US 20170209462A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0209462 A1 Bilotti et al. (43) Pub. Date: Jul. 27, 2017

(54) BTK INHIBITOR COMBINATIONS FOR Publication Classification TREATING MULTIPLE MYELOMA (51) Int. Cl. (71) Applicant: Pharmacyclics LLC, Sunnyvale, CA A 6LX 3/573 (2006.01) A69/20 (2006.01) (US) A6IR 9/00 (2006.01) (72) Inventors: Elizabeth Bilotti, Sunnyvale, CA (US); A69/48 (2006.01) Thorsten Graef, Los Altos Hills, CA A 6LX 3/59 (2006.01) (US) A63L/454 (2006.01) (52) U.S. Cl. CPC ...... A61 K3I/573 (2013.01); A61K 3 1/519 (21) Appl. No.: 15/252,385 (2013.01); A61 K3I/454 (2013.01); A61 K 9/0053 (2013.01); A61K 9/48 (2013.01); A61 K (22) Filed: Aug. 31, 2016 9/20 (2013.01) (57) ABSTRACT Disclosed herein are pharmaceutical combinations, dosing Related U.S. Application Data regimen, and methods of administering a combination of a (60) Provisional application No. 62/212.518, filed on Aug. BTK inhibitor (e.g., ibrutinib), an immunomodulatory agent, 31, 2015. and a steroid for the treatment of a hematologic malignancy. US 2017/0209462 A1 Jul. 27, 2017

BTK INHIBITOR COMBINATIONS FOR Subject in need thereof comprising administering pomalido TREATING MULTIPLE MYELOMA mide, ibrutinib, and dexamethasone, wherein pomalido mide, ibrutinib, and dexamethasone are administered con CROSS-REFERENCE TO RELATED currently, simulataneously, and/or co-administered. APPLICATION 0008. In some aspects, provided herein is a method of treating a hematologic malignancy in a subject in need 0001. This application claims the benefit of U.S. Provi thereof, comprising administering to the Subject a therapeu sional Application No. 62/212.518, filed Aug. 31, 2015, tically effective amount of a combination comprising an which is incorporated herein by reference in its entirety. immunomodulatory agent, a BTK inhibitor, and a steroid, BACKGROUND wherein an immunomodulatory agent, a BTK inhibitor, and a steroid are administered concurrently. 0002 Bruton's tyrosine kinase (Btk), a member of the 0009. In some aspects, provided herein is a method of Tec family of non-receptor tyrosine kinases, is a key sig treating a hematologic malignancy in a subject in need naling enzyme expressed in all hematopoietic cells types thereof, comprising administering to the Subject a therapeu except T lymphocytes and natural killer cells. Btk plays an tically effective amount of a combination comprising essential role in the B-cell signaling pathway linking cell pomalidomide, ibrutinib, and dexamethasone following a surface B-cell receptor (BCR) stimulation to downstream dosing regimen wherein the dosing regimen comprises intracellular responses. administering pomalidomide, ibrutinib, and dexamethasone 0003) 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyra concurrently. Zolo3,4-dipyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is also known by its IUPAC name as 1-((3R)-3-4-amino-3- DETAILED DESCRIPTION (4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl)pip eridin-1-yl)prop-2-en-1-one or 2-Propen-1-one, 1-(3R)-3- Certain Terminology 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo 3,4-d 0010 Unless defined otherwise, all technical and scien pyrimidin-1-yl)-1-piperidinyl-, and has been given the tific terms used herein have the same meaning as is com USAN name, ibrutinib. The various names given for ibru monly understood by one of skill in the art to which the tinib are used interchangeably herein. Ibrutinib is an inhibi claimed subject matter belongs. It is to be understood that tor of Btk. the foregoing general description and the following detailed description are exemplary and explanatory only and are not SUMMARY restrictive of any Subject matter claimed. In this application, 0004 Disclosed herein are pharmaceutical combinations, the use of the singular includes the plural unless specifically dosing regimens, and methods that comprise a combination stated otherwise. It must be noted that, as used in the of a TEC inhibitor, an immunomodulatory agent, and a specification and the appended claims, the singular forms steroid for the treatment of a hematologic malignancy. Also “a,” “an and “the include plural referents unless the described herein are methods of administrating a combina context clearly dictates otherwise. In this application, the use tion of a TEC inhibitor, an immunomodulatory agent, and a of “or” means “and/or unless stated otherwise. Further steroid for treatment of multiple myeloma. In some more, use of the term “including as well as other forms, instances, the TEC inhibitor is a BTK, ITK, TEC, RLK, or such as “include”, “includes,” and “included,” is not limit BMX inhibitor. In some instances, the BTK inhibitor is ing. ibrutinib. In some instances, the immunomodulatory agent is 0011 AS used herein, ranges and amounts can be pomalidomide. In some instances the steroid is dexametha expressed as “about a particular value or range. About also SO. includes the exact amount. Hence “about 5 uL' means 0005. In some embodiments, provided herein is a phar “about 5 uL and also “5 uL.” Generally, the term “about” maceutical combination that comprises a TEC inhibitor, an includes an amount that would be expected to be within immunomodulatory agent, and a steroid. In some instances, experimental error. The term “about when used before a the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX numerical value indicates that the value may vary within a inhibitor. In some instances, the TEC inhibitor is an ITK reasonable range, such as within +10%, 5% or +1% of the inhibitor. In some instances, the TEC inhibitor is a BTK stated value. inhibitor. In some instances, the BTK inhibitor is ibrutinib. 0012. The section headings used herein are for organiza In some instances, the immunomodulatory agent is tional purposes only and are not to be construed as limiting pomalidomide. In some instances, the steroid is dexametha the subject matter described. Sone. In some instances, the pharmaceutical combination is 0013 As used herein, the terms “individual(s)', 'subject administered for the treatment of a hematologic malignancy. (s)' and “patient(s) mean any mammal. In some embodi In some instances, the hematologic malignancy is multiple ments, the mammal is a human. In some embodiments, the myeloma. mammal is a non-human. None of the terms require or are 0006. In some instances, provided herein is a dosing limited to situations characterized by the Supervision (e.g., regimen for the treatment of a hematologic malignancy in a constant or intermittent) of a health care worker (e.g., a Subject in need thereof comprising administering an immu doctor, a registered nurse, a nurse practitioner, a physician’s nomodulatory agent, a BTK inhibitor, and a steroid, wherein assistant, an orderly or a hospice worker). the immunomodulatory agent, the Btk inhibitor, and the 0014. The terms “co-administration,” “simultaneous steroid are administered concurrently, simulataneously, and/ administration,” “concurrently,” or the like, and any gram or co-administered. matical version thereof, as used herein, are meant to encom 0007. In some instances, provided herein is a dosing pass administration of the selected therapeutic agents to a regimen for the treatment of a hematologic malignancy in a single patient, and are intended to include treatment regi US 2017/0209462 A1 Jul. 27, 2017

mens in which the agents are administered by the same or tially homogeneous population of antibodies, i.e., the indi different route of administration or at the same or different vidual antibodies comprising the population are identical time; however, all agents (i.e., all three agents) are admin except for possible naturally occurring mutations that may istered during the same cycle (even though the administra be present in minor amounts. tion of the agents is begun, initiated, or occurs on different 0020 “Antibody fragments’ comprise a portion of an days of that cycle). In some embodiments, “co-administra intact antibody, preferably the antigen-binding or variable tion,” “simultaneously,” and concurrently are interchange region of the intact antibody. Examples of antibody frag able. In some embodiments, the patients have not been ments include Fab, Fab, F(ab')2, and Fv fragments: diabod administered Btk inhibitor, such as ibrutinib, prior to initia ies; linear antibodies (Zapata et al. (1995) Protein Eng. tion of the dosing regimen disclosed herein. 10:1057-1062); single-chain antibody molecules; and mul 0015 The terms “effective amount” or “therapeutically tispecific antibodies formed from antibody fragments. effective amount, as used herein, refer to a sufficient Papain digestion of antibodies produces two identical anti amount of an agent or a compound, or a combination or two gen-binding fragments, called “Fab' fragments, each with a or more agents or compounds, or a sufficient amount of an single antigen-binding site, and a residual "Fo' fragment, individual agent or compound in a combination of two or whose name reflects its ability to crystallize readily. Pepsin more agents or compounds, being administered which will treatment yields an F(ab')2 fragment that has two antigen relieve to some extent one or more of the symptoms of the combining sites and is still capable of cross-linking antigen. disease or condition being treated. The result can be reduc 0021 “Fv is the minimum antibody fragment that con tion and/or alleviation of the signs, symptoms, or causes of tains a complete antigen recognition and binding site. This a disease, or any other desired alteration of a biological region consists of a dimer of one heavy- and one light-chain system. For example, an “effective amount” for therapeutic variable domain in tight, non-covalent association. It is in uses is the amount of the composition including a compound this configuration that the three CDRs of each variable as disclosed herein required to provide a clinically signifi domain interact to define an antigen-binding site on the cant decrease in disease symptoms without undue adverse surface of the V-V, dimer. Collectively, the six CDRs side effects. An appropriate “effective amount in any indi confer antigen-binding specificity to the antibody. However, vidual case may be determined using techniques, such as a even a single variable domain (or half of an Fv comprising dose escalation study. An "effective amount of a compound only three CDRS specific for an antigen) has the ability to disclosed herein is an amount effective to achieve a desired recognize and bind antigen, although at a lower affinity than pharmacologic effect or therapeutic improvement without the entire binding site. undue adverse side effects. It is understood that “an effect 0022. The Fab fragment also contains the constant amount’ or “a therapeutically effective amount can vary domain of the light chain and the first constant domain (C) from subject to subject, due to variation in metabolism of of the heavy chain. Fab fragments differ from Fab' fragments ibrutinib, age, weight, general condition of the Subject, the by the addition of a few residues at the carboxy terminus of condition being treated, the severity of the condition being the heavy chain C. domain including one or more cysteines treated, and the judgment of the prescribing physician. By from the antibody hinge region. Fab'-SH is the designation way of example only, therapeutically effective amounts may herein for Fab' in which the cysteine residue(s) of the be determined by routine experimentation, including but not constant domains bear a free thiol group. Fab' fragments are limited to a dose escalation clinical trial. produced by reducing the F(ab')2 fragments heavy chain 0016. The terms "enhance' or "enhancing means to disulfide bridge. Other chemical couplings of antibody frag increase or prolong either in potency or duration a desired ments are also known. effect. By way of example, "enhancing the effect of thera 0023 The “light chains of antibodies (immunoglobu peutic agents refers to the ability to increase or prolong, lins) from any vertebrate species can be assigned to one of either in potency or duration, the effect of therapeutic agents two clearly distinct types, called kappa (K) and lambda (W), on during treatment of a disease, disorder or condition. An based on the amino acid sequences of their constant "enhancing-effective amount,” as used herein, refers to an domains. amount adequate to enhance the effect of a therapeutic agent 0024 Depending on the amino acid sequence of the in the treatment of a disease, disorder or condition. When constant domain of their heavy chains, immunoglobulins used in a patient, amounts effective for this use will depend can be assigned to different classes. There are five major on the severity and course of the disease, disorder or classes of human immunoglobulins: IgA, Ig|D, IgE, IgG, and condition, previous therapy, the patient’s health status and IgM, and several of these may be further divided into response to the drugs, and the judgment of the treating Subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, physician. and IgA2. The heavy-chain constant domains that corre 0017 “Antibodies' and “immunoglobulins’ (Igs) are spond to the different classes of immunoglobulins are called glycoproteins having the same structural characteristics. The alpha, delta, epsilon, gamma, and mu, respectively. The terms are used synonymously. In some instances the antigen Subunit structures and three-dimensional configurations of specificity of the immunoglobulin may be known. different classes of immunoglobulins are well known. Dif 0018. The term “antibody' is used in the broadest sense ferent isotypes have different effector functions. For and covers fully assembled antibodies, antibody fragments example, human IgG1 and IgG3 isotypes have ADCC (anti that can bind antigen (e.g., Fab., F(ab'). Fv, single chain body dependent cell-mediated cytotoxicity) activity. antibodies, diabodies, antibody chimeras, hybrid antibodies, 0025. The suffix "ene' appended to a group indicates that bispecific antibodies, humanized antibodies, and the like), Such a group is a diradical. By way of example only, a and recombinant peptides comprising the forgoing. methylene is a diradical of a methyl group, that is, it is a 0019. The terms “monoclonal antibody” and “m Ab” as —CH2— group; and an ethylene is a diradical of an ethyl used herein refer to an antibody obtained from a substan group, i.e., —CH2CH2—. US 2017/0209462 A1 Jul. 27, 2017

0026. As used herein, C-C, includes C-C, C-C . . . pound described herein, thereby forming a prodrug. Any C-C, i.e., one to two carbon atoms, one to three carbon amine, or carboxyl side chain on the compounds described atoms . . . one to X carbon atoms. herein can be amidified. The procedures and specific groups 0027. An “alkyl group refers to a saturated, branched or to make Such amides are found in Sources such as Greene straight chain hydrocarbon group. The “alkyl moiety and Wuts, Protective Groups in Organic Synthesis, 3" Ed., optionally has 1 to 10 carbon atoms (whenever it appears John Wiley & Sons, New York, N.Y., 1999, which is herein, a numerical range such as "1 to 10” refers to each incorporated herein by reference for this disclosure. integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group is selected from a moiety having 0032. The term “ester” refers to a chemical moiety with 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to formula —COOR, where R is selected from alkyl, and including 10 carbon atoms, although the present defi cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) nition also covers the occurrence of the term “alkyl where and heteroalicyclic (bonded through a ring carbon). Any no numerical range is designated). The alkyl group of the hydroxy, or carboxyl side chain on the compounds described compounds described herein may be designated as "C-C, herein can be esterified. The procedures and specific groups alkyl or similar designations. By way of example only, to make Such esters are found in sources such as Greene and "C-C alkyl” indicates that there are one to four carbon Wuts, Protective Groups in Organic Synthesis, 3" Ed., John atoms in the alkyl chain, i.e., the alkyl chain is selected from Wiley & Sons, New York, N.Y., 1999, which is incorporated methyl, ethyl, propyl, iso-propyl. n-butyl, iso-butyl, sec herein by reference for this disclosure. butyl, and t-butyl. Thus C-C alkyl includes C-C alkyl and C-C alkyl. Alkyl groups are optionally Substituted or 0033. As used herein, the term “ring refers to any unsubstituted. Typical alkyl groups include, but are in no covalently closed structure. Rings include, for example, way limited to, methyl, ethyl, propyl, isopropyl, butyl, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, heteroaryls and non-aromatic heterocycles), aromatics (e.g., butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and the like. “Lower alkyl having 1 to 6 carbon atoms. and non-aromatic heterocycles). Rings can be optionally 0028. The term “alkenyl refers to a hydrocarbon group Substituted. Rings can be monocyclic or polycyclic. containing at least one double bond formed by two carbon atoms that is not part of an aromatic group. An example of 0034. As used herein, the term “ring system” refers to an alkenyl group is C(R)=C(R) R, wherein R refers to one, or more than one ring. the remaining portions of the alkenyl group, which are either 0035. The term “membered ring can embrace any cyclic the same or different. The alkenyl moiety is optionally structure. The term “membered' is meant to denote the branched, straight chain, or cyclic (in which case, it is also number of skeletal atoms that constitute the ring. Thus, for known as a “cycloalkenyl group). Depending on the struc example, cyclohexyl, pyridine, pyran and thiopyran are ture, an alkenyl group includes a monoradical or a diradical 6-membered rings and cyclopentyl, pyrrole, furan, and thio (i.e., an alkenylene group). Alkenyl groups are optionally Substituted. Non-limiting examples of an alkenyl group phene are 5-membered rings. include -CH=CH, -C(CH)—CH, -CH=CHCH 0036. The term “fused refers to structures in which two —C(CH)—CHCH. Alkenylene groups include, but are not or more rings share one or more bonds. limited to, CH-CH , —C(CH)—CH-, 0037. The term “aromatic' refers to a planar ring having -CH=CHCH-, -CH=CHCHCH and –C(CH) a delocalized U-electron system containing 4n+2 at electrons, —CHCH-. Alkenyl groups optionally have 2 to 10 car where n is an integer. Aromatic rings can be formed from bons, and if a “lower alkenyl having 2 to 6 carbon atoms. five, six, seven, eight, nine, or more than nine atoms. 0029. The term “alkynyl refers to a branched or straight Aromatics can be optionally substituted. The term “aro chain hydrocarbon group containing at least one triple bond matic' includes both carbocyclic aryl (e.g., phenyl) and formed by two carbon atoms. An example of an alkynyl heterocyclic aryl (or "heteroaryl' or "heteroaromatic') group is —C=C-R, wherein R refers to the remaining groups (e.g., pyridine). The term includes monocyclic or portions of the alkynyl group, which is either the same or fused-ring polycyclic (i.e., rings which share adjacent pairs different. The “R” portion of the alkynyl moiety may be of carbon atoms) groups. branched, straight chain, or cyclic. Depending on the struc ture, an alkynyl group includes a monoradical or a diradical 0038. As used herein, the term “aryl refers to an aro (i.e., an alkynylene group). Alkynyl groups are optionally matic ring wherein each of the atoms forming the ring is a Substituted. Non-limiting examples of an alkynyl group carbon atom. Aryl rings can be formed by five, six, seven, include, but are not limited to. —C=CH, —C=CCH eight, nine, or more than nine carbon atoms. Aryl groups can —C=CCHCH. —C=C , and —C=CCH - Alkynyl be optionally substituted. Examples of aryl groups include, groups optionally have 2 to 10 carbons, and if a “lower but are not limited to phenyl, naphthalenyl, phenanthrenyl, alkynyl having 2 to 6 carbon atoms. anthracenyl, fluorenyl, and indenyl. Depending on the struc 0030. An “alkoxy' group refers to an (alkyl)O— group, ture, an aryl group can be a monoradical or a diradical (i.e., where alkyl is as defined herein. an arylene group). 0031. An "amide' is a chemical moiety with the formula 0039. The term “cycloalkyl” refers to a monocyclic or —C(O)NHR or -NHC(O)R, where R is selected from polycyclic radical that contains only carbon and hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring and is optionally saturated, or partially unsaturated. carbon) and heteroalicyclic (bonded through a ring carbon). Cycloalkyl groups include groups having from 3 to 10 ring In some embodiments, an amide moiety forms a linkage atoms. Illustrative examples of cycloalkyl groups include between an amino acid or a peptide molecule and a com the following moieties: US 2017/0209462 A1 Jul. 27, 2017

nyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepa nyl, oxazepinyl, diazepinyl, thiazepinyl, 1.2.3,6-tetrahydro pyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl. 4H-pyranyl, dioxanyl, 1.3-dioxolanyl, pyrazolinyl, dithi s anyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydro A. D. furanyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, azabi cyclo[3.1.0 hexanyl, 3-azabicyclo4.1.0 heptanyl, s 3H-indolyl and quinolizinyl. Examples of aromatic hetero O D D cyclic (heteroaryl) groups are pyridinyl, imidazolyl pyrim idinyl, pyrazolyl, triazolyl pyrazinyl, tetrazolyl, furyl, thie nyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzo O furanyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadi azolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothio s phenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox V-A O. O. O. alinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the groups listed above, are option ally C-attached or N-attached where such is possible. For s instance, a group derived from pyrrole includes pyrrol-1-yl At CCO CO (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol 3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups CO) include benzo-fused ring systems and ring systems substi tuted with one or two oxo (=O) moieties such as pyrrolidin and the like. Depending on the structure, a cycloalkyl group 2-one. Depending on the structure, a heterocycle group can is either a monoradical or a diradical (e.g., a cycloalkylene be a monoradical or a diradical (i.e., a heterocyclene group). group), and if a “lower cycloalkyl having 3 to 8 carbon 0041. The terms “heteroaryl” or, alternatively, “het atOmS. eroaromatic' refers to an aromatic group that includes one or 0040. The term “heterocycle” refers to heteroaromatic more, Such as one to four, ring heteroatoms selected from and heteroalicyclic groups containing one to four heteroa nitrogen, oxygen and Sulfur. Heteroaryl rings can be formed toms each selected from O, S and N, wherein each hetero by five, six, seven, eight, nine, or more than nine, e.g., up to cyclic group has from 4 to 10 atoms in its ring system, and fourteen, ring atoms. An N-containing "heteroaromatic' or with the proviso that the ring of said group does not contain "heteroaryl moiety refers to an aromatic group in which at two adjacent O or Satoms. Herein, whenever the number of least one of the skeletal atoms of the ring is a nitrogen atom. carbon atoms in a heterocycle is indicated (e.g., C-C, Illustrative examples of heteroaryl groups include the fol heterocycle), at least one other atom (the heteroatom) must lowing moieties: be present in the ring. Designations such as "C-C hetero cycle” refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring. It is understood that the heterocylic ring can have additional heteroatoms in the ring. Designations such as “4-6 mem bered heterocycle” refer to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, S in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms). In heterocycles that O 2 C. C. have two or more heteroatoms, those two or more heteroa toms can be the same or different from one another. Het erocycles can be optionally substituted. Binding to a het ( ( ) ( . erocycle can be at a heteroatom or via a carbon atom. Non-aromatic heterocyclic groups include groups having only 4 atoms in their ring system, but aromatic heterocyclic groups must have at least 5 atoms in their ring system. The heterocyclic groups include benzo-fused ring systems. An example of a 4-membered heterocyclic group is azetidinyl (derived from azetidine). An example of a 5-membered heterocyclic group is thiazolyl. An example of a 6-mem bered heterocyclic group is pyridyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahy drofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropy SCC ranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, aZetidi US 2017/0209462 A1 Jul. 27, 2017 and the like. Depending on the structure, a heteroaryl group and the like. The term heteroalicyclic also includes all ring can be a monoradical or a diradical (i.e., a heteroarylene forms of the carbohydrates, including but not limited to the group). monosaccharides, the disaccharides and the oligosaccha 0042. As used herein, the term “non-aromatic hetero rides. Depending on the structure, a heterocycloalkyl group cycle”, “heterocycloalkyl or "heteroalicyclic” refers to a can be a monoradical or a diradical (i.e., a heterocycloalky non-aromatic ring wherein one or more, Such as one to four, lene group). atoms forming the ring are a heteroatom. A “non-aromatic 0043. The term “halo” or, alternatively, “halogen” or heterocycle' or "heterocycloalkyl group refers to a “halide” means fluoro, chloro, bromo and iodo. cycloalkyl group that includes at least one heteroatom 0044) The term “haloalkyl, refers to alkyl structures in selected from nitrogen, oxygen and Sulfur. In some embodi which at least one hydrogen is replaced with a halogen atom. ments, the radicals are fused with an aryl or heteroaryl. In certain embodiments in which two or more hydrogen Heterocycloalkyl rings can be formed by three, four, five, atoms are replaced with halogen atoms, the halogen atoms six, seven, eight, nine, or more than nine, e.g., up to fourteen, are all the same as one another. In other embodiments in ring atoms. Heterocycloalkyl rings can be optionally Sub which two or more hydrogen atoms are replaced with stituted. In certain embodiments, non-aromatic heterocycles halogenatoms, the halogen atoms are not all the same as one contain one or more carbonyl (=O) or thiocarbonyl groups another. Such as, for example, oxo- and thio-containing groups. 0045. The term “fluoroalkyl,” as used herein, refers to Examples of heterocycloalkyls include, but are not limited alkyl group in which at least one hydrogen is replaced with to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic a fluorine atom. Examples of fluoroalkyl groups include, but carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropy are not limited to. —CF, —CH2CF, —CFCF ran, piperidine, 1,3-dioxin, 1.3-dioxane, 1,4-dioxin, 1.4- —CHCHCF and the like. dioxane, piperazine, 1.3-oxathiane, 1,4-oxathin, 1.4-oxathi 0046. As used herein, the term "heteroalkyl refers to ane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, optionally Substituted alkyl radicals in which one or more, Succinimide, barbituric acid, thiobarbituric acid, dioxopip Such as one to three or one to two, skeletal chain atoms is a erazine, hydantoin, dihydrouracil, morpholine, trioxane, heteroatom, e.g., oxygen, nitrogen, Sulfur, silicon, phospho hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydro rus or combinations thereof. The heteroatom(s) are placed at furan, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, any interior position of the heteroalkyl group or at the pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1.3- position at which the heteroalkyl group is attached to the dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazo remainder of the molecule. Examples include, but are not line, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, limited to. —CH2—O-CH —CH2—CH2—O—CH, thiazoline, thiazolidine, and 1.3-oxathiolane. Illustrative CH NH CH, —CH2—CH NH CH, —CH examples of heterocycloalkyl groups, also referred to as N(CH) CH, CH-CH NH-CH —CH2— non-aromatic heterocycles, include: CH, N(CH)—CH, —CH, S CH, CH, —CH CH, —S(O)—CH, —CH2—CH2—S(O), CH, -CH=CH-O CH, -Si(CH), —CH-CH=N- OCH and —CH=CH N(CH)—CH. In addition, in Some embodiments, up to two heteroatoms are consecutive, such as, by way of example, —CH2—NH OCH and —CH2—O—Si(CH). 0047. The term "heteroatom” refers to an atom other than carbon or hydrogen. Heteroatoms are typically indepen dently selected from oxygen, Sulfur, nitrogen, silicon and phosphorus, but are not limited to these atoms. In embodi C. C C C C, D, ments in which two or more heteroatoms are present, the two or more heteroatoms can all be the same as one another, or some or all of the two or more heteroatoms can each be () (OO different from the others. 0048. The term “bond' or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. OOO 0049. The term "moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule. 0050. The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s), by way of example, individu ally and independently selected from cyano, halo, acyl, nitro, haloalkyl, fluoroalkyl, amino, including mono- and di-Substituted amino groups, and the protected derivatives thereof, or LR, wherein each L is independently selected from a bond, —O—, —C(=O)— —S— —S(=O)—, S(=O) NH-, - NR , -NHC(O) , C(O) US 2017/0209462 A1 Jul. 27, 2017

