Figure 7 shows the dissolution profile for 200 mg IR film-coated tablets in 50 mM phosphate buffer pH 6.8, 0.25% SDS, 75 RPM at 37 °C at t=0 and 40 °C/75 %RH, 1 month, as described in Example 2.

[0017] Figure 8A shows the dissolution profiles of 200 mg tablets having different hardness values (17.5, 24, and 29.5 kp), as described in Example 2.

[0018] Figure 8B shows the dissolution profiles of 200 mg IR film-coated tablets in 50 mM phosphate buffer pH 6.8, 0.25% SDS, 75 RPM at 37 °C at t=0 and 30 °C/65% RH (18 months); 30 °C/75% RH (18 months); and 40 °C/75 % RH (6 months), as described in Example 2.

[0019] Figure 8C the dissolution profiles of 200 mg IR film-coated tablets in 50 mM phosphate buffer pH 6.8, 0.25% SDS, 75 RPM at 37 °C at t=0 and 30 °C/65% RH (12 months); 30 °C/75% RH (12 months); and 40 °C/75 % RH (6 months), as described in Example 2.

[0020] Figure 8D the dissolution profiles of 200 mg IR film-coated tablets in 50 mM phosphate buffer pH 6.8, 0.25% SDS, 75 RPM at 37 °C at t=0 and 30 °C/65% RH (9 months); 30 °C/75% RH (9 months); and 40 °C/75 % RH (6 months), as described in Example 2.

[0021] Figure 8E the dissolution profiles of 200 mg IR film-coated tablets in 50 mM phosphate buffer pH 6.8, 0.25% SDS, 75 RPM at 37 °C at t=0 and 30 °C/65% RH (9 months); 30 °C/75% RH (9 months); and 40 °C/75 % RH (6 months), packaged in blisters as described in Example 2.

[0022] Figure 9 shows a comparison of bulk and tapped density of tablets having a DL of 20%, 25%, and 32%, as described in Example 2.

[0023] Figure 10 shows a comparison of Carr's index of tablets having a DL of 20%, 25%, and 32%, as described in Example 2.

[0024] Figure 11 shows a comparison of the PSD of the initial blends from 25% and 32% DL, as described in Example 2.

[0025] Figure 12 shows a PSD comparison of the PSD of the final blends from 25% and 32% DL, as described in Example 2.

[0026] Figure 13 shows a PSD comparison of the dissolution profiles of the 25% and 32% DL, as described in Example 2.

[0027] Figure 14 shows the preliminary mean (+SD) plasma Compound A concentration-time profiles after once daily administration of Compound A cycle 1 day 1 .

[0028] Figure 15 shows the preliminary mean (+SD) plasma Compound A concentration-time profiles after once daily administration of Compound A cycle 1 day 15.

[0029] Figure 16 shows dose normalized C_max at Cycle 1 Day 1 for 100 mg and 200 mg tablets. [0030] Figure 17 shows dose normalized C_max at Cycle 1 Day 15 for 100 mg and 200 mg tablets.

[0031] Figure 18 shows dose normalized AUG at Cycle 1 Day 1 for 100 mg and 200 mg tablets.

[0032] Figure 19 shows dose normalized AUG at Cycle 1 Day 15 for 100 mg and 200 mg tablets.

[0033] Figure 20 shows the dissolution profile for 300 mg IR film-coated tablets in 50 mM phosphate buffer pH

6.8, 0.25% SDS, 75 RPM at 37 °C at t=0 and 40 °C/75 %RH, 1 and 3 months, as described in Example 7.

DETAILED DESCRIPTION maceutical compositions comprising Compound A: , wherein the compositions are suitable for oral administration.

[0035] In some embodiments, provided herein are pharmaceutical compositions for providing 1-40 wt%

Compound some embodiments, the disclosed pharmaceutical compositions comprise 1-40 wt% Compound A, a diluent, a disintegrant, and a lubricant. In some embodiments, the disclosed pharmaceutical compositions further comprise a polyol. In some embodiments, provided herein are pharmaceutical compositions comprising Compound A, a diluent in an amount of 45-75 wt%, a polyol in an amount of 3-25 wt%, a disintegrant in an amount of 1-10 wt%, and a lubricant in an amount of 0.5-7%, wherein the pharmaceutical compositions are free of a reducing sugar. In some embodiments, the pharmaceutical compositions further comprise a coating (e.g., a film-coating). The disclosed pharmaceutical compositions are suitable for oral administration. In some embodiments, the disclosed pharmaceutical compositions are a tablet.

[0036] The disclosed pharmaceutical compositions advantageously are capable of providing a high drug loading of Compound A in solid dosage forms suitable for oral administration (e.g., tablets). In some embodiments, the disclosed pharmaceutical compositions provide a high drug loading (DL) of Compound A. As used herein, a high drug loading refers to dosage forms comprising more than 20 wt% Compound A, such as at least 25 wt% Compound A per unit dosage (e.g., 25-40 wt% Compound A). For example, in some instances a high DL dosage form may comprise 25, 30, 32, 35, 37.5, or 40 wt% Compound A. By way of example, in some embodiments, the disclosure provides tablets comprising 40 wt% Compound A. In embodiments having a high drug loading, the disclosed compositions reduce the pill burden of patients administered high dosages of Compound A using conventional dosage forms. Moreover, pharmaceutical compositions disclosed herein provide improved handling during manufacture and provide suitable in vivo pharmacokinetics (PK). For example, the 200 mg tablets (25% DL) show suitable in vivo PK. See, for example, Figures 16-19.

[0037] Further, the disclosed composition advantageously reduces or prevents chemical degradation of the composition by including a polyol, such as mannitol, as a brittle diluent, while overcoming the unfavorable higher sticking propensity that typically accompanies the inclusion of polyol in such compositions by including an increased amount of lubricant, all without affecting compression or dissolution.

[0038] In vitro-in vivo correlation (IVIVC) for a pharmaceutically active ingredient bridges the gap between laboratory-based experiments (in vitro) and real-life biological systems (in vivo). While it is understood that correlations exist (e.g., between in vitro dissolution and in vivo absorption), limited progress has been made towards a comprehensive model capable of predicting in vivo performance based on in vitro properties due to the complex array of factors that must be considered, particularly during the early development of a drug when limited data is available. See, for example, Lu, Ying, Sungwon Kim, and Kinam Park. "In vitro-in vivo correlation: Perspectives on model development." International Journal of Pharmaceutics 418.1 (2011): 142-148, which describes some of the challenges involved with developing predictive IVIVCs. For example, some of the factors include a) biological variability due to genetic differences; b) complexity of modeling in vivo systems comprising multiple organs, tissues, and physiological processes; and c) scaling small scale in vitro experiments to larger scale in vivo systems to account for factors such as, dosing, concentrations, and kinetics. Addressing these challenges requires a multidisciplinary approach involving expertise in pharmacology, biochemistry, physiology, biostatistics, and computational modeling.

[0039] In addition, once an IVIVC is developed correlating a physiological response to the drug substance and specific delivery system is challenging and requires large amounts of pharmacokinetic/pharmacodynamic (PK/PD) data in order to develop a predictive model useful in the development of suitable clinical formulations. See, for example, Zou, Huixi, et al. "Application of pharmacokinetic-pharmacodynamic modeling in drug delivery: development and challenges." Frontiers in Pharmacology 11 (2020): 543082. The process is challenging in the early stages of development when data is limited. For example, a delivery system must be selected/designed for each active ingredient followed by evaluation of the PK properties (e.g., absorption, plasma exposure, and target site exposure) and the PD properties (target binding/activation, transducer process, biological effects and response). Typically, the PK/PD properties are evaluated in preclinical studies, wherein the results are used to development a suitable dosing regimen which can be further evaluated in clinical studies, wherein the ultimate goal is the development of an approved drug product.

[0040] In some embodiments, the disclosed pharmaceutical compositions are an immediate release composition. As used herein, the term "immediate release” (IR) refers to a pharmaceutical composition developed to dissolve without delaying or prolonging dissolution or absorption of a drug. Generally, an IR tablet or capsule is swallowed whole and instantaneously disintegrates to make the drug available for absorption and subsequent pharmacologic action. Immediate-release products are used when the rapid onset of action of a drug is advantageous and usually include disintegrants (e.g., croscarmellose sodium) as excipients. The components rapidly disintegrate, de-aggregate, and/or dissolve, when they come into contact with water or with the gastrointestinal tract.

[0041] In general, 70% to 80% of a drug in an IR formulation should be released, preferably within an hour, and certainly within 4 hours, after ingestion. For poorly soluble drugs, a longer dissolution time may be considered normal. In certain embodiments, 70% to 80% of the drug in an IR formulation is released within one hour. In certain embodiments, at least 85% of the drug in an IR formulation is released within 60 min in an aqueous medium. In certain embodiments, 70% to 80% of the drug in an IR formulation is released within 4 hours.

COMPOUND A

[0042] The disclosed pharmaceutical compositions comprise Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise Compound A as the free base. In some embodiments, the disclosed pharmaceutical compositions comprise Compound A as a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, and which do not possess any own properties that are undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. Thus, preferred "pharmaceutically acceptable salts" include the acetate, bromide, chloride, formate, fumarate, maleate, mesylate, nitrate, oxalate, phosphate, sulfate, tartrate and tosylate salt of Compound A.

[0043] The disclosed pharmaceutical compositions comprise 1-40 wt% Compound A. Accordingly, In some embodiments, the pharmaceutical compositions comprise 1 wt% Compound A, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 1-20 wt% Compound A, for example, 3-17 wt% Compound A, 5-15 wt% Compound A and 8-12 wt% Compound A.

[0044] In some embodiments, the disclosed pharmaceutical compositions comprise 20-40 wt% Compound A, for example, 23-38 wt%, 25-35 wt%, and 28-32 wt% Compound A.

