GRANULAR COMPOSITION OF AN ERK INHIBITOR AND USES THEREOF

FIELD OF THE INVENTION

The present invention relates to a granular composition of an ERK inhibitor, and to such a granular composition as the product of a process. The invention also relates to pharmaceutical compositions comprising the granular composition of the present invention, and to methods of using the granular composition for treating a cellular proliferative disorder in a patient. BACKGROUND OF THE INVENTION

ERK inhibitors have promising therapeutic potential against BRAF-mutant tumors, BRAF-MEK inhibitor resistant tumors, or RAS-mutant tumors, and have been shown to be well-tolerated with clinical activity against a wide range of tumor types. US Patent Nos. 8,716,483, and 8,546,404, and International Publication No. WO 2016/100147 describe ERK inhibitors, including (S)-N-(3-(6-isopropoxypyridin-3-yl)-lH-indazol-5-yl)-l-(2-(4 -(4-(4- (l-methyl-lH-l,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-l -(2H)-yl)-2-oxoethyl)-3- (methylthio)pyrrolidine-3-carboxamide (Compound A), and pharmaceutically acceptable salts thereof:

Compound A is known to be shear sensitive. In the dry powder state, exposure to shear stresses typical of commercial processing results in conversion of a thermodynamically stable crystalline phase of Compound A to a less stable amorphous phase.

In order to avoid chemical degradation of the final drug product dosage units, the ideal active pharmaceutical ingredient (API) would have low amorphous content, and higher bulk density. The present invention provides a free-flowing, bulk density composition comprising Compound A, having improved stability and properties which allows for efficient preparation of tablets and capsules suitable for safe and effective oral administration to a patient.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a free-flowing granular composition (the “Granular Composition of Compound A”) comprising: (i) a hydrochloride salt of Compound A, wherein Compound A is: and (ii) a one or more binders.

In another aspect, the present invention provides pharmaceutical compositions comprising a Granular Composition of Compound A.

In another aspect, the present invention provides a method for treating cancer in a patient, said method comprising administering to said patient a Granular Composition of Compound A.

The Granular Compositions of Compound A can be useful, for example, for treating a cellular proliferative disorder in a patient, and for preparing solid dosage forms. Without being bound by any specific theory, it is believed that Granular Compositions of Compound A exert their physiological effects by inhibiting the ERK signaling pathway.

The details of the invention are set forth in the accompanying detailed description below.

Although any methods and materials similar to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel Granular Compositions of Compound A, and methods of using the Granular Compositions of Compound A for treating a cellular proliferative disorder in a patient.

Definitions and Abbreviations

The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name and an ambiguity exists between the structure and the name, it is to be understood that the structure predominates. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

The term “patient” (alternatively “subject”) as used herein refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female. The mammal may be one or more selected from the group consisting of humans, bovine (e.g., cows), porcine (e.g, pigs), ovine (e.g., sheep), capra (e.g, goats), equine (e.g, horses), canine (e.g., domestic dogs), feline (e.g., house cats), Lagomorpha (rabbits), rodents (e.g., rats or mice), Procyon lotor (e.g., raccoons). In particular embodiments, the patient is human.

The term “subject in need thereof’ as used herein refers to a subject diagnosed with, or suspected of having, a cell-proliferation disorder, such as a cancer, as defined herein.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts.

The term “dosage form” refers to a pharmaceutical product comprising a Granular Composition of Compound A, wherein the pharmaceutical product is in the form suitable for administration. The dosage form comprises a mixture of active drug component(s) and nondrug component(s) (excipient(s)), along with other non-reusable material that may not be considered either ingredient or packaging (such as a capsule shell, for example). The term “dosage form” also refers to a chemical formulation comprising a Granular Composition of Compound A, and any blends involved, without considering its ultimate configuration as a consumable product such as a tablet or capsule. Depending on the method/route of administration, dosage forms may exist in several types. These include, but are not limited to, liquid, solid, and semisolid dosage forms. Non-limiting dosage forms include pills, tablets, capsules, suspensions, drinks or syrups. A dosage form can be administered various ways, including orally and intravenously.

The term "effective amount" as used herein, refers to an amount of Granular Composition of Compound A, and/or an additional therapeutic agent, or a composition thereof that is effective in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a patient suffering from a cellular proliferative disorder. In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.

The term "in substantially purified form,” as used herein, refers to the physical state of a compound after the compound is isolated from a synthetic process (e.g., from a reaction mixture), a natural source, or a combination thereof.

The terms “administration of’ and or “administering” a compound should be understood to include providing a compound described herein, or a pharmaceutically acceptable salt thereof, and compositions of the foregoing to a subject.

“Treat” or “treating” a cell-proliferation disorder as used herein means to administer a Granular Composition of Compound A or a combination thereof, to a subject having a cell-proliferation disorder, such as cancer, or diagnosed with a cell-proliferation disorder, such as cancer, to achieve at least one positive therapeutic effect, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth. Such “treatment” may result in a slowing, interrupting, arresting, controlling, or stopping of the progression of a cell- proliferation disorder as described herein but does not necessarily indicate a total elimination of the cell-proliferation disorder or the symptoms of the cell-proliferation disorder. Positive therapeutic effects in cancer can be measured in a number of ways (See. W. A. Weber, J. Nucl. Med. 50: 1 S-10S (2009)). For example, with respect to tumor growth inhibition, according to NCI standards, a T/C £ 42% is the minimum level of anti-tumor activity. A T/C < 10% is considered a high anti-tumor activity level, with T/C (%) = Median tumor volume of the treated/Median tumor volume of the control x 100. In some embodiments, the treatment achieved by a combination therapy of the disclosure is any of PR, CR, OR, PFS, DFS, and OS. PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced SD. DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients. In some embodiments, response to a combination therapy of the disclosure is any of PR, CR, PFS, DFS, or OR that is assessed using RECIST 1.1 response criteria. The treatment regimen for a combination therapy of the disclosure that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the disclosure may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi ² -test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-test.

The terms “treatment regimen”, “dosing protocol”, and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination therapy of the disclosure.

As used herein, the term “antibody” refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, and chimeric antibodies. “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic. As used herein, the term “antibody” encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen binding portion thereof that competes with the intact antibody for specific binding, fusion proteins comprising an antigen binding portion, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site.

As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment” refers to a fragment of an antibody that retains the ability to bind specifically to the antigen, e.g., fragments that retain one or more CDR regions. An antibody that “specifically binds to” PD-1 or PD-L1 is an antibody that exhibits preferential binding to PD-1 or PD-L1 (as appropriate) as compared to other proteins, but this specificity does not require absolute binding specificity. An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives. Antibodies, or binding fragments thereof, will bind to the target protein with an affinity that is at least two fold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins.

Antigen binding portions include, for example, Fab, Fab’, F(ab’)2, Fd, Fv, fragments including complementarity determining regions (CDRs), and single chain variable fragment antibodies (scFv), and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the PD-1 or PD-L1. An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereol), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy-chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

As used herein, the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.

As used herein, the term “immune response” relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non specific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell-proliferation, immune cell differentiation, and cytokine expression. The term “pharmaceutically acceptable carrier” refers to any inactive substance that is suitable for use in a formulation for the delivery of a therapeutic agent. A carrier may be an antiadherent, binder, coating, disintegrant, filler or diluent, preservative (such as antioxidant, antibacterial, or antifungal agent), sweetener, absorption delaying agent, wetting agent, emulsifying agent, buffer, and the like. Examples of suitable pharmaceutically acceptable carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), dextrose, vegetable oils (such as olive oil), saline, buffer, buffered saline, and isotonic agents such as sugars, polyalcohols, sorbitol, and sodium chloride.

The term “subject in need thereof’ as used herein refers to a subject diagnosed with, or suspected of having, a cell -proliferation disorder, such as a cancer, as defined herein.

As used herein, the terms “treatment” and “treating” refer to all processes in which there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of a disease or disorder described herein. The terms do not necessarily indicate a total elimination of all disease or disorder symptoms.

“Variable regions” or “V region” or “V chain” as used herein means the segment of IgG chains which is variable in sequence between different antibodies. A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. Typically, the variable regions of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C-terminal, both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Rabat, et al:, National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Rabat (1978) Adv. Prot. Chem. 32:1-75; Rabat, et al, (1977) J. Biol. Chem. 252:6609-6616; Chothia, etal, (1987) J Mol. Biol. 196:901-917 or Chothia, et al, (1989) Nature 342:878-883.

“Conservatively modified variants” or “conservative substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g., charge, side-chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity or other desired property of the protein, such as antigen affinity and/or specificity. “Consists essentially of,” and variations such as “consist essentially of’ or “consisting essentially of,” as used throughout the specification and claims, indicate the inclusion of any recited elements or group of elements, and the optional inclusion of other elements, of similar or different nature than the recited elements, that do not materially change the basic or novel properties of the specified dosage regimen, method, or composition.

“Diagnostic anti-PD-L monoclonal antibody” means a mAh that specifically binds to the mature form of the designated PD-L (PD-L1 or PD-L2) expressed on the surface of certain mammalian cells. A mature PD-L lacks the presecretory leader sequence, also referred to as leader peptide. The terms “PD-L” and “mature PD-L” are used interchangeably herein, and shall be understood to mean the same molecule unless otherwise indicated or readily apparent from the context.

