Film coated solid dosage forms for management of dysgeusia

Abstract

The present invention relates to a film coated solid dosage form comprising a core and a film coat, wherein the core comprises a KAT6 inhibitor and at least one pharmaceutically acceptable excipient, and further wherein the film coated solid dosage form reduces frequency or severity of dysgeusia in a subject being treated for cancer with the KAT6 inhibitor.

Description

[0001] PC073228A

[0002] - 1 -

[0003] FILM COATED SOLID DOSAGE FORMS FOR MANAGEMENT OF DYSGEUSIA Background of the Invention

[0004] KAT6A and KAT6B are histone lysine acetyltransferases that acetylate H3K23, and their

[0005] 5 enzymatic functions are involved in fundamental cellular processes, including gene transcription, cellular senescence, tissue development, and maintenance of normal hematopoietic stem cells (Huang, F., et al., Regulation of KAT6 Acetyltransferases and Their Roles in Cell Cycle Progression, Stem Cell Maintenance, and Human Disease. Mol Cell Biol. 2016, 36(14): 1900-7). KAT6A has been implicated in promoting tumorigenesis in a variety of

[0006] 10 cancers with KAT6A amplifications and over-expression observed in breast cancer, prostate cancer, ovarian cancer, uterine cervix cancer, lung adenocarcinoma, colon & rectal adenocarcinomas and medulloblastoma (Yu, L., et al., Identification of MYST3 as a novel epigenetic activator of ERa frequently amplified in breast cancer. Oncogene 2017, 36(20) :2910- 8; Tsherniak, A., et al., Defining a cancer dependency map. Ce / / 2017; 170(3)(Jul):564-576.e16;

[0007] 15 Zack, T. I., et al., Pan-cancer patterns of somatic copy number alteration. Nat Genet. 2013, 45:1134-1140; and Northcott, P.A., et al., Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat Genet. 2009, 41(4):465-72). KAT6A chromosomal translocations have been observed in AML (See Huang F, et al.,; Borrow, J., et al., The translocation t(8; 16)(p11 ;p13) of acute myeloid leukaemia fuses a putative

[0008] 20 acetyltransferase to the CREB-binding protein. Nat. Genet. 1996; 14(1):33-41; and Shima, H., et al., Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ- TIF2 fusion. Int J Hematol. 2014; 99(1 ):21 -31 ). KAT6 inhibition has therapeutic potential in multiple disease settings, including breast, prostate and NSCLC.

[0009] 2-Methoxy- / V-{4-methoxy-6-[(1 / 7-pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl}benzene-1-

[0010] 25 sulfonamide, also known by its synonym / V-(6-((1 H-pyrazol-1-yl)methyl)-4- methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide (referred to herein as “Compound A” or “COMPD A”), is a potent and selective catalytic inhibitor of KAT6 histone acetyltransferases, KAT6A and KAT6B. Compound A is currently in a phase 3 clinical trial in combination with fulvestrant for the treatment of cancer, and has the following structure: Preparation of Compound A, including an anhydrous crystalline Form 1 of Compound A free acid, is described in International Publication No. WO 2020 / 254946 and in U.S. Patent No. 11 ,492,346. Combination therapies including Compound A are described in International Publication No. WO 2022 / 013369. The contents of each of the foregoing documents are incorporated herein by reference in their entireties.

[0011] The safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of Compound A monotherapy and fulvestrant combination in heavily pretreated estrogen receptor positive (ER+) human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (mBC) was recently reported (Mukohara, T., et al., Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial. Nature Medicine 2024, 30:2242- 2250). Dysgeusia, an altered or impaired sense of taste, was identified as a treatment-related adverse event (TRAE) in the phase 1 trial of Compound A. 83.2% of clinical trial participants experienced dysgeusia of any grade. No grade 3-4 dysgeusia was reported.

[0012] In the dose escalation part of the phase 1 study (part 1), 29 patients (mBC, n = 12; castration-resistant prostate cancer (CRPC), n = 15; non-small cell lung cancer (NSCLC, n = 2)) were enrolled in part 1A and received Compound A monotherapy once a day (QD) at five dose levels (1 mg (n = 8), 2 mg (n = 4), 5 mg (n = 4), 8 mg (n = 7) and 15 mg (n = 6)). Dysgeusia (6.9%) was a reported TRAE leading to dose reduction in more than one patient.

[0013] In the monotherapy group of the phase 1 study (part 2A), 35 patients with ER+HER2- mBC received Compound A as monotherapy at 5 mg QD. The most frequent all-causality TEAEs of any grade were dysgeusia (30 (85.7%)), neutropenia (24 (68.6%)), anemia (18 (51.4%)) and leukopenia (16 (45.7%)). The most frequent TRAEs of any grade were dysgeusia (30 / 35 (85.7%); Grade 1 26 (74.3%), Grade 2 4 (11.4%)), neutropenia (24 (68.6%)), anemia and leukopenia (16 (45.7%) each). No events of dysgeusia led to dose reductions or treatment discontinuation.

[0014] In the combination group of the phase 1 study (parts 1B and 2B, 43 patients with ER+HER2- mBC received Compound A at 5 mg QD, in combination with fulvestrant 500 mg. The most frequent all-causality TEAEs of any grade were dysgeusia (37 (86.0%)), neutropenia (28 (65.1%)), fatigue (24 (55.8%)) and anemia (19 (44.2%)). The most frequent TRAEs of any grade were dysgeusia (36 (83.7%); Grade 1 (25 (58.1%), Grade 2 (11 (25.6%)), neutropenia (28 (65.1%)), anemia and fatigue (18 (41.9%) each). No events of dysgeusia led to dose modifications or treatment discontinuation.

[0015] At the recommended dose for expansion (RDE dose) of 5 mg QD (n = 78), the most frequent TRAE was dysgeusia (84.6%), with the majority as Grade 1 (65.4%). No treatment discontinuation was reported as a result of dysgeusia. Dysgeusia was reported as a frequent TEAE in taxane- or platinum-based chemotherapy ranging from 42% to 93%. Dysgeusia has been reported as a frequent TEAE in immunotherapy T cell engagers, other epigenetic inhibitors and HDAC inhibitors. Preliminary preclinical research has shown that epigenetic changes of gene clusters in the taste bud might alter taste. However, the exact mechanism of action of dysgeusia related to KAT6 inhibition remains unknown. Patients have reported symptom improvement or resolution after prolonged treatment interruption or discontinuation, suggesting a reversible process.