[0045] In some embodiments, the disclosed pharmaceutical compositions comprise 1 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 20 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 25 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 30 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 32 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 37.5 wt% Compound A. In some embodiments, the disclosed pharmaceutical compositions comprise 40 wt% Compound A. DILUENT

[0046] The disclosed pharmaceutical compositions comprise a diluent. As used herein, a "diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used without limitation to increase the bulk of a potent drug whose mass is too small for manufacture or administration and/or to improve the consistency of a composition for processing and handling, and/or to improve stability, and binding ability of a composition comprising the drug. Nonlimiting examples of suitable diluents include, for example, lactose, lactose monohydrate, microcrystalline cellulose, and a combination thereof. In some embodiments, the disclosed pharmaceutical compositions comprise microcrystalline cellulose.

[0047] In some embodiments, the pharmaceutical compositions comprise more than one diluent. For example, in some embodiments, the pharmaceutical compositions comprise lactose monohydrate. In some embodiments, the diluent comprises microcrystalline cellulose. In some embodiments, the diluent comprises lactose monohydrate and microcrystalline cellulose.

[0048] In some embodiments, the disclosed pharmaceutical compositions are free of a reducing sugar (e.g., lactose). In embodiments wherein the disclosed pharmaceutical composition is free of a reducing sugar, the pharmaceutical composition comprises a polyol (e.g., mannitol), as described herein.

[0049] The disclosed pharmaceutical compositions comprise a suitable amount of diluent. Typically, the pharmaceutical compositions disclosed herein comprise about 50-80 wt% diluent of the composition (e.g., 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, and 80 wt%, including amounts in between the listed point values). For example, in some embodiments, the disclosed pharmaceutical compositions comprise 45-75 wt% diluent, 50-70 wt%, 50-65 wt%, or 55-65 wt% diluent. In some embodiments, the disclosed pharmaceutical compositions comprise 71.25 wt% diluent. In some embodiments, the disclosed pharmaceutical compositions comprise 57 wt% diluent. In some embodiments, the disclosed pharmaceutical compositions comprise 58.25 wt% diluent. In some embodiments, the disclosed pharmaceutical compositions comprise 55.75 wt% diluent.

[0050] In some cases, the disclosed pharmaceutical compositions comprise 45-75 wt%, 50-70 wt%, 50-65 wt%, or 55-65 wt% of microcrystalline cellulose. In some cases, the disclosed pharmaceutical compositions comprise 55.75 wt% of microcrystalline cellulose. In some cases, the disclosed pharmaceutical compositions comprise 57 wt% of microcrystalline cellulose. In some cases, the disclosed pharmaceutical compositions comprise 58.25 wt% of microcrystalline cellulose. In some cases, the disclosed pharmaceutical compositions comprise 71 .25 wt% of microcrystalline cellulose.

POLYOL

[0051] In some embodiments, the disclosed pharmaceutical compositions further comprise a polyol. Nonlimiting examples of suitable polyols (e.g., sugar alcohols) include mannitol, sorbitol, xylitol, erythritol, isomalt, lactitol, hydrogenated starch hydrolysates, or a combination thereof. In some embodiments, the disclosed pharmaceutical compositions comprise mannitol, sorbitol, or a combination thereof. In some embodiments, the disclosed pharmaceutical compositions comprise mannitol.

[0052] In embodiments comprising a polyol, the disclosed pharmaceutical compositions comprise a suitable amount of polyol. In some embodiments, the polyol is present in an amount of 3-25 wt% (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25 wt% of the composition, including amounts in between the recited values (e.g., 8.75, 13.75, 23.75 wt% of the composition),. For example, in some embodiments, the polyol is present in 3-15 wt%, 8-10 wt%, and 15-20 wt% of the composition. In some embodiments, the polyol is present in 5-15 wt% or 13-15 wt% of the composition.

[0053] In some embodiments, the disclosed pharmaceutical compositions comprise 23.75 wt% polyol. In some embodiments, the disclosed pharmaceutical compositions comprise 19 wt% polyol. In some embodiments, the disclosed pharmaceutical compositions comprise 14 wt% polyol. In some embodiments, the disclosed pharmaceutical compositions comprise 13.75 wt% polyol. In some embodiments, the disclosed pharmaceutical compositions comprise 7 wt% polyol. In some embodiments, the disclosed pharmaceutical compositions comprise 8.75 wt% polyol.

[0054] In some embodiments, the disclosed pharmaceutical compositions comprise 23.75 wt% mannitol. In some embodiments, the disclosed pharmaceutical compositions comprise 19 wt% mannitol. In some embodiments, the disclosed pharmaceutical compositions comprise 14 wt% mannitol. In some embodiments, the disclosed pharmaceutical compositions comprise 13.75 wt% mannitol. In some embodiments, the disclosed pharmaceutical compositions comprise 7 wt% mannitol. In some embodiments, the disclosed pharmaceutical compositions comprise 8.75 wt% mannitol.

[0055] Alternatively, or in addition, in some embodiments, the amount of polyol present is considered relative to the amount of diluent present. For example, in some embodiments the diluent and polyol are present in a weight ratio of 1 :10 to 10:1 (e.g., 1 :10, 1 :9, 1 :8, 1 :7, 1 :6, 1 :5, 1 :4, 1 :3, 1 :2, 1 :1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1). In some embodiments, the diluent and polyol are present in a weight ratio of 1 :5 to 5:1. In some embodiments, the diluent and polyol are present in a weight ratio of 8:1. In some embodiments, the diluent and polyol are present in a weight ratio of 3:1. By way of example, in some embodiments, the 5 mg, 20 mg, and 100 mg tablets comprise, inter alia, a 3:1 weight ratio of diluent to polyol (e.g., see Tables 1 and 2 of Example 1). In some cases, the diluent and polyol are present in a weight ratio of 4: 1 . In some cases, the diluent and polyol are present in a weight ratio of 6.5:1.

DISINTEGRANT

[0056] The disclosed pharmaceutical compositions comprise a disintegrant. As used herein, a “disintegrant” refers to an ingredient added to solid dosage forms to facilitate their breakup or disintegration when exposed to moisture or fluids in the body. Nonlimiting examples of suitable disintegrants include, for example, croscarmellose sodium, alginic acid, bentonite, powdered cellulose, guargalactomannan, carboxymethylcellulose calcium, carmellose sodium, sodium starch glycolate, low-substituted carboxymethylcellulose sodium, low- substituted hydroxypropyl cellulose, crospovidone, or a combination thereof. In some embodiments, the disintegrant comprises a cellulose derivative. In some embodiments, the disintegrant comprises croscarmellose sodium.

[0057] The disclosed pharmaceutical compositions comprise a suitable amount of disintegrant. In some embodiments, the disintegrant is present in an amount of 1-10 wt% of the composition (e.g., 1, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, and 10 wt% disintegrant). For example, in some embodiments, the disclosed compositions comprise 1-9 wt% disintegrant (e.g., 2-8, 3-7, 3-6, 3-5, and 3-4 wt% disintegrant). In some embodiments, the disclosed compositions comprise 2-5 wt% (e.g., 2-3, 2-4, 3-4, 3-5, and 4-5 wt%) distintegrant. In some embodiments, the disclosed compositions comprise 3 wt% disintegrant. In some embodiments, the disclosed compositions comprise 3 wt% croscarmellose sodium.

LUBRICANT

[0058] The disclosed pharmaceutical compositions comprise a lubricant. As used herein, a "lubricant” refers to a substance added to solid dosage forms to reduce friction during manufacturing processes thereby preventing sticking of the formulation to the equipment facilitating the release of tablets from molds or punches and ensuring uniformity in tablet weight and helping to maintain the integrity of the dosage form. Nonlimiting examples of suitable lubricants include, for example, magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, a polyethylene glycol, silicon dioxide, talc, beeswax, hydrogenated vegetable oil, or a combination thereof. In some embodiments, the lubricant comprises a stearate. In some embodiments, the lubricant comprises magnesium stearate.

[0059] The disclosed pharmaceutical compositions comprise a suitable amount of lubricant. In some embodiments, the lubricant is present in an amount of 0.5-7 wt% of the composition (e.g., 0.5-7, 1-6.5, 1.5-6.0, and 2.0-5.5 wt%). In some embodiments, the lubricant is present in an amount of 1-5 wt% of the composition (e.g., 1-4, 1-3, 1-2, 1.1-1.5 wt% lubricant). In some embodiments, the lubricant is present in an amount 1 to 1.3 wt% (e.g., 1.0, 1.1, and 1.3 wt% lubricant). In some embodiments, the lubricant is present in an amount of 0.5- 1.5 wt%. In some embodiments, the disclosed compositions comprise 1 wt% lubricant. In some embodiments, the disclosed compositions comprise 1 .25 wt% lubricant.

[0060] The lubricant can be intragranular and/or extragranular. In some embodiments, the lubricant is intragranular. In some embodiments, the lubricant is extragranular. In some embodiments, the lubricant is both extragranular and intragranular. In some embodiments, the amount lubricant is equally distributed intra- and extragranular (e.g., 1 :1). In some embodiments, more of the lubricant is extragranular (e.g., 1.5:1). Without wishing to be bound to any particular theory, it is believed that embodiments comprising more lubricant extragranularly provide improved handling properties during manufacturing of tablets using compression. For example, in some instances the compressed tablet blends were observed to stick to the tooling equipment. This "sticking and picking” issue was improved when additional lubricant (e.g., magnesium stearate) was added extragranularly (0.5 wt% IG; 0.75 wt% EG). Moreover, tablets comprising additional lubricant were found to have suitable physical properties (e.g., dissolution, hardness). As shown in Figure 1, tablets comprising 0.75 wt% magnesium stearate (EG) showed the same dissolution profile as tablets comprising 0.5 wt% magnesium stearate (EG). In some embodiments, the pharmaceutical compositions comprise 0.5 wt% intragranular lubricant and 0.75 wt% extragranular lubricant. In some embodiments, the pharmaceutical compositions comprise 0.5 wt% intragranular magnesium stearate and 0.75 wt% extragranular magnesium stearate.

TABLET COMPOSITIONS

[0061] The pharmaceutical composition disclosed herein include Compound A (e.g., in an amount of 1-40 wt%)„ a diluent (e.g., in an amount of 45-75 wt%), optionally a polyol (e.g., in an amount of 3-25 wt%), a disintegrant (e.g., in an amount of 1-10 wt%), and a lubricant (e.g., in an amount of 0.5-7%). In some embodiments, the disclosed pharmaceutical compositions are free of a reducing sugar.

