[0034] Unless otherwise specified, the terms "solid form," "solid forms," and related terms, when used herein to refer to lenalidomide, refer to a physical form comprising lenalidomide, which is not predominantly in a liquid or a gaseous state. As used herein, the terms "solid form" and "solid forms" encompass semi-solids. Solid forms may be crystalline, amorphous, partially crystalline, partially amorphous, or mixtures of forms. A "single -component" solid form comprising lenalidomide consists essentially of lenalidomide. A "multiple-component" solid form comprising lenalidomide comprises a significant quantity of one or more additional species, such as ions and/or molecules, within the solid form. For example, in particular embodiments, a crystalline multiple -component solid form comprising lenalidomide further comprises one or more species non-covalently bonded at regular positions in the crystal lattice. For another example, in particular embodiments, an amorphous multiple-component solid form comprising lenalidomide further comprises one or more polymer(s), and lenalidomide is dispersed in a solid matrix that comprises the polymer(s).

[0035] Unless otherwise specified, the term "crystalline" and related terms used herein, when used to describe a substance, component, product, or form, mean that the substance, component, product, or form is substantially crystalline, for example, as determined by X-ray diffraction, (see, e.g. , Remington 's Pharmaceutical Sciences, 18^th ed., Mack Publishing, Easton PA, 173 (1990); The United States

Pharmacopeia, 23^rd ed., 1843-1844 ( 1995)).

[0036] Unless otherwise specified, the term "crystal form," "crystal forms," and related terms herein refer to crystalline modifications comprising a given substance, including single-component crystal forms and multiple-component crystal forms, and including, but not limited to, polymorphs, solvates, hydrates, co-crystals, other molecular complexes, salts, solvates of salts, hydrates of salts, co-crystals of salts, and other molecular complexes of salts, and polymorphs thereof. In some embodiments, a crystal form of a substance may be substantially free of amorphous forms and/or other crystal forms. In other

embodiments, a crystal form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of one or more amorphous form(s) and/or other crystal form(s) on a weight basis. Crystal forms of a substance may be obtained by a number of methods. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as, e.g. , in nanopores or capillaries, recrystallization on surfaces or templates such as, e.g. , on polymers, recrystallization in the presence of additives, such as, e.g. , co- crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, and solvent-drop grinding.

[0037] Unless otherwise specified, the terms "polymorph," "polymorphic form," "polymorphs," "polymorphic forms," and related terms herein refer to two or more crystal forms that consist essentially of the same molecule, molecules or ions. Different polymorphs may have different physical properties, such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates, and/or vibrational spectra as a result of a different arrangement or conformation of the molecules or ions in the crystal lattice. The differences in physical properties exhibited by polymorphs may affect pharmaceutical parameters, such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g. , tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically a more stable polymorph) or both (e.g. , tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility/dissolution differences, in the extreme case, some polymorphic transitions may result in lack of potency or, at the other extreme, toxicity. In addition, the physical properties of the crystal may be important in processing; for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (e.g. , particle shape and size distribution might be different between polymorphs).

[0038] Unless otherwise specified, the term "cocrystal" or "co-crystal," as used herein, refers to a crystalline material comprised of two or more non-volative compounds bond together in a crystal lattice by non-covalent interactions.

[0039] Unless otherwise specified, the term "pharmaceutical cocrystal" or "cocrystal" of an active pharmaceutical ingredient (API), as used herein, refers to a crystalline material comprised of an API and one or more non-volative compound(s) (refered herein as a coformer). The API and the coformer interact through non-covalent forces in a crystal lattice.

[0040] Unless otherwise specified, the term "amorphous," "amorphous form," and related terms used herein mean that the substance, component, or product referred to is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, an amorphous form of a substance may be substantially free of crystal forms. In other embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more crystal forms on a weight basis. In other embodiments, an amorphous form of a substance may comprise additional components or ingredients (for example, an additive, a polymer, or an excipient that may serve to further stabilize the amorphous form). In some embodiments, amorphous form may be a solid solution. Amorphous forms of a substance can be obtained by a number of methods. Such methods include, but are not limited to, heating, melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, ball-milling, cryo-grinding, spray drying, and freeze drying. [0041] Unless otherwise specified, the term "solid dispersion", as used herein, refers to a solid state which comprises at least two constituents, wherein one constituent is homogenously dispersed significantly evenly throughout the other constituent or constituents. It includes solid or glassy solutions, i.e. , the dispersion of the constituents is in such a way that the composition is chemically and physically homogenous in nature. In one embodiment, the first constituent is an active pharmaceutical ingredient (API), and the second constituent is a matrix that comprises a polymer, wherein the API is dispersed significantly uniformly within the matrix (the polymer). The API may be present in an amorphous state or in fine crystalline dispersed form. Also, the API may be available as a mixture of amorphous and crystalline forms. A solid dispersion can comprise more than two constituents. For example, two or more API can be dispersed into the matrix, and the matrix can comprise two or more polymers. Without limitation, solid dispersions may be physically classified as a eutectic mixture, a solid solution, a glass solution or suspension, an amorphous precipitate in a glassy or crystalline carrier, a complex, a complexed formation or a combination of the different systems. In addition, solid dispersions may be prepared using various techniques known to those skilled in the art, such as by co-dissolving the API and polymer in a solvent then spray -drying, spray-congealing, evaporation, curing or microwaving, blending and direct compression, mechanical admixture at an elevated but non-melting temperature, wet granulation, extrusion-spheronization, melt fusion, hot melt extrusion and the like. A "solid matrix" refers to a matrix that is solid.

[0042] Unless otherwise specified, the term "polymer", as used herein, refers to a compound comprising repeating structural units (monomers) connected by covalent chemical bonds. Polymers may be further derivatized, crosslinked, grafted or end-capped. Non-limiting examples of polymers include copolymers, terpolymers, quaternary polymers, and homologues. The term "copolymer" refers to a polymer consisting essentially of two or more different types of repeating structural units (monomers).

[0043] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with doses, amounts, or weight percents of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percent within 30%, within 20%, within 15%, within 10%, or within 5%, of the specified dose, amount, or weight percent.

[0044] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numeric value or range of values which is provided to characterize a particular solid form, e.g. , a specific temperature or temperature range, such as, for example, that describes a melting, dehydration, desolvation, or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in analysis by, for example, IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the solid form. Techniques for characterizing crystal forms and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single- crystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid- state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In certain embodiments, the terms "about" and "approximately," when used in this context, indicate that the numeric value or range of values may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. For example, in some

embodiments, the value of an XRPD peak position may vary by up to ±0.2 degrees 2Θ while still describing the particular XRPD peak.

[0045] As used herein, and unless otherwise specified, a crystalline or amorphous form that is "pure," i.e. , substantially free of other crystalline or amorphous forms, contains less than about 10% by weight of one or more other crystalline or amorphous forms, less than about 5% by weight of one or more other crystalline or amorphous forms, less than about 3% by weight of one or more other crystalline or amorphous forms, or less than about 1% by weight of one or more other crystalline or amorphous forms.

[0046] As used herein, and unless otherwise specified, a solid form that is "substantially physically pure" is substantially free from other solid forms. In certain embodiments, a crystal form that is substantially physically pure contains less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other solid forms on a weight basis. The detection of other solid forms can be accomplished by any method apparent to a person of ordinary skill in the art, including, but not limited to, diffraction analysis, thermal analysis, elemental combustion analysis and/or spectroscopic analysis.

[0047] As used herein, and unless otherwise specified, a solid form that is "substantially chemically pure" is substantially free from other chemical compounds (i.e., chemical impurities). In certain embodiments, a solid form that is substantially chemically pure contains less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of one or more other chemical compounds on a weight basis. The detection of other chemical compounds can be accomplished by any method apparent to a person of ordinary skill in the art, including, but not limited to, methods of chemical analysis, such as, e.g., mass spectrometry analysis, spectroscopic analysis, thermal analysis, elemental combustion analysis and/or chromatographic analysis.

[0048] As used herein, and unless otherwise indicated, a chemical compound, solid form, or composition that is "substantially free" of another chemical compound, solid form, or composition means that the compound, solid form, or composition contains, in certain embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2% 0.1%, 0.05%, or 0.01% by weight of the other compound, solid form, or composition.

[0049] As used herein, and unless otherwise specified, the term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable, relatively non-toxic acids, including inorganic acids and organic acids. In some embodiments, suitable acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, carbonic, citric, dihydrogenphosphoric, ethenesulfonic, fumaric, galactunoric, gluconic, glucuronic, glutamic, hydrobromic, hydrochloric, hydriodic, isobutyric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, monohydrogencarbonic, monohydrogen-phosphoric, monohydrogensulfuric, mucic, nitric, pamoic, pantothenic, phosphoric, phthalic, propionic, suberic, succinic, sulfuric, tartaric, toluenesulfonic acid (including /j>-toluenesulfonic, ra-toluenesulfonic, and o-toluenesulfonic acids), and the like (see, e.g., S. M. Berge et al, J. Pharm. Sci., 66: 1-19 (1977); and Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). In some embodiments, suitable acids are strong acids (e.g. , with pKa less than about 1), including, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, methanesulfonic, benzene sulfonic, toluene sulfonic, naphthalene sulfonic, naphthalene disulfonic, pyridine-sulfonic, or other substituted sulfonic acids. Also included are salts of other relatively non-toxic compounds that possess acidic character, including amino acids, such as aspartic acid and the like, and other compounds, such as aspirin, ibuprofen, saccharin, and the like. Acid addition salts can be obtained by contacting the neutral form of a compound with a sufficient amount of the desired acid, either neat or in a suitable solvent. As solids, salts can exist in crystalline or amorphous forms, or mixtures thereof. Salts can also exist in polymorphic forms.

[0050] Unless otherwise specified, the terms "solvate" and "solvated," as used herein, refer to a solid form of a substance which contains solvent. The terms "hydrate" and "hydrated" refer to a solvate wherein the solvent is water. "Polymorphs of solvates" refer to the existence of more than one solid form for a particular solvate composition. Similarly, "polymorphs of hydrates" refer to the existence of more than one solid form for a particular hydrate composition. The term "desolvated solvate," as used herein, refers to a solid form of a substance which can be made by removing the solvent from a solvate. The terms "solvate" and "solvated," as used herein, can also refer to a solvate of a salt, co-crystal, or molecular complex. The terms "hydrate" and "hydrated," as used herein, can also refer to a hydrate of a salt, co-crystal, or molecular complex.

[0051] As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" refer to the eradication or amelioration of a disease or disorder, or of one or more symptoms associated with the disease or disorder. In certain embodiments, the terms refer to minimizing the spread or worsening of the disease or disorder resulting from the administration of one or more prophylactic or therapeutic agents to a subject with such a disease or disorder. In some embodiments, the terms refer to the administration of a compound provided herein, with or without other additional active agent, after the onset of symptoms of a particular disease.

[0052] As used herein, and unless otherwise specified, the terms "prevent," "preventing" and "prevention" refer to the prevention of the onset, recurrence or spread of a disease or disorder, or of one or more symptoms thereof. In certain embodiments, the terms refer to the treatment with or

administration of a compound provided herein, with or without other additional active compound, prior to the onset of symptoms, particularly to patients at risk of a disease or disorder provided herein. The terms encompass the inhibition or reduction of a symptom of a particular disease. Patients with familial history of a disease in particular are candidates for preventive regimens in certain embodiments. In addition, patients who have a history of recurring symptoms are also potential candidates for the prevention. In this regard, the term "prevention" may be interchangeably used with the term "prophylactic treatment."

[0053] As used herein, and unless otherwise specified, the terms "manage," "managing" and "management" refer to preventing or slowing the progression, spread, or worsening of a disease or disorder, or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a prophylactic and/or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a patient who had suffered from the particular disease in an attempt to prevent or minimize the recurrence of the disease or one or more symptoms thereof.

[0054] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or management of the disease or disorder. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0055] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder, or one or more symptoms thereof, or prevent the recurrence of the disease or disorder, or one or more symptoms thereof. A prophylactically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease or disorder. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0056] Unless otherwise specified, the term "composition" as used herein is intended to encompass a product comprising the specified ingredient(s) (and in the specified amount(s), if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredient(s) in the specified amount(s). By "pharmaceutically acceptable," it is meant a diluent, excipient, or carrier in a formulation must be compatible with the other ingredient(s) of the formulation and not deleterious to the recipient thereof.

[0057] Unless otherwise specified, the term "subject" is defined herein to include animals, such as mammals, including, but not limited to, primates (e.g. , humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In specific embodiments, the subject is a human.

[0058] Unless otherwise specified, to the extent that there is a discrepancy between a depicted chemical structure of a compound provided herein and a chemical name of a compound provided herein, the chemical structure shall control.

SOLID DISPERSIONS COMPRISING LENALIDOMIDE AND A POLYMER

[0059] In some embodiments, provided herein is a solid dispersion comprising a compound of Formula (I):

(I),

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof, and a polymer. [0060] In one embodiment, the compound (i.e. , the compound of Formula (I), i.e. , lenalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof) is dispersed in a solid matrix that comprises the polymer.

[0061] In one embodiment, the polymer is a hydrophilic polymer. In one embodiment, the polymer is a water soluble polymer.

[0062] Non-limiting examples of polymers useful herein include cellulose esters and cellulose ethers, polyalkylene oxides, polyacrylates and polymethacrylates, homopolymers and copolymers of N- vinyl lactams, polyacrylamides, vinyl acetate polymers, graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, oligo- and polysaccharides, and mixtures of two or more thereof.

[0063] In one embodiment, the polymer is a cellulose ether polymer. In one embodiment, the polymer is methyl cellulose, ethyl cellulose, (hydroxyalkyl)cellulose (e.g. , hydroxyethyl cellulose (HEC) or hydroxypropyl cellulose (HPC)), or (hydroxyalkyl)alkyl -cellulose (e.g. , hydroxypropyl methyl cellulose (HPMC or hypromellose)). In one embodiment, the polymer is methyl cellulose. In another embodiment, the polymer is ethyl cellulose. In another embodiment, the polymer is HEC. In another embodiment, the polymer is HPC. In another embodiment, the polymer is HPMC.

[0064] In one embodiment, the polymer is a cellulose ester polymer. In one embodiment, the polymer is cellulose phthalate (e.g. , cellulose acetate phthalate or hydroxypropyl methyl cellulose phthalate (HPMC-P)) or cellulose succinate (e.g. , hydroxylpropyl methyl cellulose succinate (HPMC-S) or hydroxypropyl methyl cellulose acetate succinate (HPMC -AS)). In one embodiment, the polymer is HPMC-P. In another embodiment, the polymer is HPMC-AS.

[0065] The cellulose ether and ester polymers can have various viscosity grades. In one

embodiment, the HPMC is HPMC E3, HPMC E5, HPMC E6, HPMC E15, HPMC K3, HPMC A4, or HPMC A15. In one embodiment, the HPMC-AS is HPMC-AS LF, HPMC-AS MF, HPMC-AS HF, HPMC-AS LG, HPMC-AS MG, or HPMC-AS HG. In one embodiment, the HPMC-P is HPMC-P 50 or HPMC-P 55. In one embodiment, the polymer is HPMC-P. In one embodiment, the polymer is HPMC-P 50. In one embodiment, the polymer is HPMC-AS LG. In one embodiment, the polymer is HPMC-AS MG. In one embodiment, the polymer is HPMC-AS HG.