[0016] Accordingly, it would be advantageous to reduce the frequency and / or severity of dysgeusia in patients receiving a KAT6 inhibitor, such as Compound A, for treatment of cancer. It would be advantageous to provide a dosage form that reduces the frequency of dysgeusia in patients receiving a KAT6 inhibitor, such as Compound A, for treatment of cancer. It would be advantageous to provide a dosage form that reduces the frequency of dysgeusia in patients receiving a KAT6 inhibitor, such as Compound A, for treatment of cancer. These, and other advantages of the present invention, are apparent from the description below.

[0017] Summary of the Invention

[0018] The present invention provides a film coated solid dosage form comprising a KAT6 inhibitor that may be useful for reducing frequency or severity of dysgeusia in a subject being treated for cancer with the KAT6 inhibitor. The present invention also provides methods of using the film coated solid dosage form. This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used in isolation as an aid in determining the scope of the claimed subject matter.

[0019] According to Embodiment 1 of the invention, there is provided a film coated solid dosage form comprising a core and a film coat, wherein the core comprises a KAT6 inhibitor and at least one pharmaceutically acceptable excipient

[0020] According to Embodiment 2 of the invention, there is provided a film coated solid dosage form comprising a core and a film coat, wherein the core comprises: a) a KAT6 inhibitor; b) at least one filler; c) a disintegrant; and d) a lubricant.

[0021] Described below are embodiments of the invention, where for convenience Embodiment 1 (E1) and Embodiment 2 (E2) are identical to the embodiments provided above. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0022] Brief Description of the Drawings

[0023] FIGURE 1 shows the flow diagram of the manufacturing process of Compound A film- coated tablets as 0.5 mg dosage forms.

[0024] FIGURE 2 shows the flow diagram of the manufacturing process of Compound A film- coated tablets as 5 mg dosage forms.

[0025] Detailed Description of the Invention

[0026] The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0027] E1 A film coated solid dosage form, as defined above.

[0028] E2 A film coated solid dosage form, as defined above.

[0029] E3 The film coated solid dosage form of embodiment 1, wherein the core further comprises: a) at least one filler; b) a disintegrant; and c) a lubricant.

[0030] E4 The film coated solid dosage form of any one of embodiments 1 to 3, wherein the KAT6 inhibitor is 2-methoxy- / V-{4-methoxy-6-[(1 / 7-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene- 1 -sulfonamide, or a pharmaceutically acceptable salt thereof.

[0031] E5 The film coated solid dosage form of any one of embodiments 1 to 3, wherein the KAT6 inhibitor is Form 1 of 2-methoxy- / V-{4-methoxy-6-[(1 / 7-pyrazol-1-yl)methyl]-1,2-benzoxazol-3- yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof.

[0032] E6 The film coated solid dosage form of any one of embodiments 1 to 3, wherein the KAT6 inhibitor is Form 5 of 2-methoxy- / V-{4-methoxy-6-[(1 / 7-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3- yl}benzene-1 -sulfonamide, or a pharmaceutically acceptable salt thereof. E7 The film coated solid dosage form any one of embodiments 1 to 6, wherein the KAT6 inhibitor is about 0.5 percent by weight to about 5 percent by weight of the core.

[0033] E8 The film coated solid dosage form of any one of embodiments 1 to 6, wherein the KAT6 inhibitor is about 0.5 percent by weight; about 1 .0 percent by weight; about 2.0 percent by weight; about 3.0 percent by weight; about 4.0 percent by weight; or about 5 percent by weight of the core.

[0034] E9 The film coated solid dosage form of any one of embodiments 1 to 6, wherein the KAT6 inhibitor is about 0.5 percent by weight or about 5 percent by weight of the core.

[0035] E10 The film coated solid dosage form of any one of embodiments 1 to 6, wherein the KAT6 inhibitor is about 0.5 percent by weight of the core.

[0036] E11 The film coated solid dosage form of any one of embodiments 1 to 6, wherein the KAT6 inhibitor is about 5 percent by weight of the core.

[0037] E12 The film coated solid dosage form of any one of embodiments 1 to 6, wherein the dosage form comprises 2-methoxy- / V-{4-methoxy-6-[(1 / 7-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3- yl}benzene-1 -sulfonamide, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5 mg; in an amount of about 1 mg; in an amount of about 2 mg; in an amount about 3 mg; in an amount about 4 mg; or in an amount of about 5 mg.

[0038] E13 The film coated solid dosage form of embodiment 2 or 3, wherein the filler is about 90 percent by weight to about 94.5 percent by weight of the core.

[0039] E14 The film coated solid dosage form of embodiment 2 or 3, wherein the disintegrant is about 4.0 percent by weight of the core.

[0040] E15 The film coated solid dosage form of embodiment 2 or 3, wherein the lubricant is about 1.0 percent by weight of the core.

[0041] E16 The film coated solid dosage form of embodiment 2 or 3, wherein the film coat is about 3.0 percent by weight of the core. E17 The film coated solid dosage form of embodiment 2, 3 or 13, wherein the filler is microcrystalline cellulose silicified and lactose monohydrate.

[0042] E18 The film coated solid dosage form of embodiment 2, 3 or 14, wherein the disintegrant is crospovidone type B.

[0043] E19 The film coated solid dosage form of embodiment 2, 3, or 15, wherein the lubricant is magnesium stearate.

[0044] E20 The film coated solid dosage form of any one of embodiments 1 to 19, wherein the film coated solid dosage form reduces frequency or severity of dysgeusia in a subject being treated for cancer with the KAT6 inhibitor.

[0045] E21 The film coated solid dosage form of embodiment 20, wherein the frequency of dysgeusia is reduced as compared to the frequency of dysgeusia in a non-film coated tablet.