[0062] In some embodiments, the disclosure provides a pharmaceutical composition comprising (1) 1-40 wt% Compound A; (2) 45-75 wt% microcrystalline cellulose; (3) 3-25 wt% mannitol; (4) 1-10 wt% croscarmellose; and (5) 0.5-7 wt% magnesium stearate, in the form of a tablet. In some embodiments, the pharmaceutical composition is free of reducing sugars and suitable for oral administration.

[0063] In some embodiments, the disclosure provides a pharmaceutical composition comprising (1) 1 wt% Compound A free base; (2) 71.25 wt% microcrystalline cellulose; (3) 23.75 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 wt% magnesium stearate, in the form of a tablet.

[0064] In some embodiments, the disclosure provides a pharmaceutical composition comprising (1) 20 wt% Compound A free base; (2) 57 wt% microcrystalline cellulose; (3) 19 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 wt% magnesium stearate, in the form of a tablet.

[0065] In some embodiments, the disclosure provides a pharmaceutical composition comprising (1) 25 wt% Compound A free base; (2) 57 wt% microcrystalline cellulose; (3) 14 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 wt% magnesium stearate, in the form of a tablet.

[0066] In some embodiments, the disclosure provides a pharmaceutical composition comprising (1) 25 wt% Compound A free base; (2) 57 wt% microcrystalline cellulose; (3) 13.75 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 .25 wt% magnesium stearate, in the form of a tablet.

[0067] In some embodiments, the disclosure provides a pharmaceutical composition comprising (1) 30 wt% Compound A free base; (2) 57 wt% microcrystalline cellulose; (3) 8.75 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 .25 wt% magnesium stearate, in the form of a tablet.

[0068] In some embodiments, the disclosure provides a pharmaceutical composition comprising (1) 32 wt% Compound A free base; (2) 57 wt% microcrystalline cellulose; (3) 7 wt% mannitol; (4) 3 wt% croscarmellose; and (5) 1 wt% magnesium stearate, in the form of a tablet.

[0069] In some embodiments, the disclosure provides a pharmaceutical composition comprising (1) 37.5 wt% Compound A free base; (2) 58.25 wt% microcrystalline cellulose; (3) 3 wt% croscarmellose; and (4) 1 .25 wt% magnesium stearate, in the form of a tablet. [0070] In some embodiments, the disclosure provides a pharmaceutical composition comprising (1) 40 wt% Compound A free base; (2) 55.75 wt% microcrystalline cellulose; (3) 3 wt% croscarmellose; and (4) 1 .25 wt% magnesium stearate, in the form of a tablet.

COATING

[0071] In some embodiments, the disclosed pharmaceutical compositions comprise a coating. A coating may contain, for example, a film-coating (e.g., membrane forming agent such as a polymer), a plasticizer (which provides plasticity, flexibility, and extensibility to a coating membrane), a water-soluble base (e.g., lactose or sodium chloride), a dispersing agent (which prevents particles or tablets from adhering and aggregating after the coating). These components may be dissolved or dispersed in an appropriate solvent, such as water, alcohol, or the like, to prepare the coating composition.

[0072] Exemplary membrane forming agents include, for example, a water-insoluble polymer or a water- soluble polymer. The membrane forming agent is not particularly limited, so long as it is pharmaceutically acceptable and biocompatible. These membrane forming agents may be added alone or as a combination thereof in an appropriate amount(s).

[0073] Exemplary water-insoluble polymer include, but are not limited to, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, beeswax, carnauba wax, cetyl alcohol, cetyl stearyl alcohol, glyceryl behenate, lipids, fats, resins such as shellac or the like, cellulose derivatives such as ethyl cellulose, cellulose acetate, polyacrylate derivatives such as aminoalkylmethacryl copolymer (product name: Eudragit RS), polymethacrylate derivatives such as methacrylate copolymer (product name: Eudragit L), hydroxypropylmethyl cellulose acetate succinate, polylactic acid, and polyglycolic acid.

[0074] Exemplary water-soluble polymers include, but are not limited to, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, carmellose sodium, methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, and polyvinyl alcohol.

[0075] In some embodiments, the coating comprises polyvinyl alcohol. In some embodiments, the coating further comprises one or more of titanium dioxide, polyethylene glycol, talc, and a coloring agent. Some exemplary coating compositions include ethylcellulose, polymethacrylates, as well as coating products sold by OPADRY™. In some embodiments, the coating agent is Opadry Clear, Opadry Blue 13B50579, Opadry White 33628707, Opadry QX 321 A180025, or Opadry II (33G28707). In some embodiments the coating agent is Opadry White 33628707. In some embodiments the coating agent is Opadry QX 321 A180025.

[0076] In embodiments where the pharmaceutical compositions comprise a coating, the weight percentages of the excipients discussed throughout are with respect to the total weight of the composition before the coating composition is applied. In some embodiments, the disclosed pharmaceutical compositions comprise a coating in an amount of 3 wt% of the composition before the coating composition is applied. FREE OF REDUCING SUGARS

[0077] In some embodiments, the disclosed pharmaceutical compositions are free of a reducing sugar (e.g., lactose). Reducing sugars include those sugars comprising a free aldehyde or ketone functional group which can act as a reducing agent. Nonlimiting examples of reducing sugars include, for example, glucose, fructose, galactose, lactose, maltose, and combinations thereof.

Without wishing to be bound to any particular theory, compositions free of a reducing sugar disclosed herein minimize the likelihood of the compositions undergoing decomposition via the Maillard reaction thereby improving stability of the disclosed compositions. In some instances, compositions were shown to produce Compound A- lactose adducts under various conditions - see, e.g., Example 9.

[0078] As used herein, "free of a reducing sugar” refers to the composition comprising less than 5 wt% of a reducing sugar (e.g., 4.5, 4.0, 3.5, 3.0, 2.5, 2.0, 1.5, or 1.0 wt% or less of a reducing sugar). In some embodiments, the disclosed compositions comprise less than 1 wt% of a reducing sugar (e.g., 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, or 0.01 wt% or less of a reducing sugar). In some embodiments, the disclosed compositions are devoid of a reducing sugar.

[0079] In some embodiments, the disclosed pharmaceutical compositions comprise mannitol as a nonreducing sugar. In some instances, mannitol can be used in lieu of lactose. Without wishing to be bound to any particular theory, use of mannitol in the pharmaceutical compositions disclosed herein results in tablets having comparable compactability as tablets comprising lactose but withimproved compressibility and flow properties as compared to lactose.

METHODS OF TREATMENT

[0080] The disclosure provides methods of treating a disease or disorder responsive to inhibiting protein arginine methyltransferase 5 (PRMT5) comprising administering to the subject a therapeutically effective amount of the disclosed compositions comprising Compound A.

[0081] As used herein, a "therapeutically effective amount” of Compound A means an amount effective to treat or to prevent development of, or to alleviate the existing symptoms of, the patient being treated. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. Generally, a "therapeutically effective amount” refers to that amount of Compound A described herein that results in achieving the desired effect. For example, a therapeutically effective amount of Compound A described herein decreases MTAP activity by at least 5%, compared to control, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%.

[0082] In some embodiments, the disclosure provides a method of treating a cancer in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of the composition of the disclosed compositions comprising Compound A. In some embodiments, the cancer is a MTAP-null cancer. The term "MTAP-null cancer” refers to a cancer that lacks expression of the enzyme methylthioadenosine phosphorylase (MTAP). MTAP-null cancers include MTAP-deficiency in at least 1% of disease cells, and in some cases, at least 20% of disease cells. The terms "MTAP-null" and "MTAP-deleted" are used interchangeably.

[0083] Nonlimiting examples of suitable cancer include ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, pancreatic, and bladder cancer. In some embodiments the cancer is ovarian cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is lymphoid. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is colon. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is gastric. In some embodiments, the cancer is pancreatic. In some embodiments, the cancer is bladder cancer. In some embodiments the cancer is MTAP-null ovarian cancer, MTAP-null lung cancer, MTAP-null lymphoid cancer, MTAP-null glioblastoma, MTAP-null colon cancer, MTAP-null melanoma, MTAP-null gastric cancer, MTAP-null esophageal cancer, MTAP-null gastroesophageal junction (GEJ) cancer, MTAP-null biliary tract cancer (BTC), MTAP-null pancreatic cancer, MTAP-null bladder cancer, MTAP-null glioma, an MTAP-null solid tumor, MTAP-null head and neck squamous cell carcinoma (HNSCC), MTAP-null gallbladder cancer, and MTAP-null mesothelioma. In some embodiments the MTAP-null cancer is lung cancer. In some embodiments, the MTAP-null lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the MTAP-null NSCLC is squamous. In some embodiments the MTAP- null NSCLC is non-squamouns. In some embodiments, the MTAP-null cancer is pancreatic cancer. In some embodiments, the MTAP-null pancreatic cancer is MTAP-null pancreatic adenocarcinoma (e.g., MTAP-null pancreatic ductal adenocarcinoma). In some embodiments, the MTAP-null cancer is esophageal cancer. In some embodiments, the MTAP-null esophageal cancer is esophageal squamous cell carcinoma or esophageal adenocarcinoma.

[0084] In some embodiments, the methods comprise administering Compound A in an amount ranging from 40 mg to 1600 mg. In some cases, Compound A is administered in a divided daily dose, such as two, three, four, five, or six times a day. In some embodiments, the methods comprise administering 40 mg, 120 mg, 240 mg, 480 mg, 960 mg, or 1600 mg of Compound A to the patient once daily. In some embodiments, the methods comprise administering 40 mg, 120 mg, 240 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 960 mg, 1000 mg, 1100 mg, 1200 mg, or 1600 mg of Compound A to the patient once daily. In some embodiments, the methods comprise administering 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 960 mg, 1000 mg, 1100 mg, or 1200 mg of Compound A to the patient once daily. In some embodiments, the methods comprise administering 800 mg, 900 mg, or 1200 mg of Compound A to the patient once daily.