[0066] In one embodiment, the polymer is a polyalkylene oxide. In one embodiment, the polymer is a high molecular weight polyalkylene oxide. In one embodiment, the polymer is polyethylene oxide (PEG or PEO) or copolymers of ethylene oxide and propylene oxide (poloxamers). Suitable PEGs include, without limitation, PEG 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG 8000, PEG 20000 and mixtures thereof. Suitable poloxamers include, without limitation, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, poloxamer 407 and mixtures thereof. In one embodiment, the polymer is poly(ethylene glycol) methyl. In one embodiment, the polymer is polyethylene glycol 6000 (PEG 6000).

[0067] In one embodiment, the polymer is a polyacrylate or polymethacrylate. In one embodiment, the polymer is methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl methacrylate copolymer, butyl methacrylate/2-dimethylaminoethyl methacrylate copolymer, poly(hydroxyalkyl acrylates), or poly(hydroxyalkyl methacrylates). Suitable polyacrylate or polymethacrylate include, without limitation, those sold under the Eudragit™ trademark of Rohm GmbH as Eudragit RS 100, Eudragit L 100, Eudragit L 100-55, and Eudragit S 100, products of other manufacturers equivalent thereto, and mixtures thereof. In one embodiment, the polymer is Eudragit RS 100. In another embodiment, the polymer is Eudragit S 100.

[0068] In one embodiment, the polymer is a homopolymer or copolymer of N-vinyl lactams. In one embodiment, the polymer is a homopolymer or copolymer of N-vinyl pyrrolidone. In one embodiment, the polymer is a homopolymer of polyvinylpyrrolidone (PVP or povidone) or a copolymer (e.g. , those comprising monomers of N-vinyl pyrrolidone and vinyl acetate (copovidone) or N-vinyl pyrrolidone and vinyl propionate). Suitable povidones include, without limitation, those having a K- value (a measure of viscosity of an aqueous solution of the povidone) of about 12, about 15, about 17, about 25, about 30 or about 90, and mixtures thereof. In one embodiment, the polymer is polyvinylpyrrolidone K30. In another embodiment, the polymer is poly(l-vinylpyrrolidone-co-vinyl acetate).

[0069] In one embodiment, the polymer is a polyacrylamide.

[0070] In one embodiment, the polymer is a vinyl acetate polymer (e.g., copolymers of vinyl acetate and crotonic acid, polyvinyl acetate, polyvinyl alcohol, or partially hydrolyzed polyvinyl acetate).

[0071] In one embodiment, the polymer is a graft copolymer of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate (e.g., Soluplus™ of BASF or equivalent product).

[0072] In one embodiment, the polymer is an oligo- or polysaccharide (e.g. , carrageenans, galactomannans, or xanthan gum).

[0073] In one embodiment, the polymer is methyl cellulose, ethyl cellulose, Eudragit RS 100, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose, Eudragit S 100, hydroxypropyl methylcellulose phthalate 50 (HPMC-P), hydroxypropyl methylcellulose AS-LG (HPMC AS LG), polyethylene glycol) methyl, polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone K30, poly(l-vinylpyrrolidone-co-vinyl acetate) (PVP-VA), sureteric, or pluronic F- 68.

[0074] In one embodiment, the polymer is methyl cellulose, ethyl cellulose, Eudragit RS 100, Eudragit S 100, hydroxyethyl cellulose, HPMC, or HPMC-P.

[0075] In one embodiment, the compound (i.e. , the compound of Formula (I), i.e. , lenalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof) is present in an amount of from about 1% to about 50% by weight of the solid dispersion, from about 1% to about 45% by weight of the solid dispersion, from about 1% to about 40% by weight of the solid dispersion, from about 1% to about 35% by weight of the solid dispersion, from about 1% to about 30% by weight of the solid dispersion, from about 1% to about 25% by weight of the solid dispersion, from about 1% to about 20% by weight of the solid dispersion, from about 1% to about 15% by weight of the solid dispersion, from about 1% to about 10% by weight of the solid dispersion, or from about 1% to about 5% by weight of the solid dispersion.

[0076] In one embodiment, the compound is present in an amount of about 1% by weight of the solid dispersion, about 2% by weight of the solid dispersion, about 3% by weight of the solid dispersion, about 4% by weight of the solid dispersion, about 5% by weight of the solid dispersion, about 7.5% by weight of the solid dispersion, about 10% by weight of the solid dispersion, about 12.5% by weight of the solid dispersion, about 15% by weight of the solid dispersion, about 20% by weight of the solid dispersion, about 25% by weight of the solid dispersion, about 30% by weight of the solid dispersion, about 35% by weight of the solid dispersion, about 40% by weight of the solid dispersion, about 45% by weight of the solid dispersion, or about 50% by weight of the solid dispersion.

[0077] In one embodiment, the compound is present in an amount of from about 1% to about 50% by weight of the solid dispersion. In one embodiment, the compound is present in an amount of from about 2.5% to about 25% by weight of the solid dispersion. In one embodiment, the compound is present in an amount of from about 2.5% to about 15% by weight of the solid dispersion. In one embodiment, the compound is present in an amount of from about 5% to about 10% by weight of the solid dispersion. In one embodiment, the compound is present in an amount of from about 2.5% to about 7.5% by weight of the solid dispersion. In one embodiment, the compound is present in an amount of about 5% by weight of the solid dispersion. In one embodiment, the compound is present in an amount of about 10% by weight of the solid dispersion. In one embodiment, the compound is present in an amount of about 20% by weight of the solid dispersion. [0078] In one embodiment, the compound is substantially non-crystalline. In one embodiment, no more than about 20%, no more than about 15%, no more than about 10%, no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, or no more than about 1% of the compound is crystalline as observed by X-ray powder diffraction.

[0079] In one embodiment, no more than about 5% of the compound is crystalline as observed by X- ray powder diffraction. In one embodiment, no more than about 2% of the compound is crystalline as observed by X-ray powder diffraction. In one embodiment, no more than about 1% of the compound is crystalline as observed by X-ray powder diffraction.

[0080] In one embodiment, no more than about 5% of the compound is. In one embodiment, no more than about 2% of the compound is crystalline. In one embodiment, no more than about 1% of the compound is crystallinen.

[0081] In one embodiment, the crystalline form of the compound is Form 1 of the compound. A representative XRPD pattern of Form 1 of lenalidomide is provided in FIG. 1. In certain embodiments, the XRPD pattern comprises peaks at approximately 15.8, 22.2, and 26.7 degrees 2Θ, plus or minus 0.2 degrees 2Θ. Polymorphs of lenalidomide have been described in WO 2005/023192, the entirety of which is incorporated herein by reference.

[0082] In one embodiment, the compound is amorphous.

[0083] In one embodiment, provided herein is a process for preparing a solid dispersion provided herein, comprising (a) providing a solution of the compound (/^'. e. , the compound of Formula (I), /^'. e. , lenalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof) and the polymer in a solvent system; and (b) removing the solvent to provide the solid dispersion.

[0084] In one embodiment, the solvent system is 1,4-dioxane, tetrahydroiuran, acetone, ethanol, water, or a mixture thereof. In one embodiment, the solvent system is 1,4-dioxane, tetrahydroiuran, acetone, water, or a mixture thereof. In one embodiment, the solvent system is 1,4-dioxane, a mixture of tetrahydroiuran and water, or a mixture of acetone and water.

[0085] In one embodiment, the solvent is 1,4-dioxane.

[0086] In one embodiment, the solvent is a mixture of tetrahydroiuran and water. In one

embodiment, the mixture has from about 75% to about 99% of tetrahydroiuran by volume and from about 1% to about 25% of water by volume. In one embodiment, the mixture has from about 85% to about 97.5% of tetrahydroiuran by volume and from about 2.5% to about 15% of water by volume. In one embodiment, the mixture has from about 90% to about 95% of tetrahydroiuran by volume and from about 5% to about 10% of water by volume. In one embodiment, the solvent is a 95/5 (v/v) mixture of tetrahydrofuran and water. In one embodiment, the solvent is a 90/10 (v/v) mixture of tetrahydrofuran and water.

[0087] In one embodiment, the solvent is a mixture of acetone and water. In one embodiment, the mixture has from about 75% to about 99% of acetone by volume and from about 1% to about 25% of water by volume. In one embodiment, the mixture has from about 85% to about 97.5% of acetone by volume and from about 2.5% to about 15% of water by volume. In one embodiment, the mixture has from about 90% to about 95% of acetone by volume and from about 5% to about 10% of water by volume. In one embodiment, the solvent is a 95/5 (v/v) mixture of acetone and water. In one embodiment, the solvent is a 90/10 (v/v) mixture of acetone and water.

[0088] In one embodiment, the solvent is removed by freeze evaporation.

[0089] In one embodiment, provided herein is a process for preparing a solid dispersion provided herein, comprising melting a mixture of the compound and the polymer.

[0090] In one embodiment, provided herein is a solid dispersion comprising from about 2.5% to about 25% (by weight of the solid dispersion) of substantially non-crystalline lenalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof, and a cellulose ether or cellulose ester polymer. In one embodiment, the amount of lenalidomide is from about 2.5% to about 15% by weight of the solid dispersion. In one embodiment, the amount of lenalidomide is from about 5% to about 10% by weight of the solid dispersion.

[0091] In one embodiment, the solid dispersion comprises about 20% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises methyl cellulose. In one embodiment, the solid dispersion comprises about 10% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises methyl cellulose. In one embodiment, the solid dispersion comprises about 5% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises methyl cellulose. In one embodiment, the solid dispersion is obtained by freeze drying a solution of lenalidomide and methyl cellulose in a mixture solvent of tetrahydrofuran and water. In one embodiment, the ratio of tetrahydrofuran to water is about 90/10 v/v.

[0092] In one embodiment, the solid dispersion comprises about 20% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises ethyl cellulose. In one embodiment, the solid dispersion comprises about 10% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises ethyl cellulose. In one embodiment, the solid dispersion comprises about 5% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises ethyl cellulose. In one embodiment, the solid dispersion is obtained by freeze drying a solution of lenalidomide and ethyl cellulose in a solvent of 1,4-dioxane.

[0093] In one embodiment, the solid dispersion comprises about 20% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises hydroxy ethyl cellulose. In one embodiment, the solid dispersion comprises about 10% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises hydroxyethyl cellulose. In one embodiment, the solid dispersion comprises about 5% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises hydroxyethyl cellulose. In one embodiment, the solid dispersion is obtained by freeze drying a solution of lenalidomide and hydroxyethyl cellulose in a mixture solvent of acetone and water. In one embodiment, the ratio of acetone to water is about 95/5 v/v.

[0094] In one embodiment, the solid dispersion comprises about 20% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises HPMC-P. In one embodiment, the solid dispersion comprises about 10% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises HPMC-P. In one embodiment, the solid dispersion comprises about 5% by weight of amorphous lenalidomide, dispersed in a solid matrix that comprises HPMC-P. In one embodiment, the solid dispersion is obtained by freeze drying a solution of lenalidomide and HPMC-P in a mixture solvent of tetrahydroiuran and water. In one embodiment, the ratio of tetrahydroiuran to water is about 90/10 v/v.

[0095] In one embodiment, provided herein is a solid dispersion comprising from about 2.5% by weight to about 25% by weight of substantially non-crystalline lenalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof, and a polyacrylate or polymethacrylate polymer. In one embodiment, the amount of lenalidomide is from about 2.5% by weight to about 15% by weight. In one embodiment, the amount of lenalidomide is from about 5% to about 10% by weight.

[0096] In one embodiment, provided herein is a solid dispersion comprising from about 2.5% to about 25% by weight of the solid dispersion of substantially non-crystalline lenalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof, and a polyalkylene oxide polymer. In one embodiment, the amount of lenalidomide is from about 2.5% to about 15% by weight of the solid dispersion. In one embodiment, the amount of lenalidomide is from about 5% to about 10% by weight of the solid dispersion.

[0097] While not intending to be bound by any particular theory, certain solid dispersions provided herein exhibit physical properties, e.g., stability, solubility and/or dissolution rate, appropriate for use in clinical and therapeutic dosage forms. In one embodiment, certain solid dispersions provided herein are appropriate for use in a pediatric (liquid) formulation. In some embodiments, such properties can be determined using techniques such as X-ray diffraction, microscopy, IR spectroscopy and thermal analysis, as described herein and known in the art.

SOLID FORMS COMPRISING LENALIDOMIDE AND A COFORMER

[0098] In one embodiment, provided herein are solid forms (e.g. , crystal forms, amorphous forms, or mixtures thereof) comprising (a) lenalidomide, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) a coformer. In one embodiment, provided herein are solid forms (e.g. , crystal forms, amorphous forms, or mixtures thereof) comprising (a) a free base of lenalidomide, or a solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) a coformer.

Lenalidomide can be synthesized or obtained according to a method known in the literature or based upon the teachings herein.

[0099] In one embodiment, lenalidomide can be prepared according to methods described in, for example, U.S. Pat. Nos. 6,281,230 and 5,635,517, the entireties of which are incorporated herein by reference.

[00100] The coformer can be any pharmaceutically acceptable coformer known in the art. In one embodiment, the coformer is saccharin, nicotinamide, 4-hydroxybenzamide, salicylic acid, succinic acid, L(-)-malic acid, L(+)-arginine, fumaric acid, lactamide, or urea.

[00101] In one embodiment, the coformer is 4-hydroxybenzamide.

[00102] In one embodiment, solid forms provided herein may be a crystal form or an amorphous form or mixtures thereof (e.g., mixtures of crystal forms, or mixtures of crystal and amorphous forms), which comprises (a) lenalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) a coformer. In one embodiment, provided herein is a crystal form comprising (a) lenalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) a coformer. In one embodiment, provided herein is a cocrystal comprising (a) lenalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) a coformer. In one embodiment, provided herein is an amorphous form comprising (a) lenalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) a coformer. In one embodiment, provided herein is a mixture comprising (i) a cocrystal comprising (a) lenalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) a coformer; and (ii) a second form of lenalidomide or a

pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof. In one embodiment, the second solid form is a crystalline form of lenalidomide. In one embodiment, the crystalline form is Form 1 of lenalidomide. In one embodiment, the second solid form is an amorphous form of lenalidomide. In one embodiment, provided herein is a mixture comprising (i) a cocrystal comprising (a) lenalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) a coformer; and (ii) a second solid form of the coformer.

[00103] In one embodiment, provided herein is an unsolvated solid form comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is an anhydrous solid form comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is an unsolvated crystal form comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is an anhydrous crystal form comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is an unsolvated amorphous form comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is an anhydrous amorphous form comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is a solvated solid form comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is a hydrated solid form comprising (a) lenalidomide and (b) a coformer (e.g. , a hydrate having a stoichiometric or non-stoichiometric amount of water). In one embodiment, provided herein is a hydrated form of (a) lenalidomide and (b) a coformer, including, but not limited to, a hemihydrate, a monohydrate, a dihydrate, a trihydrate, and the like. In one embodiment, the hydrated form is substantially crystalline. In one embodiment, the hydrated form is substantially amorphous. In one embodiment, the anhydrous form is substantially crystalline. In one embodiment, the anhydrous form is substantially amorphous. In one embodiment, provided herein is an unsolvated cocrystal comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is an anhydrous cocrystal comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is a hydrated cocrystal comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is a solvated cocrystal comprising (a) lenalidomide and (b) a coformer.

