EA040951B1 - DOSAGE FORMS CIS-4-[2-{[(3S,4R)-3-FLUOROXAN-4-YL]AMINO}-8-(2,4,6-TRICHLORORANINO)-9H-PURINE-9-YL]-1 -METHYLCYCLOHEXANE-1-CARBOXAMIDE AND THEIR USE IN A METHOD FOR CANCER TREATMENT - Google Patents

Description

This application claims the benefit of U.S. Provisional Application No. 62/568107, filed October 4, 2017, the entire contents of which are incorporated herein by reference.

1. Technical field to which the invention belongs

Compositions and dosage forms of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2,4,6trichloroanilino)-9H-purin-9-yl] - 1-methylcyclohexane-1-carboxamide, alternatively referred to as (1s,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-(( 2,4,6-trichlorophenyl)amino)-9H-purin9-yl)-1-methylcyclohexane-1-carboxamide, or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph thereof, and such formulations for use in the treatment, prevention or treatment of cancer.

2. State of the art

It was shown that cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9Hpurin-9-yl]-1 -methylcyclohexane-1-carboxamide or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph thereof has anti-cancer activity. Illustrative examples of applications are presented in US patent No. 9512124 and US patent publication No. 2017/0281633. Illustrative examples of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8(2,4,6-trichloroanilino)-9H-purin-9-yl]-1 polymorphs -methylcyclohexane-1-carboxamide are proposed in US patent application No. 2017/0281633.

There is a need for additional uses and formulations of cis-4-[2-{[(3S,4R)-3fluoroxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H-purine-9- yl]-1-methylcyclohexane-1-carboxamide or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph thereof for the treatment of cancer.

3. Summary of the invention

In certain embodiments, this document provides a capsule containing compound 1 (cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2,4,6- trichloroanilino)-9H-purin9-yl]-1-methylcyclohexane-1-carboxamide) or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph thereof in an amount equal to 30-40% by weight of the capsule, excipient in an amount equal to 50-60% by weight of the capsule and tocofersolan in an amount equal to 5-15% by weight of the capsule.

In certain embodiments of the invention, this document provides a capsule containing 60-70% of compound 1 (cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2, 4,6-trichloroanilino)9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide) or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph thereof by weight, 20-30% of excipient by weight and 5-15% tocofersolan by weight.

In certain embodiments of the invention, this document provides a capsule containing 45-55% of compound 1 (cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2, 4,6-trichloroanilino)9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide) or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph thereof by weight, 35-45% of excipient by weight and 5-15% tocofersolan by weight.

In certain embodiments of the invention, this document provides a capsule containing 45-55% of compound 1 (cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2, 4,6-trichloroanilino)9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide) or a pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph thereof by weight and 45-55% of excipient by weight .

In certain embodiments, this document provides a capsule containing 0.5-3% of the citrate salt of Compound 1 (cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8 -(2,4,6trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide) by weight, 10-30% microcrystalline cellulose (e.g. Avicel PH102) by weight, 55-75% mannitol ( e.g. Parteck M200) by weight, 0.5-3% sodium lauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7% crospovidone by weight, 0.2-1% colloidal silicon dioxide (e.g. AEROSIL 200 ) by weight and 0.5-3% magnesium stearate by weight.

In certain embodiments, this document provides a capsule containing 2-12% of the citrate salt of Compound 1 (cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-( 2,4,6trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide) by weight, 10-30% microcrystalline cellulose (e.g. Avicel PH102) by weight, 50-70% mannitol (e.g. Parteck M200) by weight, 0.5-3% sodium lauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7% crospovidone by weight, 0.2-1% colloidal silicon dioxide (e.g. AEROSIL 200) by weight weight and 0.5-3% magnesium stearate by weight.

In certain embodiments, this document provides a capsule containing 5-20% of the citrate salt of Compound 1 (cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-( 2,4,6trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide) by weight, 10-30% microcrystalline cellulose (e.g. Avicel PH102) by weight, 50-70% mannitol (e.g. Parteck M200) by weight, 0.5-3% sodium lauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7% crospovidone

- 1 040951 by weight, 0.2-1% colloidal silicon dioxide (eg AEROSIL 200) by weight and 0.5-3% magnesium stearate by weight.

In certain embodiments of the invention, this document provides a tablet containing 15-25% of compound 1 (cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2, 4,6-trichloroanilino)9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide) or its pharmaceutically acceptable salt isotopologue, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph by weight, 32-43% microcrystalline cellulose (e.g. Avicel PH102) by weight, 32-43% mannitol (e.g. EMPROVE Parteck) by weight, 2-6% croscarmellose sodium (e.g. Ac-Di-Sol) by weight, 0.3-0.7% colloidal silica (eg AEROSIL 200) by weight and 0.5-1.5% magnesium stearate by weight.

In one embodiment of the invention, AEROSIL 200 is a colloidal silicon dioxide with a surface area of from about 175 to about 225 m ² /g (eg, about 200 m ² /g). In one embodiment, the Ac-Di-Sol is croscarmellose sodium. In one embodiment, the EMPROVE Parteck is mannitol.

4. Brief description of graphic materials

In FIG. 1 illustrates the mixing process for preparing compound 1 formulations.

In FIG. 2 illustrates the dissolution profiles of study 1 formulations in gelatin capsules under dissolution conditions 1 in table. 4.

In FIG. 3 illustrates the dissolution profiles of study 1 formulations in capsules of hydroxypropyl methylcellulose (HPMC - English: hydroxypropyl methylcellulose) under dissolution conditions 1 in table. 4.

In FIG. 4 illustrates the dissolution profiles of study 1 formulations in gelatin capsules under dissolution conditions 2 in table. 5.

In FIG. 5 illustrates the dissolution profiles of study 1 formulations in HPMC capsules under dissolution conditions 2 in table. 5.

In FIG. 6 illustrates the dissolution profiles of the study 2 formulations in gelatin capsules under dissolution conditions 1 in table. 4.

In FIG. 7 illustrates the dissolution profiles of the study 2 compositions in HPMC capsules under dissolution conditions 1 in table. 4.

In FIG. 8 illustrates the dissolution profiles of the study 2 formulations in gelatin capsules under dissolution conditions 2 in table. 5.

In FIG. 9 illustrates the dissolution profiles of the study 2 compositions in HPMC capsules under dissolution conditions 2 in table. 5.

In FIG. 10 illustrates the dissolution profiles of the study of 3 formulations in gelatin capsules under dissolution conditions 2 in table. 5.

In FIG. 11 illustrates the dissolution profiles of the study of 4 formulations in gelatin capsules under dissolution conditions 3 in table. 5.

In FIG. 12 illustrates the plasma concentration of Compound 1 24 hours post-dose following administration of Composition F4-1 of Study 4 formulations in Table 1. eleven.

In FIG. 13 illustrates the plasma concentration of Compound 1 24 hours post-dose following administration of composition F4-5 of Study 4 formulations in Table 1. eleven.

In FIG. 14 illustrates the plasma concentration of Compound 1 24 hours post-dose following administration of composition F4-7 of study formulations 4 in Table. eleven.

In FIG. 15 illustrates the comparison of AUC and C _max for formulations F4-1, F4-5, and F4-7 of formulations of Study 4 in two groups of pH controlled dogs as indicated in Table 15. 13.

In FIG. 16 illustrates the dissolution profiles of formulations F18-1 to F18-6 from Table 1. 18 with a basket speed of 100 rpm and simulated fasting intestinal juice (FaSSIF) with a pH of 6.5, as indicated in table. 19.

In FIG. 17 illustrates that formulations F18-2 and F18-5 containing citric acid and encapsulated in gelatin shell capsules exhibited capsule friability after 3 months at 40°C/75% RH and capsule failure after 1 month at 50°C/75 %R.H.

In FIG. 18 illustrates the release profiles of each composition in table. 27 in 0.1N HCl.

In FIG. 19 illustrates the release profiles of each composition in table. 27 in acetate buffer pH 4.5 (50 mM).

In FIG. 20 illustrates the release profiles of each composition in table. 27 in phosphate buffer pH 6.8 (50 mM).

In FIG. 21 illustrates the dissolution profiles of the improved 25 mg formulation (F27-15, Table 27) with apparatus I at 100 rpm in 0.1N HCl, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer.

In FIG. 22 illustrates the dissolution profiles of the traditional formulation (F4-1, in Table 11) with apparatus I at 100 rpm in 0.1 N HCl, acetate buffer pH 4.5 and phosphate buffer pH 6.8.

In FIG. 23 illustrates the high variability in dissolution of the improved formulation (F27-15, Table 27) with HPMC capsule shells (25 mg content) at neutral pH.

In FIG. 24 illustrates that no dissolution variability of the improved formulation was observed (F27-15, Table 27) with gelatin capsule shells (25 mg content) at neutral pH.

In FIG. 25 illustrates the high variability when dissolving the improved formulation (F27-15, Table 27) with HPMC capsule shells (25 mg content) at neutral pH in a dissolution medium with 0.5% SlS.

In FIG. 26 illustrates that dissolution variability of the improved formulation was not observed (F27-15, Table 27) with gelatin capsule shells (25 mg content) at neutral pH in dissolution medium with 0.5% SLS.

In FIG. 27 illustrates that only the SLS formulation (F27-13 in Table 27) behaved similarly in HPMC capsule shells in dissolution media with 0.5% SLS and without 0.5% SLS.

In FIG. 28 illustrates that only the SLS formulation (F27-13 in Table 27) behaved similarly in gelatin capsule shells in dissolution medium with 0.5% SLS and without 0.5% SLS.

In FIG. 29 illustrates that only the CA+SLS formulation (F27-10 in Table 27) behaved differently in HPMC capsule shells in dissolution media with 0.5% SLS and without 0.5% SLS.

In FIG. 30 illustrates that the HPMC capsules retained the gelatinous and lumpy residual solids in the basket at the end of dissolution.

In FIG. 31 illustrates a flow chart of the 600 g study 1 process for the preparation of 600 g formulations.

In FIG. 32 illustrates a process flow diagram for 600 g Study 2 for the preparation of 600 g formulations.

In FIG. 33 illustrates the process flow diagram for the production of 2 kg technical batches.

In FIG. 34 illustrates the dissolution profiles of Compound 1 formulations when dissolved in intestinal buffer for 90 minutes.

In FIG. 35 illustrates the dissolution profiles of Compound 1 formulations when dissolved in intestinal buffer and composition.

In FIG. 36 illustrates a dissolution comparison in PVA-P formulations (capsule B, capsule E, and capsule H).

In FIG. 37 illustrates a dissolution comparison in PVP VA64 formulations (capsule C and capsule F).

In FIG. 38 illustrates a dissolution comparison in HPMC formulations (capsule A, capsule D, and capsule G).

In FIG. 39 illustrates the glass transition temperature as a function of relative humidity.

In FIG. 40 illustrates the reversible and irreversible heat flux of capsule A and capsule H at less than 5% relative humidity.

In FIG. 41 illustrates the reversible and irreversible heat flux of capsule A and capsule H at 75% relative humidity.

In FIG. 42 illustrates the reversible and irreversible heat flux of capsule G and capsule E at less than 5% relative humidity.

In FIG. 43 illustrates the reversible and irreversible heat flux of capsule G and capsule E at 75% relative humidity.

In FIG. 44 illustrates the stability of the capsule A suspension in methocel.

In FIG. 45 illustrates the stability of the H capsule suspension in methocel.

In FIG. 46 illustrates the stability of the capsule G suspension in methocel.

In FIG. 47 illustrates the stability of the capsule E suspension in methocel.

In FIG. 48 illustrates the stability of the suspension, visualized by polarized light microscopy (PLM), capsule A in the methocel.

In FIG. 49 illustrates suspension stability, visualized by PLM, of the H capsule in the methocel.

In FIG. 50 illustrates the suspension stability visualized by PLM of the G capsule in the methocel.

In FIG. 51 illustrates suspension stability, visualized by PLM, of capsule E in methocel.

In FIG. 52 illustrates the results of the plasma concentration profile after a single oral administration of Capsule G in male CD-1 mice.

In FIG. 53 illustrates the results of the plasma concentration profile after a single oral administration of capsule E in male CD-1 mice.

In FIG. 54 illustrates the results of the plasma concentration profile after a single oral administration of Capsule I in male CD-1 mice.

In FIG. 55 illustrates the results of the plasma concentration profile after a single oral administration of Capsule J in male CD-1 mice.

In FIG. 56 illustrates a comparison of concentration profile results after a single oral administration of Capsule G, Capsule E, Capsule I, and Capsule J.

- 3 040951

In FIG. 57 illustrates the dissolution of tablet A, tablet B and tablet C in phosphate buffer pH 2.

In FIG. 58 illustrates the dissolution of tablet A (middle curve), tablet B (upper curve) and tablet C (lower curve) in phosphate buffer pH 5 and 0.1% sodium laureth sulfate.

In FIG. 59 illustrates that the citrate salt has a better dissolution profile than the free base monohydrate.

In FIG. 60 illustrates a spray-drying process to obtain a spray-dried dispersion composition of Compound 1.

5. Detailed description of the invention

5.1. Definitions.

As used herein, the terms containing and including may be used interchangeably. The terms containing and including should be construed as indicating the presence of the indicated features or components, but not excluding the presence or addition of one or more features or components, or groups thereof. In addition, the terms containing and including are intended to include examples covered by the term consisting of. Therefore, the term consisting of may be used in place of the terms containing and including to provide more specific embodiments of the invention.

The term consisting of means that an item has at least 90%, 95%, 97%, 98%, or 99% of the claimed features or components of which it is composed. In another embodiment of the invention, the term consisting of excludes from the scope of any subsequent presentation any other features or components except those that are not essential to achieve a technical effect.

As used herein, the term or should be interpreted as including or meaning any one or any combination. Therefore, A, B or C means any of the following: A; IN; WITH; A and B; A and C; B and C; A, B, and C. An exception to this definition will only occur if the combination of elements, functions, steps, or activities is mutually exclusive in some way.

Generally, the nomenclature used herein and the laboratory methods in organic chemistry, medicinal chemistry, and pharmacology described herein are well known and widely used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as generally understood by those skilled in the art to which this disclosure pertains.

The term compound 1 refers to cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2,4,6trichloroanilino)-9H-purin-9-yl]- 1-methylcyclohexane-1-carboxamide, alternatively referred to as (1s,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2, 4,6-trichlorophenyl)amino)-9Hpurin-9-yl)-1-methylcyclohexane-1-carboxamide having the structure:

and its pharmaceutically acceptable salts, tautomers, solvates, hydrates, co-crystals, clathrates or polymorphs. In certain embodiments, Compound 1 refers to cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H- purin-9-yl]-1-methylcyclohexane1-carboxamide and pharmaceutically acceptable salts, tautomers, solvates, hydrates, co-crystals, clathrates or polymorphs thereof. In certain embodiments of the invention, compound 1 refers to the polymorph (1s,4s)-4-(2-(((3S,4R)-3-fluorotetrahydro-2H-pyran-4-yl)amino)-8-((2, 4,6trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-1-carboxamide, such as, inter alia, free base forms A-I, citrate forms Y and Z, and HCl salt forms 1-7 as described in US Publication No. 2017/0283418.

As used herein, unless otherwise indicated, the term pharmaceutically acceptable salt(s) includes, but is not limited to, salts of the acidic or base moieties of Compound 1. The base moieties are capable of forming a wide range of salts with a variety of inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are acids that form non-toxic acid addition salts, for example salts containing pharmacologically acceptable anions. Suitable organic acids include, but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, acetic, formic, oxalic, propionic,

- 4 040951 tartaric, salicylic, citric, gluconic, lactic, almond, cinnamic, oleic, halotannic, aspartic, stearic, palmitic, glycolic, glutamic, gluconic, glucaronic, sugar, isonicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic acids, or pamic (for example, 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) acids. Suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, or nitric acids. Compounds that contain an amine moiety, can form pharmaceutically acceptable salts with a variety of amino acids in addition to the acids mentioned above.Chemical moieties that are acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations.Examples of such salts are alkali or alkaline earth metal salts and, in particular, salts of calcium, magnesium, sodium, lithium, c inca, potassium or iron.

As used herein, and unless otherwise indicated, the term solvate means a compound as provided herein, or a salt thereof, which additionally contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

A pharmaceutically acceptable excipient refers to a substance that facilitates the administration of an active agent to a subject, for example by altering the stability of the active agent or altering absorption by the subject upon administration.

A pharmaceutically acceptable excipient generally does not have a significant adverse toxicological effect on the patient. Examples of pharmaceutically acceptable excipients include, for example, water, NaCl (including saline solutions), saline, 1/2 saline, sucrose, glucose, bulking agents, buffers, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors , alcohols, oils, gelatins, carbohydrates such as amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and dyes, and the like. One skilled in the art will appreciate that other pharmaceutical excipients known in the art are useful in this invention and include those listed, for example, in Handbook of Pharmaceutical Excipients, Rowe R.C., Shesky P.J., and Quinn M.E., 6th Ed. ., The Pharmaceutical Press, RPS Publishing (2009). The terms bulking agent and buffer are used in accordance with the simple and conventional meaning in the art.

Used in this document, unless otherwise indicated, the term about, when used in connection with doses, amounts or mass fractions of ingredients of a composition or dosage form, means a dose, amount or mass fraction that is recognized by one of ordinary skill in the art, provides a pharmacological an effect equivalent to that which was obtained from the specified dose, amount or mass fraction. In particular, the term about means a dose, amount or mass fraction within 30%, 25%, 20%, 15%, 10% or 5% of the indicated dose, amount or mass fraction.

As used herein, the term administer or administer refers to the physical delivery to a subject of a substance as it exists outside the body. Administration includes all forms known in the art for delivery of therapeutic agents, including but not limited to topical, mucosal, injection, intradermal, intravenous, intramuscular delivery, or other method of physical delivery described herein or known in the art. (e.g., implanting a subject with a slow release device such as a mini-osmotic pump; liposomal formulations; buccal; sublingual; palatal; gingival; nasal; vaginal; rectal; intra-arteriole; intraperitoneal; intraventricular; intracranial; or transdermal).

An effective amount is an amount sufficient to achieve the effect for which it is administered (eg, to treat a disease or reduce one or more symptoms of a disease or condition). Thus, administering to a subject an amount of a compound described herein refers to administering an amount effective to achieve the desired therapeutic result. Thus, a therapeutically effective amount of a compound described herein, for the purposes of this invention, is determined by such considerations as are known in the art. The term therapeutically effective amount of a composition described herein refers to an amount of a composition that, when administered, is sufficient to treat one or more of the symptoms of the disease described herein (eg, cancer). Administration of a compound described herein may be determined according to factors such as, for example, disease state, age, sex, and weight of the individual. A therapeutically effective amount also refers to any toxic or deleterious effects of Compound 1 that are outweighed by the therapeutically beneficial effects. Illustrative examples of diseases to be treated are presented in US patent No. 9512124 and US patent publication No. 2017/0281633.

Used in this document, unless otherwise indicated, the terms treat, treat

- 5 040951 treatment and treatment refers to the elimination or reduction of the intensity of the disease or disorder or one or more symptoms associated with the disease or disorder. In some embodiments, the terms refer to minimizing the spread or complication of a disease or disorder by administering one or more prophylactic or therapeutic agents to a patient with such disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without another additional active agent, after the onset of symptoms of a particular disease. Illustrative examples of diseases to be treated are presented in US patent No. 9512124 and US patent publication No. 2017/0281633.

As used herein, unless otherwise indicated, the terms prevent, prevent, and prevent refer to preventing the onset, recurrence, or spread of a disease or disorder or one or more of its symptoms. In some embodiments, the terms refer to treatment with or by administering a compound provided herein with or without another additional active compound prior to the onset of symptoms, particularly in relation to patients at risk for the disease or disorder provided herein. . The terms encompass the suppression or reduction of the manifestation of a symptom of a particular disease. Patients with a family history of the disease, in particular, are candidates for prophylactic regimens in some embodiments. In addition, patients with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term prevention may be used interchangeably with the term prophylactic treatment. Illustrative examples of preventable diseases are provided in US Pat. No. 9,512,124 and US Patent Publication No. 2017/0281633.

As used herein, and unless otherwise indicated, the terms contain, exercise containment, and containment refer to preventing or slowing the progression, spread, or aggravation of a disease or disorder, or one or more of its symptoms. Often, the positive effects that a patient receives from a prophylactic and/or therapeutic agent do not lead to the elimination of the disease or disorder. In this regard, the term containment encompasses the treatment of a patient who has suffered from a particular disease in an attempt to prevent or minimize the recurrence of the disease or to increase the length of time during which he maintains a state of remission. Illustrative examples of diseases for which care should be provided are presented in US patent No. 9512124 and US patent publication No. 2017/0281633.