[0085] The efficacy of a given treatment for cancer can be determined by the skilled clinician. However, a treatment is considered "effective treatment," as the term is used herein, if any one or all of the signs or symptoms of e.g., a tumor are altered in a beneficial manner or other clinically accepted symptoms are improved, or even ameliorated, e.g., by at least 10% following treatment with an agent as described herein. Efficacy can also be measured by a failure of an individual to worsen as assessed by hospitalization or need for medical interventions (i.e., progression of the disease is halted). Methods of measuring these indicators are known to those of skill in the art and/or described herein. EMBODIMENTS

1 . A pharmaceutical composition comprising

(1) 1-40 wt% Compound A: (Compound A);

(2) a diluent;

(3) a disintegrant; and

(4) a lubricant, wherein the pharmaceutical composition is suitable for oral administration.

2. The pharmaceutical composition of embodiment 1 , wherein the diluent is selected from lactose, lactose monohydrate, microcrystalline cellulose, and a combination thereof.

3. The pharmaceutical composition of embodiment 1 or 2, wherein the diluent comprises microcrystalline cellulose.

4. The pharmaceutical composition of any one of embodiments 1-3, further comprising a polyol.

5. The pharmaceutical composition of embodiment 4, wherein the polyol comprises mannitol, sorbitol, or a combination thereof.

6. The pharmaceutical composition of embodiment 4 or 5, wherein the polyol comprises mannitol.

7. The pharmaceutical composition of any one of embodiments 4-6, wherein the polyol is present in an amount of 3-25 wt% of the composition.

8. The pharmaceutical composition of embodiment 7, wherein the polyol is present in an amount of 3-15 wt% of the composition.

9. The pharmaceutical composition of embodiment 8, wherein the polyol is present in amount of 8-10 wt% of the composition.

10. The pharmaceutical composition of embodiment 7, wherein the polyol is present in an amount of 15-20 wt% of the composition.

11 . The pharmaceutical composition of any one of embodiments 5-10, wherein the diluent and polyol are present in a weight ratio of 1 :10 to 10:1.

12. The pharmaceutical composition of embodiment 11, wherein the diluent and polyol are present in a weight ratio of 1 :5 to 5:1.

13. The pharmaceutical composition of embodiment 11, wherein the diluent and polyol are present in a weight ratio of 8:1.

14. The pharmaceutical composition of embodiment 11 or 12, wherein the diluent and polyol are present in a weight ratio of 3: 1.

15. The pharmaceutical composition of any one of embodiments 1-14, wherein Compound A is present in an amount of 1-20 wt% of the composition.

16. The pharmaceutical composition of embodiment 15, wherein Compound A is present in an amount of 20 wt% of the composition.

17. The pharmaceutical composition of embodiment 15, wherein Compound A is present in an amount of 1 wt% of the composition.

18. The pharmaceutical composition of any one of embodiments 1-14, wherein Compound A is present in an amount of greater than 20 to 40 wt% of the composition.

19. The pharmaceutical composition of embodiment 18, wherein Compound A is present in an amount of 40 wt% of the composition.

20. The pharmaceutical composition of embodiment 18, wherein Compound A is present in an amount of 37.5 wt% of the composition.

21. The pharmaceutical composition of embodiment 18, wherein Compound A is present in an amount of 32 wt% of the composition.

22. The pharmaceutical composition of embodiment 18, wherein Compound A is present in an amount of 30 wt% of the composition.

23. The pharmaceutical composition of embodiment 18, wherein Compound A is present in an amount of 25 wt% of the composition.

24. The pharmaceutical composition of any one of embodiments 1-23, wherein the disintegrant comprises croscarmellose sodium, alginic acid, bentonite, powdered cellulose, guargalactomannan, carboxymethylcellulose calcium, carmellose sodium, sodium starch glycolate, low-substituted carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose, crospovidone, or a combination thereof.

25. The pharmaceutical composition of embodiment 24, wherein the disintegrant comprises croscarmellose sodium.

26. The pharmaceutical composition of any one of embodiments 1-25, wherein the disintegrant is present in an amount of 1-10 wt% of the composition.

27. The pharmaceutical composition of embodiment 26, wherein the disintegrant is present in an amount of 3 wt% of the composition.

28. The pharmaceutical composition of any one of embodiments 1-27, wherein the lubricant comprises magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, a polyethylene glycol, silicon dioxide, talc, beeswax, hydrogenated vegetable oil, or a combination thereof.

29. The pharmaceutical composition of embodiment 28, wherein the lubricant comprises magnesium stearate.

30. The pharmaceutical composition of any one of embodiments 1-29, wherein the lubricant is intragranular.

31 . The pharmaceutical composition of any one of embodiments 1 -29, wherein the lubricant is extragranular.

32. The pharmaceutical composition of embodiment 30, wherein the lubricant is extragranular and intragranular.

33. The pharmaceutical composition of any one of embodiments 1-32, wherein the lubricant is present in an amount of 0.5-7 wt% of the composition.

34. The pharmaceutical composition of embodiment 33, wherein the lubricant is present in an amount of 1 wt% to 1 .3 wt%.

35. The pharmaceutical composition of any one of embodiments 1-34, wherein the pharmaceutical composition is a tablet.

36. The pharmaceutical composition of any one of embodiments 1-35, as an immediate release composition.

37. The pharmaceutical composition of any one of embodiments 1-36, wherein Compound A is present as a pharmaceutically acceptable salt.

38. The pharmaceutical composition of any one of embodiments 1-36, wherein Compound A is present as a free base.

39. A pharmaceutical composition comprising

(1) 1 wt% Compound A free base;

(2) 71 .25 wt% microcrystalline cellulose;

(3) 23.75 wt% mannitol;

(4) 3 wt% croscarmellose; and

(5) 1 wt% magnesium stearate, in the form of a tablet.

40. A pharmaceutical composition comprising

(1) 20 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 19 wt% mannitol;

(4) 3 wt% croscarmellose; and

(5) 1 wt% magnesium stearate, in the form of a tablet.

41 . A pharmaceutical composition comprising

(1) 25 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 14 wt% mannitol;

(4) 3 wt% croscarmellose; and

(5) 1 wt% magnesium stearate, in the form of a tablet.

42. A pharmaceutical composition comprising

(1) 30 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 8.75 wt% mannitol;

(4) 3 wt% croscarmellose; and

(5) 1.25 wt% magnesium stearate, in the form of a tablet.

43. A pharmaceutical composition comprising

(1) 25 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 13.75 wt% mannitol;

(4) 3 wt% croscarmellose; and

(5) 1.25 wt% magnesium stearate, in the form of a tablet.

44. A pharmaceutical composition comprising

(1) 30 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 8.75 wt% mannitol;

(4) 3 wt% croscarmellose; and

(5) 1.25 wt% magnesium stearate, in the form of a tablet.

45. A pharmaceutical composition comprising

(1) 32 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 7 wt% mannitol;

(4) 3 wt% croscarmellose; and

(5) 1 wt% magnesium stearate, in the form of a tablet. 46. A pharmaceutical composition comprising

(1) 37.5 wt% Compound A free base;

(2) 58.25 wt% microcrystalline cellulose;

(3) 3 wt% croscarmellose; and

(4) 1.25 wt% magnesium stearate, in the form of a tablet.

47. A pharmaceutical composition comprising

(1) 40 wt% Compound A free base;

(2) 55.757 wt% microcrystalline cellulose;

(3) 3 wt% croscarmellose; and

(4) 1.25 wt% magnesium stearate, in the form of a tablet.

48. The pharmaceutical composition of any one of embodiments 1-47, further comprising a coating.

49. The pharmaceutical composition of embodiment 48, wherein the coating is a film-coating.

50. The pharmaceutical composition of any one of embodiments 1-49 free of a reducing sugar (e.g., lactose).

51 . A method of treating a cancer in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of the composition of any one of embodiments 1-50.

52. The method of embodiment 51 , wherein the cancer is selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, pancreatic and bladder cancer.

FURTHER EMBODIMENTS

1 A. A pharmaceutical composition comprising

(1) 1-40 wt% Compound A: (Compound A);

(2) a diluent;

(3) a disintegrant; and

2A. The pharmaceutical composition of embodiment 1 A, wherein the diluent is selected from lactose, lactose monohydrate, microcrystalline cellulose, and a combination thereof.

3A. The pharmaceutical composition of embodiment 1 A or 2A, wherein the diluent comprises microcrystalline cellulose.

4A. The pharmaceutical composition of any one of embodiments 1 A-3A, further comprising a polyol.

5A. The pharmaceutical composition of embodiment 4A, wherein the polyol comprises mannitol, sorbitol, or a combination thereof.

6A. The pharmaceutical composition of embodiment 4A or 5A, wherein the polyol comprises mannitol.

7A. The pharmaceutical composition of any one of embodiments 4A-6A, wherein the polyol is present in an amount of 3-25 wt% of the composition.

8A. The pharmaceutical composition of embodiment 7A, wherein the polyol is present in an amount of 3-15 wt% of the composition.

9A. The pharmaceutical composition of embodiment 8A, wherein the polyol is present in amount of 8-10 wt% of the composition.

10A. The pharmaceutical composition of embodiment 7A, wherein the polyol is present in an amount of 15-20 wt% of the composition.

11 A. The pharmaceutical composition of any one of embodiments 5A-10A, wherein the diluent and polyol are present in a weight ratio of 1 :10 to 10:1.

12A. The pharmaceutical composition of embodiment 11 A, wherein the diluent and polyol are present in a weight ratio of 1 :5 to 5: 1 .

13A. The pharmaceutical composition of embodiment 11 A, wherein the diluent and polyol are present in a weight ratio of 8: 1.

14A. The pharmaceutical composition of embodiment 11 A or 12A, wherein the diluent and polyol are present in a weight ratio of 3:1 .

15A. The pharmaceutical composition of any one of embodiments 1 A-14A, wherein Compound A is present in an amount of 1-20 wt% of the composition.

16A. The pharmaceutical composition of embodiment 15A, wherein Compound A is present in an amount of 20 wt% of the composition.

17A. The pharmaceutical composition of embodiment 15A, wherein Compound A is present in an amount of 1 wt% of the composition.

18A. The pharmaceutical composition of any one of embodiments 1 A-14A, wherein Compound A is present in an amount of greater than 20 to 40 wt% of the composition. 19A. The pharmaceutical composition of embodiment 18A, wherein Compound A is present in an amount of 40 wt% of the composition.