NH-, -S(=O)NH-, -NHS(=O), , –OC(O)NH-, about 280 mg/day to about 840 mg/day. In some embodi —NHC(O)O—, -(substituted or unsubstituted C-C alky ments, ibrutinib is administered at a dosage of about 400 lene), or -(Substituted or unsubstituted C-C alkenylene); mg/day to about 840 mg/day. In some embodiments, ibru and each R is independently selected from H., (substituted or tinib is administered at a dosage of about 560 mg/day to unsubstituted C-C alkyl), (substituted or unsubstituted about 840 mg/day. In some embodiments, ibrutinib is C-C cycloalkyl). (Substituted or unsubstituted heterocy administered at a dosage of about 700 mg/day. In some cloalkyl), (substituted or unsubstituted aryl), (substituted or embodiments, the dosing regimen comprises administration unsubstituted heteroaryl), or (substituted or unsubstituted of an additional therapeutic agent. In some embodiments, heteroalkyl). The protecting groups that form the protective the multiple myeloma is relapsed or refractory multiple derivatives of the above substituents include those found in myeloma. In some embodiments, the multiple myeloma is sources such as Greene and Wuts, above. metastasized multiple myeloma. In some embodiments, the Subject has received at least one prior therapy. In some Overview embodiments, the subject has received at least two prior 0051. In some embodiments, a pharmaceutical combina therapies. In some embodiments, the prior therapy com tion is provided. The pharmaceutical combination may com prises lenalidomide. In some embodiments, the prior therapy prise three active ingredients: a Btk inhibitor, an immuno comprises carfilzomib. In some embodiments, the prior modulatory agent (IMiD), and dexamethasone. In some therapy comprises bortezomib. embodiments, the pharmaceutical combination is in separate 0053. In some embodiments, a method of treating a dosage forms. In some embodiments, the pharmaceutical multiple myeloma in a subject in need thereof is provided. combination is in three separate dosage forms, wherein each The method comprises administering to the Subject a phar active ingredient is in a separate dosage form from the other maceutical combination as described herein. In some active ingredients. In some embodiments, the pharmaceuti embodiments, the pharmaceutical combination may com cal combination is in combined dosage forms. In some prise a Btk inhibitor, an immunomodulatory agent (IMiD), embodiments, the pharmaceutical combination is adminis dexamethasone, and a pharmaceutically acceptable excipi tered for the treatment of multiple myeloma. In some ent. In some embodiments, the pharmaceutical combination embodiments, the multiple myeloma is relapsed or refrac is in separate dosage forms. In some embodiments, the tory multiple myeloma. In some embodiments, the multiple pharmaceutical combination is in combined dosage forms. myeloma is metastasized multiple myeloma. In some In some embodiments, the pharmaceutical combination is embodiments, the immunomodulatory agent is pomalido administered for the treatment of multiple myeloma. In mide. In some embodiments, the Btk inhibitor is ibrutinib. Some embodiments, the multiple myeloma is relapsed or 0052. In some embodiments, a dosing regimen for the refractory multiple myeloma. In some embodiments, the treatment of multiple myeloma is provided. The dosing multiple myeloma is metastasized multiple myeloma. In regimen may comprise administering to a subject a combi Some embodiments, the immunomodulatory agent is nation of three active ingredients, which are a Btk inhibitor, pomalidomide. In some embodiments, the Btk inhibitor is an immunomodulatory agent, and dexamethasone. In some ibrutinib. embodiments, the Btkinhibitor is ibrutinib. In some embodi 0054. In some embodiments, a method of treating a ments, the immunomodulatory agent is pomalidomide. In relapsed or refractory multiple myeloma is provided. The Some embodiments, the dosing regimen may comprise method comprises administering to the Subject a pharma administering to the Subject a combination comprising ibru ceutical combination as described herein. In some embodi tinib. pomalidomide, and dexamethasone. In some embodi ments, the pharmaceutical combination is in separate dosage ments, ibrutinib, pomalidomide, and dexamethasone are forms. In some embodiments, the pharmaceutical combina administered concurrently. In some embodiments, ibrutinib, tion is in combined dosage forms. In some embodiments, the pomalidomide, and dexamethasone are co-administered. In pharmaceutical combination is administered for the treat Some embodiments, ibrutinib, pomalidomide, and dexam ment of multiple myeloma. In some embodiments, the ethasone are administered simultaneously. In some embodi multiple myeloma is relapsed or refractory multiple ments, ibrutinib, pomalidomide, and dexamethasone are myeloma. In some embodiments, the multiple myeloma is administered in cycles comprising, or consisting of 28 days. metastasized multiple myeloma. In some embodiments, the In some embodiments, ibrutinib, pomalidomide, and dex immunomodulatory agent is pomalidomide. In some amethasone are administered simultaneously. In some embodiments, the Btk inhibitor is ibrutinib. embodiments, pomalidomide is administered on days 1-21 0055. In some embodiments, a method of treating mul of each cycle. In some embodiments, dexamethasone is tiple myeloma in a subject in need thereof is provided. The administered on days 1, 8, 15, and 22 of each cycle. In some method is based upon the dosing regimen as described embodiments, ibrutinib is administered on days 1-28 of each herein. In some embodiments, The dosing regimen may cycle. In some embodiments, pomalidomide is administered comprise administering to a Subject a combination compris at a dosage of about 3 mg/day to about 5 mg/day. In some ing a Btk inhibitor, an immunomodulatory agent, and dex embodiments, pomalidomide is administered at a dosage of amethasone. In some embodiments, the Btk inhibitor is about 4 mg/day. In some embodiments, dexamethasone is ibrutinib. In some embodiments, the immunomodulatory administered at a dosage of about 20 mg/day to about 60 agent is pomalidomide. In some embodiments, the dosing mg/day. In some embodiments, dexamethasone is adminis regimen may comprise administering to the Subject a com tered at a dosage of about 40 mg/day. In some embodiments, bination comprising ibrutinib, pomalidomide, and dexam ibrutinib is administered orally. In some embodiments, ibru ethasone. In some embodiments, the ibrutinib, pomalido tinib is administered once a day, two times per day, three mide, and dexamethasone are administered in cycles times per day, four times per day, or five times per day. In comprising, or consisting of 28 days. In some embodiments, Some embodiments, ibrutinib is administered at a dosage of ibrutinib, pomalidomide, and dexamethasone are adminis US 2017/0209462 A1 Jul. 27, 2017

tered simultaneously. In some embodiments, pomalidomide is administered orally. In some embodiments, ibrutinib is is administered on days 1-21 of each cycle. In some embodi administered once a day, two times per day, three times per ments, dexamethasone is administered on days 1, 8, 15, and day, four times per day, or five times per day. In some 22 of each cycle. In some embodiments, ibrutinib is admin embodiments, ibrutinib is administered at a dosage of about istered on days 1-28 of each cycle. In some embodiments, 280 mg/day to about 840 mg/day. In some embodiments, pomalidomide is administered at a dosage of about 3 mg/day ibrutinib is administered at a dosage of about 400 mg/day to to about 5 mg/day. In some embodiments, pomalidomide is about 840 mg/day. In some embodiments, ibrutinib is administered at a dosage of about 4 mg/day. In some administered at a dosage of about 560 mg/day to about 840 embodiments, dexamethasone is administered at a dosage of mg/day. In some embodiments, ibrutinib is administered at about 20 mg/day to about 60 mg/day. In some embodiments, a dosage of about 700 mg/day. In some embodiments, the dexamethasone is administered at a dosage of about 40 dosing regimen comprises administration of an additional mg/day. In some embodiments, ibrutinib is administered therapeutic agent. In some embodiments, the multiple orally. In some embodiments, ibrutinib is administered once myeloma is relapsed or refractory multiple myeloma. In a day, two times per day, three times per day, four times per Some embodiments, the multiple myeloma is metastasized day, or five times per day. In some embodiments, ibrutinib multiple myeloma. In some embodiments, the Subject has is administered at a dosage of about 280 mg/day to about received at least one prior therapy. In some embodiments, 840 mg/day. In some embodiments, ibrutinib is administered the Subject has received at least two prior therapies. In some at a dosage of about 400 mg/day to about 840 mg/day. In embodiments, the prior therapy comprises lenalidomide. In Some embodiments, ibrutinib is administered at a dosage of Some embodiments, the prior therapy comprises carfilzomib. about 560 mg/day to about 840 mg/day. In some embodi In some embodiments, the prior therapy comprises bort ments, ibrutinib is administered at a dosage of about 700 eZomib. mg/day. In some embodiments, the dosing regimen com prises administration of an additional therapeutic agent. In Immunomodulatory Agents Some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma. In some embodiments, the 0057 Immunomodulatory agents (or “immunomodula multiple myeloma is metastasized multiple myeloma. In tory drugs” or IMiDs) are a class of drugs that constitute Some embodiments, the Subject has received at least one thalidomide and its analogues. Exemplary immunomodula prior therapy. In some embodiments, the Subject has tory agents include, but are not limited to, pomalidomide received at least two prior therapies. In some embodiments, (e.g., CC-4047 or Pomalyst(R), lenalidomide (i.e., Rev the prior therapy comprises lenalidomide. In some embodi limid(R), thalidomide (e.g., Thalomid(R), and apremilast. ments, the prior therapy comprises carfilzomib. In some embodiments, the prior therapy comprises bortezomib. Dosing Regimen 0056. In some embodiments, a method of treating a 0058. In some embodiments, the dosing regimen com relapsed or refractory multiple myeloma in a Subject in need prises administration of a TEC inhibitor, an immunomodu thereof is provided. The method is based upon the dosing latory agent, and a steroid concurrently in at least one cycle. regimen as described herein. In some embodiments, the In some embodiments, the immunomodulatory agent is dosing regimen may comprise administering to a subject a pomalidomide. In some embodiments, the Steroid is dexam combination comprising a Btk inhibitor, an immunomodu ethasone. In some embodiments, the TEC inhibitor is an ITK latory agent, and dexamethasone. In some embodiments, the inhibitor. In some embodiments, the TEC inhibitor is a BTK Btk inhibitor is ibrutinib. In some embodiments, the immu inhibitor. In some instances, the BTK inhibitor is ibrutinib. nomodulatory agent is pomalidomide. In some embodi In some embodiments, the immunomodulatory agent is ments, the invention relates to the co-administration of a first lenalidomide. amount of ibrutinib; a second amount of an immunomodu latory agent; and a third amount of dexamethasone, wherein 0059. In some embodiments, each cycle comprises or the first amount, second amount, and third amount, taken consists of 28 days. In some embodiments, each cycle together, are therapeutically effective. In some embodi comprises or consists of less than 28 days or more than 28 ments, the dosing regimen may comprise administering to days. For example, each cycle may comprise or consist of 14 the Subject a combination comprising ibrutinib, pomalido days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, mide, and dexamethasone. In some embodiments, the ibru 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, or 27 tinib. pomalidomide, and dexamethasone are administered days. in cycles comprising, or consisting of 28 days. In some 0060. In some embodiments, the immunomodulatory embodiments, ibrutinib, pomalidomide, and dexamethasone agent is administered on day 1, day 2, day 3, day 4, day 5, are administered simultaneously. In some embodiments, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, pomalidomide is administered on days 1-21 of each cycle. In day 14, day 15, day 16, day 17, day 18, day 19, day 20, and Some embodiments, dexamethasone is administered on days day 21 of each cycle comprising 28 days (i.e., on days 1-21). 1, 8, 15, and 22 of each cycle. In some embodiments, In some embodiments, the immunomodulatory agent may be ibrutinib is administered on days 1-28 of each cycle. In some administered for less than 21 days of each 28-day cycle. In embodiments, pomalidomide is administered at a dosage of Some embodiments, the immunomodulatory agent may be about 3 mg/day to about 5 mg/day. In some embodiments, administered on greater than 21 days of each 28-day cycle. pomalidomide is administered at a dosage of about 4 In some embodiments, the immunomodulatory agent is not mg/day. In some embodiments, dexamethasone is adminis administered on consecutive days. In some embodiments, tered at a dosage of about 20 mg/day to about 60 mg/day. In this dosing regimen is followed for any number of cycles. In Some embodiments, dexamethasone is administered at a Some embodiments, this dosing regimen is followed for at dosage of about 40 mg/day. In some embodiments, ibrutinib least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles. In some US 2017/0209462 A1 Jul. 27, 2017

embodiments, this dosing regimen is followed for more than mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg. 12 cycles. In some embodiments, the immunomodulatory about 110 mg, about 120 mg, about 125 mg, about 130 mg. agent is pomalidomide. about 135 mg, about 140 mg, about 180 mg, about 220 mg. 0061. In some embodiments, the amount of immuno about 260 mg, about 300 mg, about 350 mg, about 400 mg. modulatory agent that is administered is about 1 mg/day; about 420 mg, 560 mg, 700 mg. or about 840 mg. about 2 mg/day; about 3 mg/day; about 4 mg/day; about 5 0066. In some embodiments, the amount of an ITK mg/day; about 6 mg/day; about 7 mg/day; or about 8 inhibitor that is administered is from 10 mg/day up to, and mg/day. In some embodiments, less than about 1 mg/day including, 1000 mg/day. In some embodiments, the amount may be administered. In some embodiments, more than of an ITK inhibitor that is administered is from about 40 about 8 mg/day may be administered. In some embodiments, mg/day to 900 mg/day, about 40 mg/day to 840 mg/day, the amount of immunomodulatory agent administered may about 80 mg/day to 600 mg/day, about 100 mg/day to 500 vary during each administration, due to physician discretion. mg/day, about 140 mg/day to 420 mg/day, or about 560 In some embodiments, the immunomodulatory agent is mg/day to 840 mg/day. In some embodiments, the amount of pamolidomide. an ITK inhibitor that is administered per day is about 10 mg. 0062. In some embodiments, the steroid is administered about 11 mg, about 12 mg, about 13 mg, about 14 mg, about on day 1, day 8, day 15, and day 22 of each cycle comprising 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 or consisting of 28 days. In some embodiments, the steroid mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg. is administered on one day per week (or weekly). In some about 40 mg, about 45 mg, about 50 mg, about 55 mg, about embodiments, the steroid is administered on more than one 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 day per week. In some embodiments, the steroid is not mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg. administered on one day per week, i.e., the steroid may be about 110 mg, about 120 mg, about 125 mg, about 130 mg. administered on one day every two weeks or on two days about 135 mg, about 140 mg, about 180 mg, about 220 mg. every week. In some embodiments, this dosing regimen is about 260 mg, about 300 mg, about 350 mg, about 400 mg. followed for any number of cycles. In some embodiments, about 420 mg, 560 mg, 700 mg. or about 840 mg. this dosing regimen is followed for at least 1, 2, 3, 4, 5, 6, 0067. In some embodiments, the amount of a BTK 7, 8, 9, 10, 11, or 12 cycles. In some embodiments, this inhibitor that is administered is from 10 mg/day up to, and dosing regimen is followed for more than 12 cycles. In some including, 1000 mg/day. In some embodiments, the amount embodiments, the steroid is dexamethasone. of a BTK inhibitor that is administered is from about 40 0.063. In some embodiments, the amount of steroid that is mg/day to 900 mg/day, about 40 mg/day to 840 mg/day, administrered is about 1 mg/day to about 60 mg/day; about about 80 mg/day to 600 mg/day, about 100 mg/day to 500 10 mg/day to about 50 mg/day; or about 20 mg/day to about mg/day, about 140 mg/day to 420 mg/day, or about 560 40 mg/day. In some embodiments, the amount of steroid that mg/day to 840 mg/day. In some embodiments, the amount of is administered is about 20 mg/day. In some embodiments, a BTK inhibitor that is administered per day is about 10 mg. the amount of steroid that is administered is about 40 about 11 mg, about 12 mg, about 13 mg, about 14 mg, about mg/day. In some embodiments, the amount of Steroid that is 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 administered is age-dependent. In some embodiments, the mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg. steroid is dexamethasone. about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 0064. In some embodiments, a dosing regimen described 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 herein is administered to the subject over a period of time of mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg. up to 5 years, 4 years, 3 years, 2 years, or 1 year. In some about 110 mg, about 120 mg, about 125 mg, about 130 mg. instances, the combination dosing regime is administered for about 135 mg, about 140 mg, about 180 mg, about 220 mg. a period of up to 40 cycles, 35 cycles, 30 cycles, 25 cycles, about 260 mg, about 300 mg, about 350 mg, about 400 mg. 20 cycles, 15 cycles, 14 cycles, 13 cycles, 12 cycles, 11 about 420 mg, 560 mg, 700 mg. or about 840 mg. cycles, or 10 cycles. In some instances, the dosing regimen 0068. In some embodiments, the amount of ibrutinib that is administered for a period of up to 20 cycles. In some is administered is from 10 mg/day up to, and including, 1000 instances, the dosing regimen is administered for a period of mg/day. In some embodiments, the amount of ibrutinib that up to 15 cycles. In some instances, the dosing regimen is is administered is from about 40 mg/day to 900 mg/day, administered for a period of up to 13 cycles. In some about 40 mg/day to 840 mg/day, about 80 mg/day to 600 instances, the dosing regimen is administered for a period of mg/day, about 100 mg/day to 500 mg/day, about 140 mg/day up to 12 cycles. to 420 mg/day, or about 560 mg/day to 840 mg/day. In some 0065. In some embodiments, the amount of a TEC inhibi embodiments, the amount of ibrutinib that is administered tor that is administered is from 10 mg/day up to, and per day is about 10 mg, about 11 mg, about 12 mg, about 13 including, 1000 mg/day. In some embodiments, the amount mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, of a TEC inhibitor that is administered is from about 40 about 18 mg, about 19 mg, about 20 mg, about 25 mg, about mg/day to 900 mg/day, about 40 mg/day to 840 mg/day, 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 about 80 mg/day to 600 mg/day, about 100 mg/day to 500 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg. mg/day, about 140 mg/day to 420 mg/day, or about 560 about 75 mg, about 80 mg, about 85 mg, about 90 mg, about mg/day to 840 mg/day. In some embodiments, the amount of 95 mg, about 100 mg, about 110 mg, about 120 mg, about a TEC inhibitor that is administered per day is about 10 mg. 125 mg, about 130 mg, about 135 mg, about 140 mg, about about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 180 mg, about 220 mg, about 260 mg, about 300 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 350 mg, about 400 mg, about 420 mg, about 560 mg, 700 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg. mg, or about 840 mg. In some embodiments, the amount of about 40 mg, about 45 mg, about 50 mg, about 55 mg, about ibrutinib that is administered is about 40 mg/day. In some 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 embodiments, the amount of ibrutinib that is administered is US 2017/0209462 A1 Jul. 27, 2017

about 50 mg/day. In some embodiments, the amount of treatment, but can nevertheless be routinely determined in a ibrutinib that is administered is about 60 mg/day. In some manner known in the art according to the particular circum embodiments, the amount of ibrutinib that is administered is stances Surrounding the case, including, e.g., the specific about 70 mg/day. In some embodiments, the amount of agent being administered, the route of administration, and ibrutinib that is administered is about 420 mg/day. In some the Subject or host being treated. In general, however, doses embodiments, the amount of ibrutinib that is administered is employed for adult human treatment will typically be in the about 560 mg/day. In some embodiments, the amount of range of 0.02-5000 mg per day, or from about 1-1500 mg per ibrutinib that is administered is about 700 mg/day. In some day. The desired dose may conveniently be presented in a embodiments, the amount of ibrutinib that is administered is single dose or as divided doses administered simultaneously about 840 mg/day. (or over a short period of time) or at appropriate intervals, 0069. In some embodiments, the TEC inhibitor (e.g., ITK for example as two, three, four or more Sub-doses per day. inhibitor or BTK inhibitor) is administered once per day, 0076. In some embodiments, the TEC inhibitor, immu twice per day, three times per day, once daily, every other nomodulatory agent, and steroid are not co-administered day, once a week, twice a week, three times a week, every with a strong CYP3A inhibitor or a strong CYP3A inducer. other week, three times a month, once a month, or intermit Examples of strong CYP3A inhibitors include, but are not tently. limited to, ketoconazole, ritonavir, indinavir, nelfinavir, 0070. In some embodiments, ibrutinib is administered saquinavir, boceprevir, telaprevir, and nefazodone. once per day, twice per day, three times per day, once daily, Examples of strong CYP3A inducers include, but are not every other day, once a week, twice a week, three times a limited to, rifampin, carbamazepine, phenytoin, and St. week, every other week, three times a month, once a month, John's Wort. or intermittently. In some embodiments, ibrutinib is admin 0077. In some embodiments, the TEC inhibitor, immu istered once per day. In some embodiments, ibrutinib is nomodulatory agent, and steroid are not co-administered administered as a maintenance therapy. with a strong CYP1A2 inhibitor, such as fluvoxamine or 0071. In some embodiments, ibrutinib is administered ciprofloxacin. daily during each cycle. In some embodiments, each cycle 0078. The pharmaceutical composition described herein comprises 28 days. in some instances is in unit dosage forms Suitable for single 0072. In some embodiments, the TEC inhibitor is admin administration of precise dosages. In unit dosage form, the istered oral, parenteral (e.g., intravenous, Subcutaneous, or formulation is divided into unit doses containing appropriate intramuscular), buccal, intranasal, rectal or transdermal quantities of one or more compound. In some cases, the unit administration routes. In some embodiments, the TEC dosage is in the form of a package containing discrete inhibitor is administered orally. In some embodiments, the quantities of the formulation. Non-limiting examples are ITK inhibitor is administered orally. In some instances, the packaged tablets or capsules, and powders in vials or BTK inhibitor is administered orally. In some instances, ampoules. In some cases, aqueous Suspension compositions ibrutinib is administered orally. are packaged in single-dose non-reclosable containers. 0073. In the case wherein the patient’s status does Alternatively, multiple-dose reclosable containers in other improve, upon the doctor's discretion the administration of cases are used, in which case it is typical to include a the compounds in some cases is given continuously; alter preservative in the composition. By way of example only, natively, the dose of drug being administered in some cases formulations for parenteral injection presented in unit dos is temporarily reduced or temporarily Suspended for a cer age form, include, but are not limited to ampoules, or in tain length of time (i.e., a "drug holiday'). In some embodi multi-dose containers, with an added preservative. ments, the length of the drug holiday varies between 2 days 0079. In certain embodiments, the invention relates to and 1 year, including by way of example only, 2 days, 3 any of the pharmaceutical compositions or methods days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 described herein, wherein the pharmaceutical composition days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, or method comprises ibrutinib or its use; and the unit dosage 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, of ibrutinib is a capsule comprising 140 mg of ibrutinib. In 300 days, 320 days, 350 days, or 365 days. The dose certain embodiments, the unit dosage of ibrutinib is a reduction during a drug holiday may be from 10%-100%, capsule comprising 140 mg of ibrutinib, croScarmellose including, by way of example only, 10%, 15%, 20%, 25%, Sodium, magnesium Stearate, microcrystalline cellulose, and 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, Sodium lauryl Sulfate. 80%, 85%, 90%, 95%, or 100%. In some embodiments, the 0080. In certain embodiments, the invention relates to drug holiday may be for ibrutinib, pomalidomide, dexam any of the pharmaceutical compositions or methods ethasone, or a combination thereof. described herein, wherein the pharmaceutical composition 0074. Once improvement of the patient’s conditions has or method comprises pomalidomide or its use; and the unit occurred, a maintenance dose is administered if necessary. dosage of pomalidomide is a capsule comprising 1 mg, 2 Subsequently, the dosage or the frequency of administration, mg, 3 mg, or 4 mg of pomalidomide. In certain embodi or both, in certain cases, is reduced, as a function of the ments, the unit dosage of pomalidomide is a capsule com symptoms, to a level at which the improved disease, disorder prising 1 mg, 2 mg, 3 mg. or 4 mg of pomalidomide, or condition is retained. In certain cases, patients require mannitol, pregelatinized starch, and sodium Stearyl fumar intermittent treatment on a long-term basis upon any recur ate. rence of symptoms. 0081. In certain embodiments, the invention relates to 0075. The amount of a given agent that will correspond any of the pharmaceutical compositions or methods to Such an amount will vary depending upon factors such as described herein, wherein the pharmaceutical composition the particular compound, the severity of the disease, the or method comprises dexamethasone or its use; and the unit identity (e.g., weight) of the Subject or host in need of dosage of dexamethasone is a tablet comprising 0.5 mg, 0.75 US 2017/0209462 A1 Jul. 27, 2017

mg, 1 mg, 1.5 mg, 2 mg, 4 mg. or 6 mg of dexamethasone. wherein: In certain embodiments, the invention relates to any of the pharmaceutical compositions or methods described herein, A is N: wherein the pharmaceutical composition or method com prises dexamethasone or its use; and the unit dosage of I0086 R is phenyl-O-phenyl or phenyl-S-phenyl: dexamethasone is an elixir comprising 1 mg/mL of dexam R and R are independently H; ethasone. In certain embodiments, the invention relates to R is L-X-La-G, wherein, any of the pharmaceutical compositions or methods L is optional, and when present is a bond, optionally described herein, wherein the pharmaceutical composition substituted or unsubstituted alkyl, optionally substituted or or method comprises dexamethasone or its use; and the unit unsubstituted cycloalkyl, optionally substituted or unsubsti dosage of dexamethasone is an elixir comprising 0.5 mg/5 tuted alkenyl, optionally substituted or unsubstituted alky mL of dexamethasone. In certain embodiments, the inven nyl: tion relates to any of the pharmaceutical compositions or X is optional, and when present is a bond, —O—, methods described herein, wherein the pharmaceutical com position or method comprises dexamethasone or its use; and the unit dosage of dexamethasone is a solution comprising 0.5 mg/5 mL of dexamethasone. 0082 The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condi tion to be treated, the mode of administration, the require L is optional, and when present is a bond, Substituted or ments of the individual subject, the severity of the disease or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, condition being treated, and the judgment of the practitioner. substituted or unsubstituted alkenyl, substituted or unsub 0083 Toxicity and therapeutic efficacy of such therapeu stituted alkynyl, substituted or unsubstituted aryl, substi tic regimens are determined in some instances by standard tuted or unsubstituted heteroaryl, substituted or unsubsti pharmaceutical procedures in cell cultures or experimental tuted heterocycle: animals, including, but not limited to, the determination of or L., X and La taken together form a nitrogen containing the LD50 (the dose lethal to 50% of the population) and the heterocyclic ring: ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeu G is tic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50. Compounds exhibiting high 0087 therapeutic indices are preferred. In some instances, the data obtained from cell culture assays and animal studies are used in formulating a range of dosage for use in human. The O R6 O dosage of Such compounds lies preferably within a range of circulating concentrations that include the ED50 with mini mal toxicity. The dosage may vary within this range depend 21 R7, 2n ing upon the dosage form employed and the route of Rs administration utilized. O O R6 O R6 Btk Inhibitor Compounds and Pharmaceutically Acceptable \/ Salts. Thereof 0084. The Btk inhibitor compound described herein (i.e., wers. v. S. . ibrutinib) is selective for Btk and kinases having a cysteine Rs Rs residue in an amino acid sequence position of the tyrosine O R6 kinase that is homologous to the amino acid sequence | position of cysteine 481 in Btk. The Btkinhibitor compound | 2 R7, can form a covalent bond with Cys 481 of Btk (e.g., via a RO Rs Michael reaction). 0085. In some embodiments, the Btk inhibitor is a com pound of Formula (A) having the structure: wherein, R. R., and Rs are independently selected from the group consisting of H, halogen, CN, OH, substituted or unsubsti R R Formula (A) tuted alkyl or substituted or unsubstituted heteroalkyl or 3 n1 2 substituted or unsubstituted cycloalkyl, substituted or unsub N R stituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; N1| N y, each Ro is independently selected from the group consisting 4. N^ of H, substituted or unsubstituted lower alkyl, and substi V tuted or unsubstituted lower cycloalkyl: R4; each Ro is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl: O US 2017/0209462 A1 Jul. 27, 2017

two Rogroups can together form a 5-, 6-, 7-, or 8-membered 0.091 acid addition salts formed by reacting ibrutinib heterocyclic ring; or with an inorganic acid, which includes hydrochloric Ro and R can together form a 5-, 6-, 7-, or 8-membered acid, hydrobromic acid, Sulfuric acid, nitric acid, phos heterocyclic ring; or each R is independently selected from phoric acid, hydroiodic acid, hydrofluoric acid, phos the group consisting of H and Substituted or unsubstituted phorous acid, and the like. alkyl; or a pharmaceutically acceptable salt thereof. In some 0092. The term “pharmaceutically acceptable salts' in embodiments, L., X and La taken together form a nitrogen reference to ibrutinib refers to a salt of ibrutinib, which does containing heterocyclic ring. In some embodiments, the not cause significant irritation to a mammal to which it is nitrogen containing heterocyclic ring is a piperidine group. administered and does not substantially abrogate the bio In some embodiments, G is logical activity and properties of the compound. 0093. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addi tion forms (solvates). Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, In some embodiments, the compound of Formula (A) is methyl isobutyl ketone (MIBK), methyl ethyl ketone 1-(3R)-3-4-amino-3-(4-phenoxyphenyl)pyrazolo 3,4-d (MEK), acetone, nitromethane, tetrahydrofuran (THF), pyrimidin-1-yl)piperidin-1-ylprop-2-en-1-one. dichloromethane (DCM), dioxane, heptanes, toluene, ani 0088. “Ibrutinib' or “1-((R)-3-(4-amino-3-(4-phenoxy sole, acetonitrile, and the like. In one aspect, Solvates are phenyl)-1H-pyrazolo 3,4-dpyrimidin-1-yl)piperidin-1-yl) formed using, but limited to, Class 3 solvent(s). Categories prop-2-en-1-one” or “1-((3R)-3-4-amino-3-(4-phenoxy of solvents are defined in, for example, the International phenyl)-1H-pyrazolo 3,4-dpyrimidin-1-yl)piperidin-1- Conference on Harmonization of Technical Requirements yl)prop-2-en-1-one” or “2-Propen-1-one, 1-(3R)-3-4- for Registration of Pharmaceuticals for Human Use (ICH), amino-3-(4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin “Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). Hydrates are formed when the solvent is 1-yl)-1-piperidinyl- or ibrutinib or any other suitable name water, or alcoholates are formed when the solvent is alcohol. refers to the compound with the following structure: In some embodiments, Solvates of ibrutinib, or pharmaceu tically acceptable salts thereof, are conveniently prepared or formed during the processes described herein. In some embodiments, solvates of ibrutinib are anhydrous. In some embodiments, ibrutinib, or pharmaceutically acceptable O salts thereof, exist in unsolvated form. In some embodi ments, ibrutinib, or pharmaceutically acceptable salts thereof, exist in unsolvated form and are anhydrous. 0094. In yet other embodiments, ibrutinib, or a pharma NH ceutically acceptable salt thereof, is prepared in various forms, including but not limited to, amorphous phase, crys N1 N talline forms, milled forms and nano-particulate forms. In Some embodiments, ibrutinib, or a pharmaceutically accept DO4. N able salt thereof, is amorphous. In some embodiments, ibrutinib, or a pharmaceutically acceptable salt thereof, is amorphousand anhydrous. In some embodiments, ibrutinib, or a pharmaceutically acceptable Salt thereof, is crystalline. In some embodiments, ibrutinib, or a pharmaceutically acceptable salt thereof, is crystalline and anhydrous. 0095. In some embodiments, ibrutinib is prepared as outlined in U.S. Pat. No. 7,514,444, incorporated by refer 0089. A wide variety of pharmaceutically acceptable salts CCC. may be formed from ibrutinib and includes: 0096. In some embodiments, the Btk inhibitor is PCI 0090 acid addition salts formed by reacting ibrutinib 45292, PCI-45466, AVL-101/CC-101 (Avila Therapeutics/ with an organic acid, which includes aliphatic mono Celgene Corporation), AVL-263/CC-263 (Avila Therapeu and dicarboxylic acids, phenyl-substituted alkanoic tics/Celgene Corporation), AVL-292/CC-292 (Avila acids, hydroxyl alkanoic acids, alkanedioic acids, aro Therapeutics/Celgene Corporation), AVL-291/CC-291 matic acids, aliphatic and aromatic sulfonic acids, (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila amino acids, etc. and include, for example, acetic acid, Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS trifluoroacetic acid, propionic acid, glycolic acid, pyru 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/ Vic acid, oxalic acid, maleic acid, malonic acid, Suc Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), cinic acid, fumaric acid, tartaric acid, citric acid, ben CTA-056, GDC-0834 (Genentech), HY-11066 (also, Zoic acid, cinnamic acid, mandelic acid, CTK4I7891, HMS3265G21, HMS3265G22, methanesulfonic acid, ethanesulfonic acid, p-toluene HMS3265H21, HMS3265H22,439574-61-5, AG-F-54930), Sulfonic acid, salicylic acid, and the like; ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37