The terms subject, patient, subject in need, and patient in need are used interchangeably herein and refer to a living organism suffering from one or more of the diseases described herein (e.g., cancer) that can be treated by administering a composition, described in this document. Non-limiting examples of organisms include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In embodiments of the invention, the subject is a human. A person can be between the ages of 1 and 100 years old. In embodiments of the invention, the subjects herein may be characterized by the disease being treated (eg, a subject having cancer or a subject having a solid tumor). Illustrative examples of diseases to be treated are presented in US patent No. 9512124 and US patent publication No. 2017/0281633.

As used herein, unless otherwise indicated, a therapeutically effective amount of a compound is an amount sufficient to provide therapeutic utility in the treatment or control of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic utility in the treatment or control of a disease or disorder. The term "therapeutically effective amount" may include an amount that improves overall therapy, reduces or eliminates the symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

Finally, in general, the technical description of one embodiment of the invention may be combined with that disclosed in other embodiments of the invention presented herein.

5.2. Connection 1.

A compound suitable for use in the methods and compositions provided herein is compound 1: cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2 ,4,6-trichloroanilino)-9Hpurin-9-yl]-1-methylcyclohexane-1-carboxamide, alternatively referred to as (1s,4s)-4-(2-(((3S,4R)-3fluorotetrahydro-2H-pyran- 4-yl)amino)-8-((2,4,6-trichlorophenyl)amino)-9H-purin-9-yl)-1-methylcyclohexane-6 040951

1-carboxamide having the structure

and its isotopologues, pharmaceutically acceptable salts, tautomers, solvates, hydrates, co-crystals, clathrates or polymorphs.

Compound 1 can be obtained in accordance with the methods described in the examples presented in this document, or described in US patent No. 9512124, the description of which is incorporated herein by reference in its entirety. The connection can also be synthesized in accordance with other methods, obvious to experts in the art based on the data presented in this document.

In some embodiments, Compound 1 is a solid. In some embodiments, Compound 1 is a hydrate. In some embodiments, Compound 1 is solvated. In some embodiments, Compound 1 is anhydrous.

In some embodiments, Compound 1 is amorphous. In some embodiments, Compound 1 is crystalline. In certain embodiments of the invention, compound 1 is in the crystalline form described in US Publication No. 2017/0283418, which is incorporated by reference herein in its entirety. Solid forms of compound 1 can be obtained in accordance with the methods described in the description of US publication No. 2017/0283418. Solid forms may also be prepared in accordance with other methods obvious to those skilled in the art.

In one aspect, this document provides stable formulations of Compound 1. In one embodiment, formulations of Compound 1 comprise the solid form of cis-4-[2-{[(3S,4R)-3fluoroxan-4-yl]amino}-8-( 2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide. In one embodiment, the formulations of Compound 1 contain the amorphous form cis-4[2-{[(3S,4R)-3-fluorooxαn-4-yl]amino}-8-(2,4,6-trichloroanilino)-9H- purin-9-yl]-1-methylcyclohexane-1 carboxamide. In one embodiment, formulations of Compound 1 contain the crystalline form cis-4-[2-{[(3S,4R)-3-fluoroκsan-4-yl]amino}-8-(2,4,6-trichloroαnilino)-9H -purin-9-yl]1-methylcyclohexane-1-carboxamide.

The formulations provided herein may be used in the preparation of individual unit dosage forms. The compositions and dosage forms provided herein contain Compound 1. The compositions and dosage forms may additionally contain one or more excipients.

Formulations for oral administration provided herein may be provided as, but not limited to, compressed capsules, tablets, compressible tablets, chewable lozenges, instant tablets, multi-compressed or enteric-coated tablets, sugar-coated or coated tablets. .

5.2.1. Citrate salt form Y.

Also provided herein are solid forms of Compound 1 which include citrate salts.

In certain embodiments, provided herein is the citrate salt of Form Y.

In one embodiment, the Form Y citrate salt is the solid form of Compound 1. In another embodiment, the Form Y citrate salt is crystalline. In another embodiment, the Form Y citrate salt is anhydrous.

In certain embodiments, the solid form provided herein, eg Form Y, is the citrate salt of Compound 1 and is substantially crystalline, as indicated, for example, by X-ray powder diffraction measurements. In one embodiment, the solid form provided herein, such as Form Y, has one or more characteristic X-ray powder diffraction peaks at approximately 4.8, 6.6, 9.6, 13.6, 14.4, 15.4 , 16.0, 16.9, 18.0, 18.9, 19.2, 19.9, 20.1, 20.9, 21.8, 22.4, 22.7, 23.2, 23 .4, 24.0, 24.1, 24.3, 25.1, 26.7, 27.0, 27.9, 28.5, 29.0, 29.6, 30.2, 30.4 , 30.8, 31.1, 31.6, 32.3, 33.1, 33.5, 34.0, 34.6 or 35.1° 2Θ (± 0.2° 2θ) or (± 0 ,1° 2θ). In a specific embodiment, the invention

- 7 040951 proposed in this document, the solid form, for example form Y, has one, two, three, four, five, six, seven, eight, nine, ten or eleven characteristic peaks of powder x-ray diffraction at approximately 4.8, 6, 6, 9.6, 15.4, 16.0, 16.9, 18.9, 19.2, 19.9, 20.9, or 28.5° 2θ (± 0.2° 2θ). In another embodiment, the solid form provided herein has one, two, three, or four characteristic X-ray powder diffraction peaks at approximately 4.8, 9.6, 18.9, or 19.2° 2θ (± 0.2° 2θ ). In one embodiment, the solid form is Form Y citrate salt. In another embodiment, Form Y citrate salt has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two, thirty three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, or forty characteristic X-ray powder diffraction peaks.

In certain embodiments, the crystalline form exhibits a TGA thermogram including a total weight loss of about 0.1% of the total sample weight between about 50°C and about 150°C when heated from about 50°C to about 220°C. .

In one embodiment of the invention, this document provides a crystalline citrate salt of compound 1 having a differential scanning calorimetry (DSC) thermogram containing an endothermic event with an initial temperature at about 213° C. and a maximum temperature peak at about 217° C. (when heated from about 25 °C to about 260°C).

In yet another embodiment of the invention, the citrate salt of Form Y is substantially pure. In some embodiments, substantially pure Form Y contains substantially no other solid forms, such as an amorphous solid. In certain embodiments, the substantially pure form Y citrate salt is at least about 95% pure, at least about 96% pure, at least about 97% pure, at least about 98% pure, at least about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

5.2.2. Citrate salt form Z.

In certain embodiments, provided herein is the citrate salt of Form Z.

In one embodiment, the Form Z citrate salt is the solid form of Compound 1. In another embodiment, the Form Z citrate salt is crystalline. In another embodiment, the citrate salt of Form Z is anhydrous. In another embodiment, the citrate salt of Form Z is a hydrate. In one embodiment, the Form Z citrate salt is a non-stoichiometric hydrate. In yet another embodiment of the invention, the citrate salt of form Z is a channel hydrate. In yet another embodiment of the invention, the citrate salt of form Z is a non-stoichiometric channel hydrate. In yet another embodiment of the invention, the citrate salt of Form Z is a solvate.

In certain embodiments, the solid form provided herein, such as Form Z, is substantially crystalline, as indicated, for example, by X-ray powder diffraction measurements. In one embodiment, the solid form provided herein, for example Form Z, has one or more characteristic X-ray powder diffraction peaks at approximately 4.6, 6.6, 9.4, 13.1, 14.1, 15.3 , 15.6, 17.4, 18.8, 19.0, 19.9, 20.4, 21.1, 21.9, 22.2, 22.7, 23.5, 23.9, 25 .2, 26.3, 26.8, 27.8, 28.3, 28.7, 29.8, 31.2, 31.9, 32.6, 33.7, 35.1, 35.9 , 37.4 or 38.0° 2θ (± 0.2° 2θ) or (± 0.1° 2θ). In a particular embodiment, the solid form provided herein has one, two, three, or four characteristic X-ray powder diffraction peaks at approximately 9.4, 18.8, 19.0, or 28.7° 2θ (± 0.2° 2θ ). In one embodiment, the solid form is the citrate salt of Form Z. In another embodiment, the citrate salt of Form Z has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two or thirty three characteristic peaks of powder x-ray diffraction.

In certain embodiments, the crystalline form exhibits a TGA thermogram including a total weight loss of about 0.1% of the total sample weight between about 50°C and about 150°C when heated from about 25°C to about 300°C. . In certain embodiments, the crystalline form is the anhydrous form of Compound 1.

In one embodiment of the invention, this document provides a crystalline

- 8 040951 a citrate salt form of compound 1 having a DSC thermogram containing an endothermic event with an initial temperature at about 217°C and a maximum temperature peak at about 221°C, when heated from about 25°C to about 260°C.

In certain embodiments, the hydrate exhibits a TGA thermogram including an overall weight loss of about 2% of the total sample weight, between about 25°C and about 200°C, when heated from about 25°C to about 300°C. In certain embodiments, the crystalline form is the hydrate of the citrate form of Compound 1.

In certain embodiments, the non-stoichiometric hydrate form exhibits a TGA thermogram including an overall weight loss of about 1.7% of the total sample weight, between about 50°C and about 200°C, when heated from about 50°C to about 300°C. In certain embodiments, the crystalline form is a non-stoichiometric hydrate of the citrate form of Compound 1.

In certain embodiments, the solvate exhibits a TGA thermogram including an overall weight loss of about 1.3% of the total sample weight, between about 25°C and about 200°C, when heated from about 25°C to about 300°C. In certain embodiments, the crystalline form is a solvate of the citrate form of Compound 1.

In yet another embodiment of the invention, the citrate salt of Form Z is substantially pure. In some embodiments, substantially pure Form Z contains substantially no other solid forms, such as an amorphous solid. In certain embodiments, the substantially pure form Z citrate salt is at least about 95% pure, at least about 96% pure, at least about 97% pure, at least about 98% pure, at least about 98.5%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%.

Form Y and form Z of the citrate salt of Compound 1 can be prepared according to the methods described in the examples provided herein or described in US Publication No. 2017/0283418 A1, the disclosure of which is incorporated herein by reference in its entirety. Solid forms can also be synthesized in accordance with other methods obvious to experts in the art based on the data presented in this document.

5.2.3. Capsules.

Capsules containing Compound 1 are provided herein. In certain embodiments, the capsule contains the citrate salt of Compound 1. In another embodiment, the capsule contains the citrate salt of Compound 1 and sodium lauryl sulfate.

In one embodiment, the capsule contains Compound 1. In one embodiment, the capsule contains an excipient. In one embodiment of the invention, the capsule contains tocofersolan (TPGS). In certain embodiments of the invention, the capsule contains 20-30%, 30-40%, 40-50% or 50-60% of compound 1 by weight. In certain embodiments, the capsule contains 35-45%, 45-55%, or 55-65% excipient by weight. In certain embodiments of the invention, the capsule contains 5-15% TPSG by weight. In certain embodiments, the capsule contains 20-30% Compound 1 by weight, 60-70% excipient by weight, and 5-15% TPGS by weight. In certain embodiments, the capsule contains 45-55% Compound 1 by weight, 35-45% excipient by weight, and 5-15% TPGS by weight. In certain embodiments, the capsule contains 45-55% Compound 1 by weight and 45-55% excipient by weight. In certain embodiments of the invention, the excipient is hydroxypropyl methylcellulose (HPMC). In certain embodiments of the invention, the excipient is a polyvinyl acetate phthalate polymer (PVA-P). In certain embodiments of the invention, the excipient is a vinyl pyrrolidone vinyl acetate copolymer (PVP VA64).

In certain embodiments, this document provides a capsule formulation containing 35-45% Compound 1 by weight, 50-60% HPMC by weight, and 5-15% TPGS by weight. In certain embodiments, the capsule contains 37% Compound 1 by weight, 53% HPMC by weight, and 10% TPGS by weight.

In certain embodiments, this document provides a capsule formulation containing 20-30% Compound 1 by weight, 60-70% HPMC by weight, and 5-15% TPGS by weight. In certain embodiments, the capsule contains 25% Compound 1 by weight, 65% HPMC by weight, and 10% TPGS by weight.

In certain embodiments, this document provides a capsule formulation containing 20-30% Compound 1 by weight, 60-70% PVA-P by weight, and 5-15% TPGS by weight. In certain embodiments, the capsule contains 25% Compound 1 by weight, 65% PVA-P by weight, and 10% TPGS by weight.

In certain embodiments, this document provides a capsule formulation containing 20-30% Compound 1 by weight, 60-70% PVP V64 by weight, and 5-15% TPGS by weight. In certain embodiments, the capsule contains 25% Compound 1 by weight,

65% PVP VA64 by weight and 10% TPGS by weight.

In certain embodiments, this document provides a capsule formulation containing 45-55% Compound 1 by weight, 35-45% HPMC by weight, and 5-15% TPGS by weight. In certain embodiments, the capsule contains 50% Compound 1 by weight, 40% HPMC by weight, and 10% TPGS by weight.

In certain embodiments of the invention, this document provides a capsule formulation containing 45-55% Compound 1 by weight, 35-45% PVA-P by weight and 5-15% TPGS by weight. In certain embodiments, the capsule contains 50% Compound 1 by weight, 40% PVA-P by weight, and 10% TPGS by weight.

In certain embodiments, this document provides a capsule formulation containing 45-55% Compound 1 by weight, 35-45% PVP VA64 by weight, and 5-15% TPGS by weight. In certain embodiments, the capsule contains 50% Compound 1 by weight, 40% PVP VA64 by weight, and 10% TPGS by weight.

In certain embodiments, this document provides a capsule formulation containing 45-55% Compound 1 by weight and 45-55% HPMC by weight. In certain embodiments, the capsule contains 50% Compound 1 by weight and 50% HPMC by weight.

In certain embodiments, this document provides a capsule formulation containing 45-55% Compound 1 by weight and 45-55% PVA-P by weight. In certain embodiments, the capsule contains 50% Compound 1 by weight and 50% PVA-P by weight.

In certain embodiments of the invention, this document provides a capsule formulation containing an amount of Compound 1 in gelatin capsules. In certain embodiments of the invention, this amount of compound 1 is 100-150 mg. In certain embodiments of the invention, this amount of compound 1 is 125 mg.

In certain embodiments of the invention, this document provides a capsule formulation containing an amount of Compound 1 in HPMC capsules. In certain embodiments of the invention, this amount of compound 1 is 100-150 mg. In certain embodiments of the invention, this amount of compound 1 is 125 mg.

In certain embodiments, this document provides a capsule formulation comprising Compound 1 and microcrystalline cellulose (Avicel) in a gelatin capsule. In certain embodiments of the invention, this capsule further contains sodium laureth sulfate. In certain embodiments of the invention, compound 1 and Avicel are present in the capsule in a 2:1 ratio. In certain embodiments of the invention, the total mass of compound 1 and Avicel is between 100-120 mg. In certain embodiments of the invention, the total mass of compound 1 and Avicel is 110 mg.

In certain embodiments of the invention, the capsule contains the citrate salt of compound 1, microcrystalline cellulose (eg, Avicel PH102), mannitol (eg, Parteck M200), citric acid; sodium lauryl sulfate, cross-linked polyvinylpyrrolidone (eg Kollidon CL), colloidal silicon dioxide and stearic acid. In certain embodiments, the capsule contains 5-25% Compound 1 citrate by weight, 15-60% microcrystalline cellulose (e.g. Avicel PH102) by weight, 15-60% mannitol (e.g. Parteck M200) by weight, 5-20 % citric acid by weight; 2.5-10% sodium lauryl sulfate by weight, 2-8% cross-linked polyvinylpyrrolidone (e.g. Kollidon CL) by weight, 0.3-1.5% colloidal silica by weight and 0.5-2% stearic acid by weight . In certain embodiments, the capsule contains about 13.36% Compound 1 citrate by weight, about 33.02% microcrystalline cellulose (e.g., Avicel PH102) by weight, about 33.02% mannitol (e.g., Parteck M200) by weight, about 10% citric acid by weight; about 5% sodium lauryl sulfate by weight, about 4% crosslinked polyvinylpyrrolidone (eg Kollidon CL) by weight, about 0.6% colloidal silica by weight and about 1% stearic acid by weight. In certain embodiments of the invention, the capsule contains 5-25% citrate salt of compound 1 by weight and 2.5-10% sodium lauryl sulfate by weight. In certain embodiments, the capsule contains about 13.36% Compound 1 citrate salt by weight and about 5% sodium lauryl sulfate by weight.

In certain embodiments of the invention, the capsule contains the citrate salt of compound 1 and sodium lauryl sulfate. In certain embodiments, the capsule contains 0.5-3% Compound 1 citrate salt by weight and 0.5-3% sodium lauryl sulfate by weight. In certain embodiments, the capsule contains about 1.79% Compound 1 citrate salt by weight and about 1.0% sodium lauryl sulfate by weight. In certain embodiments, the capsule contains 2-12% Compound 1 citrate salt by weight and 0.5-3% sodium lauryl sulfate by weight. In certain embodiments, the capsule contains about 6.70% Compound 1 citrate salt by weight and about 1.0% sodium lauryl sulfate by weight. In certain embodiments, the capsule contains 5-20% Compound 1 citrate salt by weight and

- 10 040951

0.5-3% sodium lauryl sulfate by weight. In certain embodiments, the capsule contains about 10.72% Compound 1 citrate salt by weight and about 1.0% sodium lauryl sulfate by weight.

In certain embodiments, the capsule contains the citrate salt of compound 1, microcrystalline cellulose (eg, Avicel PH102), mannitol (eg, Parteck M200), sodium lauryl sulfate, fumaric acid, crospovidone, colloidal silicon dioxide (eg, Aerosil 200), and magnesium stearate. In certain embodiments of the invention, the capsule contains 0.5-3% citrate salt of compound 1 by weight, 10-30% microcrystalline cellulose (for example, Avicel PH102) by weight, 55-75% mannitol (for example, Parteck M200) by weight, 0 5-3% sodium lauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7% crospovidone by weight, 0.2-1% aerosil 200 by weight and 0.5-3% magnesium stearate by weight. In certain embodiments, the capsule contains about 1.79% citrate salt of Compound 1 by weight, about 21.65% microcrystalline cellulose (e.g., Avicel PH102) by weight, about 64.96% mannitol (e.g., Parteck M200) by weight, about 1.0% sodium lauryl sulfate by weight, about 5.0% fumaric acid by weight, about 4.0% crospovidone by weight, about 0.6% colloidal silicon dioxide (e.g. Aerosil 200) by weight, and about 1.0 % magnesium stearate by weight. In certain embodiments, the capsule contains 0.5-3% Compound 1 citrate salt by weight and 0.5-3% sodium lauryl sulfate by weight. In certain embodiments, the capsule contains about 1.79% Compound 1 citrate salt by weight and about 1.0% sodium lauryl sulfate by weight.

In certain embodiments of the invention, the capsule contains 2-12% citrate salt of compound 1 by weight, 10-30% microcrystalline cellulose (for example, Avicel PH102) by weight, 50-70% mannitol (for example, Parteck M200) by weight, 0.5 -3% sodium lauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7% crospovidone by weight, 0.2-1% colloidal silicon dioxide (e.g. Aerosil 200) by weight and 0.5-3% stearate magnesium by weight. In certain embodiments, the capsule contains about 6.70% Compound 1 citrate by weight, about 20.42% microcrystalline cellulose (e.g., Avicel PH102) by weight, about 61.28% mannitol (e.g., Parteck M200) by weight, about 1.0% sodium lauryl sulfate by weight, about 5.0% fumaric acid by weight, about 4.0% crospovidone by weight, about 0.6% colloidal silicon dioxide (e.g. Aerosil 200) by weight, and about 1.0 % magnesium stearate by weight. In certain embodiments, the capsule contains 2-12% Compound 1 citrate salt by weight and 0.5-3% sodium lauryl sulfate by weight. In certain embodiments, the capsule contains about 6.70% Compound 1 citrate salt by weight and about 1.0% sodium lauryl sulfate by weight.

In certain embodiments of the invention, the capsule contains 5-20% citrate salt of compound 1 by weight, 10-30% microcrystalline cellulose (for example, Avicel PH102) by weight, 50-70% mannitol (for example, Parteck M200) by weight, 0.5 -3% sodium lauryl sulfate by weight, 2-8% fumaric acid by weight, 1-7% crospovidone by weight, 0.2-1% colloidal silicon dioxide (e.g. Aerosil 200) by weight and 0.5-3% stearate magnesium by weight. In certain embodiments, the capsule contains about 10.72% Compound 1 citrate by weight, about 19.41% microcrystalline cellulose (e.g., Avicel PH102) by weight, about 58.27% mannitol (e.g., Parteck M200) by weight, about 1.0% sodium lauryl sulfate by weight, about 5.0% fumaric acid by weight, about 4.0% crospovidone by weight, about 0.6% colloidal silicon dioxide (e.g. Aerosil 200) by weight, and about 1.0 % magnesium stearate by weight. In certain embodiments of the invention, the capsule contains 5-20% citrate salt of compound 1 by weight and 0.5-3% sodium lauryl sulfate by weight. In certain embodiments, the capsule contains about 10.72% Compound 1 citrate by weight and about 1.0% sodium lauryl sulfate by weight.