20A. The pharmaceutical composition of embodiment 18, A wherein Compound A is present in an amount of 37.5 wt% of the composition.

21 A. The pharmaceutical composition of embodiment 18A, wherein Compound A is present in an amount of 32 wt% of the composition.

22A. The pharmaceutical composition of embodiment 18A, wherein Compound A is present in an amount of 30 wt% of the composition.

23A. The pharmaceutical composition of embodiment 18A, wherein Compound A is present in an amount of 25 wt% of the composition.

24A. The pharmaceutical composition of any one of embodiments 1 A-23A, wherein the disintegrant comprises croscarmellose sodium, alginic acid, bentonite, powdered cellulose, guargalactomannan, carboxymethylcellulose calcium, carmellosoe sodium, sodium starch glycolate, low-substituted carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose, crospovidone, or a combination thereof.

25A. The pharmaceutical composition of embodiment 24A, wherein the disintegrant comprises croscarmellose sodium.

26A. The pharmaceutical composition of any one of embodiments 1 A-25A, wherein the disintegrant is present in an amount of 1-10 wt% of the composition.

27A. The pharmaceutical composition of embodiment 26A, wherein the disintegrant is present in an amount of 3 wt% of the composition.

28A. The pharmaceutical composition of any one of embodiments 1 A-27A, wherein the lubricant comprises magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, a polyethylene glycol, silicon dioxide, talc, beeswax, hydrogenated vegetable oil, or a combination thereof.

29A. The pharmaceutical composition of embodiment 28A, wherein the lubricant comprises magnesium stearate.

30A. The pharmaceutical composition of any one of embodiments 1 A-29A, wherein the lubricant is intragranular.

31 A. The pharmaceutical composition of any one of embodiments 1 A-29A, wherein the lubricant is extragranular.

32A. The pharmaceutical composition of embodiment 31 A, wherein the lubricant is extragranular and intragranular.

33A. The pharmaceutical composition of any one of embodiments 1 A-32A, wherein the lubricant is present in an amount of 0.5-7 wt% of the composition. 34A. The pharmaceutical composition of embodiment 33A, wherein the lubricant is present in an amount of 1 wt% to 1 .3 wt%.

35A. A pharmaceutical composition comprising

(1) Compound (Compound A), or a pharmaceutically acceptable salt thereof;

(2) a diluent in an amount of 45-75 wt%;

(3) a polyol in an amount of 3-25 wt%;

(4) a disintegrant in an amount of 1-10 wt%; and

(5) a lubricant in an amount of 0.5-7 wt%, wherein the pharmaceutical composition is free of a reducing sugar and is suitable for oral administration.

36A. The pharmaceutical composition of embodiment 35A, comprising 1-40 wt% Compound A, or a pharmaceutically acceptable salt thereof.

37A. The pharmaceutical composition of embodiment 36A, comprising 20-40 wt% Compound A, or a pharmaceutically acceptable salt thereof.

38A. The pharmaceutical composition of embodiment 37 A, comprising 20 wt% of Compound A, or a pharmaceutically acceptable salt thereof.

39A. The pharmaceutical composition of embodiment 37 A, comprising 30 wt% of Compound A, or a pharmaceutically acceptable salt thereof.

40A. The pharmaceutical composition of any one of embodiments 35A-39A, comprising 50-65 wt% diluent.

41 A. The pharmaceutical composition of embodiment 40A, comprising 57 wt% diluent.

42A. The pharmaceutical composition of any one of embodiments 35-41, comprising 5-15 wt% polyol.

43A. The pharmaceutical composition of embodiment 42A, comprising 8.75 wt% polyol.

44A. The pharmaceutical composition of embodiment 42A, comprising 13.75 wt% polyol.

45A. The pharmaceutical composition of any one of embodiment 35A-44A, comprising 2-5 wt% disintegrant.

46A. The pharmaceutical composition of embodiment 45A, comprising 3 wt% disintegrant. 47A. The pharmaceutical composition of any one of embodiments 35A-46A, comprising 1-1 .5 wt% lubricant.

48A. The pharmaceutical composition of embodiment 47 A, comprising 1 .25 wt% lubricant.

49A. The pharmaceutical composition of any one of embodiments 35A-48A, comprising intragranular and extragranular lubricant.

50A. The pharmaceutical composition of any one of embodiments 35A-49A, comprising 0.5 wt% intragranular lubricant and 0.75% extragranular lubricant.

51 A. The pharmaceutical composition of any one of embodiments 35A-50A, wherein the diluent is microcrystalline cellulose.

52A. The pharmaceutical composition of any one of embodiments 35A-51 A, wherein the polyol is mannitol.

53A. The pharmaceutical composition of any one of embodiments 35A-52A, wherein the disintegrant is croscarmellose sodium, alginic acid, bentonite, powdered cellulose, guargalactomannan, carboxymethylcellulose calcium, carmellose sodium, sodium starch glycolate, low-substituted carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose, crospovidone, or a combination thereof.

54A. The pharmaceutical composition of embodiment 53A, wherein the disintegrant is croscarmellose sodium.

55A. The pharmaceutical composition of any one of embodiments 35A-54A, wherein the lubricant is magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, a polyethylene glycol, silicon dioxide, talc, beeswax, hydrogenated vegetable oil, or a combination thereof.

56A. The pharmaceutical composition of embodiment 55A, wherein the lubricant is magnesium stearate.

57A. A pharmaceutical composition comprising:

(1) Compound (Compound A) , or a pharmaceutically acceptable salt thereof, in an amount of 1-40%;

(2) microcrystalline cellulose in an amount of 45-75 wt%;

(3) mannitol in an amount of 3-25 wt%;

(4) croscarmellose in an amount of 1-10 wt%; and

(5) magnesium stearate in an amount of 0.5-7 wt%; wherein the pharmaceutical composition is free of reducing sugars and is suitable for oral administration.

58A. The pharmaceutical composition of any one of embodiments 1 A-57A, wherein the pharmaceutical composition is a tablet.

59A. The pharmaceutical composition of any one of embodiments 1 A-58A, wherein the pharmaceutical composition is an immediate release composition.

60A. The pharmaceutical composition of any one of embodiments 1 A-59A, wherein Compound A is present as a pharmaceutically acceptable salt.

61 A. The pharmaceutical composition of any one of embodiments 1 A-59A, wherein Compound A is present as a free base.

62A. A pharmaceutical composition comprising

(1) 1 wt% Compound A free base;

(2) 71 .25 wt% microcrystalline cellulose;

(3) 23.75 wt% mannitol;

(4) 3 wt% croscarmellose; and

(5) 1 wt% magnesium stearate, wherein the pharmaceutical composition is in the form of a tablet.

63A. A pharmaceutical composition comprising

(1) 20 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 19 wt% mannitol;

(4) 3 wt% croscarmellose; and

64A. A pharmaceutical composition comprising

(1) 25 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 14 wt% mannitol;

(4) 3 wt% croscarmellose; and

65A. A pharmaceutical composition comprising

(1) 25 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 13.75 wt% mannitol; (4) 3 wt% croscarmellose; and

(5) 1.25 wt% magnesium stearate, wherein the pharmaceutical composition is in the form of a tablet.

66A. A pharmaceutical composition comprising

(1) 30 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 8.75 wt% mannitol;

(4) 3 wt% croscarmellose; and

67A. A pharmaceutical composition comprising

(1) 32 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 7 wt% mannitol;

(4) 3 wt% croscarmellose; and

68A. A pharmaceutical composition comprising

(1) 37.5 wt% Compound A free base;

(2) 58.25 wt% microcrystalline cellulose;

(3) 3 wt% croscarmellose; and

(4) 1.25 wt% magnesium stearate, wherein the pharmaceutical composition is in the form of a tablet.

69A. A pharmaceutical composition comprising

(1) 40 wt% Compound A free base;

(2) 55.75 wt% microcrystalline cellulose;

(3) 3 wt% croscarmellose; and

70A. The pharmaceutical composition of any one of embodiments 1 A-69A, further comprising a coating.

71 A. The pharmaceutical composition of embodiment 70A, wherein the coating is a film-coating.

72A. The pharmaceutical composition of any one of embodiments 1 A-34A and 62A-69A free of a reducing sugar.

73A. A method of treating a cancer in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of the composition of any one of embodiments 1 A-72A.

74A. The method of embodiment 73A, wherein the cancer is a MTAP-null cancer.

75A. The method of embodiment 73A or 74A, wherein the cancer is selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, esophageal, gastroesophageal junction (GEJ) cancer, biliary tract cancer (BTC), pancreatic, bladder cancer, glioma, solid tumor, head and neck squamous cell carcinoma (HNSCC), gallbladder cancer, and mesothelioma.

76A. The method of embodiment 75A, wherein the lung cancer is non-small cell lung cancer (NSCLC).

77A. The method of embodiment 76A, wherein the pancreatic cancer is pancreatic adenocarcinoma.

78A. The method of embodiment 77A, wherein the esophageal cancer is esophageal squamous cell carcinoma or esophageal adenocarcinoma.

EXAMPLES

[0086] The following examples further illustrate the disclosed methods of treatment, but of course, should not be construed as in any way limiting its scope.

[0087] The following abbreviations are used in the Examples: Mg stearate refers to magnesium stearate; MCC refers to microcrystalline cellulose; DL refers to drug loading; QTPP refers to quality target product profile; RRT refers to relative retention time; RH refers to relative humidity; PSD refers to particle size distribution; SDS refers to sodium dodecyl sulfate.

General Methods

[0088] Dry Granulation Process: An illustrative dry granulation manufacturing process (e.g., roller compaction) suitable for preparing the disclosed dosage forms is described herein.

[0089] De-lumping (sieving): During manufacturing a suitable metal screen was used to de-lump Compound A, microcrystalline cellulose, mannitol, and croscarmellose sodium. It was observed that the Compound A agglomerates and sticks to the screen even after a microcrystalline wash was performed. A similar observation of screen sticking was made using the Vorti-Siev during lead lot manufacturing for both the 1% drug load and 20% drug load formulations which made the delumping step time consuming. Although sticking to the sieve was observed, the assay values and content uniformity for the lead lot 5 mg, 20 mg and 100 mg tablets all met the QTPP criteria. In some instances, co-milling was used to reduce the time for the de-lumping step.