[00104] Certain embodiments herein provide solid forms comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is a solid form comprising (a) lenalidomide and (b) a coformer that is substantially crystalline. In one embodiment, provided herein is a cocrystal comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is a solid form comprising a cocrystal comprising (a) lenalidomide and (b) a coformer. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising (a) lenalidomide and (b) a coformer and (ii) an amorphous form of lenalidomide. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising (a) lenalidomide and (b) a coformer and (ii) one or more additional crystal forms of lenalidomide. [00105] Solid forms provided herein can be prepared by the methods described herein, or by techniques, including, but not limited to, heating, cooling, freeze drying, spray drying, lyophilization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, solvent recrystallization, antisolvent addition, slurry recrystallization, crystallization from the melt, desolvation, recrystallization in confined spaces, such as, e.g. , in nanopores or capillaries, recrystallization on surfaces or templates, such as, e.g. , on polymers, recrystallization in the presence of additives, such as, e.g. , co-crystal counter- molecules, desolvation, dehydration, rapid cooling, slow cooling, exposure to solvent and/or water, drying, including, e.g. , vacuum drying, vapor diffusion, sublimation, grinding (including, e.g. , cryo- grinding and solvent-drop grinding), microwave-induced precipitation, sonication-induced precipitation, laser-induced precipitation, and precipitation from a supercritical fluid. The particle size of the resulting solid forms, which can vary (e.g. , from nanometer dimensions to millimeter dimensions), can be controlled, e.g. , by varying crystallization conditions, such as, e.g. , the rate of crystallization and/or the crystallization solvent system, or by particle-size reduction techniques, e.g. , grinding, milling, micronizing, or sonication.

[00106] In some embodiments, the cocrystal comprising (a) lenalidomide and (b) a coformer can be obtained by crystallization from certain solvent systems, for example, solvent systems comprising one or more of the following solvents: acetone, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), methanol, 1,4-dioxane, N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), water, acetonitrile, and isopropyl alcohol. Other examples of solvent systems are provided herein elsewhere. In certain embodiments, a solid form provided herein (e.g. , a cocrystal comprising (a) lenalidomide and (b) a coformer) can be obtained by slurry crystallization, evaporation crystallization, cooling crystallization, precipitation crystallization, saturated (API) solution co-crystallization, slurry conversion, and wet co- grinding.

[00107] In certain embodiments, cocrystals can be prepared using solid-state methods such as solid- state grinding and solvent-drop grinding. In certain embodiments, cocrystals can be prepared using high- throughput screening. In certain embodiments cocrystals can be prepared using solution-based crystallization.

[00108] In certain embodiments, slurry crystallization is effected by adding solvent or solvent mixtures to a solid substrate, and the slurry is stirred, and optionally heated to various temperatures. In certain embodiments, the slurry is heated at about 25 °C, about 50 °C, about 80 °C, or about 100 °C. In certain embodiments, upon heating and cooling, the residual solvents of the slurry can be removed by wicking, or other suitable methods, such as filtration, centrifugation, or decantation, and the crystals can be dried in air or under vacuum. [00109] In certain embodiments, evaporation crystallization is effected by adding a solvent or solvent mixture to a solid substrate, and allowing the solvent or solvent mixture to evaporate under ambient conditions. In certain embodiments, the residual solvent can be removed by wicking, or other suitable methods, such as filtration, centrifugation, or decantation, and the crystals can be dried in air or under vacuum.

[00110] In certain embodiments, precipitation crystallization is effected by adding a solvent or solvent mixture to a solid substrate, and subsequently adding an anti-solvent. In certain embodiments, the resultant mixture stands for a period of time, e.g. , overnight, and under certain conditions, for example at room temperature. In certain embodiments, the residual solvent can be removed by wicking, or other suitable methods, such as filtration, centrifugation, or decantation, and the crystals can be dried in air or under vacuum.

[00111] In certain embodiments, cooling crystallization is effected by adding a solvent or solvent mixture to a solid substrate at elevated temperature, and allowing the resultant mixture to stand for a period of time at a reduced temperature. In certain embodiments, the elevated temperature is, for example, about 30 °C, about 40 °C, about 50 °C, about 60 °C, about 70 °C, or about 80 °C. In certain embodiments, the reduced temperature is, for example, about 15 °C, about 10 °C, about 5 °C, about 0 °C, about -5 °C, about -10 °C, about -15 °C, or about -20 °C. The residual solvent can be removed by wicking, or other suitable methods, such as filtration, centrifugation, or decantation, and the crystals can be dried in air or under vacuum.

[00112] In certain embodiments, saturated API solution co-crystallization is effected by adding the coformer to a saturated solution of the API, stirring the mixture for a period of time at ambient temperature.

[00113] In certain embodiments, the wet co-grinding is effected by grinding a mixture of the API and coformer in a small amount of solvent.

[00114] In certain embodiments, the non-covalent forces are one or more hydrogen bonds (H-bonds). The coformer may be H-bonded directly to the API or may be H-bonded to an additional molecule which is bound to the API. The additional molecule may be H-bonded to the API or bound ionically or covalently to the API. The additional molecule could also be a different API. In certain embodiments, the co-crystals may include one or more solvate molecules in the crystalline lattice, i.e., solvates of co- crystals, or a co-crystal further comprising a solvent or compound that is a liquid at room temperature. In certain embodiments, the co-crystals may be a co-crystal between a coformer and a salt of an API. In certain embodiments, the non-covalent forces are pi-stacking, guest-host complexation and/or van der Waals interactions. Hydrogen bonding can result in several different intermolecular configurations. For example, hydrogen bonds can result in the formation of dimers, linear chains, or cyclic structures. These configurations can further include extended (two-dimensional) hydrogen bond networks and isolated triads.

[00115] In certain embodiments, the co-crystals include an acid addition salt or base addition salt of an API. Acid addition salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethane sulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p- chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene- 1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutaric acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. Base addition salts include, but are not limited to, inorganic bases such as sodium, potassium, lithium, ammonium, calcium and magnesium salts, and organic bases such as primary, secondary and tertiary amines (e.g. , isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, and N-ethylpiperidine).

[00116] The ratio of API to coformer may be stoichiometric or non-stoichiometric. In one embodiment, the ratio of API to coformer is about 5 : 1, 4: 1, 3 : 1, 2.5 : 1, 2: 1, 1.5 : 1, 1 : 1, 1 : 1.5, 1 :2, 1 :2.5, 1 :3, 1 :4, or 1 :5. In one embodiment, the ratio of API to coformer is about 1 : 1. In one embodiment, the co-crystal comprises more than one coformers. In one embodiment, the co-crystal comprises two coformers.

[00117] The compounds provide herein may also contain an unnatural proportion of an atomic isotope at one or more of the atoms that constitute such a compound. For example, the compound may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) sulfur-35 (³⁵S), or carbon-14 (¹⁴C). Radiolabeled compounds are useful as therapeutic agents, e.g. , cancer therapeutic agents, research reagents, e.g. , binding assay reagents, and diagnostic agents, e.g. , in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed herein. In certain embodiments, a compound provided herein contains unnatural proportion(s) of one or more isotopes, including, but not limited to, hydrogen (^H), deuterium (²H), tritium (³H), carbon-1 1 (^UC), carbon-12 (¹²C), carbon-13 (¹³C), carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-14 (¹⁴0), oxygen-15 (¹⁵0), oxygen-16 (¹⁶0), oxygen-17 (¹⁷0), oxygen-18 (¹⁸0), fluorine-17 (¹⁷F), fluorine-18 (¹⁸F), phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36 (³⁶S), chlorine-35 (³⁵C1), chlorine-36 (³⁶C1), chlorine-37 (³⁷C1), bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), iodine- 123 (¹²³I), iodine- 125 (¹²⁵I), iodine-127 (¹²⁷I), iodine- 129 (¹²⁹I), and iodine- 131 (¹³¹I). In certain embodiments, a compound provided herein contains unnatural proportion(s) of one or more isotopes in a stable form, that is, non-radioactive, including, but not limited to, hydrogen (¾), deuterium (²H), carbon- 12 (¹²C), carbon- 13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-16 (¹⁶0), oxygen-17 (¹⁷0), oxygen-18 (¹⁸0), fluorine- 17 (¹⁷F), phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-36 (³⁶S), chlorine-35 (³⁵C1), chlorine-37 (³⁷C1), bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), and iodine- 127 (¹²⁷I). In certain embodiments, a compound provided herein contains unnatural proportion(s) of one or more isotopes in an unstable form, that is, radioactive, including, but not limited to, tritium (³H), carbon-1 1 (^UC), carbon- 14 (¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴0), oxygen- 15 (¹⁵0), fluorine-18 (¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S), chlorine-36 (³⁶C1), iodine-123 (¹²³I), iodine- 125

125 129 131

('"I), iodine-129 ("T), and iodine- 131 (^1J1I). In certain embodiments, in a compound as provided herein, any hydrogen can be²H, for example, or any carbon can be¹³C, for example, or any nitrogen can be¹⁵N, for example, or any oxygen can be¹⁸0, for example, where feasible according to the judgment of one of skill. In certain embodiments, a compound provided herein contains unnatural proportions of deuterium (D). In exemplary embodiments, provided herein are isotopologues of lenalidomide, as disclosed in WO 2012/177678, which is incorporated by reference herein in its entirety. In one embodiment, provided herein are solid forms (e.g. , crystal forms, amorphous forms, or mixtures thereof) of isotopologues of lenalidomide provided herein.

[00118] In another embodiment, provided herein are compositions comprising one or more solid form(s) comprising (a) lenalidomide or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and (b) a coformer. Also provided herein are compositions comprising: (i) one or more solid form(s) provided herein (e.g., one or more crystal forms, one or more amorphous forms, and mixtures thereof), and (ii) other active ingredient(s).

[00119] While not intending to be bound by any particular theory, certain solid forms provided herein exhibit physical properties, solubility, dissolution rate, bioavailablity, physical stability, chemical stability, flowability, fractability, or compressibility, appropriate for use in clinical and therapeutic dosage forms. In certain embodiments, a given API may form different cocrystals with many different counter- molecules, and some of these cocrystals may exhibit enhanced solubility or stability. In certain embodiments pharmaceutical cocrystals increase the bioavailability or stability profile of a compound without the need for chemical (covalent) modification of the API.

Cocrystal Comprising Lenalidomide and 4-Hydroxybenzamide

[00120] Certain embodiments herein provide solid forms comprising lenalidomide and 4- hydroxybenzamide. In one embodiment, provided herein is a solid form comprising lenalidomide and 4- hydroxybenzamide that is substantially crystalline. In one embodiment, provided herein is a cocrystal comprising lenalidomide and 4-hydroxybenzamide. In one embodiment, provided herein is a solid form comprising a cocrystal comprising lenalidomide and 4-hydroxybenzamide. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising lenalidomide and 4-hydroxybenzamide and (ii) a second solid form of lenalidomide. In one embodiment, the second solid form of lenalidomide is Form 1 of lenalidomide. In another embodiment, the second solid form of lenalidomide is amorphous lenalidomide. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising lenalidomide and 4-hydroxybenzamide and (ii) a second solid form of 4-hydroxybenzamide.

[00121] In some embodiments, the cocrystal comprising lenalidomide and 4-hydroxybenzamide provided herein is Form HBA1.

[00122] In some embodiments, Form HBA1 is obtained by adding 4-hydroxybenzamide to a solution saturated with lenalidomide. In one embodiment, Form HBA1 is obtained by adding 4- hydroxybenzamide to a solution saturated with lenalidomide, stirring the mixture (e.g. , at ambient temperature for about 4 hours), removing any undissolved solid, and then slowly evaporating the mother liquid. In one embodiment, the solvent is a mixture of 1,4-dioxane and water. In one embodiment, the solvent is a 90: 10 (v/v) mixture of 1,4-dioxane and water.

[00123] In some embodiments, Form HBA1 has a molar ratio of lenalidomide to 4-hydroxybenzamide of from about 5: 1 to about 1 :5. In one embodiment, the molar ratio of lenalidomide to 4- hydroxybenzamide is from about 2: 1 to about 1 :2. In some embodiments, the molar ratio of lenalidomide to 4-hydroxybenzamide is about 1 : 1.

[00124] A representative overlay of XRPD patterns of Form 1 of lenalidomide, cocrystal Form HBA1 before exposure to AAC, and Form 1, cocrystal Form HBA1, and 4-hydroxybenzamide obtained after exposure to AAC is provided in FIG. 2. In some embodiments, Form HBA1 is characterized by one or more XRPD peaks (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or more peaks) selected from peaks located at the following or approximately the following positions: 17.1, 17.7, 18.4, 20.0, 22.2, 22.9, 24.4, 26.0, 26.9, and 32.7 degrees 2Θ, plus or minus 0.2 degrees 2Θ. In some embodiments, Form HBAl is characterized by 3 of the peaks. In some embodiments, Form HBAl is characterized by 5 of the peaks. In some embodiments, Form HBAl is characterized by 7 of the peaks. In some embodiments, Form HBAl is characterized by all of the peaks.

[00125] In some embodiments, Form HBAl is characterized by an XRPD pattern comprising peaks at approximately 17.7, 20.0, and 26.0 degrees 2Θ, plus or minus 0.2 degrees 2Θ. In certain embodiments, the XRPD pattern further comprises peaks at approximately 17.1 and 22.9 degrees 2Θ, plus or minus 0.2 degrees 2Θ. In certain embodiments, the XRPD pattern further comprises peaks at approximately 22.2 and 26.9 degrees 2Θ, plus or minus 0.2 degrees 2Θ. In one embodiment, Form HBAl is characterized by an XRPD pattern comprising peaks at approximately 17.1, 17.7, 18.4, 20.0, 22.2, 22.9, 24.4, 26.0, 26.9, and 32.7 degrees 2Θ, plus or minus 0.2 degrees 2Θ.

[00126] In some embodiments, the XRPD peaks above (degrees 2Θ peaks) are when analyzed using copper Ka radiation. In some embodiments, Form HBAl is characterized by an XRPD pattern comprising is characterized by an XRPD diffraction pattern which matches the Form HBAl XRPD pattern presented in FIG. 2.

[00127] In some embodiments, Form HBAl exhibits a mass loss of about 18.0%, as determined by TGMS, upon heating from about 40 °C to about 220 °C. Without being limited by a particular theory, the mass loss corresponds to loss of 1,4-dioxane. In one embodiment, the mass loss corresponds to loss of about 0.7 molecule of 1,4-dioxane per molecule of lenalidomide. In one embodiment, Form HBAl is characterized by a TGMS spectrum which matches the TGMS spectrum presented in FIG. 3.

[00128] In some embodiments, Form HBAl exhibits an endothermic event, as determined by DSC, between about 100 to about 170 °C. Without being limited by a particular theory, the event corresponds to the loss of 1,4-dioxane. In one embodiment, Form HBAl is characterized by a DSC spectrum which matches the DSC spectrum presented in FIG. 4.

[00129] In one embodiment, Form HBAl is a 1,4-dioxane solvate.

METHODS OF TREATMENT, PREVENTION AND MANAGEMENT

[00130] Provided herein are methods of treating, preventing, and/or managing various diseases or disorders using a solid dispersion or solid form provided herein. In certain embodiments, provided are methods of treating, managing, and preventing various diseases and disorders, which comprise administering to a patient in need of such treatment, prevention or management a therapeutically or prophylactically effective amount of a solid dispersion or solid form provided herein. Examples of diseases and disorders are described herein.