5.2.4. Pills.

This document provides tablets containing compound 1. In certain embodiments of the invention, compound 1 is an HCl salt. In certain embodiments of the invention, compound 1 is a citrate salt.

In certain embodiments of the invention, this document provides a tablet containing compound 1 and a filler, disintegrant, lubricant, acidulant, surfactant, polymer and/or glidant. In certain embodiments of the invention, the filler is microcrystalline cellulose (eg, Avicel PH102), mannitol, lactose, or starch. In certain embodiments, the disintegrant is croscarmellose sodium (eg, Ac-Di-sol), sodium starch glycolate, or Kollidon CL. In certain embodiments, the lubricant is magnesium stearate, stearic acid, or sodium stearyl fumarate. In certain embodiments, the acidifier is tartaric acid, fumaric acid, or citric acid. In certain embodiments, the surfactant is sodium laureth sulfate, VE-TPGS, or hydrogenated castor oil. In certain embodiments, the polymer is HEC, HPC, PEG4000, PVP K30, Pluronic F127, PVP VA64, or SB-beta-CD. In certain embodiments, the glidant is Aerosil 200. In certain embodiments, the ratio of compound 1 to excipient is about 1:5. In a specific embodiment of the invention, the ratio of compound 1 to disintegrant is about 2:1. In certain embodiments of the invention, the ratio of compound 1 to lubricant is about 20:1. In certain embodiments of the invention, the ratio of compound 1 to acidulant is about 1:1. In certain embodiments of the invention, the ratio of compound 1 to surfactant is about 20:1. In certain embodiments of the invention, the ratio of compound 1 to polymer is about 1:2. In certain embodiments of the invention, the ratio of compound 1 to glidant is about 20:1.

In certain embodiments, this document provides a tablet containing 15-25% Compound 1 by weight, 32-43% microcrystalline cellulose (e.g. Avicel PH102) by weight, 32-43% mannitol (e.g. Emprove Parteck) by weight, 2-6% croscarmellose sodium (e.g. Ac-Di-Sol) by weight, 0.3-0.7% colloidal silicon dioxide (e.g. Aerosil 200) by weight and 0.5-1.5% magnesium stearate by weight . In certain embodiments, the tablet contains 20% Compound 1 by weight, 37.25% microcrystalline cellulose (e.g. Avicel PH102) by weight, 37.25% mannitol (e.g. Emprove Parteck) by weight, 4% croscarmellose sodium (e.g. , Ac-Di-Sol) by weight, 0.5% colloidal silicon dioxide (eg Aerosil 200) by weight and 1% magnesium stearate by weight. In certain embodiments of the invention, the total weight of the tablet is between 225-275 mg. In certain embodiments of the invention, the total weight of the tablet is 250 mg. In certain embodiments of the invention, compound 1 is an HCl salt. In certain embodiments of the invention, compound 1 is a citrate salt.

In certain embodiments, this document provides a tablet containing 15-25% Compound 1 by weight, 32-43% microcrystalline cellulose (e.g. Avicel PH102) by weight, 32-43% mannitol (e.g. Emprove Parteck) by weight, 2-6% croscarmellose sodium (e.g. Ac-Di-Sol) by weight, 0.3-0.7% colloidal silicon dioxide (e.g. Aerosil 200) by weight and 0.5-1.5% magnesium stearate by weight . In certain embodiments, the tablet contains 20% Compound 1, 37.25% microcrystalline cellulose (e.g. Avicel PH102) by weight, 37.25% mannitol (e.g. Emprove Parteck) by weight, 4% croscarmellose sodium (e.g. Ac -Di-Sol) by weight, 0.5% colloidal silicon dioxide (eg Aerosil 200) by weight and 1% magnesium stearate by weight. In certain embodiments of the invention, the total weight of the tablet is between 225-275 mg. In certain embodiments of the invention, the total weight of the tablet is 250 mg.

In certain embodiments, this document provides a tablet containing 15-25% Compound 1 HCl salt by weight, 32-43% microcrystalline cellulose (e.g., Avicel PH102) by weight, 32-43% mannitol (e.g., Emprove Parteck) by weight. by weight, 2-6% croscarmellose sodium (e.g. Ac-Di-Sol) by weight, 0.3-0.7% colloidal silicon dioxide (e.g. Aerosil 200) by weight and 0.5-1.5% magnesium stearate by weight. In certain embodiments, the tablet contains 20% Compound 1 HCl salt by weight, 37.25% microcrystalline cellulose (e.g. Avicel PH102) by weight, 37.25% mannitol (e.g. Emprove Parteck) by weight, 4% croscarmellose sodium (eg Ac-Di-Sol) by weight, 0.5% colloidal silicon dioxide (eg Aerosil 200) by weight and 1% magnesium stearate by weight. In certain embodiments of the invention, the total weight of the tablet is between 225-275 mg. In certain embodiments of the invention, the total weight of the tablet is 250 mg.

In certain embodiments of the invention, this document provides a tablet containing 15-25% citrate salt of compound 1 by weight, 32-43% microcrystalline cellulose (for example, Avicel PH102) by weight, 32-43% mannitol (for example, Emprove Parteck) by weight. by weight, 2-6% croscarmellose sodium (e.g. Ac-Di-Sol) by weight, 0.3-0.7% colloidal silicon dioxide (e.g. Aerosil 200) by weight and 0.5-1.5% magnesium stearate by weight. In certain embodiments of the invention, this tablet contains 20% citrate salt of compound 1 by weight, 37.25% microcrystalline cellulose (for example, Avicel PH102) by weight, 37.25% mannitol (for example, Emprove Parteck) by weight, 4% croscarmellose sodium (eg Ac-Di-Sol) by weight, 0.5% colloidal silicon dioxide (eg Aerosil 200) by weight and 1% magnesium stearate by weight. In certain embodiments of the invention, the total weight of the tablet is between 225-275 mg. In certain embodiments of the invention, the total weight of the tablet is 250 mg.

5.2.5. Spray-dried dispersion composition.

In certain embodiments, provided herein is a spray-dried dispersion formulation of Compound 1.

In certain embodiments, the spray-dried dispersion composition provided herein can be prepared by the spray-drying process of Compound 1 as illustrated in FIG. 60. In certain embodiments, the spray drying method comprises

- 12 040951

1) mixing compound 1 and excipient with a solvent (eg acetone, methanol, water or mixtures thereof);

2) heating the mixture to a certain temperature (for example, about 80°C);

3) drying the mixture by spraying; And

4) collecting the resulting solids.

In certain embodiments of the invention, the excipient is a polymer. In another embodiment, the excipient is a polymer selected from the group consisting of HPMCAS-M, PVP VA64, PVA-P, and HPMC E3. In one embodiment of the invention, the solvent is acetone. In another embodiment of the invention, the solvent is a mixture of methanol and water (eg v/v 9:1) or a mixture of acetone and water (eg v/v 9:1).

In certain embodiments, the spray-dried dispersion formulation contains Compound 1 free base, HPMC, TPGS, microcrystalline cellulose (eg, Avicel PH102), mannitol, cross-linked polyvinylpyrrolidone (eg, Kollidon CL), colloidal silica, and stearic acid. In certain embodiments, the spray-dried dispersion formulation contains about 10-40% Compound 1 free base by weight, about 15-60% HPMC by weight, about 2-10% TPGS by weight, about 10-40% microcrystalline cellulose (e.g., Avicel PH102) by weight, about 10-40% mannitol by weight, about 2-8% cross-linked polyvinylpyrrolidone (e.g. Kollidon CL) by weight, about 0.3-1.5% colloidal silica by weight and about 0.5 -2% stearic acid by weight. In certain embodiments, the spray-dried dispersion formulation contains about 20% Compound 1 free base by weight, about 28.6% HPMC by weight, about 5.4% TPGS by weight, about 20.2% microcrystalline cellulose (e.g., Avicel PH102 ) by weight, about 20.2% mannitol by weight, about 4% crosslinked polyvinylpyrrolidone (eg Kollidon CL) by weight, about 0.6% colloidal silica by weight and about 1% stearic acid by weight.

5.3. Sets.

Also provided are pharmaceutical packages or kits that contain the pharmaceutical compositions or dosage forms provided herein. Illustrative examples of kits include a notice in the form prescribed by a government agency regulating the manufacture, use, or sale of a pharmaceutical product, which notice reflects the approval of the manufacturing, use, or sale agency for administration to a human. 5.4. Application methods.

Compound 1 formulations described herein may be used as medicaments for the treatment, prevention, or amelioration of conditions in animals or humans. Accordingly, this document provides formulations of Compounds 1 described herein that can be used in all methods as described herein. In particular, the formulations of Compound 1 provided herein are for use in methods of treating or preventing cancer. For example, the compounds of Compound 1 provided herein are for use in methods of treating cancer. Methods provided herein include administering an effective amount of one or more formulations of Compounds 1 described herein to a subject in need thereof. It should be understood that the methods described herein also include treatment with a pharmaceutical composition such as those below.

In another aspect, provided herein are methods for treating or preventing cancer comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some embodiments, the cancer is a solid tumor or a hematologic tumor. In some embodiments, the cancer is not melanoma.

In some embodiments, the solid tumor is melanoma, colorectal cancer, gastric cancer, head and neck cancer, thyroid cancer, bladder cancer, CNS cancer, lung cancer, pancreatic cancer, and soft tissue cancer. In one embodiment, the solid tumor is endocrine cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, duodenal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC), esophageal cancer, thyroid cancer, or pancreatic cancer.

In other embodiments, the cancer is bladder cancer, breast cancer (e.g., Her positive, Her negative, or EGFR positive breast cancer), CNS cancer (including neuroblastoma and glioma), colon cancer, gastrointestinal cancer (e.g., , stomach cancer, and colon cancer), endocrine cancer (such as thyroid or adrenal cancer), female genital cancer (such as cervical cancer, clear cell ovarian cancer, vulvar cancer, uterine cancer, or ovarian cancer), head cancer and neck, hematopoietic cancer (for example, leukemia or myeloma), kidney cancer, liver cancer, lung cancer (for example, NSCLC or SCLC), melanoma, pancreatic cancer, prostate cancer, or soft tissue cancer (for example, sarcoma or osteosarcoma).

Also provided herein are methods of treating or preventing hepatocellular carcinoma (HCC) comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein.

Also provided herein are methods of treating or preventing colorectal cancer (CRC), melanoma, gastric cancer, HCC, lung cancer, pancreatic cancer, leukemia, or multiple myeloma, comprising administering to a subject in need thereof an effective amount of a compound 1 formulation. , as described herein, or its pharmaceutical composition, as described herein. In one embodiment of the invention, CRC, gastric cancer or HCC is a cancer characterized by a β-catenin mutation. Also provided herein are methods of treating or preventing colorectal cancer (CRC), gastric cancer, HCC, lung cancer, pancreatic cancer, leukemia, and multiple myeloma, comprising administering, as described herein, to a subject in need thereof, an effective amount of a composition compound 1 as described in this document.

In another embodiment, provided herein are methods for treating leukemia comprising administering a composition of Compound 1 as described herein or a pharmaceutical composition thereof. The leukemia may be chronic myelogenous leukemia (CML - chronic myelogenous leukemia). In another embodiment, the leukemia is acute myelogenous leukemia (AML - acute myelogenous leukemia). In one embodiment, the leukemia is FLT-3 mutated AML.

In another embodiment of the invention, provided herein are methods for treating lymphoma comprising administering a composition of Compound 1 as described herein, or a pharmaceutical composition thereof. The lymphoma may be Burkitt's lymphoma. In one embodiment, the leukemia is Hodgkin's lymphoma. In another embodiment of the invention, the leukemia is a B-cell lymphoma. In another embodiment of the invention, the leukemia is a T-cell lymphoma. In yet another embodiment of the invention, the lymphoma is primary effusion lymphoma (PEL).

Compound 1 formulations exhibit antiproliferative activity in a variety of cancer cell lines. The antiproliferative activity in these cancer cell lines indicates that Compound 1 formulations are useful in the treatment of cancers, including hematopoietic and solid tumors. In one embodiment, the hematopoietic and solid tumors are selected from bladder cancer, breast cancer, CNS cancer (e.g., neuroblastoma, medulloblastoma, and glioma), colon cancer, duodenal cancer, endocrine system cancer (e.g., thyroid cancer, and cancer adrenal glands), female genitourinary system cancer (eg, uterine cancer, cervical cancer, ovarian cancer, and vulvar cancer), head and neck cancer (eg, esophageal cancer), hematopoietic and lymphoid cancers (eg, lymphoma, leukemia, and myeloma), cancer kidney, liver cancer, lung cancer (eg, NSCLC and SCLC), pancreatic cancer, prostate cancer, skin cancer (eg, melanoma and carcinoma), soft tissue cancer (eg, sarcoma and osteosarcoma), stomach cancer, and testicular cancer. In one embodiment, the hematopoietic and solid tumors are selected from bladder cancer, breast cancer, CNS cancer (e.g., neuroblastoma, medulloblastoma, and glioma), colon cancer, duodenal cancer, endocrine system cancer (e.g., thyroid cancer, and cancer adrenal glands), female genitourinary tract cancers (eg, uterine, cervical, and vulvar cancers), head and neck cancers, hematopoietic and lymphoid cancers (eg, lymphoma, leukemia, and myeloma), kidney cancer, liver cancer, lung cancer (eg. , NSCLC, and SCLC), pancreatic cancer, prostate cancer, skin cancer (eg, melanoma and carcinoma), soft tissue cancer (eg, sarcoma and osteosarcoma), stomach cancer, and testicular cancer.

In another embodiment, the Compound 1 formulations described herein induce apoptosis in a variety of cancer cell lines. The induction of apoptosis indicates that the Compound 1 formulations described herein are useful in the treatment of cancers, including hematopoietic and solid tumors. In one embodiment, the hematopoietic and solid tumors are selected from bladder cancer, breast cancer, CNS cancer (e.g., neuroblastoma and glioma), colon cancer, duodenal cancer, endocrine system cancer (e.g., thyroid cancer, and adrenal cancer) , cancer of the female genitourinary system (eg, uterine cancer, cervical cancer, ovarian cancer, and vulvar cancer), head and neck cancer (eg, esophageal cancer), hematopoietic and lymphoid cancer (eg, lymphoma, leukemia, and myeloma), kidney cancer, liver cancer, lung cancer (eg, NSCLC and SCLC), pancreatic cancer, prostate cancer, skin cancer (eg, melanoma and carcinoma), soft tissue cancer (eg, sarcoma and osteosarcoma), stomach cancer, and testicular cancer. In one embodiment, the hematopoietic and solid tumors are selected from bladder cancer, breast cancer, CNS cancer (e.g., neuroblastoma and glioma), colon cancer, duodenal cancer, endocrine system cancer (e.g., thyroid cancer, and adrenal cancer) , female genitourinary cancer

- 14 040951 systems (eg vulvar cancer), head and neck cancers (eg esophageal cancer), hematopoietic and lymphoid cancers (eg lymphoma and leukemia), kidney cancer, liver cancer, lung cancer (eg NSCLC and SCLC), pancreatic cancer, prostate cancer, skin cancer (eg melanoma), soft tissue cancer (eg sarcoma and osteosarcoma), gastric cancer and testicular cancer. In one embodiment, the hematopoietic and solid tumors are selected from bladder cancer, breast cancer, CNS cancer (e.g., medulloblastoma, neuroblastoma, and glioma), colon cancer, duodenal cancer, endocrine system cancer (e.g., thyroid cancer, and adrenal glands), cancers of the female genitourinary system (eg, placental cancer, uterine cancer, cervical cancer, ovarian cancer, and vulvar cancer), head and neck cancers (eg, esophageal cancer), hematopoietic and lymphoid cancers (eg, lymphomas, leukemia, and myeloma ), kidney cancer, liver cancer, lung cancer (eg, NSCLC and SCLC), pancreatic cancer, prostate cancer, skin cancer (eg, melanoma and carcinoma), soft tissue cancer (eg, sarcoma and osteosarcoma), stomach cancer, and cancer testicles.

Also provided herein are methods of treating or preventing cancer characterized by a BRAF mutation and/or a beta-catenin mutation (alternatively referred to as a CTNNB1 mutation) comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the cancer is characterized by a BRAF mutation. In another embodiment of the invention, the cancer is characterized by a beta-catenin mutation. In yet another embodiment of the invention, the cancer is characterized by an activated beta-catenin pathway. In some such embodiments, the CRC cancer or melanoma was characterized by a BRAF mutation. In other embodiments, the cancer is a CRC characterized by a beta-catenin mutation further containing an EGFR mutation or increased EGFR activity EGFR). In still other embodiments, the cancer is a gastric cancer characterized by a beta-catenin mutation further comprising a KRAS mutation (i.e., a gastric cancer characterized by an activated beta-catenin pathway and a KRAS mutation). In another embodiment, the cancer is an HCC characterized by an activated beta-catenin pathway. In some such embodiments, the BRAF mutation is BRAF V660E. In some such embodiments, the BRAF mutation is BRAF V600E. In some such embodiments, the BRAF mutation is one or more of BRAF V600E, BRAF T119S, or BRAF G596R. In some such embodiments, the beta-catenin mutation is one or more of the S33Y, G34E, S45del, or S33C beta-catenin mutations. In some such embodiments, the EGFR mutation is one or more of EGFR E282K, G719S, P753S, or V1011M. In some such embodiments, the KRAS mutation is A146T, G12C, G12D, G12V, G13D, or Q61L.

Also provided herein are methods for treating or preventing cancer expressing PD-L1, comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the cancer expressing PD-L1 is melanoma, lung cancer, renal cell carcinoma (RCC), or HCC.

Also provided herein are methods of treating or preventing cancer characterized by a BRAF mutation, comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the cancer characterized by the BRAF mutation is CRC, thyroid cancer, melanoma, or lung cancer. In some such embodiments, the cancer characterized by the BRAF mutation is CRC, thyroid cancer, or lung cancer. In some such embodiments, the BRAF mutation is BRAF V660E. In some such embodiments, the BRAF mutation is BRAF V600E. In other embodiments, the BRAF mutation is one or more of BRAF V600E, BRAF T119S, or BRAF G596R.

Also provided herein are methods of treating or preventing cancer characterized by an NRAS mutation, comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the cancer characterized by the NRAS mutation is melanoma.

Also provided herein are methods of treating or preventing cancer characterized by a KRAS mutation comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the cancer characterized by the KRAS mutation is CRC, pancreatic cancer, or lung cancer.

Also provided herein are methods of treating or preventing cancer characterized by a beta-catenin mutation, comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. Also provided herein are methods of treating or preventing cancer characterized by an activated beta-catenin pathway, comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the cancer characterized by the beta-catenin mutation is CRC, gastric cancer, HCC, or sarcoma. In some such embodiments, the cancer characterized by the activated beta-catenin pathway is CRC, gastric cancer, HCC, or sarcoma.

This document also provides methods of treating or preventing hepatocellular carcinoma (HCC) comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the HCC is characterized by a beta-catenin mutation and/or overexpression of YAP. In some such embodiments, the HCC is characterized by an activated betacatenin pathway and/or increased expression of YAP amplification. In some embodiments of the invention, the increased expression of YAP is due to amplification or mutation.

Also provided herein are methods of treating or preventing colorectal cancer (CRC) comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the CRC is characterized by a BRAF mutation and/or a beta-catenin mutation. In some such embodiments, the CRC is characterized by a BRAF mutation and/or an activated betacatenin pathway.

Also provided herein are methods of treating or preventing gastric cancer comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the gastric cancer is characterized by a beta-catenin mutation. In some such embodiments, the gastric cancer is characterized by an activated beta-catenin pathway.

Also provided herein are methods for treating or preventing melanoma comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the melanoma is characterized by a BRAF mutation and/or an NRAS mutation.

Also provided herein are methods for predicting response to treatment with a compound 1 formulation described herein in a patient having a cancer characterized by a gene mutation, the method comprising

a) obtaining a biological test sample from a cancer patient;

b) obtaining a gene sequence of one or more genes selected from BRAF, NRAS, KRAS and/or CTNNB1 in said biological test sample;

c) comparing said gene sequence(s) with the wild-type biological sample gene sequence(s), wherein the presence of the mutation indicates an increased likelihood of responding to the Compound 1 formulation described herein for treating said cancer patient.

In some such embodiments, the method further comprises administering an effective amount of a Compound 1 formulation as described herein.

In addition, this document provides methods for predicting the therapeutic efficacy of the composition of compound 1 described herein for the treatment of a patient having a cancer characterized by a gene mutation, and the method includes

a) obtaining a biological test sample from a cancer patient;

b) obtaining the gene sequence(s) of one or more genes selected from BRAF, NAS, KRAS and/or CTNNB1 in said biological test sample;

c) comparing said gene sequence(s) with the wild-type biological sample gene sequence(s), wherein the presence of the mutation indicates an increased likelihood of therapeutic efficacy of said compound 1 formulation described herein treatment in said patient.

In some such embodiments, the method further comprises administering an effective amount of a Compound 1 formulation as described herein.