[0090] Final blending: During tablet compression of the 20% drug load dosage forms (20 mg and 100 mg) sticking of Compound A to the tablet punches and agglomeration of Compound A on the punches was observed. To help mitigate sticking and agglomeration, the number of revolutions for final blending was increased from 24- 60 to 75 to further lubricate Compound A with magnesium stearate. Example 1 : 5 mg, 20 mg, and 100 mg tablets (1% and 20% DL)

[0091] This example demonstrates tablets in accordance with embodiments of the disclosure and illustrative manufacturing processes therefor. Tablets comprising Compound A, mannitol, croscarmellose sodium, magnesium stearate were prepared as shown in Tables 1 and 2.

T able 1 . Composition of 5 mg IR T ablets ^a The quantity used was adjusted to correct for the assay value of the drug substance batch used. MCC and mannitol was adjusted to maintain a 3:1 ratio. ^a The quantity used was adjusted to correct for the assay value of the drug substance batch used. MCC and mannitol was adjusted to maintain a 3:1 ratio.

Manufacturing Process

[0092] Tablets comprising 5 mg (1% DL), 20 mg and 100 mg (20% DL) of Compound A were manufactured via dry granulation using the roller compaction (RC) process described herein and illustrated in Figure 2.

Step 1. The tablet components (Compound A, MCC, mannitol, and croscarmellose sodium) were delumped using a suitable metal screen and blender. The de-lumping step was performed using either preblending and de-lumping or co-milling.

Step 2. The materials from Step 1 were blended with pre-screened magnesium stearate. Step 3. The blend from Step 2 was roller compacted into ribbons, which were milled (e.g., roller compactor equipped with a mill).

Step 4. The milled blend from Step 3 was blended with pre-screened magnesium stearate.

Step 5. The final blend from Step 4 was compressed into tablets on a rotary tablet press. The tablet appearance, weight, thickness, and hardness were tested throughout compression.

[0093] Table 3 shows that the characterization of the pre-blend (prior to roller compaction process) and final blend (after roller compaction process). The roller compaction process increased the bulk/tap density for both the 1% drug load (DL) and 20% DL blends. As a result, the flow of the final blend was improved compared to the pre-blend, especially for the 20% DL. For both the 1% and 20% DL blends, the powder flow was adequate for the tablet compression process on a rotary press running at 20 rotations per minute (RPM). Table 4 shows the content uniformity and acceptable label claims attained for all three tablet strengths. able 4. Content Uniformity and Label Claim for Lead Lot Tablets

[0094] Figure 3 shows the granule particle size distribution (PSD) after the roller compaction process. Except for the 25 mesh and pan, the granule PSD was similar between the 1% DL and 20% DL formulations. The 1% DL granules had more fines compared to the 20% DL granules as shown by the higher percent of granules in the pan. The 20% DL formulation had larger granules formed as demonstrated by the higher percent of granules retained on the 25 mesh sieve.

[0095] Figure 4 shows the impact of tablet hardness on the friability of the three tablet strengths (5 mg, 20 mg, and 100 mg). For all tablet hardnesses evaluated, the QTPP criteria for friability (< 1%) was met for all three tablet strengths. However, the lowest evaluated tablet hardness of 3 kp for the 20 mg strength tablet approached the limit of the QTPP criteria.

[0096] Figures 5A-C show the impact of tablet hardness on the disintegration time for the three tablet strengths. For all tablet hardnesses evaluated, the QTPP criteria for disintegration (< 300 s) was met for all three tablet strengths. However, the highest evaluated tablet hardness of 9 kp for the 20 mg strength tablet approached the limit of the QTPP criteria. Stability of Dosage Forms

[0097] The stability of the dosage forms was evaluated using a bracketing strategy. The 5 mg (1 % drug load) and 100 mg (20% drug load) tablets were packaged in high-density polyethylene (HDPE) bottles (30 count) with child-resistant closures (CRC) containing a foil induction seal liner. Bottles also contained 1 gram of desiccant (2 x 0.5 g sachets). The bottles were stored at the long term (2-8 °C), accelerated (30 °C/65% RH and 40 °C/75%RH), and contingency (-20 °C) storage conditions. Stability results up to one month are summarized in Tables 6 and 7.

[0098] Stability data for the clinical lot showed no significant changes in appearance, assay, total impurities, morpholine, water content and dissolution after 1 month under -20 °C, 24 months at 30 °C/65% RH, and 6 months at 40 °C/75% RH storage conditions (Tables 5 and 6). The stability indicates that tablets comprising Compound A were stable for at least 36 months at the recommended storage condition (2 to 8 °C). All dissolution profiles after 24 month storage were consistent with an immediate release profile.

Physical Stability

[0099] Compound A has a single CF3 moiety. Due to rotational dynamics of the CF3 and the presence of two unique molecular conformers in Free Base From 1, two fluorine resonances are observed by solid-state NMR that are specific to Compound A Free Base Form 1 . The crystalline form of Compound A was selectively monitored by ¹⁹F solid-state NMR spectroscopy excluding out all excipients. The drug substance in the 5 mg and 20 mg lead lot tablets largely conformed to Compound A Free Base Form 1 by ¹⁹F solid-state NMR. However, a third minor ¹⁹F resonance was observed that was unidentified. This third resonance appeared to broaden in only the 5 mg 1% DL DP tablet, but not in the drug substance (uncompressed and compressed) and 20 mg 20% DL tablet. The apparent broadening of the third resonance for the 5 mg tablet also was observed in the final blend used to compress the 5 mg tablet (post-roller compaction step) but did not appear in the pre-blend (pre-roller compaction step). Interestingly, the broadening of the third resonance decreased in tablets that were stored for 2 days under a 40 °°C/75% RH open condition.

Example 2: Film-Coated 200 mg IR Tablet (25% DL)

[0100] This example demonstrates an oral dosage form and its manufacture according in accordance with embodiments of the invention. Immediate-release tablets comprising 200 mg Compound A (25% DL) and a filmcoating were prepared as shown in Table 7. Compared to the 20 mg and 100 mg tablets (20% DL), the 200 mg tablets were characterized by an increase in compound A concentration, in increased change in tablet size relative to the 100 mg tablets, increased levels of extra-granular magnesium stearate (0.75%) to improve manufacturing; and decreased levels of mannitol (13.75%) to accommodate increased amount of drug.

Manufacturing Process

[0101] The 200 mg film-coated tablets were prepared via a dry granulation process using a roller compaction similar to the process of Example 1. The process is summarized herein and illustrated in Figure 6.

Step 1. Compound A and pre-screened (using suitable metal screen) microcrystalline cellulose, mannitol and croscarmellose sodium were blended using a suitable blender.

Step 2. The blend from Step 1 was de-lumped using a conical mill.

Step 3. The mixture from Step 2 was blended using a suitable blender.

Step 4. The blend from Step 3 was lubricated by adding pre-screened (using suitable metal screen) magnesium stearate to the blender in Step 3.

Step 5. The blend was compacted into ribbons using roller compaction and subsequently milled into granular blend using a roller compactor equipped with an oscillating mill. Step 6. The granular blend was lubricated with pre-screened magnesium stearate (using suitable metal screen) using a suitable blender.

Step 7. The final blend from Step 6 was compressed into tablets on a rotary tablet press. The tablet appearance, weight, thickness and hardness were tested throughout compression.

Step 8. The tablets from Step 7 were film-coated in a pan coater using a suspension of Opadry® II in purified water. The tablet appearance and weight were tested throughout compression.

Step 9. The film-coated tablets were packaged into HDPE bottles and/or blister cards.

Stability of Dosage Form

[0102] The stability of the 200 mg IR film-coated tablets was evaluated as described herein. The tablets were packaged into 50 count 325 cc HDPE bottles and polypropylene child resistant closure with foil induction seals without desiccant. The bottled tablets were placed on stability at 30 °C/65 %RH (long term storage) and 40 °C/75 %RH (accelerated storage).

[0103] The release (t=0) data and 1 -month stability data under 40 °C/ 75% RH storage conditions demonstrated no significant changes in description, assay, organic impurities, water content and dissolution after one month under 40 °C/75 %RH storage conditions. See Figure 7.

[0104] The stability of 200 mg tablets also were conducted under at 5°C, 30 °C/65 % RH (Recommended Storage Conditions, RSC), 30 °C/75% RH and 40 °C/75% RH (Accelerated Storage Conditions, ASC) using UHPLC for assay and impurity analysis and Karl Fischer analysis for water content. The tablets were packaged in 325 cc HDPE bottles without desiccant to maximize headspace interactions to represent a worst case scenario. The results indicated that tablets are stable for up to 4 months at 5 °C, 12 months at 30 °C/65% RH (RSC), and 6 months at 40 °C/75% RH.

Tablet Hardness

[0105] The impact of tablet hardness on dissolution was evaluated on tablets comprising, inter alia, 200 mg Compound A and 1 .25% magnesium stearate as a lubricant. The dissolution profiles were determined for tablets having three hardness levels (17.5 kp, 24 kp, and 29.5 kp) under the following conditions: 50 mM phosphate buffer, pH 6.8, 0.3% SDS.

[0106] As shown in Figure 8A, a dissolution slowdown was observed during the first 10 minutes at 30 kp and 24 kp compared to the tablets having a hardness of 17.5 kp.

[0107] Development Stability. Release (t=0) data and 18-month stability data under 30 °C/65% RH and 30 °C/75% RH storage conditions, 6-month stability data under 40 °C/75% RH storage conditions are summarized in Figure 8B. As clinical packaging was not finalized at the start of the development batch stability study, the 50- count 325 cc HDPE bottle configuration was chosen to simulate a worst-case scenario. All release and stability results met specification criterion. Stability data show no significant changes in description, assay, organic impurities, water content and dissolution after 6-month under 40 °C/75% RH storage conditions and up to 18 months at long term storage condition of 30 °C/65% RH and 30 °C/75% RH.

