WO2021252316A1 - Composition granulaire d'un inhibiteur d'erk et ses utilisations - Google Patents

Composition granulaire d'un inhibiteur d'erk et ses utilisations Download PDF

Info

Publication number
WO2021252316A1
WO2021252316A1 PCT/US2021/036091 US2021036091W WO2021252316A1 WO 2021252316 A1 WO2021252316 A1 WO 2021252316A1 US 2021036091 W US2021036091 W US 2021036091W WO 2021252316 A1 WO2021252316 A1 WO 2021252316A1
Authority
WO
WIPO (PCT)
Prior art keywords
granular composition
compound
cancer
free
flowing granular
Prior art date
Application number
PCT/US2021/036091
Other languages
English (en)
Inventor
Aaron S. Cote
Feng Li
Rekha GANGAM
Xiujuan Jia
Joseph Leon KUKURA II
Claudia Neri
Robert O'connor
Luke Ryan SCHENCK
Original Assignee
Merck Sharp & Dohme Corp.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp & Dohme Corp. filed Critical Merck Sharp & Dohme Corp.
Publication of WO2021252316A1 publication Critical patent/WO2021252316A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • 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.
  • 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.
  • 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.
  • the ideal active pharmaceutical ingredient 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.
  • 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.
  • the present invention provides pharmaceutical compositions comprising a Granular Composition of Compound A.
  • 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 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.
  • the term “patient” 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).
  • the patient is human.
  • subject in need thereof refers to a subject diagnosed with, or suspected of having, a cell-proliferation disorder, such as a cancer, as defined herein.
  • 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.
  • 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).
  • drug 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.
  • 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.
  • an effective amount 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.
  • 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.
  • substantially purified form 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.
  • administering 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.
  • T/C £ 42% is the minimum level of anti-tumor activity.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • immunoglobulins 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • subject in need thereof refers to a subject diagnosed with, or suspected of having, a cell -proliferation disorder, such as a cancer, as defined herein.
  • 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.
  • 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).
  • CDRs complementarity determining regions
  • FR relatively conserved framework regions
  • the CDRs are usually aligned by the framework regions, enabling binding to a specific epitope.
  • both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • Constantly 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:
  • TPS tumor proportion score
  • TPS 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.
  • isolated 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.).
  • 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.
  • 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.
  • T/C £ 42% is the minimum level of anti-tumor activity.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • imaging techniques e.g., bone scan, ultrasound, CT or MRI scans.
  • a range of 3 to 7 days is intended to include 3, 4, 5, 6, and 7 days.
  • 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.
  • 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.
  • 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.
  • a binding agent e.g, antibody fragment, affibody, and the like
  • Techniques for detecting and measuring PD-L mRNA expression include RT-PCR and realtime quantitative RT-PCR.
  • Binder Density refers to the weight of a powder or granular material per unit volume
  • Tip Density 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.
  • Reynolds Number 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.
  • Carr Index 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.
  • sugar alcohol 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 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.
  • 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
  • step (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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the shear rate in step (b) is greater than 24,000 s 1 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • step (a) the hydrochloride salt of Compound A in the slurry is in substantially purified form.
  • step (a) the amount of the hydrochloride salt of Compound A in the slurry is from about 50 to about 99 wt/wt%.
  • step (a) the amount of the hydrochloride salt of Compound A in the slurry is from about 80 to about 95 wt/wt%.
  • step (a) the slurry contains less than 10% of Compound A in amorphous form
  • step (a) the slurry contains less than 5% of Compound A in amorphous form.
  • step (a) the slurry contains less than 3% of Compound A in amorphous form.
  • step (a) the slurry contains less than 2% of Compound A in amorphous form.
  • step (a) the slurry contains less than 1% of Compound A in amorphous form.
  • free-flowing granular composition comprises the HC1 form 1 salt of Compound A, as described in International Publication No. WO 2016/100147.
  • the free-flowing granular composition comprises particles having a particle size from about 25 to about 400 microns.
  • the free-flowing granular composition comprises particles having a particle size from about 50 to about 250 microns.
  • the free-flowing granular composition comprises from about 0.5% to about 4% residual solvent.
  • the free-flowing granular composition comprises from about 0.5% to about 2% residual solvent.
  • the free-flowing granular composition comprises less than about 0.5% residual solvent.
  • 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.
  • a binder which is a polymer selected from: a cellulosic polymer, a methacrylate, a vinyl polymer, a copolymer, and polyethylene glycol.
  • 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).
  • a binder which is selected from ethyl cellulose, methyl cellulose, hydroxylpropyl cellulose, hydroxylpropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxylpropyl methyl cellulose
  • 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.