[0046] E22 The film coated solid dosage form of embodiment 21 , wherein the reduction of frequency is less than about 5%; less than about 10%; less than about 15%; less than about 20%; less than about 25%; less than about 30%; less than about 40%; or less than about 50%.

[0047] E23 The film coated solid dosage form of embodiment 20, wherein the severity of dysgeusia is reduced is reduced as compared to the severity of dysgeusia in a non-film coated tablet.

[0048] E24 The film coated solid dosage form of embodiment 23, wherein the severity is reduced from Grade 2 to Grade 1.

[0049] E25 A method of reducing frequency or severity of dysgeusia in a subject being treated for cancer with a KAT6 inhibitor comprising administering to the subject a film-coated solid dosage form according to any one of embodiments 1 to 24.

[0050] E26 The film coated solid dosage form of any one of embodiments 1 to 24 or the method of embodiment 25, wherein the film coated solid dosage form is a tablet.

[0051] Each of the embodiments described herein may be combined with any other embodiment(s) described herein not inconsistent with the embodiment(s) with which it is combined. Definitions

[0052] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0053] The invention described herein suitably may be practiced in the absence of any element(s) not specifically disclosed herein.

[0054] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "a" substituent includes one or more substituents.

[0055] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of a KAT6 inhibitor) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg means 5 mg ± 10%, i.e. , it may vary between 4.5 mg and 5.5 mg.

[0056] As used herein, a “KAT6 inhibitor” includes an inhibitor of KAT6A, an inhibitor of KAT6B, and an inhibitor of KAT6A and KAT6B. KAT6 inhibitors are disclosed in International Publication No. WO2019 / 043139A1; International Publication No WO2019 / 243491 A1; International Publication No. W02020 / 002587; and International Application Serial No. PCT / IB2020 / 055667. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0057] As used herein, a “compound” is an active pharmaceutical ingredient (API), such as a KAT6 inhibitor.

[0058] The abbreviation “w / w”” means the amount by weight of a substance dissolved in a known amount (by weight) of liquid. The terms “percent by weight” and “weight percent” and the abbreviations “% w / w”, “percent w / w”, “wt%” are interchangeable and express as a percentage the number of grams of one ingredient in 100 g of solution. As a mathematical expression, the weight percent or the percent of solute in a solution is equal to the weight of solute / weight of solvents 00.

[0059] The term “pharmaceutically acceptable” means that a compound and any salt thereof, or excipient, or composition is suitable for oral administration to a subject or patient.

[0060] A "pharmaceutical composition" refers to a mixture of one or more compounds, or a pharmaceutically acceptable salt thereof, as an active ingredient, and at least one pharmaceutically acceptable excipient.

[0061] "Excipient" as used herein describes any ingredient other than an active pharmaceutical ingredient or compound. The choice of excipient will to a large extent depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0062] As used herein, "excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, carriers, diluents and the like that are physiologically compatible. Examples of excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof, and may include isotonic agents, for example, sugar, sodium chloride, or polyalcohol such as mannitol, or sorbitol in the composition. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may, if desired, contain additional excipients such as flavorings, binders / binding agents, lubricating agents, disintegrants, sweetening or flavoring agents, coloring matters or dyes, and the like. For example, for oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in hard filled gelatin capsules. Non-limiting examples of excipients, therefore, also include lactose or milk sugar and high molecular weight polyethylene glycols.

[0063] Examples of excipients also include pharmaceutically acceptable substances such as wetting agents or minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the compound.

[0064] Salts

[0065] The term “pharmaceutically acceptable salt”, as used herein, unless otherwise indicated, refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. Salts encompassed within the term “pharmaceutically acceptable salts” refer to the compounds which are generally prepared by reacting the free base or free acid with a suitable organic or inorganic acid, or a suitable organic or inorganic base, respectively, to provide a salt of the compound that is suitable for administration to a subject or patient.

[0066] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphathalenedisulfonic acid and xinofoate salts.

[0067] Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0068] Pharmaceutical Compositions

[0069] The invention is directed to a film coated solid dosage form comprising a KAT6 inhibitor, such as Compound A, and at least one excipient. The film coated solid dosage form comprising Compound A is administered to a subject being treated for cancer to reduce the frequency or severity of dysgeusia in the subject.

[0070] Acceptable excipients are nontoxic to subjects at the dosages and concentrations employed, and may comprise one or more of the following: 1) buffers such as phosphate, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol; 5) alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than about 10 residues) polypeptides; 7) proteins such as serum albumin, gelatin, or immunoglobulins; 8) hydrophilic polymers such as polyvinylpyrrolidone; 9) amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; 11) chelating agents such as EDTA; 12) sugars such as sucrose, mannitol, trehalose or sorbitol; 13) salt-forming counter-ions such as sodium, metal complexes (e.g., Zn-protein complexes), or 14) non-ionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamers or polyethylene glycol (PEG).

[0071] A “solid dosage form” of the present invention is a pharmaceutically acceptable solid dosage form that is safe for oral administration to humans, where all excipients in the dosage form are pharmaceutically acceptable for use in oral formulations, in other words safe for human ingestion. In frequent embodiments, the solid dosage form is a tablet.

[0072] A “film coated solid dosage form” of the present invention is a solid dosage form that has been film coated. The film coated solid dosage form of the present invention includes a core that is film coated. A film coat is a thin layer of polymer that is sprayed onto solid dosage forms, such as tablets, capsules, pellets, or granules. A film coat generally includes a polymer, plasticizer, and pigment. One of ordinary skill in the art would recognize a suitable film coating system, such as Opadry® (Colorcon), which combines polymer, plasticizer, and pigment in a dry concentrate to create a coating on tablets. A suitable film coating for the film coated solid dosage form” of the present invention is Opadry® II PINK (85F140030).

[0073] Film coated solid dosage forms of the invention may include at least one filler, a disintegrant and a lubricant. Preferably, the film coated solid dosage form of the invention includes two fillers.