[00131] Also provided herein are methods of using the solid dispersion or solid form provided herein in the treatment, prevention, or management of conditions and disorders including, but not limited to: cancer, including hematologic cancer or solid tumor, for example, multiple myeloma; leukemia including but not limited to acute lymphoblastic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia; lymphoma including but not limited to Hodgkins and Non-Hodgkins lymphoma (B-cell and T-cell lymphomas, including follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, indolent lymphomas and others), sarcoma, prostate cancer, or small cell lung cancer; glioma, neuroblastoma, scleroderma; amyloidosis; pain; myelofibrosis;

myeloproliferative disease, for example, myelofibrosis with myeloid metaplasia (MMM);

myelodysplastic syndromes; diffuse systemic sclerosis; macular degeneration; an immunodeficiency disorder; a CNS disorder; a CNS injury; atherosclerosis; hemoglobinopathy; anemia, for example, sickle cell anemia; an inflammatory disease; an autoimmune disease; a viral disease; a genetic disease; an allergic disease; a bacterial disease; an ocular neovascular disease; a choroidal neovascular disease; a retina neovascular disease; and rubeosis. In a specific embodiment, provided herein are methods of using these compositions for the treatment in patients with transfusion-dependent anemia due to Low- or Intermediate- 1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

[00132] In another embodiment, provided herein are methods of using the solid dispersion or solid form provided herein in combination with a second, third, or fourth agent in the treatment , prevention, or management of conditions and disorders including, but not limited to: cancer, including hematologic cancer or solid tumor, for example, multiple myeloma; leukemia including but not limited to acute lymphoblastic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia; lymphoma including but not limited to Hodgkins and Non- Hodgkins lymphoma (B-cell and T-cell lymphomas, including follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, indolent lymphomas and others), sarcoma, prostate cancer, or small cell lung cancer; glioma, neuroblastoma, scleroderma; amyloidosis; pain; myelofibrosis; myeloproliferative disease, for example, myelofibrosis with myeloid metaplasia (MMM); myelodysplastic syndromes;

diffuse systemic sclerosis; macular degeneration; an immunodeficiency disorder; a CNS disorder; a CNS injury; atherosclerosis; hemoglobinopathy; anemia, for example, sickle cell anemia; an inflammatory disease; an autoimmune disease; a viral disease; a genetic disease; an allergic disease; a bacterial disease; an ocular neovascular disease; a choroidal neovascular disease; a retina neovascular disease; and rubeosis. In a specific embodiment, provided herein are methods of using these compositions in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.

[00133] Examples of diseases and disorders include, but are not limited to: cancer, including hematologic cancer or solid tumor, for example, multiple myeloma, leukemia, lymphoma, sarcoma; amyloidosis; an immunodeficiency disorder; a CNS disorder; a CNS injury; sickle cell anemia; an inflammatory disease; an autoimmune disease; a viral disease; a genetic disease; Central Nervous System Tumors including glioma, nervous system noeplasms, neuroepithleoma, neruofibroma,

[00134] In one embodiment the disease is multiple myeloma. In certain embodiments the solid dispersion or solid form is used to treat multiple myeloma in patients who have received at least one prior therapy. In certain embodiments the solid dispersion or solid form is administered in combination with dexamethasone for the treatment of myltiple myeloma in patients who have received at least one prior therapy.

[00135] In one embodiment the disease is transfusion-dependent anemia due to Low- or Intermediate- 1-risk myelodyspastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

[00136] In one embodiment, provided herein is a method of treating, preventing and/or managing a disease provided herein, comprising administering to a patient in need of such treatment, prevention and/or management a therapeutically or prophylactically effective amount of a solid dispersion or solid form comprising lenalidomide as described herein and a therapeutically or prophylactically effective amount of a second active agent.

[00137] In one embodiment, provided herein are pharmaceutical compositions, single unit dosage forms, and kits, comprising a solid dispersion or solid form comprising lenalidomide as described herein, a second active ingredient, and/or blood or cells for transplantation therapy. For example, a kit may comprise a solid dispersion or solid form comprising lenalidomide as described herein, stem cells for transplantation, an immunosuppressive agent, and an antibiotic or other drug. [00138] The cytokines used in the methods provided herein may be naturally-occurring cytokines, or may be an artificial derivative or analog of the cytokines. For example, analogs or derivatives of erythropoietin that may be used in combination with a solid form or compound provided herein include, but are not limited to, Aranesp^™ and Darbopoietin^™.

[00139] Cytokines used may be purified from natural sources or recombinantly produced. Examples of recombinant cytokines that may be used in the methods provided herein include filgrastim, or recombinant granulocyte-colony stimulating factor (G-CSF), which is sold in the United States under the trade name Neupogen® (Amgen, Thousand Oaks, CA); sargramostim, or recombinant GM-CSF, which is sold in the United States under the trade name Leukine® (Immunex, Seattle, WA); recombinant Epo, which is sold in the United States under the trade name Epogen® (Amgen, Thousand Oaks, CA); and methionyl stem cell factor (SCF), which is sold in the United States under the trade name Ancestim™ Recombinant and mutated forms of GM-CSF can be prepared as described in U.S. patent nos. 5,391,485; 5,393,870; and 5,229,496; all of which are incorporated herein by reference. Recombinant and mutated forms of G-CSF can be prepared as described in U.S. patent nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; all of which are incorporated herein by reference.

[00140] Other cytokines may be used which encourage the survival and/or proliferation of hematopoietic precursor cells and immunologically active poietic cells in vitro or in vivo, or which stimulate the division and differentiation of committed erythroid progenitors in cells in vitro or in vivo. Such cytokines include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), IL-10, IL-12, and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b; and G-CSF.

[00141] When administered to a person having a hemoglobinopathy, a solid dispersion or solid form comprising lenalidomide as described herein, particularly in the presence of Epo, particularly in the presence of the combination of TNFa, SCF, Flt-3L and GM-CSF, or more particularly in the presence of Epo and SCF, induces the production of erythrocytes, and the production of fetal hemoglobin as well as the production of AHSP. As noted above, cytokines used may include purified or recombinant forms, or analogs or derivatives of specific cytokines.

[00142] A solid dispersion or solid form comprising lenalidomide as described herein may also be administered in conjunction with one or more second compounds known to have, or suspected of having, a beneficial effect on a hemoglobinopathy. In this context, "beneficial effect" means any reduction of any symptom of a hemoglobinopathy or anemia. [00143] For example, with specific reference to the hemoglobinopathy sickle cell anemia, the second compound can be a compound, other than a lenalidomide or a derivative thereof, that is known or suspected to induce the production of fetal hemoglobin. Such compounds include hydroxyurea, and butyrates or butyrate derivatives. The second compound may also be a compound that relaxes blood vessels, such as nitrous oxide, e.g., exogenously-applied or administered nitrous oxide. The second compound may also be a compound that binds directly to hemoglobin S, preventing it from assuming the sickle-inducing conformation. For example, the plant extract known as HEMOXIN™ (NIPRISAN™; see United States Patent No. 5,800,819), which is an extract of a mixture of about 12 to about 17 parts by weight of Piper guineense seeds, from about 15 to about 19 parts by weight of Pterocarpus osun stem, from about 12 to about 18 parts by weight of Eugenia caryophyllata fruit, and from about 25 to about 32 parts by weight of Sorghum bicolor leaves, and optionally 15-22 parts by weight potash, wherein the mixture is extracted with cold water, has antisickling activity. The second compound may also be a Gardos channel antagonist. Examples of Gardos channel antagonists include clotrimazole and triaryl methane derivatives. The second compound may also be one that reduces red blood cell adhesion, thereby reducing the amount of clotting pervasive in sickle cell anemia.

[00144] Other hemoglobinopathies may be treated with a second compound known or suspected to be efficacious for the specific condition. For example, β thalassemia may additionally be treated with the second compound Deferoxamine, an iron chelator that helps prevent the buildup of iron in the blood, or folate (vitamin B9). Thalassemia or sickle cell anemia may also be treated with protein C as the second compound (U.S. Patent No. 6,372,213). There is some evidence that herbal remedies can ameliorate symptoms of hemoglobinopathies, e.g., thalassemia; such remedies, and any of the specific active compounds contained therein, may also be used as a second compound in the method provided herein. See, e.g., Wu Zhikui et al. "The Effect of Bushen Shengxue Fang on β-thalassemia at the Gene Level," Journal of Traditional Chinese Medicine 18(4): 300-303 (1998); U.S. Patent No. 6,538,023 "Therapeutic Uses of Green Tea Polyphenols for Sickle Cell Disease". Treatment of autoimmune hemolytic anemia can include corticosteroids as the second compound.

[00145] Second compounds that are proteins may also be derivatives or analogs of other proteins. Such derivatives may include, but are not limited to, proteins that lack carbohydrate moieties normally present in their naturally occurring forms (e.g. , nonglycosylated forms), pegylated derivatives, and fusion proteins, such as proteins formed by fusing IgGl or IgG3 to the protein or active portion of the protein of interest. See, e.g., Penichet, M.L. and Morrison, S.L., J. Immunol. Methods 248:91-101 (2001).

[00146] Cytokines and/or other compounds potentially useful in the treatment of anemia or a hemoglobinopathy may be administered at the same time as lenalidomide or a derivative thereof. In this regard, the cytokines or other compounds may be administered as formulations separate from a solid dispersion or solid form comprising lenalidomide, or, where possible, may be compounded with a solid dispersion or solid form comprising lenalidomide for administration as a single pharmaceutical composition. Alternatively, the cytokines, the other compounds, or both, may be administered separately from a solid dispersion or solid form comprising lenalidomide used in the methods provided herein, and may follow the same or different dosing schedules. In one embodiment, a solid dispersion or solid form comprising lenalidomide as described herein, cytokines, and/or any other compound useful to treat anemia or a hemoglobinopathy, are administered at the same time, but in separate pharmaceutical formulations for flexibility in administration.

[00147] In addition to the treatment combinations outlined herein, the treated individual may be given transfusions. Such transfusions may be of blood, for example matched blood, or of a blood substitute such as Hemospan™ or Hemospan™ PS (Sangart).

[00148] In any of the treatment combinations described herein, the treated individual is eukaryotic. In one embodiment, the treated individual is a mammal, for example a human.

[00149] The methods described herein may be used to treat any anemia, including anemia resulting from a hemoglobinopathy. Hemoglobinopathies and anemias treatable by the methods provided herein may be genetic in origin, such as sickle-cell anemia or thalassemias. The hemoglobinopathy may be due to a disease, such as cancer, including, but not limited to, cancers of the hematopoietic or lymphatic systems. Other conditions treatable using the methods provided herein include hypersplenism, splenectomy, bowel resection, and bone marrow infiltration. The methods described herein may also be used to treat anemia resulting from the deliberate or accidental introduction of a poison, toxin, or drug. For example, anemias resulting from cancer chemotherapies may be treated using the methods provided herein. As such, the methods described herein may be employed when anemia or a hemoglobinopathy is the primary condition to be treated, or is a secondary condition caused by an underlying disease or treatment regimen.

[00150] In one embodiment, provided herein is a method of treating or managing a pediatric cancer, comprising administering to a patient in need of such treatment or management a therapeutically or prophylactically effective amount of a solid dispersion or solid form comprising lenalidomide as described herein.

[00151] In one embodiment, the pediatric cancer is a CNS cancer (pediatric CNS cancer). In one embodiment, the CNS cancer includes, but are not limited to, primary central nervous system lymphoma ("PCNSL"), primary vitreoretinal lymphoma ("PVRL"), intra-ocular lymphoma, central nervous system blastoid mantle cell lymphoma, central nervous system tumors, central nervous system solid tumors, central nervous system cancerous conditions, neuroblastoma, mantle cell lymphoma ("MCL"), lymphocytic lymphoma of intermediate differentiation, intermediate lymphocytic lymphoma ("ILL"), diffuse poorly differentiated lymphocytic lymphoma ("PDL"), centrocytic lymphoma, diffuse small- cleaved cell lymphoma ("DSCCL"), follicular lymphoma, mantle zone lymphoma, and any type of the mantle cell lymphomas that can be seen under the microscope (nodular, diffuse, blastic and mantle zone lymphoma).

[00152] In one embodiment, the CNS cancer is located at meninges, pituitary, pineal, nasal cavity, frontal lobe, temporal lobe, parietal lobe, occipital lobe, cerebrum, ventricle, cerebellum, brain stem, spinal cord, cauda equina, cranial nerves, other parts of brain, or other parts of the nervous system.

[00153] In one embodiment, the pediatric cancer is a pediatric solid tumor. In one embodiment, the pediatric cancer is a CNS tumor (pediatric CNS tumor). In one embodiment, the CNS tumor is a brain tumor. In one embodiment, the CNS tumor is a spinal cord tumor.

[00154] In one embodiment, the pediatric cancer is gliomas. In some embodiments, the gliomas is located at frontal lobe, temporal lobe, parietal lobe, occipital lobe, cerebrum, ventricle, cerebellum, brain stem, spinal cord, cauda equine, cranial nerves, other parts of brain, and other parts of the nervous system. In some embodiments, the gliomas is selected from the group consisting of glioblastoma, astrocytoma (e.g., anaplastic astrocytoma, diffuse astrocytoma, pilocytic astrocytoma), oligoastrocytic tumors, oligodendroglioma, ependymal tumors, and glioma malignant NOS. In one embodiment, the gliomas is fibrillary astrocytomas, juvenile pilocytic astrocytoma (JPA), oligodendrogliomas, ependymomas, glioblastoma multiforme, or pleomorphic xanthoastrocytomas. In one embodiment, the glioma is diffuse intrinsic brain stem gliomas (DIPG).

[00155] In one embodiment, the glioma is a WHO grade I glioma. In one embodiment, the glioma is a WHO grade II glioma. In one embodiment, the glioma is a WHO grade III glioma. In one embodiment, the glioma is a WHO grade IV glioma.

[00156] In one embodiment, the pediatric cancer is meduloblastomas. In one embodiment, the meduloblastomas include, but are not limited to, classical medulloblastoma, large cell/anaplastic medulloblastoma, nodular desmoplastic medulloblastoma, and medulloblastoma with extensive nodularity.

[00157] In one embodiment, the pediatric cancer is ependymomas. In one embodiment, the ependymomas include, but are not limited to, myxopapillary ependymoma (WHO grade I), grade II ependymoma (cellular, papillary, clear cell, tanycytic) and anaplastic ependymoma (WHO grade III). [00158] In one embodiment, the pediatric cancer is ntral nervous system germ cell tumors, craniopharyngiomas, choroid plexus tumors, meningiomas, or atypical teratoid rhabdoid tumors.

[00159] In one embodiment, the diseases or disorders are various forms of leukemias such as chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia, including leukemias that are relapsed, refractory, or resistant, as disclosed in U.S. publication no. 2006/0030594, published February 9, 2006, which is incorporated in its entirety by reference.

[00160] The term "leukemia" refers malignant neoplasms of the blood-forming tissues. The leukemia includes, but is not limited to, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, and acute myeloblastic leukemia. The leukemia can be relapsed, refractory or resistant to conventional therapy. The term "relapsed" refers to a situation where patients who have had a remission of leukemia after therapy have a return of leukemia cells in the marrow and a decrease in normal blood cells. The term "refractory or resistant" refers to a circumstance where patients, even after intensive treatment, have residual leukemia cells in their marrow.