  • 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.
  • the free-flowing granular composition comprises a binder, which is hydroxypropyl cellulose.
  • 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.
  • 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.
  • 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%.
  • a pharmaceutical composition comprising an effective amount of a Granular Composition of Compound A, and a pharmaceutically acceptable carrier.
  • 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.
  • 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.
  • (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.
  • the Granular Composition of Compound A can optionally be employed in combination with one or more additional therapeutic agents selected from anticancer agents.
  • 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.
  • the HC1 form 1 salt of Compound A was prepared using the methods described in International Publication No. WO 2016/100147.
  • 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.
  • 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%.
  • 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.
  • Table 2 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.
  • 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.
  • 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
  • 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.
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • cancer cancer
  • benign papillomatosis benign papillomatosis
  • gestational trophoblastic diseases include, but are not limited to, cancers, benign papillomatosis, and gestational trophoblastic diseases.
  • malignant refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • the cellular proliferative disorder is selected from cancer, benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases.
  • 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).
  • the cellular proliferative disorder being treated is cancer.
  • 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.
  • the amount administered is effective to treat cancer in the patient.
  • 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.
  • 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.
  • 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.
  • 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, leiomyosar
  • cancer examples 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.
  • cancerous cell includes a cell afflicted by any one of the above-identified conditions.
  • 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).
  • the cancer is AIDS-related.
  • 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.
  • NSCLC metastatic non-small cell lung cancer
  • the NSCLC is non-squamous. In other embodiments, the NSCLC is squamous.
  • the cancer exhibits high PD-L1 expression [(Tumor Proportion Score (TPS) >50%)] and was not previously treated with platinum-containing chemotherapy.
  • the patient has a tumor with PD-L1 expression (TPS >1%), and was previously treated with platinum-containing chemotherapy.
  • the patient had disease progression on or after receiving platinum-containing chemotherapy.
  • the PD-L1 TPS is determined by an FDA-approved test.
  • the patient’s tumor has no EGFR or ALK genomic aberrations.
  • 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.
  • the invention comprises a method of treating recurrent or metastatic head and neck squamous cell cancer (HNSCC) in a human patient.
  • HNSCC head and neck squamous cell cancer
  • the patient was previously treated with platinum-containing chemotherapy.
  • 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.
  • the patient has relapsed after 1, 2, 3 or more lines of therapy for cHL.
  • 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.
  • the patient is not eligible for cisplatin-containing chemotherapy.
  • the patient has disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
  • 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.
  • 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.
  • 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.
  • the patient s tumor expresses PD-L1 [Combined Positive Score (CPS) >1]
  • the patient has disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy.
  • 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.
  • 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.
  • the cancer is selected from brain and spinal cancers.
  • the brain and spinal cancer is selected from the group consisting of anaplastic astrocytomas, glioblastomas, astrocytomas, and estheosioneuroblastomas (also known as olfactory blastomas).
  • 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 aplastic
  • the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and suprantentorial primordial neuroectodermal tumors (sPNET).
  • the brain or spinal cancer is a metastatic brain tumor or tumors.
  • 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.
  • the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.
  • the cancer is selected from leukemia and cancers of the blood.
  • 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.
  • the cancer is selected from skin cancers.
  • the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers.
  • the skin cancer is unresectable or metastatic melanoma.
  • the cancer is selected from cancers of the reproductive system.
  • 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.
  • the cancer is a breast cancer selected from the group consisting of ductal carcinomas and phyllodes tumors.
  • the breast cancer may be male breast cancer or female breast cancer.
  • the breast cancer is triple negative breast cancer.
  • the breast cancer is ER+/HER2- breast cancer.
  • 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.
  • the cancer is selected from cancers of the gastrointestinal system.
  • 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.
  • 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.
  • the cancer is selected from liver and bile duct cancers.
  • the cancer is liver cancer (also known as hepatocellular carcinoma).
  • 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.
  • the cancer is selected from kidney and bladder cancers.
  • the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers.
  • the cancer is a bladder cancer selected from the group consisting of urothelial carcinoma (a transitional cell carcinoma), squamous cell carcinomas, and adenocarcinomas.
  • the cancer is selected from bone cancers.