[0074] The term “filler” used herein may refer to an excipient that provides bulk and volume to a tablet or to an excipient that is a binder or binding agent. Filler may refer to excipients that both provide bulk and volume to a tablet and serve as a binding agent. Binding agents include microcrystalline cellulose (MCC) and silicified microcrystalline cellulose, also known as microcrystalline cellulose silicified (SMCC). MCC and SMCC are excipients which may improve binding capability, e.g., adhesion between particles, in tablet formulations. SMCC also shows improved resistance to the degrading effects of magnesium stearate compared with regular MCC. In a tablet formulation, lactose monohydrate primarily acts as a filler to provide bulk and volume to the tablet, essentially making up the majority of the tablet's weight while also contributing to its flowability and compressibility, allowing for proper tablet formation. It may also function as a binding agent.

[0075] The term “disintegrant” or “disintegrating agent” used herein may refer to an excipient A disintegrant is an additive that promotes disintegration, which is the breakage of a tablet into small fragments when in contact with a liquid medium. In doing so, the surface area available for dissolution is increased and drug dissolution is accelerated. Disintegrants the tablet disintegrate quickly to release the medication effectively. Disintegrants include starch, and super disintegrants, such as croscarmellose sodium, crospovidone, and sodium starch glycolate. Crospovidone Type B is an example of a "superdisintegrant" in a tablet formulation, meaning its primary role is to rapidly break down the tablet upon contact with water, allowing for quick dissolution and absorption of the active drug ingredient within the body.

[0076] In a tablet formulation, magnesium stearate acts as a lubricant, primarily reducing friction between powder particles during compression, preventing them from sticking to the tablet press tooling ("punch sticking"), and ensuring smooth ejection of the formed tablets from the machine, thereby maintaining the integrity of the dosage form and facilitating efficient manufacturing.

[0077] Administration and Dosina

[0078] The film coated dosage form comprising Compound A of the present invention is administered to a subject being treated for cancer to reduce the frequency or severity of dysgeusia in the subject.

[0079] "Treat" or "treating" a cancer and / or a cancer-associated disease as used herein means to administer a monotherapy or combination therapy according to the present invention to a subject, participant or patient having a cancer, or diagnosed with a cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" or “therapy,” as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reducing the proliferation of (or destroying) neoplastic or cancerous cell; inhibiting metastasis or neoplastic cells; shrinking or decreasing the size of tumor; remission of the cancer; decreasing symptoms resulting from the cancer; increasing the quality of life of those suffering from the cancer; decreasing the dose of other medications required to treat the cancer; delaying the progression the cancer; curing the cancer; overcoming one or more resistance mechanisms of the cancer; and I or prolonging survival of patients the cancer. Positive therapeutic effects in cancer may be measured in a number of ways (see, for example, W. A. Weber, J. Nucl. Med. 50:1S-10S (2009)).

[0080] As used herein, the terms, “subject”, “participant” and “patient,” are used interchangeably, to a human. Human subjects may be of any gender. In an embodiment, a human is an adult human.

[0081] An “amount” for use and for treating a subject refers to an amount that provides, in single or multiple doses, alone, or in combination with one or more other agents, a detectable response of any duration of time (transient, medium or long term), a desired outcome in or an objective or subjective benefit to a subject of any measurable or detectable degree or for any duration of time (e.g., for hours, days, months, years, in remission or cured). Such amounts typically are effective to ameliorate a disease, or one, multiple or all adverse effects I symptoms, consequences or complications of the disease, to a measurable extent, although reducing or inhibiting a progression or worsening of the disease, or providing stability (i.e., not worsening) state of the disease, is considered a satisfactory outcome. The term “therapeutically effective amount” also means an amount of an agent, alone, or in combination with one or more other agents, effective for producing a desired therapeutic effect upon administration to a subject, for example, to stem the growth, or result in the shrinkage, of a cancerous tumor. In reference to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing the size of the tumor, (2) inhibiting (that is, slowing to some extent, preferably stopping) tumor metastasis emergence, (3) inhibiting to some extent (that is, slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, and / or (4) relieving to some extent (or, preferably, eliminating) one or more signs or symptoms associated with the cancer. Therapeutic or pharmacological effectiveness of the doses and administration regimens may also be characterized as the ability to induce, enhance, maintain or prolong disease control and / or overall survival in patients with these specific tumors, which may be measured as prolongation of the time before disease progression.

[0082] As used herein, “ameliorate” refers to any reduction in the extent, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular disease. “Symptom” refers to any subjective evidence of disease or of a subject's condition.

[0083] Embodiments of the present invention provide a dose, dosage and dosing regimen comprising administering to a subject an amount, or a therapeutically effective amount, of Compound A or a pharmaceutically acceptable salt thereof. The amount, or the therapeutically effective amount, may be a daily dose in the range of from about 0.1 mg to about 15 mg. In another embodiment, a daily dose is from about 1 mg to about 15 mg, a daily dose is from about 1 mg to about 10 mg, from about 1 mg to about 8 mg, a daily dose is from about 0.1 mg to about 8 mg, from about 1 mg to about 5 mg, from about 0.1 mg to about 5 mg, or from about 0.5 mg to about 5 mg. In another embodiment, a daily dose is from about 0.1 mg to less than 1 mg or from about 0.1 mg to about 0.75 mg. In preferred embodiments, the daily dose is about 0.5 mg, 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg or about 8 mg. In preferred embodiments, the daily dose is about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg. In preferred embodiments, the daily dose is 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg or 8 mg. In preferred embodiments, the daily dose is 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg.

[0084] Therapeutic Methods and Uses

[0085] KAT6 inhibitors, such as Compound A, act as Lysine Acetyl Transferase (KAT) inhibitors of the MYST family and are useful in the treatment of abnormal cell growth, such as cancer. In particular, Compound A acts as an inhibitor of KAT6 and / or KAT7. The film-coated solid dosage form of the present invention may be used in the treatment of abnormal cell growth, such as cancer.