[00161] In another embodiment, the diseases or disorders are various types of lymphomas, including Non-Hodgkin's lymphoma (NHL). The term "lymphoma" refers a heterogenous group of neoplasms arising in the reticuloendothelial and lymphatic systems. "NHL" refers to malignant monoclonal proliferation of lymphoid cells in sites of the immune system, including lymph nodes, bone marrow, spleen, liver, and gastrointestinal tract. Examples of NHL include, but are not limited to, mantle cell lymphoma (MCL), lymphocytic lymphoma of intermediate differentiation, intermediate lymphocytic lymphoma (ILL), diffuse poorly differentiated lymphocytic lymphoma (PDL), centrocytic lymphoma, diffuse small-cleaved cell lymphoma (DSCCL), follicular lymphoma, and any type of the mantle cell lymphomas that can be seen under the microscope (nodular, diffuse, blastic and mentle zone lymphoma).

[00162] Examples of diseases and disorders associated with, or characterized by, undesired angiogenesis include, but are not limited to, inflammatory diseases, autoimmune diseases, viral diseases, genetic diseases, allergic diseases, bacterial diseases, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, and rubeosis (neovascularization of the angle). Specific examples of the diseases and disorders associated with, or characterized by, undesired angiogenesis include, but are not limited to, arthritis, endometriosis, Crohn's disease, heart failure, advanced heart failure, renal impairment, endotoxemia, toxic shock syndrome, osteoarthritis, retrovirus replication, wasting, meningitis, silica-induced fibrosis, asbestos-induced fibrosis, veterinary disorder, malignancy-associated hypercalcemia, stroke, circulatory shock, periodontitis, gingivitis, macrocytic anemia, refractory anemia, and 5q-deletion syndrome. [00163] Other disease or disorders treated, prevented, or managed include, but not limited to, viral, genetic, allergic, and autoimmune diseases. Specific examples include, but are not limited to, HIV, hepatitis, adult respiratory distress syndrome, bone resorption diseases, chronic pulmonary inflammatory diseases, dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, meningitis, psoriasis, fibrotic disease, cachexia, graft versus host disease, graft rejection, auto-immune disease, rheumatoid spondylitis, Crohn's disease, ulcerative colitis, inflammatory-bowel disease, multiple sclerosis, systemic lupus erythrematosus, ENL in leprosy, radiation damage, cancer, asthma, or hyperoxic alveolar injury.

[00164] In certain embodiments, a solid dispersion or solid form provided herein, or a composition comprising a solid dispersion or solid form provided herein, is administered orally, parenterally, topically, or mucosally.

[00165] In certain embodiments, a solid dispersion or solid form provided herein, or a composition comprising a solid dispersion or solid form provided herein, is administered at a dosing frequency of once, twice, thrice, or four times daily. In certain embodiments, a solid dispersion or solid form provided herein, or a composition comprising a solid dispersion or solid form provided herein, comprises lenalidomide in an amount of from about 0.1 to about 100 mg, from about 0.5 to about 50 mg, from, about 0.5 to about 25 mg, from about 1 mg to about 10 mg, from about 0.5 to about 5 mg, or from about 1 mg to about 5 mg. In certain embodiments, provided herein is a single unit dosage form suitable for oral administration to a human comprising: an amount equal to or greater than about 1, 2, 3, 4, or 5 mg of the active ingredient of a solid dispersion or solid form comprising lenalidomide as provided herein; and a pharmaceutically acceptable excipient. In one embodiment, the amount of the active ingredient is about 0.5 mg. In another embodiment, the amount of the active ingredient is about 1 mg. In another embodiment, the amount of the active ingredient is about 2 mg. In another embodiment, the amount of the active ingredient is about 4 mg.

[00166] In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice daily, once every other day, once every week, once every two weeks, or once every three weeks, in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. In one embodiment, the second active agent is administered orally and once or twice daily, once every other day, once every week, once every two weeks, or once every three weeks, in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, from about 10 to about 200 mg, from about 10 to about 100 mg, or from about 20 to about 50 mg. In specific embodiments, the second active agent is administered once every week in an amount of about 40 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount(s) of compounds provided herein and any optional additional active agents concurrently administered to the patient.

[00167] As discussed elsewhere herein, also encompassed is a method of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. A solid dispersion or solid form comprising lenalidomide as provided herein and other active ingredients can be administered to a patient prior to, during, or after the occurrence of the adverse effect associated with conventional therapy.

[00168] In one embodiment of the methods provided herein, the subject is a child or young adult. In one embodiment, the subject is 3 to 21 years of age.

COMBINATION THERAPY

[00169] In certain embodiments, methods provided herein comprise administering a solid dispersion or solid form provided herein in combination with one or more second active agents, and/or in combination with radiation therapy, blood transfusions, or surgery.

[00170] In certain embodiments, a solid dispersion or solid form provided herein can be used with or combined with other pharmacologically active compounds ("second active agents") in methods and compositions provided herein. It is believed that certain combinations work synergistically in the treatment of particular types of cancers, and certain diseases and conditions associated with, or characterized by, undesired angiogenesis. A solid dispersion or solid form comprising lenalidomide as described herein can also work to alleviate adverse effects associated with certain second active agents, and some second active agents can be used to alleviate adverse effects associated with lenalidomide.

[00171] One or more second active ingredients or agents can be used in the methods and compositions provided herein together with a solid dispersion or solid form provided herein . Second active agents can be large molecules (e.g., proteins, or monoclonal antibodies (e.g., Rituximab or Elotuzmab)) or small molecules (e.g. , synthetic inorganic, organometallic, or organic molecules).

[00172] Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Typical large molecule active agents are biological molecules, such as naturally occurring or artificially made proteins. Proteins that are particularly useful in the methods and compositions provided herein include proteins that stimulate the survival and/or proliferation of hematopoietic precursor cells and immunologically active poietic cells in vitro or in vivo. Others stimulate the division and differentiation of committed erythroid progenitors in cells in vitro or in vivo. Particular proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), IL-10, IL-12, and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.

[00173] Particular proteins that can be used in the methods and compositions provided herein include, but are not limited to: filgrastim, which is sold in the United States under the trade name Neupogen.RTM. (Amgen, Thousand Oaks, Calif); sargramostim, which is sold in the United States under the trade name Leukine. RTM. (Immunex, Seattle, Wash.); and recombinant EPO, which is sold in the United States under the trade name Epogen.RTM. (Amgen, Thousand Oaks, Calif).

[00174] Recombinant and mutated forms of GM-CSF can be prepared as described in U.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496; all of which are incorporated herein by reference. Recombinant and mutated forms of G-CSF can be prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291;

5,528,823; and 5,580,755; all of which are incorporated herein by reference.

[00175] Large molecule active agents may be administered in the form of anti -cancer vaccines. For example, vaccines that secrete, or cause the secretion of, cytokines such as IL-2, G-CSF, and GM-CSF can be used in the methods, pharmaceutical compositions, and kits provided herein. See, e.g., Emens, L. A., et al, Curr. Opinion Mol. Ther. 3(l):77-84 (2001).

[00176] In one embodiment, the large molecule active agent reduces, eliminates, or prevents an adverse effect associated with the administration of a solid dispersion or solid form provided herein. Depending on the particular active agents provided herein and the disease or disorder being treated, adverse effects can include, but are not limited to, drowsiness and somnolence, dizziness and orthostatic hypotension, neutropenia, infections that result from neutropenia, increased HIV-viral load, bradycardia, Stevens-Johnson Syndrome and toxic epidermal necrolysis, and seizures (e.g. , grand mal convulsions). A specific adverse effect is neutropenia.

[00177] Second active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of a solid dispersion or solid form provided herein. However, like some large molecules, many are believed to be capable of providing a synergistic effect when

administered with (e.g. , before, after or simultaneously) a solid dispersion or solid form provided herein. Examples of small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids. [00178] Examples of anti-cancer agents include, but are not limited to: acivicin; aclarubicin;

acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;

bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide;

cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin;

dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;

hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine

hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;

methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; taxane, paclitaxel; pegaspargase; peliomycin;

pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride;

semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;

teloxantrone hydrochloride; temoporfm; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate;

trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride, and proteasome inhibitors such as bortezomib, carfilzomib, ixazomib, decitibine, and romedepsin. In one embodiment, the anti-cancer agent is taxane, paclitaxel, bortezomib, carfilzomib, ixazomib, decitibine, or romedepsin. [00179] Other anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5- ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1 ; antiandrogen, prostatic carcinoma; antiestrogen;

antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1 ; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives;

balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene;

bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino- triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-po hyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam;

cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine;

docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate;

exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;

fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin;

fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors;

gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin;

ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec.RTM.); imiquimod; immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase;

metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol;

mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim;Erbitux, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract;

myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense.RTM.); O.sup.6- benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;

parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;

picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium;

porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;

pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated;

rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors;

sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist;

suradista; suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfm; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin;

thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin;

tirapazamine; titanocene bichloride; topsentin; toremifene; translation inhibitors; tretinoin;

triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; velaresol; veramine; verdins; verteporfin; vinorelbine;

vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

[00180] Specific second active agents include, but are not limited to, rituximab, oblimersen

(Genasense.RTM.), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron.RTM.), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa.RTM., taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g. , PEG INTRON- A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil.RTM.), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt.RTM.), sulindac, and etoposide.

[00181] Administration of a solid dispersion or solid form provided herein and the second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated. A preferred route of administration for a solid dispersion or solid form provided herein is orally. Preferred routes of administration for the second active agents or ingredients provided herein are known to those of ordinary skill in the art. See, e.g., Physicians' Desk Reference, 1755-1760 (56.sup.th ed., 2002).

[00182] In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1,000 mg, from about 5 to about 500 mg, from about 10 to about 375 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount(s) of the first active agetn provided herein and any optional additional active agents concurrently administered to the patient. In a particular embodiment, the second active agent is rituximab, oblimersen (Genasense.RTM.), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or a combination thereof.

[00183] In a specific embodiment, a solid dispersion or solid form provided herein is administered in combination with rituximab to patients with leukemias. In a specific embodiment, the solid dispersion or solid form is administered in an amount of from about 5 to about 25 mg per day of the active agent to patients with chronic lymphocytic leukemia in combination with rituximab in an amount of 375 mg/m².

[00184] In another embodiment, a solid dispersion or solid form provided herein is administered in combination with fludarabine, carboplatin, and/or topotecan to patients with refractory or relapsed or high-risk acute myelogenous leukemia.

[00185] In another embodiment, a solid dispersion or solid form provided herein is administered in combination with liposomal daunorubicin, topotecan and/or cytarabine to patients with unfavorable karotype acute myeloblasts leukemia.

[00186] In another embodiment, a solid dispersion or solid form provided herein is administered alone or in combination with a second active ingredient such as vinblastine or fludarabine to patients with various types of lymphoma, including, but not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or relapsed or refractory low grade follicular lymphoma.

[00187] In another embodiment, GM-CSF, G-CSF or EPO is administered subcutaneously during about five days in a four or six week cycle in an amount of from about 1 to about 750 mg/m²/day, preferably in an amount of from about 25 to about 500 mg/m²/day, more preferably in an amount of from about 50 to about 250 mg/m²/day, and most preferably in an amount of from about 50 to about 200 mg/m²/day. In a certain embodiment, GM-CSF may be administered in an amount of from about 60 to about 500 mcg/m² intravenously over 2 hours, or from about 5 to about 12 mcg/m²/day subcutaneously. In a specific embodiment, G-CSF may be administered subcutaneously in an amount of about 1 mcg/kg/day initially and can be adjusted depending on rise of total granulocyte counts. The maintenance dose of G-CSF may be administered in an amount of about 300 (in smaller patients) or 480 meg subcutaneously. In a certain embodiment, EPO may be administered subcutaneously in an amount of 10,000 Unit 3 times per week.

[00188] Also provided herein is a method of increasing the dosage of an anti-cancer drug or agent that can be safely and effectively administered to a patient, which comprises administering to a patient (e.g. , a human) a solid dispersion or solid form provided herein, or a pharmaceutically acceptable derivative, salt, solvate, clathrate, hydrate, or prodrug thereof. Patients that can benefit by this method are those likely to suffer from an adverse effect associated with anti-cancer drugs for treating a specific cancer of the blood, skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal, kidney, prostate, breast, colorectal, or combinations thereof. The administration of a solid dispersion or solid form provided herein alleviates or reduces adverse effects which are of such severity that it would otherwise limit the amount of anti-cancer drug.

[00189] In one embodiment, a solid dispersion or solid form provided herein can be administered orally and daily in an amount of from about 0.10 to about 150 mg, and preferably from about 1 to about 50 mg, more preferably from about 5 to about 25 mg of the active agent prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient. In a particular embodiment, a solid dispersion or solid form provided herein in combination with specific agents such as heparin, aspirin, Coumadin, or G-CSF to avoid adverse effects that are associated with anticancer drugs such as but not limited to neutropenia or thrombocytopenia.

[00190] In another embodiment, provided herein is a method of treating, preventing and/or managing cancer, which comprises administering a solid dispersion or solid form provided herein in conjunction with (e.g., before, during, or after) conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer. The combined use of the solid dispersion or solid form provided herein and conventional therapy may provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that solid dispersion or solid form provided herein may provide additive or synergistic effects when given concurrently with conventional therapy.

[00191] In one embodiment, provided herein is a method of reducing, treating and/or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. A solid dispersion or solid form provided herein and other active ingredient can be administered to a patient prior to, during, or after the occurrence of the adverse effect associated with conventional therapy.

[00192] In one embodiment, a solid dispersion or solid form provided herein can be administered in an amount of from about 0.10 to about 150 mg, and preferably from about 1 to about 50 mg, more preferably from about 5 to about 25 mg of the active agent orally and daily alone, or in combination with a second active agent disclosed herein, prior to, during, or after the use of conventional therapy

USE WITH TRANSPLANTATION THERAPY

[00193] Compounds provided herein can be used to reduce the risk of Graft Versus Host Disease (GVHD). In one embodiment, provided herein is a method of treating, preventing and/or managing cancer, which comprises administering the solid dispersion or solid form provided herein in conjunction with transplantation therapy.

[00194] The treatment of cancer is often based on the stages and mechanism of the disease. For example, as inevitable leukemic transformation develops in certain stages of cancer, transplantation of peripheral blood stem cells, hematopoietic stem cell preparation or bone marrow may be necessary. The combined use of the solid dispersion or solid form provided herein and transplantation therapy provides a unique and unexpected synergism. In particular, without being limited by a particular theory, a solid dispersion or solid form comprising lenalidomide provided herein exhibits immunomodulatory activity that may provide additive or synergistic effects when given concurrently with transplantation therapy in patients with cancer.

[00195] A solid dispersion or solid form provided herein can work in combination with

transplantation therapy reducing complications associated with the invasive procedure of transplantation and risk of GVHD. In one embodiment, provided herein is a method of treating, preventing and/or managing cancer which comprises administering to a patient (e.g. , a human) a solid dispersion or solid form provided herein before, during, or after the transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow. Examples of stem cells suitable for use in the methods provided herein are disclosed in U.S. patent publication nos.