US 2017/0209462 A1 Jul. 27, 2017 13

-continued - s n-- O O- F J. N-1-

-O OPh

NH2 NH2 N1S-N N1 N-\

l 2 NX l 4N/N

US 2017/0209462 A1 Jul. 27, 2017 14

-continued

N |C o s

FC | N - O leN NH N1 N

HN - N - NH2

N21 e O , N \ . ~~ O - US 2017/0209462 A1 Jul. 27, 2017 15

C -continued

O Cl, NH2

N21

lsN NH Nrs O

s

O ? N O 21

NH CuOO CO N ls O or a pharmaceutically acceptable salt thereof. 076228, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor Additional TEC Family Kinase Inhibitors compound described in WO 2007/058832, which is incor 0099 BTK is a member of the Tyrosine-protein kinase porated by reference in its entirety. In some embodiments, (TEC) family of kinases. In some embodiments, the TEC the Itk inhibitor is an Itk inhibitor compound described in family comprises BTK, ITK, TEC, RLK and BMX. In some WO 2004/016610, which is incorporated by reference in its embodiments, a TEC family kinase inhibitor inhibits the entirety. In some embodiments, the Itk inhibitor is an Itk kinase activity of BTK, ITK, TEC, RLK and BMX. In some inhibitor compound described in WO 2004/016611, which is embodiments, a TEC family kinase inhibitor is a BTK incorporated by reference in its entirety. In some embodi inhibitor, which is disclosed elsewhere herein. In some ments, the Itk inhibitor is an Itk inhibitor compound embodiments, a TEC family kinase inhibitor is an ITK described in WO 2004/016600, which is incorporated by inhibitor. In some embodiments, a TEC family kinase inhibi reference in its entirety. In some embodiments, the Itk tor is a TEC inhibitor. In some embodiments, a TEC family inhibitor is an Itk inhibitor compound described in WO kinase inhibitor is a RLK inhibitor. In some embodiments, a 2004/016615, which is incorporated by reference in its TEC family kinase inhibitor is a BMK inhibitor. entirety. In some embodiments, the Itk inhibitor is an Itk 0100. In some embodiments, the ITK inhibitor covalently inhibitor compound described in WO 2005/026175, which is binds to Cysteine 442 of ITK. In some embodiments, the Itk incorporated by reference in its entirety. In some embodi inhibitor is an Itk inhibitor compound described in WO ments, the Itk inhibitor is an Itk inhibitor compound 2002/0500071, which is incorporated by reference in its described in WO 2006/065946, which is incorporated by entirety. In some embodiments, the Itk inhibitor is an Itk reference in its entirety. In some embodiments, the Itk inhibitor compound described in WO 2005/070420, which is inhibitor is an Itk inhibitor compound described in WO incorporated by reference in its entirety. In some embodi 2007/027594, which is incorporated by reference in its ments, the Itk inhibitor is an Itk inhibitor compound entirety. In some embodiments, the Itk inhibitor is an Itk described in WO2005/079791, which is incorporated by inhibitor compound described in WO 2007/017455, which is reference in its entirety. In some embodiments, the Itk incorporated by reference in its entirety. In some embodi inhibitor is an Itkinhibitor compound described in WO2007/ ments, the Itk inhibitor is an Itk inhibitor compound US 2017/0209462 A1 Jul. 27, 2017 16 described in WO 2008/025820, which is incorporated by incorporated by reference in its entirety. In some embodi reference in its entirety. In some embodiments, the Itk ments, the Itk inhibitor is an Itk inhibitor compound inhibitor is an Itk inhibitor compound described in WO described in WO 2014/093383, which is incorporated by 2008/025821, which is incorporated by reference in its reference in its entirety. In some embodiments, the Itk entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor is an Itkinhibitor compound described in U.S. Pat. inhibitor compound described in WO 2008/025822, which is No. 8,759.358, which is incorporated by reference in its incorporated by reference in its entirety. In some embodi entirety. In some embodiments, the Itk inhibitor is an Itk ments, the Itk inhibitor is an Itk inhibitor compound inhibitor compound described in WO 2014/105958, which is described in WO 2011/017219, which is incorporated by incorporated by reference in its entirety. In some embodi reference in its entirety. In some embodiments, the Itk ments, the Itk inhibitor is an Itk inhibitor compound inhibitor is an Itk inhibitor compound described in WO described in US 2014/0256704, which is incorporated by 2011/090760, which is incorporated by reference in its reference in its entirety. In some embodiments, the Itk entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor is an Itk inhibitor compound described in US inhibitor compound described in WO 2009/158571, which is 2014/0315909, which is incorporated by reference in its incorporated by reference in its entirety. In some embodi entirety. In some embodiments, the Itk inhibitor is an Itk ments, the Itk inhibitor is an Itk inhibitor compound inhibitor compound described in US 2014/0303161, which described in WO 2009/051822, which is incorporated by is incorporated by reference in its entirety. In some embodi reference in its entirety. In some embodiments, the Itk ments, the Itk inhibitor is an Itk inhibitor compound inhibitor is an Itk inhibitor compound described in US described in WO 2014/145403, which is incorporated by 2011/0281850, which is incorporated by reference in its reference in its entirety. entirety. In some embodiments, the Itk inhibitor is an Itk 0101. In some embodiments, the Itkinhibitor has a struc inhibitor compound described in WO 2014/082085, which is ture selected from the group consisting of

N Y, O y O, S. N

N O

OH US 2017/0209462 A1 Jul. 27, 2017

-continued

21

O N

Hematologic Malignancies Small lymphocytic lymphoma (SLL), high risk CLL, a non-CLL/SLL lymphoma, or prolymphocytic leukemia 0102 Disclosed herein are pharmaceutical combinations, (PLL). In some embodiments, the cancer is follicular lym methods, and dosing regimen for administering a combina phoma (FL), diffuse large B-cell lymphoma (DLBCL), tion of three active ingredients: a TEC inhibitor, an immu mantle cell lymphoma (MCL), Waldenström's macroglobu nomodulary agent, and a steroid for the treatment of a linemia, multiple myeloma, extranodal marginal Zone B cell hematologic malignancy. In some embodiments, the hema lymphoma, nodal marginal Zone B cell lymphoma, Burkitt's tologic malignancy is a leukemia, a lymphoma, a myeloma, lymphoma, non-Burkitt high grade B cell lymphoma, pri a non-Hodgkin’s lymphoma, a Hodgkin’s lymphoma, a mary mediastinal B-cell lymphoma (PMBL), immunoblastic T-cell malignancy, or a B-cell malignancy. In some embodi large cell lymphoma, precursor B-lymphoblastic lymphoma, ments, the hematological malignancy is a treatment naive B cell prolymphocytic leukemia, lymphoplasmacytic lym hematological malignancy. In some embodiments the hema phoma, splenic marginal Zone lymphoma, plasma cell tological malignancy is a relapsed or refractory hematologi myeloma, plasmacytoma, mediastinal (thymic) large B cell cal malignancy. lymphoma, intravascular large B cell lymphoma, primary 0103) In some embodiments, the hematologic malig effusion lymphoma, or lymphomatoid granulomatosis. In nancy is a T-cell malignancy. In some embodiments, the some embodiments, DLBCL is further divided into sub T-cell malignancy is peripheral T-cell lymphoma not other types: activated B-cell diffuse large B-cell lymphoma (ABC wise specified (PTCL-NOS), anaplastic large cell lym DLBCL), germinal center diffuse large B-cell lymphoma phoma, angioimmunoblastic lymphoma, cutaneous T-cell (GCB DLBCL), and Double-Hit (DH) DLBCL. In some lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic embodiments, ABC-DLBCL is characterized by a CD79B NK-cell lymphoma, enteropathy-type T-cell lymphoma, mutation. In some embodiments, ABC-DLBCL is charac hematosplenic gamma-delta T-cell lymphoma, lymphoblas terized by a CD79A mutation. In some embodiments, the tic lymphoma, nasal NK/T-cell lymphomas, or treatment ABC-DLBCL is characterized by a mutation in MyD88, related T-cell lymphomas. A20, or a combination thereof. In some embodiments, the 0104. In some embodiments, the hematologic malig cancer is acute or chronic myelogenous (or myeloid) leu nancy is a B-cell proliferative disorder. In some embodi kemia, myelodysplastic syndrome, or acute lymphoblastic ments, the cancer is chronic lymphocytic leukemia (CLL), leukemia. US 2017/0209462 A1 Jul. 27, 2017

0105. In some embodiments, the cancer is multiple (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's myeloma. In some embodiments, the cancer is diffuse large macroglobulinemia, extranodal marginal Zone B cell lym B-cell lymphoma (DLBCL). In some embodiments, the phoma, nodal marginal Zone B cell lymphoma, Burkitt's cancer is activated B-cell diffuse large B-cell lymphoma lymphoma, non-Burkitt high grade B cell lymphoma, pri (ABC-DLBCL). In some embodiments, the cancer is folli mary mediastinal B-cell lymphoma (PMBL), immunoblastic cular lymphoma (FL). In some embodiments, the cancer is large cell lymphoma, precursor B-lymphoblastic lymphoma, multiple myeloma. In some embodiments, the cancer is B cell prolymphocytic leukemia, lymphoplasmacytic lym chronic lymphocytic leukemia (CLL). In some embodi phoma, splenic marginal Zone lymphoma, plasma cell ments, the cancer is Small lymphocytic lymphoma (SLL). In myeloma, plasmacytoma, mediastinal (thymic) large B cell Some embodiments, the cancer is non-CLL/SLL lymphoma. lymphoma, intravascular large B cell lymphoma, primary In some embodiments, the cancer is high risk CLL or high effusion lymphoma, and lymphomatoid granulomatosis. risk SLL. In some embodiments, the cancer is PLL. In some 0109. In some embodiments, described herein methods embodiments, the cancer is MCL. In some embodiments, the and dosing regimen for administering a combination of a cancer is Waldenström's macroglobulinemia. TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), an 0106. In some embodiments, a cancer is a treatment immunomodulatory agent (e.g., pomalidomide), and a ste naive cancer. In some instances, a treatment-naive cancer is roid (e.g., dexamethasone) for the treatment of multiple a cancer that has not been treated by a therapy, such as for myeloma. example by a TEC inhibitor, an immunomodulatory agent, 0110. In some embodiments, described herein methods and/or by an additional therapeutic agent disclosed else and dosing regimen for administering a combination of a where herein. In some embodiments, a treatment-naive TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), an cancer is a hematologic cancer. immunomodulatory agent (e.g., pomalidomide), and a ste 0107. In some embodiments, the treatment-naive hema roid (e.g., dexamethasone) for the treatment of CLL. tologic cancer is a leukemia, a lymphoma, a myeloma, a 0111. In some embodiments, described herein methods non-Hodgkin’s lymphoma, a Hodgkin’s lymphoma, a T-cell and dosing regimen for administering a combination of a malignancy, or a B-cell malignancy. In some embodiments, TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), an the treatment-naive hematologic cancer is a B-cell malig immunomodulatory agent (e.g., pomalidomide), and a ste nancy. In some embodiments, the B-cell malignancy is roid (e.g., dexamethasone) for the treatment of SLL. chronic lymphocytic leukemia (CLL), Small lymphocytic 0.112. In some embodiments, described herein methods lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, and dosing regimen for administering a combination of a prolymphocytic leukemia (PLL), follicular lymphoma (FL), TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), an diffuse large B-cell lymphoma (DLBCL), mantle cell lym immunomodulatory agent (e.g., pomalidomide), and a ste phoma (MCL), Waldenström's macroglobulinemia, multiple roid (e.g., dexamethasone) for the treatment of PLL. myeloma, extranodal marginal Zone B cell lymphoma, nodal 0113. In some embodiments, described herein methods marginal Zone B cell lymphoma, Burkitt's lymphoma, non and dosing regimen for administering a combination of a Burkitt high grade B cell lymphoma, primary mediastinal TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), an B-cell lymphoma (PMBL), immunoblastic large cell lym immunomodulatory agent (e.g., pomalidomide), and a ste phoma, precursor B-lymphoblastic lymphoma, B cell pro roid (e.g., dexamethasone) for the treatment of DLBCL. lymphocytic leukemia, lymphoplasmacytic lymphoma, 0114. In some embodiments, described herein methods splenic marginal Zone lymphoma, plasma cell myeloma, and dosing regimen for administering a combination of a plasmacytoma, mediastinal (thymic) large B cell lymphoma, TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), an intravascular large B cell lymphoma, primary effusion lym immunomodulatory agent (e.g., pomalidomide), and a ste phoma, or lymphomatoid granulomatosis. In some embodi roid (e.g., dexamethasone) for the treatment of MCL. ments, the treatment-naive hematologic cancer is CLL. In 0.115. In some embodiments, described herein methods Some embodiments, the treatment-naive hematologic cancer and dosing regimen for administering a combination of a is SLL. In some embodiments, the treatment-naive hema TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), an tologic cancer is DLBCL. In some embodiments, the treat immunomodulatory agent (e.g., pomalidomide), and a ste ment-naive hematologic cancer is mantle cell lymphoma. In roid (e.g., dexamethasone) for the treatment of Walden Some embodiments, the treatment-naive hematologic cancer ström's macroglobulinemia. is FL. In some embodiments, the treatment-naive hemato 0116. In some embodiments, described herein methods logic cancer is Waldenstrom's macroglobulinemia. In some and dosing regimen for administering a combination of a embodiments, the treatment-naive hematologic cancer is BTK inhibitor, an immunomodulatory agent, and a steroid multiple myeloma. In some embodiments, the treatment for the treatment of a hematologic malignancy selected from naive hematologic cancer is Burkitt's lymphoma. In some the group consisting of multiple myeloma, chronic lympho embodiments, the treatment-naive hematologic cancer is cytic leukemia (CLL), Small lymphocytic lymphoma (SLL). PLL. high risk CLL, non-CLL/SLL lymphoma, prolymphocytic 0108. In some embodiments, described herein methods leukemia (PLL), follicular lymphoma (FL), diffuse large and dosing regimen for administering a combination of a B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), TEC inhibitor (e.g., ITK inhibitor or a BTK inhibitor), a Waldenstrom's macroglobulinemia, extranodal marginal proteasome inhibitor, and a steroid for the treatment of a Zone B cell lymphoma, nodal marginal Zone B cell lym hematologic malignancy selected from the group consisting phoma, Burkitt's lymphoma, non-Burkitt high grade B cell of multiple myeloma, chronic lymphocytic leukemia (CLL), lymphoma, primary mediastinal B-cell lymphoma (PMBL), Small lymphocytic lymphoma (SLL), high risk CLL, non immunoblastic large cell lymphoma, precursor B-lympho CLL/SLL lymphoma, prolymphocytic leukemia (PLL), fol blastic lymphoma, B cell prolymphocytic leukemia, lym licular lymphoma (FL), diffuse large B-cell lymphoma phoplasmacytic lymphoma, splenic marginal Zone lym US 2017/0209462 A1 Jul. 27, 2017