In some embodiments, provided herein are methods for treating and preventing cancer metastases comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some embodiments, the cancer is a metastatic cancer, in particular a metastatic solid tumor or a metastatic hematologic cancer, wherein the solid tumor and hematologic cancer are as described herein. In other embodiments, provided herein are methods for treating and preventing cancer metastases comprising administering to a subject in need thereof an effective amount of a Compound 1 formulation as described.

- 16 040951 in this document. In yet another aspect, provided herein are methods for killing cancer stem cells in a subject, comprising administering to the subject in need thereof an effective amount of a Compound 1 formulation as described herein. In other embodiments, provided herein are methods for inducing differentiation in cancer stem cells in a subject, comprising administering to the subject in need thereof an effective amount of a Compound 1 formulation as described herein. In other embodiments, provided herein are methods for inducing cancer stem cell death in a subject, comprising administering to the subject in need thereof an effective amount of a Compound 1 formulation as described herein. In some such embodiments, the cancer is a solid tumor or hematologic cancer, as described herein.

In one embodiment, provided herein are methods of achieving, according to the Objective Response Evaluation in Solid Tumors (RECIST 1.1) criteria, complete response, partial response, or disease stabilization in a patient, comprising administering an effective amount of a Compound 1 formulation described herein to the patient having cancer, in particular a solid tumor, as described herein. In another embodiment of the invention, this document provides methods for improving progression-free survival, which are calculated using the Kaplan-Meier method.

In one embodiment, provided herein are methods of preventing or delaying, according to the Objective Response Evaluation Criteria for Solid Tumors (RECIST 1.1), progressive disease in a patient, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having a solid tumor as described in this document. In one embodiment of the invention, the prevention or delay of progressive disease is characterized or achieved by a change in the total size of the target lesions, for example, between -30 and +20% compared to pre-treatment. In another embodiment of the invention, the change in the size of the target lesions is a decrease in the overall size of more than 30%, for example, a decrease in the size of the target lesions by more than 50% compared to pre-treatment. In another embodiment of the invention, prophylaxis is characterized or achieved by reducing the size or delaying the progression of off-target lesions compared to prior treatment. In one embodiment of the invention, prophylaxis is achieved or characterized by a reduction in the number of targeted lesions compared to prior treatment. In another case, prevention is achieved or characterized by a reduction in the number or quality of off-target lesions compared to prior treatment. In one embodiment of the invention, prophylaxis is achieved or characterized by the absence or disappearance of target lesions compared to prior treatment. In another embodiment, prevention is achieved or is characterized by the absence or disappearance of off-target lesions compared to prior treatment. In another embodiment of the invention, prevention is achieved or characterized by the prevention of new lesions compared to prior treatment. In yet another embodiment of the invention, prevention is achieved or characterized by the prevention of clinical signs or symptoms of disease progression compared to prior treatment, such as cancer-related cachexia or increased pain.

In certain embodiments, provided herein are methods of reducing the size of targeted lesions in a patient compared to prior treatment, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having a cancer, particularly a solid tumor, as described herein. .

In certain embodiments, provided herein are methods of reducing the size of an off-target lesion in a patient compared to pre-treatment, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having a cancer, particularly a solid tumor, as described herein. .

In certain embodiments, provided herein are methods for achieving a reduction in the number of targeted lesions in a patient compared to prior treatment, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having a cancer, particularly a solid tumor, as described herein. document.

In certain embodiments, provided herein are methods for achieving a reduction in off-target lesions in a patient compared to pre-treatment, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having a cancer, particularly a solid tumor, as described herein. document.

In certain embodiments, provided herein are methods for achieving resolution of all targeted lesions in a patient, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having a cancer, particularly a solid tumor, as described herein.

- 17 040951

In certain embodiments, provided herein are methods for achieving resolution of all non-target lesions in a patient, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having a cancer, particularly a solid tumor, as described herein.

In certain embodiments, provided herein are methods of treating cancer, particularly a solid tumor, as described herein, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having a cancer, particularly a solid tumor, wherein the treatment results in to a complete response, partial response, or stabilization of the disease, as defined by the Objective Response Evaluation Criteria for Solid Tumors (RECIST 1.1).

In certain embodiments, provided herein are methods for treating cancer, particularly a solid tumor, as described herein, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having a cancer, particularly a solid tumor, as described. herein, wherein the treatment results in a reduction in the size of the target lesion, a reduction in the size of the non-target lesion, and/or no new target lesions and/or non-target lesions compared to the pre-treatment.

In certain embodiments, provided herein are methods of treating cancer, particularly a solid tumor, as described herein, comprising administering an effective amount of a Compound 1 formulation, as described herein, to a patient having a cancer, particularly a solid tumor, as described herein, wherein the treatment results in the prevention or slowing of clinical progression such as cancer-related cachexia or increased pain.

In another embodiment, this document provides methods for inducing a therapeutic response characterized by International Workshop Criteria (IWC) for NHL (see Cheson B.D., Pfistner B., Juweid M.E. et. al., Revised Response Criteria for Malignant Lymphoma , J. Clin. Oncol., 2007, 25, 579-586) in a patient, comprising administering an effective amount of the Compound 1 formulation described herein to a patient having cancer, in particular hematological cancer, such as lymphoma, as described herein . In another embodiment, this document provides methods for achieving complete remission, partial remission, or disease stabilization as defined by the International Workshop (IWC) criteria for NHL in a patient, comprising administering an effective amount of Compound 1 described herein to a patient having cancer. , in particular hematological cancers such as lymphoma, as described herein. In another embodiment, this document provides methods for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, disease-free survival, or lymphoma-free survival, as defined by the International Workshop (IWC) criteria for NHL in a patient, comprising administering an effective amount compound 1 described herein to a patient having cancer, in particular hematological cancer such as lymphoma, as described herein.

In another embodiment, this document provides methods for inducing a therapeutic response as measured by the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie B.G.M., Harousseau J-L., Miguel J.S. et al., International uniform response criteria for multiple myeloma. Leukemia, 2006, 10, 10: 1-7) in a patient, comprising administering an effective amount of the Compound 1 formulation to a patient having cancer, in particular multiple myeloma. In another embodiment, provided herein are methods of achieving a strong complete response, complete response, very good partial response, or partial response as defined by the International Uniform Response Criteria for Multiple Myeloma (IURC) in a patient, comprising administering an effective amount of a compound 1 formulation described herein, a patient having cancer, in particular multiple myeloma. In another embodiment of the invention, provided herein are methods of achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having cancer, especially multiple myeloma.

In another embodiment of the invention, this document provides methods for inducing a therapeutic response, evaluated according to the criteria of the Working Group on Response Assessment for Neuro-Oncology (RANO - Response Assessment for Neuro-Oncology) for GBM (see Wen P., Macdonald D.R., Reardon D.A. et al ., Updated response criteria assessment for high-grade gliomas: Response assessment in neuro-oncology working group, J. Clin. Oncol., 201, 28: 1963-1972) in a patient, comprising administering an effective amount of Compound 1 formulation described herein document, a patient with cancer, in particular glioblastoma multiforme (GBM - glioblastoma multiforme). In one embodiment of the invention, RANO will be used to determine the proportion of subjects without progression

- 18 040951 6 months after day 1 of treatment compared to subjects evaluated for efficacy in the GBM type.

In another embodiment of the invention, this document provides methods for improving the status of a patient according to the criteria of the Eastern United Oncological Group (ECOG Eastern Cooperative Oncology Group), comprising administering an effective amount of the compound 1 composition described herein, to a patient having cancer, in particular a solid tumor or hematological cancer, as described in this document.

In another embodiment, provided herein are methods of inducing a therapeutic response as measured by positron emission tomography (PET) of a patient, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having cancer, particularly a solid tumor or hematologic cancer, as described in this document. In certain embodiments, provided herein are methods of treating cancer, particularly a solid tumor or hematologic cancer, as described herein, comprising administering an effective amount of a Compound 1 formulation described herein to a patient having a cancer, particularly a solid tumor, or hematologic cancer, as described herein, wherein the treatment results in a decrease in the metabolic activity of the tumor, eg as measured by PET imaging.

In addition, this document provides methods for treating patients who have previously been treated for cancer, in particular solid tumor or hematological cancer, as described herein, as well as those who have not previously been treated. Such methods include the introduction of the composition of compound 1 described in this document. Because patients with cancer have different clinical presentations and different clinical outcomes, the treatment provided to a patient may vary depending on his/her prognosis. Those skilled in the art can easily determine, without undue experimentation, the particular secondary agents, types of surgery, and types of non-drug standard therapies that can be effectively used to treat a particular cancer patient.

The composition of Compound 1 provided herein can be used in any of the methods described above.

6. Examples

The following examples are presented for purposes of illustration and not limitation. Compounds are named using the automatic naming tool provided by ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures with support for Cahn-Ingold-Prelog stereochemistry rules. One skilled in the art can modify the techniques set forth in the illustrative examples to obtain the desired products.

Conditional abbreviations used.

vnt Butylated hydroxytoluene SA Lemon acid si Content uniformity FaSSGF Imitation of gastric juice on an empty stomach FaSSIF Imitation of intestinal juice on an empty stomach FeSSGF Imitation of gastric juice in a full state FeSSIF Imitation of intestinal juice in a fed state FIH Human studies for the first time ΗΡ-β-CD hydroxypropyl-beta-cyclodextrin LDCs Hydroxypropylcellulose NRMS Hydroxypropyl methylcellulose MCC Microcrystalline cellulose PEG Polyethylene glycol PVA-P Polyvinyl acetate phthalate polymer PVP VA64 Vinylpyrrolidone-vinyl acetate copolymer SA Stearic acid SD Spray drying SLS Sodium lauryl sulfate SMB Sodium Metabisulphite SDD Spray Drying Dispersion SSF Sodium fumarate TPGS Tocofersolan

6.1. Obtaining spray-dried dispersion compositions.

Spray-dried dispersion formulations of compound 1 were obtained by the drying method

- 19 040951 compound 1 by spraying, as shown in FIG. 60. The spray drying method included (1) mixing Compound 1 with a solvent at 25°C to form a slurry;

(2) heating the suspension to about 80°C (78-88°C);

(3) spray drying under the conditions of Table. 1 or 2 to obtain a spray-dried dispersion composition; and (4) collecting the resulting solid.

Table 1

Spray Drying Conditions Part A

column number Content of active substance in composition dry base [wt. %] Description of composition Resin type Loading the polymer into the solution [wt. %] Solvent Solids content of spray solution [wt. %] Lot size [g] Raw yield [%] 1 10 10%A:HPM CAS-M HPMCASM 3.6 Acetone 4 2 100 2 25 25%A:HPM CAS-M HPMCASM 3.6 Acetone 4 0.8 87 3 25 25%A:PVP VA64 PVP VA64 3.6 Acetone 4 0.8 82 4 25 25%A:PVAP PVA-P 3.6 9/1 MeOH/Water 4 0.8 90 5 25 10%A:NRM CEZ NRMS E3 3.6 9/1 MeOH/Water 4 0.8 64 6 25 25/65/10 A:PVP VA64:TPGS PVP VA64 3 Acetone 4 1 91 7 25 25/65/10 A:PVAP:TPGS PVA-P 3 Acetone 4 1 94 8 25 25/65/10A:HPMC E3:TPGS NRMS E3 2 9/1 Methanol/water 4 1 25 9 50 50% A:PVAP PVA-P 2 9/1 Acetone/water 4 0.5 100 10 50 50% A:HPMC E3 NRMS E3 2 9/1 Methanol/water 4 0.5 37 eleven 50 50/40/10A:HPMC E3:TPGS NRMS E3 2 9/1 Methanol/water 4 0.5 52 12 50 50/40/10 A:PVAP:TPGS PVA-P 2 9/1 Acetone/water 4 0.5 52 13 50 50/40/10A:PVP PVP VA64 2 Acetone 4 0.5 94 VA64:TPGS

- 20 040951

table 2

Conditions part B

column number The content of the active substance in the composition of the dry base [May. %] Description of composition Resin type Loading the polymer into the solution [May. %] Solvent Solids content of spray solution [wt%] Lot size [g] Raw yield [%] 1 10 10%A:HPM CAS-M HPMCASM 3.6 Acetone 4 2 100 2 25 25%A:HPM CAS-M HPMCASM 3.6 Acetone 4 0.8 87 3 25 25%A:PVP VA64 PVP VA64 3.6 Acetone 4 0.8 82 4 25 25%A:PVAP PVA-P 3.6 9/1 MeOH/Water 4 0.8 90 5 25 10%A:NRM CEZ NRMS E3 3.6 9/1 MeOH/Water 4 0.8 64 6 25 25/65/10 A:PVP VA64:TPGS PVP VA64 3 Acetone 4 1 91 7 25 25/65/10 A:PVAP:TPGS PVA-P 3 Acetone 4 1 94 8 25 25/65/10A:HPMC E3:TPGS NRMS E3 2 9/1 Methanol/water 4 1 25 9 50 50% A:PVAP PVA-P 2 9/1 Acetone/water 4 0.5 100 10 50 50% A:HPMC E3 NRMS E3 2 9/1 Methanol/water 4 0.5 37 eleven 50 50/40/10A:HPMC E3:TPGS NRMS E3 2 9/1 Methanol/water 4 0.5 52 12 50 50/40/10 A:PVAP:TPGS PVA-P 2 9/1 Acetone/water 4 0.5 52 13 50 50/40/10A:PVP PVP VA64 2 Acetone 4 0.5 94 VA64:TPGS

6.2. Summary of Animal Compound 1 Pharmacokinetic (PK) Studies.

Compound 1 contains a basic fragment and has a pH dependent solubility profile. It is expected that in the normal pH range in the stomach, solubility and bioavailability will vary, resulting in PK variability within and between patients. In-vitro and in-vivo evaluations of a variety of Blend in Capsule (BIC) formulations have been undertaken to minimize the dependence of pH on drug release.

A systematic formulation development was carried out, as a result of which three formulations were selected (traditional formulation (F4-1 in Table 11) (A), improved formulation (F15, Table 27) (B) and dispersion obtained by spray drying ( column 1, tables 1, 2) (SDD) (C)) for evaluation in a PK study in dogs. Formulation A (traditional excipients) showed the greatest variability in exposure and decreased exposure with increasing gastric pH. Composition C (SDD) showed the highest effects, but had a moderate decrease in exposure at elevated gastric pH.

Formulation B was recommended as the basis for the development of the first use of the composition in humans (FIH - First In Human). Mixing an acidulant (eg, citric acid) and a surfactant (eg, sodium lauryl sulfate) provided a synergistic effect in controlling the local pH while increasing drug solubility. Both Formulations B and C have shown the potential to reduce the effects of gastric pH. Formulation C used an amorphous SDD drug intermediate.

6.3. Study of 1 prototype formulations.

Seven mixtures of Compound 1 were prepared using the method described in FIG. 1 to evaluate the release (dissolution) of the drug. The composition of each mixture is illustrated in table. 3. Functional excipients were grouped into three classes: acidifiers (tartaric acid, fumaric acid and citric acid), precipitation inhibitors (PEG4000 and hydroxypropyl cellulose) and solubilizer (hydroxypropyl beta-cyclodextrin).

- 21 040951

Table 3

Compositions of Prototype Formulations (Study 1)

(% w/w) F1-1 F1-2 F1-3 F1-4 F1-5 F1-6 F1-7 Citrate salt of compound 1 26.7 MSS RN 102 33.8 23.8 Mannitol 33.8 23.8 Wine acid 20 Fumarovaya acid 20 Lemon acid 20 PEG4000 20 LDCs 20 ΗΡ-β-CD 20 Kollidon CL 4.0 Colloidal SiO ₂ 0.6 Stearic acid 1.0 General 100 Total weight (mg) 250

HPC=hydroxypropyl cellulose;

HP-β-CD=hydroxypropyl-beta-cyclodextrin;

MCC=microcrystalline cellulose;

PEG=polyethylene glycol.

Dissolution Condition 1 (Table 4) was used to evaluate the release of Study 1 formulations (Section 6.3) in gelatin (FIG. 2) and HPMC (FIG. 3) shell capsules. The two-step dissolution condition 2 (Table 5) was also used to evaluate the release of study 1 formulations in gelatin (FIG. 4) and HPMC (FIG. 5) shell capsules.

Dissolution conditions 1.

Table 4

Study 1. 2 Dissolution Method Formulation (FaSSIF)

Dissolution parameter Settings Apparatus USP Apparatus II (vane) Dissolution medium FaSSIF (pH 6.8) Medium volume 900 ml Medium temperature 37±0.5°C RPM (RPM) 75 rpm for the first 60 min and at infinity (250 rpm for the next 15 min) Sampling time 10, 15, 20, 30, 45, 60 and 75 minutes Sample volume 1.5 ml (without medium change) Flush volume 3.0 ml Discharge volume 2.0 ml Filter 10 µm full flow UHMW PE filter Analysis HPLC (UV 230 nm)

RPM=revolutions per minute;

USP=USP;

FaSSIF = simulated fasting intestinal juice.

- 22 040951

dissolution conditions 2.

Table 5

Dissolution Method for Composition Study 1 (two-step)

Dissolution parameter Settings Apparatus USP Apparatus II (vane) Medium Temperature RPM (RPM) 37°С±0.5°С 75 rpm The volume of selected samples 1.5 ml (without medium change) Flush volume 3.0 ml Discharge volume 2.0 ml Filter 10 µm full flow UHMW PE filter Analysis HPLC (UV 230 nm) Dissolution medium 1 0.lN HC1 (pH ~ 1.2, for gastric pH) Medium volume 750 ml Sampling time 10, 15, 20, 30, 45 and 60 Dissolution medium 2 0.2M tribasic sodium phosphate was added to the vessel. Adjusted the pH in the vessel to 6.80 ± 0.05 Medium volume 250 ml Sampling time 10, 15, 20, 30, 45 and 60 (after addition)

RPM=revolutions per minute;

USP=USP;

FaSSIF = simulated fasting intestinal juice.

Findings from Study 1 include the exclusion of excipients (tartaric acid, hydroxypropyl cellulose, and HP-e-CD) from consideration due to their undemonstrated ability to mitigate the effects of gastric pH as measured by percent drug release.

Compound 1 was precipitated during the buffer step (pH 6.8) of the 2-step dissolution in F1-2 (tartaric acid) gelatin capsules.

The released percentage of F1-5 (PEG4000) was low under FaSSIF conditions.

The percentage released F1-6 (FLPC) was low in both FaSSIF and 2-step dissolution.

6.4. Study of 2 prototype formulations.

Six mixtures of Compound 1 were prepared according to the method shown in FIG. 1 to evaluate the release (dissolution) of the drug. The composition of each mixture is illustrated in table. 6. Formulations were evaluated based on combinations of different functional excipients such as surfactant (SLS), acidifier+precipitation inhibitor (fumaric acid or citric acid+PEG4000), acidifier+surfactant (citric acid+SLS), inhibitor precipitation+surfactant (PEG4000+SLS), acidifier+precipitation inhibitor+surfactant (citric acid+PEG4000+SLS).

See table. 7.

- 23 040951

Table 6

Prototype Formulation Compositions (Study 2)________

(% w/w) F2-1 F2-2 F2-3 F2-4 F2-5 F2-6 citrate salt connections 1 26.72 MSS RN 102 13.84 13.84 28.84 18.84 18.84 8.84 Mannitol 13.84 13.84 28.84 18.84 18.84 8.84 Fumarovaya acid 20 Lemon acid 20 20 20 PEG4000 20 20 20 20 SLS 10 10 10 10 Kollidon CL 4.0 Colloidal SiO ₂ 0.6 Stearic acid 1.0 General 100 Total weight (mg) 250

MCC=microcrystalline cellulose;

PEG=polyethylene glycol;

SLS=sodium lauryl sulfate.

In addition to the above six improved drug release (dissolution) formulations, one mixture was also prepared containing a spray-dried dispersion (SDD) of Compound 1. The composition of the SDD formulation mixture is illustrated in Table 1. 7.

Intermediate SDD was prepared in the following ways: compound 1 was dissolved in acetone in vessel 1. HPMC and TPGS were dissolved in water (heated to HPMC/TPGS solution at a ratio of 4:6 and mixed to obtain a clear and homogeneous solution. The solution was then fed into the Buchi B-290 at the desired flow rate and inlet temperature.

The SDD intermediate powder was obtained in a collection vessel.

A mixture of 10 g of the formulation was prepared according to the method described in FIG. 1, where Compound 1 was SDD.

- 24 040951

Table 7

Compositions of Prototype Formulation F2-7 in Study 2 (SDD)

Component % May ./May. Weight per capsule (mg) Free base compound 1 20 135.1 mg intermediate SDD connections (37/53/10 Compound 1 Free Base /HPMC/TPGS) (54.0% May/May of composition) NRMS 28.6 TPGS 5.4 MSS RN 102 20.2 50.45 Mannitol 20.2 50.45 Kollidon CL 4.0 10 Colloidal SiO ₂ 0.6 1.5 Stearic acid 1.0 2.5 General 100 250

HPMC=hydroxypropyl methylcellulose;

MCC=microcrystalline cellulose;

TPGS=vitamin E (n-a-tocopheryl) polyethylene glycol 1000 succinate.