“CPS” or “combined positive score” refers to an algorithm for determining a PD- L1 expression score from a tumor sample of a patient. The CPS is useful in selecting patients for treatment with particular treatment regimens including methods of treatment comprising administration of an anti-PD-1 antibody in which expression of PD-L1 is associated with a higher response rate in a particular patient population relative to same patient population that does not express PD-L1. The CPS is determined by determining the number of viable PD-L1 positive tumor cells, the number of viable PD-L1 negative tumor cells, and the number of viable PD-L1 positive mononuclear inflammatory cells (MIC) in a tumor tissue from a patient having a tumor and calculating the CPS using the following formula:

(# PD-L1 positive tumor cells) + (# PD-L1 positive MIC) x 100%

(# PD-L1 positive tumor cells) + (PD-L1 negative tumor cells).

“TPS” or “tumor proportion score” is the percentage of tumor cells expressing PD-L1 on the cell membrane. TPS typically includes the percentage of neoplastic cells expressing PD-L1 at any intensity (weak, moderate, or strong), which can be determining using an immunohistochemical assay using a diagnostic anti-human PD-L1 mAh, e.g. antibody 20C3 and antibody 22C3, described, supra. Cells are considered to express PD-L1 if membrane staining is present, including cells with partial membrane staining.

“Homology” refers to sequence similarity between two polypeptide sequences when they are optimally aligned. When a position in both of the two compared sequences is occupied by the same amino acid monomer subunit, e.g., if a position in a light chain CDR of two different Abs is occupied by alanine, then the two Abs are homologous at that position. The percent of homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared x 100. For example, if 8 of 10 of the positions in two sequences are matched when the sequences are optimally aligned then the two sequences are 80% homologous. Generally, the comparison is made when two sequences are aligned to give maximum percent homology.

The term “isolated” as used in reference to an antibody or fragment thereof refers to the purification status and, in such context, means the named molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term “isolated” is not intended to refer to a complete absence of such material or to an absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.

“Kabat” as used herein means an immunoglobulin alignment and numbering system pioneered by Elvin A. Kabat ((1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.).

“Monoclonal antibody” or “mAh” or “Mab”, as used herein, refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific for different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

“RECIST 1.1 Response Criteria” as used herein means the definitions set forth in Eisenhauer, E.A. et al, Eur. J. Cancer 45:228-247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured.

“Tissue Section” refers to a single part or piece of a tissue, e.g., a thin slice of tissue cut from a sample of a normal tissue or of a tumor.

“Treat” or “treating” a cell-proliferation disorder as used herein means to administer a Granular Composition of Compound A or a combination thereof, to a subject having a cell-proliferation disorder, such as cancer, or diagnosed with a cell-proliferation disorder, such as cancer, to achieve at least one positive therapeutic effect, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth. Such “treatment” may result in a slowing, interrupting, arresting, controlling, or stopping of the progression of a cell- proliferation disorder as described herein but does not necessarily indicate a total elimination of the cell-proliferation disorder or the symptoms of the cell-proliferation disorder. Positive therapeutic effects in cancer can be measured in a number of ways (See. W. A. Weber, J. Nucl. Med. 50: 1 S-10S (2009)). For example, with respect to tumor growth inhibition, according to NCI standards, a T/C £ 42% is the minimum level of anti-tumor activity. A T/C < 10% is considered a high anti-tumor activity level, with T/C (%) = Median tumor volume of the treated/Median tumor volume of the control x 100. In some embodiments, the treatment achieved by a combination therapy of the disclosure is any of PR, CR, OR, PFS, DFS, and OS. PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced SD. DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients. In some embodiments, response to a combination therapy of the disclosure is any of PR, CR, PFS, DFS, or OR that is assessed using RECIST 1.1 response criteria. The treatment regimen for a combination therapy of the disclosure that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the disclosure may not be effective in achieving a positive therapeutic effect in every subject, it should do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student’s t-test, the chi ² -test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-test.

The terms “treatment regimen”, “dosing protocol”, and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination therapy of the disclosure.

“Tumor” as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

The term “tumor size” refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.

It is understood that wherever embodiments are described herein with the language “comprising,” otherwise analogous embodiments described in terms of “consisting of’ and/or “consisting essentially of’ are also provided.

Unless expressly stated to the contrary, all ranges cited herein are inclusive; i.e., the range includes the values for the upper and lower limits of the range as well as all values in between. As an example, temperature ranges, percentages, ranges of equivalents, and the like described herein include the upper and lower limits of the range and any value in the continuum there between. Numerical values provided herein, and the use of the term “about”, may include variations of ± 1%, ± 2%, ±3%, ± 4%, ± 5%, ± 10%, ± 15%, and ± 20% and their numerical equivalents. All ranges also are intended to include all included sub-ranges, although not necessarily explicitly set forth. For example, a range of 3 to 7 days is intended to include 3, 4, 5, 6, and 7 days. In addition, the term "or," as used herein, denotes alternatives that may, where appropriate, be combined; that is, the term "or" includes each listed alternative separately as well as their combination.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure relates. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word “comprise,” or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Any example(s) following the term “e.g.” or “for example” is not meant to be exhaustive or limiting.

Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.

“PD-L1” expression as used herein means any detectable level of expression of the designated PD-L protein on the cell surface or of the designated PD-L mRNA within a cell or tissue. PD-L protein expression may be detected with a diagnostic PD-L antibody in an IHC assay of a tumor tissue section or by flow cytometry. Alternatively, PD-L protein expression by tumor cells may be detected by PET imaging, using a binding agent (e.g, antibody fragment, affibody, and the like) that specifically binds to PD-L1. Techniques for detecting and measuring PD-L mRNA expression include RT-PCR and realtime quantitative RT-PCR.

The term “Bulk Density,” as used herein, refers to the weight of a powder or granular material per unit volume

The term “Tap Density,” as used herein, refers to an increased bulk density attained after mechanically tapping a container containing a sample of powder or granular material. The tapped density is obtained by mechanically tapping a graduated measuring cylinder or vessel containing the sample.

The term “Reynolds Number,” or “Re,” as used herein, is a dimensionless quantity in fluid mechanics and serves as an indication of the transition from laminar to turbulent flow. The Reynolds number is the ratio of inertial forces to viscous forces within a fluid which is subjected to relative internal movement due to different fluid velocities.

The term “Hausner Ratio,” as used herein, is used to represent an indication of the flowability of a powder or granular material. A Hausner ratio greater than 1.25 is considered to be an indication of poor flowability. The Hausner ratio is calculated using the formula H =

Rt/Pb, where PT is the tapped density, and Pb is the freely settled bulk density.

The term “Carr Index,” as used herein, is used represent an indication of the compressibility of a powdered or granular material. A Carr index greater than 25 is considered to be an indication of poor flowability. The Carr index is calculated using the formula C = 100[(PT- Pb)/ PT], where PT is the tapped density, and Pb is the freely settled bulk density, where is the freely settled bulk density of the powder, and is the tapped bulk density of the powder The term "sugar alcohol,” as used herein, refers to an organic compound, derived from a sugar, and having one hydroxyl group (-OH) attached to each carbon atom. A sugar alcohol can occur naturally or be produced industrially by hydrogenation of sugars. Non-limiting examples of sugar alcohols include sorbitol, mannitol, and erythritol.

The Granular Composition of Compound A

The present invention provides a free-flowing granular composition (the “Granular Composition of Compound A”) comprising: (i) a hydrochloride salt of Compound A, wherein the structure of Compound A is: and (ii) one or more binders.

In another aspect, the invention provides a free-flowing granular composition (the “Granular Composition of Compound A”) comprising: (i) a hydrochloride salt of Compound A, wherein the structure of Compound A is: and (ii) one or more binders, wherein the free-flowing granular composition is made by a process comprising the steps: (a) obtaining a slurry comprising: (i) a hydrochloride salt of Compound A, and (ii) one or more binders; and

(b) feeding the slurry of step (a) into a thin film evaporator under shear, temperature, and pressure conditions sufficient to provide turbulent mixing for a time of up to 10 minutes, wherein said turbulent mixing is sufficient to generate a free-flowing granular composition comprising: (i) the hydrochloride salt of Compound A, and (ii) the one or more binders, wherein the free-flowing granular composition has less than 5% residual solvent.

In one embodiment, in step (a), the individual crystals of the hydrochloride salt of Compound A that are present in the slurry of step (i), have a particle size from about 0.1 to about 100 microns.

In another embodiment, in step (a), the individual crystals of the hydrochloride salt of Compound A that are present in the slurry of step (i), have a particle size from about 0.1 to about 75 microns.

In another embodiment, in step (a), the individual crystals of the hydrochloride salt of Compound A that are present in the slurry of step (i), have a particle size from about 0.1 to about 40 microns.

In one embodiment, the temperature in step (b) is from about 40°C to about 180°C. In another embodiment, the temperature in step (b) is from about 50°C to about 100°C.