phoma, plasma cell myeloma, plasmacytoma, mediastinal 0.126 In some embodiments, described herein methods (thymic) large B cell lymphoma, intravascular large B cell and dosing regimen for administering a combination of lymphoma, primary effusion lymphoma, and lymphomatoid ibrutinib, an immunomodulatory agent (e.g., pomalido granulomatosis. mide), and a steroid (e.g., dexamethasone) for the treatment 0117. In some embodiments, described herein methods of CLL. and dosing regimen for administering a combination of a 0127. In some embodiments, described herein methods BTK inhibitor, an immunomodulatory agent (e.g., and dosing regimen for administering a combination of pomalidomide), and a steroid (e.g., dexamethasone) for the ibrutinib, immunomodulatory agent (e.g., pomalidomide), treatment of multiple myeloma. and a steroid (e.g., dexamethasone) for the treatment of SLL. 0118. In some embodiments, described herein methods 0128. In some embodiments, described herein methods and dosing regimen for administering a combination of a and dosing regimen for administering a combination of BTK inhibitor, an immunomodulatory agent (e.g., ibrutinib, immunomodulatory agent (e.g., pomalidomide), pomalidomide), and a steroid (e.g., dexamethasone) for the and a steroid (e.g., dexamethasone) for the treatment of PLL. treatment of CLL. 0129. In some embodiments, described herein methods 0119. In some embodiments, described herein methods and dosing regimen for administering a combination of and dosing regimen for administering a combination of a ibrutinib, immunomodulatory agent (e.g., pomalidomide), BTK inhibitor BTK inhibitor, an immunomodulatory agent and a steroid (e.g., dexamethasone) for the treatment of (e.g., pomalidomide), and a steroid (e.g., dexamethasone) DLBCL. for the treatment of SLL. 0.130. In some embodiments, described herein methods 0120 In some embodiments, described herein methods and dosing regimen for administering a combination of and dosing regimen for administering a combination of a ibrutinib, immunomodulatory agent (e.g., pomalidomide), BTK inhibitor BTK inhibitor, an immunomodulatory agent and a steroid (e.g., dexamethasone) for the treatment of (e.g., pomalidomide), and a steroid (e.g., dexamethasone) MCL. for the treatment of PLL. 0.131. In some embodiments, described herein methods 0121. In some embodiments, described herein methods and dosing regimen for administering a combination of and dosing regimen for administering a combination of a ibrutinib, immunomodulatory agent (e.g., pomalidomide), BTK inhibitor BTK inhibitor, an immunomodulatory agent and a steroid (e.g., dexamethasone) for the treatment of (e.g., pomalidomide), and a steroid (e.g., dexamethasone) Waldenström's macroglobulinemia. for the treatment of DLBCL. (0132) In some embodiments, described herein methods 0122. In some embodiments, described herein methods and dosing regimen for administering a combination of a and dosing regimen for administering a combination of a TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor such BTK inhibitor BTK inhibitor, an immunomodulatory agent as ibrutinib), immunomodulatory agent (e.g., pomalido (e.g., pomalidomide), and a steroid (e.g., dexamethasone) mide), and a steroid (e.g., dexamethasone) for the treatment for the treatment of MCL. of a treatment-naive hematologic malignancy selected from 0123. In some embodiments, described herein methods the group consisting of multiple myeloma, chronic lympho and dosing regimen for administering a combination of a cytic leukemia (CLL), Small lymphocytic lymphoma (SLL). BTK inhibitor BTK inhibitor, an immunomodulatory agent high risk CLL, non-CLL/SLL lymphoma, prolymphocytic (e.g., pomalidomide), and a steroid (e.g., dexamethasone) leukemia (PLL), follicular lymphoma (FL), diffuse large for the treatment of Waldenström's macroglobulinemia. B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), 0124. In some embodiments, described herein methods Waldenstrom's macroglobulinemia, extranodal marginal and dosing regimen for administering a combination of Zone B cell lymphoma, nodal marginal Zone B cell lym ibrutinib, a proteasome inhibitor, and a steroid for the phoma, Burkitt's lymphoma, non-Burkitt high grade B cell treatment of a hematologic malignancy selected from the lymphoma, primary mediastinal B-cell lymphoma (PMBL), group consisting of multiple myeloma, chronic lymphocytic immunoblastic large cell lymphoma, precursor B-lympho leukemia (CLL), Small lymphocytic lymphoma (SLL), high blastic lymphoma, B cell prolymphocytic leukemia, lym risk CLL, non-CLL/SLL lymphoma, prolymphocytic leuke phoplasmacytic lymphoma, splenic marginal Zone lym mia (PLL), follicular lymphoma (FL), diffuse large B-cell phoma, plasma cell myeloma, plasmacytoma, mediastinal lymphoma (DLBCL), mantle cell lymphoma (MCL), (thymic) large B cell lymphoma, intravascular large B cell Waldenstrom's macroglobulinemia, extranodal marginal lymphoma, primary effusion lymphoma, and lymphomatoid Zone B cell lymphoma, nodal marginal Zone B cell lym granulomatosis. phoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), Relapsed or Refractory Hematologic Malignancy immunoblastic large cell lymphoma, precursor B-lympho I0133. In some embodiments, the hematologic cancer is a blastic lymphoma, B cell prolymphocytic leukemia, lym relapsed or refractory hematologic cancer. In some embodi phoplasmacytic lymphoma, splenic marginal Zone lym ments, the relapsed or refractory hematologic cancer is a phoma, plasma cell myeloma, plasmacytoma, mediastinal leukemia, a lymphoma, a myeloma, a non-Hodgkin’s lym (thymic) large B cell lymphoma, intravascular large B cell phoma, a Hodgkin’s lymphoma, T-cell malignancy, or a lymphoma, primary effusion lymphoma, and lymphomatoid B-cell malignancy. granulomatosis. I0134. In some embodiments, the relapsed or refractory 0125. In some embodiments, described herein methods hematologic cancer is a T-cell malignancy. In some embodi and dosing regimen for administering a combination of ments, the relapsed or refractory T-cell malignancy is ibrutinib, an immunomodulatory agent (e.g., pomalido peripheral T-cell lymphoma not otherwise specified (PTCL mide), and a steroid (e.g., dexamethasone) for the treatment NOS), anaplastic large cell lymphoma, angioimmunoblastic of multiple myeloma. lymphoma, cutaneous T-cell lymphoma, adult T-cell leuke US 2017/0209462 A1 Jul. 27, 2017 20 mia/lymphoma (ATLL), blastic NK-cell lymphoma, large B-cell lymphoma (DLBCL), mantle cell lymphoma enteropathy-type T-cell lymphoma, hematosplenic gamma (MCL), Waldenstrom's macroglobulinemia, extranodal delta T-cell lymphoma, lymphoblastic lymphoma, nasal marginal Zone B cell lymphoma, nodal marginal Zone B cell NK/T-cell lymphomas, or treatment-related T-cell lympho lymphoma, Burkitt's lymphoma, non-Burkitt high grade B aS cell lymphoma, primary mediastinal B-cell lymphoma 0135) In some embodiments, the relapsed or refractory (PMBL), immunoblastic large cell lymphoma, precursor hematologic cancer is a B-cell proliferative disorder. In B-lymphoblastic lymphoma, B cell prolymphocytic leuke Some embodiments, the relapsed or refractory cancer is mia, lymphoplasmacytic lymphoma, splenic marginal Zone chronic lymphocytic leukemia (CLL), Small lymphocytic lymphoma, plasma cell myeloma, plasmacytoma, mediasti lymphoma (SLL), high risk CLL, a non-CLL/SLL lym nal (thymic) large B cell lymphoma, intravascular large B phoma, or prolymphocytic leukemia (PLL). In some cell lymphoma, primary effusion lymphoma, and lympho embodiments, the cancer is follicular lymphoma, diffuse matoid granulomatosis. large B-cell lymphoma (DLBCL), mantle cell lymphoma 0.138. In some embodiments, described herein are meth (MCL), Waldenström's macroglobulinemia, multiple ods and dosing regimen for administering a combination of myeloma, extranodal marginal Zone B cell lymphoma, nodal a TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), marginal Zone B cell lymphoma, Burkitt's lymphoma, non immunomodulatory agent (e.g., pomalidomide), and a ste Burkitt high grade B cell lymphoma, primary mediastinal roid (e.g., dexamethasone) for the treatment of relapsed or B-cell lymphoma (PMBL), immunoblastic large cell lym refractory multiple myeloma. phoma, precursor B-lymphoblastic lymphoma, B cell pro 0.139. In some embodiments, described herein are meth lymphocytic leukemia, lymphoplasmacytic lymphoma, ods and dosing regimen for administering a combination of splenic marginal Zone lymphoma, plasma cell myeloma, a TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), plasmacytoma, mediastinal (thymic) large B cell lymphoma, an immunomodulatory agent (e.g., pomalidomide), and a intravascular large B cell lymphoma, primary effusion lym steroid (e.g., dexamethasone) for the treatment of relapsed or phoma, or lymphomatoid granulomatosis. In some embodi refractory CLL. ments, the relapsed or refractory DLBCL is further divided 0140. In some embodiments, described herein are meth into subtypes: activated B-cell diffuse large B-cell lym ods and dosing regimen for administering a combination of phoma (ABC-DLBCL), germinal center diffuse large B-cell a TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), lymphoma (GCB DLBCL), and Double-Hit (DH) DLBCL. an immunomodulatory agent (e.g., pomalidomide), and a In some embodiments, ABC-DLBCL is characterized by a steroid (e.g., dexamethasone) for the treatment of relapsed or CD79B mutation. In some embodiments, ABC-DLBCL is refractory SLL. characterized by a CD79A mutation. In some embodiments, 0.141. In some embodiments, described herein are meth the ABC-DLBCL is characterized by a mutation in MyD88, ods and dosing regimen for administering a combination of A20, or a combination thereof. In some embodiments, the a TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), cancer is acute or chronic myelogenous (or myeloid) leu an immunomodulatory agent (e.g., pomalidomide), and a kemia, myelodysplastic syndrome, or acute lymphoblastic steroid (e.g., dexamethasone) for the treatment of relapsed or leukemia. refractory PLL. 0136. In some embodiments, the cancer is relapsed or 0142. In some embodiments, described herein are meth refractory multiple myeloma. In some embodiments, the ods and dosing regimen for administering a combination of cancer is relapsed or refractory diffuse large B-cell lym a TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), phoma (DLBCL). In some embodiments, the cancer is an immunomodulatory agent (e.g., pomalidomide), and a relapsed or refractory activated B-cell diffuse large B-cell steroid (e.g., dexamethasone) for the treatment of relapsed or lymphoma (ABC-DLBCL). In some embodiments, the can refractory DLBCL. cer is relapsed or refractory follicular lymphoma (FL). In 0143. In some embodiments, described herein are meth Some embodiments, the cancer is relapsed or refractory ods and dosing regimen for administering a combination of multiple myeloma. In some embodiments, the cancer is a TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), relapsed or refractory chronic lymphocytic leukemia (CLL). an immunomodulatory agent (e.g., pomalidomide), and a In some embodiments, the cancer is relapsed or refractory steroid (e.g., dexamethasone) for the treatment of relapsed or Small lymphocytic lymphoma (SLL). In some embodiments, refractory MCL. the cancer is relapsed or refractory non-CLL/SLL lym 0144. In some embodiments, described herein are meth phoma. In some embodiments, the cancer is relapsed or ods and dosing regimen for administering a combination of refractory high risk CLL or high risk SLL. In some embodi a TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), ments, the cancer is relapsed or refractory PLL. In some an immunomodulatory agent (e.g., pomalidomide), and a embodiments, the cancer is relapsed or refractory MCL. In steroid (e.g., dexamethasone) for the treatment of relapsed or Some embodiments, the cancer is relapsed or refractory refractory Waldenström's macroglobulinemia. Waldenström's macroglobulinemia. (0145. In some embodiments, described herein methods 0137 In some embodiments, described herein methods and dosing regimen for administering a combination of a and dosing regimen for administering a combination of a BTK inhibitor and an immunomodulatory agent (e.g., TEC inhibitor (e.g., ITK inhibitor or a BTK inhibitor), a pomalidomide) for the treatment of a relapsed or refractory proteasome inhibitor, and a steroid for the treatment of a hematologic malignancy selected from the group consisting relapsed or refractory hematologic malignancy selected of multiple myeloma, chronic lymphocytic leukemia (CLL), from the group consisting of multiple myeloma, chronic Small lymphocytic lymphoma (SLL), high risk CLL, non lymphocytic leukemia (CLL), Small lymphocytic lymphoma CLL/SLL lymphoma, prolymphocytic leukemia (PLL), fol (SLL), high risk CLL, non-CLL/SLL lymphoma, prolym licular lymphoma (FL), diffuse large B-cell lymphoma phocytic leukemia (PLL), follicular lymphoma (FL), diffuse (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's US 2017/0209462 A1 Jul. 27, 2017 macroglobulinemia, extranodal marginal Zone B cell lym intravascular large B cell lymphoma, primary effusion lym phoma, nodal marginal Zone B cell lymphoma, Burkitt's phoma, and lymphomatoid granulomatosis. lymphoma, non-Burkitt high grade B cell lymphoma, pri 0154. In some embodiments, described herein are meth mary mediastinal B-cell lymphoma (PMBL), immunoblastic ods and dosing regimen for administering a combination of large cell lymphoma, precursor B-lymphoblastic lymphoma, ibrutinib, an immunomodulatory agent (e.g., pomalido B cell prolymphocytic leukemia, lymphoplasmacytic lym mide), and a steroid (e.g., dexamethasone) for the treatment phoma, splenic marginal Zone lymphoma, plasma cell of relapsed or refractory multiple myeloma. myeloma, plasmacytoma, mediastinal (thymic) large B cell 0.155. In some embodiments, described herein are meth lymphoma, intravascular large B cell lymphoma, primary ods and dosing regimen for administering a combination of effusion lymphoma, and lymphomatoid granulomatosis. ibrutinib, an immunomodulatory agent (e.g., pomalido 0146 In some embodiments, described herein are meth mide), and a steroid (e.g., dexamethasone) for the treatment ods and dosing regimen for administering a combination of of relapsed or refractory CLL. a BTK inhibitor, an immunomodulatory agent (e.g., 0156. In some embodiments, described herein are meth pomalidomide), and a steroid (e.g., dexamethasone) for the ods and dosing regimen for administering a combination of treatment of relapsed or refractory multiple myeloma. ibrutinib, an immunomodulatory agent (e.g., pomalido 0147 In some embodiments, described herein are meth mide), and a steroid (e.g., dexamethasone) for the treatment ods and dosing regimen for administering a combination of of relapsed or refractory SLL. a BTK inhibitor, an immunomodulatory agent (e.g., 0157. In some embodiments, described herein are meth pomalidomide), and a steroid (e.g., dexamethasone) for the ods and dosing regimen for administering a combination of treatment of relapsed or refractory CLL. ibrutinib, an immunomodulatory agent (e.g., pomalido 0148. In some embodiments, described herein are meth mide), and a steroid (e.g., dexamethasone) for the treatment ods and dosing regimen for administering a combination of of relapsed or refractory PLL. a BTK inhibitor, an immunomodulatory agent (e.g., 0158. In some embodiments, described herein are meth pomalidomide), and a steroid (e.g., dexamethasone) for the ods and dosing regimen for administering a combination of treatment of relapsed or refractory SLL. ibrutinib, an immunomodulatory agent (e.g., pomalido 0149. In some embodiments, described herein are meth mide), and a steroid (e.g., dexamethasone) for the treatment ods and dosing regimen for administering a combination of of relapsed or refractory DLBCL. a BTK inhibitor, an immunomodulatory agent (e.g., 0159. In some embodiments, described herein are meth pomalidomide), and a steroid (e.g., dexamethasone) for the ods and dosing regimen for administering a combination of treatment of relapsed or refractory PLL. ibrutinib, an immunomodulatory agent (e.g., pomalido 0150. In some embodiments, described herein are meth mide), and a steroid (e.g., dexamethasone) for the treatment ods and dosing regimen for administering a combination of of relapsed or refractory MCL. a BTK inhibitor, an immunomodulatory agent (e.g., (0160. In some embodiments, described herein are meth pomalidomide), and a steroid (e.g., dexamethasone) for the ods and dosing regimen for administering a combination of treatment of relapsed or refractory DLBCL. ibrutinib, an immunomodulatory agent (e.g., pomalido 0151. In some embodiments, described herein are meth mide), and a steroid (e.g., dexamethasone) for the treatment ods and dosing regimen for administering a combination of of relapsed or refractory Waldenström's macroglobulinemia. a BTK inhibitor, an immunomodulatory agent (e.g., 0.161. In some embodiments, the relapsed or refractory pomalidomide), and a steroid (e.g., dexamethasone) for the hematologic cancer is a relapsed or refractory ibrutinib treatment of relapsed or refractory MCL. resistant hematologic cancer. In some embodiments, 0152. In some embodiments, described herein are meth described herein methods and dosing regimen for adminis ods and dosing regimen for administering a combination of tering a combination of ibrutinib, an immunomodulatory a BTK inhibitor, an immunomodulatory agent (e.g., agent, and a steroid for the treatment of a relapsed or pomalidomide), and a steroid (e.g., dexamethasone) for the refractory ibrutinib-resistant hematologic malignancy treatment of relapsed or refractory Waldenström's macro selected from the group consisting of chronic lymphocytic globulinemia. leukemia (CLL), Small lymphocytic lymphoma (SLL), high 0153. In some embodiments, described herein methods risk CLL, non-CLL/SLL lymphoma, prolymphocytic leuke and dosing regimen for administering a combination of mia (PLL), follicular lymphoma (FL), diffuse large B-cell ibrutinib, an immunomodulatory agent, and a steroid for the lymphoma (DLBCL), mantle cell lymphoma (MCL), treatment of a relapsed or refractory hematologic malig Waldenstrom's macroglobulinemia, multiple myeloma, nancy selected from the group consisting of multiple extranodal marginal Zone B cell lymphoma, nodal marginal myeloma, chronic lymphocytic leukemia (CLL), Small lym Zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt phocytic lymphoma (SLL), high risk CLL, non-CLL/SLL high grade B cell lymphoma, primary mediastinal B-cell lymphoma, prolymphocytic leukemia (PLL), follicular lym lymphoma (PMBL), immunoblastic large cell lymphoma, phoma (FL), diffuse large B-cell lymphoma (DLBCL), precursor B-lymphoblastic lymphoma, B cell prolympho mantle cell lymphoma (MCL), Waldenstrom's macroglobu cytic leukemia, lymphoplasmacytic lymphoma, splenic mar linemia, extranodal marginal Zone B cell lymphoma, nodal ginal Zone lymphoma, plasma cell myeloma, plasmacytoma, marginal Zone B cell lymphoma, Burkitt's lymphoma, non mediastinal (thymic) large B cell lymphoma, intravascular Burkitt high grade B cell lymphoma, primary mediastinal large B cell lymphoma, primary effusion lymphoma, and B-cell lymphoma (PMBL), immunoblastic large cell lym lymphomatoid granulomatosis. phoma, precursor B-lymphoblastic lymphoma, B cell pro lymphocytic leukemia, lymphoplasmacytic lymphoma, Metastasized Hematlogic Malignancy splenic marginal Zone lymphoma, plasma cell myeloma, 0162. In some embodiments, the hematologic cancer is a plasmacytoma, mediastinal (thymic) large B cell lymphoma, metastasized hematologic cancer. In some embodiments, the US 2017/0209462 A1 Jul. 27, 2017 22 metastasized hematologic cancer is a leukemia, a lym (0166 In some embodiments, described herein methods phoma, a myeloma, a non-Hodgkin’s lymphoma, a Hodg and dosing regimen for administering a combination of a kin's lymphoma, a T-cell malignancy, or a B-cell malig TEC inhibitor (e.g., ITK inhibitor or a BTK inhibitor), an nancy. immunomodulatory agent, and a steroid for the treatment of a metastasized hematologic malignancy selected from the 0163. In some embodiments, the metastasized hemato group consisting of chronic lymphocytic leukemia (CLL), logic cancer is a T-cell malignancy. In some embodiments, Small lymphocytic lymphoma (SLL), high risk CLL, non the T-cell malignancy is peripheral T-cell lymphoma not CLL/SLL lymphoma, prolymphocytic leukemia (PLL), fol otherwise specified (PTCL-NOS), anaplastic large cell lym licular lymphoma (FL), diffuse large B-cell lymphoma phoma, angioimmunoblastic lymphoma, cutaneous T-cell (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic macroglobulinemia, multiple myeloma, extranodal marginal NK-cell lymphoma, enteropathy-type T-cell lymphoma, Zone B cell lymphoma, nodal marginal Zone B cell lym hematosplenic gamma-delta T-cell lymphoma, lymphoblas phoma, Burkitt's lymphoma, non-Burkitt high grade B cell tic lymphoma, nasal NK/T-cell lymphomas, or treatment lymphoma, primary mediastinal B-cell lymphoma (PMBL), related T-cell lymphomas. immunoblastic large cell lymphoma, precursor B-lympho 0164. In some embodiments, the metastasized hemato blastic lymphoma, B cell prolymphocytic leukemia, lym logic cancer is a B-cell proliferative disorder. In some phoplasmacytic lymphoma, splenic marginal Zone lym embodiments, the metastasized hematologic cancer is phoma, plasma cell myeloma, plasmacytoma, mediastinal chronic lymphocytic leukemia (CLL), Small lymphocytic (thymic) large B cell lymphoma, intravascular large B cell lymphoma (SLL), high risk CLL, a non-CLL/SLL lym lymphoma, primary effusion lymphoma, and lymphomatoid phoma, or prolymphocytic leukemia (PLL). In some granulomatosis. embodiments, the metastasized hematologic cancer is folli (0167. In some embodiments, described herein are meth cular lymphoma (FL), diffuse large B-cell lymphoma ods and dosing regimen for administering a combination of (DLBCL), mantle cell lymphoma (MCL), Waldenström’s a TEC inhibitor (e.g., an ITK inhibitor or a BTK inhibitor), macroglobulinemia, multiple myeloma, extranodal marginal an immunomodulatory agent (e.g., pomalidomide), and a Zone B cell lymphoma, nodal marginal Zone B cell lym steroid (e.g., dexamethasone) for the treatment of metasta phoma, Burkitt's lymphoma, non-Burkitt high grade B cell sized multiple myeloma. lymphoma, primary mediastinal B-cell lymphoma (PMBL), (0168. In some embodiments, described herein methods immunoblastic large cell lymphoma, precursor B-lympho and dosing regimen for administering a combination of a blastic lymphoma, B cell prolymphocytic leukemia, lym BTK inhibitor, an immunomodulatory agent, and a steroid phoplasmacytic lymphoma, splenic marginal Zone lym for the treatment of a metastasized hematologic malignancy phoma, plasma cell myeloma, plasmacytoma, mediastinal selected from the group consisting of chronic lymphocytic (thymic) large B cell lymphoma, intravascular large B cell leukemia (CLL), Small lymphocytic lymphoma (SLL), high lymphoma, primary effusion lymphoma, or lymphomatoid risk CLL, non-CLL/SLL lymphoma, prolymphocytic leuke granulomatosis. In some embodiments, DLBCL is further mia (PLL), follicular lymphoma (FL), diffuse large B-cell divided into subtypes: activated B-cell diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), lymphoma (ABC-DLBCL), germinal center diffuse large Waldenstrom's macroglobulinemia, multiple myeloma, B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) extranodal marginal Zone B cell lymphoma, nodal marginal DLBCL. In some embodiments, ABC-DLBCL is character Zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt ized by a CD79B mutation. In some embodiments, ABC high grade B cell lymphoma, primary mediastinal B-cell DLBCL is characterized by a CD79A mutation. In some lymphoma (PMBL), immunoblastic large cell lymphoma, embodiments, the ABC-DLBCL is characterized by a muta precursor B-lymphoblastic lymphoma, B cell prolympho tion in MyD88, A20, or a combination thereof. In some cytic leukemia, lymphoplasmacytic lymphoma, splenic mar embodiments, the cancer is acute or chronic myelogenous ginal Zone lymphoma, plasma cell myeloma, plasmacytoma, (or myeloid) leukemia, myelodysplastic syndrome, or acute mediastinal (thymic) large B cell lymphoma, intravascular lymphoblastic leukemia. large B cell lymphoma, primary effusion lymphoma, and 0165. In some embodiments, the metastasized hemato lymphomatoid granulomatosis. logic cancer is diffuse large B-cell lymphoma (DLBCL). In (0169. In some embodiments, described herein methods Some embodiments, the metastasized hematologic cancer is and dosing regimen for administering a combination of a activated B-cell diffuse large B-cell lymphoma (ABC BTK inhibitor, an immunomodulatory agent (e.g., DLBCL). In some embodiments, the metastasized hemato pomalidomide), and a steroid (e.g., dexamethasone) for the logic cancer is follicular lymphoma (FL). In some embodi treatment of metastasized multiple myeloma. ments, the metastasized hematologic cancer is multiple (0170. In some embodiments, described herein methods myeloma. In some embodiments, the metastasized hemato and dosing regimen for administering a combination of logic cancer is chronic lymphocytic leukemia (CLL). In ibrutinib, an immunomodulatory agent, and a steroid for the Some embodiments, the metastasized hematologic cancer is treatment of a metastasized hematologic malignancy Small lymphocytic lymphoma (SLL). In some embodiments, selected from the group consisting of chronic lymphocytic the metastasized hematologic cancer is non-CLL/SLL lym leukemia (CLL), Small lymphocytic lymphoma (SLL), high phoma. In some embodiments, the metastasized hemato risk CLL, non-CLL/SLL lymphoma, prolymphocytic leuke logic cancer is high risk CLL or high risk SLL. In some mia (PLL), follicular lymphoma (FL), diffuse large B-cell embodiments, the metastasized hematologic cancer is PLL. lymphoma (DLBCL), mantle cell lymphoma (MCL), In some embodiments, the metastasized hematologic cancer Waldenstrom's macroglobulinemia, multiple myeloma, is MCL. In some embodiments, the metastasized hemato extranodal marginal Zone B cell lymphoma, nodal marginal logic cancer is Waldenström's macroglobulinemia. Zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt US 2017/0209462 A1 Jul. 27, 2017

high grade B cell lymphoma, primary mediastinal B-cell 14),t(14:16), tC6:14),t(11:14), deletion 17p13, deletion 13, lymphoma (PMBL), immunoblastic large cell lymphoma, chromosome 1 abnormalities, hyperdiploidy. precursor B-lymphoblastic lymphoma, B cell prolympho 0180 Disclosed herein, in certain embodiments, are dos cytic leukemia, lymphoplasmacytic lymphoma, splenic mar ing regimens and methods for treatment of multiple ginal Zone lymphoma, plasma cell myeloma, plasmacytoma, myeloma comprising administering to a subject in need mediastinal (thymic) large B cell lymphoma, intravascular thereof a combination comprising a TEC inhibitor such as large B cell lymphoma, primary effusion lymphoma, and ITK or BTK inhibitor, an immunomodulatory agent (e.g., lymphomatoid granulomatosis. pomalidomide), and a steroid (e.g., dexamethasone). In 0171 In some embodiments, described herein are meth Some instances, also described herein include dosing regi ods and dosing regimen for administering a combination of mens and methods for treatment of multiple myeloma com ibrutinib, an immunomodulatory agent (e.g., pomalido prising a combination comprising an ITK inhibitor, an mide), and a steroid (e.g., dexamethasone) for the treatment immunomodulatory agent (e.g., pomalidomide), and a ste of metastasized multiple myeloma. roid (e.g., dexamethasone). In some instances, additionally 0172. In some embodiments, described herein are meth described herein include dosing regimens and methods for ods and dosing regimen for administering a combination of treatment of multiple myeloma comprising a combination ibrutinib, an immunomodulatory agent (e.g., pomalido comprising a BTK inhibitor, an immunomodulatory agent mide), and a steroid (e.g., dexamethasone) for the treatment (e.g., pomalidomide), and a steroid (e.g., dexamethasone). In of metastasized CLL. Some instances, further described herein include dosing 0173. In some embodiments, described herein are meth regimens and methods for treatment of multiple myeloma ods and dosing regimen for administering a combination of comprising a combination comprising ibrutinib, pomalido ibrutinib, an immunomodulatory agent (e.g., pomalido mide, and dexamethasone. mide), and a steroid (e.g., dexamethasone) for the treatment of metastasized SLL. Additional Therapeutic Agents 0174. In some embodiments, described herein are meth ods and dosing regimen for administering a combination of 0181 Disclosed herein include methods and dosing regi ibrutinib, an immunomodulatory agent (e.g., pomalido men of administering a combination of a TEC inhibitor (e.g., mide), and a steroid (e.g., dexamethasone) for the treatment an ITK inhibitor or a BTK inhibitor), an immunomodulatory of metastasized PLL. agent, a steroid, and an additional therapeutic agent. In some 0175. In some embodiments, described herein are meth embodiments, the additional therapeutic agent is a chemo ods and dosing regimen for administering a combination of therapeutic agent, analgesic, a proteosome inhibitor, a tar ibrutinib, an immunomodulatory agent (e.g., pomalido geted therapy, or a combination thereof. In some embodi mide), and a steroid (e.g., dexamethasone) for the treatment ments, the additional therapeutic agent is a B cell receptor of metastasized DLBCL. pathway inhibitor. In some embodiments, the B cell receptor 0176). In some embodiments, described herein are meth pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, ods and dosing regimen for administering a combination of a CD19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K ibrutinib, an immunomodulatory agent (e.g., pomalido inhibitor, a Blink inhibitor, a PLCY inhibitor, a PKCB inhibi mide), and a steroid (e.g., dexamethasone) for the treatment tor, or a combination thereof. In some embodiments, the of metastasized MCL. additional therapeutic agent is an antibody, B cell receptor 0177. In some embodiments, described herein are meth signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an ods and dosing regimen for administering a combination of mTOR inhibitor, a radioimmunotherapeutic, a DNA dam ibrutinib, an immunomodulatory agent (e.g., pomalido aging agent, a proteosome inhibitor, a histone deacetylase mide), and a steroid (e.g., dexamethasone) for the treatment inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an of metastasized Waldenström's macroglobulinemia. Hsp90 inhibitor, a telomerase inhibitor, a Jak1/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a Multiple Myeloma combination thereof. 0182. In some embodiments, the additional therapeutic 0.178 Multiple myeloma is a B cell malignancy charac agent comprises an analgesic Such as acetaminophen. terized by the latent accumulation in bone marrow of secretory plasm cells with a low proliferative index and an 0183 In some embodiments, the additional therapeutic extended life span. In some embodiments, treatment for agent is an agent selected from the group consisting of an multiple myeloma includes Steroids, chemotherapy, protea inhibitor of LYN, an inhibitor of SYK, an inhibitor of JAK, Some inhibitors, immunomodulatory drugs, and stem cell an inhibitor of PI3K, an inhibitor of PLCY, an inhibitor of transplants. In some embodiments, when plasma cells which MAPK, an inhibitor of MEK and an inhibitor of NFkB. are protein making cells become cancerous, these cells 0184. In some embodiments, the additional therapeutic Switch into the production of a single protein refer to as agent is an agent selected from the group consisting of myeloma protein. In some instances, a myeloma protein is bendamustine, bortezomib, idelalisib (GS-1101), vorinostat, an abnormal immunoglobulin fragment or immunoglobulin everolimus, panobinostat, temsirolimus, romidepsin, Vor light chain that is produced in excess by an abnormal clonal inostat, fludarabine, cyclophosphamide, mitoxantrone, pen proliferation of plasma cells. In some embodiments, to statine, prednisone, etopside, and procarbazine. myeloma protein is also called M protein, M component, 0185. In some embodiments the additional therapeutic spike protein, or paraprotein. agent is bendamustine. In some embodiments, bortezomib is 0179. In some embodiments, a subject with multiple administered in combination with rituximab. myeloma has a genomic aberration. In some embodiments, 0186. In some embodiments, the additional therapeutic the genomic aberration is a chromosomal abnormality. In agent is bortezomib. In some embodiments, bendamustine is Some embodiments, the chromosomal abnormality is t(4. administered in combination with rituximab. US 2017/0209462 A1 Jul. 27, 2017 24

0187. In some embodiments, the additional therapeutic mus, gefitinib, imatinib, lapatinib. nilotinib, paZonanib, agent is a multi-agent therapeutic regimen. In some embodi Sorafenib, Sunitinib, temsirolimus: Other Antineoplastic ments the additional therapeutic agent comprises the Hyper Agents such as for example alitretinoin, altretamine, amza CVAD regimen (cyclophosphamide, Vincristine, doxorubi crine, anagrelide, arsenic trioxide, asparaginase, beXarotene, cin, methotrexate and cytarabine). In some embodiments, bortezomib, celecoxib, denileukin diftitox, estramustine, the HyperCVAD regimen is administered in combination hydroxycarbamide, irinotecan, lonidamine, masoprocol, with rituximab. miltefosein, mitoguaZone, mitotane, oblimersen, pegaspar 0188 In some embodiments the additional therapeutic gase, pentostatin, romidepsin, sitimagene ceradenovec, agent comprises the R-CHOP regiment (rituximab, cyclo tiazofurine, topotecan, tretinoin, Vorinostat; Estrogens Such phosphamide, doxorubicin, Vincristine, and prednisone). as for example diethylstilbenol, ethinylestradiol, fosfestrol, 0189 In some embodiments the additional therapeutic polyestradiol phosphate; Progestogens such as for example agent comprises the FCR regimen (FCR (fludarabine, cyclo gestonorone, medroxyprogesterone, megestrol; Gonadotro phosphamide, rituximab). pin Releasing Hormone Analogs such as for example buser 0190. In some embodiments the additional therapeutic elin, goserelin, leuprorelin, triptorelin; Anti-Estrogens Such agent comprises the FCMR regimen (fludarabine, cyclo as for example fulvestrant, tamoxifen, toremifene; Anti phosphamide, mitoxantrone, rituximab). Androgens such as for example bicalutamide, flutamide, 0191 In some embodiments the additional therapeutic nilutamide, Enzyme Inhibitors, aminoglutethimide, anastro agent comprises the FMR regimen (fludarabine, mitoxan Zole, exemestane, formestane, letrozole, Vorozole. Other trone, rituximab). Hormone Antagonists such as for example abarelix, 0.192 In some embodiments the additional therapeutic degarelix. Immunostimulants such as for example histamine agent comprises the PCR regimen (pentostatin, cyclophos dihydrochloride, mi?amurtide, pidotimod, plerixafor, roqui phamide, rituximab). nimex, thymopentin; Immunosuppressants such as for 0193 In some embodiments the additional therapeutic example everolimus, gusperimus, leflunomide, mycopheno agent comprises the PEPC regimen (prednisone, etoposide, lic acid, sirolimus; Calcineurin Inhibitors such as for procarbazine, cyclophosphamide). example ciclosporin, tacrolimus; Other Immunosuppres 0194 In some embodiments the additional therapeutic sants such as for example azathioprine, lenalidomide, agent comprises radioimmunotherapy with 'Y-ibritu methotrexate, thalidomide; and Radiopharmaceuticals such momab tiuxetan or ''I-tositumomab. as for example, iobenguane. (0195 In some embodiments, the additional therapeutic (0197) In some embodiments, the additional therapeutic agent is an autologous stem cell transplant. agent is selected from the group consisting of interferons, 0196. In some embodiments, the additional therapeutic interleukins, Tumor Necrosis Factors, and Growth Factors, agent is selected from the group consisting of Nitrogen or the like. Mustards Such as for example, bendamustine, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, 0.198. In some embodiments, the additional therapeutic prednimustine, trofosfamide: Alkyl Sulfonates like busulfan, agent is selected from the group consisting of ancestim, mannosulfan, treosulfan; Ethylene Imines like carboquone, filgrastim, lenograstim, molgramoStim, pegfilgrastim, sar thiotepa, triaziquone; Nitrosoureas like carmustine, fote gramostim; Interferons such as for example interferon alfa mustine, lomustine, nimustine, ranimustine, Semustine, natural, interferon alfa-2a, interferon alfa-2b, interferon alfa streptozocin, Epoxides such as for example, etoglucid: con-1, interferon alfa-n1, interferon beta natural, interferon Other Alkylating Agents such as for example dacarbazine, beta-1a, interferon beta-1b, interferon gamma, peginterferon mitobronitol, pipobroman, temozolomide; Folic Acid Ana alfa-2a, peginterferon alfa-2b: Interleukins such as for logues such as for example methotrexate, permetrexed, example aldesleukin, oprelvekin; Other Immunostimulants pralatrexate, raltitrexed; Purine Analogs such as for example Such as for example BCG vaccine, glatiramer acetate, his cladribine, clofarabine, fludarabine, mercaptopurine, nelara tamine dihydrochloride, immunocyanin, lentinan, mela bine, tioguanine: Pyrimidine Analogs such as for example noma vaccine, mi?amurtide, pegademase, pidotimod, aZacitidine, capecitabine, carmofur, cytarabine, decitabine, plerixafor, poly I:C, poly ICLC, roquinimex, tasonermin, fluorouracil, gemcitabine, tegafur, Vinca Alkaloids Such as thymopentin: Immunosuppressants such as for example for example vinblastine, Vincristine, Vindesine, Vinflunine, abatacept, abetimus, alefacept, antilymphocyte immuno vinorelbine: Podophyllotoxin Derivatives such as for globulin (horse), antithymocyte immunoglobulin (rabbit), example etoposide, teniposide; Colchicine derivatives Such eculizumab, efalizumab, everolimus, gusperimus, lefluno as for example demecolcine; Taxanes Such as for example mide, muromab-CD3, mycophenolic acid, natalizumab, docetaxel, paclitaxel, paclitaxel poliglumex: Other Plant sirolimus; TNF alpha Inhibitors such as for example adali Alkaloids and Natural Products such as for example trabect mumab, afelimomab, certolizumab pegol, etanercept, goli edin; Actinomycines Such as for example dactinomycin; mumab, infliximab, Interleukin Inhibitors such as for Antracyclines such as for example aclarubicin, daunorubi example anakinra, basiliximab, canakinumab, daclizumab, cin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pira mepolizumab, rilonacept, tocilizumab, ustekinumab., Cal rubicin, valrubicin, Zorubincin; Other Cytotoxic Antibiotics cineurin Inhibitors such as for example ciclosporin, tacroli Such as for example bleomycin, ixabepilone, mitomycin, mus; and Other Immunosuppressants such as for example plicamycin; Platinum Compounds such as for example car azathioprine, lenalidomide, methotrexate, thalidomide. boplatin, cisplatin, oxaliplatin, satraplatin: Methylhydra 0199. In some embodiments, the additional therapeutic Zines Such as for example procarbazine; Sensitizers such as agent is selected from the group consisting of Adalimumab, for example aminolevulinic acid, efaproxiral, methyl amin Alemtuzumab, Basiliximab, Bevacizumab, Cetuximab, Cer olevulinate, porfimer sodium, temoporfin; Protein Kinase tolizumab pegol, Daclizumab, Eculizumab, Efalizumab, Inhibitors such as for example dasatinib, erlotinib, everoli Gemtuzumab, Ibritumomab tiuxetan, Infliximab, Mur US 2017/0209462 A1 Jul. 27, 2017

