WO2017011314A1 - Btk and hdac combinations - Google Patents

Abstract

Methods of treating a lymphoma comprising co-administering to an individual in need thereof a Btk inhibitor and an HDAC inhibitor compound are provided.

Description

BTK AND HDAC COMBINATIONS

RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 62/191,177, filed on July 10, 2015 and U.S. Provisional Application No. 62/259,532, filed November 24, 2015. The entire teachings of those applications are incorporated herein by reference.

FIELD OF INVENTION

[0002] The present invention relates to Btk inhibitor combinations for the treatment of hematological malignancies.

BACKGROUND

[0003] Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cells types except T lymphocytes and natural killer cells. Btk plays an essential role in the B-cell signaling pathway linking cell surface B-cell receptor (BCR) stimulation to downstream intracellular responses.

[0004] 1 -((R)-3 -(4-amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 - yl)piperidin-l-yl)prop-2-en-l-one is also known by its JUPAC name as l-{(3R)-3-[4-amino- 3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-<i]pyrimidin- 1 -yljpiperidin- 1 -yl }prop-2-en- 1 -one or 2- Propen-1 -one, l-[(3R)-3-[4-amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3,4-<i]pyrimi din- 1-yl]- 1-piperidinyl-, and has been given the US AN name, ibrutinib. The various names given for ibrutinib are used interchangeably herein.

SUMMARY OF INVENTION

[0005] In some embodiments, a method of treating a hematological malignancy, such as a lymphoma is provided. The method comprises co-administering to an individual in need thereof a Btk inhibitor and an HDAC inhibitor compound. Preferably, the co-administration provides a synergistic therapeutic effect compared to administration of the Btk inhibitor or the HDAC inhibitor alone. An exemplary Btk inhibitor is ibrutinib. An exemplary HDAC inhibitor is abexinostat or a salt thereof. In some embodiments, the salt of abexinostat is abexinostat HC1, abexinostat tosylate, or combinations thereof. In some embodiments, the lymphoma is relapsed and/or refractory. In some embodiments, the lymphoma is a Hodgkin lymphoma. In some embodiments, the lymphoma is a non-Hodgkin's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma. Exemplary B-cell lymphomas include diffuse large B-cell lymphoma (DLBCL) and/or activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). ABC-DLBCL may be characterized by a mutation in MYD88. In some embodiments, the mutation is at position 265 of MYD88, such as an L265P mutation. Additional exemplary lymphomas include follicular lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, Waldenstrom

macroglobulinemia, or combinations thereof. In some embodiments, the non-Hodgkin's lymphoma is a T-cell lymphoma. An exemplary T-cell lymphoma is peripheral T-cell lymphoma. In some embodiments, the lymphoma is not small lymphocytic lymphoma. Preferably, each of ibrutinib and abexinostat is administered orally. Preferably, ibrutinib is administered daily. In some embodiments, ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day. In some embodiments, ibrutinib is administered at a dosage of about 560 mg/day. In some embodiments, abexinostat or a salt thereof is administered in cycles consisting of 7 days of consecutive administration of abexinostat or a salt thereof followed by 7 consecutive days with no administration of abexinostat or a salt thereof. In some embodiments, the cycles of 7 consecutive days of daily administration of abexinostat or a salt thereof comprises daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof. In some embodiments, the daily administration of about 40 mg to about 80 mg of abexinostat or salt thereof comprises twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof. In some embodiments, the twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises administration of each dosage about 4-6 hours apart.