[0086] “Abnormal cell growth” or “cancer” as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; (3) any tumors that proliferate by receptor tyrosine kinases; (4) any tumors that proliferate by aberrant serine / threonine kinase activation; (5) benign and malignant cells of other proliferative diseases in which aberrant serine / threonine kinase activation occurs; (6) any tumors that proliferate by aberrant signaling, metabolic, epigenetic and transcriptional mechanism; and (7) benign and malignant cells of other proliferative diseases in which aberrant signaling, metabolic, epigenetic and transcriptional mechanism occur.

[0087] For convenience, certain well-known abbreviations, may be used herein, including: hormone receptor positive (HR+), estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-), non-small cell lung cancer (NSCLC) and castration resistant prostate cancer (CRPC).

[0088] Additional embodiments relate to methods of reducing frequency or severity of dysgeusia in a subject in need thereof comprising administering to the subject an amount of Compound A in a film coated dosage form that is effective in treating cancer.

[0089] In another embodiment, the cancer is selected from the group consisting of lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, hepatic carcinoma, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, hematology malignancy, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, and pituitary adenoma, or a combination of two or more of the foregoing cancers.

[0090] In another embodiment, the cancer is breast, lung, colon, brain, prostate, stomach, pancreatic, ovarian, melanoma, endocrine, uterine, testicular, or bladder.

[0091] In another embodiment, the cancer is breast, lung, prostate, pancreatic, or ovarian.

[0092] In another embodiment, the cancer is breast cancer.

[0093] In another embodiment, the cancer is metastatic breast cancer.

[0094] In another embodiment, the breast cancer is HR+ breast cancer.

[0095] In another embodiment, the breast cancer is ER+ breast cancer.

[0096] In another embodiment, the breast cancer is HR+ HER2- breast cancer.

[0097] In another embodiment, the breast cancer is ER+ HER2- breast cancer. In another embodiment, the breast cancer is locally advanced or metastatic HR+ HER2- breast cancer.

[0098] In another embodiment, the breast cancer is locally advanced or metastatic ER+ HER2- breast cancer.

[0099] In another embodiment, the breast cancer is HR+ HER2- metastatic breast cancer.

[0100] In another embodiment, the breast cancer is ER+ HER2- metastatic breast cancer.

[0101] In another embodiment, the lung cancer is non-small cell lung cancer.

[0102] In another embodiment, the lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0103] In another embodiment, the prostate cancer is castration resistant prostate cancer.

[0104] In another embodiment, the prostate cancer is locally advanced or metastatic castration resistant prostate cancer.

[0105] Additional embodiments relate to methods of reducing frequency or severity of dysgeusia in a subject in need thereof comprising administering to the subject an amount of Compound A in a film coated dosage form that is effective in treating a hematologic tumor.

[0106] In another embodiment, the hematologic tumor is leukemia, lymphoma or multiple myeloma.

[0107] In another embodiment, the hematologic tumor is leukemia or lymphoma.

[0108] Another embodiment relates to methods of treating cancer in a patient with locally advanced or metastatic HR+HER2- breast cancer, locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC whose disease progressed on or is intolerant to standard therapy.

[0109] Another embodiment relates to methods of treating cancer in a patient with locally advanced or metastatic HR+HER2- breast cancer, locally advanced or metastatic ER+HER2- breast cancer, CRPC, or NSCLC whose disease progressed on or is intolerant to standard therapy.

[0110] Another embodiment relates to methods of treating cancer in a patient with locally advanced or metastatic 2L+ HR+HER2- breast cancer or locally advanced or metastatic 2L+ ER+HER2 breast cancer who has progressed after at least 1 prior line of treatment with an endocrine therapy and CDK4 / 6 inhibitor. In an embodiment thereof, the patient is administered a combination of a film coated solid dosage form of Compound A and fulvestrant.

[0111] Another embodiment relates to methods of treating cancer in a patient with locally advanced or metastatic 2L+ HR+HER2- breast cancer or locally advanced or metastatic 2L+ ER+HER2 breast cancer who has progressed after at least 1 prior line of treatment with an endocrine therapy and CDK4 / 6 inhibitor. In an embodiment thereof, the patient is administered a combination of film coated solid dosage form of Compound A with letrozole and palbociclib. Another embodiment relates to methods of treating cancer in a patient with advanced or metastatic 2L+ HR+HER2- breast cancer, ER+HER2- breast cancer who has progressed after at least 1 prior line of CDK4 / 6 inhibitor and 1 line of endocrine therapy. In an embodiment thereof, the patient is administered a film coated solid dosage form of Compound A.

[0112] Another embodiment relates to methods of treating cancer in a patient with advanced or metastatic 2-4L fulvestrant-naive HR+HER2- breast cancer, ER+HER2- breast cancer whose disease has progressed after 1 line of a CDK4 / 6 inhibitor and 1 line of endocrine therapy and who must not have received more than 3 lines of systemic therapies in advanced or metastatic setting. In an embodiment thereof, the patient is administered a film coated solid dosage form of Compound A and fulvestrant.

[0113] Further embodiments relate to methods of reducing frequency or severity of dysgeusia in a subject in need thereof comprising administering to the subject an amount of Compound A in a film coated dosage form that is effective in treating cancer in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, antihormones, and anti-androgens.

[0114] Yet more embodiments relate to a method of reducing frequency or severity of dysgeusia in a subject being treated for a disorder associated with angiogenesis, comprising administering to the subject an amount of Compound A in a film coated solid dosage form that is effective in treating said disorder in combination with one or more anti-tumor agents listed above. Such disorders include cancerous tumors such as melanoma; ocular disorders such as age-related macular degeneration, presumed ocular histoplasmosis syndrome, and retinal neovascularization from proliferative diabetic retinopathy; rheumatoid arthritis; bone loss disorders such as osteoporosis, Paget’s disease, humoral hypercalcemia of malignancy, hypercalcemia from tumors metastatic to bone, and osteoporosis induced by glucocorticoid treatment; coronary restenosis; and certain microbial infections including those associated with microbial pathogens selected from adenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp., Bordetella pertussis, and group A Streptococcus.