  • 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).
  • the cancer is selected from lung cancers.
  • the lung cancer is selected from the group consisting of non-small cell lung cancers, small cell lung cancers, bronchial tumors, and pleuropulmonary blastomas.
  • the cancer is selected from malignant mesothelioma.
  • the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids.
  • the cancer is selected from sarcomas.
  • 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.
  • the cancer is selected from lymphomas.
  • 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.
  • 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 e.g., T-cell lymphomas.
  • the cancer is selected from glandular cancers.
  • 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.
  • the cancer is selected from thyroid cancers.
  • the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas.
  • the cancer is selected from germ cell tumors.
  • the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors.
  • the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas.
  • the cancer is selected from heart tumors.
  • the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosacroma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.
  • the cancer is a metastatic tumor, for example, liver metastases from colorectal cancer or pancreatic cancer; and brain metastases from lung or breast cancer.
  • the cancer is selected from the group consisting of solid tumors and lymphomas.
  • the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas.
  • the cancer is selected from the group consisting of malignant melanoma, head and neck squamous cell carcinoma, breast adenocarcinoma, and lymphomas.
  • 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, gamm
  • the cancer is classified as stage III cancer or stage IV cancer. In some instances of these embodiments, the cancer is not surgically resectable.
  • a Granular Composition of Compound A 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • 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.
  • 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.
  • the Granular Composition of Compound A is administered intravenously.
  • 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.
  • the Granular Composition of Compound A is administered topically.
  • the Granular Composition of Compound A is formulated as a cream that can be applied topically.
  • the Granular Composition of Compound A is administered sublingually.
  • a pharmaceutical preparation comprising a Granular Composition of Compound A is in unit dosage 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.
  • the present compositions can contain from about 0.1% to about 99% of a Granular Composition of Compound A by weight or volume.
  • 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.
  • 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.
  • 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.
  • 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.
  • the therapy cycle can be repeated according to the judgment of the skilled clinician.
  • 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.
  • 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.
  • kits 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.
  • cancer-related symptoms e.g., pain
  • 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.
  • 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.
  • the dosage is from about 10 to about 1000 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 200 to about 400 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses.
  • 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.
  • 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.
  • 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.
  • 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.
  • the cellular proliferative disorder treated is cancer.
  • therapeutic agents in the combination 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • the Granular Composition of Compound A, and the additional therapeutic agent(s) are present in the same composition.
  • this composition is suitable for oral administration.
  • this composition is suitable for intravenous administration.
  • this composition is suitable for intertumoral administration.
  • this composition is suitable for subcutaneous administration.
  • 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.
  • 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.
  • 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.
  • 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.
  • PD-1 programmed cell death protein 1
  • PD- Ll programmed death-ligand 1
  • RTKs receptor tyrosine kinases
  • 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.
  • 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.
  • 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.
  • aromatase inhibitors include but are not limited to: Anastrozole (e.g., Arimidex), Letrozole (e.g., Femara), Exemestane (Aromasin), Fadrozole and Formestane (e.g., Lentaron).
  • antiestrogens include but are not limited to: Tamoxifen (e.g., Nolvadex), Fulvestrant (e.g., Faslodex), Raloxifene (e.g., Evista), and Acolbifene.
  • LHRH analogues include but are not limited to: Goserebn (e.g., Zoladex) and Leuprobde (e.g., Leuprobde Acetate, such as Lupron or Lupron Depot).
  • 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).
  • trastuzumab e.g., Herceptin
  • Gefitinib e.g., Iressa
  • Erlotinib e.g., Erlotinib HC1, such as Tarc
  • 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.
  • 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-d
  • hypoxia activatable compound is tirapazamine.
  • proteosome inhibitors include but are not limited to lactacystin and MLN-341 (Velcade).
  • 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.
  • the epothilones are not included in the microtubule inhibitors/microtubule-stabilising agents.
  • 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
  • inhibitors of mitotic kinesins 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,
  • 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.
  • 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.
  • “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-[
  • HMG-CoA reductase inhibitor refers to inhibitors of 3-hydroxy-3- methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitors include but are not limited to lovastatin, simvastatin, pravastatin, Fluvastatin, atorvastatin, rosuvastatin and cerivastatin.
  • 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).