[0006] In some embodiments, a composition comprising a therapeutically effective amount of a Btk inhibitor, a HDAC inhibitor, and a pharmaceutically acceptable excipient, for use in the treatment of a hematological malignancy, such as lymphoma, is provided. Preferably, the composition provides a synergistic therapeutic effect compared to

administration of the Btk inhibitor or the HDAC inhibitor alone. An exemplary Btk inhibitor is ibrutinib. An exemplary HDAC inhibitor is abexinostat or a salt thereof. In some embodiments, the salt of abexinostat is abexinostat HC1, abexinostat tosylate, or

combinations thereof. In some embodiments, the composition is in a combined dosage form. In some embodiments, the composition is in a separate dosage form. In some embodiments, the composition is in the form of a capsule. In some embodiments, the composition is in the form of a tablet. In some embodiments, the composition further comprises zinc. In some embodiments, the lymphoma is relapsed and/or refractory. In some embodiments, the lymphoma is a Hodgkin lymphoma. In some embodiments, the lymphoma is a non- Hodgkin's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma. Exemplary B-cell lymphomas include diffuse large B-cell lymphoma (DLBCL) and/or activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). ABC -DLBCL may be characterized by a mutation in MYD88. In some embodiments, the mutation is at position 265 of MYD88, such as an L265P mutation. Additional exemplary lymphomas include follicular lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, Waldenstrom macroglobulinemia, or combinations thereof. In some

embodiments, the non-Hodgkin's lymphoma is a T-cell lymphoma. An exemplary T-cell lymphoma is peripheral T-cell lymphoma. In some embodiments, the lymphoma is not small lymphocytic lymphoma. In some embodiments, the combination of ibrutinib and abexinostat is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of abexinostat alone. In some embodiments, the combination of ibrutinib and abexinostat is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of ibrutinib alone.

[0007] In some embodiments, a method of reducing the development or preventing the development of Btk inhibitor resistance in an individual in need thereof having a

hematological malignancy such as a lymphoma is provided. The method comprises administering to the individual a combination comprising a Btk inhibitor and HDAC inhibitor. Preferably, the co-administration provides a synergistic therapeutic effect compared to administration of the Btk inhibitor or the HDAC inhibitor alone. An exemplary Btk inhibitor is ibrutinib. An exemplary HDAC inhibitor is abexinostat or a salt thereof. In some embodiments, the salt of abexinostat is abexinostat HC1, abexinostat tosylate, or combinations thereof. In some embodiments, the lymphoma is relapsed and/or refractory. In some embodiments, the lymphoma is a Hodgkin lymphoma. In some embodiments, the lymphoma is a non-Hodgkin's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma. Exemplary B-cell lymphomas include diffuse large B-cell lymphoma (DLBCL) and/or activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). ABC-DLBCL may be characterized by a mutation in MYD88. In some embodiments, the mutation is at position 265 of MYD88, such as an L265P mutation. Additional exemplary lymphomas include follicular lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, Waldenstrom macroglobulinemia, or combinations thereof. In some embodiments, the non-Hodgkin's lymphoma is a T-cell lymphoma. An exemplary T-cell lymphoma is peripheral T-cell lymphoma. In some embodiments, the lymphoma is not small lymphocytic lymphoma.

[0008] In some embodiments, a method of treating a Btk-inhibitor-resistant

hematological malignancy, such as a lymphoma is provided. The method comprises administering to an individual in need thereof a combination comprising Btk inhibitor and HDAC inhibitor. Preferably, the co-administration provides a synergistic therapeutic effect compared to administration of the Btk inhibitor or the HDAC inhibitor alone. An exemplary Btk inhibitor is ibrutinib. An exemplary HDAC inhibitor is abexinostat or a salt thereof. In some embodiments, the salt of abexinostat is abexinostat HC1, abexinostat tosylate, or combinations thereof. In some embodiments, the lymphoma is relapsed and/or refractory. In some embodiments, the lymphoma is a Hodgkin lymphoma. In some embodiments, the lymphoma is a non-Hodgkin's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma. Exemplary B-cell lymphomas include diffuse large B-cell lymphoma (DLBCL) and/or activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). ABC-DLBCL may be characterized by a mutation in MYD88. In some embodiments, the mutation is at position 265 of MYD88, such as an L265P mutation. Additional exemplary lymphomas include follicular lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, Burkitt lymphoma, Waldenstrom macroglobulinemia, or combinations thereof. In some embodiments, the non-Hodgkin's lymphoma is a T-cell lymphoma. An exemplary T-cell lymphoma is peripheral T-cell lymphoma. In some embodiments, the lymphoma is not small lymphocytic lymphoma. Preferably, each of ibrutinib and abexinostat is administered orally. Preferably, ibrutinib is administered daily. In some embodiments, ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day. In some embodiments, ibrutinib is administered at a dosage of about 560 mg/day. In some embodiments, abexinostat or a salt thereof is administered in cycles consisting of 7 days of consecutive administration of abexinostat or a salt thereof followed by 7 consecutive days with no administration of abexinostat or a salt thereof. In some embodiments, the cycles of 7 consecutive days of daily administration of abexinostat or a salt thereof comprises daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof. In some embodiments, the daily administration of about 40 mg to about 80 mg of abexinostat or salt thereof comprises twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof. In some embodiments, the twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises administration of each dosage about 4-6 hours apart. [0009] In some embodiments, a method of increasing sensitivity of a Btk inhibitor in an individual in need thereof is provided. The method includes the step of administering a combination comprising a Btk inhibitor and a HDAC inhibitor compound. In some embodiments, the Btk inhibitor is ibrutinib and the HDAC inhibitor is abexinostat.