2002/0123141, 2003/0235909 and 2003/0032179, the entireties of which are incorporated herein by reference.

[00196] In one embodiment, a solid dispersion or solid form provided herein is administered to patients with leukemia before, during, or after the transplantation of autologous peripheral blood progenitor cell.

[00197] In another embodiment, a solid dispersion or solid form provided herein is administered to patients with relapsed leukemia after the stem cell transplantation.

CYCLING THERAPY

[00198] In certain embodiments, the prophylactic or therapeutic agents provided herein are cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest (i.e. , discontinuation of the administration) for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment. [00199] Consequently, in one embodiment, a solid dispersion or solid form provided herein is administered daily in a single or divided doses in a four to six week cycle with a rest period of about a week or two weeks. Cycling therapy further allows the frequency, number, and length of dosing cycles to be increased. Thus, another embodiment encompasses the administration of a solid dispersion or solid form provided herein for more cycles than are typical when it is administered alone. In yet another embodiment, a solid dispersion or solid form provided herein is administered for a greater number of cycles than would typically cause dose-limiting toxicity in a patient to whom a second active ingredient is not also being administered.

[00200] In one embodiment, a solid dispersion or solid form provided herein is administered daily and continuously for three or four weeks at a dose of the active ingredient of from about 0.1 mg to about 5 mg per day, followed by a rest of one or two weeks. In other embodiments, the dose can be from about 1 mg to about 5 mg per day (e.g., 1, 2, 3, or 4 mg/day), given on Days 1-21 of each 28-day cycle until disease progression , followed by a rest of 7 days on Days 22-28 of each 28-day cycle, for example, in patients with relapsed and refractory multiple myeloma who are refractory to their last myeloma therapy and have received at least 2 prior therapies that included bortezomib.

[00201] In one embodiment, the solid dispersion or solid form provided herein is administered to patients with leukemia in an amount of from about 0.10 to about 150 mg of the active agent per day for 21 days followed by seven days rest in a 28 day cycle. In one embodiment, the solid dispersion or solid form is administered to patients with refractory or relapsed chronic lymphocytic leukemia in an amount of about 25 mg of the active agent per day for 21 days followed by seven days rest in a 28 day cycle.

[00202] In one embodiment, a solid dispersion or solid form provided herein and a second active ingredient are administered orally, with administration of the solid dispersion or solid form provided herein occurring 30 to 60 minutes prior to the second active ingredient, during a cycle of four to six weeks. In another embodiment, the combination of a solid dispersion or solid form provided herein and a second active ingredient is administered by intravenous infusion over about 90 minutes every cycle.

[00203] In a specific embodiment, one cycle comprises the administration of from about 5 to about 25 mg/day of the active agent in the solid dispersion or solid form and from about 50 to about 750 mg/m²/day of a second active ingredient daily for three to four weeks and then one or two weeks of rest. In one embodiment, rituximab can be administered in an amount of 375 mg/m² as an additional active agent to patients with refractory or relapsed chronic lymphocytic leukemia. Typically, the number of cycles during which the combinatorial treatment is administered to a patient will be from about one to about 24 cycles, more typically from about two to about 16 cycles, and even more typically from about four to about three cycles. PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS

[00204] Pharmaceutical compositions can be used in the preparation of single unit dosage forms comprising one or more solid dispersions or solid forms provided herein. In one embodiment, provided herein are pharmaceutical compositions and dosage forms comprising one or more solid dispersions or solid forms comprising a compound provided herein, or a pharmaceutically acceptable salt, solvate (e.g. , hydrate), stereoisomer, co-crystal, clathrate, or prodrug thereof. Pharmaceutical compositions and dosage forms provided herein can further comprise one or more pharmaceutically acceptable excipients or carriers.

[00205] In some embodiments, pharmaceutical compositions and dosage forms provided herein can also comprise one or more additional active ingredients. Examples of optional second, or additional, active ingredients are disclosed herein elsewhere.

[00206] In one embodiment, single unit dosage forms provided herein are suitable for oral, parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules or hard gelatin capsules; cachets; troches; lozenges;

dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g. , aqueous or nonaqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g. , crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient. In one embodiment, the single dosage forms provided herein are tablets, caplets, or capsules comprising one or more solid dispersions or solid forms provided herein. In one embodiment, the single dosage forms provided herein are tablets or capsules comprising one or more solid dispersions or solid forms provided herein.

[00207] The composition, shape, and type of dosage forms will typically vary depending on their use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease. These and other ways in which specific dosage forms are used will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

[00208] In one embodiment, pharmaceutical compositions and dosage forms comprise one or more excipients or carriers. Suitable excipients are known to those skilled in the art of pharmacy, and non- limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, in one embodiment, provided are pharmaceutical compositions and dosage forms that contain little, if any, lactose or other mono- or di-saccharides. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient. Lactose-free compositions provided herein can comprise excipients which are known in the art and are listed in the U.S. Pharmacopeia (USP) 25-NF20 (2002), which is incorporated herein in its entirety.

[00209] Also provided are anhydrous pharmaceutical compositions and dosage forms comprising active ingredient(s), since water may facilitate the degradation of some compounds. Anhydrous pharmaceutical compositions and dosage forms can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, in one embodiment, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[00210] Also provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[00211] Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. In one embodiment, dosage forms comprise the active ingredient in an amount of from about 0.10 to about 50 mg, or from about 0.50 to about 30 mg. In other embodiments, dosage forms comprise an active ingredient provided herein in an amount of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 12.5, 15, 20, or 25 mg. In one embodiment, dosage forms comprise an active ingredient provided herein in an amount of about 1, 2.5, 5, 10, 15, 20, or 25 mg.

[00212] In other embodiments, dosage forms comprise a second active ingredient in an amount from about 1 mg to about 1000 mg, from about 5 mg to about 500 mg, from about 10 mg to about 350 mg, from about 5 mg to about 250 mg, from about 5 mg to about 100 mg, from about 10 mg to about 100 mg, from about 10 mg to about 50 mg, or from about 50 mg to about 200 mg. In one embodiment, the specific amount of the second active agent will depend on the specific agent used, the diseases or disorders being treated or managed, and the amount(s) of a compound provided herein, and any optional additional active agents concurrently administered to the patient.

[00213] In particular embodiments, provided herein is a pharmaceutical composition comprising a solid dispersion or solid form comprising lenalidomide as provided herein and a pharmaceutically acceptable excipient or carrier. In particular embodiments, provided herein is a pharmaceutical composition comprising a cocrystal comprising lenalidomide and a coformer provided herein and a pharmaceutically acceptable excipient or carrier. In particular embodiments, provided herein is a pharmaceutical composition comprising an amorphous solid dispersion comprising lenalidomide provided herein and a pharmaceutically acceptable excipient or carrier. Exemplary embodiments of formulations of lenalidomide are described in, for example, U.S. Patent Nos. 5,635,517, 6,335,349, 6,316,471, 6,476,052, 7,041,680, and 7,709,502; and U.S. Patent Application Publication No. 2011/0045064; the entireties of which are incorporated herein by reference.

Oral Dosage Forms

[00214] Pharmaceutical compositions that are suitable for oral administration can be provided as discrete dosage forms, such as, but not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In one embodiment, such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy known to those skilled in the art. See generally, Remington 's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA ( 1990). As used herein, oral administration also includes buccal, lingual, and sublingual administration.

[00215] In one embodiment, the oral dosage form provided herein is a tablet. In one embodiment, the oral dosage form provided herein is a capsule. In one embodiment, the oral dosage form provided herein is a caplet.

[00216] In one embodiment, oral dosage forms provided herein are prepared by combining the active ingredients in an intimate admixture with one or more pharmaceutically acceptable carrier or excipient, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide, according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g. , powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[00217] In one embodiment, oral dosage forms are tablets or capsules, in which case solid excipients are employed. In specific embodiments, capsules comprising one or more solid dispersions or solid forms comprising lenalidomide as provided herein can be used for oral administration. In one embodiment, the total amount of lenalidomide in the capsule is about 0.5, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 6, about 7, about 8, about 9, about 10, about 12.5, about 15, about 20, or about 25 mg. In one embodiment, the total amount of lenalidomide in the capsule is about 1, about 2.5, about 5, about 10, about 15, about 20, or about 25 mg. Each capsule can contain lenalidomide as the active ingredient and one or more of the following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In specific embodiments, the 5 mg and 25 mg capsule shell can contain gelatin, titanium dioxide and black ink. In specific

embodiments, the 2.5 mg and 10 mg capsule shell can contain gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. In specific embodiments, the 15 mg capsule shell can contain gelatin, FD&C blue #2, titanium dioxide and black ink. In another embodiment, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

[00218] In certain embodiments, the dosage form is a tablet, wherein the tablet is manufactured using standard, art-recognized tablet processing procedures and equipment. In certain embodiments, the method for forming the tablets is direct compression of a powdered, crystalline and/or granular composition comprising a solid dispersion or solid form provided herein, alone or in combination with one or more excipients, such as, for example, carriers, additives, polymers, or the like. In certain embodiments, as an alternative to direct compression, the tablets may be prepared using wet granulation or dry granulation processes. In certain embodiments, the tablets are molded rather than compressed, starting with a moist or otherwise tractable material. In certain embodiments, compression and granulation techniques are used.

[00219] In certain embodiments, the dosage form is a capsule, wherein the capsules may be manufactured using standard, art-recognized capsule processing procedures and equipments. In certain embodiments, soft gelatin capsules may be prepared in which the capsules contain a mixture comprising a solid dispersion or solid form provided herein and vegetable oil or non-aqueous, water miscible materials, such as, for example, polyethylene glycol and the like. In certain embodiments, hard gelatin capsules may be prepared containing granules of solid dispersions or solid forms provided herein in combination with a solid pulverulent carrier, such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. In certain embodiments, a hard gelatin capsule shell may be prepared from a capsule composition comprising gelatin and a small amount of plasticizer such as glycerol. In certain embodiments, as an alternative to gelatin, the capsule shell may be made of a carbohydrate material. In certain embodiments, the capsule composition may additionally include polymers, colorings, flavorings and opacifiers as required. In certain embodiments, the capsule comprises HPMC.

[00220] Examples of excipients or carriers that can be used in oral dosage forms provided herein include, but are not limited to, diluents (bulking agents), lubricants, disintegrants, fillers, stabilizers, surfactants, preservatives, coloring agents, flavoring agents, binding agents (binders), excipient supports, glidants, permeation enhancement excipients, plasticizers and the like, e.g., as known in the art. It will be understood by those in the art that some substances serve more than one purpose in a pharmaceutical composition. For instance, some substances are binders that help hold a tablet together after compression, yet are also disintegrants that help break the tablet apart once it reaches the target delivery site. Selection of excipients and amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works available in the art. [00221] In certain embodiments, dosage forms provided herein comprise one or more binders.

Binders may be used, e.g. , to impart cohesive qualities to a tablet or a capsule, and thus ensure that the formulation remains intact after compression. Suitable binders include, but are not limited to, starch (including potato starch, corn starch, and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone (PVP), cellulosic polymers (including hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose (HEC), carboxymethyl cellulose and the like), veegum, carbomer (e.g., carbopol), sodium, dextrin, guar gum, hydrogenated vegetable oil, magnesium aluminum silicate, maltodextrin, polymethacrylates, povidone (e.g. , KOLLIDON, PLASDONE), microcrystalline cellulose, among others. Binding agents also include, e.g. , acacia, agar, alginic acid, cabomers, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioner's sugar, copovidone, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose,

hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethylacrylates, povidone, sodium alginate, sodium

carboxymethylcellulose, starch, pregelatinized starch, stearic acid, sucrose, and zein. In one embodiment, the binding agent can be, relative to the weight of the dosage form, in an amount of from about 50% to about 99% w/w. In certain embodiments, a suitable amount of a particular binder is determined by one of ordinary skill in the art.

[00222] Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, Marcus Hook, PA), and mixtures thereof. In one embodiment, a specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM.

[00223] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre -gelatinized starch, and mixtures thereof. The binder or filler in a pharmaceutical composition is, in one embodiment, present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[00224] In certain embodiments, dosage forms provided herein comprise one or more diluents.

Diluents may be used, e.g., to increase bulk so that a practical size tablet or capsule is ultimately provided. Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. , EUDRAGIT), potassium chloride, sodium chloride, sorbitol and talc, among others. Diluents also include, e.g. , ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl

palmitostearate, isomalt, kaolin, lacitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, microcrystalline cellulose, microcrystalline silicified cellulose, powered cellulose, polydextrose, polymethylacrylates, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, sulfobutylether- -cyclodextrin, talc, tragacanth, trehalose, and xylitol. Diluents may be used in amounts calculated to obtain a desired volume for a tablet or capsule. The amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.

[00225] Disintegrants may be used in the compositions to provide tablets or capsules that disintegrate when exposed to an aqueous environment. Dosage forms that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredient(s) may be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. In one embodiment, pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, or from about 1 to about 5 weight percent of disintegrant.

[00226] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. [00227] Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g. , peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

[00228] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium

carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[00229] In one embodiment, a solid oral dosage form comprises a compound provided herein, and one or more excipients selector from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin. In one embodiment, capsules comprise one or more solid dispersion or solid forms comprising lenalidomide as provided herein, and one or more of the following inactive ingredients: mannitol, pregelatinized starch, sodium stearyl fumarate, gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink, black ink, FD&C red 3, and a combination thereof.

[00230] The pharmaceutical compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film -coated tablets. Enteric -coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to,

hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.

[00231] The tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants.

Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

[00232] The pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of

microorganisms. Suitable preservatives are those as described herein, including methyl- and propylparabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.

[00233] The pharmaceutical compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g. , acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. , water, to be measured conveniently for administration.

[00234] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[00235] The pharmaceutical compositions provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.

[00236] The pharmaceutical compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide. [00237] Coloring and flavoring agents can be used in all of the above dosage forms.

[00238] The pharmaceutical compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.

EXAMPLES

[00239] Certain embodiments provided herein are illustrated by the following non-limiting examples. Characterization Methods

High-throughput X-ray powder diffraction

[00240] XRPD patterns were obtained using the Crystallics T2 high-throughput XRPD set-up. The plates were mounted on a Bruker GADDS diffractometer equipped with a Hi-Star area detector. The XRPD platform was calibrated using Silver Behenate for the long d-spacings and Corundum for the short d-spacings.

[00241] Data collection was carried out at room temperature using monochromatic CuKa radiation in the 2Θ region between 1.5° and 41.5°, which is the most distinctive part of the XRPD pattern. The diffraction pattern of each well was collected in two 2Θ ranges ( 1.5° < 2Θ < 21.5° for the first frame, and 19.5° < 2Θ < 41.5° for the second) with an exposure time of 90s for each frame. No background subtraction or curve smoothing was applied to the XRPD patterns.

[00242] The carrier material used during XRPD analysis was transparent to X-rays and contributed only slightly to the background.

DSC

[00243] Melting properties were obtained from DSC thermograms, recorded with a heat flux DSC822e instrument (Mettler-Toledo GmbH, Switzerland). The DSC822e was calibrated for temperature and enthalpy with a small piece of indium (m.p. = 156.6°C; 5Hf = 28.45 J/g). Samples (approximately 2 mg) were sealed in standard 40 μΐ aluminum pans, pin-holed and heated in the DSC from 25°C to 350 °C, at a heating rate of 10 °C/min, unless described differently in the experiment. Dry N2 gas, at a flow rate of 50 ml/min was used to purge the DSC equipment during measurement.