[0115] Some embodiments relate to a method of reducing frequency or severity of dysgeusia in a subject in need thereof comprising administering to the subject an amount of Compound A in a film coated solid dosage form, in combination with an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors (e.g., inhibiting the means by which regulatory molecules that govern the fundamental processes of cell growth, differentiation, and survival communicated within the cell), and antiproliferative agents, which amounts are together effective in treating said abnormal cell growth. Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2) inhibitors, MMP- 9 (matrix-metalloprotienase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors, may be used in conjunction with Compound A in a film coated solid dosage form in the methods described herein.

[0116] Tyrosine kinase inhibitors may also be combined with Compound A in a film coated solid dosage form.

[0117] VEGF inhibitors, for example, sutent and axitinib, may also be combined with Compound A in a film coated solid dosage form.

[0118] ErbB2 receptor inhibitors may be administered in combination with Compound A in a film coated solid dosage form. Various other compounds, such as styrene derivatives, have also been shown to possess tyrosine kinase inhibitory properties, and some of tyrosine kinase inhibitors have been identified as erbB2 receptor inhibitors.

[0119] Epidermal growth factor receptor (EGFR) inhibitors may be administered in combination with Compound A in a film coated solid dosage form.

[0120] PI3K inhibitors, such as PI3K alpha or PI3K beta inhibitors, may be administered in combination with Compound A in a film coated solid dosage form.

[0121] Mammalian target of rapamycin (mTOR) inhibitors may be administered in combination with Compound A in a film coated solid dosage form. c-Met inhibitors may be administered in combination with Compound A in a film coated solid dosage form.

[0122] CDK inhibitors may be administered in combination with Compound A in a film coated solid dosage form.

[0123] MEK inhibitors may be administered in combination with Compound A in a film coated solid dosage form.

[0124] PARP inhibitors may be administered in combination with Compound A in a film coated solid dosage form.

[0125] JAK inhibitors may be administered in combination with Compound A in a film coated solid dosage form.

[0126] An antagonist of a Programmed Death 1 protein (PD-1) may be administered in combination with Compound A in a film coated solid dosage form.

[0127] An antagonist of Programmed Death-Ligand 1 (PD-L1) may be administered in combination with Compound A in a film coated solid dosage form.

[0128] Other antiproliferative agents that may be used with Compound A in a film coated solid dosage form include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr. Compound A in a film coated solid dosage form may also be used with other agents useful in treating abnormal cell growth or cancer, including, but not limited to, agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase.

[0129] Compound A in a film coated solid dosage form may be applied as a sole therapy or may involve one or more other anti-tumor substances, for example those selected from, for example, mitotic inhibitors, alkylating agents, anti-metabolites, growth factor inhibitors, cell cycle inhibitors, intercalating antibiotics, enzymes, and anti-hormones.

[0130] Compound A in a film coated solid dosage form may be used alone or in combination with one or more of a variety of anti-cancer agents or supportive care agents. For example, Compound A in a film coated solid dosage form may be used with cytotoxic agents. Some embodiments also contemplate the use of Compound A in a film coated solid dosage form with hormonal therapy. Further, some embodiments provide Compound A in a film coated solid dosage form alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.

[0131] Compound A in a film coated solid dosage form may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and / or biological response modifiers. In this regard, the following is a non-limiting list of examples of secondary agents that may be used with Compound A in a film coated solid dosage form.

[0132] Kits

[0133] Another aspect of the invention provides kits comprising a film coated solid dosage form comprising Compound A, such as a tabley. A kit may include, in addition to a film coated solid dosage form of Compound A, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes a film coated solid dosage form of Compound A and a diagnostic agent.

[0134] In yet another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains a first film coated solid dosage form comprising Compound A in quantities sufficient to carry out the methods of the invention. In another embodiment, the kit comprises a film coated solid dosage form of Compound A in quantities sufficient to carry out the methods of the invention and a container for the dosage.

[0135] Examples

[0136] Example 1 : Preparation of Compound A 0.5 ma and 5 ma Film-Coated Tablets

[0137] The composition of the film-coated tablets as 0.5 mg and 5 mg dosage forms of Form 1 of Compound A, including the compositions of the tablet and the film-coat are set forth below in Tables 1-3, respectively. Compound A tablets at strengths of 0.5 mg and 5 mg were conventional tablet formulations using well-precedented pharmacopoeial excipients in typical concentrations. The 0.5 mg strength was manufactured by a conventional direct compression process using a 0.5% active blend compressed into an oval shaped tablet of 100 mg fill weight. The 5 mg strength was manufactured using a conventional dry granulation process from a 5% active blend compressed into a round tablet of 100 mg fill weight. The 0.5 mg and 5 mg tablets were film coated.

[0138] The flow diagram for the manufacturing process for the film-coated tablets as 0.5 mg and 5 mg dosage forms of Compound A is provided in FIGURE 1 and FIGURE 2, respectively, and set forth in the numbered steps below.

[0139] Process Description for 0.5 mg Film-Coated Tablets

[0140] 1. Blend approximately one third of the microcrystalline cellulose silicified.

[0141] 2. Add Compound A to the blended microcrystalline cellulose silicified, followed by the lactose monohydrate and crospovidone Type B and blend.

[0142] 3. Mill one third of microcrystalline cellulose silicified.

[0143] 4. Mill the blend from Step 2 and pass the remaining one third of the microcrystalline cellulose silicified through the mill. Blend the resulting milled powders.

[0144] 5. Add the magnesium stearate and blend.

[0145] 6. Compress using a suitable tablet press.

[0146] 7. Film coat using a suitable film coater.

[0147] Process Description for 5 mg Film-Coated Tablets

[0148] 1. Blend approximately half of the microcrystalline cellulose silicified.

[0149] 2. In a second blender mix the lactose monohydrate and crosovidone type B. This step is applicable to batch size of or greater than 5 Kg.

[0150] 3. Add Compound A to the blended microcrystalline cellulose silicified, followed by the lactose monohydrate and crospovidone type B blend and mix. 4. Mill the blend from Step 3 and pass the remaining amount of microcrystalline cellulose silicified through the mill. Blend the resultant milled powders.

[0151] 5. Add the intra-granular magnesium stearate and blend.

[0152] 6. Roller compact and mill, then blend.