[0010] In some embodiments, a method of treating a hematological malignancy is provided. The method comprises co-administering to an individual in need thereof abexinostat or a salt thereof and a BCL-2 inhibitor. In some embodiments, the abexinostat or a salt thereof and the BCL-2 inhibitor are co-administered simultaneously, sequentially, or intermittently. In some embodiments, the co-administration provides a synergistic therapeutic effect compared to the administration of abexinostat or a salt thereof or the BCL- 2 inhibitor alone. In some embodiments, the BCL-2 inhibitor is ABT-199. In some embodiments, the method further comprises the step of co-administering a Btk inhibitor. In some embodiments, the abexinostat or a salt thereof, the BCL-2 inhibitor, and the Btk inhibitor are co-administered simultaneously, sequentially, or intermittently. In some embodiments, the co-administration of abexinostat or a salt thereof, the BCL-2 inhibitor, and the Btk inhibitor provides a synergistic therapeutic effect compared to the administration of the Btk inhibitor alone, or a combination of the Btk inhibitor and the BCL-2 inhibitor. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the salt of abexinostat is abexinostat HC1, abexinostat tosylate, or a combination thereof. In some embodiments, the hematological malignancy is a relapsed or refractory hematological malignancy. In some embodiments, the hematological malignancy is a treatment naive hematological malignancy. In some embodiments, the hematological malignancy is a lymphoma. In some embodiments, the lymphoma is a non-Hodgkin lymphoma. In some embodiments, the lymphoma is a Hodgkin lymphoma. In some embodiments, the non- Hodgkin' s lymphoma is a B-cell lymphoma. In some embodiments, the B-cell lymphoma is a diffuse large B-cell lymphoma (DLBCL). In some embodiments, the DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the ABC- DLBCL is characterized by a mutation in MYD88. In some embodiments, the mutation is at position 265 of MYD88. In some embodiments, the mutation is an L265P mutation. In some embodiments, the B-cell lymphoma is follicular lymphoma. In some embodiments, the B- cell lymphoma is mantle cell lymphoma. In some embodiments, the B-cell lymphoma is marginal zone B-cell lymphoma. In some embodiments, the B-cell lymphoma is Burkitt lymphoma. In some embodiments, the B-cell lymphoma is Waldenstrom

macroglobulinemia. In some embodiments, the B-cell lymphoma is germinal B-cell diffuse large B-cell lymphoma (GCB-DLBCL). In some embodiments, the non-Hodgkin's lymphoma is T-cell lymphoma. In some embodiments, the T-cell lymphoma is a peripheral T-cell lymphoma. In some embodiments, the T-cell lymphoma is a cutaneous T-cell lymphoma. In some embodiments, ibrutinib is administered orally. In some embodiments, abexinostat or a salt thereof is administered orally. In some embodiments, ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day. In some embodiments, abexinostat or a salt thereof is administered in cycles consisting of 7 consecutive days of daily administration of abexinostat or a salt thereof followed by 7 consecutive days with no administration of abexinostat or a salt thereof. In some embodiments, the cycles of 7 consecutive days of daily administration of abexinostat or a salt thereof comprises the daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof. In some embodiments, the daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof. In some embodiments, the twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises administration of each dosage about 4-6 hours apart.