TGMS

[00244] Mass loss due to solvent or water loss from the crystals was determined by TGA/SDTA. Monitoring the sample weight, during heating in a TGA/SDTA851e instrument (Mettler-Toledo GmbH, Switzerland), resulted in a weight vs. temperature curve. The TGA/SDTA85 le was calibrated for temperature with indium and aluminum. Samples were weighed into 100 μΐ aluminum crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25 to 300°C at a heating rate of 10°C min-1. Dry N2 gas was used for purging.

Dynamic Vapor Sorption

[00245] Moisture sorption isotherms were collected on a DVS-1 system from Surface

Measurement Systems (London, UK). Typical sample size was between 7 to 1 1 mg of solid material. The relative humidity was cycled between 45% to 95% (sorption) to 0% (desorption) and back to 45% (sorption) in steps of 10% at a constant temperature of 25 °C. Weight equilibration per step was set with a holding time of 60 minutes. After the profile was finished, the sample was measured by HT-XRPD to verify if crystallization had occurred.

Example 1 Lenalidomide Starting Material Characterization

[00246] Lenalidomide were provided as a white powder for the solid dispersion and co-crystal screen studies. For reference purposes XRPD, DSC, TGMS and HPLC were used to characterize the compound. The XRPD analysis (FIG. 1) showed the lenalidomide starting material is crystalline, and the crystalline form is designated "Form 1" of lenalidomide. The HPLC analysis showed a single peak indicating the compound is 100% pure (area %). The TGMS analysis showed a gradual mass loss of 3.6% prior to melting, likely due to the loss of residual solvent. Two endothermic events were observed at 166.3 °C and 171.7 °C, followed by melting at 269.2 °C It is likely that the first two endotherms are attributed to the solvent loss.

[00247] A quantitative solubility determination at room temperature was performed. Suspensions of lenalidomide were prepared in various solvents and were equilibrated at room temperature for 24 hours. The concentration of lenalidomide in the liquid phase was determined by HPLC-DAD analysis. The results are summarized in the table below. The remaining solids were collected by centrifugation, dried overnight under ambient conditions and analyzed by HT-XRPD. After exposure to accelerated aging conditions (AAC, 40 °C/75% RH) for 2 days, the solids were re-analyzed by HT-XRPD.

[00248] Among the neat solvents tested, lenalidomide appeared to be more soluble in 1,4-dioxane, tetrahydrofuran, and methanol. The XRPD analysis of the solids showed conversion to other solid forms, namely Form 2, Form 3, and Form 4. In chloroform the starting material Form 1 remained the same. Upon exposure for 2 days at 40 °C and 75% RH, all solid forms were physically stable except for Form 4 which converted to Form 1. [00249] Based on the limited solubility determined in most of neat organic solvents, the solubility of lenalidomide was qualitatively determined in several solvent mixtures. For that small aliquots of solvent were added to lenalidomide until dissolution was visually assessed. The results are also reported in the table below. In most of the solvent mixtures, lenalidomide was more soluble than in neat solvents.

[00250] Prior to the co-crystal and amorphous solid dispersion screen, the chemical stability of lenalidomide at elevated temperature was investigated. The API was dissolved in acetonitrile and heated at 60 °C for 1 hour. Subsequently, the chemical purity of the sample was assessed to 100% by HPLC analysis. Therefore, maximum temperature used for the co-crystal formation experiments was set at 60

Example 2 Amorphous Solid Dispersion Screening by Freeze Drying

[00251] In total 135 amorphous solid dispersion screening experiment was performed by freeze drying with 15 polymer excipients at 3 API loadings (about 5%, 10%, and 20% (w%)). Three solvents were used: 1,4-dioxane, tetrahydrofuran/water (90/10, v/v) and acetone/water (95/5 v/v).

[00252] Approximately 5 mg of lenalidomide was weighed into 1.4 ml HPLC vials together with the excipient, followed by the addition of 800-1300 μΐ of solvent to reach a concentration of approximately 5- 7 mg/mL (corresponding to the solubility of lenalidomide in the solvent mixtures). The samples were freeze dried and left under full vacuum at ambient temperature for 24 hours. The resulting materials were analyzed by HT-XRPD. The materials were then subjected to 40 °C and 75% RH for two weeks and reanalyzed by HT-XRPD. The results of the screen are shown in the table below.

1, 2, 3, 4: traces of the crystalline lenalidomide Forms 1, 2, 3 or 4was observed.

Am: the sample appeared to be amorphous lenalidomide by HT-XRPD.

Am powder: the sample looked powdery.

Am glassy: the sample looked like glass or film.

Oily: the sample was sticky.

L.C: Low crystalline

Shade: amorphous samples remained amorphous after the accelerated stress conditions for two weeks. Crystalline polymers such as polyethylene glycol 6000, pluronic F-68, sureteric and hydroxyethyl cellulose are designated with their abbreviations.

* = deliquescent

[00253] Among the three solvent systems investigated (1,4-dioxane, THF/water (90/10), and acetone/water (95/5)), more stable amorphous dispersions were identified with 1,4-dioxane.

[00254] With several cellulose derivatives such as ethyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl methylcellulose phthalate 50 (HPMC-P), hydroxypropylmethyl cellulose AS LG (HPMC AS LG), stable amorphous materials were obtained from the three solvents.

[00255] Amorphous materials were also obtained with Eudragit RS 100 and Eudragit S 100. For these polymers, more amorphous dispersions were obtained from 1,4-dioxane with all three drug loadings (5, 10 and 20%) than the other two solvent mixtures.

[00256] For the experiments performed with polyethylene glycol methyl, polyethylene glycol 6000, polyvinylpyrrolidone K30, polyvinylpyrrolidone-co-vinyl acetate, sureteric and pluronic P68, the samples were mostly oily, mixtures of API and crystalline polymer, or amorphous (powders or glassy) that became deliquescent after the stability study.

[00257] Dispersions from acetone/water (95/5) led in most of the cases to glassy materials and a maximum drug load of 10%. The 20% drug load showed the formation of the crystalline API (Form 4) in several experiments. The residual solvent of the samples selected for further analysis was approximately 3 - 4%, while the same dispersions from THF/water (90/10) or 1,4-dioxane showed slightly higher solvent content. From the DSC traces it seems after the solvent loss crystallization of the API is not occurring; therefore, it might be possible to reduce the solvent content by additional drying.

[00258] The samples from 1,4-dioxane that had high residual solvent levels were further dried under vacuum at 40 °C for 24 hours. Upon drying the samples remained amorphous and the solvent content was reduced to half of the initial content.

[00259] No glass transition was observed in the DSC thermograms. The chemical stability of the samples was confirmed by HPLC analyses and was 100% (area%) for most of the samples.

[00260] Selected stable amorphous dispersions identified in the screening experiments were further analyzed. Solids were analyzed for their physical stability under accelerated aging conditions (40 °C/70% RH) for 2 weeks. After the exposure, the physical form was determined again by HT-XRPD analysis. The physico-chemical characterization of the forms was done by TGMS, DSC and HPLC analysis to determine the solvation state of the form, thermal events and chemical purity respectively. The results are summarized in the table below.

20% drug load 25-100 (broad) 4.6% of THF 100 Am Am Hydroxypropylmethyl and water

cellulose phthalate 50

THF/water (90/10)

Am: the sample appeared to be amorphous lenalic omide by HT-X PD.

Example 3 Scale-up, Solubility and Stability Studies of Amorphous Solid Dispersions

[00261] Four amorphous lenalidomide solid dispersions are scaled-up to obtain approximately 3 g of material with the conditions described in the table below. The samples are further analyzed by HR-XRPD, (m)DSC, TGMS, HPLC and FTIR.

[00262] Chemical and physical stability are tested at 25 °C/65% RH and 40 °C/75% RH. The samples are analyzed by HT-XRPD after 1 week, 2 weeks, 1 month, 2 months and 3 months. If crystallization is observed in the XRPD patterns the experiment is stopped. The samples that remain amorphous after 3 months are further analyzed by HR-XRPD, (m)DSC, TGMS and HPLC.

[00263] Solubility determination of lenalidomide released from the dispersions is performed in water, Simulated Gastric Fluid USP, Simulated Intestinal Fluid USP (with enzymes), HPMC E5 (2 wt%) in water and glycerin (5 wt%) in water. The quantitative solubility of the candidates is determined after 2, 3, 4 and 24 hours at 25 °C and 37 °C. The crystalline compound is taken as control as well as a physical mixture of lenalidomide and the polymer. Suspensions are prepared and the concentration of the compound in solution is determined by HPLC-DAD analysis. All solubility determinations are done in triplicate. Visual observations and pH are recorded.

[00264] Solubility determination of lenalidomide from dispersions in buffers with pH 4, 5, 6 and 7 at 25 °C. The concentration of API in solution is determined by HPLC-DAD analysis after 2, 4, 8 and 24 hours. Visual observations and pH are recorded.

[00265] Gastric precipitation tests (equivalent to the dose of lenalidomide2) with the successful dispersions. Four precipitation tests are performed with each dispersion. A solution (depending on the solubility results in buffers) containing lenalidomide (amount based on the API dose) is added to the following conditions: 150 mL 0.1 N HCl at 25 °C; 150 mL 0.1 N HCl at 37 °C; 250 mL 0.1 N HC1 at 25 °C; and 250 mL 0.1 N HC1 at 37 °C. The pH and

concentration of API in solution are determined after 1, 2, 3 and 4 hours.

[00266] The solubility of selected lenalidomide amorphous dispersions is determined in 4 organic solvents: ethanol, acetonitrile, acetone/water 95/5 and tetrahydrofuran at 25 °C after 24 hours equilibration. The solubility determinations are done in triplicate.

Example 4 Preparation of Cocrystal Comprising Lenalidomide and a Coformer

[00267] The co-crystal screen on lenalidomide was carried out with 10 chemically divers co-formers. The screen included three different co-crystallization methods, each in six solvent systems.

[00268] Method A (cooling -evaporative co-crystallization): 120 cooling evaporative experiments were performed in 1.8 ml HPLC vials, with 10 co-formers, two API:CF ratios and 6 different solvents (see table below). In addition, 6 control experiments containing only the API and solvent were performed. Approximately 20 mg of API was solid dosed in the vial, followed by the co-former and addition of solvent and magnetic stirring bean. Subsequently, the experiments were subjected to a temperature profile in the Crystal 16™. This temperature profile consisted on heating the mixture to 60 °C for one hour and slowly cooled to 5 °C and aging for 48 hours. After completion of the temperature profile the solids were separated from the liquids by centrifugation. Both the solids and liquids were dried over night at room temperature under 0 mbar. The obtained clear solutions were also over night evaporated at room temperature under 0 mbar. All solids were analyzed by XRPD and subsequently exposed in the measuring plate to accelerated ageing conditions (40 °C/75% RH) for 48 hours before being re-analyzed by XRPD.

[00269] Method B (co-crystallization from saturated solutions): The experiments were performed by using 10 co-formers and 6 solvents (see table below). Slurries of the API were prepared by weighing about 20 mg of lenalidomide. Subsequently, between 2-7 mL of solvent was added to each experiment to have a close to saturated solution, depending on the solubility of lenalidomide in the solvent or solvent mixture selected. The slurries were left stirring over night (16 hours) at room temperature. After this time, the slurries were filtered so a saturated solution was obtained. The solid co-formers were added to the saturated solutions until precipitation was observed. Subsequently, the solids were separated from the liquids and analyzed by XRPD after drying. The mother liquors after separation of solids were also evaporated. When no solids precipitated, the vials were placed under vacuum until dryness and the dry solids were analyzed by XRPD. Subsequently, the solids were placed in a climate chamber at 40 °C and 75% RH for 2 days after which they were re-analyzed by XRPD.

[00270] Method C (wet grinding co-crystallization): About 20 mg of the API was weighed into a stainless steel grinding vial together with a slight molar excess of co-former (API:CF 1 : 1.1), 10 of solvent and two steel balls. Vials were mounted in a Retsch MM301 ball mill and the API was grinded at 30Hz. After one hour, the solids were collected and analyzed by XRPD. Six control experiments were performed with only the API and the solvent. Subsequently, the solids were exposed in the measuring plate to accelerated ageing conditions (40 °C/75% RH) for 48 hours and re-analyzed by XRPD.

[00271] The 10 co-formers selected for this study were saccharin, nicotinamide, 4-hydroxybenzamide, salicylic acid, succinic acid, L(-)-malic acid, L(+)-arginine, fumaric acid, lactamide, and urea.

[00272] The solvents used for each methods are listed in the following Table.

[00273] Analysis of the XRPD diffractograms showed that in almost all cooling-evaporative co- crystallization experiments physical mixtures between lenalidomide and the co-former were present.

[00274] Analysis of the XRPD diffractograms showed that in almost all saturated solutions co- crystallization experiments physical mixtures of lenalidomide and the co-formers were obtained. In one experiment with 4-hydroxybenzamide in 1,4-dioxane/water (90/10) a new XRPD pattern different from the API and the co-former was identified.

[00275] All diffractograms from the co-grinding experiments showed that physical mixtures of lenalidomide and the co-former were obtained from the experiments.

4-hydroxybenzamide

[00276] Form HBA1 is a potential co-crystal formed by lenalidomide and 4-hydroxybenzamide. This co-crystal was obtained from saturated API solutions using 1,4-dioxane/water (90/10, v/v). The stability study on this form indicated that dissociation into neat API and co-former after 2 days at 40 °C and 75% RH had occurred (FIG. 2). [00277] The thermal analysis of HBA1 showed one broad endothermic event between 100-170 °C. This endotherm was attributed to the solvent loss observed in the TGMS (FIG. 3). A mass loss of 18.0% between 40 to 220 °C corresponding to 1,4-dioxane was observed prior to the thermal decomposition (FIG. 4). 18% of 1,4-dioxane corresponds to 0.7 molecule of 1,4-dioxane per molecule of API. The HPLC analysis showed the presence of 4-hydroxybenzamide and lenalidomide and confirmed a chemical purity of 100% (area%).

Example 5 Assays

TNFa Inhibition Assay in PBMC

[00278] Peripheral blood mononuclear cells (PBMC) from normal donors are obtained by Ficoll Hypaque (Pharmacia, Piscataway, NJ, USA) density centrifugation. Cells are cultured in RPMI 1640 (Life Technologies, Grand Island, NY, USA) supplemented with 10% AB+human serum (Gemini Bio- products, Woodland, CA, USA), 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin (Life Technologies).

[00279] PBMC (2 x 10⁵ cells) are plated in 96-well flat-bottom Costar tissue culture plates (Corning, NY, USA) in triplicate. Cells are stimulated with LPS (from Salmonella abortus equi, Sigma cat. no. L- 1887, St. Louis, MO, USA) at 1 ng/mL final in the absence or presence of compounds. Compounds provided herein are dissolved in DMSO (Sigma) and further dilutions are done in culture medium immediately before use. The final DMSO concentration in all assays can be about 0.25%. Compounds are added to cells 1 hour before LPS stimulation. Cells are then incubated for 18-20 hours at 37 °C in 5 % CO₂, and supematants are then collected, diluted with culture medium and assayed for TNFa levels by ELISA (Endogen, Boston, MA, USA). IC50S are calculated using non-linear regression, sigmoidal dose- response, constraining the top to 100% and bottom to 0%, allowing variable slope (GraphPad Prism v3.02).