Dissolution Condition 1 (Table 4) was used to evaluate the release of Study 2 formulations in gelatin (FIG. 6) and HPMC (FIG. 7) shell capsules. Dissolution Condition 3 (Table 8) was also used to evaluate the release of Study 2 formulations in gelatin (FIG. 8) and HPMC (FIG. 9) capsule shells.

Among the compositions presented in table. 6, SLS alone (F2-3) and in combination with acid (F2-4) or polymer (F2-5) provide a higher percentage release compared to other formulations, suggesting that SLS is important for fast and immediate release of Compound 1. The combination of acid and polymer (F2-1, F2-2) does not produce a synergistic effect. Similarly, the combination of SLS, acid and polymer (F2-6) does not result in complete release of Compound 1 in gelatin capsules until time infinity and has a slightly slower release in FLPMC capsules. Therefore, PEG4000 does not improve drug release and was therefore excluded from further evaluation. SDD (F2-7) has a slower release profile, but releases completely before infinity

The solubility of compound 1 was determined at various percentages of sodium lauryl sulfate (SLS). 0.03% SLS was chosen as the medium for dissolution conditions 3. Samples were filtered using a 0.2 µm nylon syringe filter and analyzed by UHPLC-UV using the method parameters listed in Table 1. 9.

Table 8

Solubility of compound 1 citrate with SLS in phosphate buffer at pH 6.5

%SLS Solubility (mg salt/ml) 0.01 0.000 0.02 0.001 0.03 0.054 0.05 0.336 0.1 0.807

SLS=sodium lauryl sulfate.

- 25 040951

Table 9

UHPLC Conditions for Composition Stability

UHPLC parameter Settings Column Waters Acquity UPLC CSH С18 dimensions 3.0x150mm Particle size 1.7 µm Column temperature 45°С Autosampler temperature 5°С mobile phases A: 0.01% TFA in water B: Acetonitrile Injection volume 4 µl Flow rate 0.5 ml/min Run time 26 min Wavelength detector 244 nm Gradient Time (min) A% IN% 0.0 90 10 1.0 90 10 14.0 50 50 20.0 10 90 21.0 10 90 21.1 90 10 26.0 90 10

6.5. Study of 3 prototype formulations.

Study 3 included the capsules prepared in Studies 1 and 2. F3-1 was F1-1 from Study 1 filled into size #00 white opaque gelatin capsules. F3-2 was F1-4 from Study 1 filled into white opaque gelatin capsules. size #00 gelatin capsules. F3-3 was F1-3 from Study 2 filled into size #00 white opaque gelatin capsules. F3-4 was pure intermediate SDD powder filled into size #00 white opaque gelatin capsules. due to the low bulk density of the intermediate SDD, a maximum amount of 108.08 mg was filled into the capsule shell, equivalent to a 40 mg dose of Compound 1 free base. F3-5 corresponded to F2-7 from Study 2, compressed into a tablet. 200 mg of the F3-5 mixture was compressed into one tablet using a Carver press using a compaction force of 2000 pounds and a standard flat face tool. F3-6 contained formulation components similar to F3-5 but with an increased level of disintegrant (Kollidon CL) of 10% instead of 4%. F3-6 was received in the same way as in study 2 was received F2-7. To compare the dissolution profile with F3-4 and F3-5, F3-6 contained 200mg of the blend filled into size #0 gelatin capsules to provide the same 40mg dosage as found in F3-4 and F3-5. The composition of each mixture is illustrated in table. 3.

- 26 040951

Table 10

Prototype Formulation Compositions (Study 3)

(% May ./May.) F3-1 F3-2 F3-3 F3-4 F3-5 F3-6 Citrate salt of compound 1 26.7 Connection 1 SDD ¹ 100 54.0 54.0 MSS RN 102 33.8 23.8 28.84 20.2 17.2 Mannitol 33.8 23.8 28.84 20.2 17.2 Lemon acid 20 SLS 10 Kollidon CL 4.0 4.0 10.0 Colloidal SiO ₂ 0.6 0.6 0.6 Stearic acid 1.0 1.0 1.0 General 100 Total weight (mg) 250 108.08 200 200 Compound 1 milligram 50 40

MCC=microcrystalline cellulose;

SLS=sodium lauryl sulfate;

F3-1=F1-1 (Study 1);

F3-2=F1-4 (Study 1);

F3-3=F2-3 (study 2);

F3-5 (compressed into a tablet)=F2-7 (study 2 received as a capsule).

¹ SDD=37/53/10% w/w/w, free base of compound 1/HPMC/TPGS.

Since there was no significant difference in dissolution rates between gelatin capsules and HPMC capsules of the same formulation in Study 1 and Study 2, gelatin capsules were selected in subsequent dissolution evaluations. Dissolution Condition 3 (Table 8) was used to evaluate the release of Study 3 formulations (FIG. 10). Study 3 includes the gelatin capsules prepared in Studies 1 and 2 and analyzed using Dissolution Method 3, also used to evaluate Study 2 samples (FIG. 8).

F3-1 was prepared in Study 1 as F1-1. F3-2 was prepared in Study 1 as F1-4. F3-3 was prepared in Study 2 as F2-3. F3-4 contained only an intermediate SDD filled into capsules. F3-5 was received in Study 2, as was F2-7 SDD, and compressed into a tablet. F3-6 was the new SDD formulation for Study 3.

F3-3 showed the fastest drug release of all six formulations, confirming the findings of Study 2, i.e. SLS has made a key contribution to enhancing the drug release profile. F3-2 (citric acid) showed a dissolution profile similar to that of F3-1 (traditional), implying that acid alone is not as effective as SLS in enhancing drug dissolution. The dissolution of the new F3-6 SDD formulation was improved compared to the original SDD formulation, most likely due to the increased levels of baking powder in the formulation. However, it was still slower than the F3-3, an improved SLS lineup. F3-5 (SDD tablet) did not disintegrate, and the addition of a super disintegrant (eg, Ac-Di-Sol, croscarmellose sodium) would likely be beneficial for drug release if tablet formulations are investigated in the future.

6.6. Study of 4 prototype formulations.

Study 4 evaluated acidifier, surfactant, and combinations of acidifier and surfactant. Seven mixtures of Compound 1 were prepared according to the method outlined in FIG. 1 to evaluate the release (dissolution) of the drug. The composition of each mixture is illustrated in table. 11. In this study, the drug content values were reduced from 26.7% (50 mg dose) to 13.36% (20 mg dose) and the content weight was set to 200 mg to match the dose content required in the PK study on animals.

Table 11 _________ Prototype Formulation Compositions (Study 4) _________

(% w/w) F4-1 F4-2 F4-3 F4-4 F4-5 F4-6 F4-7 citrate salt connections 1 13.36 Connection 1 SDD ¹ 27.88 MSS RN 102 40.52 35.52 35.52 38.02 33.02 33.02 33.26 Mannitol 40.52 35.52 35.52 38.02 33.02 33.02 33.26 Lemon acid 10 10 Fumarovaya acid 10 10 SLS 5 5 5 Kollidon CL 4 Colloidal SiO ₂ 0.6 Stearic acid 1 General 100 Total weight (mg) 200

MCC=microcrystalline cellulose;

SLS=sodium lauryl sulfate.

¹ SDD=37/53/10% w/w/w, free base of compound 1/HPMC/TPGS.

Dissolution Condition 3 (Table 8) was used to evaluate the release of study formulations 4 (Figure 11) in gelatin-coated capsules.

The citric acid+SLS (F4-5) formulation was superior to the other formulations in release upon dissolution, although the difference is not significant under the dissolution conditions used. The dosage in Study 4 was reduced from 50 mg per capsule used in Studies 1-3 to 20 mg per capsule to mimic the dosage used in the subsequent animal PK study.

Disintegration of the SDD (F4-7) capsules is slow due to the large amount of non-polar HPMC in the spray-dried intermediate.

F4-1 (traditional), F4-5 (improved: citric acid+SLS) and F4-7 (adapted: SDD) are selected for 1-month stability assessment (section 6.7) and evaluation in the PK study in dogs (section 6.8) .

6.7. Preliminary stability results for selected capsule formulations.

Three selected formulations from study 4 (section 6.6) were evaluated for stability under open dish conditions. Analysis and impurities were evaluated for storage up to 1 month at 25°C/60% relative humidity (RH - relative humidity) and 40°C/75% relative humidity RH. Liquid chromatography was used to evaluate the samples.

- 28 040951

Table 12

HPLC and impurity analysis results for selected formulations

Compound Anali 3 RRT Total impurity content 0.36 0.41 0.84 0.89 0.95 0.96 0.98 1.04 1.10 F4-1 Initial 85.7 But BUT BUT QL 0.51 BUT 0.33 QL 0.32 1.16 2W 40°C/75% RH 90.9 But But But QL 0.50 0.06 0.32 QL 0.31 1.20 1M 25°C/60% RH 90.5 But But But QL 0.50 But 0.32 QL 0.32 1.14 1M 40°C/75% RH 90.0 But But But QL 0.50 But 0.32 QL 0.32 1.14 F4-5 Initial 85.3 But But But QL 0.50 QL 0.33 QL 0.31 1.15 2W 40°C/75% RH 87.8 But But QL QL 0.51 QL 0.33 QL 0.31 1.15 1M 25°C/60% RH 88.2 <QL QL BUT QL 0.51 QL 0.33 QL 0.31 1.15 1M 40°C/75% RH 71.9 <QL QL BUT QL 0.51 QL 0.33 QL 0.30 1.15 F4-7 Initial 95.5 BUT 0.05 But QL 0.52 QL 0.40 QL 0.31 1.28 2W 40°C/75% RH 96.3 BUT QL But 0.06 0.52 QL 0.39 QL 0.31 1.27 1M 25°C/60% RH 95.7 BUT QL But QL 0.52 BUT 0.39 QL 0.31 1.22 1M 40°C/75% RH 93.3 BUT QL But 0.08 0.52 BUT 0.39 QL 0.31 1.29

QL=limit of quantitation=0.05%;

RRT (relative retention time)=relative retention time;

shaded cells=change observed;

BUT=not defined.

No significant changes were observed in the assay except for F4-5 at 1 month 40°C/75%RH. As there was no change in the impurity profile, this result was likely related to the weight of the capsule contents or the extraction technique used in the assay method.

No significant changes (>0.10%) for impurities were observed in any of the formulations. F4-5 had equivalent impurity values (no >QL). F4-1 and F4-7 each had one impurity, the content of which increases >QL under the condition of 40°C/75%RH. The result of F4-1 (RRT 0.96) with impurity was not reproduced for the 1 month sample, 40°C/75%RH, and was not similar in the related sample. The result with the F4-7 admixture (RRT 0.89) was indeed repeated at 2 weeks and 1 month in the 40°C/75%RH samples and was similar in the related sample.

Acceptable stability was demonstrated for the three formulations when stored for 1 month at 25°C/60%RH and 40°C/75%RH.

6.8. Review of FC on dogs.

Three formulations were tested in a PK study in animals to evaluate the effects and identify the first prototype in a human formulation.

In this study, 15 fasting male dogs (5 per group) were administered two doses of pentagastrin (0.006 mg/kg) to increase intramuscular gastric acid secretion separated by a period of 60 minutes. One 20 mg capsule of Compound 1 (equivalent to ~2 mg/kg) was administered 30 min after

- 29 040951 second dose of pentagastrin.

After a 1 week washout period, all animals were fasted and given an oral dose of 40 mg famotidine to inhibit gastric acid production approximately 30 minutes prior to administration of one 20 mg Compound 1 capsule.

The gastric pH of each animal was measured prior to the administration of the pre-treatment and prior to the administration of Compound 1. Blood samples were taken from each animal to obtain Compound 1 concentrations.

The compositions tested in this study are described in table. 11 and summarized below.

F4-1. Traditional composition: 10% compound 1.

F4-5. Improved composition: 10% compound 1 + 10% citric acid + 5% SLS.

F4-7. Fitted Formulation: Spray-dried intermediate (10% active compound, 14.8% HPMC, 2.8% TPGS) with conventional excipients.

In table. 13 lists the gastric pH and PK results for the study. In FIG. 12, 13 and 14 illustrate the plasma concentration of Compound 1 over 24 hours post-dose. In FIG. 15 illustrates a comparison of AUC and Cmax in three different formulations in two groups of pH controlled dogs.

Table 13

Mean pharmacokinetic parameters after a single oral administration of compound 1 capsules to male beagle dogs

Compound Pretreatment Gastric pH ¹ Tmax (h) ² С _t ah (ng/ml) AUC ₂₄ 4 (ng*h/ml) F1 (Standard) Pentagastrin 3.4 (2.2-5.0) 2.0 (1.04.0) 492+160 3520+1610 famotidine 7.5 (7.1-7.9) 2.0 (1.04.0) 292+80.4 2160+726 F5 (Improved) Pentagastrin 2.7 (2.2-3.8) 4.0 (2.04.0) 385+65.9 2610+926 famotidine 7.5 (7.3-7.7) 2.0 (1.04.0) 382+84.6 2610+936 F7 (fitted) Pentagastrin 2.4 (1.9-3.2) 2.0 (2.0) 686+131 3610+1070 famotidine 7.1 (5.5-7.7) 2.0 (2.04.0) 475+112 3370+877

AUC _{24 h} = area under the plasma concentration curve from time 0 to 24 h post-dose;

C _max = maximum plasma concentration;

T _max = time to reach maximum plasma concentration (C _max ).

¹ pH of the stomach was measured before the introduction of compound 1; average for each group and range.

² T _max values are reported as median (range), while other parameters are reported as mean ± SD (n=5).

The traditional formulation (F4-1) showed the greatest variability in effect between the two pH treatment groups and was not proposed as an FIH formulation.

The adjusted formulation (F4-7) containing SDD shows higher _Cmax and AUC than the improved formulation (F4-5) and shows less variability compared to F4-1.

The improved formulation (F4-5) containing crystalline API showed the most consistent C _max and AUC values under both low and high gastric pH conditions. Mean C _max and AUC were approximately equivalent to F4-1 and mean AUC was 75% and C _max was approximately 65% of F4-7 results.

The improved formulation was chosen for the FIH formulation due to more consistent PK results over the pH range studied and the elimination of scatter due to spray drying (SDD) manufacturing.

6.9. Conclusions.

The clinical impact of compound 1 may vary depending on the pH of the patient's stomach. Systematic formulation design was undertaken to minimize the impact of gastric pH variability on exposure, thereby reducing intra- and inter-patient PK variability.

An improved formulation containing citric acid and sodium lauryl sulfate showed minimal variability in effect with changes in gastric pH in an animal PK study.

The adjusted formulation containing SDD had the highest overall exposure and showed moderate variability with respect to gastric pH exposure. Given the range of doses,

- 30 040951 of interest for clinical studies, it is the variability of exposure, and not the absolute impact, that is of greatest interest. The formulation required an additional spray drying step in the manufacturing process and offered little advantage over the improved formulation.

6.10. Summary of the study for the development of the first use of compound 1 in humans (FIH).

Compound 1 is for the treatment of colorectal cancer. A large proportion of patients taking proton pump inhibitors (PPIs) may have a higher stomach pH than normal patients. Compound 1 has a pH-dependent solubility profile, resulting in potential intra- and inter-patient PK variability. The development of the capsule formulation mixture was undertaken to minimize the pH dependence of drug release.

An improved formulation combining an acidulant (citric acid) and a surfactant (sodium lauryl sulfate) to control local pH and increase drug solubility shows minimal change in Compound 1 exposure in dogs pretreated with pentagastrin (increases gastric acid secretion) or famotidine (inhibits production of stomach acid). This formulation was the starting formulation for the FIH formulation development studies.

Systematic development and evaluation (stability and dissolution) of formulations containing traditional excipients, acidifiers, surfactants, antioxidants and lubricants has been carried out. The combination of surfactant and acidulant improved chemical stability compared to surfactant alone, with fumaric acid having better chemical stability than citric acid. Formulations containing citric acid (low dose in gelatin capsules) showed degradation of the capsule shell in accelerated stability tests. Therefore, fumaric acid was chosen as the acidifier instead of citric acid in the formulation. Based on Accelerated Stability Program (ASAP) data, the FIH formulation had an estimated shelf life of three years at room temperature, regardless of packaging and desiccant addition.

The addition of a surfactant and an acidulant to the conventional formulation reduced the dissolution release profile differences across the physiological pH range, with the pH 6.8 buffer system having the fastest release. Dissolution variability between capsules has been noted in formulations containing fumaric acid and sodium laureth sulfate filled into HPMC capsule shells. It should be noted that dissolution variability was substantially minimized when the same formulation was filled into gelatin shell capsules. Thus, gelatin capsule shells have been recommended for this formulation.

FIH formulations have been successfully scaled up to 2 kg. The clinical dosage range is 1 to 150 mg and a conventional mixture may not cover the entire range. In addition, the morphology of the acicular particles of the drug substance led to a deterioration in the fluidity of mixtures with a high drug load. Studies initially targeted three capsule sizes (1, 5, and 25 mg), however, when balancing drug content for passable flow and capsule size, the maximum capsule content was reduced to 20 mg. Blend flow, capsule uniformity stratification, and stuffing pin buildup can be manufacturing issues that were controlled during development.

6.11. Introduction.

The goal of the Compound 1 Human First Use (FIH) study development program was to develop an oral dosage form with an appropriate phase and immediate release and a manufacturing method that would consistently meet the safety and efficacy requirements for the determination of the target product quality profile (QTPP - Quality Target Product Profile) throughout the intended shelf life of the product.

The Prototype Blend Capsule (BIC) was selected based on previous PK animal studies as the starting point for the development of the FIH formulation. Information from the original Targeted Drug Profile (TPP) was used as the basis for drug development, which is summarized in Table 1. 14.

Table 14

Target drug profile (baseline for FIH)

Dosage form Solid oral formulation (mixture formulated in a capsule) Dose Target range from 1 to 150 mg derived from multiple dosage form options Storage Room temperature

Tab. 31 040951 represents the current form of target drug quality profiling and lists the type of information that was used to provide further guidance in the development of FIH formulations.

Table 15

Determination of the target drug quality profile (initial for FIH)

Delivery/release characteristics Appropriate dissolution profile for a solid oral dosage form with immediate release Safety features and efficiency Analysis: from 90 to 110% instructions for the use of the drug. Content Uniformity: Complies with USP <905>. Associated substances (decomposers): as per the description provided. Microbiological purity: meets USP <61> and USP <62>. Patient compliance regimens and treatment regimens Capsule no larger than size #0 Best before date >18 months at room temperature

6.12. Development and evaluation of formulations.

Based on a PK study in dogs, an improved blend (F4-5) containing an acidulant and a surfactant in gelatin capsules was selected as the base formulation for the development of the FIH formulation (Table 16). A one month stability study of F4-5 showed no change in the impurity profile after storage at 25°C/60%RH and 40°C/75%RH.

Table 16

Composition of Prototype Formula in PK Studies in Dogs

Component Composition F5 (% w/w) Compound 1 13.36 Avicel RN102 33.02 Mannitol 33.02 Lemon acid 10 Sodium lauryl sulfate 5 Kollidon CL 4 colloidal silicon dioxide 0.6 Stearic acid 1 Total percentage 100 Total weight (mg) 200 Capsule content (mg) 20

6.13. The choice of dosage and drug.

The predicted clinical dose range is 1 to 150 mg, and three dosage forms (1, 5 and 25 mg) have been selected.

A preliminary evaluation of several variants of the content of the drug was carried out based on the bulk density and the potential size of the dosage unit of the resulting mixtures (Table 17). Considering the lower weight limit of the capsule content of 75 mg in terms of manufacturability, it was determined that the lowest drug content is 1.8% for a dosage of 1 mg. The desired capsule size is size 1 or below in terms of patient compliance with the regimen and treatment regimen. Therefore, the traditional blending approach was considered inapplicable to the dry blending process. As a result, drug levels of 6.8 and 22.5% were chosen to provide a dosage of 5 mg and 25 mg, respectively. The low drug content of 1.8% and the high drug content of 22.5% were evaluated for chemical stability and dissolution, respectively, in subsequent formulation studies.

Table 17

Characteristics of the composition and dosage form

Content (mg) Drug content (%) Bulk density (g/ml) Target Content Weight (mg) Capsule size Maximum content weight (mg) % of capsule volume 1 L8 0.44 75 4 92 82 5 1.8 0.44 375 00 400 94 5 6.8 0.41 100 3 123 81 25 13.5 0.32 250 00 291 86 25 22.5 0.30 150 lei 162 93

6.14. Evaluation of the stability of the composition and dissolution.

The base formulation (Table 16) selected from the animal PK study was optimized to achieve the desired formulation stability and dissolution profile. Experiments have been carried out for

- 32 040951 determining the appropriate types and levels of excipients for inclusion in the FIH.