omonab-CD3, Natalizumab, Panitumumab, Ranibizumab, rafenib, RO5185426, SAR1031 68, SCH 727965, SGI-1176, Tositumomab, and Trastuzumab, or the like, or a combina SGX523, SNS-314, TAK-593, TAK-901, TKI258, TLN tion thereof. 232, TTP607, XL147, XL228, XL281RO5126766, XL418, 0200. In some embodiments, the additional therapeutic XL765. agent is selected from the group consisting of Monoclonal 0203. In some embodiments, the additional therapeutic Antibodies such as for example alemtuzumab, bevacizumab, agent is selected from the group consisting of inhibitors of catumaxomab, cetuximab, edrecolomab, gemtuzumab, pani mitogen-activated protein kinase signaling, e.g., U0126, tumumab, trastuzumab. Immunosuppressants, eculizumab, PD98059, PD184352, PD0325901, ARRY-142886, efalizumab, muromab-CD3, natalizumab; TNF alpha Inhibi SB239063, SP600 125, BAY 43-9006, wortmannin, or tors such as for example adalimumab, afelimomab, certoli LY294.002; Syk inhibitors; mTOR inhibitors; and antibodies Zumab pegol, golimumab, infliximab, Interleukin Inhibitors, (e.g., rituxan). basiliximab, canakinumab, daclizumab, mepolizumab, 0204. In some embodiments, the additional therapeutic tocilizumab, ustekinumab; Radiopharmaceuticals, ibritu agent is selected from the group consisting of Adriamycin, momab tiuxetan, to situmomab. Others Monoclonal Anti Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; bodies such as for example abagovomab, adecatumumab, aclarubicin; acodazole hydrochloride; acronine; adoZelesin; alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, aldesleukin; altretamine; ambomycin; ametantrone acetate; anti-MET monoclonal antibody MetMab, apolizumab, aminoglutethimide; amsacrine; anastrozole; anthramycin; apomab, arcitumomab, basiliximab, bispecific antibody asparaginase; asperlin; azacitidine; azetepa; azotomycin; 2B1, blinatumomab, brentuximab vedotin, capromab pen batimastat; benzodepa; bicalutamide; bisantrene hydrochlo detide, cixutumumab, claudiximab, conatumumab, dacetu ride; bisnafide dimesylate: bizelesin: bleomycin sulfate; Zumab, denosumab, eculizumab, epratuZumab, epratu brequinar sodium; bropirimine; buSulfan, cactinomycin; Zumab, ertumaXomab, etaracizumab, figitumumab, calusterone; caracemide; carbetimer, carboplatin: carmus fresolimumab, galiximab, ganitumab, gemtuzumab ozo tine; carubicin hydrochloride; carZelesin; cedefingol; gamicin, glembatumumab, ibritumomab, inotuZumab ozo chlorambucil; cirolemycin; cladribine; crisinatol mesylate; gamicin, ipilimumab, lexatumumab, lintuZumab, lintu cyclophosphamide; cytarabine; dacarbazine; daunorubicin Zumab, lucatumumab, mapatumumab, matuZumab, hydrochloride; decitabine; dexormaplatin; deZaguanine; milatuZumab, monoclonal antibody CC49, necitumumab, deZaguanine mesylate; diaziquone: doxorubicin; doxorubi nimotuZumab, oregovomab, pertuZumab, ramacurimab, cin hydrochloride; droloxifene; droloxifene citrate; dromo ranibizumab, siplizumab, Sonepcizumab, tanezumab, to situ stanolone propionate; duazomycin; edatrexate; efornithine momab, trastuzumab, tremelimumab, tucotuzumab celmo hydrochloride; elsamitrucin; enloplatin; enpromate; epipro leukin, VeltuZumab, Visilizumab, Volocliximab, and Zalutu pidine; epirubicin hydrochloride; erbulozole; esorubicin mumab. hydrochloride; estramustine; estramustine phosphate 0201 In some embodiments, the additional therapeutic Sodium; etanidazole; etoposide; etoposide phosphate: eto agent is selected from the group consisting of agents that prine; fadrozole hydrochloride; fazarabine; fenretinide; affect the tumor micro-environment such as cellular signal floxuridine; fludarabine phosphate; fluorouracil; flurocit ing network (e.g., phosphatidylinositol 3-kinase (PI3K) sig abine; fosquidone; fostriecin Sodium; gemcitabine, gemcit naling pathway, signaling from the B-cell receptor and the abine hydrochloride; hydroxyurea; idarubicin hydrochlo IgE receptor). In some embodiments, the additional thera ride; ifosfamide; iimofosine; interleukin Il (including peutic agent is a PI3K signaling inhibitor or a syc kinase recombinant interleukin II, or rlL2), interferon alfa-2a: inter inhibitor. In one embodiment, the syk inhibitor is R788. In feron alfa-2b; interferon alfa-n1; interferon alfa-n3; inter another embodiment is a PKCY inhibitor such as by way of feron beta-1a; interferon gamma-1 b; iproplatin; irinotecan example only, enZastaurin. hydrochloride; lanreotide acetate; letrozole; leuprolide 0202) Examples of agents that affect the tumor micro acetate; liaroZole hydrochloride; lometrexol Sodium, lomus environment include PI3K signaling inhibitor, Syc kinase tine; losoxantrone hydrochloride; masoprocol; maytansine; inhibitor, Protein Kinase Inhibitors such as for example mechlorethamine hydrochloride; megestrol acetate; dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapa melengestrol acetate; melphalan; menogaril; mercaptopu tinib. nilotinib, paZonanib, Sorafenib, Sunitinib, temsiroli rine; methotrexate, methotrexate sodium; metoprine; mus; Other Angiogenesis Inhibitors such as for example meturedepa; mitindomide; mitocarcin; mitocromin: mitogil GT-111, JI-101, R1530; Other Kinase Inhibitors such as for lin; mitomalcin, mitomycin; mitosper, mitotane; mitoxan example AC220, AC480, ACE-041, AMG 900, AP24534, trone hydrochloride; mycophenolic acid; nocodaZoie; Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1152, nogalamycin; Ormaplatin; OXisuran: pegaspargase; peliomy AZD7762, AZD8055, AZD8931, bafetinib, BAY 73-4506, cin; pentamustine; peplomycin Sulfate; perfosfamide; pipo BGJ398, BGT226, BI 811283, BI6727, BIBF 1120, BMW broman; piposulfan, piroXantrone hydrochloride; plicamy 2992, BMS-690154, BMS-777607, BMS-863233, BSK cin; plomestane; porfimer Sodium; porfiromycin; 461364, CAL-101, CEP-11981, CYC116, DCC-2036, prednimustine; procarbazine hydrochloride; puromycin; dinaciclib, dovitinib lactate, E7050, EMD 1214063, ENMD puromycin hydrochloride; pyrazofurin: riboprine; rogletim 2076, fostamatinib disodium, GSK2256098, GSK690693, ide; Safingol; Safingol hydrochloride; semustine; simtraZene; INCB18424, INNO-406, JNJ-26483327, JX-594, KX2-391, sparfosate sodium; sparsomycin; Spirogermanium hydro linifanib, LY2603618, MGCD265, MK-0457, MK1496, chloride; spiromustine; spiroplatin; streptonigrin: Streptozo MLN8054, MLN8237, MP470, NMS-1116354, NMS cin; Sulofenur; talisomycin; tecogalan Sodium, tegafur, 1286937, ON 01919. Na, OSI-027, OSI-930, Btk inhibitor, teloxantrone hydrochloride; temoporfin, teniposide; teroX PF-00562271, PF-02341066, PF-03814735, PF-04217903, irone; testolactone; thiamiprine; thioguanine; thiotepa; PF-04554878, PF-0469 1502, PF-3758309, PHA-73.9358, tiazofurin; tirapazamine; toremifene citrate; trestolone PLC3397, progenipoietin, R547, R763, ramucirumab, rego acetate; triciribine phosphate; trimetrexate; trimetrexate glu US 2017/0209462 A1 Jul. 27, 2017 26 curonate; triptorelin; tubulozole hydrochloride: uracil mus disaccharide peptide; lipophilic platinum compounds; lisso tard; uredepa; vapreotide; verteporfin; vinblastine sulfate; clinamide 7: lobaplatin: lombricine; lometrexol; lonidamine: Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorel texaphyrin; lysofylline; lytic peptides; maitansine; mannos bine tartrate; Vinrosidine sulfate; Vinzolidine sulfate; Voro tatin A; marimastat; masoprocol; maspin; matrilysin inhibi Zole; Zeniplatin: Zinostatin; and Zorubicin hydrochloride. tors; matrix metalloproteinase inhibitors; menogaril; mer 0205. In some embodiments, the additional therapeutic barone; meterelin; methioninase; metoclopramide: MIF agent is selected from the group consisting of 20-epi-1, 25 inhibitor, mifepristone; miltefosine; mirimostim; mis dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclaru matched double stranded RNA; mitoguaZone; mitolactol; bicin; acylfulvene; adecypenol; adoZelesin; aldesleukin; mitomycin analogues; mitonafide; mitotoxin fibroblast ALL-TK antagonists; altretamine; ambamustine; amidox; growth factor-Saporin; mitoxantrone; mofarotene; molgra amifostine; aminolevulinic acid; amrubicin; amsacrine; mostim; monoclonal antibody, human chorionic gonadotro anagrelide; anastrozole; andrographolide; angiogenesis phin; monophosphoryl lipid A+myobacterium cell wall sk; inhibitors; antagonist D; antagonist G.; antarelix; anti-dor mopidamol; multiple drug resistance gene inhibitor, mul salizing morphogenetic protein-1, antiandrogen, prostatic tiple tumor Suppressor 1-based therapy; mustard anticancer carcinoma; antiestrogen; antineoplaston; antisense oligo agent; mycaperoxide B; mycobacterial cell wall extract; nucleotides; aphidicolin glycinate; apoptosis gene modula myriaporone; N-acetyldinaline; N-substituted benzamides: tors; apoptosis regulators; apurinic acid; ara-CDP-DL nafarelin; nagrestip; naloxone-pentazocine; napavin; naph PTBA, arginine deaminase; asulacrine; atamestane; terpin, nartograstim; nedaplatin; memorubicin; neridronic atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azase acid; neutral endopeptidase; nilutamide; nisamycin; nitric tron; azatoxin; azatyrosine; baccatin III derivatives; balanol: oxide modulators; nitroxide antioxidant; nitrullyn; O6-ben batimastat; BCR/ABL antagonists; benzochlorins; benzoyl Zylguanine; octreotide; okicenone; oligonucleotides; staurosporine; beta lactam derivatives; beta-alethine; beta onapristone; ondansetron; ondansetron; oracin; oral clamycin B; betulinic acid; bFGF inhibitor; bicalutamide: cytokine inducer, ormaplatin: osaterone; Oxaliplatin: bisantrene; bisaziridinylspermine; bisnafide; bistratene A: oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic bizelesin; breflate; bropirimine; budotitane; buthionine sul acid; panaxytriol; panomifene; parabactin; paZelliptine; foXimine; calcipotriol; calphostin C; camptothecin deriva pegaspargase; peldesine; pentosan polysulfate Sodium; pen tives; canarypox IL-2, capecitabine; carboxamide-amino tostatin: pentrozole; perflubron; perfosfamide; perillyl alco triazole; carboxyamidotriazole; CaRest M3; CARN 700; hol; phenazinomycin; phenylacetate; phosphatase inhibi cartilage derived inhibitor, carzelesin; casein kinase inhibi tors; picibanil; pilocarpine hydrochloride; pirarubicin; tors (ICOS); castanospermine; cecropin B; cetrorelix; chlo piritrexim; placetin A; placetin B; plasminogen activator rins; chloroquinoxaline Sulfonamide; cicaprost, cis-porphy inhibitor; platinum complex; platinum compounds; plati rin, cladribine; clomifene analogues; clotrimazole; num-triamine complex; porfimer Sodium; porfiromycin; collismycin A; collismycin B; combretastatin A4, combret prednisone; propyl bis-acridone; prostaglandin J2, protea astatin analogue; conagenin; crambescidin 816; crisinatol; Some inhibitors; protein A-based immune modulator, pro cryptophycin 8; cryptophycin A derivatives; curacin A; tein kinase C inhibitor; protein kinase C inhibitors, microal cyclopentanthraquinones; cycloplatam, cypemycin; cytara gal; protein tyrosine phosphatase inhibitors; purine bine ocfosfate; cytolytic factor, cytostatin; dacliximab; nucleoside phosphorylase inhibitors; purpurins; pyrazolo decitabine; dehydrodidemnin B; deslorelin; dexifosfamide: acridine; pyridoxylated hemoglobin polyoxyethylerie con dexraZoxane; dexVerapamil, diaziquone; didemnin B; didox; jugate; rafantagonists; raltitrexed; ramosetron; ras farnesyl diethylnorspermine; dihydro-5-azacytidine; 9-dioxamycin; protein transferase inhibitors: ras inhibitors: ras-GAP inhibi diphenyl spiromustine; docosanol; dolasetron: doxifluridine; tor; retelliptine demethylated; rhenium Re 186 etidronate; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomus rhizoxin: ribozymes: RII retinamide: rogletimide; rohi tine; edelfosine; edrecolomab; eflornithine; elemene; emite tukine; romurtide; roquinimex: rubiginone B1; ruboxyl, fur, epirubicin; epristeride; estramustine analogue; estrogen Safingol; Saintopin; SarCNU; sarcophytol A. SargramoStim; agonists; estrogen antagonists; etanidazole; etoposide phos Sdi 1 mimetics; semustine; senescence derived inhibitor 1; phate; exemestane: fadrozole; fazarabine; fenretinide; fil sense oligonucleotides; signal transduction inhibitors; signal grastim; finasteride; flavopiridol; flezelastine; fluasterone; transduction modulators; single chain antigen-binding pro fludarabine; fluorodaunorunicin hydrochloride; forfenimex: tein; sizofiran; Sobuzoxane, Sodium borocaptate; sodium formestane; fostriecin, fotemustine, gadolinium texaphyrin, phenylacetate; Solverol; somatomedin binding protein; Son gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; ermin; sparfosic acid; spicamycin D; spiromustine; spleno gemcitabine; glutathione inhibitors; hepsulfam; heregulin; pentin; spongistatin 1; squalamine; stem cell inhibitor, stem hexamethylene bisacetamide; hypericin; ibandronic acid; cell division inhibitors; stipiamide; stromelysin inhibitors: idarubicin; idoxifene; idramantone, ilmofosine; illomastat; Sulfinosine; Superactive vasoactive intestinal peptide antago imidazoacridones; imiquimod; immunostimulant peptides; nist; Suradista; Suramin; Swainsonine; synthetic gly insulin-Such as for example growth factor-1 receptor inhibi cosaminoglycans; tallimustine; tamoxifen methiodide; tau tor; interferon agonists; interferons; interleukins; ioben romustine; taZarotene; tecogalan Sodium, tegafur, guane; iododoxorubicin; ipomeanol, 4-, iroplact; irsoglad tellurapyrylium; telomerase inhibitors; temoporfin, temoZo ine; isobengaZole; isohomohalicondrin B; itasetron; lomide; teniposide; tetrachlorodecaoxide; tetraZomine; jasplakinolide; kahalalide F. lamellarin-N triacetate; lan thaliblastine; thiocoraline; thrombopoietin; thrombopoietin reotide; leinamycin; lenograstim; lentinan Sulfate; leptolsta mimetic; thymalfasin; thymopoietin receptor agonist; thy tin, letrozole; leukemia inhibiting factor, leukocyte alpha motrinan; thyroid stimulating hormone; tin ethyl etiopurpu interferon; leuprolide+estrogen-progesterone; leuprorelin; rin; tirapazamine; titanocene bichloride; top sentin; tore levamisole; liarozole; linear polyamine analogue; lipophilic mifene; totipotent stem cell factor; translation inhibitors: US 2017/0209462 A1 Jul. 27, 2017 27 tretinoin; triacetyluridine; triciribine; trimetrexate; triptore moto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser. lin; tropisetron; turosteride; tyrosine kinase inhibitors; tyr HCI, and RPR-258062A), Vitilevuamide, Tubulysin A, phostins; UBC inhibitors: ubenimex: urogenital sinus-de Canadensol, Centaureidin (also known as NSC-106969), rived growth inhibitory factor; urokinase receptor T-138067 (Tularik, also known as T-67, TL-138067 and antagonists; vapreotide; variolin B; vector system, erythro TI-138067), COBRA-1 (Parker Hughes Institute, also cyte gene therapy; velaresol; Veramine; Verdins; verteporfin; known as DDE-261 and WHI-261), H10 (Kansas State Vinorelbine; Vinxaltine; vitaxin; Vorozole; Zanoterone; Zeni University), H16 (Kansas State University). Oncocidin A1 platin: Zilascorb; and Zinostatin stimalamer. (also known as BTO-956 and DIME), DDE-313 (Parker 0206. In some embodiments, the additional therapeutic Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker agent is selected from the group consisting of alkylating Hughes Institute), SPA-1 (Parker Hughes Institute, also agents, antimetabolites, natural products, or hormones, e.g., known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai nitrogen mustards (e.g., mechloroethamine, cyclophosph School of Medicine, also known as MF-569), Narcosine amide, chlorambucil, etc.), alkyl Sulfonates (e.g., buSulfan), (also known as NSC-5366), Nascapine, D-24851 (Asta nitrosoureas (e.g., carmustine, lomusitne, ete.), and triaZenes Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cy (decarbazine, etc.). Examples of antimetabolites include but toskeleton/Mt. Sinai School of Medicine, also known as are not limited to folic acid analog (e.g., methotrexate), or MF-191), TMPN (Arizona State University), Vanadocene pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine mercaptopurine, thioguanine, pentostatin). (also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. 0207. In some embodiments, the additional therapeutic Sinai School of Medicine), A-204197 (Abbott), T-607 (Tui agent is selected from the group consisting of nitrogen arik, also known as T-900607), RPR-115781 (Aventis), mustards (e.g., mechloroethamine, cyclophosphamide, Eleutherobins (such as DeSmethyleleutherobin, Desaet chlorambucil, meiphalan, etc.), ethylenimine and methyl yleleutherobin, 1soeleutherobin A, and Z-Eleutherobin), Car melamines (e.g., hexamethlymelamine, thiotepa), alkyl Sul ibaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta fonates (e.g., buSulfan), nitrosoureas (e.g., carmustine, Medica), D-68144 (Asta Medica), Diazonamide A, lomusitne, Semustine, Streptozocin, etc.), and triaZenes (de A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, carbazine, ete.). Examples of antimetabolites include, but TUB-245 (Aventis), A-259754 (Abbott), DioZostatin, (-)- are not limited to folic acid analog (e.g., methotrexate), or Phenylahistin (also known as NSCL-96F037), D-68838 pyrimidine analogs (e.g., fluorouracil, floXouridine, Cytara (Asta Medica), D-68836 (Asta Medica), Myoseverin B, bine), purine analogs (e.g., mercaptopurine, thioguanine, D-43411 (Zentaris, also known as D-81862), A-289099 pentostatin. (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA 110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), 0208. In some embodiments, the additional therapeutic D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phos agent is selected from the group consisting of agents that act phate sodium, BPR-OY-007 (National Health Research by arresting cells in the G2-M phases due to stabilized Institutes), and SSR-250411 (Sanofi). microtubules, e.g., Erbulozole (also known as R-55104), 0209. In some embodiments, the additional therapeutic Dolastatin 10 (also known as DLS-10 and NSC-376128), agent is not a strong CYP3A inhibitor or a strong CYP3A Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A- inducer. Examples of strong CYP3A inhibitors include, but 296), ABT-751 (Abbott, also known as E-7010), Altorhyr are not limited to, ketoconazole, ritonavir, indinavir, nelfi tins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins navir, saquinavir, boceprevir, telaprevir, and nefazodone. (such as Spongistatin 1, Spongistatin 2, Spongistatin 3. Examples of strong CYP3A inducers include, but are not Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin limited to, rifampin, carbamazepine, phenytoin, and St. 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydro John's Wort. chloride (also known as LU-103793 and NSC-D-669356), 0210. In some embodiments, the additional therapeutic Epothilones (such as Epothilone A, Epothilone B, Epoth agent is not a strong CYP1A2 inhibitor, such as fluvoxamine ilone C (also known as desoxyepothilone A or dEpoA), or ciprofloxacin. Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B), Epothilone E. Epothilone F, Epoth Pharmaceutical Compositions/Formulations ilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone 0211 Disclosed herein, in certain embodiments, are phar B, 21-aminoepothilone B (also known as BMS-310705), maceutical compositions or combinations for treating a B 21-hydroxyepothilone D (also known as Desoxyepothilone cell proliferative disorder in an individual in need thereof F and dEpoF), 26-fluoroepothilone), Auristatin PE (also comprising a TEC inhibitor (e.g., an ITK inhibitor, a BTK known as NSC-654663), Soblidotin (also known as TZT inhibitor, e.g., a covalent BTK inhibitor), an immunomodu 1027), LS-4559-P (Pharmacia, also known as LS-4577), latory agent, and a steroid, and optionally a pharmaceuti LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 cally acceptable excipient. Also disclosed herein, in certain (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), embodiments, are compositions or combinations for treating Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fuji a B cell proliferative disorder in an individual in need sawa, also known as WS-9885B), GS-164 (Takeda), GS-198 thereof comprising a covalent Btk inhibitor (e.g., an irre (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF versible covalent BTK inhibitor, e.g., ibrutinib), an immu 223651 (BASF, also known as ILX-651 and LU-223651), nomodulatory agent, and a steroid, and optionally a phar SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), maceutically acceptable excipient. In some embodiments, AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 the B cell proliferative disorder is refractory to the covalent (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin BTK inhibitor (e.g., an irreversible covalent BTK inhibitor, 52 (also known as LY-355703), AC-7739 (Ajinomoto, also e.g., ibrutinib). In some embodiments, the B cell prolifera known as AVE-8063A and CS-39.HCI), AC-7700 (Ajino tive disorder is relapsed or refractory to an immunomodu US 2017/0209462 A1 Jul. 27, 2017 28 latory agent. In some embodiments, the B cell proliferative phosphate, bicarbonate, sulfate, thiosulfate or bisulfite disorder is relapsed or refractory to an immunomodulatory anions; suitable salts include Sodium chloride, potassium agent (i.e., lenalidomide). In some embodiments, the B cell chloride, sodium thiosulfate, sodium bisulfite and ammo proliferative disorder is relapsed or refractory to a prote nium sulfate. osome inhibitor (i.e., bortezomib and/or or carfilzomib). In 0218. The term “pharmaceutical combination” as used some embodiments, the B cell proliferative disorder is herein, means a product that results from the mixing or relapsed or refractory to an immunomodulatory agent (e.g., combining of more than one active ingredient and includes lenalidomide) and a proteosome inhibitor (e.g., bortezomib). both fixed and non-fixed combinations of the active ingre In some embodiments, the B cell proliferative disorder is dients. The term “fixed combination' means that the active relapsed or refractory to an immunomodulatory agent (e.g., ingredients, e.g., a compound described herein and a co lenalidomide) and a proteosome inhibitor (e.g., carfilzomib). agent, are both administered to a patient simultaneously in In some embodiments, the B cell proliferative disorder is the form of a single entity or dosage. The term “non-fixed relapsed or refractory. In some embodiments, the B cell combination” means that the active ingredients, e.g., a proliferative disorder is multiple myeloma. compound described herein and a co-agent, are administered 0212. In some embodiments, the covalent BTK inhibitor to a patient as separate entities either simultaneously, con is a compound of Formula (A). In some embodiments, the currently or sequentially with no specific intervening time covalent Btk inhibitor is (R)-1-(3-(4-amino-3-(4-phenoxy limits, wherein such administration provides effective levels phenyl)-1H-pyrazolo 3,4-dpyrimidin-1-yl)piperidin-1-yl) of the two compounds in the body of the patient. The latter prop-2-en-1-one (i.e., PCI-32765/ibrutinib). also applies to cocktail therapy, e.g., the administration of 0213 Pharmaceutical compositions or combinations of a three or more active ingredients. covalent Btk inhibitor (e.g., an irreversible covalent Btk 0219. The pharmaceutical formulations described herein inhibitor, e.g., ibrutinib), a proteasome inhibitor, and a are administered by any Suitable administration route, steroid are formulated in a conventional manner using one or including but not limited to, oral, parenteral (e.g., intrave more physiologically acceptable carriers including excipi nous, Subcutaneous, intramuscular), intranasal, buccal, topi ents and auxiliaries which facilitate processing of the active cal, rectal, or transdermal administration routes. compounds into preparations which can be used pharma 0220. The pharmaceutical compositions or combinations ceutically. Proper formulation is dependent upon the route of described herein are formulated into any Suitable dosage administration chosen. A Summary of pharmaceutical com form, including but not limited to, aqueous oral dispersions, positions described herein is found, for example, in Rem liquids, gels, Syrups, elixirs, slurries, Suspensions and the ington: The Science and Practice of Pharmacy, Nineteenth like, for oral ingestion by an individual to be treated, solid Ed (Easton, Pa.; Mack Publishing Company, 1995); Hoover, oral dosage forms, aerosols, controlled release formulations, John E., Remington's Pharmaceutical Sciences, Mack Pub fast melt formulations, effervescent formulations, lishing Co., Easton, Pa. 1975; Liberman, H. A. and Lach lyophilized formulations, tablets, powders, pills, dragees, man, L., Eds. Pharmaceutical Dosage Forms, Marcel capsules, delayed release formulations, extended release Decker, New York, N.Y., 1980; and Pharmaceutical Dosage formulations, pulsatile release formulations, multiparticu Forms and Drug Delivery Systems, Seventh Ed. (Lippincott late formulations, and mixed immediate release and con Williams & Wilkins 1999). trolled release formulations. In some embodiments, the 0214. A pharmaceutical composition or combinations, as compositions are formulated into capsules. In some embodi used herein, refers to a mixture of a covalent Btk inhibitor ments, the compositions are formulated into solutions (for (e.g., an irreversible covalent Btk inhibitor, e.g., ibrutinib), example, for IV administration). a proteasome inhibitor, and a steroid with other chemical 0221) The pharmaceutical solid dosage forms described components, such as carriers, stabilizers, diluents, dispers herein optionally include a compound described herein and ing agents, Suspending agents, thickening agents, and/or one or more pharmaceutically acceptable additives such as excipients. a compatible carrier, binder, filling agent, Suspending agent, 0215 Pharmaceutical compositions or combinations are flavoring agent, Sweetening agent, disintegrating agent, dis optionally manufactured in a conventional manner. Such as, persing agent, Surfactant, lubricant, colorant, diluent, solu by way of example only, by means of conventional mixing, bilizer, moistening agent, plasticizer, stabilizer, penetration dissolving, granulating, dragee-making, levigating, emulsi enhancer, Wetting agent, anti-foaming agent, antioxidant, fying, encapsulating, entrapping or compression processes. preservative, or one or more combination thereof. 0216. In certain embodiments, compositions or combi 0222. In still other aspects, using standard coating pro nations also include one or more pH adjusting agents or cedures, such as those described in Remington's Pharma buffering agents, including acids such as acetic, boric, citric, ceutical Sciences, 20th Edition (2000), a film coating is lactic, phosphoric and hydrochloric acids; bases such as provided around the compositions. In some embodiments, Sodium hydroxide, Sodium phosphate, Sodium borate, the compositions are formulated into particles (for example Sodium citrate, sodium acetate, sodium lactate and tris for administration by capsule) and some or all of the hydroxymethylaminomethane; and buffers such as citrate/ particles are coated. In some embodiments, the compositions dextrose, Sodium bicarbonate and ammonium chloride. Such are formulated into particles (for example for administration acids, bases and buffers are included in an amount required by capsule) and some or all of the particles are microen to maintain pH of the composition in an acceptable range. capsulated. In some embodiments, the compositions are 0217. In other embodiments, compositions or combina formulated into particles (for example for administration by tions also include one or more salts in an amount required to capsule) and some or all of the particles are not microen bring osmolality of the composition into an acceptable capsulated and are uncoated. range. Such salts include those having sodium, potassium or 0223) In certain embodiments, compositions provided ammonium cations and chloride, citrate, ascorbate, borate, herein also include one or more preservatives to inhibit US 2017/0209462 A1 Jul. 27, 2017 29 microbial activity. Suitable preservatives include mercury like. See, e.g., Remington. The Science and Practice of containing Substances such as merfen and thiomersal; sta Pharmacy, Nineteenth Ed (Easton, Pa.; Mack Publishing bilized chlorine dioxide; and quaternary ammonium com Company, 1995); Hoover, John E., Remington's Pharma pounds Such aS benzalkonium chloride, ceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; cetyltrimethylammonium bromide and cetylpyridinium Liberman, H. A. and Lachman, L., Eds. Pharmaceutical chloride. Dosage Forms, Marcel Decker, New York, N.Y., 1980; and 0224. In some embodiments, “antifoaming agents' Pharmaceutical Dosage Forms and Drug Delivery Systems, reduce foaming during processing which result in coagula Seventh Ed. (Lippincott Williams & Wilkins 1999). tion of aqueous dispersions, bubbles in the finished film, or 0229 “Dispersing agents.’’ and/or "viscosity modulating generally impair processing. Exemplary anti-foaming agents agents' include materials that control the diffusion and include silicon emulsions or Sorbitan sesquoleate. homogeneity of a drug through liquid media or a granulation 0225. In some embodiments, “antioxidants' include, for method or blend method. In some embodiments, these example, butylated hydroxytoluene (BHT), sodium ascor agents also facilitate the effectiveness of a coating or eroding bate, ascorbic acid, sodium metabisulfite and tocopherol. In matrix. Exemplary diffusion facilitators/dispersing agents certain embodiments, antioxidants enhance chemical stabil include, e.g., hydrophilic polymers, electrolytes, Tween R 60 ity where required. or 80, PEG, polyvinylpyrrolidone (PVP; commercially 0226. In some embodiments, formulations described known as Plasdone(R), and the carbohydrate-based dispers herein benefit from antioxidants, metal chelating agents, ing agents such as, for example, hydroxypropyl celluloses thiol containing compounds and other general stabilizing (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methyl agents. Examples of Such stabilizing agents, include, but are celluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) and HPMC K10OM), carboxymethylcellulose sodium, about 0.1% to about 1% w/v methionine, (c) about 0.1% to methylcellulose, hydroxyethylcellulose, hydroxypropylcel about 2% w/v monothioglycerol, (d) about 1 mM to about 10 lulose, hydroxypropylmethylcellulose phthalate, hydroxy mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, propylmethylcellulose acetate stearate (HPMCAS), non (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% crystalline cellulose, magnesium aluminum silicate, to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, triethanolamine, polyvinyl alcohol (PVA), vinyl pyrroli (j) dextran Sulfate, (k) cyclodextrins, (1) pentosan polysulfate done/vinyl acetate copolymer (S630), 4-(1,1,3,3-tetrameth and other heparinoids, (m) divalent cations such as magne ylbutyl)-phenol polymer with ethylene oxide and formalde sium and zinc, or (n) combinations thereof. hyde (also known as tyloxapol), poloxamers (e.g., Pluronics 0227 “Binders' impart cohesive qualities and include, F68(R), F88(R), and F108 R, which are block copolymers of e.g., alginic acid and salts thereof; cellulose derivatives Such ethylene oxide and propylene oxide); and poloxamines (e.g., as carboxymethylcellulose, methylcellulose (e.g., Metho Tetronic 908R), also known as Poloxamine 908R, which is cel(R), hydroxypropylmethylcellulose, hydroxyethylcellu a tetrafunctional block copolymer derived from sequential lose, hydroxypropylcellulose (e.g., Klucel(R), ethylcellulose addition of propylene oxide and ethylene oxide to ethylene (e.g., Ethocel(R), and microcrystalline cellulose (e.g., Avi diamine (BASF Corporation, Parsippany, N.J.)), polyvi cel(R); microcrystalline dextrose; amylose; magnesium alu nylpyrrolidone K12, polyvinylpyrrolidone K17, polyvi minum silicate; polysaccharide acids; bentonites; gelatin: nylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer; crospovi polyvinylpyrrolidone/vinyl acetate copolymer (S-630), done; poVidone; starch; pregelatinized Starch; tragacanth, polyethylene glycol, e.g., the polyethylene glycol can have dextrin, a Sugar, such as Sucrose (e.g., Dipac.R.), glucose, a molecular weight of about 300 to about 6000, or about dextrose, molasses, mannitol, Sorbitol. Xylitol (e.g., Xyl 3350 to about 4000, or about 7000 to about 5400, sodium itabR), and lactose; a natural or synthetic gum Such as carboxymethylcellulose, methylcellulose, polysorbate-80, acacia, tragacanth, ghatti gum, mucilage of isapol husks, Sodium alginate, gums, such as, e.g., gum tragacanth and polyvinylpyrrolidone (e.g., Poly Vidone(R). CL, Kollidon(R) gum acacia, guar gum, Xanthans, including Xanthan gum, CL, Polyplasdone RXL-10), larch arabogalactan, Veegum(R), Sugars, cellulosics, such as, e.g., sodium carboxymethylcel polyethylene glycol, waxes, sodium alginate, and the like. lulose, methylcellulose, Sodium carboxymethylcellulose, 0228. In some embodiments, a “carrier' or “carrier mate polysorbate-80, Sodium alginate, polyethoxylated Sorbitan rials” include any commonly used excipients in pharmaceu monolaurate, polyethoxylated Sorbitan monolaurate, povi tics and should be selected on the basis of compatibility with done, carbomers, polyvinyl alcohol (PVA), alginates, chito compounds disclosed herein, Such as, compounds of ibru sans and combinations thereof. Plasticizers such as cellulose tinib, and the release profile properties of the desired dosage or triethyl cellulose can also be used as dispersing agents. form. Exemplary carrier materials include, e.g., binders, Dispersing agents particularly useful in liposomal disper Suspending agents, disintegration agents, filling agents, Sur sions and self-emulsifying dispersions are dimyristoyl phos factants, Solubilizers, stabilizers, lubricants, wetting agents, phatidyl choline, natural phosphatidyl choline from eggs, diluents, and the like. “Pharmaceutically compatible carrier natural phosphatidyl glycerol from eggs, cholesterol and materials' may include, but are not limited to, acacia, isopropyl myristate. gelatin, colloidal silicon dioxide, calcium glycerophosphate, 0230 Combinations of one or more erosion facilitator calcium lactate, maltodextrin, glycerine, magnesium sili with one or more diffusion facilitator are also used in the cate, polyvinylpyrrollidone (PVP), cholesterol, cholesterol present compositions. esters, Sodium caseinate, soy lecithin, taurocholic acid, 0231. The term "diluent” refers to chemical compounds phosphotidylcholine, Sodium chloride, tricalcium phos that are used to dilute the compound of interest prior to phate, dipotassium phosphate, cellulose and cellulose con delivery. In some embodiments, diluents are also used to jugates, Sugars Sodium Stearoyl lactylate, carrageenan, stabilize compounds because they provide a more stable monoglyceride, diglyceride, pregelatinized Starch, and the environment. Salts dissolved in buffered solutions (which US 2017/0209462 A1 Jul. 27, 2017 30 also can provide pH control or maintenance) are utilized as phosphate, calcium Sulfate, microcrystalline cellulose, cel diluents in the art, including, but not limited to a phosphate lulose powder, dextrose, dextrates, dextran, starches, prege buffered saline solution. In certain embodiments, diluents latinized starch, Sucrose, Xylitol, lactitol, mannitol, Sorbitol, increase bulk of the composition to facilitate compression or Sodium chloride, polyethylene glycol, and the like. create sufficient bulk for homogenous blend for capsule 0237 "Flavoring agents' and/or “sweeteners' useful in filling. Such compounds include e.g., lactose, starch, man the formulations described herein, include, e.g., acacia nitol, Sorbitol, dextrose, microcrystalline cellulose Such as syrup, acesulfame K, alitame, anise, apple, aspartame, Avicel(R: dibasic calcium phosphate, dicalcium phosphate banana, Bavarian cream, berry, black currant, butterscotch, dihydrate; tricalcium phosphate, calcium phosphate; anhy calcium citrate, camphor, caramel, cherry, cherry cream, drous lactose, spray-dried lactose; pregelatinized starch, chocolate, cinnamon, bubble gum, citrus, citrus punch, compressible Sugar, such as DiPacR (Amstar); mannitol, citrus cream, cotton candy, cocoa, cola, cool cherry, cool hydroxypropylmethylcellulose, hydroxypropylmethylcellu citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, lose acetate Stearate, Sucrose-based diluents, confectioner's fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza Sugar, monobasic calcium Sulfate monohydrate, calcium (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, sulfate dihydrate; calcium lactate trihydrate, dextrates: lime, lemon cream, monoammonium glyrrhizinate (Mag hydrolyzed cereal Solids, amylose; powdered cellulose, cal naSweet(R), maltol, mannitol, maple, marshmallow, men cium carbonate; glycine, kaolin; mannitol, Sodium chloride; thol, mint cream, mixed berry, neohesperidine DC, neotame, inositol, bentonite, and the like. orange, pear, peach, peppermint, peppermint cream, Pro 0232. The term "disintegrate” includes both the dissolu sweetR) Powder, raspberry, root beer, rum, saccharin, tion and dispersion of the dosage form when contacted with safrole, Sorbitol, spearmint, spearmint cream, Strawberry, gastrointestinal fluid. “Disintegration agents or disinte Strawberry cream, Stevia, Sucralose, Sucrose, sodium sac grants' facilitate the breakup or disintegration of a Sub charin, saccharin, aspartame, acesulfame potassium, manni stance. Examples of disintegration agents include a starch, tol, talin, Sylitol. Sucralose, Sorbitol, Swiss cream, tagatose, e.g., a natural starch Such as corn starch or potato starch, a tangerine, thaumatin, tutti fruitti, Vanilla, walnut, water pregelatinized starch such as National 1551 or Amijel R, or melon, wild cherry, wintergreen, xylitol, or any combination sodium starch glycolate such as Promogel(R) or Explotab(R), of these flavoring ingredients, e.g., anise-menthol, cherry a cellulose Such as a wood product, methylcrystalline cel anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, lulose, e.g., Avicel(R), Avicel(R) PH101, Avicel(RPH102, Avi honey-lemon, lemon-lime, lemon-mint, menthol-eucalyp cel(R) PH105, Elcema(R) P100, Emcocel(R), Vivacel(R), Ming tus, orange-cream, Vanilla-mint, and mixtures thereof. TiaR), and Solka-FlocR, methylcellulose, croscarmellose, or 0238 “Lubricants' and "glidants' are compounds that a cross-linked cellulose, such as cross-linked sodium car prevent, reduce or inhibit adhesion or friction of materials. boxymethylcellulose (Ac-Di-SolR), cross-linked carboxym Exemplary lubricants include, e.g., Stearic acid, calcium ethylcellulose, or cross-linked croScarmellose, a cross hydroxide, talc, sodium Stearyl fumerate, a hydrocarbon linked Starch Such as Sodium starch glycolate, a cross-linked Such as mineral oil, or hydrogenated vegetable oil such as polymer Such as crospovidone, a cross-linked polyvinylpyr hydrogenated soybean oil (SteroteXCR), higher fatty acids rolidone, alginate such as alginic acid or a salt of alginic acid and their alkali-metal and alkaline earth metal salts, such as Such as sodium alginate, a clay Such as Veegum R. HV aluminum, calcium, magnesium, zinc, Stearic acid, sodium (magnesium aluminum silicate), a gum Such as agar, guar, Stearates, glycerol, talc, waxes, Stearowet(R), boric acid, locust bean, Karaya, pectin, or tragacanth, Sodium starch Sodium benzoate, sodium acetate, Sodium chloride, leucine, glycolate, bentonite, a natural Sponge, a Surfactant, a resin a polyethylene glycol (e.g., PEG-4000) or a methoxypoly Such as a cation-exchange resin, citrus pulp, sodium lauryl ethylene glycol such as CarbowaxTM, sodium oleate, sodium Sulfate, Sodium lauryl Sulfate in combination starch, and the benzoate, glyceryl behenate, polyethylene glycol, magne like. sium or sodium lauryl Sulfate, colloidal silica Such as 0233 “Drug absorption' or “absorption' typically refers SyloidTM, Cab-O-Silr), a starch such as corn starch, silicone to the process of movement of drug from site of adminis oil, a surfactant, and the like. tration of a drug across a barrier into a blood vessel or the site of action, e.g., a drug moving from the gastrointestinal 0239. A “measurable serum concentration' or “measur able plasma concentration” describes the blood serum or tract into the portal vein or lymphatic system. blood plasma concentration, typically measured in mg, or ng 0234. An "enteric coating is a substance that remains of therapeutic agent per mL, dL, or L of blood serum, Substantially intact in the stomach but dissolves and releases absorbed into the bloodstream after administration. As used the drug in the Small intestine or colon. Generally, the enteric herein, measurable plasma concentrations are typically mea coating comprises a polymeric material that prevents release Sured in ng/mL or Lig/mL. in the low pH environment of the stomach but that ionizes at a higher pH, typically a pH of 6 to 7, and thus dissolves 0240 “Pharmacodynamics' refers to the factors which sufficiently in the small intestine or colon to release the determine the biologic response observed relative to the active agent therein. concentration of drug at a site of action. 0235 "Erosion facilitators’ include materials that control 0241 "Pharmacokinetics' refers to the factors which the erosion of a particular material in gastrointestinal fluid. determine the attainment and maintenance of the appropriate Erosion facilitators are generally known to those of ordinary concentration of drug at a site of action. skill in the art. Exemplary erosion facilitators include, e.g., 0242 “Plasticizers' are compounds used to soften the hydrophilic polymers, electrolytes, proteins, peptides, and microencapsulation material or film coatings to make them amino acids. less brittle. Suitable plasticizers include, e.g., polyethylene 0236 “Filling agents’ include compounds such as lac glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, tose, calcium carbonate, calcium phosphate, dibasic calcium PEG 3350, and PEG 800, stearic acid, propylene glycol, US 2017/0209462 A1 Jul. 27, 2017