[0011] In some embodiments, a method of treating a hematological malignancy is provided. The method comprises co-administering to an individual in need thereof abexinostat or a salt thereof and a BCL-2 inhibitor. In some embodiments, abexinostat or a salt thereof and the BCL-2 inhibitor are co-administered simultaneously, sequentially, or intermittently. In some embodiments, the co-administration provides a synergistic therapeutic effect compared to the administration of abexinostat or a salt thereof or the BCL- 2 inhibitor alone. In some embodiments, the BCL-2 inhibitor is ABT-199. In some embodiments, the method further comprises co-administering a Btk inhibitor. In some embodiments, the abexinostat or a salt thereof, the BCL-2 inhibitor, and the Btk inhibitor are co-administered simultaneously, sequentially, or intermittently. In some embodiments, the co-administration of abexinostat or a salt thereof, the BCL-2 inhibitor, and the Btk inhibitor provides a synergistic therapeutic effect compared to the administration of one or more of the following: (1) the Btk inhibitor alone; (2) the abexinostat or a salt thereof alone; (3) the combination of the Btk inhibitor and the BCL-2 inhibitor; (4) the combination of abexinostat or a salt thereof and the BCL-2 inhibitor; and/or (5) the combination of the Btk inhibitor and the abexinostat or a salt thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the salt of abexinostat is abexinostat HC1, abexinostat tosylate, or a combination thereof. In some embodiments, the hematological malignancy is a relapsed or refractory hematological malignancy. In some embodiments, the hematological malignancy is a treatment naive hematological malignancy. In some embodiments, the hematological malignancy is a lymphoma. In some embodiments, the hematological malignancy is a non- Hodgkin lymphoma. In some embodiments, the lymphoma is a Hodgkin lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma. In some embodiments, the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the ABC-DLBCL is characterized by a mutation in MYD88. In some embodiments, the mutation in MYD88 is a mutation at position 265 of MYD88. In some embodiments, the mutation in MYD88 is an L265P mutation. In some embodiments, the B- cell lymphoma is follicular lymphoma. In some embodiments, the B-cell lymphoma is mantle cell lymphoma. In some embodiments, the B-cell lymphoma is marginal zone B-cell lymphoma. In some embodiments, the B-cell lymphoma is Burkitt lymphoma. In some embodiments, the B-cell lymphoma is Waldenstrom macroglobulinemia. In some

embodiments, the B-cell lymphoma is germinal B-cell diffuse large B-cell lymphoma (GCB- DLBCL). In some embodiments, the non-Hodgkin's lymphoma is a T-cell lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a peripheral T-cell lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a cutaneous T-cell lymphoma. In some embodiments, ibrutinib is administered orally. In some embodiments, the abexinostat or a salt thereof is administered orally. In some embodiments, the ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day. In some embodiments, the abexinostat or a salt thereof is administered in cycles consisting of 7 consecutive days of daily

administration of abexinostat or a salt thereof followed by 7 consecutive days with no administration of abexinostat or a salt thereof. In some embodiments, the cycles of 7 consecutive days of daily administration of abexinostat or a salt thereof comprises the daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof. In some embodiments, the daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof. In some embodiments, the twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises administration of each dosage about 4-6 hours apart.

[0012] In some embodiments, a method of treating a CNS malignancy in an individual in need thereof is provided. The method comprises the step of administering to the individual abexinostat or a salt thereof. In some embodiments, the abexinostat or a salt thereof is abexinostat HC1, abexinostat tosylate, or a combination thereof. In some embodiments, the CNS malignancy is a primary CNS lymphoma. In some embodiments, the CNS malignancy is a secondary CNS lymphoma.