  • FPTase famesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type I
  • Rab GGPTase also called Rab GGPTase
  • Angiogenesis inhibitor refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • 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, dexamethas
  • 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(chloroacetyl)carbamate, acetyldinanaline, 5-amino-l-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-lH-l,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate,
  • 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)).
  • agents that modulate or inhibit the coagulation and fibrinolysis systems 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]).
  • 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.
  • MMP matrix metalloprotease
  • 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.
  • 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.
  • RTKs receptor tyrosine kinases
  • agents that interfere with receptor tyrosine kinases refers to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression.
  • 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,
  • 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
  • “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, selumetin
  • the invention also encompasses combination therapies comprising NSAIDs which are selective COX-2 inhibitors.
  • 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.
  • 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 - a2b ⁇ , a5bi, a6b ⁇ 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 . a2b ⁇ , a5b ⁇ , a6b ⁇ and a6b4 integrins.
  • Combinations with additional therapeutic agents, other than anti-cancer agents, are also contemplated in the instant methods.
  • PPAR-g i.e., PPAR-gamma
  • PPAR-d i.e., PPAR-delta
  • 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).
  • 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) phen
  • 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.
  • 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.
  • 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.
  • 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.
  • P450 inhibitors including: xenobiotics, quinidine, tyramine, ketoconazole, testosterone, quinine, methyrapone, caffeine, phenelzine, doxorubi
  • 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 talino
  • 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.
  • bisphosphonates including but not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clo
  • a Granular Composition of Compound A may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors.
  • 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.
  • 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 intrave
  • 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
  • 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).
  • 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.
  • a second compound selected from: an estrogen receptor
  • 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.
  • the PD-1 antagonist is an anti-PD-1 antibody, or antigen binding fragment thereof.
  • the PD-1 antagonist is an anti-PD- L1 antibody, or antigen binding fragment thereof.
  • the PD-1 antagonist is an anti-PD-1 antibody, independently selected from pembrolizumab, nivolumab, cemiplimab, sintilimab, tislelizumab, atezolizumab (MPDL3280A), camrelizumab and toripalimab.
  • the PD-L1 antagonist is an anti-PD-Ll antibody independently selected from atezolizumab, durvalumab and avelumab.
  • the PD-1 antagonist is pembrolizumab.
  • 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.
  • the method comprises administering 2 mg/kg of pembrolizumab to the patient about every three weeks.
  • the patient is a pediatric patient.
  • the PD-1 antagonist is nivolumab.
  • 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.
  • the PD-1 antagonist is cemiplimab.
  • the method comprises administering 350 mg of cemiplimab to the patient about every 3 weeks.
  • the PD-1 antagonist is atezolizumab.
  • the method comprises administering 1200 mg of atezolizumab to the patient about every three weeks.
  • the PD-1 antagonist is durvalumab.
  • the method comprises administering 10 mg/kg of durvalumab to the patient about every two weeks.
  • the PD-1 antagonist is avelumab.
  • the method comprises administering 800 mg of avelumab to the patient about every two weeks.
  • the anti human PD-1 antibody 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • the cancer occurs as one or more solid tumors or lymphomas.
  • the cancer is selected from the group consisting of advanced or metastatic solid tumors and lymphomas.
  • 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.
  • 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
  • the cellular proliferative disorder is a cancer that has metastasized, for example, a liver metastases from colorectal cancer.
  • 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.
  • the anti -human PD-1 antibody (or antigen binding fragment thereol) is administered by intravenous infusion or subcutaneous injection.
  • 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).
  • compositions comprising a Granular Composition of Compound A, a pharmaceutically acceptable carrier, and pembrolizumab.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • neurokinin- 1 receptor antagonists especially 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.
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.
  • phenothiazines for example prochlorperazine, fluphenazine, thioridazine and mesoridazine
  • metoclopramide metoclopramide or dronabinol.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • the Granular Composition of Compound A, and the one or more additional therapeutic agents are provided in the same container.
  • the Granular Composition of Compound A, and the one or more additional therapeutic agents are provided in separate containers.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des compositions granulaires d'un inhibiteur d'ERK (composé A) : et, de telles compositions granulaires en tant que produit d'un procédé. L'invention concerne également des compositions pharmaceutiques comprenant la composition granulaire de la présente invention, et des procédés d'utilisation de la composition granulaire pour le traitement d'un trouble prolifératif cellulaire chez un patient.
PCT/US2021/036091 2020-06-12 2021-06-07 Composition granulaire d'un inhibiteur d'erk et ses utilisations WO2021252316A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063038216P 2020-06-12 2020-06-12
US63/038,216 2020-06-12