oleic acid, triethyl cellulose and triacetin. In some embodi Dosage Forms ments, plasticizers can also function as dispersing agents or 0250 In some embodiments, the compositions described Wetting agents. herein is formulated for administration to a subject via any 0243 “Solubilizers” include compounds such as triace conventional means including, but not limited to, oral, tin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium parenteral (e.g., intravenous, Subcutaneous, or intramuscu lauryl sulfate, sodium doccusate, vitamin ETPGS, dimethy lar), buccal, intranasal, rectal or transdermal administration lacetamide, N-methylpyrrolidone, N-hydroxyethylpyrroli routes. In some embodiments, the composition is formulated done, polyvinylpyrrolidone, hydroxypropylmethyl cellu for administration in a combined dosage form. In some lose, hydroxypropyl cyclodextrins, ethanol, n-butanol, embodiments, the composition is formulated for adminis isopropyl alcohol, cholesterol, bile salts, polyethylene glycol tration in a separate dosage forms. As used herein, the term 200-600, glycofurol, transcutol, propylene glycol, and dim “Subject' is used to mean an animal, preferably a mammal, ethyl isosorbide and the like. including a human or non-human. The terms “individual(s)'. “subject(s) and “patient(s) are used interchangeably 0244 “Stabilizers’ include compounds such as any anti herein, and mean any mammal. In some embodiments, the oxidation agents, buffers, acids, preservatives and the like. mammal is a human. In some embodiments, the mammal is 0245 "Steady state,” as used herein, is when the amount a non-human. None of the terms require or are limited to of drug administered is equal to the amount of drug elimi situations characterized by the Supervision (e.g., constant or nated within one dosing interval resulting in a plateau or intermittent) of a health care worker (e.g., a doctor, a constant plasma drug exposure. registered nurse, a nurse practitioner, a physicians assistant, an orderly or a hospice worker). 0246 'Suspending agents' include compounds such as 0251 Moreover, the pharmaceutical compositions polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, poly described herein, which include ibrutinib and/or an antican vinylpyrrolidone K17, polyvinylpyrrolidone K25, or poly cer agent can be formulated into any suitable dosage form, vinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copo including but not limited to, aqueous oral dispersions, liq lymer (S630), polyethylene glycol, e.g., the polyethylene uids, gels, syrups, elixirs, slurries, Suspensions and the like, glycol can have a molecular weight of about 300 to about for oral ingestion by a patient to be treated, Solid oral dosage 6000, or about 3350 to about 4000, or about 7000 to about forms, aerosols, controlled release formulations, fast melt 5400, sodium carboxymethylcellulose, methylcellulose, formulations, effervescent formulations, lyophilized formu hydroxypropylmethylcellulose, hydroxymethylcellulose lations, tablets, powders, pills, dragees, capsules, delayed acetate stearate, polysorbate-80, hydroxyethylcellulose, release formulations, extended release formulations, pulsa Sodium alginate, gums, such as, e.g., gum tragacanth and tile release formulations, multiparticulate formulations, and gum acacia, guar gum, Xanthans, including Xanthan gum, mixed immediate release and controlled release formula Sugars, cellulosics, such as, e.g., sodium carboxymethylcel tions. lulose, methylcellulose, Sodium carboxymethylcellulose, 0252 Pharmaceutical preparations for oral use are hydroxypropylmethylcellulose, hydroxyethylcellulose, obtained by mixing one or more Solid excipient with one or polysorbate-80, Sodium alginate, polyethoxylated Sorbitan more of the compounds described herein, optionally grind monolaurate, polyethoxylated Sorbitan monolaurate, povi ing the resulting mixture, and processing the mixture of done and the like. granules, after adding Suitable auxiliaries, if desired, to 0247 “Surfactants' include compounds such as sodium obtain tablets or dragee cores. Suitable excipients include, lauryl sulfate, sodium docusate. Tween 60 or 80, triacetin, for example, fillers such as Sugars, including lactose, vitamin E TPGS, sorbitan monooleate, polyoxyethylene Sucrose, mannitol, or Sorbitol; cellulose preparations such Sorbitan monooleate, polysorbates, polaxomers, bile salts, as, for example, maize starch, wheat starch, rice starch, glyceryl monostearate, copolymers of ethylene oxide and potato starch, gelatin, gum tragacanth, methylcellulose, propylene oxide, e.g., Pluronic R (BASF), and the like. microcrystalline cellulose, hydroxypropylmethylcellulose, Some other surfactants include polyoxyethylene fatty acid Sodium carboxymethylcellulose; or others such as: polyvi glycerides and vegetable oils, e.g., polyoxyethylene (60) nylpyrrolidone (PVP or povidone) or calcium phosphate. If hydrogenated castor oil; and polyoxyethylene alkylethers desired, disintegrating agents may be added. Such as the and alkylphenyl ethers, e.g., Octoxynol 10, octoxynol 40. In cross-linked croScarmellose Sodium, polyvinylpyrrolidone, Some embodiments, Surfactants may be included to enhance agar, oralginic acid or a salt thereof Such as sodium alginate. physical stability or for other purposes. 0253 Dragee cores are provided with suitable coatings. For this purpose, concentrated Sugar Solutions may be used, 0248 "Viscosity enhancing agents' include, e.g., methyl which may optionally contain gum arabic, talc, polyvi cellulose, Xanthan gum, carboxymethyl cellulose, hydroxy nylpyrrolidone, carbopol gel, polyethylene glycol, and/or propyl cellulose, hydroxypropylmethyl cellulose, hydroxy titanium dioxide, lacquer Solutions, and Suitable organic propylmethyl cellulose acetate Stearate, hydroxypropylm Solvents or solvent mixtures. Dyestuffs or pigments may be ethyl cellulose phthalate, carbomer, polyvinyl alcohol, added to the tablets or dragee coatings for identification or alginates, acacia, chitosans and combinations thereof. to characterize different combinations of active compound 0249 “Wetting agents’ include compounds such as oleic doses. acid, glyceryl monostearate, Sorbitan monooleate, Sorbitan 0254 Pharmaceutical preparations which are used orally monolaurate, triethanolamine oleate, polyoxyethylene Sor include push-fit capsules made of gelatin, as well as Soft, bitan monooleate, polyoxyethylene Sorbitan monolaurate, sealed capsules made of gelatin and a plasticizer, Such as Sodium docusate, Sodium oleate, Sodium lauryl Sulfate, glycerol or Sorbitol. The push-fit capsules contain the active sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ingredients in admixture with filler Such as lactose, binders ammonium salts and the like. Such as starches, and/or lubricants such as talc or magnesium US 2017/0209462 A1 Jul. 27, 2017 32

Stearate and, optionally, stabilizers. In soft capsules, the particles of ibrutinib and/or an anticancer agent, are not active compounds may be dissolved or Suspended in Suitable microencapsulated and are uncoated. liquids, Such as fatty oils, liquid paraffin, or liquid polyeth 0259 Suitable carriers for use in the solid dosage forms ylene glycols. In addition, stabilizers may be added. All described herein include, but are not limited to, acacia, formulations for oral administration should be in dosages gelatin, colloidal silicon dioxide, calcium glycerophosphate, Suitable for Such administration. calcium lactate, maltodextrin, glycerine, magnesium sili 0255. In some embodiments, the solid dosage forms cate, sodium caseinate, Soy lecithin, Sodium chloride, trical disclosed herein may be in the form of a tablet, (including cium phosphate, dipotassium phosphate, sodium Stearoyl a Suspension tablet, a fast-melt tablet, a bite-disintegration lactylate, carrageenan, monoglyceride, diglyceride, pregela tablet, a rapid-disintegration tablet, an effervescent tablet, or tinized starch, hydroxypropylmethylcellulose, hydroxypro a caplet), a pill, a powder (including a sterile packaged pylmethylcellulose acetate Stearate. Sucrose, microcrystal powder, a dispensable powder, or an effervescent powder) a line cellulose, lactose, mannitol and the like. capsule (including both soft or hard capsules, e.g., capsules 0260 Suitable filling agents for use in the solid dosage made from animal-derived gelatin or plant-derived HPMC, forms described herein include, but are not limited to, or “sprinkle capsules), Solid dispersion, Solid solution, lactose, calcium carbonate, calcium phosphate, dibasic cal bioerodible dosage form, controlled release formulations, cium phosphate, calcium Sulfate, microcrystalline cellulose, pulsatile release dosage forms, multiparticulate dosage cellulose powder, dextrose, dextrates, dextran, starches, forms, pellets, granules, or an aerosol. In other embodi pregelatinized starch, hydroxypropylmethycellulose ments, the pharmaceutical formulation is in the form of a (HPMC), hydroxypropylmethycellulose phthalate, hydroxy powder. In still other embodiments, the pharmaceutical propylmethylcellulose acetate stearate (HPMCAS), sucrose, formulation is in the form of a tablet, including but not Xylitol, lactitol, mannitol, Sorbitol, Sodium chloride, poly limited to, a fast-melt tablet. Additionally, pharmaceutical ethylene glycol, and the like. formulations described herein may be administered as a 0261. In order to release the compound of ibrutinib, a single capsule or in multiple capsule dosage form. In some proteasome inhibitor, and/or a steroid from a solid dosage embodiments, the pharmaceutical formulation is adminis form matrix as efficiently as possible, disintegrants are often tered in two, or three, or four, capsules or tablets. used in the formulation, especially when the dosage forms 0256 In some embodiments, Solid dosage forms, e.g., are compressed with binder. Disintegrants help rupturing the tablets, effervescent tablets, and capsules, are prepared by dosage form matrix by Swelling or capillary action when mixing particles ofibrutinib and/or an anticancer agent, with moisture is absorbed into the dosage form. Suitable disin one or more pharmaceutical excipients to form a bulk blend tegrants for use in the Solid dosage forms described herein composition. When referring to these bulk blend composi include, but are not limited to, natural starch Such as corn tions as homogeneous, it is meant that the particles of starch or potato starch, a pregelatinized starch Such as ibrutinib and/or an anticancer agent, are dispersed evenly National 1551 or Amijel R, or sodium starch glycolate such throughout the composition so that the composition may be as Promogel(R) or Explotab(R), a cellulose such as a wood readily subdivided into equally effective unit dosage forms, product, methylcrystalline cellulose, e.g., Avicel(R), Avicel(R) Such as tablets, pills, and capsules. The individual unit PH101, Avice1(R) PH102, Avice1(R) PH105, Elcema(R) P100, dosages may also include film coatings, which disintegrate Emcocel(R), Vivacel(R), Ming TiaR), and Solka-FlocR, meth upon oral ingestion or upon contact with diluent. These ylcellulose, croScarmellose, or a cross-linked cellulose. Such formulations can be manufactured by conventional pharma as cross-linked sodium carboxymethylcellulose (Ac-Di cological techniques. SolR), cross-linked carboxymethylcellulose, or cross-linked croScarmellose, a cross-linked Starch Such as Sodium starch 0257 Conventional pharmacological techniques include, glycolate, a cross-linked polymer Such as crospovidone, a e.g., one or a combination of methods: (1) dry mixing, (2) cross-linked polyvinylpyrrolidone, alginate Such as alginic direct compression, (3) milling, (4) dry or non-aqueous acid or a salt of alginic acid Such as sodium alginate, a clay granulation, (5) wet granulation, or (6) fusion. See, e.g., Such as Veegum R. HV (magnesium aluminum silicate), a Lachman et al., The Theory and Practice of Industrial gum Such as agar, guar, locust bean, Karaya, pectin, or Pharmacy (1986). Other methods include, e.g., spray drying, tragacanth, Sodium starch glycolate, bentonite, a natural pan coating, melt granulation, granulation, fluidized bed sponge, a Surfactant, a resin Such as a cation-exchange resin, spray drying or coating (e.g., Wurster coating), tangential citrus pulp, Sodium lauryl Sulfate, sodium lauryl Sulfate in coating, top spraying, tableting, extruding and the like. combination starch, and the like. 0258. In some embodiments, the pharmaceutical solid 0262 Binders impart cohesiveness to solid oral dosage dosage forms described herein include a compound form formulations: for powder filled capsule formulation, described herein and one or more pharmaceutically accept they aid in plug formation that can be filled into soft or hard able additives such as a compatible carrier, binder, filling shell capsules and for tablet formulation, they ensure the agent, Suspending agent, flavoring agent, Sweetening agent, tablet remaining intact after compression and help assure disintegrating agent, dispersing agent, Surfactant, lubricant, blend uniformity prior to a compression or fill step. Mate colorant, diluent, Solubilizer, moistening agent, plasticizer, rials suitable for use as binders in the solid dosage forms stabilizer, penetration enhancer, wetting agent, anti-foaming described herein include, but are not limited to, carboxym agent, antioxidant, preservative, or one or more combination ethylcellulose, methylcellulose (e.g., Methocel(R), hydroxy thereof. In still other aspects, using standard coating proce propylmethylcellulose (e.g., Hypromellose USP Pharma dures, such as those described in Remington's Pharmaceu coat-603, hydroxypropylmethylcellulose acetate stearate tical Sciences, 20th Edition (2000), a film coating is pro (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxy vided around the formulation of ibrutinib and/or an propylcellulose (e.g., Klucel(R), ethylcellulose (e.g., Etho anticancer agent. In another embodiment, some or all of the cel(R), and microcrystalline cellulose (e.g., Avicel(R), micro US 2017/0209462 A1 Jul. 27, 2017 crystalline dextrose, amylose, magnesium aluminum about 5400, vinyl pyrrolidone/vinyl acetate copolymer silicate, polysaccharide acids, bentonites, gelatin, polyvi (S630), sodium carboxymethylcellulose, methylcellulose, nylpyrrolidone/vinyl acetate copolymer, crospovidone, hydroxy-propylmethylcellulose, polysorbate-80, hydroxy povidone, starch, pregelatinized starch, tragacanth, dextrin, ethylcellulose, sodium alginate, gums, such as, e.g., gum a Sugar, such as Sucrose (e.g., DipaccR), glucose, dextrose, tragacanth and gum acacia, guar gum, Xanthans, including molasses, mannitol, Sorbitol. Xylitol (e.g., Xylitab (R), lac Xanthan gum, Sugars, cellulosics. Such as, e.g., Sodium tose, a natural or synthetic gum Such as acacia, tragacanth, carboxymethylcellulose, methylcellulose, sodium car ghatti gum, mucilage of isapol husks, starch, polyvinylpyr boxymethylcellulose, hydroxypropylmethylcellulose, rolidone (e.g., Povidone(R). CL, Kollidon R. CL, Polyplas hydroxyethylcellulose, polysorbate-80, sodium alginate, done(R) XL-10, and Povidone(R) K-12), larch arabogalactan, polyethoxylated Sorbitan monolaurate, polyethoxylated Sor VeegumR), polyethylene glycol, waxes, Sodium alginate, and bitan monolaurate, povidone and the like. the like. 0270. Suitable antioxidants for use in the solid dosage 0263. In general, binder levels of 20-70% are used in forms described herein include, for example, e.g., butylated powder-filled gelatin capsule formulations. Binder usage hydroxytoluene (BHT), sodium ascorbate, and tocopherol. level in tablet formulations varies whether direct compres 0271. It should be appreciated that there is considerable Sion, wet granulation, roller compaction, or usage of other overlap between additives used in the solid dosage forms excipients such as fillers which itself can act as moderate described herein. Thus, the above-listed additives should be binder. Formulators skilled in art can determine the binder taken as merely exemplary, and not limiting, of the types of level for the formulations, but binder usage level of up to additives that can be included in Solid dosage forms 70% in tablet formulations is common. described herein. The amounts of such additives can be 0264 Suitable lubricants or glidants for use in the solid readily determined by one skilled in the art, according to the dosage forms described herein include, but are not limited particular properties desired. to, Stearic acid, calcium hydroxide, talc, corn starch, sodium 0272. In other embodiments, one or more layers of the Stearyl fumerate, alkali-metal and alkaline earth metal salts, pharmaceutical formulation are plasticized. Illustratively, a Such as aluminum, calcium, magnesium, Zinc, Stearic acid, plasticizer is generally a high boiling point Solid or liquid. Sodium Stearates, magnesium Stearate, Zinc Stearate, waxes, Suitable plasticizers can be added from about 0.01% to Stearowet(R), boric acid, sodium benzoate, Sodium acetate, about 50% by weight (w/w) of the coating composition. Sodium chloride, leucine, a polyethylene glycol or a Plasticizers include, but are not limited to, diethyl phthalate, methoxypolyethylene glycol such as CarbowaxTM, PEG citrate esters, polyethylene glycol, glycerol, acetylated glyc 4000, PEG 5000, PEG 6000, propylene glycol, sodium erides, triacetin, polypropylene glycol, polyethylene glycol, oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl triethyl citrate, dibutyl sebacate, Stearic acid, Stearol, Stear benzoate, magnesium or sodium lauryl Sulfate, and the like. ate, and castor oil. 0265 Suitable diluents for use in the solid dosage forms 0273 Compressed tablets are solid dosage forms pre described herein include, but are not limited to, Sugars pared by compacting the bulk blend of the formulations (including lactose. Sucrose, and dextrose), polysaccharides described above. In various embodiments, compressed tab (including dextrates and maltodextrin), polyols (including lets which are designed to dissolve in the mouth will include mannitol. Xylitol, and Sorbitol), cyclodextrins and the like. one or more flavoring agents. In other embodiments, the 0266 The term “non water-soluble diluent” represents compressed tablets will include a film surrounding the final compounds typically used in the formulation of pharmaceu compressed tablet. In some embodiments, the film coating ticals, such as calcium phosphate, calcium Sulfate, starches, can provide a delayed release of ibrutinib or the second modified Starches and microcrystalline cellulose, and micro agent, from the formulation. In other embodiments, the film cellulose (e.g., having a density of about 0.45 g/cm, e.g., coating aids in patient compliance (e.g., Opadry(R) coatings Avicel, powdered cellulose), and talc. or Sugar coating). Film coatings including Opadry(R) typi 0267 Suitable wetting agents for use in the solid dosage cally range from about 1% to about 3% of the tablet weight. forms described herein include, for example, oleic acid, In other embodiments, the compressed tablets include one or glyceryl monostearate, Sorbitan monooleate, Sorbitan mono more excipients. laurate, triethanolamine oleate, polyoxyethylene Sorbitan 0274. In some embodiments, a capsule is prepared, for monooleate, polyoxyethylene Sorbitan monolaurate, quater example, by placing the bulk blend of the formulation of nary ammonium compounds (e.g., Polyguat 10(R), sodium ibrutinib or the second agent, described above, inside of a oleate, sodium lauryl Sulfate, magnesium Stearate, sodium capsule. In some embodiments, the formulations (non-aque docusate, triacetin, vitamin E TPGS and the like. ous Suspensions and solutions) are placed in a soft gelatin 0268 Suitable surfactants for use in the solid dosage capsule. In other embodiments, the formulations are placed forms described herein include, for example, sodium lauryl in standard gelatin capsules or non-gelatin capsules Such as Sulfate, Sorbitan monooleate, polyoxyethylene Sorbitan capsules comprising HPMC. In other embodiments, the monooleate, polysorbates, polaxomers, bile salts, glyceryl formulation is placed in a sprinkle capsule, wherein the monostearate, copolymers of ethylene oxide and propylene capsule may be Swallowed whole or the capsule may be oxide, e.g., Pluronic R (BASF), and the like. opened and the contents sprinkled on food prior to eating. In 0269 Suitable suspending agents for use in the solid Some embodiments, the therapeutic dose is split into mul dosage forms described here include, but are not limited to, tiple (e.g., two, three, or four) capsules. In some embodi polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, poly ments, the entire dose of the formulation is delivered in a vinylpyrrolidone K17, polyvinylpyrrolidone K25, or poly capsule form. vinylpyrrolidone K30, polyethylene glycol, e.g., the poly 0275. In various embodiments, the particles of ibrutinib, ethylene glycol can have a molecular weight of about 300 to a proteasome inhibitor, and/or a steroid, and one or more about 6000, or about 3350 to about 4000, or about 7000 to excipients are dry blended and compressed into a mass. Such US 2017/0209462 A1 Jul. 27, 2017 34 as a tablet, having a hardness Sufficient to provide a phar known by one of ordinary skill in the art. Such known maceutical composition that Substantially disintegrates methods include, e.g., spray drying processes, spinning within less than about 30 minutes, less than about 35 disk-solvent processes, hot melt processes, spray chilling minutes, less than about 40 minutes, less than about 45 methods, fluidized bed, electrostatic deposition, centrifugal minutes, less than about 50 minutes, less than about 55 extrusion, rotational Suspension separation, polymerization minutes, or less than about 60 minutes, after oral adminis at liquid-gas or solid-gas interface, pressure extrusion, or tration, thereby releasing the formulation into the gastroin spraying solvent extraction bath. In addition to these, several testinal fluid. chemical techniques, e.g., complex coacervation, Solvent 0276. In another aspect, dosage forms may include evaporation, polymer-polymer incompatibility, interfacial microencapsulated formulations. In some embodiments, one polymerization in liquid media, in situ polymerization, in or more other compatible materials are present in the micro liquid drying, and desolvation in liquid media could also be encapsulation material. Exemplary materials include, but are used. Furthermore, in some embodiments, other methods not limited to, pH modifiers, erosion facilitators, anti-foam Such as roller compaction, extrusion/spheronization, coacer ing agents, antioxidants, flavoring agents, and carrier mate Vation, or nanoparticle coating are also used. rials such as binders, Suspending agents, disintegration 0281. In one embodiment, the particles of compounds of agents, filling agents, Surfactants, solubilizers, stabilizers, any of ibrutinib or an anticancer agent are microencapsu lubricants, wetting agents, and diluents. lated prior to being formulated into one of the above forms. 0277 Materials useful for the microencapsulation In still another embodiment, some or most of the particles described herein include materials compatible with ibrutinib are coated prior to being further formulated by using stan and/or an anticancer agent, which sufficiently isolate the dard coating procedures, such as those described in Rem compound of any of ibrutinib or an anticancer agent, from ington's Pharmaceutical Sciences, 20th Edition (2000). other non-compatible excipients. Materials compatible with 0282. In other embodiments, the solid dosage formula compounds of any of ibrutinib or an anticancer agent, are tions of the compounds of any of ibrutinib and/or an those that delay the release of the compounds of any of anticancer agent are plasticized (coated) with one or more ibrutinib or an anticancer agent, in vivo. layers. Illustratively, a plasticizer is generally a high boiling 0278 Exemplary microencapsulation materials useful for point solid or liquid. Suitable plasticizers can be added from delaying the release of the formulations including com about 0.01% to about 50% by weight (w/w) of the coating pounds described herein, include, but are not limited to, composition. Plasticizers include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel(R) or diethyl phthalate, citrate esters, polyethylene glycol, glyc Nisso HPC, low-substituted hydroxypropyl cellulose ethers erol, acetylated glycerides, triacetin, polypropylene glycol, (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) polyethylene glycol, triethylcitrate, dibutyl sebacate, Stearic such as Seppi film-LC, Pharmacoat(R), Metolose SR, Metho acid, Stearol, Stearate, and castor oil. cel(R)-E, Opadry YS, PrimaFlo, Benecel MP824, and Bene 0283. In other embodiments, a powder including the cel MP843, methylcellulose polymers such as Methocel(R)- formulations with a compound of any of ibrutinib and/or an A, hydroxypropylmethylcellulose acetate Stearate Aqoat anticancer agent, described herein, may be formulated to (HF-LS, HF-LG.HF-MS) and MetoloseR), Ethylcelluloses include one or more pharmaceutical excipients and flavors. (EC) and mixtures thereof such as E461, Ethocel(R), Aqua Such a powder may be prepared, for example, by mixing the lon R-EC, Surelease.R., Polyvinyl alcohol (PVA) such as formulation and optional pharmaceutical excipients to form Opadry AMB, hydroxyethylcelluloses such as Natrosol(R), a bulk blend composition. Additional embodiments also carboxymethylcelluloses and salts of carboxymethylcellu include a suspending agent and/or a wetting agent. This bulk loses (CMC) such as AqualonR-CMC, polyvinyl alcohol blend is uniformly Subdivided into unit dosage packaging or and polyethylene glycol co-polymers such as Kollicoat IRR, multi-dosage packaging units. monoglycerides (My verol), triglycerides (KLX), polyethyl 0284. In still other embodiments, effervescent powders ene glycols, modified food starch, acrylic polymers and are also prepared in accordance with the present disclosure. mixtures of acrylic polymers with cellulose ethers such as Effervescent salts have been used to disperse medicines in EudragitR) EPO, Eudragit R. L30D-55, Eudragit R FS 30D water for oral administration. Effervescent salts are granules Eudragit R L100-55, EudragitR) L100, EudragitR) S100, or coarse powders containing a medicinal agent in a dry Eudragit R. RD100, EudragitR) E100, EudragitR) L12.5, mixture, usually composed of sodium bicarbonate, citric Eudragit R S12.5, Eudragit R NE30D, and Eudragit R NE acid and/or tartaric acid. When salts of the compositions 40D, cellulose acetate phthalate, sepifilms such as mixtures described herein are added to water, the acids and the base of HPMC and stearic acid, cyclodextrins, and mixtures of react to liberate carbon dioxide gas, thereby causing “effer these materials. Vescence.” Examples of effervescent salts include, e.g., the 0279. In still other embodiments, plasticizers such as following ingredients: Sodium bicarbonate or a mixture of polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, Sodium bicarbonate and sodium carbonate, citric acid and/or PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene tartaric acid. Any acid-base combination that results in the glycol, oleic acid, and triacetin are incorporated into the liberation of carbon dioxide can be used in place of the microencapsulation material. In other embodiments, the combination of sodium bicarbonate and citric and tartaric microencapsulating material useful for delaying the release acids, as long as the ingredients were Suitable for pharma of the pharmaceutical compositions is from the USP or the ceutical use and result in a pH of about 6.0 or higher. National Formulary (NF). In yet other embodiments, the 0285. In some embodiments, the solid dosage forms microencapsulation material is Klucel. In still other embodi described herein is formulated as enteric coated delayed ments, the microencapsulation material is methocel. release oral dosage forms, i.e., as an oral dosage form of a 0280 Microencapsulated compounds of any of ibrutinib pharmaceutical composition as described herein which ulti or an anticancer agent may be formulated by methods lizes an enteric coating to affect release in the Small intestine US 2017/0209462 A1 Jul. 27, 2017