In another embodiment, the temperature in step (b) is from about 55°C to about 65°C. In still another embodiment, the temperature in step (b) is about 60°C.

In one embodiment, the shear rate in step (b) is greater than 24,000 s ¹ .

In one embodiment, step (b) is carried out under vacuum. In another embodiment, step (b) is carried out under vacuum of from about -600 mmHg to -760 mmHg. In another embodiment, step (b) is carried out under vacuum of from about -740 mmHg to -760 mmHg. In another embodiment, step (b) is carried out under vacuum of from about -740 mmHg to -750 mmHg.

In one embodiment, in step (b), the shear, temperature and pressure conditions comprise: (i) shear rates greater than 24,000 s ¹ , (ii) temperature between about 40°C and 180°C, and (iii) vacuum.

In another embodiment, in step (b), the shear, temperature and pressure conditions comprise: (i) shear rates greater than 24,000 s ¹ , (ii) temperature between about 40°C and 180°C, (iii) vacuum of from about -600 mmHg to -760 mmHg, and (iv) a Reynolds Number above 2,100. In another embodiment, in step (b), the shear, temperature and pressure conditions comprise: (i) shear rates greater than 24,000 s ¹ , (ii) temperature between about 50°C and 70°C, (iii) vacuum of from about -740 mmHg to -760 mmHg, and (iv) a Reynolds Number above 4,000.

In one embodiment, in step (a), the hydrochloride salt of Compound A in the slurry is the HC1 form 1 salt, as described in International Publication No. WO 2016/100147.

In one embodiment, in step (a), the hydrochloride salt of Compound A in the slurry is in substantially purified form.

In one embodiment, in step (a), the amount of the hydrochloride salt of Compound A in the slurry is from about 50 to about 99 wt/wt%.

In another embodiment, in step (a), the amount of the hydrochloride salt of Compound A in the slurry is from about 80 to about 95 wt/wt%.

In one embodiment, in step (a), the slurry contains less than 10% of Compound A in amorphous form

In another embodiment, in step (a), the slurry contains less than 5% of Compound A in amorphous form.

In another embodiment, in step (a), the slurry contains less than 3% of Compound A in amorphous form.

In still another embodiment, in step (a), the slurry contains less than 2% of Compound A in amorphous form.

In still another embodiment, in step (a), the slurry contains less than 1% of Compound A in amorphous form.

In one embodiment, free-flowing granular composition comprises the HC1 form 1 salt of Compound A, as described in International Publication No. WO 2016/100147.

In one embodiment, the free-flowing granular composition comprises particles having a particle size from about 25 to about 400 microns.

In another embodiment, the free-flowing granular composition comprises particles having a particle size from about 50 to about 250 microns.

In one embodiment, the free-flowing granular composition comprises from about 0.5% to about 4% residual solvent.

In another embodiment, the free-flowing granular composition comprises from about 0.5% to about 2% residual solvent.

In another embodiment, the free-flowing granular composition comprises less than about 0.5% residual solvent.

In one embodiment, the free-flowing granular composition comprises a binder, which is a polymer selected from: a cellulosic polymer, a methacrylate, a vinyl polymer, a copolymer, and polyethylene glycol.

In another embodiment, the free-flowing granular composition comprises a binder, which is selected from ethyl cellulose, methyl cellulose, hydroxylpropyl cellulose, hydroxylpropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxylpropyl methyl cellulose phthalate, poly(butyl 14 methacrylate-co-(2- dimethylaminoethyl), poly(methacylic acid-co-ethyl acrylate), poly(methacylic acid-co-methyl acrylate), l-ethenylpyrrolidin-2-one, copovidone, soluplus, polyethylene oxide (PEO), polyoxyethylene (POE)), and poly(acrylic acid).

In another embodiment, the free-flowing granular composition comprises a binder, which is a water-soluble excipient, selected from: a salt, a sugar, a sugar alcohol, a monosaccharide, a disaccharide, an amino acid, and a polysaccharide.

In still another embodiment, the free-flowing granular composition comprises a binder, which is hydroxypropyl cellulose.

In one embodiment, the free-flowing granular composition has a bulk density of from about 0.25 to about 0.60. In another embodiment, the free-flowing granular composition has a bulk density of from about 0.40 to about 0.50.

In one embodiment, the free-flowing granular composition has a tapped density of from about 0.30 to about 0.70. In another embodiment, the free-flowing granular composition has a tapped density of from about 0.50 to about 0.60.

In one embodiment, the yield of the Granular Composition of Compound A is 10% or more. In one embodiment, the yield is from about 40% to about 100%. In one embodiment, the yield is from about 75% to about 95%.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising an effective amount of a Granular Composition of Compound A, and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of (a), further comprising a second therapeutic agent selected from the group consisting of anticancer agents.

(c) The pharmaceutical composition of (b), wherein the anticancer agent is an anti -human PD-1 antibody (or antigen-binding fragment thereoi).

(d) A pharmaceutical combination that comprises: (i) a Granular Composition of Compound A, and (ii) a second therapeutic agent selected from the group consisting of anticancer agents, wherein the Granular Composition of Compound A, and the second therapeutic agent are each employed in an amount that renders the combination effective for inhibiting replication of cancer cells, or for treating cancer and/or reducing the likelihood or severity of symptoms of cancer.

(e) The combination of (d), wherein the second therapeutic agent is an anti human PD-1 antibody (or antigen-binding fragment thereof).

(1) A method of inhibiting cancer cell replication in a subject in need thereof which comprises administering to the subject an effective amount of a Granular Composition of Compound A.

(g) A method of treating cancer and/or reducing the likelihood or severity of symptoms of cancer in a subject in need thereof which comprises administering to the subject an effective amount of a Granular Composition of Compound A.

(h) The method of (g), wherein the Granular Composition of Compound A. is administered in combination with an effective amount of at least one second therapeutic agent selected from the group consisting of anticancer agents.

(i) The method of (h), wherein the second therapeutic agent is an anti-human PD-1 antibody (or antigen-binding fragment thereof).

(j) A method of inhibiting cancer cell replication in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).

(k) A method of treating cancer and/or reducing the likelihood or severity of symptoms of cancer in a subject in need thereof which comprises administering to the subject the pharmaceutical composition of (a), (b) or (c) or the combination of (d) or (e).

The present invention also includes Granular Compositions of Compound A for use (i) in, (ii) as a medicament for, or (iii) in the preparation of a medicament for: (a) medicine; (b) inhibiting cancer cell replication or (c) treating cancer and/or reducing the likelihood or severity of symptoms of cancer. In these uses, the Granular Composition of Compound A can optionally be employed in combination with one or more additional therapeutic agents selected from anticancer agents.

It is further to be understood that the embodiments of compositions and methods provided as (a) through (k) above are understood to include all embodiments of the compounds, including such embodiments as result from combinations of embodiments. Non-limiting examples of the Granular Composition of Compound A are described in the Examples below.

EXAMPLES

General Methods

Solvents, reagents, and intermediates that are commercially available were used as received. Reagents and intermediates that are not commercially available were prepared in the manner as described below. 'H NMR spectra were obtained on a Bruker Avance 500 (500 MHz; Bruker Corporation, Billerica, Massachusets) and are reported as ppm downfield from Me4Si with number of protons, multiplicities, and coupling constants in Hertz indicated parenthetically. Raman spectroscopy was used to quantify the level of amorphous Compound A in the granular compositions of the present invention.

EXAMPLE 1

Preparation of Compound A Hydrochloride Salt

The HC1 form 1 salt of Compound A was prepared using the methods described in International Publication No. WO 2016/100147.

EXAMPLE 2

Chemical Degradation Studies

Compound A is known to be shear sensitive. In the dry powder state, exposure to shear stresses typical of commercial processing results in conversion of a thermodynamically stable crystalline phase to a less stable amorphous phase. This amorphous phase is more prone to chemical degradation when subjected to typical commercial processes that result in shear induced phase-conversion. Such processes include isolation and drying during drug substance processing, and roller compaction dry powder densification during drug product processing.

Table 1 provides a comparison of the extent of chemical degradation of the HC1 form 1 salt of Compound A having low amorphous levels vs. the HC1 form 1 salt of Compound A having higher levels of amorphous material. Here, material is provided with low levels (3-4%) of Compound A in amorphous form, which is representative of the levels of amorphous material present in the Granular Compositions of Compound A. This is compared to material having higher levels (25-30%), of Compound A in amorphous form, which is typical when the HC1 salt of Compound A is subjected to roller compaction and other processing operations. The higher amorphous levels were generated by adding pure amorphous material to the purified HC1 form 1 salt of Compound A, so that the amorphous level was present in an amount of 25-30%.

Table 1

The data in Table 1 clearly show that the material having less amorphous material is far less prone to chemical degradation than material having higher amounts of amorphous material.

EXAMPLE 3

Preparation of an Exemplary Granular Composition of Compound A

The HC1 form 1 salt of Compound A (1984.9 g, having an amorphous level of 3.6 +/- 2.8 wt%, as detected by a Raman spectroscopy), was slurried with hydroxypropyl cellulose (220 g, low viscosity, SL grade) in isopropyl alcohol (17.6 L), to provide a slurry with a total solids content of 125g/L. Care was taken to not let the suspension concentration approach 150g/L, where increased viscosity can make pumping and line clogging more difficult.