IL-2 and MIP-3a Production by T Cells

[00280] PBMC are depleted of adherent monocytes by placing 1 x 10⁸ PBMC in 10 ml complete medium (RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/ml streptomycin) per 10 cm tissue culture dish, in 37°C, 5 % CO₂ incubator for 30-60 minutes. The dish is rinsed with medium to remove all non-adherent PBMC. T cells are purified by negative selection using the following antibody (Pharmingen) and Dynabead (Dynal) mixture for every 1 x 10⁸ non-adherent PBMC: 0.3 ml Sheep anti-mouse IgG beads, 15 μΐ anti-CD16, 15 μΐ anti-CD33, 15 μΐ anti-CD56, 0.23 ml anti-CD19 beads, 0.23 ml anti-HLA class II beads, and 56 μΐ anti-CD 14 beads. The cells and bead/antibody mixture is rotated end-over-end for 30-60 minutes at 4°C. Purified T cells are removed from beads using a Dynal magnet. Typical yield is about 50% T cells, 87- 95% CD3⁺ by flow cytometry.

[00281] Tissue culture 96-well flat-bottom plates are coated with anti-CD3 antibody OKT3 at 5 μg/ml in PBS, 100 μΐ per well, incubated at 37°C for 3-6 hours, then washed four times with complete medium 100 μΐ/well just before T cells are added. Compounds are diluted to 20 times of final in a round bottom tissue culture 96-well plate. Final concentrations are about 10 μΜ to about 0.00064 μΜ. A 10 mM stock of compounds provided herein is diluted 1 :50 in complete for the first 20x dilution of 200 μΜ in 2 % DMSO and serially diluted 1 :5 into 2 % DMSO. Compound is added at 10 μΐ per 200 μΐ culture, to give a final DMSO concentration of 0.1 %. Cultures are incubated at 37°C, 5 % CO₂ for 2-3 days, and supernatants analyzed for IL-2 and MIP-3ot by ELISA (R&D Systems). IL-2 and MIP-3ot levels are normalized to the amount produced in the presence of an amount of a compound provided herein, and EC50S calculated using non-linear regression, sigmoidal dose-response, constraining the top to 100 % and bottom to 0 %, allowing variable slope (GraphPad Prism v3.02).

Cell Proliferation Assay

[00282] Cell lines Namalwa, MUTZ-5, and UT-7 are obtained from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (Braunschweig, Germany). The cell line KG-1 is obtained from the American Type Culture Collection (Manassas, VA, USA). Cell proliferation as indicated by³H- thymidine incorporation is measured in all cell lines as follows.

[00283] Cells are plated in 96-well plates at 6000 cells per well in media. The cells are pre-treated with compounds at about 100, 10, 1, 0.1, 0.01, 0.001, 0.0001 and 0 μΜ in a final concentration of about 0.25 % DMSO in triplicate at 37°C in a humidified incubator at 5 % CO₂ for 72 hours. One microcurie of³H-thymidine (Amersham) is then added to each well, and cells are incubated again at 37°C in a humidified incubator at 5 % CO₂ for 6 hours. The cells are harvested onto UniFilter GF/C filter plates (Perkin Elmer) using a cell harvester (Tomtec), and the plates are allowed to dry overnight. Microscint 20 (Packard) (25 μΐ/well) is added, and plates are analyzed in TopCount NXT (Packard). Each well is counted for one minute. Percent inhibition of cell proliferation is calculated by averaging all triplicates and normalizing to the DMSO control (0 % inhibition). Each compound is tested in each cell line in three separate experiments. Final IC₅₀s are calculated using non-linear regression, sigmoidal dose-response, constraining the top to 100 % and bottom to 0 %, allowing variable slope. (GraphPad Prism v3.02). Immunoprecipitation and Immunoblot

[00284] Namalwa cells are treated with DMSO or an amount of a compound provided herein for 1 hour, then stimulated with 10 U/ml of Epo (R&D Systems) for 30 minutes. Cell lysates are prepared and either immunoprecipitated with Epo receptor Ab or separated immediately by SDS-PAGE. Immunoblots are probed with Akt, phospo-Akt (Ser473 or Thr308), phospho-Gabl (Y 627), Gabl, IRS2, actin and IRF- 1 Abs and analyzed on a Storm 860 Imager using ImageQuant software (Molecular Dynamics).

Cell Cycle Analysis

[00285] Cells are treated with DMSO or an amount of a compound provided herein overnight.

Propidium iodide staining for cell cycle is performed using CycleTEST PLUS (Becton Dickinson) according to manufacturer's protocol. Following staining, cells are analyzed by a FACSCalibur flow cytometer using ModFit LT software (Becton Dickinson).

Apoptosis Analysis

[00286] Cells are treated with DMSO or an amount of a compound provided herein at various time points, then washed with annexin-V wash buffer (BD Biosciences). Cells are incubated with annexin-V binding protein and propidium iodide (BD Biosciences) for 10 minutes. Samples are analyzed using flow cytometry.

Lucif erase Assay

[00287] Namalwa cells are transfected with 4 μg of APl-luciferase (Stratagene) per 1 x 10⁶ cells and 3 μΐ Lipofectamine 2000 (Invitrogen) reagent according to manufacturer's instructions. Six hours post- transfection, cells are treated with DMSO or an amount of a compound provided herein. Luciferase activity is assayed using luciferase lysis buffer and substrate (Promega) and measured using a luminometer (Turner Designs).

[00288] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the disclosure and are encompassed by the appended claims. [00289] All of the patents, patent applications and publications referred to herein are incorporated herein in their entireties. Citation or identification of any reference in this application is not an admission that such reference is available as prior art. The full scope of the disclosure is better understood with reference to the appended claims.

Claims

CLAIMS What is claimed is:

1. A solid dispersion comprising a compound of Formula (I):

(I),

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof, wherein the compound of Formula (I) is dispersed in a solid matrix that comprises at least one polymer.

2. The solid dispersion of claim 1, wherein the polymer is a hydrophilic polymer.

3. The solid dispersion of claim 1, wherein the polymer is selected from the group consisting of cellulose esters and cellulose ethers, polyalkylene oxides, polyacrylates and polymethacrylates, homopolymers and copolymers of N-vinyl lactams, polyacrylamides, vinyl acetate polymers, graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, oligo- and

polysaccharides, and mixtures of two or more thereof.

4. The solid dispersion of claim 3, wherein the polymer is a cellulose ester or cellulose ether.

5. The solid dispersion of claim 3, wherein the polymer is a polyalkylene oxide.

6. The solid dispersion of claim 3, wherein the polymer is a polyacrylate or polymethacrylate.

7. The solid dispersion of claim 1, wherein the polymer is methyl cellulose, ethyl cellulose, Eudragit RS 100, hydroxyethyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose, Eudragit S 100, hydroxypropyl methylcellulose phthalate 50 (HPMC-P), hydroxypropyl methylcellulose AS-LG (HPMC AS LG), polyethylene glycol) methyl, polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone K30, poly(l-vinylpyrrolidone-co-vinyl acetate) (PVP-VA), sureteric, or pluronic F- 68.

8. The solid dispersion of claim 7, wherein the polymer is methyl cellulose, ethyl cellulose, Eudragit RS 100, Eudragit S 100, hydroxyethyl cellulose, HPMC, or HPMC-P.

9. The solid dispersion of claim 8, wherein the polymer is methyl cellulose.

10. The solid dispersion of claim 8, wherein the polymer is ethyl cellulose.

1 1. The solid dispersion of claim 8, wherein the polymer is hydroxyethyl cellulose.

12. The solid dispersion of claim 8, wherein the polymer is HPMC-P.

13. The solid dispersion of any one of claims 1 to 12, wherein the compound of Formula (I) is present in an amount of from about 1% to about 50% by weight of the solid dispersion.

14. The solid dispersion of claim 13, wherein the compound of Formula (I) is present in an amount of from about 2.5% to about 25% by weight of the solid dispersion.

15. The solid dispersion of claim 14, wherein the compound of Formula (I) is present in an amount of from about 5% to about 10% by weight of the solid dispersion.

16. The solid dispersion of claim 14, wherein the compound of Formula (I) is present in an amount of about 5% by weight of the solid dispersion.

17. The solid dispersion of claim 14, wherein the compound of Formula (I) is present in an amount of about 10% by weight of the solid dispersion.

18. The solid dispersion of claim 14, wherein the compound of Formula (I) is present in an amount of about 20% by weight of the solid dispersion.

19. The solid dispersion of any one of claims 1 to 18, wherein the compound of Formula (I) is substantially non-crystalline.

20. The solid dispersion of any one of claims 1 to 18, wherein no more than 5% of the compound of Formula (I) is crystalline.

21. The solid dispersion of claim 20, wherein no more than 2% of the compound of Formula (I) is crystalline.

22. The solid dispersion of claim 21, wherein no more than 1% of the compound of Formula (I) is crystalline.

23. The solid dispersion of any one of claims 20 to 22, wherein the crystalline form of the compound of Formula (I) is Form 1 of the compound of Formula (I).

24. The solid dispersion of any one of claims 1 to 18, wherein the compound of Formula (I) is amorphous.

25. The solid dispersion of claim 1, comprising about 5% by weight of the solid dispersion of an amorphous compound of Formula (I), dispersed in a solid matrix that comprises methyl cellulose.

26. The solid dispersion of claim 1, comprising about 20% by weight of the solid dispersion of an amorphous compound of Formula (I), dispersed in a solid matrix that comprises ethyl cellulose.

27. The solid dispersion of claim 1, comprising about 10% by weight of the solid dispersion of an amorphous compound of Formula (I), dispersed in a solid matrix that comprises hydroxyethyl cellulose.

28. The solid dispersion of claim 1, comprising about 20% by weight of the solid dispersion of an amorphous compound of Formula (I), dispersed in a solid matrix that comprises HPMC-P.

29. A pharmaceutical composition comprising the solid dispersion of any one of claims 1 to 28, and a pharmaceutically acceptable excipient.

30. A method of treating a disease or disorder, comprising administering to a subject having the disease or disorder a therapeutically effective amount of the solid dispersion of any one of claims 1 to 28, or the pharmaceutical composition of claim 29.

31. The method of claim 30, wherein the disease or disorder is cancer.

32. The method of claim 31, wherein the cancer is a pediatric CNS cancer.

33. The method of claim 31, wherein the cancer is glioma.

34. The method of any one of claims 30 to 33, wherein the disease or disorder is relapsed or refractory.

35. The method of any one of claims 30 to 34, further comprising administering a second active agent.

36. The method of any one of claims 30 to 35, wherein the subject is a child or young adult.

37. A process for preparing a solid dispersion of any one of claims 1-28, comprising (a) providing a solution of the compound of Formula (I) and the polymer in a solvent system; and (b) removing the solvent to provide the solid dispersion.

38. The process of claim 37, wherein the solvent system is 1,4-dioxane, tetrahydrofuran, acetone, water, or a mixture thereof.

39. The process of claim 38, wherein the solvent system is 1,4-dioxane, a mixture of tetrahydrofuran and water, or a mixture of acetone and water.

40. The process of any one of claims 37 to 39, wherein the solvent is removed by freeze evaporation.

41. A solid form comprising a compound of Formula (I) : ,

(I),

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, prodrug, or clathrate thereof; and a coformer, wherein the coformer is 4-hydroxybenzamide.

42. The solid form of claim 41, having an X-ray powder diffraction pattern comprising peaks at approximately 17.7, 20.0, and 26.0 degrees 2Θ, plus or minus 0.2 degrees 2Θ.

43. The solid form of claim 42, having an X-ray powder diffraction pattern further comprising peaks at approximately 17.1 and 22.9 degrees 2Θ, plus or minus 0.2 degrees 2Θ.

44. The solid form of claim 42, having an X-ray powder diffraction pattern which matches the XRPD pattern presented in FIG. 2.

45. The solid form of any one of claims 41 to 44, wherein the molar ratio of the compound of Formula (I) to the coformer is about 1 : 1.

46. The solid form of any one of claims 41 to 45, which is substantially crystalline.

47. The solid form of claim 46, which is substantially a cocrystal.

48. The solid form of claim 46, which is greater than 80%, greater than 90%, greater than 95%, greater than 97%, or greater than 99% a cocrystal.

49. The solid form of any one of claims 41 to 48, which is substantially pure.

50. The solid form of any one of claims 41 to 48, further comprising a second solid form of the compound of Formula (I).

51. The solid form of claim 50, wherein the second solid form of the compound of Formula (I) is Form 1 of the compound of Formula (I).

52. The solid form of claim 50, wherein the second solid form of the compound of Formula (I) is an amorphous form of the compound of Formula (I).

53. The solid form of any one of claims 41 to 48, further comprising a second solid form of the coformer.

54. A pharmaceutical composition comprising the solid form of any one of claims 41 to 53, and a pharmaceutically acceptable excipient.

55. A method of treating a disease or disorder, comprising administering to a subject having the disease or disorder a therapeutically effective amount of the solid form of any one of claims 41 to 53 or the pharmaceutical composition of claim 54.

56. The method of claim 55, wherein the disease or disorder is cancer.

57. The method of claim 55, wherein the cancer is a pediatric CNS cancer.

58. The method of claim 55, wherein the cancer is glioma.

59. The method of any one of claims 55 to 58, wherein the disease or disorder is relapsed or refractory.

60. The method of any one of claims 55 to 58, further comprising administering a second active agent.

61. The method of any one of claims 55 to 58, wherein the subject is a child or young adult.

62. The solid dispersion of any one of claims 1 to 28, or the pharmaceutical composition of claim 29 as a medicament.

63. The solid dispersion of any one of claims 1 to 28, or the pharmaceutical composition of claim 29 for use in a method of treating a disease or disorder.

64. The solid dispersion or the pharmaceutical composition for use of claim 63, wherein the disease or disorder is cancer.

65. The solid dispersion or the pharmaceutical composition for use of claim 64, wherein the cancer is a pediatric CNS cancer or a glioma.

66. The solid dispersion or the pharmaceutical composition for use of any one of claims 63 to 65, wherein the disease or disorder is relapsed or refractory.

67. The solid dispersion or the pharmaceutical composition for use of any one of claims 63 to 66, wherein the method further comprises administering a second active agent.

68. The solid dispersion or the pharmaceutical composition for use of any one of claims 63 to 67, wherein the subject is a child or young adult.

69. The solid form of any one of claims 41 to 53 or the pharmaceutical composition of claim 54 as a medicament.

70. The solid form of any one of claims 41 to 53 or the pharmaceutical composition of claim 54 for use in a method of treating a disease or disorder.

71. The solid form or the pharmaceutical composition for use of claim 70, wherein the disease or disorder is cancer.

72. The solid form or the pharmaceutical composition for use of claim 71, wherein the cancer is a pediatric CNS cancer or a glioma.

73. The solid form or the pharmaceutical composition for use of any one of claims 70 to 72, wherein the disease or disorder is relapsed or refractory.

74. The solid form or the pharmaceutical composition for use of any one of claims 70 to 73, wherein the method further comprises administering a second active agent.

75. The solid form or the pharmaceutical composition for use of any one of claims 70 to 74, wherein the subject is a child or young adult.