[0108] Clinical Stability. Release (t=0) data, 12-month stability data under 30 °C/65% RH and 30 °C/75% RH storage conditions and 6-month stability data under 40 °C/75% RH storage conditions of the batch bottled with the clinical configuration (CPTFV) are summarized in Figure 8C. Release (t=0) data, 9-month stability data under 30 °C/65% RH and 30 °C/75% RH storage conditions and 6-month stability data under 40 °C/75% RH storage conditions of the batch bottled with the commercial configuration (CSHGD) are summarized in Figure 8D and for the blister batch (CSHGC) are summarized in Figure 8E.

[0109] All release and stability results met specification criteria. Stability data show no significant changes in description, assay, organic impurities, water content and dissolution after 6-month under 40 °C/75% RH storage conditions and up to 12-month at long term storage condition of 30 °C/65% RH and 30 °C/75% RH for clinical packaging bottle, for 9-month for commercial packaging bottle and for 9-month for blister packaging (Figures 8B- E respectively).

Example 3: Uncoated 160, 200, 240, and 320 mg IR Tablet (32% DL)

[0110] This example demonstrates tablets in accordance with embodiments of the invention. Tablets having a 32% drug loading of Compound A were prepared has shown in Table 8. able 8. 32% DL tablets of Compound A

[0111] The tablets were prepared using a dry granulation roller compaction similar to the processes of Examples 1 and 2.

[0112] Various physical properties were measured for the initial and final blends, including bulk and tap densities, Carr's index, Hausner ratio, particle size distribution, and dissolution profile. A comparison of the results to tablets having 20% and/or 25% DL is shown in Tables 9-11 and Figures 9-13.

Bulk and Tapped Density

Table 9. Physical Properties of Initial and Final Blends

Particle Size Distribution (PSD)

[0113] The PSD of 32% DL tablets were compared to 25% DL tablets. The results are shown in Tables 10 and 11 and Figures 11 and 12. able 10. Comparison of PSD (32% and 25% DL) (Initial Blend) using sieve analysis % DL data reported are average and standard deviation of n=3

Dissolution Profile

[0114] The dissolution profile of 32% DL tablets were compared to 25% DL tablets. As shown in Figure 13, the dissolution profiles were found to be similar.

Example 4: Film-Coated IR Tablets (30%) and Uncoated IR Tablets (37.5%, and 40% DL)

[0115] This example demonstrates tablets (30%, 37.5%, and 40% DL) in accordance with embodiments of the invention comprising Compound A, a diluent, a disintegrant, and a lubricant. The 30% DL tablet further comprised a polyol (i.e., mannitol) and a film-coating.

[0116] Tablets having the components listed in Table 12 were prepared using a similar roller compaction as previously described herein.

Table 12. Tablets Having 30%, 37.5%, and 40% Drug Loading

Example 5 - Pharmacokinetics

[0117] The pharmacokinetic data for Compound A from 120 subjects on cycle 1 day 1 and 66 subjects on cycle 1 day 15 is shown in Figure 14. The mean observed plasma concentrations after QD and BID dosing for cycle 1 day 1 and cycle 1 day 15 are provided in Figures 14 and 15, respectively. The noncompartmental analysis PK parameters for cycle 1 day 1 and cycle 1 day 15 are presented in Tables 13 and 14.

[0118] Overall, the cycle 1 day 15 preliminary PK data for doses 40 to 1200 mg suggest: Cmax and AUCtau increased in an approximate dose-proportional manner, median t_max ranged from 1 to 2 hours, minimal accumulation resulted from multiple PO QD dosing for 15 days, and the estimated t¹ >,z ranged from approximately 7 to 16 hours. ^an=50; ^bn=9

AUC₂4h = area under the plasma concentration-time curve from time 0 to 24 hours postdose; BID= twice daily dosing; C_max = maximum observed drug concentration; C_trOugh = predose plasma concentration. CV = coefficient of variation; NR = not reported; PK = pharmacokinetic; QD= once daily dosing; ti/2,z = terminal half-life.

PK parameters estimated using nominal time/dose and presented as geometric mean (mean, %CV), %CV is not present where N < 3. t_max reported as median (min-max). Values are report to 3 significant figures except for %CV, which is reported to the nearest integer.

Table 14. Noncompartmental PK Parameter Estimates After QD Administration in Cycle 1 Day 15 ^an=2; ^bn=13; ^cn=10; ^dn=8; ^en=12; ^fn=15; gn=4; 'n=31 ; in=22

AUC₂₄h = area under the plasma concentration-time curve from time 0 to 24 hours postdose; C_max = maximum observed drug concentration; C_trOugh = predose plasma concentration. CV = coefficient of variation; NR = not reported; PK = pharmacokinetic; ti/2,_z = terminal half-life. PK parameters estimated using nominal time/dose and presented as geometric mean (mean, %CV), %CV is not present where N < 3. t_max reported as median (min- max). Values are report to 3 significant figures except for %CV, which is reported to the nearest integer.

Example 6: Pharmacokinetic Comparison of 100 mg and 200 mg Dosage Forms

[0119] This example demonstrates a pharmacokinetic comparison of 100 mg and 200 mg dosage forms.

[0120] Compound A 100 mg and 200 mg tablet strength pharmacokinetics were compared. The cycle 1 day 1 (C1D1) and cycle 1 day 15 (C1D15) Compound A dose-normalized maximum plasma concentration (C_max) and dose-normalized area under the plasma concentration time curve from time zero to 24 hours postdose (AUCo-24h) were compared with summary statistics and preliminary geometric least squares mean ratio calculations. Data is shown in Figures 16-19.

[0121] The C1D1 dose-normalized C_max geometric mean was 4.48 (48% CV) and 4.12 (40%) for 100 mg and 200 mg tablets, respectively. The C1D15 dose-normalized Cmax geometric mean was 5.80 (41%) and 5.68 (42%) for 100 mg and 200 mg tablets, respectively. The C1D1 dose-normalized AUCo-24h geometric mean was 55.0 (53%) and 55.9 (42%) for 100 mg and 200 mg tablets, respectively. The C1D15 dose-normalized AUCo-24h geometric mean was 67.0 (46% CV) and 79.8 (45%) for 100 mg and 200 mg tablets, respectively. The geometric least squares mean ratio for C_max on cycle 1 day 1 and cycle 1 day 15 were 0.919 (90% Cl: 0.789, 1.07) and 0.978 (0.782, 1 .22), respectively. The geometric least squares mean ratio for AUCo-24h on cycle 1 day 1 and cycle 1 day 15 were 1.02 (0.870, 1.19) and 1.19 (0.953, 1.49), respectively. Overall, the preliminary data suggest the C_max and AUC₀-24h are comparable between 100 mg and 200 mg tablet strength.

[0122] Observed C_max for cycle 1 day 1 and day 15 showed no difference in exposure between 100 mg and 200 mg tablets. Observed AUG for cycle 1 day 1 showed no difference in exposure between 100 mg and 200 mg tablets. Observed AUG for cycle 1 day 15 showed minimal increase in exposure of 200 mg tablet compared to 100 mg tablet, but within acceptable range (0.8 - 1 .25). These data demonstrate that there is no difference in exposure across doses for 100 mg tablets vs. 200 mg tablets.

Table 15. PK Data Summary (100 mg vs. 200 mg)

Table 16. Geometric Least Squares Mean Ration Result

Example 7: Film-Coated 300 mg IR Tablet (30% DL)

[0123] This example demonstrates an oral dosage form and its manufacture according in accordance with embodiments of the invention. Immediate-release tablets comprising 300 mg Compound A (30% DL) and a filmcoating were prepared as shown in Table 17.

[0124] The 300 mg film-coated tablets were prepared using a process based on the procedure described in Example 2.

Table 17. Composition of 300 mg IR film-coated tablets Stability of Dosage Forms

[0125] The stability of the 300 mg IR film-coated tablets was evaluated as described in Example 2.

[0126] The release (t=0) data and 1 and 3 months stability data under 40 °C/ 75% RH storage conditions demonstrated no significant changes in description, assay, organic impurities, water content and dissolution after one month under 40 °C/75 % RH storage conditions. See Figure 20.

[0127] Compound A 300 mg film-coated tablets were stable for 3 months at 30 °C/65% RH (RSC), 30 °C/75 % RH and 40 °C/75% RH (ASC) conditions.

[0128] Using the open dish stability data Compound A 300 mg film-coated tablets were predicted to have a shelf-life stability of greater than 3 years using the ASAP Prime software for the Compound A 300 mg tablets.

Example 8 - Diluent Comparison

[0129] This example demonstrates the benefits of mannitol as a diluent in the disclosed pharmaceutical compositions. The three granulates shown in Table 18comprising 3:1 MCC:diluent were prepared using dry granulation of the components shown.

Table 18.

[0130] The granulate compositions were evaluated for stability under the conditions listed in Tables 19 and 20, which show the amount of Compound A (Table 19) and the total impurities (Table 20) after the evaluation.

Table 19. Amount of Compound A

Table 20. Total Impurities

[0131] As shown in Tables 19 and 20, Composition 2 comprising Compound A and mannitol exhibited the best stability during the evaluations showing the least amount of degradation and impurity formation.

Example 9 - Maillard Reaction Assessment

[0132] Compound A was formulated in various composition formats, as shown in Table 21, then subjected to room temperature or stress conditions of 70°C/75% RH. Compound A with lactose in a solution was used as a control to confirm the LCMS signal for the expected adduct. Under both room temperature and stress conditions, the formulations containing lactose showed formation of the Compound A lactose adduct:

Exact Mass: 769.25 CF₃ > _as evidenced by an adduct peak in the UV-Vis spectroscopy chromatogram, and a peak at m/z 769.25 in a mass spectrometry spectrum. These data indicate the likelihood of Compound A undergoing a Maiilard reaction in athe presence of reducing sugars, demonstrating the stability advantage of formulations disclosed herein.

Table 21

[0133] The foregoing examples are merely illustrative of embodiments of the disclosed processes described herein and are not intended to limit the disclosed methods. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the disclosure which is defined in the appended claims.