[0153] 7. Add the extra-granular magnesium stearate and blend.

[0154] 8. Compress using a suitable tablet press.

[0155] 9. Film coat using a suitable film coater.

[0156] Table 1. Composition of Compound A Film-Coated Tablet 0.5 mg a. Based on a theoretical potency of 1.0. Batch quantity may be adjusted based on the actual potency of the Compound A. a. Quantity of Microcrystalline Cellulose Silicified may be adjusted to account for potency changes of the Compound A ensure consistent tablet weight. c. Film coating suspension prepared to 18 % w / w solids content. d. Processing aid. Essentially removed during processing. e. Based on tablet core weight plus 3 % w / w gain of dye(s). Table 2. Composition of Compound A Film-Coated Tablet 5 mg a. Based on a theoretical potency of 1.0. Batch quantity may be adjusted based on the actual potency of the Compound A. b. Quantity of Microcrystalline Cellulose Silicified may be adjusted to account for potency changes of the Compound A ensure consistent tablet weight. c. Film coating suspension prepared to 18 % w / w solids content. d. Processing aid. Essentially removed during processing. e. Based on tablet core weight plus 3 % w / w gain of dye(s). Table 3. Composition of the Film Coating System

[0157] One of ordinary skill in pharmaceutical manufacturing would understand that the values provided in Tables 1-2 are theoretical formulations for a single unit (the QQ formula (Qua Que)). When a pharmaceutical product is scaled up to multiple units, the quantity for each component is multiplied by the number of units required. Due to differences in balance accuracy and tolerances, in calculating back from the weights used to manufacture a batch, there is a potential for slight differences in the QQ values. Additionally, during manufacturing, certain limits are allowed on the accuracy of filling the capsules and the weight of the capsule shell; however, as a percentage of the weight measured, these values will be the same as the QQ formula. This is recognized within the industry and with the regulators.

[0158] The equipment and parameters to be used in the manufacture of the clinical lots may vary depending on the batch size. The quality of Compound A will be verified by in process tests and conformance to acceptance criteria.

[0159] Example 2: Preparation of 2-methoxy-A / -(4-methoxy-6-K1 H-pyrazol-1-yl)methyll-1,2- benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5 - Requires No Seed

[0160] The synthesis of 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3- yl}benzene-1 -sulfonamide Form 1 was described in International Publication No. WO 2020 / 254946 and in U.S. Patent No. 11 ,492,346.

[0161] 2-Methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1- sulfonamide, Form 1 (about 6.0 g) and 120 mL acetonitrile were added to a suitable round bottom vessel, such as a EasyMax® vessel with overhead stirrer and agitated at 460 revolutions per minute (RPM) to give a white slurry. The mixture was heated to 78 °C over 10 minutes and held at this temperature until a yellow solution was seen. Solution was cooled to 70°C at 0.5 K / min and held for 1 hour, during which spontaneous nucleation was observed. The slurry was cooled to -10°C at 0.1 K / min and held at this temperature overnight. A 5 mL aliquot of slurry was filtered through a Buchner funnel, washed with 2 x 0.5 mL acetonitrile and put into a vacuum oven at 50°C to dry. The result was dried solid, 2-methoxy- / V-{4-methoxy-6-[(1H- pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, Form 5.

[0162] Example 3: Preparation of 2-methoxy-A / -(4-methoxy-6-K1H-pyrazol-1-yl)methyll-1,2- benzoxazol-3-yl)benzene-1 -sulfonamide, Form 5 (anhydrous free form) - Seeded Recrystalization

[0163] 2-Methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1- sulfonamide, Form 1 (89.70 g), 540 mL toluene and 1260 mL acetonitrile were added to a suitable vessel, such as a 2 L Reactor-Ready™ vessel equipped with overhead stirrer. The vessel was agitated at 370 RPM and a white slurry formed. The slurry was heated rapidly to 74°C and held until dissolution was observed. The resulting solution was cooled to 65°C at 0.2 K / min and seeded with 898 mg 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2- benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5 to give a thin slurry. The mixture was held at 65°C for 1 hour, cooled to 0°C at 0.1 K / min and held at this temperature overnight. The resulting solid material was 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]-1 ,2- benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5.

[0164] Example 4: Physical Characterization of 2-methoxy-A / -(4-methoxy-6-r(1H-pyrazol-1- yl)methyll-1,2-benzoxazol-3-yl}benzene-1 -sulfonamide. Form 5

[0165] Powder X-Ray Diffraction

[0166] PXRD was determined for 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)methyl]-1,2- benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5.

[0167] Table 4. PXRD peak list with relative intensities for 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1- yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5. PXRD peaks are in degrees 20 each ± 0.20.

[0168] 13C solid-state NMR was determined for 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]- 1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5.

[0169] Table 5.13C solid-state NMR peak list for 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1-yl)methyl]- 1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5. Each peak is ± 0.2 ppm.

[0170] Raman spectra was collected for 2-methoxy- / V-{4-methoxy-6-[(1H-pyrazol-1-yl)rnethyl]-1 ,2- benzoxazol-3-yl}benzene-1 -sulfonamide, Form 5.

[0171] Table 6. Raman peak list with relative intensities for 2-methoxy- / V-{4-methoxy-6-[(1 H-pyrazol-1- yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1-sulfonamide, Form 5.

[0172] Each wavenumber is ± 0.2 cm-1.

[0173] Example 5: Phase 1 Compound A Clinical Trial: Film Coated Tablet Substudy Overview

[0174] Compound A is being investigated in an ongoing open-label, multi-center, multiple-dose Phase 1 study in adult patients to evaluate safety, tolerability, PK, and PD of Compound A in locally advanced or metastatic selected solid tumors (ER+HER2- breast cancer, CRPC, or NSCLC) and early signs of clinical efficacy of Compound A as a single in combination with an antiestrogen; and in combination with a CDK4 inhibitor and an antiestrogen. The patients in this trial are intolerant of or resistant to standard therapy. (NCT04606446) Between 16 November 2020 and 30 September 2023 (study ongoing), 108 patients were screened and 107 patients were enrolled and received at least one dose of Compound A in a non-filmed coated tablet dosage form. The safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of Compound A monotherapy and fulvestrant combination in heavily pretreated estrogen receptor positive (ER+) human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (mBC) was recently reported. (Mukohara, T., et al., Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial. Nature Medicine 2024, 30:2242-2250.) Patients in the phase 1 study reported in Nature Medicine received Compound A non-film coated tablets.