The resulting slurry was delivered to a Thin-Film Evaporator (Artisan 0.5 sq ft thin film evaporator; Artisan Industries Inc., Stoughton, Massachusetts), at a rate of 2.5 L/hr using a peristaltic pump with 1/8” internal diameter flexible tubing. The thin-film evaporator instrument had the following settings: run rotor speed of 1800 rpm, jacket temperature of 60°C, and vacuum pressure range of approximately -740 to -750 mmHg. The condenser was set to - 15°C. This provided an exemplary Granular Composition of Compound A having approximately 12% residual solvent. Material was intentionally under- dried in this case to try to minimize amorphous formation, knowing that as a dry powder, material is more prone to convert to the amorphous phase upon shear exposure. The resulting the resulting composition was further tray dried at 40-60°C to a final residual solvent level of less than 0.5% by weight. The skilled artisan will be able to adjust the thin-film evaporation conditions to achieve an optimal balance of residual solvent levels and amorphous content.

Table 2, below, sets forth various properties of the neat HC1 form 1 salt of Compound A, and the exemplary Granular Composition made using the method described in this Example.

Table 2

EXAMPLE 4

Density and Flow Measurements

The bulk and tapped densities, and the powder flow metrics of the Granular Composition of Compound A that was made using the method described in Example 3, are presented in Table 3 below. The bulk density and tapped density of the samples were measured using standard USP procedures. The Hausner Ratio and Carr Index were calculated using the measured bulk and tapped densities and the formulas described above herein.

Table 3

The higher bulk and tapped density, and the improved flow characteristics (as indicated by the lower Hausner Ratio and lower Carr Index) of the exemplary Granular

Composition of Compound A, indicates that Granular Compositions of Compound A are more amenable to direct encapsulation than the neat HC1 Salt form 1 of Compound A. Further, as indicated above herein, using the Granular Composition of Compound A as the active pharmaceutical ingredient vs. neat HC1 Salt form 1 of Compound A also avoids the roller compaction dry granulation process, a step that results in the presence of higher levels of amorphous material during drug product processing. Uses of the Granular Composition of Compound A

Treatment or Prevention of Cellular Proliferation Disorders

The present disclosure also relates to methods of treating a cellular proliferative disorder, said methods comprising administering to a subject in need thereof a Granular Composition of Compound A.

The Granular Compositions of Compound A disclosed herein are potentially useful in treating diseases or disorders including, but not limited to, cellular proliferative disorders. Cellular proliferation disorders include, but are not limited to, cancers, benign papillomatosis, and gestational trophoblastic diseases. The terms “cancer”, “cancerous”, or “malignant” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

In specific embodiments, the cellular proliferative disorder is selected from cancer, benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases. In particular embodiments, the gestational trophoblastic disease is selected from the group consisting of hydati diform moles, and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental-site trophoblastic tumors, and epithelioid trophoblastic tumors). In a particular embodiment, the cellular proliferative disorder being treated is cancer.

Accordingly, one embodiment provides for methods for treating cancer in a patient, the methods comprising administering to the patient an effective amount of a Granular Composition of Compound A. In a specific embodiment, the amount administered is effective to treat cancer in the patient. In another specific embodiment, the amount administered is effective to inhibit cancer cell replication or cancer cell metastasis in the patient.

Another embodiment includes the use of the Granular Compositions of Compound A, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer.

Yet another embodiment includes Granular Compositions of Compound A, for use in the treatment of cancer.

In one embodiment, the cancer is metastatic. In another embodiment, the cancer is relapsed. In another embodiment, the cancer is refractory. In yet another embodiment, the cancer is relapsed and refractory.

In one embodiment, the patient has previously received treatment for cancer. In another embodiment, the patient has not previously received treatment for cancer. In one embodiment, the patient has previously received systemic treatment for cancer. In another embodiment, the patient has not previously received systemic treatment for cancer.

In other embodiments, the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient.

The Granular Compositions of Compound A and methods provided herein are useful for the treatment of cancer. Cancers that may be treated using the compounds, compositions and methods disclosed herein include, but are not limited to: (1) Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; (2) Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell; (3) Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colorectal, rectal; (4) Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); (5) Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; (6) Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; (7) Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); (8) Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; (9) Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelomonocytic (CMML), myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and (11) Adrenal glands: neuroblastoma. Examples of cancer that may be treated using the compounds, compositions and methods of the invention include thyroid cancer, anaplastic thyroid carcinoma, epidermal cancer, head and neck cancer (e.g., squamous cell cancer of the head and neck), sarcoma, tetracarcinoma, hepatoma and multiple myeloma.

The term "cancerous cell" as used herein, includes a cell afflicted by any one of the above-identified conditions.

In particular embodiments, the cancer is selected from brain and spinal cancers, cancers of the head and neck, leukemia and cancers of the blood, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, liver and bile duct cancers, kidney and bladder cancers, bone cancers, lung cancers, metastatic microsatellite instability -high (MSI- H) cancer, mismatch repair deficient cancer, malignant mesothelioma, sarcomas, lymphomas, glandular cancers, thyroid cancers, heart tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancers, and cancers of unknown primary origin (i.e., cancers in which a metastasized cancer is found but the original cancer site is not known). In particular embodiments, the cancer is AIDS-related.

In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In still another embodiment, the cancer is CRC. In another embodiment, the cancer is RCC. In another embodiment, the cancer is HCC. In one embodiment, the cancer is skin cancer. In another embodiment, the skin cancer is melanoma. In another embodiment, the cancer is ovarian cancer. In yet another embodiment, the cancer is pancreatic cancer. In another embodiment, the cancer is a primary or metastatic brain cancer. In still another embodiment, the cancer is CRC. One embodiment comprises a method of treating unresectable or metastatic melanoma in a human patient. In some embodiments, the method comprises treating resected high-risk stage III melanoma.

Another embodiment comprises a method of treating metastatic non-small cell lung cancer (NSCLC) in a human patient. In some embodiments, the NSCLC is non-squamous. In other embodiments, the NSCLC is squamous.

In some embodiments, the cancer exhibits high PD-L1 expression [(Tumor Proportion Score (TPS) >50%)] and was not previously treated with platinum-containing chemotherapy. In alternative embodiments, the patient has a tumor with PD-L1 expression (TPS >1%), and was previously treated with platinum-containing chemotherapy. In specific embodiments, the patient had disease progression on or after receiving platinum-containing chemotherapy.

In certain embodiments the PD-L1 TPS is determined by an FDA-approved test.

In certain embodiments of the method for treating NSCLC, the patient’s tumor has no EGFR or ALK genomic aberrations.

In certain embodiments of the method for treating NSCLC, the patient’s tumor has an EGFR or ALK genomic aberration and had disease progression on or after receiving treatment for the EGFR or ALK aberration(s) prior to receiving combination therapy of the invention.

In one embodiment, the invention comprises a method of treating recurrent or metastatic head and neck squamous cell cancer (HNSCC) in a human patient. In some embodiments, the patient was previously treated with platinum-containing chemotherapy. In certain embodiments, the patient had disease progression during or after platinum-containing chemotherapy.

One embodiment comprises a method of treating refractory classical Hodgkin lymphoma (cHL) in a human patient. In certain embodiments, the patient has relapsed after 1, 2, 3 or more lines of therapy for cHL. In specific embodiments, the patient is an adult patient. In alternative embodiments the patient is a pediatric patient.

Another embodiment comprises a method of treating locally advanced or metastatic urothelial carcinoma in a human patient. In certain embodiments, the patient is not eligible for cisplatin-containing chemotherapy. In further embodiments, the patient has disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. In specific embodiments, the patient’s tumor expresses PD-L1 (CPS >10).

One embodiment comprises a method of treating unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors in a human patient. In specific embodiments, the patient had disease progression following prior anti-cancer treatment.

Another embodiment comprises a method of treating unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient colorectal cancer in a human patient. In specific embodiments, the patient had disease progression following prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Yet another embodiment comprises a method of treating recurrent locally advanced or metastatic gastric cancer or recurrent locally advanced or metastatic gastroesophageal junction adenocarcinoma in a human patient. In specific embodiments, the patient’s tumor expresses PD-L1 [Combined Positive Score (CPS) >1] In some embodiments, the patient has disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy. In some embodiments, the patient has disease progression on or after two or more prior lines of therapy including HER2/neu- targeted therapy.

Still another embodiment comprises a method of treating non-Hodgkin lymphoma in a human patient. In certain embodiments, the non-Hodgkin lymphoma is primary mediastinal large B-cell lymphoma.

Another embodiment comprises a method of treating breast cancer in a human patient in specific embodiments, the breast cancer is triple negative breast cancer. In other specific embodiments, the breast cancer is ER+/HER2- breast cancer.

One embodiment comprises a method of treating cancer in a human patient comprising, wherein the patient has a tumor with a high mutational burden.