[0013] In some embodiments, a method of treating a cutaneous T-cell lymphoma is provided. The method comprises the step of administering to the individual abexinostat or a salt thereof. In some embodiments, the abexinostat or a salt thereof is abexinostat HC1, abexinostat tosylate, or a combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Various aspects of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0015] FIG. 1 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat (PCI-24781) on the cell growth of a GCB-DLBCL cell line (HT cell line).

[0016] FIG. 2 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat on the cell growth of a GCB-DLBCL cell line (SUDHL6 cell line).

[0017] FIG. 3 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat on the cell growth of a GCB-DLBCL cell line (SUDHL10 cell line).

[0018] FIG. 4 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the cell growth of a GCB-DLBCL cell line (WSU-NHL cell line).

[0019] FIG. 5 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the cell growth of a GCB-DLBCL cell line (SUDHL5 cell line).

[0020] FIG. 6 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the cell growth of a GCB-DLBCL cell line (SUDHL4 cell line). [0021] FIG. 7 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the cell growth of a GCB-DLBCL cell line (LY8 cell line).

[0022] FIG. 8 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the cell growth of a GCB-DLBCL cell line (SUDHL8 cell line).

[0023] FIG. 9 is a chart showing the EC50 (μΜ) of ibrutinib alone or ibrutinib + PCI- 24781 (abexinostat) in various GCB-DLBCL cell lines.

[0024] FIG. 10 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the cell growth of a follicular lymphoma (FL) cell line (SC-1 cell line).

[0025] FIG. 11 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the cell growth of a follicular lymphoma (FL) cell line (WSU-FSCCL cell line).

[0026] FIG. 12 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the cell growth of a follicular lymphoma (FL) cell line (NFS 1.0 C-l cell line).

[0027] FIG. 13 illustrates a graphical representation of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the cell growth of a follicular lymphoma (FL) cell line (DoHH2 cell line).

[0028] FIG. 14 is a chart showing the EC50 (μΜ) of ibrutinib alone or ibrutinib + PCI- 24781 (abexinostat) in various follicular lymphoma (FL) cell lines.

[0029] FIG. 15 is a graphical representation of the relative gene expression of the HDAC family in various follicular lymphoma (FL) cell lines.

[0030] FIGS. 16A, 16C, and 16E illustrate graphical representations of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the cell growth of three mantle cell lymphoma cell lines. FIGS. 16B, 16D, and 16F illustrate graphical representations of the combination index (CI) for the combination of ibrutinib and abexinostat.

[0031] FIG. 17A illustrates the synergy score of the drug dose matrix data for a cell viability assay in Jeko-1 cells grown in the presence of ibrutinib, abexinostat, or a

combination of the compounds. The numbers in the plot indicate the percentage of growth inhibition of cells treated for 3 days with the corresponding compound combination relative to vehicle control -treated cells. FIG. 17B shows the corresponding isobologram, in which points to the left of the diagonal line represent synergistic combinations. [0032] FIG. 17C illustrates the synergy score of the drug dose matrix data for a cell viability assay in Maver-1 cells grown in the presence of ibrutinib, abexinostat, or a combination of the compounds. The numbers in the plot indicate the percentage of growth inhibition of cells treated for 3 days with the corresponding compound combination relative to vehicle control -treated cells. FIG. 17D shows the corresponding isobologram, in which points to the left of the diagonal line represent synergistic combinations.

[0033] FIG. 17E illustrates the synergy score of the drug dose matrix data for a cell viability assay in JVM-2 cells grown in the presence of ibrutinib, abexinostat, or a combination of the compounds. The numbers in the plot indicate the percentage of growth inhibition of cells treated for 3 days with the corresponding compound combination relative to vehicle control -treated cells. FIG. 17F shows the corresponding isobologram, in which points to the left of the diagonal line represent synergistic combinations.

[0034] FIGS. 18A and 18B illustrate graphical representations of the effect of abexinostat (PCI-24781), or the combination of abexinostat and ABT-199, in SC-1 (FIG. 18A) or WSU- FSCCL (FIG. 18B) cell lines. FIG. 18C illustrates the graphical representations of the effect of abexinostat (PCI-24781), or the combination of abexinostat and ABT-199, on the relative cell growth of the NFSl .O c-1 mouse cell line. FIG. 19D is a representation of the EC50 of abexinostat (PCI-24781) when added to various cells, either alone or in combination with ABT-199.