Publications (1)

Publication Number Publication Date
WO2021252316A1 true WO2021252316A1 (fr) 2021-12-16

Family

ID=78845852

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/036091 WO2021252316A1 (fr) 2020-06-12 2021-06-07 Composition granulaire d'un inhibiteur d'erk et ses utilisations

Country Status (1)

Country Link
WO (1) WO2021252316A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170362202A1 (en) * 2014-12-18 2017-12-21 Merck Sharp & Dohme Corp. (s)-n-(3-(6-isopropoxypyridin-3-yl)-1h-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2h)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide compositions for pharmaceutical preparations
US20180000803A1 (en) * 2014-12-19 2018-01-04 Merck Sharp & Dohme Corp. (s)-n-(3-(6-isopropoxypyridin-3-yl)-1h-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2h)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide compositions for pharmaceutical preparations
US20180250232A1 (en) * 2015-09-03 2018-09-06 Merck Sharp & Dohme Corp. Process for preparing spray dried solid dispersions of (s)-n-(3-(6-isopropoxypyridin-3-yl)-1h-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2h)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide for pharmaceutical preparations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170362202A1 (en) * 2014-12-18 2017-12-21 Merck Sharp & Dohme Corp. (s)-n-(3-(6-isopropoxypyridin-3-yl)-1h-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2h)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide compositions for pharmaceutical preparations
US20180000803A1 (en) * 2014-12-19 2018-01-04 Merck Sharp & Dohme Corp. (s)-n-(3-(6-isopropoxypyridin-3-yl)-1h-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2h)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide compositions for pharmaceutical preparations
US20180250232A1 (en) * 2015-09-03 2018-09-06 Merck Sharp & Dohme Corp. Process for preparing spray dried solid dispersions of (s)-n-(3-(6-isopropoxypyridin-3-yl)-1h-indazol-5-yl)-1-(2-(4-(4-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)-3,6-dihydropyridin-1(2h)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidine-3-carboxamide for pharmaceutical preparations

Similar Documents

Publication Publication Date Title
EP2755482B1 (fr) Combinaison de mk-1775 et mk-8776 pour le traitement du cancer
US8852590B2 (en) Compositions and methods for treating cancer
US9233979B2 (en) Compounds that are ERK inhibitors
US9023865B2 (en) Compounds that are ERK inhibitors
US9226922B2 (en) Compounds that are ERK inhibitors
US20090227598A1 (en) Ret Tyrosine Kinase Inhibition
US20130287763A1 (en) Combination therapy for treating cancer comprising an igf-1r inhibitor and an akt inhibitor
WO2014062454A1 (fr) Compositions et procédés de traitement du cancer
US20140349968A1 (en) Compositions and Methods for Treating Cancer
EP1885349B1 (fr) Sulfamides pour le traitement du cancer
WO2021252316A1 (fr) Composition granulaire d'un inhibiteur d'erk et ses utilisations
US9546168B2 (en) ERK inhibitors
US20100324063A1 (en) Jak2 tyrosine kinase inhibition
EP2051737A2 (fr) Nouvelle préparation d'acide lactique de mk-0457, utilisée pour traiter le cancer
WO2015095250A1 (fr) Thérapie anticancéreuse combinée avec des inhibiteurs de wee1 et mtor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21820818

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21820818

Country of ref document: EP

Kind code of ref document: A1