In specific embodiments, the cancer is selected from brain and spinal cancers. In particular embodiments, the brain and spinal cancer is selected from the group consisting of anaplastic astrocytomas, glioblastomas, astrocytomas, and estheosioneuroblastomas (also known as olfactory blastomas). In particular embodiments, the brain cancer is selected from the group consisting of astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma), oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma), oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma), ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma); medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astorcytoma/malignant glioma, visual pathway and hypothalmic glioma, and primary central nervous system lymphoma. In specific instances of these embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and suprantentorial primordial neuroectodermal tumors (sPNET). In one embodiment, the brain or spinal cancer is a metastatic brain tumor or tumors.

In specific embodiments, the cancer is selected from cancers of the head and neck, including recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), nasopharyngeal cancers, nasal cavity and paranasal sinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g., squamous cell carcinomas, lymphomas, and sarcomas), lip cancers, oropharyngeal cancers, salivary gland tumors, cancers of the larynx (e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas), and cancers of the eye or ocular cancers. In particular embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.

In specific embodiments, the cancer is selected from leukemia and cancers of the blood. In particular embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic/ myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML, post- MDS AML, del(5q)-associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytomas and multiple myelomas. Leukemias referenced herein may be acute or chronic.

In specific embodiments, the cancer is selected from skin cancers. In particular embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers. In specific embodiments, the skin cancer is unresectable or metastatic melanoma.

In specific embodiments, the cancer is selected from cancers of the reproductive system. In particular embodiments, the cancer is selected from the group consisting of breast cancers, cervical cancers, vaginal cancers, ovarian cancers, endometrial cancers, prostate cancers, penile cancers, and testicular cancers. In specific instances of these embodiments, the cancer is a breast cancer selected from the group consisting of ductal carcinomas and phyllodes tumors. In specific instances of these embodiments, the breast cancer may be male breast cancer or female breast cancer. In some instances of these embodiments, the breast cancer is triple negative breast cancer. In other instances, the breast cancer is ER+/HER2- breast cancer. In specific instances of these embodiments, the cancer is a cervical cancer selected from the group consisting of squamous cell carcinomas and adenocarcinomas. In specific instances of these embodiments, the cancer is an ovarian cancer selected from the group consisting of epithelial cancers.

In specific embodiments, the cancer is selected from cancers of the gastrointestinal system. In particular embodiments, the cancer is selected from the group consisting of esophageal cancers, gastric cancers (also known as stomach cancers), gastrointestinal carcinoid tumors, pancreatic cancers, gall bladder cancers, colorectal cancers, and anal cancer. In instances of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas, gastrointestinal lymphomas, solid pseudopapillary tumors of the pancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomas including acinar cell carcinomas and ductal adenocarcinomas, gall bladder adenocarcinomas, colorectal adenocarcinomas, microsatellite stable colorectal cancer, advanced microsatellite stable colorectal cancer, metastatic microsatellite stable colorectal cancer and anal squamous cell carcinomas.

In specific embodiments, the cancer is selected from liver and bile duct cancers.

In particular embodiments, the cancer is liver cancer (also known as hepatocellular carcinoma).

In particular embodiments, the cancer is bile duct cancer (also known as cholangiocarcinoma); in instances of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.

In specific embodiments, the cancer is selected from kidney and bladder cancers. In particular embodiments, the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers. In particular embodiments, the cancer is a bladder cancer selected from the group consisting of urothelial carcinoma (a transitional cell carcinoma), squamous cell carcinomas, and adenocarcinomas.

In specific embodiments, the cancer is selected from bone cancers. In particular embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, chordoma (cancer of the bone along the spine).

In specific embodiments, the cancer is selected from lung cancers. In particular embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancers, small cell lung cancers, bronchial tumors, and pleuropulmonary blastomas.

In specific embodiments, the cancer is selected from malignant mesothelioma. In particular embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids.

In specific embodiments, the cancer is selected from sarcomas. In particular embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma.

In specific embodiments, the cancer is selected from lymphomas. In particular embodiments, the cancer is selected from the group consisting of Hodgkin lymphoma (e.g., classical Hodgkin refractory lymphoma), non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma), cutaneous T-cell lymphomas, primary central nervous system lymphomas.

In specific embodiments, the cancer is selected from glandular cancers. In particular embodiments, the cancer is selected from the group consisting of adrenocortical cancer (also known as adrenocortical carcinoma or adrenal cortical carcinoma), pheochromocytomas, paragangliomas, pituitary tumors, thymoma, and thymic carcinomas.

In specific embodiments, the cancer is selected from thyroid cancers. In particular embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas.

In specific embodiments, the cancer is selected from germ cell tumors. In particular embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In specific instances of these embodiments, the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas.

In specific embodiments, the cancer is selected from heart tumors. In particular embodiments, the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosacroma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.

In embodiments, the cancer is a metastatic tumor, for example, liver metastases from colorectal cancer or pancreatic cancer; and brain metastases from lung or breast cancer.

In embodiments, the cancer is selected from the group consisting of solid tumors and lymphomas. In particular embodiments, the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas. In more particular embodiments, the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, breast adenocarcinoma, and lymphomas. In aspects of such embodiments, the lymphomas are selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma/leukemia, nasal type extranodal NK/T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma/delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin lymphoma.

In particular embodiments, the cancer is classified as stage III cancer or stage IV cancer. In some instances of these embodiments, the cancer is not surgically resectable.

Compositions and Admininstration

When administered to a patient, a Granular Composition of Compound A can be administered as a component of a pharmaceutical composition that comprises a pharmaceutically acceptable excipient. Accordingly, in one embodiment, the present invention provides pharmaceutical compositions comprising an effective amount of a Granular Composition of Compound A, and one or more pharmaceutically acceptable carriers or excipients.

The Granular Compositions of Compound A are useful in preparing a medicament that is useful in treating a cellular proliferative disorder. In one embodiment, the Granular Compositions of Compound A are also useful for preparing a medicament that is useful in treating cancer.

In the pharmaceutical compositions and methods disclosed herein, the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms), and the like. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, com sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Suitable lubricants include boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.

Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents, and preservatives may also be included where appropriate.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

Additionally, the pharmaceutical compositions may be formulated in sustained release form to provide the rate-controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., anticancer activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components, and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

In one embodiment, the Granular Composition of Compound A is administered orally. In another embodiment, the Granular Composition of Compound A is administered orally in a capsule. In another embodiment, the Granular Composition of Compound A is administered orally in a tablet.

In another embodiment, the Granular Composition of Compound A is administered intravenously.

In another embodiment, the Granular Composition of Compound A is administered via subcutaneous injection. In another embodiment, the Granular Composition of Compound A is administered via intertumoral injection.

In another embodiment, the Granular Composition of Compound A is administered topically. In a specific embodiment, the Granular Composition of Compound A is formulated as a cream that can be applied topically.

In still another embodiment, the Granular Composition of Compound A is administered sublingually.

In one embodiment, a pharmaceutical preparation comprising a Granular Composition of Compound A is in unit dosage form. In such form, the preparation is subdivided into unit doses containing effective amounts of the active components.

Compositions can be prepared using techniques such as conventional mixing, granulating or coating methods; and by using solid dispersion based upon the guidance provided herein. In one embodiment, the present compositions can contain from about 0.1% to about 99% of a Granular Composition of Compound A by weight or volume. In various embodiments, the present compositions can contain, in one embodiment, from about 1% to about 70%, or from about 5% to about 60%, or from about 10% to about 50% of a Granular Composition of Compound A by weight or volume.

In one embodiment, the present invention provides compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and one or more additional therapeutic agents. In another embodiment, the present invention provides compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and one additional therapeutic agents. In another embodiment, the present invention provides compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and two additional therapeutic agents.

The quantity of a Granular Composition of Compound A in a unit dose of preparation may be varied or adjusted from about 1 mg to about 2500 mg. In various embodiments, the quantity is from about 10 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 100 mg, 1 mg to about 50 mg, 1 mg to about 20 mg, and 1 mg to about 10 mg. In other various embodiments, the quantity is from about 100 mg to about 400 mg, from about 200 mg to about 300 mg. In a specific embodiment, the quantity is about 300 mg.

Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many of the chemotherapeutic agents is described in the “Physicians’ Desk Reference” (PDR), e.g., the Physicians’ Desk Reference, 64 ^th Edition, 2010 (published by PDR Network, LLC at Montvale, NJ 07645-1725), presently accessible through www.pdr.net; the disclosures of which are incorporated herein by reference thereto.

If the patient is responding, or is stable, after completion of the therapy cycle, the therapy cycle can be repeated according to the judgment of the skilled clinician. Upon completion of multiple therapy cycles, the patient can be continued on the Granular Compositions of Compound A at the same dose that was administered in the treatment protocol. This maintenance dose can be continued until the patient progresses, or can no longer tolerate the dose (in which case the dose can be reduced and the patient can be continued on the reduced dose).

The doses and dosage regimen of the additional therapeutic agent(s) used in the combination therapies of the present invention for the treatment of cellular proliferative disorders can be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the cellular proliferative disorder. When administered in combination with one or more additional therapeutic agents, the Granular Composition of Compound A, and the additional therapeutic agent(s) can be administered simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially. This is particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another component is administered every six hours, or when the preferred pharmaceutical compositions are different, e.g., one is a tablet and one is a capsule. A kit comprising the separate dosage forms can therefore be advantageous.