[0035] FIGS. 19A-19G illustrates graphical representations of the effect of (1) ibrutinib alone; (2) ibrutinib and ABT-199; or (3) ibrutinib, ABT-199, and abexinostat (PCI-24781) in various cell lines.

DETAILED DESCRIPTION OF THE INVENTION

Certain Terminology

[0036] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

[0037] As used herein, ranges and amounts can be expressed as "about" a particular value or range. About also includes the exact amount. Hence "about 5 μΙ_," means "about 5 μΙ_," and also "5 μΐ.." Generally, the term "about" includes an amount that would be expected to be within experimental error.

[0038] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

[0039] As used herein, the term "refractory" refers to an abolishment of a response or a development of an acquired resistance to a disease in a subject to a particular course of treatment.

[0040] As used herein, the term "treatment" refers to stopping the progression of a disease, partial or complete elimination of a disease, reversing progression of a disease, stopping, reducing or reversing episodes of worsening or relapses of a disease, or prolonging episodes of remission of a disease in a subject.

[0041] As used herein, the terms "individual(s)", "subject(s)" and "patient(s)" mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. None of the terms require or are limited to situations characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician's assistant, an orderly or a hospice worker).

[0042] The terms "co-administration" (or any grammatical version thereof) or the like, as used herein, encompass administration of an Btk inhibitor compound and an HDAC inhibitor compound to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration, in the same or a different dosage form, and at the same or different time. The terms "co-administration" (or any grammatical version thereof) or the like, as used herein, also encompass administration of an HDAC inhibitor compound and a BCl-2 inhibitor compound to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration, in the same or a different dosage form, and at the same or different time. Additionally, terms "co-administration" (or any grammatical version thereof) or the like, as used herein, also encompass administration of an HDAC inhibitor, a BCl-2 inhibitor compound, and/or a Btk inhibitor compound to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration, in the same or a different dosage form, and at the same or different time.

[0043] The term "irreversible Btk inhibitor," as used herein, refers to an inhibitor of Btk that can form a covalent bond with an amino acid residue of Btk. In one embodiment, the irreversible inhibitor of Btk can form a covalent bond with a Cys residue of Btk; in particular embodiments, the irreversible inhibitor can form a covalent bond with a Cys 481 residue (or a homolog thereof) of Btk or a cysteine residue in the homologous corresponding position of another tyrosine kinase.

[0044] As used herein, "salt of abexinostat" or "abexinostat salt" may refer to abexinostat hydrochloride (abexinostat HC1), abexinostat tosylate (or "tosylate salt of abexinostat"), any other salt of abexinostat, and combinations and mixtures thereof. An exemplary salt of abexinostat may be a mixture or combination of abexinostat HC1 and abexinostat tosylate.

[0001] As used herein, "CNS malignancy" refers to a primary cancer, neoplasm or tumor of the brain or related tissues that grows in an uncontrolled manner, possibly invading nearby tissue and/or metastasizing (spreading) to other sites via the bloodstream. Gliomas refer to tumors that begin in the glial (supportive) tissue of the CNS. The most common gliomas include astrocytomas, ependymomas, oligodendrogliomas, and tumors with mixtures of two or more of these cell types. CNS malignancy may be used interchangeably with "tumor", or "brain cancer." Specific CNS malignancies suitable for treatment using the compositions and methods of the invention include, but are not limited to: astrocytic tumors such as juvenile pilocytic, subependymal, well differentiated or moderately differentiated anaplastic astrocytoma; anaplastic astrocytoma; glioblastoma multiforme; ependymal tumors such as myxopapillary and well-differentiated ependymoma, anaplastic ependymoma,

ependymoblastoma; oligodendroglial tumors including well-differentiated oligodendroglioma and anaplastic oligodendroglioma; mixed tumors such as mixed astrocytoma-ependymoma, mixed astrocytoma-oligodendroglioma, mixed astrocytomaependymoma-oligodendroglioma; medulloblastoma; and any other infiltrating or non-infiltrating CNS tumors or cancers. CNS malignancies also refer to Secondary CNS lymphomas.