6.15. Effect of excipient level on dissolution of 10% citric acid and 5% SLS were used in the base formulation. To optimize excipient levels, six 25 mg gelatin capsule formulations were prepared as controls: F18-1 (traditional) and with different levels of acidifier (citric acid - CA) and surfactant (sodium lauryl sulfate - SLS) (Table 18) . The dissolution of each formulation in FaSSIF pH 6.5 was evaluated and the results are shown in Table 1. 19 and shown in Fig. 16.

Table 18

Composition F18-1-F18-6. Various levels of acidifier and surfactant

Component Composition (% w/w) F18-1 | F18-2 | | F18-3 | F18-4j | F18-5j 1F18-6 Compound 1 22.5 Aerosil 200 0.6 Crospovidone 4 magnesium stearate 1 Citric acid, anhydrous 0 0 0 5 10 5 Sodium lauryl sulfate 0 1 2.5 0 5 2.5 Avicel RN 102 18.0 17.7 17.4 16.7 14.2 16.1 Mannitol 54.0 53.3 52.1 50.2 42.7 48.3

Table 19

Comparison of dissolution of F18-1-F18-6 in baskets, 100 rpm, pH 6.5 FaSSIF

Dissolved % (normalized to 100% at infinity) in FaSSIF 10 min 15 minutes 20 minutes 30 min 45 min 60 min 75 min fl 16.0 42.9 63.0 75.1 83.1 88.7 100.0 F2 63.8 82.2 87.4 91.0 94.2 96.3 100.0 F3 64.0 82.2 86.7 90.6 93.5 95.9 100.0 F4 53.5 75.9 83.3 89.2 93.6 96.3 100.0 F5 65.4 86.6 90.8 93.7 95.5 96.4 100.0 F6 69.1 88.5 92.8 95.5 96.7 97.7 100.0 Dissolved % (as is) in FaSSIF fl 13.7 36.8 54.0 64.4 71.2 76.0 85.7 F2 57.0 73.2 77.3 80.8 83.4 85.4 89.1 F3 57.7 74.4 79.0 82.4 85.2 87.1 90.5 F4 46.7 66.3 72.7 77.8 81.7 84.0 87.3 F5 60.9 80.7 84.6 87.3 89.0 89.8 93.2 F6 60.9 78.0 81.8 84.1 85.3 86.2 88.2

Dissolution conditions: 900 ml FaSSIF, apparatus I (basket), 100 rpm;

FaSSIF = simulated intestinal fluid in a fed state (pH 6.5 and contained mM sodium taurocholate, 0.75 mM lecithin).

The slowest dissolution was with the conventional formulation (F18-1) without acidulant or surfactant. F18-6 (5% CA and 2.5% SLS) had the fastest release profile, slightly faster than F18-5 (5% CA and 5% SLS). Both showed faster release than F18-2 (1% SLS), F18-3 (2.5% SLS) and F18-4 (5% CA), indicating a synergistic effect of the acidifier in combination with the surfactant on drug dissolution. Release profiles with 1% surfactant level were comparable to 5% SLS. Therefore, a base formulation containing 5% CA and 1% SLS was selected for subsequent formulation development studies.

6.16. Stability studies with a variety of diluents, acidifiers, antioxidants and lubricants.

Stability studies evaluating the various components of the formulation have been studied.

Citric acid (CA) and stearic acid (SA) showed degradation in an excipient compatibility study. Therefore, alternative acidifiers and lubricants have been evaluated to reduce potential stability risks. Composition F20-1 (traditional) is the control. In addition, 8 additional trains were prepared. F20-2 contains CA+SLS. F20-3 and F20-4 include either butylated hydroxytoluene (BHT) or sodium metabisulfite (SMB) as an antioxidant. F20-5 and F20-6 contain either CA or SLS. F20-7 contains an alternative acidifier (fumaric acid). F20-8 and F20-9 contains stearic acid or sodium stearyl fumarate as an alternative lubricant (SA or SSF).

The composition of the compositions are listed in table. 20. The formulations were enclosed in capsules with hard gelatin shells. The capsules were packed in hermetically sealed bottles made of

HDPE (7 per bottle) and were evaluated for stability at 50°C/75%RH.

Table 20

Screened Composition Component 1 mg and Function

Component Composition (% w/m) F20-1 | F20-2 | F20-3 | F20-4 | F20-5 | F20-6 | F20-7 | F20-8 | F20-9 Compound 1 1.84 Baking Powder: Crospovidone 4 Glidant: Aerosil 200 0.6 Thinner: Avicel PH102 23.14 21.64 21.62 21.62 21.89 22.89 21.89 21.64 21.64 Thinner: Mannitol 69.42 64.92 64.85 64.85 65.67 68.67 65.67 64.92 64.92 Solubilizer: SLS 0 1 1 1 0 1 0 1 1 Acidifier Lemon acid 0 5 5 5 5 0 0 5 5 Fumaric acid 0 0 0 0 0 0 5 0 0 Antioxidant Butylated hydroxytoluene 0 0 oh 1 0 0 0 0 0 0 Sodium metabisulfite 0 0 0 oh 1 0 0 0 0 0 Lubricant magnesium stearate 1 1 1 1 1 1 1 0 0 Stearic acid 0 0 0 0 0 0 0 1 0 Sodium fumarate 0 0 0 0 0 0 0 0 1

SLS=sodium lauryl sulfate.

6.17. Evaluation of the transformation form of compound 1.

The compositions were evaluated by powder X-ray diffraction analysis (XRPD) initially and after 1 month storage at 50°C/75%RH to assess the conversion or disproportionation of the polymorphic form of the citrate salt of compound 1 (Table 21). Disappearance of drug peaks was observed at lower diffraction angles, but shape change from Form B to Form A or salt disproportionation was difficult to detect at a drug level of 1.84%. XRPD was also run on traditional and improved formulations with higher DL content (22% DL). No evidence of change in shape or disproportionation of the salt was found.

Table 21

Summary of powder X-ray diffraction (XRPD) results for F1-F9

Sample original 1 month (50°C/75%RH) 8204-014-F1 Crystal No major change (peak at 5.5°20 disappears) 8204-014-F2 Crystal Drug peaks disappear 8204-014-F3 Crystal Drug peaks disappear 8204-014-F4 Crystal Drug peaks disappear and peak at 26.1 °20 decreases significantly 8204-014-F5 Crystal Drug peaks disappear 8204-014-F6 Crystal Drug peaks disappear 8204-014-F7 Crystal Peaks at 5.5 and 28.8°20 disappear 8204-014-F8 Crystal Drug peaks disappear 8204-014-F9 Crystal Drug peaks disappear

Note. The main peaks of form B of compound 1, which are easily distinguishable, are three peaks between 4 and 7° 2θ.

6.18. The appearance of the capsule.

The appearance of the capsule was evaluated after 1 month when stored at 50°C/75%RH. All formulations containing CA showed significant degradation of the capsule shell. Citric acid is hygroscopic and it has been suggested that absorption of moisture results in brittleness of the capsule shells.

6.19. Chemical stability.

Decomposition (RRT 0.88) was only observed for formulations F20-1, F20-6, F20-7 after 1 month storage at 50°C/75%RH (Table 22). These formulations do not contain citric acid. Decomposition product formula RRT 0.88 according to mass spectrometry C ₂₄ H ₂₆ Cl3N ₇ O ₂ . This corresponds to the loss of hydrogen fluoride.

- 34 040951

This impurity is observed under alkaline conditions.

No degradation in the formulation was observed (F20-2).

Table 22

Results of the effect of % impurities on stability for 1 mg of formulations 1-9

Time Initial impurity % Compound F20-1 F20-2 F20-3 F20-4 F20-5 F20-6 F20-7 F20-8 F209 RRT 0.88 Des-F 91516 0.52 0.51 0.52 0.5 0.52 0.52 0.51 0.51 0.51 SS-20048 0.36 0.36 0.36 0.36 0.36 0.36 0.36 0.36 0.36 RRT 1.10 0.13 Bis-F 91516 0.32 0.32 0.32 0.32 0.32 0.32 0.32 0.32 0.32 total impurities 1.2 1.2 1.2 1.3 1.2 1.2 1.2 1.2 1.2 Time 1 month at 50C/75%RH Compound fl F2 F3 F4 F5 F6 F7 F8 F9 RRT 0.88 0.15 0.31 0.09 Des-F 91516 0.52 0.52 0.52 0.52 0.52 0.52 0.52 0.52 0.52 SS-20048 0.36 0.37 0.36 0.36 0.36 0.37 0.36 0.36 0.36 RRT 1.10 Bis-F 91516 0.32 0.32 0.32 0.33 0.33 0.32 0.33 0.32 0.32 total impurities 1.4 1.2 1.2 1.2 1.2 1.5 1.3 1.2 1.2

Note. Only peaks > quantitative level are reported.

6.20. Stability studies on capsules with two acidifiers and HPMC/gelatin shells.

Five 1 mg formulations encapsulated in gelatin or hydroxypropyl methylcellulose (HPMC) coated capsules were made and evaluated for stability. F20-2, F20-5, F20-6 and F20-7 have previously been described in Table. 20. The new formulation, F23-14, contains fumaric acid (FA) as an acidulant, which has been replaced by citric acid. The compositions are listed in table. 23.

Table 23

Composition of formulations 1 mg

Component Composition (% May/May) F20-2 F20-5 F20-6 F20-7 F23-14 Compound 1 1.84 Crospovidone 4 Aerosil 200 0.6 magnesium stearate 1 Avicel PH102 21.64 21.89 22.89 21.89 21.64 Mannitol 64.92 65.67 68.67 65.67 64.92 Acidifier Lemon acid 5 5 0 0 0 Fumaric acid 0 0 0 5 5 Sodium lauryl sulfate 1 0 1 0 1

The appearance of the capsule and the formation of the degradation product RRT 0.88 was monitored for stability, and the results up to 3 months are presented in table. 24.

Formulations F20-2 and F20-5 containing citric acid and encapsulated in gelatin capsules exhibited capsule friability after 3 months at 40°C/75%RH and capsule breakage after 1 month at 50°C/75%RH. No change in appearance was noted for any of the other capsule shell formulations.

Formulation F6, containing SLS and no acidulant, had the highest level of degradation product RRT of 0.88. The addition of an acidifier improved the chemical stability. Formulation F23-14 (FA+SLS) showed lower RRT levels of 0.88 than formulation F20-2 (CA+SLS).

F23-14 (FA+SLS) and F20-7 (FA) in HPMC and gelatin casings and F20-5 (CA) in FLPMC casings showed acceptable results in the accelerated stability test.

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Table 24

Stability results for 1 mg formulations

% RRT 0.88 product degradation Appearance of the capsule Compound Shell 40°C/75%RH 50°C/75%RH 40°C/75%RH 50°C/75%RH 1 Mo 3 Mo 1 Mo 2Mo 3 Mo 1 Mo F2 (CA+SLS) NRMS 0.02 0.06 0.11 0.17 Without changes Without changes Wish n 0 0.04 0 NT fragility brittleness F5 (SA) NRMS 0 0.03 0.05 0.08 Without changes Without changes Wish n 0 0.03 0 NT fragility brittleness F6 (SLS) NRMS 0.04 0.17 0.2 0.40 Without changes Without changes Wish n 0.03 0.13 0.31 NT Without changes Without changes F7 (FA) NRMS 0 0 0 0.02 Without changes Without changes Wish n 0 0 0.09 NT Without changes Without changes F14 (FA+SLS) NRMS 0 0 0.02 0.03 Without changes Without changes Wish n 0 0 0.03 0.03 Without changes Without changes

CA=citric acid;

FA=fumaric acid;

NT=not tested;

SLS=sodium lauryl sulfate.

The Accelerated Stability Testing Program (ASAP) was performed for mixtures of formulations F23-14 (FA+SLS) and F20-5 (CA) (Table 25). Formulation F23-14 showed lower levels of RRT 0.88 degradation product throughout the study.

Table 25

ASAP stability conditions and product degradation levels RRT 0.88

Sample Time (days) Storage conditions %RRT 0.88 F5-CA F14-FA+SLS 1 0 original BUT BUT 2 0 BUT But 3 8 52°C/60% RH BUT But 4 14 0.02 But 5 7 60°C/ll%RH 0.01 But 6 14 0.01 But 7 1 70°C/28% RH BUT But 8 eleven 0.13 0.02 9 1 69°C/81%RH 0.04 0.02 10 2 0.06 0.05 eleven 1 79°C/9% RH 0.02 BUT 12 7 0.14 0.04 13 3 49°C/85% RH BUT BUT 14 14 0.01 0.02 15 1 79°C/49% RH 0.10 0.05 16 2 0.18 0.07

A moisture corrected Arrhenius equation (ie ASAP Prime version 4.0.1) was used to evaluate stability results. Activation energy (Ea) and moisture sensitivity (B) to degradation were evaluated and listed in Table 1. 26. Term B demonstrated that formulations have low to moderate sensitivity to moisture mediated degradation. The activation energy of both formulations was equivalent to lower than the other formulations tested (average 27 kcal/mol for 69 formulations tested) and in combination should result in a stable dosage form. This is confirmed by the high probability of meeting the proposed shelf life under a variety of scenarios. Based on the model forecast, F23-14 was expected to show a long

- 36 040951 stability at 25°C/60%RH with or without desiccant.

Table 26

Degradation kinetics and shelf life probability

Parameter F20-5 (SA) F23-14 (FA+SLS) Activation energy (E _a , kcal / mol) ^a 36.8 kcal/mol 27.2 kcal/mol Moisture Sensitivity Coefficient (B) ^b 0.025 0.032 Correlation coefficient (R ² ) 0.987 0.918 Probability of passing the description 1.0% op. at 25°C/60%RH, 3 years 100.00 99.95 1.0% op. at 40°C/75%RH, 6 months 100.00 100.00 1.0% op. at 25°C/60%RH, 3 years, 1.0 g desiccant 100.00 99.99 1.0% op. at 40°C/75%RH, 6 months, 1.0 g desiccant 100.00 100.00 0.20% op. at 25°C/60%RH, 3 years 99.90 ^96.86d 0.20% op. at 40°C/75%RH, 6 months 99.97 96.24 0.20% op. at 25°C/60%RH, 3 years, 1.0 g desiccant 99.67 99.36 0.20% op. at 40°C/75%RH, 6 months, 1.0 g desiccant 99.98 99.93

CA=citric acid;

FA=fumaric acid;

SLS=sodium lauryl sulfate;

^a The average impurity activation energy is 27 kcal/mol.

^b Average moisture sensitivity factor for impurities is 0.034.

^c Probability of passing the description.

^d Decrease in the probability of matching the description is likely due to poor model fit (too little expansion during the study to properly model the data).

The simulation assumed 7 counts in a 100 cm HDPE bottle that was heat sealed.

6.21. Dissolution of high drug formulations F10, F12, F13, F15, F16.

Five 25 mg high drug (23%) preparations were prepared and filled into gelatin capsules. F27-10 (CA+SLS) and F27-11 (traditional) were controls. In addition, 4 additional compositions were prepared. F27-12 and F27-16 contained either CA or FA. F27-13 contained sodium lauryl sulfate. F27-15 was similar to F10 with FA instead of CA. The composition of the compositions are listed in table. 27. Capsules were tested using apparatus I (baskets) at 100 rpm.

Table 27

Compositions of 25 mg formulations

Component Composition (% May/May) F27-10 F27-11 |F27-12 |F27-13 |F27-15 |F27-16 API 23.02 Crospovidone 4 Aerosil 200 0.6 magnesium stearate 1 Avicel RN 102 16.35 17.85 16.60 17.60 16.35 16.60 Mannitol 49.04 53.54 49.79 52.79 49.04 49.79 Lemon acid 5 0 5 0 0 0 SLS 1 0 0 1 1 0 Fumaric acid 0 0 0 0 5 5 Content weight (mg) 150

SLS=sodium lauryl sulfate.

The release profiles of each formulation in 0.1 N HCl (FIG. 18), acetate buffer pH 4.5 (50 mM) (FIG. 19), and phosphate buffer pH 6.8 (50 mM) (FIG. 20) are provided. .

At low pH, compound 1 was soluble (~1.7 mg/ml). The formulations were grouped with the traditional (F27-11) released slightly faster than formulations containing only FA (F27-16) or CA (F27-12). Formulations containing SLS were similarly grouped with

- 37 040951

F27-10 (CA+SLS) was faster releasing than F27-13 (SLS) which had a release profile similar to F27-15 (FA+SLS).

At pH 4.5, compound 1 (pKa ~5.1) was less soluble (~0.25 mg/ml) than in a more acidic environment. The formulations were grouped, with the improved formulations releasing faster than the traditional formulation. For improved formulations, F27-10 (CA+SLS) released faster than F27-15 (FA+SLS) and F27-13 (SLS), which released slightly faster than FA (F27-16) and CA (F27-12) formulations. ).

At pH 6.8, compound 1 had low solubility (0.002 mg/ml at pH 7.3). The formulations were grouped in the same order as pH 4.5, however, the separation between the groups was greater. For improved formulations, F27-10 (CA+SLS) released faster than F27-15 (FA+SLS) and F27-13 (SLS), which released faster than FA (F27-16) and CA (F27-12) formulations .

Formulations containing SLS had the slowest release rate at low pH and the fastest release at pH 6.8. Release profiles were slightly faster for SLS formulations at pH 4.5 compared to low pH media. SLS is anionic and compound 1 (pKa ~5.1) is cationic in acidic conditions. It is possible that an ionic interaction occurs between the SLS and the drug substance, creating neutral species that inhibit the release rate for these formulations.

Dissolution profiles of improved formulation 25 mg (FA+SLS) (F27-15, Table 27) using Apparatus I at 100 rpm in 0.1 N HCl, acetate buffer pH 4.5 and phosphate buffer pH 6.8 , are illustrated in FIG. 21.

The same dissolution conditions were used to evaluate the traditional formulation for comparison, and the profiles are illustrated in FIG. 22. Comparison of profiles showed that the improved FIH formulation had a consistent release profile and had less pH variability compared to the traditional formulation.

At pH 4.5 and 6.8, SLS-free formulations had a much slower release than at low pH. The combination of acidifier and SLS provided the fastest dissolution at medium and neutral pH and moderate dissolution at low pH.

6.22. Evaluation of the capsule shell composition for dissolution.

The composition of F27-15 in the table. 27 encapsulated in HPMC and gelatin shells were evaluated at pH 6.8 with 0.05% SLS and no addition to dissolution medium.

At neutral pH, the high variability of the dissolution of the composition F27-15 from the table. 27 was observed for the FA+SLS formulation with HPMC capsule shells (25 mg content) (FIG. 23) but not with gelatin capsule shells (FIG. 24).

0.5% SLS was added to the dissolution medium and the FA+SLS formulation continued to show high dissolution variability of formulation F27-15 from Table 1. 27 with HPMC capsule shells (FIG. 25) but not gelatin capsule shells (FIG. 26).

Only the SLS formulation (F27-13 in Table 27) behaved similarly (HPMC: FIG. 27, gelatin: FIG. 28), however, this phenomenon was not observed for the CA+SLS formulation (F27-10 in Table 27) in HPMC (Fig. 29).

It was assumed that the interaction between the shells of the capsules FA, SLS and HPMC led to a different release of the drug.

At the end of dissolution, the HPMC capsules retained gel-like lumpy residual solids in the basket. See fig. 30. If these gelatin materials trap Compound 1, variable dissolution profiles may occur.

6.23. Results.

Based on the results of stability and dissolution of the composition F27-15 in table. 27, which contained 5% fumaric acid and 1% SLS and was contained in hard gelatin capsules, had better overall stability and dissolution characteristics.

6.24. Method development and evaluation.

The physical properties of the drug substance, such as particle size, shape, and surface characteristics, may play a role in the feasibility of formulating the formulation. Compound 1 (citrate salt form B) crystallized in the form of a needle.

The acicular particles have poor powder flowability and low density. Compound 1 had a bulk density of 0.2 g/ml and a bulk shake volume of 0.38 g/ml. Reducing the drug loading (diluting the poor flowing component) improved the flow characteristics of the resulting mixture. The fluidity of the six traditional compositions was listed in table. 28.

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Table 28

Evaluation of the fluidity of six mixtures of prototype formulations

Component Composition (% May/May) F28-1 F28-2 F28-3 F28-4 F28-5 F28-6 Compound 1 1.8 6.74 13.48 22.46 22.46 22.46 Avicel PH102 46.3 43.83 40.46 35.97 23.98 23.98 Mannitol 46.3 43.83 40.46 35.97 47.96 Lactose 47.96 Crospovidone 4 Aerosil 200 0.6 magnesium stearate 1 FFC 11.6 5.9 3.2 2.5 2.5 2.5

FFC=Flow Function Factor.

The flow function coefficients (FFCs) were measured using torsional shear. FFC values greater than 5 had good flow properties. Formulations F28-1 and F28-2 have been evaluated to have good flow properties. The FFC value is directly related to the drug content (F28-1<F28-2<F28-3<F28-4-F28-6). Changing the ratio of Avicel to mannitol (F28-4 vs. F28-5) or replacing mannitol with lactose (F28-5 vs. F28-6) did not affect flow.