of the gastrointestinal tract. In some embodiments, the solves at pH 5.5, and AS-HG (HF), which dissolves at higher enteric coated dosage form is a compressed or molded or pH. These polymers are offered as granules, or as fine extruded tablet/mold (coated or uncoated) containing gran powders for aqueous dispersions; Poly Vinyl Acetate Phtha ules, powder, pellets, beads or particles of the active ingre late (PVAP). PVAP dissolves in pH>5, and it is much less dient and/or other composition components, which are permeable to water vapor and gastric fluids. themselves coated or uncoated. In some embodiments, the 0290. In some embodiments, the coating can, and usually enteric coated oral dosage form is also be a capsule (coated does, contain a plasticizer and possibly other coating excipi or uncoated) containing pellets, beads or granules of the ents such as colorants, talc, and/or magnesium Stearate, solid carrier or the composition, which are themselves which are well known in the art. Suitable plasticizers include coated or uncoated. triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), 0286. In some embodiments, the term “delayed release' acetyl triethyl citrate (Citroflec A2), Carbowax 400 (poly as used herein refers to the delivery so that the release is ethylene glycol 400), diethyl phthalate, tributyl citrate, accomplished at Some generally predictable location in the acetylated monoglycerides, glycerol, fatty acid esters, pro intestinal tract more distal to that which would have been pylene glycol, and dibutyl phthalate. In particular, anionic accomplished if there had been no delayed release altera carboxylic acrylic polymers usually will contain 10-25% by tions. In some embodiments the method for delay of release weight of a plasticizer, especially dibutyl phthalate, poly is coating. Any coatings should be applied to a Sufficient ethylene glycol, triethyl citrate and triacetin. Conventional thickness such that the entire coating does not dissolve in the coating techniques Such as spray or pan coating are gastrointestinal fluids at pH below about 5, but does dissolve employed to apply coatings. The coating thickness must be at pH about 5 and above. It is expected that any anionic Sufficient to ensure that the oral dosage form remains intact polymer exhibiting a pH-dependent solubility profile can be until the desired site of topical delivery in the intestinal tract used as an enteric coating in the methods and compositions is reached. described herein to achieve delivery to the lower gastroin 0291 Colorants, detackifiers, surfactants, antifoaming testinal tract. In some embodiments the polymers described agents, lubricants (e.g., carnuba wax or PEG) may be added herein are anionic carboxylic polymers. In other embodi to the coatings besides plasticizers to solubilize or disperse ments, the polymers and compatible mixtures thereof, and the coating material, and to improve coating performance some of their properties, include, but are not limited to: and the coated product. 0287. Shellac, also called purified lac, a refined product 0292. In other embodiments, the formulations described obtained from the resinous secretion of an insect. This herein, which include ibrutinib and/or an anticancer agent, coating dissolves in media of pH>7; are delivered using a pulsatile dosage form. A pulsatile 0288 Acrylic polymers. The performance of acrylic dosage form is capable of providing one or more immediate polymers (primarily their solubility in biological fluids) can release pulses at predetermined time points after a controlled vary based on the degree and type of Substitution. Examples lag time or at specific sites. Many other types of controlled of Suitable acrylic polymers include methacrylic acid copo release systems known to those of ordinary skill in the art lymers and ammonium methacrylate copolymers. The and are suitable for use with the formulations described Eudragit series E. L. S. RL, RS and NE (Rohm Pharma) are herein. Examples of Such delivery systems include, e.g., available as solubilized in organic solvent, aqueous disper polymer-based systems, such as polylactic and polyglycolic sion, or dry powders. The Eudragit series RL, NE, and RS acid, plyanhydrides and polycaprolactone; porous matrices, are insoluble in the gastrointestinal tract but are permeable nonpolymer-based systems that are lipids, including sterols, and are used primarily for colonic targeting. The Eudragit Such as cholesterol, cholesterol esters and fatty acids, or series E dissolve in the stomach. The Eudragit series L. neutral fats, such as mono-, di- and triglycerides; hydrogel L-30D and S are insoluble in stomach and dissolve in the release systems; Silastic systems; peptide-based systems; intestine; wax coatings, bioerodible dosage forms, compressed tablets 0289 Cellulose Derivatives. Examples of suitable cellu using conventional binders and the like. See, e.g., Liberman lose derivatives are: ethyl cellulose; reaction mixtures of et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. partial acetate esters of cellulose with phthalic anhydride. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceu The performance can vary based on the degree and type of tical Technology 2" Ed., pp. 751-753 (2002); U.S. Pat. Nos. substitution. Cellulose acetate phthalate (CAP) dissolves in 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, pH>6. Aquateric (FMC) is an aqueous based system and is 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, a spray dried CAP psuedolatex with particles <1 um. Other 6,465,014 and 6,932,983. components in Aquateric can include pluronics, Tweens, and 0293. In some embodiments, pharmaceutical formula acetylated monoglycerides. Other suitable cellulose deriva tions are provided that include particles of ibrutinib and/or tives include: cellulose acetate trimellitate (Eastman); meth an anticancer agent, described herein and at least one ylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl dispersing agent or Suspending agent for oral administration cellulose phthalate (HPMCP); hydroxypropylmethyl cellu to a subject. The formulations may be a powder and/or lose succinate (HPMCS); and hydroxypropylmethylcellu granules for Suspension, and upon admixture with water, a lose acetate succinate (e.g., AQOAT (Shin Etsu)). The Substantially uniform Suspension is obtained. performance can vary based on the degree and type of 0294. In some embodiments, liquid formulation dosage substitution. For example, HPMCP such as, HP-50, HP-55, forms for oral administration are aqueous Suspensions HP-55S, HP-55F grades are suitable. The performance can selected from the group including, but not limited to, phar vary based on the degree and type of substitution. For maceutically acceptable aqueous oral dispersions, emul example, Suitable grades of hydroxypropylmethylcellulose sions, Solutions, elixirs, gels, and syrups. See, e.g., Singh et acetate succinate include, but are not limited to, AS-LG al., Encyclopedia of Pharmaceutical Technology, 2" Ed., (LF), which dissolves at pH 5, AS-MG (MF), which dis pp. 754-757 (2002). In addition the liquid dosage forms may US 2017/0209462 A1 Jul. 27, 2017 36 include additives, such as: (a) disintegrating agents; (b) oxide); and poloxamines (e.g., Tetronic 908R, also known as dispersing agents; (c) wetting agents; (d) at least one pre Poloxamine 908R, which is a tetrafunctional block copoly servative, (e) viscosity enhancing agents, (f) at least one mer derived from sequential addition of propylene oxide and Sweetening agent, and (g) at least one flavoring agent. In ethylene oxide to ethylenediamine (BASF Corporation, Par Some embodiments, the aqueous dispersions can further Sippany, N.J.)). In other embodiments, the dispersing agent include a crystalline inhibitor. is selected from a group not comprising one of the following 0295. In some embodiments, the aqueous suspensions agents: hydrophilic polymers; electrolytes; Tween R. 60 or and dispersions described herein remain in a homogenous 80; PEG, polyvinylpyrrolidone (PVP); hydroxypropylcellu state, as defined in The USP Pharmacists Pharmacopeia lose and hydroxypropyl cellulose ethers (e.g., HPC, HPC (2005 edition, chapter 905), for at least 4 hours. The SL, and HPC-L): hydroxypropyl methylcellulose and homogeneity should be determined by a sampling method hydroxypropyl methylcellulose ethers (e.g., HPMC K100, consistent with regard to determining homogeneity of the HPMC K4M, HPMC K15M, HPMC K10OM, and Pharma entire composition. In one embodiment, an aqueous Suspen coat(R) USP 2910 (Shin-Etsu)); carboxymethylcellulose sion can be re-suspended into a homogenous Suspension by sodium; methylcellulose; hydroxyethylcellulose; hydroxy physical agitation lasting less than 1 minute. In another propylmethyl-cellulose phthalate: hydroxypropylmethyl embodiment, an aqueous Suspension is re-suspended into a cellulose acetate Stearate; non-crystalline cellulose; magne homogenous Suspension by physical agitation lasting less sium aluminum silicate; triethanolamine; polyvinyl alcohol than 45 seconds. In yet another embodiment, an aqueous (PVA): 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with Suspension is re-suspended into a homogenous Suspension ethylene oxide and formaldehyde; poloxamers (e.g., Pluron by physical agitation lasting less than 30 seconds. In still ics F68(R), F88(R), and F108R, which are block copolymers of another embodiment, no agitation is necessary to maintain a ethylene oxide and propylene oxide); or poloxamines (e.g., homogeneous aqueous dispersion. Tetronic 908 R, also known as Poloxamine 908 R). 0296. Examples of disintegrating agents for use in the 0298 Wetting agents suitable for the aqueous suspen aqueous Suspensions and dispersions include, but are not sions and dispersions described herein are known in the art limited to, a starch, e.g., a natural starch Such as corn starch and include, but are not limited to, cetyl alcohol, glycerol or potato starch, a pregelatinized starch Such as National monostearate, polyoxyethylene Sorbitan fatty acid esters 1551 or Amijel R, or sodium starch glycolate such as Pro (e.g., the commercially available Tweens R. Such as e.g., mogel(R) or Explotab(R); a cellulose such as a wood product, Tween 20R) and Tween 80R (ICI Specialty Chemicals)), and methylcrystalline cellulose, e.g., Avicel(R), Avicel(R) PH101, polyethylene glycols (e.g., Carbowaxs 3350R and 1450R, Avice1(R) PH102, Avicel(R) PH105, Elcema(R) P100, Emco and Carbopol 934(R) (Union Carbide)), oleic acid, glyceryl cel(R), Vivacel(R), Ming TiaR), and Solka-FlocR, methylcel monostearate, Sorbitan monooleate, Sorbitan monolaurate, lulose, croScarmellose, or a cross-linked cellulose, such as triethanolamine oleate, polyoxyethylene Sorbitan cross-linked sodium carboxymethylcellulose (Ac-Di-Sol(R), monooleate, polyoxyethylene Sorbitan monolaurate, sodium cross-linked carboxymethylcellulose, or cross-linked cros oleate, sodium lauryl Sulfate, Sodium docusate, triacetin, carmellose; a cross-linked starch Such as sodium starch vitamin E TPGS, sodium taurocholate, simethicone, phos glycolate; a cross-linked polymer Such as crospovidone; a photidylcholine and the like. cross-linked polyvinylpyrrolidone; alginate such as alginic 0299 Suitable preservatives for the aqueous suspensions acid or a salt of alginic acid such as Sodium alginate; a clay or dispersions described herein include, for example, potas Such as Veegum R. HV (magnesium aluminum silicate); a sium Sorbate, parabens (e.g., methylparaben and propylpa gum Such as agar, guar, locust bean, Karaya, pectin, or raben), benzoic acid and its salts, other esters of parahy tragacanth; sodium starch glycolate; bentonite; a natural droxybenzoic acid such as butylparaben, alcohols such as sponge; a surfactant; a resin Such as a cation-exchange resin; ethyl alcohol or benzyl alcohol, phenolic compounds such as citrus pulp; sodium lauryl Sulfate; sodium lauryl Sulfate in phenol, or quaternary compounds such as benzalkonium combination starch; and the like. chloride. Preservatives, as used herein, are incorporated into 0297. In some embodiments, the dispersing agents suit the dosage form at a concentration Sufficient to inhibit able for the aqueous Suspensions and dispersions described microbial growth. herein are known in the art and include, for example, 0300 Suitable viscosity enhancing agents for the aque hydrophilic polymers, electrolytes, Tween R. 60 or 80, PEG, ous Suspensions or dispersions described herein include, but polyvinylpyrrolidone (PVP; commercially known as Plas are not limited to, methyl cellulose, Xanthan gum, car done(R), and the carbohydrate-based dispersing agents such boxymethyl cellulose, hydroxypropyl cellulose, hydroxy as, for example, hydroxypropylcellulose and hydroxypropyl propylmethyl cellulose, Plasdon(R) S-630, carbomer, polyvi cellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxy nyl alcohol, alginates, acacia, chitosans and combinations propyl methylcellulose and hydroxypropyl methylcellulose thereof. The concentration of the Viscosity enhancing agent ethers (e.g., HPMC K100, HPMC K4M, HPMC K15M, and will depend upon the agent selected and the Viscosity HPMC K10OM), carboxymethylcellulose sodium, methyl desired. cellulose, hydroxyethylcellulose, hydroxypropylmethyl-cel 0301 Examples of sweetening agents suitable for the lulose phthalate, hydroxypropylmethyl-cellulose acetate aqueous Suspensions or dispersions described herein Stearate, noncrystalline cellulose, magnesium aluminum sili include, for example, acacia syrup, acesulfame K, alitame, cate, triethanolamine, polyvinyl alcohol (PVA), polyvi anise, apple, aspartame, banana, Bavarian cream, berry, nylpyrrolidone/vinyl acetate copolymer (Plasdone R, e.g., black currant, butterscotch, calcium citrate, camphor, cara S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with mel, cherry, cherry cream, chocolate, cinnamon, bubble ethylene oxide and formaldehyde (also known as tyloxapol), gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, poloxamers (e.g., Pluronics F68(R), F88(R), and F108(R), which cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, are block copolymers of ethylene oxide and propylene eucalyptus, eugenol, fructose, fruit punch, ginger, glycyr US 2017/0209462 A1 Jul. 27, 2017 37 rhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, classified differently by different practitioners in the field, or honey, isomalt, lemon, lime, lemon cream, monoammonium is commonly used for any of several different functions. glyrrhizinate (MagnaSweetR), maltol, mannitol, maple, Thus, the above-listed additives should be taken as merely marshmallow, menthol, mint cream, mixed berry, neohes exemplary, and not limiting, of the types of additives that peridine DC, neotame, orange, pear, peach, peppermint, can be included in formulations described herein. The peppermint cream, ProSweet(R) Powder, raspberry, root beer, amounts of such additives can be readily determined by one rum, saccharin, Safrole, Sorbitol, spearmint, spearmint skilled in the art, according to the particular properties cream, Strawberry, Strawberry cream, Stevia, Sucralose, desired. Sucrose, sodium saccharin, Saccharin, aspartame, acesul fame potassium, mannitol, talin, Sucralose, Sorbitol, Swiss Intranasal Formulations cream, tagatose, tangerine, thaumatin, tutti fruitti, Vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any 0305 Intranasal formulations are known in the art and are combination of these flavoring ingredients, e.g., anise-men described in, for example, U.S. Pat. Nos. 4,476,116, 5,116, thol, cherry-anise, cinnamon-orange, cherry-cinnamon, 817 and 6.391,452, each of which is specifically incorpo chocolate-mint, honey-lemon, lemon-lime, lemon-mint, rated by reference. Formulations that include ibrutinib and/ menthol-eucalyptus, orange-cream, Vanilla-mint, and mix or An anticancer agent, which are prepared according to tures thereof. In one embodiment, the aqueous liquid dis these and other techniques well-known in the art are pre persion can comprise a Sweetening agent or flavoring agent pared as Solutions in Saline, employing benzyl alcohol or in a concentration ranging from about 0.001% to about 1.0% other suitable preservatives, fluorocarbons, and/or other the Volume of the aqueous dispersion. In another embodi solubilizing or dispersing agents known in the art. See, for ment, the aqueous liquid dispersion can comprise a Sweet example, Ansel, H. C. et al., Pharmaceutical Dosage Forms ening agent or flavoring agent in a concentration ranging and Drug Delivery Systems, Sixth Ed. (1995). Preferably from about 0.005% to about 0.5% the volume of the aqueous these compositions and formulations are prepared with dispersion. In yet another embodiment, the aqueous liquid Suitable nontoxic pharmaceutically acceptable ingredients. dispersion can comprise a Sweetening agent or flavoring These ingredients are known to those skilled in the prepa agent in a concentration ranging from about 0.01% to about ration of nasal dosage forms and some of these can be found 1.0% the volume of the aqueous dispersion. in REMINGTON: THE SCIENCE AND PRACTICE OF 0302) In addition to the additives listed above, the liquid PHARMACY, 21st edition, 2005, a standard reference in the formulations can also include inert diluents commonly used field. The choice of suitable carriers is highly dependent in the art, such as water or other solvents, solubilizing upon the exact nature of the nasal dosage form desired, e.g., agents, and emulsifiers. Exemplary emulsifiers are ethyl Solutions, Suspensions, ointments, or gels. Nasal dosage alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, forms generally contain large amounts of water in addition benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-bu to the active ingredient. Minor amounts of other ingredients tyleneglycol, dimethylformamide, Sodium lauryl Sulfate, Such as pH adjusters, emulsifiers or dispersing agents, Sodium doccusate, cholesterol, cholesterol esters, tauro preservatives, Surfactants, gelling agents, or buffering and cholic acid, phosphotidylcholine, oils, such as cottonseed other stabilizing and solubilizing agents may also be present. oil, groundnut oil, corn germ oil, olive oil, castor oil, and The nasal dosage form should be isotonic with nasal Secre sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyl tions. ene glycols, fatty acid esters of Sorbitan, or mixtures of these 0306 For administration by inhalation described herein Substances, and the like. may be in a form as an aerosol, a mist or a powder. 0303. In some embodiments, the pharmaceutical formu Pharmaceutical compositions described herein are conve lations described herein can be self-emulsifying drug deliv niently delivered in the form of an aerosol spray presentation ery systems (SEDDS). Emulsions are dispersions of one from pressurized packs or a nebulizer, with the use of a immiscible phase in another, usually in the form of droplets. Suitable propellant, e.g., dichlorodifluoromethane, trichloro Generally, emulsions are created by vigorous mechanical fluoromethane, dichlorotetrafluoroethane, carbon dioxide or dispersion. SEDDS, as opposed to emulsions or microemul other Suitable gas. In the case of a pressurized aerosol, the sions, spontaneously form emulsions when added to an dosage unit may be determined by providing a valve to excess of water without any external mechanical dispersion deliver a metered amount. Capsules and cartridges of Such or agitation. An advantage of SEDDS is that only gentle as, by way of example only, gelatin for use in an inhaler or mixing is required to distribute the droplets throughout the insufflator may be formulated containing a powder mix of Solution. Additionally, water or the aqueous phase can be the compound described herein and a suitable powder base added just prior to administration, which ensures stability of Such as lactose or starch. an unstable or hydrophobic active ingredient. Thus, the SEDDS provides an effective delivery system for oral and Buccal Formulations parenteral delivery of hydrophobic active ingredients. 0307 Buccal formulations may be administered using a SEDDS may provide improvements in the bioavailability of variety of formulations known in the art. For example, such hydrophobic active ingredients. Methods of producing self formulations include, but are not limited to, U.S. Pat. Nos. emulsifying dosage forms are known in the art and include, 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of but are not limited to, for example, U.S. Pat. Nos. 5,858,401, which is specifically incorporated by reference. In addition, 6,667,048, and 6,960,563, each of which is specifically the buccal dosage forms described herein can further include incorporated by reference. a bioerodible (hydrolysable) polymeric carrier that also 0304. It is to be appreciated that there is overlap between serves to adhere the dosage form to the buccal mucosa. The the above-listed additives used in the aqueous dispersions or buccal dosage form is fabricated so as to erode gradually Suspensions described herein, since a given additive is often over a predetermined time period, wherein the delivery is US 2017/0209462 A1 Jul. 27, 2017 provided essentially throughout. Buccal drug delivery, as rate-controlling membranes or by trapping the compound will be appreciated by those skilled in the art, avoids the within a polymer matrix or gel. Conversely, absorption disadvantages encountered with oral drug administration, enhancers can be used to increase absorption. An absorption e.g., slow absorption, degradation of the active agent by enhancer or carrier can include absorbable pharmaceutically fluids present in the gastrointestinal tract and/or first-pass acceptable solvents to assist passage through the skin. For inactivation in the liver. With regard to the bioerodible example, transdermal devices are in the form of a bandage (hydrolysable) polymeric carrier, it will be appreciated that comprising a backing member, a reservoir containing the virtually any such carrier can be used, so long as the desired compound optionally with carriers, optionally a rate con drug release profile is not compromised, and the carrier is trolling barrier to deliver the compound to the skin of the compatible with ibrutinib and/or An anticancer agent, and host at a controlled and predetermined rate over a prolonged any other components that may be present in the buccal period of time, and means to secure the device to the skin. dosage unit. Generally, the polymeric carrier comprises hydrophilic (water-soluble and water-swellable) polymers Injectable Formulations that adhere to the wet surface of the buccal mucosa. 0311 Formulations that include a compound of ibrutinib Examples of polymeric carriers useful herein include acrylic and/or an anticancer agent, Suitable for intramuscular, Sub acid polymers and co, e.g., those known as “carbomers' cutaneous, or intravenous injection may include physiologi (Carbopol R, which may be obtained from B.F. Goodrich, is cally acceptable sterile aqueous or non-aqueous Solutions, one such polymer). Other components may also be incor dispersions, Suspensions or emulsions, and sterile powders porated into the buccal dosage forms described herein for reconstitution into sterile injectable solutions or disper include, but are not limited to, disintegrants, diluents, bind sions. Examples of Suitable aqueous and non-aqueous car ers, lubricants, flavoring, colorants, preservatives, and the riers, diluents, solvents, or vehicles including water, ethanol, like. For buccal or Sublingual administration, the composi polyols (propyleneglycol, polyethylene-glycol, glycerol, tions may take the form of tablets, lozenges, or gels formu cremophor and the like), suitable mixtures thereof, vegetable lated in a conventional manner. oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, Transdermal Formulations by the use of a coating Such as lecithin, by the maintenance 0308 Transdermal formulations described herein may be of the required particle size in the case of dispersions, and administered using a variety of devices which have been by the use of surfactants. Formulations suitable for subcu described in the art. For example, such devices include, but taneous injection may also contain additives Such as pre are not limited to, U.S. Pat. Nos. 3,598,122, 3,598,123, serving, wetting, emulsifying, and dispensing agents. Pre 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, vention of the growth of microorganisms can be ensured by 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, various antibacterial and antifungal agents. Such as para 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, bens, chlorobutanol, phenol, Sorbic acid, and the like. It may 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, also be desirable to include isotonic agents, such as Sugars, 5,869,090, 6,923,983, 6,929,801 and 6,946,144, each of sodium chloride, and the like. Prolonged absorption of the which is specifically incorporated by reference in its entirety. injectable pharmaceutical form can be brought about by the 0309 The transdermal dosage forms described herein use of agents delaying absorption, such as aluminum monos may incorporate certain pharmaceutically acceptable excipi tearate and gelatin. ents which are conventional in the art. In one embodiment, 0312 For intravenous injections, compounds described the transdermal formulations described herein include at herein may be formulated in aqueous solutions, preferably in least three components: (1) a formulation of a compound of physiologically compatible buffers such as Hank's solution, ibrutinib and An anticancer agent; (2) a penetration Ringer's solution, or physiological saline buffer. For trans enhancer, and (3) an aqueous adjuvant. In addition, trans mucosal administration, penetrants appropriate to the barrier dermal formulations can include additional components to be permeated are used in the formulation. Such penetrants Such as, but not limited to, gelling agents, creams and are generally known in the art. For other parenteral injec ointment bases, and the like. In some embodiments, the tions, appropriate formulations may include aqueous or transdermal formulation can further include a woven or nonaqueous solutions, preferably with physiologically com non-woven backing material to enhance absorption and patible buffers or excipients. Such excipients are generally prevent the removal of the transdermal formulation from the known in the art. skin. In other embodiments, the transdermal formulations 0313 Parenteral injections may involve bolus injection described herein can maintain a Saturated or Supersaturated or continuous infusion. Formulations for injection may be state to promote diffusion into the skin. presented in unit dosage form, e.g., in ampoules or in 0310. Formulations suitable for transdermal administra multi-dose containers, with an added preservative. The tion of compounds described herein may employ transder pharmaceutical composition described herein may be in a mal delivery devices and transdermal delivery patches and form suitable for parenteral injection as a sterile Suspen can be lipophilic emulsions or buffered, aqueous Solutions, sions, solutions or emulsions in oily or aqueous vehicles, dissolved and/or dispersed in a polymer oran adhesive. Such and may contain formulatory agents such as Suspending, patches may be constructed for continuous, pulsatile, or on stabilizing and/or dispersing agents. Pharmaceutical formu demand delivery of pharmaceutical agents. Still further, lations for parenteral administration include aqueous solu transdermal delivery of the compounds described herein can tions of the active compounds in water-soluble form. Addi be accomplished by means of iontophoretic patches and the tionally, Suspensions of the active compounds may be like. Additionally, transdermal patches can provide con prepared as appropriate oily injection Suspensions. Suitable trolled delivery of ibrutinib, a proteasome inhibitor, and a lipophilic solvents or vehicles include fatty oils such as steroid. The rate of absorption can be slowed by using sesame oil, or synthetic fatty acid esters, such as ethyl oleate US 2017/0209462 A1 Jul. 27, 2017 39 or triglycerides, or liposomes. Aqueous injection Suspen Such kits optionally include an identifying description or sions may contain Substances which increase the Viscosity of label or instructions relating to its use in the methods the Suspension, such as sodium carboxymethyl cellulose, described herein. Sorbitol, or dextran. Optionally, the Suspension may also 0321) A kit typically includes labels listing contents and/ contain Suitable stabilizers or agents that increase the Solu or instructions for use, and package inserts with instructions bility of the compounds to allow for the preparation of for use. A set of instructions will also typically be included. highly concentrated Solutions. Alternatively, the active 0322. In one embodiment, a label is on or associated with ingredient may be in powder form for constitution with a the container. In one embodiment, a label is on a container Suitable vehicle, e.g., sterile pyrogen-free water, before use. when letters, numbers or other characters forming the label are attached, molded or etched into the container itself a Other Formulations label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as 0314. In certain embodiments, delivery systems for phar a package insert. In one embodiment, a label is used to maceutical compounds are employed. Such as, for example, indicate that the contents are to be used for a specific liposomes and emulsions. In certain embodiments, compo therapeutic application. The label also indicates directions sitions provided herein are also include an mucoadhesive for use of the contents, such as in the methods described polymer, selected from among, for example, carboxymeth herein. ylcellulose, carbomer (acrylic acid polymer), poly(methyl 0323. In certain embodiments, the pharmaceutical com methacrylate), polyacrylamide, polycarbophil, acrylic acid/ positions are presented in a pack or dispenser device which butyl acrylate copolymer, Sodium alginate and dextran. contains one or more unit dosage forms containing a com 0315. In some embodiments, the compounds described pound provided herein. The pack, for example, contains herein are administered topically and can be formulated into metal or plastic foil. Such as a blister pack. In one embodi a variety of topically administrable compositions, such as ment, the pack or dispenser device is accompanied by Solutions, Suspensions, lotions, gels, pastes, medicated instructions for administration. In one embodiment, the pack Sticks, balms, creams or ointments. Such pharmaceutical or dispenser is also accompanied with a notice associated compounds can contain solubilizers, stabilizers, tonicity with the container in form prescribed by a governmental enhancing agents, buffers and preservatives. agency regulating the manufacture, use, or sale of pharma ceuticals, which notice is reflective of approval by the 0316. In some embodiments, the compounds described agency of the form of the drug for human or veterinary herein are also be formulated in rectal compositions such as administration. Such notice, for example, is the labeling enemas, rectal gels, rectal foams, rectal aerosols, Supposi approved by the U.S. Food and Drug Administration for tories, jelly Suppositories, or retention enemas, containing prescription drugs, or the approved product insert. In one conventional Suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvi embodiment, compositions containing a compound pro nylpyrrolidone, PEG, and the like. In suppository forms of vided herein formulated in a compatible pharmaceutical the compositions, a low-melting wax Such as, but not limited carrier are also prepared, placed in an appropriate container, to, a mixture of fatty acid glycerides, optionally in combi and labeled for treatment of an indicated condition. nation with cocoa butter is first melted. Examples 0317. In some embodiments, the pharmaceutical compo sitions are formulated such that the amount of the covalent 0324. These examples are provided for illustrative pur Btk inhibitor (e.g., an irreversible covalent Btk inhibitor, poses only and not to limit the scope of the claims provided e.g., ibrutinib) in each unit dosage form is about 140 mg per. herein. Example 1: Combination Treatment of Ibrutinib in Kits/Article of Manufacture Combination with Pomalidomide (PomalystTM) and Dexamethasone in Patients with Relapsed or 0318 Disclosed herein, in certain embodiments, are kits Relapsed and Refractory Multiple Myeloma (Phase and articles of manufacture for use with one or more 1/2b Study) methods described herein. Such kits include a carrier, pack age, or container that is compartmentalized to receive one or 0325 Brutons tyrosine kinase (BTK) is an enzyme over more containers such as vials, tubes, and the like, each of the expressed in malignant plasma cells and which may posi container(s) comprising one of the separate elements to be tively regulate the myeloma stem cell-like population. used in a method described herein. Suitable containers include, for example, bottles, vials, Syringes, and test tubes. Study Drugs In one embodiment, the containers are formed from a variety 0326 Ibrutinib will be supplied as 140 mg hard gelatin of materials such as glass or plastic. capsules for oral (PO) administration. 0319. The articles of manufacture provided herein con 0327 Pomalidomide will be supplied as hard gelatin tain packaging materials. Examples of pharmaceutical pack capsules for PO administration. aging materials include, but are not limited to, blister packs, 0328 Dexamethasone will be available as scored tablets bottles, tubes, bags, containers, bottles, and any packaging in various strengths for PO administration. material suitable for a selected formulation and intended mode of administration and treatment. Phase 1 Objectives: 0320 For example, the container(s) include ibrutinib, 0329 Primary Objectives: To determine the maximum optionally in a composition or in combination with an tolerated dose (MTD)/maximum administered dose (MAD) immunomodulatory agent and a steroid as disclosed herein. and the Phase 2b dose of the ibrutinib, pomalidomide and US 2017/0209462 A1 Jul. 27, 2017 40 dexamethasone combination. Secondary Objectives: Overall Study Design response rate (ORR) defined as a PR according to the Inter 0339. This study will be conducted in two Phases: national Myeloma Working Group (IMWG) response crite 0340 Phase 1 will be an open-label, national, multicenter ria; duration of response (DOR); the clinical benefit rate dose-finding study of the ibrutinib, pomalidomide and dex (CBR) and its duration, defined as MR according to the amethasone combination in Subjects with relapsed/refrac IMWG response criteria; to evaluate the pharmacokinetics tory MM who have received at least two prior lines of (PK) of ibrutinib and pomalidomide when given in combi therapy, including lenalidomide (LEN) and either bort nation with dexamethasone. eZomib or carfilzomib and have demonstrated disease pro gression on or within 60 days of completion of the most Phase 2b Objectives recent treatment regimen. 0341 Up to 36 patients will be enrolled in order to 0330 Primary Objective: To evaluate the effect of ibru determine the MTD/MAD and Phase 2b dose. tinib in combination with pomalidomide and dexamethasone 0342. In the dose finding portion of the study, up to four compared to placebo in combination with pomalidomide and cohorts may be explored. The study will follow a 6+3 dose dexamethasone on progression-free survival (PFS), as de-escalation design. In Cohort 1, 6 subjects will be admin assessed by the Independent Review Committee (IRC), in istered ibrutinib 840 mg PO daily in combination with subjects with relapsed/refractory MM. Secondary Objec pomalidomide 4 mg. PO Days 1-21 and dexamethasone tives: To compare the treatment arms as assessed by both (age-adjusted dose) PO on Days 1, 8, 15 and 22 of a 28-day IRC and investigator in terms of the following: ORR (PR: cycle. The dose limiting toxicity (DLT) observation period according to IMWG); DOR (Duration of Response); CBR will end following Cycle 2 Day 1 pre-dose assessments. If (>MR according to IMWG and its duration); Overall sur 2 subjects within the initial cohort of 6 subjects experience vival (OS); Time-to-progression (TTP). In addition, other a DLT, an additional 3 subjects will be enrolled at the same objectives include dose level. If 3 or more of the initial 6 subjects or the 9 0331. To evaluate the safety and tolerability of ibru subjects experience a DLT, dose de-escalation will occur. If tinib in combination with pomalidomide and dexam subject incidence of DLTs during the DLT observation ethasone. period of study treatment is <33% (ies 1 of 6 or s2 of 9), this dose level will be considered safe to proceed to Phase 2 and 0332 To evaluate the pharmacokinetics (PK) of ibru defined as the Phase 2b dose. tinib and pomalidomide when given in combination 0343 Phase 2b will be conducted as a randomized, with dexamethasone. double-blind, international, multicenter study of ibrutinib or placebo in combination with pomalidomide and dexametha Exploratory Objectives: sone in subjects with relapsed/refractory MM who have received at least two prior lines of therapy, including 0333. To evaluate potential prognostic and predictive lenalidomide (LEN) and either bortezomib or carfilzomib biomarkers relative to treatment outcomes (selected and have demonstrated disease progression on or within 60 sites for Phase 1 and all sites for Phase 2b). days of completion of the most recent treatment regimen. 0334. To assess biomarkers, (including gene expres 0344) Approximately 195 subjects will be randomized sion profiles IGEP, secreted proteins, bone turnover 1:1 between Arm A (ibrutinib in combination with and/or immunophenotypic) in Subjects with relapsed/ pomalidomide and dexamethasone) and Arm B (placebo in refractory MM (selected sites for Phase 1 and all sites combination with pomalidomide and dexamethasone) and stratified according to: for Phase 2b). 0345 2-3 vs. 4 prior therapies To evaluate and compare the treatment arms in terms of the (0346 Last regimen (no IMiD/PI vs. IMiD or PI vs. following: IMiD and PI) 0335 Time-to-next-treatment (TTNT) (Phase 2b). (0347 Age: <75 vs. >75 years (0348 Open-Label Sub-Study Treatment Arm C (Phase 0336 Patient-reported outcomes (PROs) and disease 2b Only) will enroll up to 22 subjects to receive open-label related symptoms according to European Organization ibrutinib in combination with pomalidomide and dexam for Research and Treatment of Cancer Quality of Life ethasone. For more details regarding inclusion/exclusion Questionnaire for Multiple Myeloma (EORTC QLQ criteria refer to Subjects eligible for the randomized study MY20) and Euro QoI 5 dimensions questionnaire portion (Arm A or Arm B) are not eligible for participation (EQ-5D-5L) (Phase 2b). in the sub-study (Arm C). 0337 Open-Label Sub Study Treatment Arm C (Phase 2b) Inclusion Criteria 0338 Objectives: To evaluate the efficacy and safety of Disease Related ibrutinib in combination with pomalidomide and dexam (0349) 1. Subjects with relapsed/refractory MM who ethasone in Subjects who either have: Less than a partial have received at least two prior lines of therapy includ response (