Claims

What is Claimed:

1 . A pharmaceutical composition comprising

(1) 1-40 wt% Compound A: (Compound A);

(2) a diluent;

(3) a disintegrant; and

2. The pharmaceutical composition of claim 1 , wherein the diluent is selected from lactose, lactose monohydrate, microcrystalline cellulose, and a combination thereof.

3. The pharmaceutical composition of claim 1 or 2, wherein the diluent comprises microcrystalline cellulose.

4. The pharmaceutical composition of any one of claims 1-3, further comprising a polyol.

5. The pharmaceutical composition of claim 4, wherein the polyol comprises mannitol, sorbitol, or a combination thereof.

6. The pharmaceutical composition of claim 4 or 5, wherein the polyol comprises mannitol.

7. The pharmaceutical composition of any one of claims 4-6, wherein the polyol is present in an amount of 3-25 wt% of the composition.

8. The pharmaceutical composition of claim 7, wherein the polyol is present in an amount of 3-15 wt% of the composition.

9. The pharmaceutical composition of claim 8, wherein the polyol is present in amount of 8-10 wt% of the composition.

10. The pharmaceutical composition of claim 7, wherein the polyol is present in an amount of 15- 20 wt% of the composition.

11. The pharmaceutical composition of any one of claims 5-10, wherein the diluent and polyol are present in a weight ratio of 1:10 to 10:1.

12. The pharmaceutical composition of claim 11, wherein the diluent and polyol are present in a weight ratio of 1 :5 to 5:1.

13. The pharmaceutical composition of claim 11, wherein the diluent and polyol are present in a weight ratio of 8:1.

14. The pharmaceutical composition of claim 11 or 12, wherein the diluent and polyol are present in a weight ratio of 3:1.

15. The pharmaceutical composition of any one of claims 1-14, wherein Compound A is present in an amount of 1-20 wt% of the composition.

16. The pharmaceutical composition of claim 15, wherein Compound A is present in an amount of 20 wt% of the composition.

17. The pharmaceutical composition of claim 15, wherein Compound A is present in an amount of 1 wt% of the composition.

18. The pharmaceutical composition of any one of claims 1-14, wherein Compound A is present in an amount of greater than 20 to 40 wt% of the composition.

19. The pharmaceutical composition of claim 18, wherein Compound A is present in an amount of 40 wt% of the composition.

20. The pharmaceutical composition of claim 18, wherein Compound A is present in an amount of 37.5 wt% of the composition.

21. The pharmaceutical composition of claim 18, wherein Compound A is present in an amount of 32 wt% of the composition.

23. The pharmaceutical composition of claim 18, wherein Compound A is present in an amount of 25 wt% of the composition.

24. The pharmaceutical composition of any one of claims 1-23, wherein the disintegrant comprises croscarmellose sodium, alginic acid, bentonite, powdered cellulose, guargalactomannan, carboxymethylcellulose calcium, carmellosoe sodium, sodium starch glycolate, low-substituted carboxymethylcellulose sodium, low- substituted hydroxypropyl cellulose, crospovidone, or a combination thereof.

25. The pharmaceutical composition of claim 24, wherein the disintegrant comprises croscarmellose sodium.

26. The pharmaceutical composition of any one of claims 1-25, wherein the disintegrant is present in an amount of 1-10 wt% of the composition.

27. The pharmaceutical composition of claim 26, wherein the disintegrant is present in an amount of 3 wt% of the composition.

28. The pharmaceutical composition of any one of claims 1-27, wherein the lubricant comprises magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, a polyethylene glycol, silicon dioxide, talc, beeswax, hydrogenated vegetable oil, or a combination thereof.

29. The pharmaceutical composition of claim 28, wherein the lubricant comprises magnesium stearate.

30. The pharmaceutical composition of any one of claims 1-29, wherein the lubricant is intragranular.

31. The pharmaceutical composition of any one of claims 1-29, wherein the lubricant is extragranular.

32. The pharmaceutical composition of claim 31 , wherein the lubricant is extragranular and intragranular.

33. The pharmaceutical composition of any one of claims 1-32, wherein the lubricant is present in an amount of 0.5-7 wt% of the composition.

34. The pharmaceutical composition of claim 33, wherein the lubricant is present in an amount of 1 wt% to 1 .3 wt%.

35. A pharmaceutical composition comprising

(1) Compound (Compound A), or a pharmaceutically acceptable salt thereof;

(2) a diluent in an amount of 45-75 wt%;

(3) a polyol in an amount of 3-25 wt%;

(4) a disintegrant in an amount of 1-10 wt%; and

36. The pharmaceutical composition of claim 35, comprising 1-40 wt% Compound A, or a pharmaceutically acceptable salt thereof.

37. The pharmaceutical composition of claim 36, comprising 20-40 wt% Compound A, or a pharmaceutically acceptable salt thereof.

38. The pharmaceutical composition of claim 37, comprising 20 wt% of Compound A, or a pharmaceutically acceptable salt thereof.

39. The pharmaceutical composition of claim 37, comprising 30 wt% of Compound A, or a pharmaceutically acceptable salt thereof.

40. The pharmaceutical composition of any one of claims 35-39, comprising 50-65 wt% diluent.

41 . The pharmaceutical composition of claim 40, comprising 57 wt% diluent.

42. The pharmaceutical composition of any one of claims 35-41, comprising 5-15 wt% polyol.

43. The pharmaceutical composition of claim 42, comprising 8.75 wt% polyol.

44. The pharmaceutical composition of claim 42, comprising 13.75 wt% polyol.

45. The pharmaceutical composition of any one of claim 35-44, comprising 2-5 wt% disintegrant.

46. The pharmaceutical composition of claim 45, comprising 3 wt% disintegrant.

47. The pharmaceutical composition of any one of claims 35-46, comprising 1-1.5 wt% lubricant.

48. The pharmaceutical composition of claim 47, comprising 1 .25 wt% lubricant.

49. The pharmaceutical composition of any one of claims 35-48, comprising intragranular and extragranular lubricant.

50. The pharmaceutical composition of any one of claims 35-49, comprising 0.5 wt% intragranular lubricant and 0.75% extragranular lubricant.

51 . The pharmaceutical composition of any one of claims 35-50, wherein the diluent is microcrystalline cellulose.

52. The pharmaceutical composition of any one of claims 35-51 , wherein the polyol is mannitol.

53. The pharmaceutical composition of any one of claims 35-52, wherein the disintegrant is croscarmellose sodium, alginic acid, bentonite, powdered cellulose, guargalactomannan, carboxymethylcellulose calcium, carmellose sodium, sodium starch glycolate, low-substituted carboxymethylcellulose sodium, low- substituted hydroxypropyl cellulose, crospovidone, or a combination thereof.

54. The pharmaceutical composition of claim 53, wherein the disintegrant is croscarmellose sodium.

55. The pharmaceutical composition of any one of claims 35-54, wherein the lubricant is magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, a polyethylene glycol, silicon dioxide, talc, beeswax, hydrogenated vegetable oil, or a combination thereof.

56. The pharmaceutical composition of claim 55, wherein the lubricant is magnesium stearate.

57. A pharmaceutical composition comprising: (1) Compound (Compound A) , or a pharmaceutically acceptable salt thereof, in an amount of 1-40%;

(2) microcrystalline cellulose in an amount of 45-75 wt%;

(3) mannitol in an amount of 3-25 wt%;

(4) croscarmellose in an amount of 1-10 wt%; and

58. The pharmaceutical composition of any one of claims 1-57, wherein the pharmaceutical composition is a tablet.

59. The pharmaceutical composition of any one of claims 1-58, wherein the pharmaceutical composition is an immediate release composition.

60. The pharmaceutical composition of any one of claims 1-59, wherein Compound A is present as a pharmaceutically acceptable salt.

61. The pharmaceutical composition of any one of claims 1-59, wherein Compound A is present as a free base.

62. A pharmaceutical composition comprising

(1) 1 wt% Compound A free base;

(2) 71 .25 wt% microcrystalline cellulose;

(3) 23.75 wt% mannitol;

(4) 3 wt% croscarmellose; and

63. A pharmaceutical composition comprising

(1) 20 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 19 wt% mannitol;

(4) 3 wt% croscarmellose; and

64. A pharmaceutical composition comprising (1) 25 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 14 wt% mannitol;

(4) 3 wt% croscarmellose; and

65. A pharmaceutical composition comprising

(1) 25 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 13.75 wt% mannitol;

(4) 3 wt% croscarmellose; and

66. A pharmaceutical composition comprising

(1) 30 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 8.75 wt% mannitol;

(4) 3 wt% croscarmellose; and

67. A pharmaceutical composition comprising

(1) 32 wt% Compound A free base;

(2) 57 wt% microcrystalline cellulose;

(3) 7 wt% mannitol;

(4) 3 wt% croscarmellose; and

68. A pharmaceutical composition comprising

(1) 37.5 wt% Compound A free base;

(2) 58.25 wt% microcrystalline cellulose;

(3) 3 wt% croscarmellose; and

69. A pharmaceutical composition comprising

(1) 40 wt% Compound A free base;

(2) 55.75 wt% microcrystalline cellulose; (3) 3 wt% croscarmellose; and

70. The pharmaceutical composition of any one of claims 1-69, further comprising a coating.

71. The pharmaceutical composition of claim 70, wherein the coating is a film-coating.

72. The pharmaceutical composition of any one of claims 1-34 and 62-69 free of a reducing sugar.

73. A method of treating a cancer in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of the composition of any one of claims 1-72.

74. The method of claim 73, wherein the cancer is a MTAP-null cancer.

75. The method of claim 73 or 74, wherein the cancer is selected from ovarian, lung, lymphoid, glioblastoma, colon, melanoma, gastric, esophageal, gastroesophageal junction (GEJ) cancer, biliary tract cancer (BTC), pancreatic, bladder cancer, glioma, solid tumor, head and neck squamous cell carcinoma (HNSCC), gallbladder cancer, and mesothelioma.

76. The method of claim 75, wherein the lung cancer is non-small cell lung cancer (NSCLC).

77. The method of claim 76, wherein the pancreatic cancer is pancreatic adenocarcinoma.

78. The method of claim 77, wherein the esophageal cancer is esophageal squamous cell carcinoma or esophageal adenocarcinoma.