6.25. Test 600g production 1.

Five formulations with different drug levels were developed (Table 29) to cover the expected range of FIH doses.

For a dose of 1 mg and a mass of 75 mg, the calculated drug content was calculated to be 1.8%. For the 5 mg dose, a content weight of 100 mg resulted in a drug content of 6.9%. For a dose of 25 mg, a content weight of 150 mg resulted in a drug content of 23%. Based on poor flow properties for high drug formulations (FFC=2.5, Table 28), lower DLs (drug loading) (13.81% corresponding to 250 mg content weight) were also evaluated. A dose of 20 mg was also developed, and a content weight of 250 mg resulted in a drug content of 11%.

Table 29

Composition and characteristics of the composition

Component Composition (% w/w) F29-1 F29-2 F29-3 F29-4 F29-5 Compound 1 1.84 23.02 6.91 13.81 11.05 Avicel PH102 21.64 16.35 20.37 18.65 19.34 Mannitol 64.92 49.04 61.12 55.94 58.01 Lemon acid 5 SLS 1 Crospovidone 4 Aerosil 200 0.6 magnesium stearate 1

SLS=sodium lauryl sulfate. NB Ref: 8204-015.

Five 600 g test formulations were made according to the process flow diagram illustrated in FIG. 31.

The formulations covered drug content options of 1.8-23.0% and 1-25 mg. Bulk density and bulk volume of tapping for each composition are included in the table. thirty.

Table 30

Characteristics of the composition

Characteristics F29-1 F29-2 F29-3 F29-4 F29-5 Dose content (mg) 1 ^a 25 ^a 5 ^a 25 ^a 20 ^a Drug Content(%) 1.8 23.0 6.9 13.8 11.0 Content weight (mg) 75 150 100 250 250 Bulk density (g/ml) 0.46 0.28 0.44 0.34 0.41 Bulk volume of tapping (g/ml) 0.59 0.55 0.61 0.58 0.61

^a Based on the free base; 1.0 mg of compound 1 (free base) was equivalent to 1.34 mg of compound 1 (citrate salt). The activity factor of the drug batch for these experiments was (0.725 or 1/1.38).

- 39 040951

The results of CU (content uniformity - content uniformity) for F29-1, F29-3 and F29-5 are illustrated in table. 31. Unsuccessful CU data suggests that the manual sifting used in this method may not be an effective way to deagglomerate mixtures, leading to mixture inhomogeneity. Additional tests were carried out with an improved method (replacing the cone mill with a hand sieve) and are described in the next section.

Table 31

Stratified results CU F29-1, F29-3 and F29-5

F29-1 (1 mg), 75 mg contents, Size #4 F29-3 (5 mg), 100 mg contents, Size #4 Start middle End Start middle End Weight of capsules % LC Weight of capsules % LC Weight of capsules % LC Weight of capsules % LC Weight of capsules % LC Weight of capsules % LC Average 111.3 90.4 110.8 95.1 110.3 93.8 144.4 106.5 149.9 110.8 146.9 10 8.6 STD 1.0 4.5 0.9 5.2 0.5 5.7 3.8 4.8 2.1 2.3 3.2 2.9 AV 19.0 15.9 18.3 16.4 14.9 14.1 Pass L1 No No No No Yes Yes F29-5 (20 mg), 250 mg contents, Size #1 Average 351.2 99.4 353.8 104.1 343.3 99.7 STD 7.8 4.1 14.4 5.6 24.6 10.4 AV 9.8 16.1 25.0 Pass L1 Yes No No

The 25 mg formulations of 13.8% and 23% drug content had poor fluidity and the encapsulation process was stopped several times. A spatula or hammer was used to facilitate the feeding of the powder into the hopper. It was concluded that such a high drug content is not suitable for a dry blending process.

When the drug content was reduced to 11%, the flow improved. Consequently, the maximum dosage was reduced from the initial target of 25 mg to 20 mg to ensure good processing properties and a suitable capsule size.

6.26. Test 600g production 2.

Based on the results of Test 1, two additional batches of 600 g were made: one from formulation F29-1 (low drug at 1.8%) and the second from formulation F29-5 (high drug at 11%) (Table 1). 29). Quadro Comil U3 was used for deagglomeration and Bosch GKF 702 for encapsulation to improve mixture homogeneity and make the scaling process more representative (FIG. 32). The encapsulation parameters for both batches are listed in Table. 32.

Table 32

Encapsulation Settings

Parameter F29-1 (1 mg) F29-5 (20 mg) Dosing disc 4 1 Dosing disc size (mm) 7 (fixed) 19.5 Packing pin installation 1 2 9 2 2 eleven 3 3 13 4 2 14 5 2 16

Adhesion to the needles was observed for both lots. For the 1 mg batch, sticking correlated with hard tamping (needles to maximum, maximum tamping).

Good results were obtained in terms of content weight and content uniformity (CU - content uniformity) (table. 33) with the exception of the final samples. This poor CU was due to the small lot size, not segregation, as there was not enough powder in the feed frame towards the end of the cycle. Stratified CU samples were tested during program execution to confirm this assumption.

- 40 040951

Table 33

Stratified results CU F29-1 and F29-5 F29-1 (1 mg), 75 mg contents, Size #4 F29-5 (20 mg), 250 mg content, Size #1 Start middle End Start End Capsule weight % LC Capsule weight %LC Capsule weight %LC Capsule weight % LC Capsule weight % LC Average 108.2 97.5 111.4 102.1 112.2 100.1 321.7 99.5 309.6 95.0 STD 1.5 1.2 1.2 1.5 1.4 7.0 2.3 2.0 13.4 5.8 AV 3.9 4.1 16.9 4.7 17.5 Pass L1 Yes Yes No Yes No

USP <905> Dosage Uniformity Acceptance Score (AV) <15.0 to pass requirements;

STD=standard deviation.

Based on the good performance results and acceptance rate, the process was scaled up to 2 kg technical batches.

6.27. Technical tests for 2 kg serial production.

One batch of 1, 5 and 20 mg capsules (F29-1, F29-3 and F29-5) was produced in 2 kg scale.

The composition of the composition for these parties is illustrated in table. 34.

The final formulation formulations for FIH are illustrated in section 6.28.

Table 34

2 kg technical batches 1, 5 and 20 mg

Component (% May/May) F29-1 F29-3 F29-5 Compound 1 1.80 6.73 11.05 MCC (Avicel RN 102) 21.65 20.42 19.34 Mannitol (Parteck M200) 64.95 61.25 58.01 Fumaric acid 5 SLS 1 Crospovidone (Kollidon CL) 4 Colloidal silicon dioxide (Aerosil 200) 0.6 Magnesium stearate (HyQual VG 2257) 1 Weight of content 75 mg 100 mg 250 mg Capsule ^a Size 4 Size 4 Size 1

a Capsule = hard gelatin, white opaque.

a Based on the free base; 1.0 mg of compound 1 (free base) was equivalent to 1.34 mg of compound 1 (citrate salt); the drug batch activity factor for these experiments was (0.725 or 1/1.38).

The technological scheme for the production of 2 kg technical batches is illustrated in Fig. 33. Encapsulation parameters for these batches are listed in Table. 33.

The description of this method is given below.

Weigh each raw material in separate plastic bags.

Load the dosed API and excipients except magnesium stearate into an 8-QT square vial.

Mix the material for 10 min at 25 rpm.

Load the mixed material into the cone mill. Using a 20 mesh cone mill screen, run the mixture through the cone mill at approximately 2800 rpm (40% speed).

Transfer the material to the hopper mixer. Mix the material for 15 min at 15 rpm.

Pass the dosed magnesium stearate through a 30 mesh (595 micron) sieve directly into the screen bath and add to the mixing bowl.

Mix the material for 2 min at 25 rpm.

Discharge the mixture into the supply container of the Bosch GKF702 encapsulator.

Customize your Bosch GKF702 encapsulator with the following replacement parts:

a) 75 mg content, capsule size no. 4: 7 mm fixed dosing disc;

b) 100 mg content, capsule size no. 4: 12 mm adjustable dosing disc;

c) 250 mg content, capsule size no. 1: 19.5 mm adjustable dosing disc.

Set the encapsulation speed to 90 cycles per minute. Start encapsulation and adjust the machine to provide the target mass.

- 41 040951

Collect the capsules as they exit the encapsulator onto a suitable sieve. When the capsules fill the sieve, use a vacuum to remove dust from the capsules. Place the capsules in a container with a polyethylene liner.

Pack the capsules in a container in 100 cm HDPE bottles (7 per bottle, heat-sealed).

Table 35

Encapsulation Settings

Parameter F29-1 (1 mg) F29-3 (5 mg) F29-5 (20 mg) Dosing disc 4 4 1 Dosing size disc (mm) 7 12 19.5 Machine speed (cycles/min) 90 90 90 Packing pin installation 1 2 4 9 2 2 5 10 3 2 4 eleven 4 2 5 14 5 2 9 17

Adhesion of the drug substance to the needles was observed for all batches. For the 1 mg batch, the stuffing pins were set to maximum.

Bulk density and bulk volume of tapping, as well as flow characteristics for 2 kg technical batches are listed in Table. 36. Scales of flow properties for the Carr index (compressibility) and the Hausner coefficient are described in Table. 37. The flow of mixtures was rated as very poor or passable.

Table 36

Bulk density and bulk volume of tapping and flow properties for technical batches

Property F29-1 (1 mg) F29-3 (5 mg) F29-5 (20 mg) Bulk density (g/ml) 0.4672 0.4363 0.4229 Bulk volume shakes (g/ml) 0.6088 0.6371 0.6278 Hausner coefficient 1.30 1.46 1.48 Carr index 23.3 31.5 32.6

Carr index (compressibility) = (bulk volume of tapping - bulk density) x100 / bulk volume of tapping.

Hausner coefficient=bulk volume of tapping/bulk density.

Table 37 ______________Commonly accepted scales of flow properties______________

The nature of the flow Carr index (compressibility) (%) Hausner coefficient Excellent < yu 1.00-1.11 High 11-15 1.12-1.18 Normal 16-20 1.19-1.25 The nature of the flow Carr index (compressibility) (%) Hausner coefficient passable 21-25 1.26-1.34 bad 26-31 1.35-1.45 Very bad 32-37 1.46-1.59 Very, very bad >38 > 1.60

Carr index (compressibility) = (bulk volume of tapping - bulk density) x100 / bulk volume of tapping.

Hausner's ratio = tapping bulk volume/FFC bulk density was evaluated from torsional shear and the mixtures were judged to have good flow properties (Table 38).

Table 38

Torsional Shear Fluidity Measurement

FFC F29-1 F29-3 F29-5 Test 1 15.48 10.2 6.17 Test 2 20.78 11.02 6.22 Test 3 20.56 Average 18.94 10.61 6.19

FFC=Flow Function Coefficients.

FFC values greater than 5 had good flow characteristics and all three batches had FFC>5.

- 42 040951

The particle size distribution of the compositions was evaluated using sieves, and the results are listed in table. 39.

Table 39

Particle size distribution by sieve analysis

lattice Parameter PD01-282 PD01-283 PD01-284 Sample weight (g) 5.042 5.025 5.0042 Shaking time (min) 5 5 5 Amplitude 3 5 3 420 µm Mesh #40 1.4 2.1 2.4 250 µm Mesh #60 12.7 13.0 12.5 177 µm Mesh #80 16.6 17.1 17.4 149 µm Mesh #100 11.9 11.7 12.8 125 µm Mesh №120 13.3 13.2 13.0 74 µm Mesh №200 29.2 25.4 26.6 0 bath 14.9 17.6 15.3 Average particle size (µm) 122.6 123.8 126.8

CU stratification was carried out and acceptable results were obtained for initial, intermediate and final samples, as indicated in table. 40, 41 and 42.

Table 40

Content uniformity and mass variability PD01-282 (1 mg)

Start middle End Sample %LC Weight Sample %LC Weight Sample %LC Weight 1 93.7 108.3 1 91.1 107.8 1 95.4 110.4 2 92.7 109.8 2 94.3 111.0 2 99.7 112.3 3 93.9 110.3 3 91.6 108.4 3 93.9 110.5 4 90.7 109.6 4 93.6 111.4 4 98.2 112.6 5 92.2 110.0 5 95.5 110.8 5 98.4 112.9 6 93.7 109.0 6 92.6 108.3 6 96.4 111.7 7 93.1 108.7 7 93.7 110.9 7 96.3 112.1 8 91.7 107.2 8 94.5 110.7 8 95.3 111.8 9 90.8 109.2 9 90.5 107.2 9 98.8 113.0 10 90.0 108.9 10 94.0 109.2 10 97.4 111.9 Average 92.2 109.1 Average 93.1 109.6 Average 97.0 111.9 SD 1.4 0.9 SD 1.6 1.6 SD 1.8 0.9 %RSD 1.5 0.8 %RSD 1.7 1.4 %RSD 1.9 0.8 AV 9.6 AV 9.2 AV 5.9

AV=acceptability score;

LC=declared value;

SD=standard deviation;

RSD=relative standard deviation.

- 43 040951

Table 41

Content uniformity and mass variability F3 (5 mg)

Start middle End Sample %LC Weight Sample %LC Weight Sample %LC Weight 1 94.4 136.4 1 95.4 134.98 1 97.2 136.3 2 95.3 135.8 2 97.7 137.64 2 99.5 140.8 3 97.3 138.1 3 95.3 134.45 3 99.1 139.8 4 101.3 142.2 4 97.2 137.47 4 99.4 139.2 5 97.6 138.9 5 95.4 134.64 5 98.1 138.3 6 94.3 134.1 6 102.0 142.2 6 104.5 141.7 7 97.5 136.5 7 96.4 136.81 7 98.3 138.1 8 97.1 138.6 8 95.9 134.53 8 98.9 137.9 9 97.4 138.1 9 97.8 136.71 9 100.0 138.0 10 97.6 138.2 10 98.5 138.15 10 99.5 139.1 Average 97.0 137.7 Average 97.2 136.8 Average 99.5 138.9 SD 2.0 2.2 SD 2.0 2.4 SD 1.9 1.6 %RSD 2.1 1.6 %RSD 2.1 1.7 %RSD 1.9 1.1 AV 6.4 AV 6.2 AV 4.7

AV=acceptability score;

LC=declared value;

SD=standard deviation;

RSD=relative standard deviation.

Table 42

Content uniformity and mass variability F5 (20 mg)

Start middle End Sample %LC Weight Sample %LC Weight Sample %LC Weight 1 98.7 327.5 1 94.0 319.63 1 97.0 317.4 2 98.5 328.4 2 95.4 325.48 2 99.1 321.8 3 96.3 322.2 3 98.9 331.33 3 99.3 321.6 4 96.9 326.3 4 99.2 330.39 4 98.1 318.0 5 93.9 317.8 5 97.9 328.89 5 101.5 327.2 6 98.2 330.0 6 94.3 318.8 6 93.0 307.0 7 996.8 326.0 7 94.3 317.63 7 97.9 320.3 8 96.8 321.6 8 96.0 321.43 8 97.8 317.9 9 91.8 310.8 9 97.2 327.27 9 98.3 319.5 10 94.9 320.8 10 94.2 327.76 10 96.8 316.5 Average 96.3 323.1 Average 96.1 324.9 Average 97.9 318.7 SD 2.2 5.8 SD 2.0 5.1 SD 2.2 5.1 %RSD 2.3 1.8 %RSD 2.1 1.6 %RSD 2.2 1.6 AV 7.5 AV 7.2 AV 5.8

AV=acceptability score;

LC=declared value;

SD=standard deviation;

RSD=Relative Standard Deviation 3 technical lots were tuned to a formal (ICH) stability program to support the clinical program.

6.28. Composition composition FIH.

In reviewing the data, taking into account stability, dissolution efficiency and processability, an improved formulation (containing fumaric acid and sodium lauryl sulfate) in gelatin capsules was selected for the FIH study. Three types of content of the compositions of the compositions are listed in table. 43.

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Table 43

FIH compound composition

Component Composition composition 1 mg ^a 5 mg ^a 20 mg ^a mg/cap. (% w/w) mg/cap. (% w/w) mg/cap. (% May. / May.) Compound 1 1.34 1.79 6.70 6.70 26.80 10.72 Avicel RN102 16.24 21.65 20.42 20.42 48.53 19.41 Mannitol (Parteck M200) 48.72 64.96 61.28 61.28 145.68 58.27 Sodium lauryl sulfate 0.75 1.0 1.00 1.0 2.50 1.0 Fumaric acid 3.75 5.0 5.00 5.0 12.50 5.0 Crospovidone 3.00 4.0 4.00 4.0 10.00 4.0 Aerosil 200 0.45 0.6 0.60 0.6 1.50 0.6 magnesium stearate 0.75 1.0 1.00 1.0 2.50 1.0 Weight of content 75.00 100.0 100.00 100.0 250.00 100.0 Shell capsule ⁷ Size #4 Size #4 Size #1

^a Based on the free base. 1.0 mg of compound 1 (free base) is equivalent to 1.34 mg of compound 1 (citrate salt). The actual weight of drug substance was based on the activity factor of the drug lot, corrected for the weight of mannitol to obtain the target weight of the mixture.

^b Capsule=Hard gelatin, white opaque.

6.29. Conclusions.

The development of the capsule mixture was undertaken to minimize the dependence of pH on drug release upon dissolution in vitro. The 1, 5, and 20 mg formulations were developed for First Time Human Clinical (FIH), PK-based studies in dogs, in vitro dissolution, processability, and stability. The improved formulations contained an acidulant (fumaric acid) and a surfactant (sodium lauryl sulfate) to control local pH and improve drug solubility. This combination of excipients, resulting in an improved formulation, reduces the variability in the dissolution release profile seen with traditional formulations in media of varying pH.

The dry blending process has been developed for all content options. The formulations were successfully scaled up to 2 kg. An acceptable CU has been demonstrated for a 2 kg batch. It was expected that the same method would be transferred to the technology of a contract manufacturing organization for the production of 3 kg batches of technical and clinical materials (CTMs).

6.30. Capsules A-J.

Capsules A-H were produced and tested in the following studies. The composition of each capsule is given in table. 44.

Table 44

Capsule composition

Capsule A V With D E F G n Component Mass percentage Compound 1 31% 25% 25% 50% 50% 50% 50% 50% NRMS 53% - - 40% - - 50% - PVA-P - 65% - - 40% - - 50% PVP VA 64 - - 65% - - 40% - - TPGS 10% 10% 10% 10% 10% 10% - - General 100% 100% 100% 100% 100% 100% 100% 100%

In FIG. 34 illustrates the dissolution profiles of Compound 1 of formulations when dissolved in

- 45 040951 intestinal buffer for 90 min.

In FIG. 35 illustrates the dissolution profiles of Compound 1 formulations when dissolved in intestinal buffer and composition. Capsule E shows the best performance in relation to the total amount of solubilized drug. Higher grade PVA-P formulations showed better performance compared to lower grade counterparts. The addition of TPGS to the formulation showed a positive effect on compound 1 solubility.

In FIG. 36 illustrates a dissolution comparison in PVA-P formulations (capsule B, capsule E, and capsule H). The PVA-P formulations performed better at higher levels and also with the addition of TPGS.

In FIG. 37 illustrates a dissolution comparison in PVP VA64 formulations (capsule C and capsule F). The increased content and addition of TPGS showed only marginal improvement in formulations with PVP VA64 compared to other polymers.

In FIG. 38 illustrates a dissolution comparison in HPMC formulations (capsule A, capsule D, and capsule G). Increasing the content of the drug with HPMC had little effect on the dissolution efficiency. TPGS illustrated a significant improvement in compound 1 solubility in capsule A.

In FIG. 39 illustrates the glass transition temperature as a function of relative humidity.

In FIG. 40 illustrates the reversible and irreversible heat flux of capsule A and capsule H at less than 5% relative humidity.

In FIG. 41 illustrates the reversible and irreversible heat flux of capsule A and capsule H at 75% relative humidity.

In FIG. 42 illustrates the reversible and irreversible heat flux of capsule G and capsule E at less than 5% relative humidity.

In FIG. 43 illustrates the reversible and irreversible heat flux of capsule G and capsule E at 75% relative humidity.

In FIG. 44 illustrates the stability of the capsule A suspension in methocel.

In FIG. 45 illustrates the stability of the H capsule suspension in methocel.

In FIG. 46 illustrates the stability of the capsule G suspension in methocel.

In FIG. 47 illustrates the stability of the capsule E suspension in methocel.

In FIG. 48 illustrates the stability of the suspension, visualized by polarized light microscopy (PLM), capsule A in the methocel.

In FIG. 49 illustrates suspension stability, visualized by PLM, of the H capsule in the methocel.

In FIG. 50 illustrates the suspension stability visualized by PLM of the G capsule in the methocel.

In FIG. 51 illustrates suspension stability, visualized by PLM, of capsule E in methocel.