0351) 2. Measurable disease defined by at least ONE of 0370 FCBP' and male subjects who are sexually the following: active must use TWO acceptable methods of birth 0352 Serum monoclonal protein (SPEP) > 1 g/dL. control, one highly effective method of birth control 0353 Urine monoclonal protein (UPEP) >200 mg plus one additional effective method of birth control for by 24 hour urine. at least 28 days prior to study treatment and during the study treatment period. For female and male Subjects, Laboratory these birth control requirements must be adhered to for 0354 Adequate hematologic function independent of 90 days after the last dose of ibrutinib and pomalido platelet transfusion and growth factor Support for at mide, whichever is later. Male subjects must agree to least 7 days prior to Screening and dosing (Phase 1) or not donate sperm during the study treatment period and randomization/enrollment (Phase 2b), with the excep up to 90 days after the last dose of ibrutinib and tion of pegylated G-CSF (granulocyte-colony stimulat pomalidomide, whichever is later. ing factor pegfilgrastim) and darbopoeitin which 0371. A female of childbearing potential (FCBP) is a require at least 14 days, defined as: female who: 1) has achieved menarche at Some point; or 2) 0355. Absolute neutrophil count >1500 cells/mm has not undergone a hysterectomy or bilateral oophorec (1.5x10/L). tomy; or 3) has not been naturally postmenopausal (amen 0356. Platelet count >75,000 cells/mm (75x10/L). orrhea following cancer therapy does not rule out childbear 0357 Hemoglobin >8.0 g/dL. ing potential) for at least 24 consecutive months (i.e., has 0358 Adequate hepatic and renal function defined as: had menses at any time in the preceding 24 consecutive 0359 Serum aspartate transaminase (AST) or ala months). nine transaminase (ALT) s3.0x upper limit of nor mal (ULN). Exclusion Criteria 0360 Serum creatinine <30 mg/dL AND an esti mated Creatinine Clearance >30 mL/min (Cock Disease-Related croft-Gault). 0372 Primary refractory disease defined as nonrespon 0361) Total Bilirubin s2.0 mg/dL. sive in patients who have never achieved a minimal 0362 PT/INR s1.5xULN and PTT (aPTT) is 1.5x response or better with any therapy. ULN (unless on warfarin, then INR s3.0). 0373. History of plasma cell leukemia, primary amy Demographic loidosis, POEMS syndrome within 12 months prior to first administration of study treatment. 0363 Men and women a 18 years of age. 0364 Eastern Cooperative Oncology Group (ECOG) Concurrent Conditions performance status of s2. 0374 Recent prior chemotherapy Ethical/Other 0375 Alkylators (e.g., melphalan, cyclophosph amide) and/or anthracyclines s21 days prior to first 0365 US/Canada Sites Only: All study participants administration of study treatment. must be registered into the mandatory Pomalyst 0376 High dose corticosteroids, IMiDs or protea REMSTM or Rev AidR) program, and be willing and able Some inhibitors s14 days prior to first administration to comply with the requirements of the Pomalyst of study treatment. REMSTM or Rev Aid R program as appropriate for the 0377 Monoclonal antibody sG weeks prior to first country in which the drug is being used. administration of study treatment. 0366 US/Canada Sites Only: Female subjects of child 0378 Prior exposure to Bruton's tyrosine kinase bearing potential (FCBP)' must adhere to the scheduled pregnancy testing as required in the Pomalyst REMSTM (BTK) inhibitors. or Rev Aid R program as appropriate for the country in 0379 Prior exposure to pomalidomide (except Treat which the drug is being used. ment Arm C). 0367 Ex-US Sites Only: Female subjects of childbear 0380. History of serious hypersensitivity reactions to ing potential (FCBP)' must have a negative serum or prior thalidomide, lenalidomide or pomalidomide. urine pregnancy test with a sensitivity of at least 25 0381. History of other malignancies, except: mIU/mL within 10-14 days and again within 24 hours 0382 Malignancy treated with curative intent and prior to starting Cycle 1 of pomalidomide. All Subjects with no known active disease present for >3 years must be counseled at a minimum of every 28 days before the first dose of study drug and felt to be at about pregnancy precautions and risks of fetal expo low risk for recurrence by treating physician. S. 0383 Adequately treated non-melanoma skin can 0368 US/Canada Sites Only: Male subjects must cer or lentigo maligna without evidence of disease. agree to use a latex condom during sexual contact with 0384 Adequately treated carcinoma in situ without a FCBP even if they have had a successful vasectomy. evidence of disease. 0369| Ex-US Sites Only: Male subjects must agree to 0385 Peripheral neuropathy Grade -2 with pain at use a latex condom during sexual contact with a FCBP Screening. even if they have had a successful vasectomy. All 0386 Concurrent systemic immunosuppressant Subjects must be counseled at a minimum of every 28 therapy (e.g., cyclosporine A, tacrolimus, etc., or days about pregnancy precautions and risks of fetal chronic administration of >20 mg/day of prednisone) exposure. within 28 days of the first dose of study treatment. US 2017/0209462 A1 Jul. 27, 2017 42

0387 Recent infection requiring systemic treatment 0403 Ibrutinib will be administered orally daily at a that was completed sT days before the first dose of designated dose and will be initiated on Day 1 of the first study treatment and/or uncontrolled active systemic cycle. Treatment will be continuous (without interruption) infection. until disease progression or unacceptable toxicity. 0388 Unresolved toxicities from prior anti-cancer Pomalidomide will be administered orally daily at a desig therapy, defined as having not resolved to Common nated dose on Days 1-21 of each 28-day (4 weeks) cycle Terminology Criteria for Adverse Event, Grades 1 or to until disease progression or unacceptable toxicity. Dexam the levels dictated in the inclusion/exclusion criteria ethasone will be administered orally (PO) once weekly at an with the exception of allopecia. age-adjusted dose of either 40 mg or 20 mg on Days 1, 8, 15 0389 Known bleeding disorders (e.g., von Wille and 22 of each 28-day (4 weeks) cycle until disease pro brand’s disease or hemophilia). gression or unacceptable toxicity. 0390. History of stroke or intracranial hemorrhage within 6 months prior to enrollment/randomization. TABLE 1. 0391 Known history of human immunodeficiency Ibrutinib Pomalidomide Dexamethasone virus (HIV) or active with hepatitis C virus (HCV) or (PO) (PO) (PO)f hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B Surface antigen, Cohort 1 840 mg 4 mg 40 mg (Dose Level 1) or hepatitis C antibody must have a negative poly Cohort 2 700 mg 4 mg 40 mg merase chain reaction (PCR) result before enrollment/ (Dose Level -1) randomization. Those who are PCR positive will be Cohort 3 560 mg 4 mg 40 mg excluded. (Dose Level -2) 0392 Major surgery within 4 weeks of first dose of Cohort 4 560 mg 3 mg 40 mg study treatment. (Dose Level -3) 0393 Any life-threatening illness, medical condition, Randomized Treatment or organ system dysfunction that, in the investigators Treatment Arm A opinion, could compromise the Subjects safety or put All cycles the study outcomes at undue risk. Ibrutinib PO daily 0394 Currently active, clinically significant hepatic Pomalidomide 4 mg PO daily Days 1-21 Dexamethasone Age-adjusted dose, PO on impairment (mild hepatic impairment according to the Days 1, 8, 15, and 22 Child Pugh classification. Treatment Arm B 0395 Currently active, clinically significant cardiovas All cycles cular disease. Such as uncontrolled arrhythmia or Class Placebo PO daily 3 or 4 congestive heart failure as defined by the New Pomalidomide 4 mg PO daily Days 1-21 York Heart Association Functional Classification; or a Dexamethasone Age-adjusted dose, PO on history of myocardial infarction, unstable angina, or Days 1, 8, 15, and 22 acute coronary syndrome within 6 months prior to Open-label Sub-study enrollment/randomization. Treatment Arm C 0396 QTc-470 msec calculated using Fridericia for All cycles mula (QTcF) at Screening. Ibrutinib PO daily Pomalidomide 4 mg PO daily Days 1-21 0397 Unable to swallow capsules or malabsorption Dexamethasone Age-adjusted dose, PO on syndrome, disease significantly affecting gastrointesti Days 1, 8, 15, and 22 nal function, or resection of the stomach or Small bowel, symptomatic inflammatory bowel disease or Dose will be 20 mg weekly in those >75 years of age ulcerative colitis, or partial or complete bowel obstruc tion. 0404 If 3 or more subjects in Cohort 1 (see Table 1) 0398 Requires treatment with a strong cytochrome experience a dose limiting toxicity (DLT), Cohort 2 will be P450(CYP) 3A inhibitor. enrolled. If 3 or more subjects in Cohort 2 experience a DLT. 0399 Women who are pregnant or breast-feeding. Cohort 3 will be enrolled. If 3 or more subjects in Cohort 3 04.00 Unwilling or unable to participate in all required experience a DLT, Cohort 4 will be enrolled. After the study evaluations and procedures. MTD/MAD of ibrutinib is defined and the Phase 2b dose 04.01 Unable to understand the purpose and risks of the determined, enrollment into Phase 2b will commence. study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health infor Phase 2b mation (in accordance with national and local Subject pri vacy regulations). 0405 Phase 2b will be conducted in a randomized, double-blind, international, multicenter study. Eligible Study Treatment patients will be randomized in a 1:1 ratio into 2 arms to receive either ibrutinib in combination with pomalidomide Phase 1: and dexamethasone (Treatment Arm A) or placebo in com bination with pomalidomide and dexamethasone (Treatment 0402. In the dose finding portion of the study, up to four Arm B). The dose of ibrutinib and pomalidomide in all arms cohorts may be explored and ibrutinib dose de-escalation will be based upon the MTD/MAD identified in Phase 1. All will follow the 6+3 design for MTD/MAD and the Phase 2b treatment arms will receive ibrutinib/placebo in combination dose determination. with pomalidomide and dexamethasone on the same sched US 2017/0209462 A1 Jul. 27, 2017

ule as Phase 1 (28-day cycles) until IRC confirmed disease a) a first amount of ibrutinib; progression or unacceptable toxicity. b) a second amount of an immunomodulatory agent; and 0406. The examples and embodiments described herein c) a third amount of dexamethasone, are illustrative and various modifications or changes Sug wherein the first amount, second amount, and third gested to persons skilled in the art are to be included within amount, taken together, are therapeutically effective. this disclosure. As will be appreciated by those skilled in the 34. (canceled) art, the specific components listed in the above examples 35. The method of claim 33, wherein the immunomodu may be replaced with other functionally equivalent compo latory agent is pomalidomide. 36. The method of claim 35, wherein pomalidomide is nents, e.g., diluents, binders, lubricants, fillers, and the like. administered orally. 1. A pharmaceutical combination comprising: 37. The method of claim 33, wherein the second amount a) ibrutinib; is about 3 mg/day to about 5 mg/day. b) an immunomodulatory agent; and 38. The method of claim 33, wherein the second amount c) dexamethasone. is about 4 mg/day. 2. The pharmaceutical combination of claim 1, wherein 39. The method of claim 33, wherein dexamethasone is the combination is in separate dosage forms. administered orally. 3. The pharmaceutical combination of claim 1, wherein 40. The method of claim 33, wherein the third amount is the combination is in a combined dosage form. about 20 mg/day to about 60 mg/day. 4. The pharmaceutical combination of claim 1, wherein 41. The method of claim 33, wherein the third amount is the combination is in three separate dosage forms. about 40 mg/day. 5. The pharmaceutical combination of claim 1, wherein 42. The method of claim 33, wherein ibrutinib is admin the combination is administered for the treatment of multiple istered orally. myeloma. 43. The method of claim 33, wherein ibrutinib is admin 6. The pharmaceutical combination of claim 5, wherein istered once a day, two times per day, three times per day, multiple myeloma is relapsed or refractory multiple four times per day, or five times per day. myeloma. 44. The method of claim 33, wherein the first amount is 7. The pharmaceutical combination of claim 5, wherein about 560 mg/day to about 840 mg/day. multiple myeloma is metastasized multiple myeloma. 45. The method of claim 44, wherein the first amount is 8. The pharmaceutical composition of claim 1, wherein about 700 mg/day. the immunomodulatory agent is pomalidomide. 46. The method of claim 33, further comprising admin 9. A dosing regimen for the treatment of multiple istration of an additional therapeutic agent. myeloma in a subject in need thereof comprising adminis 47. The method of claim 33, wherein the multiple tering to the Subject a combination comprising ibrutinib, myeloma is relapsed or refractory multiple myeloma. pomalidomide, and dexamethasone, wherein ibrutinib, 48. The method of claim 33, wherein the multiple pomalidomide, and dexamethasone are administered con myeloma is metastasized multiple myeloma. currently in at least one cycle. 49. The method of claim 33, wherein the subject has 10. The dosing regimen of claim 9, wherein each cycle received at least one prior therapy. comprises 28 days. 50. The method of claim 33, wherein the subject has 11. The dosing regimen of claim 9, wherein pomalido received at least two prior therapies. mide is administered on days 1-21 of each cycle. 51. The method of claim 49, wherein the prior therapy 12. The dosing regimen of claim 9, wherein dexametha comprises lenalidomide. Sone is administered on days 1, 8, 15, and 22 of each cycle. 52. The method of claim 49, wherein the prior therapy 13. The dosing regimen of claim 9, wherein ibrutinib is comprises carfilzomib. administered on days 1-28 of each cycle. 53. The method of claim 49, wherein the prior therapy 14-32. (canceled) comprises bortezomib. 33. A method of treating a multiple myeloma in a subject 54-55. (canceled) in need thereof, comprising co-administering to the Subject