The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of cancer-related symptoms (e.g., pain), inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.

Generally, a total daily dosage of a Granular Composition of Compound A alone, or when administered as combination therapy, can range from about 1 to about 2500 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of administration. In one embodiment, the dosage is from about 10 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 200 to about 400 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 500 to about 1500 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 100 to about 500 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 300 to about 4s00 mg/day, administered in a single dose or in 2-4 divided doses.

For convenience, the total daily dosage may be divided and administered in portions during the day if desired. In one embodiment, the daily dosage is administered in one portion. In another embodiment, the total daily dosage is administered in two divided doses over a 24-hour period. In another embodiment, the total daily dosage is administered in three divided doses over a 24-hour period. In still another embodiment, the total daily dosage is administered in four divided doses over a 24-hour period.

The amount and frequency of administration of a Granular Composition of Compound A will be regulated according to the judgment of the ahending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated.

Combination Therapy

In one aspect, the present methods for treating a cellular proliferative disorder can further comprise the administration of one or more additional therapeutic agents that are other than a Granular Composition of Compound A.

Accordingly, in one embodiment, the present invention provides methods for treating a cellular proliferative disorder in a patient, the method comprising administering to the patient: (i) a Granular Composition of Compound A, or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than a Granular Composition of Compound A, wherein the amounts administered are together effective to treat a cellular proliferative disorder. In one embodiment, the cellular proliferative disorder treated is cancer.

When administering a combination therapy of the invention to a patient, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, the Granular Composition of Compound A, and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet, and the like).

In one embodiment, the Granular Composition of Compound A is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the Granular Composition of Compound A, and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating cancer.

In another embodiment, the Granular Composition of Compound A, and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating cancer.

In one embodiment, the Granular Composition of Compound A, and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration. In another embodiment, this composition is suitable for intertumoral administration. In another embodiment, this composition is suitable for subcutaneous administration. In still another embodiment, this composition is suitable for parenteral administration.

Cancers and proliferative disorders that can be treated or prevented using the combination therapy methods of the present invention include, but are not limited to, those listed above.

The Granular Composition of Compound A, and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy. Accordingly, in one embodiment, the Granular Composition of Compound A, and the additional therapeutic agent(s) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating cancer.

In one embodiment, the administration of the Granular Composition of Compound A, and the additional therapeutic agent(s) may inhibit the resistance of cancer to these agents.

Combinations of the Granular Compositions of Compound A with one or more anti cancer agents are within the scope of the invention. Examples of such additional anti cancer agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Heilman (editors), 9 ^th edition (May 16, 2011), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of additional therapeutic agents would be useful based on the particular characteristics of the drugs and the cancer involved. Such additional therapeutic agents include the following: estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed death-ligand 1 (PD- Ll) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, g-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints.

The additional therapeutic agents, and classes of additional therapeutic agents, disclosed below herein, are all useful in the combination therapies of the present invention.

“Androgen receptor modulators” refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.

“Estrogen receptor modulators” refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381,

LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(l- piperidinyl)ethoxy]phenyl]-2H-l-benzopyran-3-yl]-phenyl-2,2- dimethylpropanoate, 4,4’- dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

In the treatment of breast cancer (e.g., postmenopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) the compound of formula (1) may be used with an effective amount of at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors, (b) antiestrogens, and (c) LHRH analogues; and optionally an effective amount of at least one chemotherapeutic agent. Examples of aromatase inhibitors include but are not limited to: Anastrozole (e.g., Arimidex), Letrozole (e.g., Femara), Exemestane (Aromasin), Fadrozole and Formestane (e.g., Lentaron). Examples of antiestrogens include but are not limited to: Tamoxifen (e.g., Nolvadex), Fulvestrant (e.g., Faslodex), Raloxifene (e.g., Evista), and Acolbifene.

Examples of LHRH analogues include but are not limited to: Goserebn (e.g., Zoladex) and Leuprobde (e.g., Leuprobde Acetate, such as Lupron or Lupron Depot). Examples of additional therapeutic agents useful in the present compositions and methods include, but are not limited to, the following cancer chemotherapeutic agents: Trastuzumab (e.g., Herceptin), Gefitinib (e.g., Iressa), Erlotinib (e.g., Erlotinib HC1, such as Tarceva), Bevacizumab (e.g., Avastin), Cetuximab (e.g., Erbitux), and Bortezomib (e.g., Velcade).

“Retinoid receptor modulators” refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, a- difluoromethylomithine, ILX23-7553, trans-N-(4’-hydroxyphenyl) retinamide, andN-4- carboxyphenyl retinamide.

“Cytotoxic/cytostatic agents” refers to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell’s functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/mi crotubule-stabilizing agents, inhibitors of mitotic kinesins, histone deacetylase inhibitors, inhibitors of kinases involved in mitotic progression, inhibitors of kinases involved in growth factor and cytokine signal transduction pathways, antimetabolites, biological response modifiers, hormonal/anti -hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteosome inhibitors, ubiquitin ligase inhibitors, and aurora kinase inhibitors.

Examples of cytotoxic/cytostatic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2- methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu- (hexane-l,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(ch loro)platinum (II)]tetrachloride, diarizidinylspermine, arsenic trioxide, l-(ll-dodecylamino-10-hydroxyundecyl)-3,7- dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3’-deamino-3’-morpholino-13-deoxo-10- hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, 4-demethoxy-3-deamino- 3-aziridinyl-4-methylsulphonyl-daunorubicin (see WO 00/50032), Raf kinase inhibitors (such as Bay43-9006) and mTOR inhibitors (such as Wyeth’s CCI-779).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteosome inhibitors include but are not limited to lactacystin and MLN-341 (Velcade).

Examples of microtubule inhibitors/microtubule-stabilizing agents include paclitaxel, vindesine sulfate, 3’,4’-didehydro-4’-deoxy-8’-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and 6,288,237) and BMS188797. In an example the epothilones are not included in the microtubule inhibitors/microtubule-stabilising agents.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3’,4’-0-exo-benzylidene-chartreusin, 9-methoxy-N,N- dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, l-amino-9-ethyl-5-fluoro-2,3- dihydro-9-hydroxy-4-methyl-lH,12H-benzo[de]pyrano[3’,4’: b,7]-indolizino[l,2b]quinoline- 10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2’- dimethylamino-2’-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6- dimethyl-6H-pyrido[4,3-b]carbazole-l-carboxamide, asulacrine, (5a, 5aB, 8aa,9b)-9-[2-[N-[2- (dimethylamino)ethyl] -N-methylamino] ethyl] -5-[4-hy dro0xy-3,5-dimethoxyphenyl] - 5,5a,6,8,8a,9-hexohydrofuro(3’,4’:6,7)naphtho(2,3-d)-l,3 -dioxol-6-one, 2,3-(methylenedioxy)-5- methyl-7-hydroxy-8-methoxybenzo[c]-phenanthridinium, 6,9-bis[(2- aminoethyl)amino]benzo[g]isoguinoline-5,10-dione, 5-(3-aminopropylamino)-7, 10-dihydroxy -2- (2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,l-de]acridin-6-o ne, N-[l- [2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4 -ylmethyl]formamide, N-(2- (dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy- 7H-indeno[2,l-c] quinolin-7-one, and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the human mitotic kinesin KSP, are described in Publications W003/039460, W003/050064, W003/050122, WO03/049527, WO03/049679, WO03/049678, WO04/039774, WO03/079973, W003/099211, W003/105855, W003/106417, W004/037171, W004/058148, W004/058700, WO04/126699, W005/018638, W005/019206, W005/019205, W005/018547, W005/017190,

US2005/0176776. In an example inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E, inhibitors of MCAK and inhibitors of Rab6-KIFL.

Examples of “histone deacetylase inhibitors” include, but are not limited to, SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Further reference to other histone deacetylase inhibitors may be found in the following manuscript; Miller, T.A. et al. J. Med.

Chem. 46(24):5097-5116 (2003).

“Inhibitors of kinases involved in mitotic progression” include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub-1 and inhibitors of bub-Rl. An example of an “aurora kinase inhibitor” is VX-680 (tozasertib).

“Antiproliferative agents” include antisense RNA, and DNA oligonucleotides such as G3139, ODN698, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2’-deoxy-2’-methylidenecytidine, 2’- fluoromethylene-2’-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N’-(3,4- dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L -glycero- B-L-manno-heptopyranosyl] adenine, apbdine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo- 4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][l,4]thiazin-6-yl-(S) -ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin, 5-flurouracil, alanosine, ll-acetyl-8-(carbamoyloxymethyl)-4-formyl-6- methoxy-14-oxa-l,ll-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4 ,6-trien-9-yl acetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2’-cyano-2’-deoxy-N4-palmitoyl-l-B-D- arabino furanosyl cytosine, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone and trastuzumab. Examples of monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. In one embodiment, a monoclonal antibody targeted therapeutic agent is Bexxar.

“HMG-CoA reductase inhibitor” refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin, simvastatin, pravastatin, Fluvastatin, atorvastatin, rosuvastatin and cerivastatin. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open-acid and lactone forms is included within the scope of the invention.