6.31. Pharmacokinetic studies in mice in vivo.

Table 45

Pharmacokinetic parameters of oral dosing in male mTOR+CD-1 mice

PK parameters of male CD-1 mice Average value ¹ Mean ± SD (N=4) Capsule G Capsule E Capsule A Capsule H Capsule I ² Capsule J ³ Stach (µM) 1.16 0.902 0.703 0.612 0.464±0.182 1.42±0.549 Tmax (h) 0.25 0.25 0.25 0.50 0.50±0.00 0.50±0.00 AUC _(0.beek .) (µMh) 1.12 1.00 1.36 1.41 1.24±0.24 2.49±0.68 F% 8.6 7.7 10 eleven 10 19

¹ Data obtained by non-serial sampling of two groups with n=4 per group.

² Capsule I contains 5% HPMC/1% TPGS.

³ Capsule J contains CMC/Tween.

This study evaluated the effect of two spray-dried (SDD) formulations

- 46 040951 capsules G, capsules E, capsules A and capsules H on oral exposure to compound 1 in male CD-1 mice at 10 mg/kg. The SDD formulations had 50% Compound 1 content. The overall impact was comparable between the two DSS formulations. Exposure data were also similar to those from the other three formulations tested. Overall, all formulations tested did not improve compound 1 exposure in CD-1 mice at 10 mg/kg compared to the standard formulation in CMC/Tween. The results were as expected since the solubility/dissolution of this compound was not the main limiting factor for exposure at low dose levels.

In FIG. 46 illustrates the results of the plasma concentration profile after a single oral administration of Capsule G in male CD-1 mice.

Table 46

Capsule G: tabular summary of plasma concentrations (µM)

Concentr Plasma Compound 1 Eation (µM) Time (h) Mouse 1/9 Mouse 2/10 Mouse 3/11 Mouse 4/12 Average SD 0 0.00 0.00 0.0 0.00 0.0 0.0 0.25 0.891 0.975 2.42 0.364 1.162 0.881 0.5 0.990 0.230 0.533 0.413 0.541 0.324 1 0.224 0.265 0.657 0.062 0.302 0.252 2 0.179 0.145 0.072 0.163 0.140 0.048 4 0.0156 0.0538 0.0387 0.0065 0.0287 0.0216 6 BLQ 0.0189 0.0340 0.0356 0.0221 0.0166 8 0.035 0.0270 0.0113 0.0104 0.0209 0.0121 24 BLQ BLQ BLQ BLQ BLQ NC BLQ: below the limit of quantitation; NC: not calculated.

In FIG. 52 illustrates the results of the plasma concentration profile after a single oral administration of Capsule G in male CD-1 mice.

In FIG. 47 illustrates the results of the plasma concentration profile after a single oral administration of capsule E in male CD-1 mice.

Table 47

Capsule E: tabular summary of plasma concentrations (µM)

Compound 1 plasma concentration (µM) Time (h) Mouse 1/9 Mouse 2/10 Mouse 3/11 Mouse 4/12 Average SD 0 0 0.0 0.00 0 0 0 0.25 0.570 0.601 1.622 0.817 0.902 0.492 0.5 0.293 0.978 0.539 0.277 0.522 0.327 1.0 0.273 0.225 0.248 0.178 0.231 0.040 2 0.118 0.189 0.250 0.124 0.170 0.062 4 0.0420 0.0255 0.023 0.0361 0.0317 0.0089 6 0.0341 BLQ 0.0243 0.0217 0.0200 0.0144 8 0.0109 0.0110 0.0106 0.0102 0.0107 0.0004 24 BLQ BLQ 0.00126 BLQ BLQ NC BLQ: below the limit of quantitation; NC: not calculated; values are in italics.

In FIG. 53 illustrates the results of the plasma concentration profile after a single oral administration of capsule E in male CD-1 mice.

In FIG. 48 illustrates the results of the plasma concentration profile after a single oral administration of Capsule I in male CD-1 mice.

Table 48

Capsule I: tabular summary of plasma concentrations (µM)

Concentrate] Plasma Compound 1 Eation (µM) Time (h) Mouse 1 Mouse 2 Mouse 3 Mouse 4 Average SD 0 0 0 0 0 0 0 0.5 0.357 0.377 0.736 0.385 0.464 0.182 1.5 0.150 0.092 0.223 0.191 0.164 0.056 3 0.125 0.0717 0.0926 0.171 0.115 0.043 5 0.0795 0.0568 0.0388 0.1042 0.0698 0.0283 8 0.0710 0.0326 0.0614 0.0365 0.0504 0.0187

In FIG. 54 illustrates the results of the plasma concentration profile after a single oral administration of Capsule I in male CD-1 mice.

In table. 49 illustrates the results of the plasma concentration profile after a single oral administration of Capsule J in male CD-1 mice.

- 47 040951

Table 49

Capsule J: tabular summary of plasma concentrations (µM)

Concentrate] Plasma Compound 1 Eation (µM) Time (h) Mouse 1/9 Mouse 2/10 Mouse 3/11 Mouse 4* Average SD 0 0 0 0 0 0 0 0.5 0.845 1.46 1.94 3.54 1.42 0.55 1.5 0.275 0.702 0.578 0.962 0.519 0.220 3 0.285 0.301 0.192 1.85 0.259 0.059 5 0.0500 0.0653 0.0702 0.292 0.0618 0.0105 8 0.0259 0.0621 0.0341 0.0372 0.0407 0.0190 *Mouse 4 is an outlier based on the Grubbs test and is therefore excluded from data analysis.

* Mouse 4 is an outlier based on the Grubbs test and therefore excluded from data analysis.

In FIG. 55 illustrates the results of the plasma concentration profile after a single oral administration of Capsule J in male CD-1 mice.

In FIG. 56 illustrates a comparison of concentration profile results after a single oral administration of Capsule G, Capsule E, Capsule I, and Capsule J.

6.32. Pills.

Tablets A-C were produced and tested in the following studies.

In table. 50 illustrates the composition of tablet A.

Table 50

Tablet Composition A

Ingredient Composition (% w/w) Quantity (mg per tablet) Compound 1 20 50 Microcrystalline cellulose (Avicel PH102) 37.25 93.125 EMPROVE® Parteck® 37.25 93.125 Ac-Di-Sol® 4 10 AEROSIL® 200 0.5 1.25 magnesium stearate 1 2.5 General 100 250

In table. 51 illustrates the composition of tablet B.

Table 51

Tablet Composition B

Ingredient Composition (% w/w) Quantity (mg per tablet) HC1 salt of compound 1 20 50 Microcrystalline cellulose 37.25 93.125 (Avicel РН102) EMPROVE® Parteck® 37.25 93.125 Ac-Di-Sol® 4 10 AEROSIL® 200 0.5 1.25 magnesium stearate 1 2.5 General 100 250

- 48 040951

In table. 52 illustrates the composition of tablet C.

Table 52

Tablet C composition

Ingredient Composition (% May ./May) Quantity (mg per tablet) Citrate salt of compound 1 20 50 Microcrystalline cellulose (Avicel PH102) 37.25 93.125 EMPROVE® Parteck® 37.25 93.125 Ac-Di-Sol® 4 10 AEROSIL® 200 0.5 1.25 magnesium stearate 1 2.5 General 100 250

In FIG. 57 illustrates the dissolution of tablet A, tablet B and tablet C in phosphate buffer pH 2.

In FIG. 58 illustrates the dissolution of tablet A (middle curve), tablet B (upper curve) and tablet C (lower curve) in phosphate buffer pH 5 and 0.1% sodium laureth sulfate. The HCl salt of compound 1 had higher dissolution than the free base of compound 1 and the citrate salt of compound 1.

6.33. Composition and stability study.

Solubility study: Compound 1 free base pKa was determined to be 5.14. Therefore, the solubility of compound 1 is pH dependent: 0.003 mg/ml in water (pH 8.1), 3.5 mg/ml in simulated gastric fluids (SGF - simulated gastric fluids) (pH 1.9), 0.002 mg/ml in imitation of intestinal juice (SIF - simulated intestinal fluids) (pH 7.3). The solubility in the preclinical formulation of 0.5% CMC/0.25% Tween 80 was determined to be 0.18 mg/mL at pH 8.1. The solubility values of Compound 1 in SGF and SIF under fasted and fed conditions are listed in Table 1. 53.

TABLE 53 Solubility of compound 1 free base monohydrate in biorelevant media over 24 hours

Carrier media Concentration (mg/ml) pH after 24 h FaSSIF 0.26 6.48 FeSSIF 2.07 4.94 FaSSGF 2.81 1.84

FeSSGF 0.004 6.31

Chemical Stability Study: Compound 1 free base monohydrate solid state stability was evaluated at 80°C for 2 weeks and at 40°C/75% RH, 50°C/75% RH and 60°C for up to 5 weeks. The results showed that compound 1 free base monohydrate is chemically relatively stable under all storage conditions and duration.

Physical Stability Study: The free base monohydrate lost water and turned into an anhydrous form after heating at 60 and 80°C. This anhydrous form is converted back to the monohydrate immediately when the samples are exposed to room temperature and RH>30%. If the RH is in the range of 5-30%, conversion to the monohydrate for the dehydrated form may take 1-3 days.

6.34. Solution stability study.

The stability of a solution of compound 1 free base in water, SGF (pH 1.3), SIF (pH 7.5) and 0.1N NaOH with and without light protection at 37°C was tested. The results showed that the free base of Compound 1 was relatively stable (>95% remaining) in all carrier media for 4 days except for the 0.1N NaOH sample without light protection. Significant degradation was observed for this sample, with only 88% remaining on day 1 and 61% remaining on day 4.

No significant degradation of the 6 mg/mL suspension formulation in 0.5% CMC and 0.25% Tween 80 stored at ambient temperature and 2-8°C for 7 days was observed.

6.35. Composition development.

Free base monohydrate.

To evaluate the use of Compound 1 in a capsule to support the FIH study, a dissolution study in a capsule containing 125 mg Compound 1 free base monohydrate was performed in 0.01N HCl and 0.001N HCl at 37°C. Shrinkage of the capsule shell was observed. About 80% of compound 1 is released in 0.01N HCl and only 10% in 0.001N HCl after 60 min, suggesting that the dissolution of compound 1 free base monohydrate is highly dependent

-

Claims (64)

from pH, and the development of an AIC formulation for free base monohydrate to support research FIH can be difficult. Encapsulation or other formulation approaches may be necessary. citrate salt. A study was also made of the dissolution of the citrate salt in the capsule in 0.01N HCl. The results are shown in FIG. 59, which illustrates that the citrate salt had a better dissolution profile than the free base monohydrate. This suggests that an AIC formulation approach to support FIH may be feasible for the citrate salt. CLAIM 1. Cancer treatment capsule containing cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2,4,6trichloroanilino)-9H-purine-9- yl]-1-methylcyclohexane-1-carboxamide or its pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph in an amount equal to 30-40% by weight of the capsule, excipient in an amount equal to 50-60% by weight of the capsule, and tocofersolan in an amount equal to 5-15% by weight of the capsule. 2. Capsule according to claim 1, characterized in that cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2,4,6trichloroanilino)-9H- purin-9-yl]-1-methylcyclohexane-1-carboxamide is present in an amount of about 37% by weight. 3. Capsule according to claim 1, characterized in that the excipient is hydroxypropyl methylcellulose. 4. Capsule according to claim 3, characterized in that hydroxypropyl methylcellulose is present in an amount equal to about 53% by weight. 5. Capsule according to claim 1, characterized in that tocofersolan is present in an amount equal to about 10% by weight. 6. Cancer treatment capsule containing 60-70% cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8(2,4,6-trichloroanilino)-9H -purin-9-yl]-1-methylcyclohexane-1-carboxamide or its pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph by weight, 20-30% excipient by weight and 5-15% tocofersolane by weight . 7. Capsule according to claim 6, characterized in that the excipient is hydroxypropyl methylcellulose. 8. Capsule according to claim 6, characterized in that the excipient is a polyvinyl acetate phthalate polymer. 9. Capsule according to claim 6, characterized in that the excipient is a vinyl pyrrolidone vinyl acetate copolymer. 10. Capsule according to claim 6, characterized in that this capsule contains about 65% cis-4-[2-{[(3S,4R)3-fluoroxan-4-yl]amino} -8-(2.4, 6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1 carboxamide by weight. 11. Capsule according to claim 6, characterized in that this capsule contains about 25% cis-4-[2-{[(3S,4R)3-fluoroxan-4-yl]amino} -8-(2.4, 6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1 carboxamide by weight. 12. A capsule according to claim 6, characterized in that the capsule contains about 10% tocophersolan by weight. 13. Cancer treatment capsule containing 45-55% cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8(2,4,6-trichloroanilino)-9H -purin-9-yl]-1-methylcyclohexane-1-carboxamide or its pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph by weight, 35-45% excipient by weight and 5-15% tocofersolane by weight . 14. Capsule according to claim 13, characterized in that the excipient is hydroxypropyl methylcellulose. 15. Capsule according to claim 13, characterized in that the excipient is a polyvinyl acetate phthalate polymer. 16. Capsule according to claim 13, characterized in that the excipient is a vinyl pyrrolidone vinyl acetate copolymer. 17. Capsule according to claim 13, characterized in that this capsule contains about 50% cis-4-[2{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2,4, 6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1carboxamide by weight. 18. The capsule according to claim 13, characterized in that this capsule contains about 40% of the excipient by weight. 19. A capsule according to claim 13, characterized in that the capsule contains about 10% tocophersolan by weight. 20. Cancer treatment capsule containing cis-4-[2-{[(3S,4R)-3-fluoroxan-4yl]amino}-8-(2,4,6-trichloroanilino)-9H-purine-citrate salt 9-yl]-1-methylcyclohexane-1-carboxamide and lauryl- - 50 040951 sodium sulfate. 21. Capsule according to claim 20, characterized in that this capsule contains 0.5-3% cis-4[2-{[(3 S,4R)-3-fluoroxan-4-yl]amino}-8 citrate salt -(2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1 carboxamide by weight and 0.5-3% sodium lauryl sulfate by weight. 22. The capsule according to claim 21, characterized in that this capsule contains about 1.79% of the citrate salt of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8- (2,4,6-trichloroanilino)-9H-purin-9-yl]-1methylcyclohexane-1-carboxamide by weight and about 1.0% sodium lauryl sulfate by weight. 23. The capsule according to claim 21, characterized in that this capsule additionally contains 10-30% microcrystalline cellulose by weight, 55-75% mannitol by weight, 2-8% fumaric acid by weight, 1-7% crospovidone by weight, 0.2-1% colloidal silicon dioxide by weight and 0.5-3% magnesium stearate by weight. 24. The capsule according to claim 23, characterized in that this capsule contains about 1.79% of the citrate salt of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8- (2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide by weight. 25. A capsule according to claim 23, characterized in that the capsule contains about 21.65% microcrystalline cellulose by weight. 26. A capsule according to claim 23, characterized in that the capsule contains about 64.96% mannitol by weight. 27. A capsule according to claim 23, characterized in that the capsule contains about 1.0% sodium lauryl sulfate by weight. 28. A capsule according to claim 23, characterized in that the capsule contains about 5.0% fumaric acid by weight. 29. A capsule according to claim 23, characterized in that the capsule contains about 4.0% crospovidone by weight. 30. A capsule according to claim 23, characterized in that the capsule contains about 0.6% colloidal silicon dioxide by weight. 31. A capsule according to claim 23, wherein the capsule contains about 1.0% magnesium stearate by weight. 32. Capsule according to claim 20, characterized in that this capsule contains 2-12% citrate salt of cis-4[2-{[(3 S,4R)-3-fluoroxan-4-yl]amino} -8-( 2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1 carboxamide by weight and 0.5-3% sodium lauryl sulfate by weight. 33. A capsule according to claim 32, characterized in that the capsule contains about 6.70% of the cis4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2 ,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1 carboxamide by weight and about 1.0% sodium lauryl sulfate by weight. 34. The capsule according to claim 32, characterized in that this capsule additionally contains 10-30% microcrystalline cellulose by weight, 50-70% mannitol by weight, 2-8% fumaric acid by weight, 1-7% crospovidone by weight, 0.2-1% colloidal silicon dioxide by weight and 0.5-3% magnesium stearate by weight. 35. The capsule according to claim 34, characterized in that this capsule contains about 6.70% of the citrate salt of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-ul]amino}-8- (2,4,6-trichloroanulino)-9H-nurin-9-yl]-1-methylcyclohexane1-carboxamide by weight. 36. A capsule according to claim 34, characterized in that the capsule contains about 20.42% microcrystalline cellulose by weight. 37. A capsule according to claim 34, characterized in that the capsule contains about 61.28% mannitol by weight. 38. A capsule according to claim 34, characterized in that the capsule contains about 1.0% sodium lauryl sulfate by weight. 39. A capsule according to claim 34, characterized in that the capsule contains about 5.0% fumaric acid by weight. 40. A capsule according to claim 34, characterized in that the capsule contains about 4.0% crospovidone by weight. 41. A capsule according to claim 34, characterized in that the capsule contains about 0.6% colloidal silicon dioxide by weight. 42. The capsule of claim 34, wherein the capsule contains about 1.0% magnesium stearate by weight. 43. Capsule according to claim 20, characterized in that this capsule contains 5-20% citrate salt of cis-4[2-{[(3 S,4R)-3-fluoroxan-4-yl]amino} -8-( 2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1 carboxamide by weight and 0.5-3% sodium lauryl sulfate by weight. 44. The capsule according to claim 43, characterized in that this capsule contains about 10.72% of the citrate salt of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8- (2,4,6-trichloroanilino)-9H-purin-9-yl]-1methylcyclohexane-1-carboxamide by weight and about 1.0% sodium lauryl sulfate by weight. 45. The capsule according to claim 43, characterized in that this capsule additionally contains 10-30% of the micro- - 51 040951 rocrystalline cellulose by weight, 50-70% mannitol by weight, 2-8% fumaric acid by weight, 1-7% crospovidone by weight, 0.2-1% colloidal silicon dioxide by weight and 0.5-3% magnesium stearate by weight. 46. The capsule according to claim 45, characterized in that this capsule contains about 10.72% of the citrate salt of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8- (2,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide by weight. 47. A capsule according to claim 45, characterized in that the capsule contains about 19.41% microcrystalline cellulose by weight. 48. A capsule according to claim 45, characterized in that the capsule contains about 58.27% mannitol by weight. 49. A capsule according to claim 45, characterized in that the capsule contains about 1.0% sodium lauryl sulfate by weight. 50. A capsule according to claim 45, characterized in that the capsule contains about 5.0% fumaric acid by weight. 51. A capsule according to claim 45, characterized in that the capsule contains about 4.0% crospovidone by weight. 52. A capsule according to claim 45, characterized in that the capsule contains about 0.6% colloidal silicon dioxide by weight. 53. A capsule according to claim 45, characterized in that the capsule contains about 1.0% magnesium stearate by weight. 54. Cancer treatment tablet containing 15-25% cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8(2,4,6-trichloroanilino)-9H -purin-9-yl]-1-methylcyclohexane-1-carboxamide or its isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph by weight, 32-43% microcrystalline cellulose by weight, 32-43% mannitol by weight, 2-6% croscarmellose sodium by weight, 0.3-0.7% colloidal silicon dioxide by weight and 0.5-1.5% magnesium stearate by weight. 55. Tablet according to claim 54, characterized in that this tablet contains about 20% cis-4-[2{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2.4, 6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane-1carboxamide or its isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate or polymorph by weight. 56. A tablet according to claim 54, characterized in that the tablet contains about 37.25% microcrystalline cellulose by weight. 57. A tablet according to claim 54, characterized in that the tablet contains about 37.25% mannitol by weight. 58. A tablet according to claim 54, characterized in that the tablet contains about 4% croscarmellose sodium by weight. 59. Tablet according to claim 54, characterized in that this tablet contains about 1% magnesium stearate by weight. 60. Tablet according to claim 54, characterized in that the total weight of the tablet is about 250 mg. 61. Tablet according to claim 54, characterized in that the salt of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8(2,4,6-trichloroanilino)- 9H-purin-9-yl]-1-methylcyclohexan-1-carboxamide is the HCl salt of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2 ,4,6-trichloroanilino)-9H-purin-9-yl]-1-methylcyclohexane1-carboxamide. 62. Tablet according to claim 54, characterized in that the salt of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8(2,4,6-trichloroanilino)- 9H-purin-9-yl]-1-methylcyclohexane-1-carboxamide is the citrate salt of cis-4-[2-{[(3S,4R)-3-fluoroxan-4-yl]amino}-8-(2 ,4,6-trichloroanilino)-9H-purin-9-yl]-1methylcyclohexane-1-carboxamide. 63. A method of treating cancer, comprising administering a capsule according to any one of claims 1 to 53 or a tablet according to any one of claims 54 to 62 to a patient in need thereof. 64. The use of a capsule according to any one of claims 1 to 53 or a tablet according to any one of claims 54 to 62 in a cancer treatment method comprising administering the capsule or tablet to a patient in need thereof. -