[0175] Study Design

[0176] In Part 2B of the Phase 1 study, patients with advanced or metastatic 2-4L fulvestrant- naive ER+HER2- breast cancer whose disease progressed after 1 line of a CDK4 / 6 inhibitor and 1 line of endocrine therapy and who have not received more than 3 lines of systemic therapies in advanced or metastatic setting are evaluated in a dose-expansion combination cohort using the Compound A 5 mg film coated tablet of Example 1 in combination with fulvestrant.

[0177] The Compound A 5 mg film coated tablet of Example 1 is orally administered QD in combination with fulvestrant.

[0178] Participants are to swallow the Compound A 5 mg film coated tablet whole and not to manipulate or chew the study intervention prior to swallowing. The Compound A 5 mg film coated tablets are administered QD by mouth for all cohorts on a continuous basis. The once daily dose is administered in 24 ± 3 hour intervals ( / .e., no less than 21 hours and no more than 27 hours apart). All cycles are 28 days in length.

[0179] Fulvestrant 500 mg is administered intramuscularly into the buttocks slowly (1-2 minutes per injection) as two 5 mL injections, one in each buttock, and once monthly thereafter according to product labeling and in compliance with its local prescribing information.

[0180] Treatment continues until progression of disease, uncontrollable toxicity, a decision by the patient or investigator to discontinue treatment or the study is terminated.

[0181] Outcome Measure

[0182] Safety and Tolerability as assessed by adverse event monitoring for participants enrolled in the Dose Expansion Arms

[0183] Adverse Events Adverse events (AEs) of the patients dosed with a film-coated tablet of Compound A in the Phase 1 clinical trial are documented and recorded at each patient visit using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. AEs will be characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study therapy. AEs of the patients dosed with a film- coated tablet of Compound A in the Phase 1 clinical trial will be coded according to the medical dictionary for regulatory activities (MedDRA), version 24.1. The severity of adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

[0184] It will be apparent to those skilled in the art that various modifications and variations may be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

[0185] All references cited herein, including patents, patent applications, papers, textbooks, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated by reference in their entireties. In the event that one or more of the incorporated literature and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls.

Claims

CLAIMSWe claim:

1. A film coated solid dosage form comprising a core and a film coat, wherein the core comprises a KAT6 inhibitor and at least one pharmaceutically acceptable excipient.

2. The film coated solid dosage form of claim 1 , wherein the core further comprises: a) at least one filler; b) a disintegrant; and c) a lubricant.

3. A film coated solid dosage form comprising a core and a film coat, wherein the core comprises: a) a KAT6 inhibitor; b) at least one filler; c) a disintegrant; and d) a lubricant.

4. The film coated solid dosage form of any one of claims 1 to 3, wherein the KAT6 inhibitor is 2-methoxy- / V-{4-methoxy-6-[(1 / 7-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3-yl}benzene-1 -sulfonamide, or a pharmaceutically acceptable salt thereof.

5. The film coated solid dosage form of any one of claims 1 to 3, wherein the KAT6 inhibitor is Form 1 of 2-methoxy- / V-{4-methoxy-6-[(1 / 7-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3- yl}benzene-1 -sulfonamide, or a pharmaceutically acceptable salt thereof.

6. The film coated solid dosage form of any one of claims 1 to 3, wherein the KAT6 inhibitor is Form 5 of 2-methoxy- / V-{4-methoxy-6-[(1 / 7-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3- yl}benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof.

7. The film coated solid dosage form any one of claims 1 to 6, wherein the KAT6 inhibitor is about 0.5 percent by weight to about 5 percent by weight of the core.

8. The film coated solid dosage form of any one of claims 1 to 6, wherein the KAT6 inhibitor is about 0.5 percent by weight; about 1 .0 percent by weight; about 2.0 percent by weight; about 3.0 percent by weight; about 4.0 percent by weight; or about 5 percent by weight of the core.

9. The film coated solid dosage form of any one of claims 1 to 6, wherein the dosage form comprises 2-methoxy- / V-{4-methoxy-6-[(1 / 7-pyrazol-1-yl)methyl]-1 ,2-benzoxazol-3- yl}benzene-1 -sulfonamide, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5 mg; in an amount of about 1 mg; in an amount of about 2 mg; in an amount about 3 mg; in an amount about 4 mg; or in an amount of about 5 mg.

10. The film coated solid dosage form of claim 2 or 3, wherein the filler is about 90 percent by weight to about 94.5 percent by weight of the core.

11. The film coated solid dosage form of claim 2 or 3, wherein the disintegrant is about 4.0 percent by weight of the core.

12. The film coated solid dosage form of claim 2 or 3, wherein the lubricant is about 1.0 percent by weight of the core.

13. The film coated solid dosage form of claim 2 or 3, wherein the film coat is about 3.0 percent by weight of the core.

14. The film coated solid dosage form claim 2, 3 or 10, wherein the filler is microcrystalline cellulose silicified and lactose monohydrate.

15. The film coated solid dosage form of claim 2, 3 or 11 , wherein the disintegrant is crospovidone type B.

16. The film coated solid dosage form of claim 2, 3, or 12, wherein the lubricant is magnesium stearate.

17. The film coated solid dosage form of any one of claims 1 to 16, wherein the film coated solid dosage form reduces frequency or severity of dysgeusia in a subject being treated for cancer with the KAT6 inhibitor.

18. A method of reducing frequency or severity of dysgeusia in a subject being treated for cancer with a KAT6 inhibitor comprising administering to the subject a film-coated solid dosage form according to any one of claims 1 to 16.

19. The film coated solid dosage form of claims 1 to 27 or the method of claim 18, wherein the film coated solid dosage form is a tablet.

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