“Prenyl-protein transferase inhibitor” refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including famesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase). For an example of the role of a prenyl-protein transferase inhibitor on angiogenesis see European J. of Cancer, Vol. 35, No. 9, pp.1394-1401 (1999).

“Angiogenesis inhibitor” refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-l/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-a, interleukin- 12, pentosan poly sulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib , steroidal anti-inflammatories (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl- carbonyl)-fumagillol, thalidomide, angiostatin, troponin- 1, angiotensin II antagonists.

Other examples of angiogenesis inhibitors useful in the present combinations include, but are not limited to, endostatin, ukrain, ranpimase, IM862, 5-methoxy-4-[2-methyl-3- (3-methyl-2-butenyl)oxiranyl]-l-oxaspiro[2,5]oct-6-yl(chloro acetyl)carbamate, acetyldinanaline, 5-amino-l-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-l H-l,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate,

7, 7-(carbonyl-bis[imino-N-methyl-4,2-pynOlocarbonylimino[N-met hyl-4, 2-pyrrole]- carbonylimino]-bis-(l, 3-naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2- indolinone (SU5416), or a pharmaceutically acceptable salt thereof.

Additional therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the Granular Compositions of Compound A, include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. 38:679-692 (2000)). Examples of such agents include, but are not limited to, heparin, low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]).

Further examples of angiogenesis inhibitors include a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon-a, interleukin- 12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-0-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin- 1, or an antibody to VEGF.

“Agents that interfere with cell cycle checkpoints” refers to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents. Such agents include inhibitors of ATR, ATM, the CHK1 and CHK2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7- hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

“Agents that interfere with receptor tyrosine kinases (RTKs)” refers to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression. Such agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors of RTKs as described by Bume-Jensen and Hunter, Nature, 411:355-365,

2001. Specific examples of tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-5- methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17- (allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3- (4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4- quinazolinamine, BIBX1382, 2,3,9,10,1 l,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9- methyl-9,12-epoxy-lH-diindolo[l,2,3-fg:3’,2’,r-kl]pynOlo [3,4-i][l,6]benzodiazocin-l-one, SH268, genistein, STI571, CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3- d|pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4’-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4- (4-pyridylmethyl)-l-phthalazinamine, and EMD121974, or a pharmaceutically acceptable salt thereof.

“Inhibitors of cell proliferation and survival signaling pathway” refers to compounds that inhibit signal transduction cascades downstream of cell surface receptors. Such agents include inhibitors of serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO 02/083064, WO 02/083139, WO 02/083140, US 2004-0116432, WO 02/083138, US 2004/0102360, WO 03/086404, WO 03/086279, WO 03/086394, WO 03/084473, WO 03/086403, WO 2004/041162, WO 2004/096131, WO 2004/096129, WO 2004/096135, WO 2004/096130, WO 2005/100356, WO 2005/100344, US 7,454,431, US 7,589,068), inhibitors of Raf kinase (for example BAY-43-9006), inhibitors of MEK (for example refametinib, selumetinib, trametinib, cobimetinib, CI-1040 and PD-098059), inhibitors of mTOR (for example Wyeth CCI-779), and inhibitors of PI3K (for example LY294002).

The invention also encompasses combination therapies comprising NSAIDs which are selective COX-2 inhibitors. For purposes of the specification NSAIDs which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100-fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays. Inhibitors of COX-2 that are useful in the present methods are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5//)-furanone: and 5-chloro-3- (4-methylsulfonyl)-phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof. Compounds that have been described as specific inhibitors of COX-2 and are therefore also useful in the present invention include, but are not limited to, the following: rofecoxib, etoricoxib, parecoxib, BEXTRA® and CELEBREX® or a pharmaceutically acceptable salt thereof.

As used herein, “integrin blockers” refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the a _n b3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the anb5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the a _n b3 integrin and the a _n b5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the a _n 1)b6, a _n b8, a 1 b 1 - a2bΐ, a5bi, a6bΐ and a6b4 integrins. The term also refers to antagonists of any combination of a _n b3, a _n b5, a _n b6, a _n b8, a.1 b i . a2bΐ, a5bΐ, a6bΐ and a6b4 integrins. Combinations with additional therapeutic agents, other than anti-cancer agents, are also contemplated in the instant methods. For example, combinations of the Granular Compositions of Compound A with PPAR-g (i.e., PPAR-gamma) agonists and PPAR-d (i.e., PPAR-delta) agonists are useful in the treatment of certain malignancies. PPAR-g and PPAR-d are the nuclear peroxisome proliferator-activated receptors g and d. PPAR-g agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice {Arch. Ophthamol. 2001; 119:709-717). Examples of PPAR-g agonists and PPAR- g/a agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-l,2-benzisoxazol-6-yl)oxy ]-2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy) phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid (disclosed in USSN 60/235,708 and 60/244,697), or a pharmaceutically acceptable salt thereof.

Another embodiment of the instant invention is the use of the Granular Compositions of Compound A in combination with gene therapy for the treatment of cancer. For an overview of genetic strategies to treating cancer see Hall et al., {Am. J. Hum. Genet. 61:785- 789, 1997) and Kufe et al., (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Patent No. 6,069,134, for example), a uPA/uPAR antagonist ("Adenovirus- Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998;5(8): 1105-13), and interferon gamma (J. Immunol. 2000;164:217-222).

The Granular Compositions of Compound A may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-gly coprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar), or a pharmaceutically acceptable salt thereof.

A Granular Composition of Compound A may also be administered with an immunologic-enhancing drug, such as levamisole, isoprinosine and Zadaxin, or a pharmaceutically acceptable salt thereof. A Granular Composition of Compound A may also be administered with an inhibitor of PARP, such as olaprarib, rucaparib, niraparib, and talazoparib.

A Granular Composition of Compound A may also be useful for treating or preventing cancer in combination with P450 inhibitors including: xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, methyrapone, caffeine, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafyline, cimetidine, dextromethorphan, ritonavir, indinavir, amprenavir, diltiazem, terfenadine, verapamil, cortisol, itraconazole, mibefradil, nefazodone and nelfmavir, or a pharmaceutically acceptable salt thereof.

A Granular Composition of Compound A may also be useful for treating or preventing cancer in combination with Pgp and/or BCRP inhibitors including: cyclosporin A, PSC833, GF120918, cremophorEL, fumitremorgin C, Kol32, Kol34, Iressa, Imatnib mesylate, EKI-785, C11033, novobiocin, diethylstilbestrol, tamoxifen, resperpine, VX-710, tryprostatin A, flavonoids, ritonavir, saquinavir, nelfmavir, omeprazole, quinidine, verapamil, terfenadine, ketoconazole, nifidepine, FK506, amiodarone, XR9576, indinavir, amprenavir, cortisol, testosterone, LY335979, OC144-093, erythromycin, vincristine, digoxin and talinolol, or a pharmaceutically acceptable salt thereof.

A Granular Composition of Compound A may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates, including but not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.

A Granular Composition of Compound A may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors. Examples of aromatase inhibitors include but are not limited to: anastrozole, letrozole and exemestane, or a pharmaceutically acceptable salt thereof.

A Granular Composition of Compound A may also be useful for treating or preventing cancer in combination with siRNA therapeutics.

The Granular Compositions of Compound A may also be administered in combination with g-secretase inhibitors and/or inhibitors of NOTCH signaling. Such inhibitors include compounds described in WO 01/90084, WO 02/30912, WO 01/70677, WO 03/013506, WO 02/36555, WO 03/093252, WO 03/093264, WO 03/093251, WO 03/093253, WO 2004/039800, WO 2004/039370, WO 2005/030731, WO 2005/014553, USSN 10/957,251, WO 2004/089911, WO 02/081435, WO 02/081433, WO 03/018543, WO 2004/031137, WO 2004/031139, WO 2004/031138, WO 2004/101538, WO 2004/101539 and WO 02/47671 (including LY-450139), or a pharmaceutically acceptable salt thereof.

In one embodiment, specific anticancer agents useful in the present combination therapies include, but are not limited to: pembrolizumab (Keytruda®), abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gbadel®); carmustine with Pobfeprosan 20 Implant (Gbadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone®); dromostanolone propionate (Masterone injection®); Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP- 16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserebn acetate (Zoladex Implant®); goserebn acetate (Zoladex®); histrebn acetate (Histrebn implant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®); idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L- PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin- 50®); nelarabine (Arranon®); Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); Ridaforolimus; sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®) and zoledronate (Zometa®), or a pharmaceutically acceptable salt thereof.

Thus, the scope of the instant invention encompasses the use of the Granular Compositions of Compound A in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR-g agonists, PPAR-d agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, g-secretase and/or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of the therapeutic agents listed above.

Yet another example of the invention is a method of treating cancer that comprises administering a therapeutically effective amount of a Granular Composition of Compound A in combination with paclitaxel or trastuzumab.

The therapeutic combination disclosed herein may be used in combination with one or more other active agents, including but not limited to, other anti-cancer agents that are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g., cell-proliferation disorders). In one embodiment, a Granular Composition of Compound A is combined with one or more other anti-cancer agents for use in the prevention, treatment, control amelioration, or reduction of risk of a particular disease or condition for which the Granular Compositions of Compound A are useful. Such other active agents may be administered, by a route and in an amount commonly used therefor, prior to, contemporaneously, or sequentially with a compound of the present disclosure.

The instant invention also includes a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of a Granular Composition of Compound A, and a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-g agonist, a PPAR-d agonist, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, g-secretase and/or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of the therapeutic agents listed above.

The invention further relates to a method of treating cancer in a human patient comprising administration of a Granular Composition of Compound A, and a PD-1 antagonist to the patient. The compound of the invention and the PD-1 antagonist may be administered concurrently or sequentially.

In particular embodiments, the PD-1 antagonist is an anti-PD-1 antibody, or antigen binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD- L1 antibody, or antigen binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody, independently selected from pembrolizumab, nivolumab, cemiplimab, sintilimab, tislelizumab, atezolizumab (MPDL3280A), camrelizumab and toripalimab. In other embodiments, the PD-L1 antagonist is an anti-PD-Ll antibody independently selected from atezolizumab, durvalumab and avelumab.

In one embodiment, the PD-1 antagonist is pembrolizumab. In particular sub embodiments, the method comprises administering 200 mg of pembrolizumab to the patient about every three weeks. In other sub-embodiments, the method comprises administering 400 mg of pembrolizumab to the patient about every six weeks.

In further sub-embodiments, the method comprises administering 2 mg/kg of pembrolizumab to the patient about every three weeks. In particular sub-embodiments, the patient is a pediatric patient.

In some embodiments, the PD-1 antagonist is nivolumab. In particular sub embodiments, the method comprises administering 240 mg of nivolumab to the patient about every two weeks. In other sub-embodiments, the method comprises administering 480 mg of nivolumab to the patient about every four weeks.

In some embodiments, the PD-1 antagonist is cemiplimab. In particular embodiments, the method comprises administering 350 mg of cemiplimab to the patient about every 3 weeks.

In some embodiments, the PD-1 antagonist is atezolizumab. In particular sub embodiments, the method comprises administering 1200 mg of atezolizumab to the patient about every three weeks.

In some embodiments, the PD-1 antagonist is durvalumab. In particular sub embodiments, the method comprises administering 10 mg/kg of durvalumab to the patient about every two weeks.

In some embodiments, the PD-1 antagonist is avelumab. In particular sub embodiments, the method comprises administering 800 mg of avelumab to the patient about every two weeks.

When the Granular Compositions of Compound A are administered in combination with an anti -human PD-1 antibody (or antigen-binding fragment thereof), the anti human PD-1 antibody (or antigen-binding fragment thereof) may be administered either simultaneously with, or before or after, the Granular Composition of Compound A. Either of the anti -human PD-1 antibody (or antigen-binding fragment thereol), and/or Granular Composition of Compound A of the present invention, or a pharmaceutically acceptable salt thereof, may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s). The weight ratio of the anti -human PD-1 antibody (or antigen-binding fragment thereof) to Granular Composition of Compound A of the present invention, may be varied and will depend upon the therapeutically effective dose of each agent. Generally, a therapeutically effective dose of each will be used. Combinations including at least one anti -human PD-1 antibody (or antigen-binding fragment thereof), a Granular Composition of Compound A of the present invention, and optionally other active agents will generally include a therapeutically effective dose of each active agent. In such combinations, the anti -human PD-1 antibody (or antigen-binding fragment thereol), the Granular Composition of Compound A, and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent with, or subsequent to the administration of other agent(s).

In one embodiment, this disclosure provides an anti -human PD-1 antibody (or antigen-binding fragment thereol), and/or Granular Composition of Compound A, and at least one other active agent as a combined preparation for simultaneous, separate or sequential use in treating cancer.

The disclosure also provides the use of a Granular Composition of Compound A of the present invention, for treating cancer, where the patient has previously (e.g., within 24- hours) been treated with an anti-human PD-1 antibody (or antigen-binding fragment thereol).

The disclosure also provides the use of an anti-human PD-1 antibody (or antigen-binding fragment thereol) for treating a cellular proliferative disorder, where the patient has previously (e.g., within 24-hours) been treated with a Granular Composition of Compound A of the present invention.

The present disclosure further relates to methods of treating cancer, said method comprising administering to a subject in need thereof a combination therapy that comprises (a) a Granular Composition of Compound A of the present invention, and (b) an anti -human PD-1 antibody (or antigen-binding fragment thereol); wherein the anti -human PD-1 antibody (or antigen-binding fragment thereol) is administered once every 21 days.

Additionally, the present disclosure relates to methods of treating cancer, said method comprising administering to a subject in need thereof a combination therapy that comprises: (a) a Granular Composition of Compound A of the present invention, and (b) an anti human PD-1 antibody (or antigen-binding fragment thereof. In specific embodiments, the cancer occurs as one or more solid tumors or lymphomas. In further specific embodiments, the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas. In still further specific embodiments, the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, MSI-H cancer, MMR deficient cancer, non small cell lung cancer, urothelial carcinoma, gastric or gastroesophageal junction adenocarcinoma, breast adenocarcinoma, and lymphomas. In additional embodiments, the lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (malt), nodal marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, primary effusion lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma (primary cutaneous type), anaplastic large cell lymphoma (systemic type), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma/leukemia, nasal type extranodal NK/T-cell lymphoma, enteropathy-associated T-cell lymphoma, gamma/delta hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, and Hodgkin lymphoma. In particular embodiments, the cellular proliferative disorder is a cancer that has metastasized, for example, a liver metastases from colorectal cancer. In additional embodiments, the cellular proliferative disorder is a cancer is classified as stage III cancer or stage IV cancer. In instances of these embodiments, the cancer is not surgically resectable.

In embodiments of the methods disclosed herein, the anti -human PD-1 antibody (or antigen binding fragment thereol) is administered by intravenous infusion or subcutaneous injection.

In one embodiment, the present invention provides compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and an anti human PD-1 antibody (or antigen-binding fragment thereol).

In another embodiment, the present invention provides compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and pembrolizumab.

In one embodiment, the present invention provides compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and two additional therapeutic agents, one of which is an anti -human PD-1 antibody (or antigen-binding fragment thereol), and the other of which is independently selected from the group consisting of anticancer agents.

In one embodiment, the present invention provides compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and two additional therapeutic agents, one of which is an anti -human PD-1 antibody (or antigen-binding fragment thereof), and the other of which is an inhibitor of MEK.

In another embodiment, the present invention provides compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and two additional therapeutic agents, one of which is an anti -human PD-1 antibody (or antigen-binding fragment thereof), and the other of which is an inhibitor of P ARP.

In a specific embodiment, the present invention provides compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and two additional therapeutic agents, one of which is pembrolizumab, and the other of which is an inhibitor of MEK.

In another specific embodiment, the present invention provides compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and two additional therapeutic agents, one of which is pembrolizumab, and the other of which is an inhibitor of P ARP.

A compound of the present invention may be employed in conjunction with anti emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy. For the prevention or treatment of emesis, a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin- 1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Patent Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In another example, conjunctive therapy with an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is disclosed for the treatment or prevention of emesis that may result upon administration of the Granular Compositions of Compound A.

A Granular Composition of Compound A may also be administered with an agent useful in the treatment of anemia. Such an anemia treatment agent is, for example, a continuous erythropoiesis receptor activator (such as epoetin alfa). A Granular Composition of Compound A may also be administered with an agent useful in the treatment of neutropenia. Such a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF include filgrastim.

The Granular Compositions of Compound A may be useful when co-administered with other treatment modalities, including but not limited to, radiation therapy, surgery, and gene therapy. Accordingly, in one embodiment, the methods of treating cancer described herein, unless stated otherwise, can optionally include the administration of an effective amount of radiation therapy. For radiation therapy, g-radiation is preferred.

The methods of treating cancers described herein can optionally include the administration of an effective amount of radiation (i.e., the methods of treating cancers described herein optionally include the administration of radiation therapy).

The methods of treating cancer described herein include methods of treating cancer that comprise administering a therapeutically effective amount of a Granular Composition of Compound A in combination with radiation therapy and/or in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxicytostatic agent, an antiproliferative agent, a prenyl- protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR-g agonists, PPAR-d agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, g-secretase and/or NOTCH inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), an agent that interferes with a cell cycle checkpoint, and any of the additional therapeutic agents listed herein.

Additional embodiments of the disclosure include the pharmaceutical compositions, combinations, uses and methods set forth in above, wherein it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that the embodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments. Kits

In one aspect, the present invention provides a kit comprising a therapeutically effective amount of a Granular Composition of Compound A, or a pharmaceutically acceptable salt, solvate or ester of said compound and a pharmaceutically acceptable carrier, vehicle or diluent.

In another aspect the present invention provides a kit comprising an amount of a Granular Composition of Compound A, and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more active ingredients result in a desired therapeutic effect. In one embodiment, the Granular Composition of Compound A, and the one or more additional therapeutic agents are provided in the same container. In one embodiment, the Granular Composition of Compound A, and the one or more additional therapeutic agents are provided in separate containers.