Bruton's Tyrosine Kinase (Btk)

[0045] Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cells types except T lymphocytes and natural killer cells. Btk plays an essential role in the B-cell signaling pathway linking cell surface B-cell receptor (BCR) stimulation to downstream intracellular responses.

[0046] Btk is a key regulator of B-cell development, activation, signaling, and survival (Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288). Further, Btk plays a role in a number of other hematopoietic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-a production in macrophages, IgE receptor (FcsRI) signaling in Mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen-stimulated platelet aggregation. See, e.g., C. A. Jeffries, et al., (2003), Journal of Biological Chemistry 278:26258-26264; N. J. Horwood, et al., (2003), The Journal of Experimental Medicine 197: 1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry 280(48):40261-40270; Vassilev et al. (1999), Journal of Biological Chemistry 274(3): 1646-1656, and Quek et al. (1998), Current Biology 8(20): 1137-1140.

[0047] Ibrutinib (PCI-32765) is an irreversible covalent inhibitor of Btk, inhibits proliferation, induces apoptosis, and has been shown to inhibit Btk in animal models. Further, clinical trials have demonstrated efficacy across several hematological malignancies (i.e., mantle cell lymphoma and Waldenstrom Macroglobulinemia) including relapsed/refractory hematological malignancies.

[0048] Few patients have had relapse when treated with ibrutinib. However, as more patients are treated with ibrutinib, it is important to develop effective salvage therapies.

Further, the mechanism of acquired resistance has not yet been elucidated. In addition, determining whether persistent lymphocytosis has similar resistant features can aid in treatment choices during ibrutinib therapy.

HDAC Inhibitor

[0049] Histone deacetylases (HDACs), including class I histone deacetylases FID AC 1 and HDAC2, are overexpressed in many cancers. HDACs remove acetyl groups from histones and other nuclear proteins, and induce chromatin condensation and transcriptional repression. In some embodiments, HDACs are associated with aberrant epigenetic changes associated with cancer and the downregulation of HDACs is associated with a reversal of these aberrant epigenetic changes.

[0050] "HDAC inhibitor" refers to histone deacetylase inhibitors, a class of compounds that interfere with the function of histone deacetylase (i.e., they block the activity of histone deacetylases). [0051] Inhibitors of HDACs have shown activity against several types of cancers in clinical trials. HDAC inhibitors promote acetylation of histone proteins, which decondenses chromatin into its active form and reverses the epigenetic silencing of transcription factors and tumor suppressor genes that regulate cell growth. In some embodiments, proteins such as p21, p53, and F-kB have been implicated as targets of HDAC inhibitors.

BCL-2 Inhibitor

[0052] The BCL-2 gene prevents apoptosis of some cells, including lymphocytes and can be highly expressed in cancers in the lymph nodes, spleen, and other organs of the immune system. ABT-Exemplary BCL-2 inhibitors include ABT-199 (GDC-0199 or venetoclax).

Hematological Malignancies

[0053] Hematological malignancies are a diverse group of cancer that affects the blood, bone marrow, and lymph nodes.

Lymphomas

[0054] A lymphoma is a cancer that starts in the cells of the lymphatic system. Two main types of lymphomas are Hodgkin lymphoma and non-Hodgkin lymphoma. Exemplary non- Hodgkin lymphomas include, but are not limited to, B-cell lymphomas. Exemplary B-cell lymphomas include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (i.e., extranodal marginal zone B-cell lymphoma or mucosa-associated lymphoid tissue (MALT), nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, hairy cell leukemia, primary central nervous system leukemia, and the like. Subtypes of DLBCL include activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), primary mediastinal B-cell lymphoma, and intravascular large B-cell lymphoma), and germinal center diffuse large B-cell lymphoma (GCB-DLBCL). In some embodiments, ABC-DLBCL is

characterized by a CD79B mutation. In some embodiments, ABC-DLBCL is characterized by a CD79A mutation. In some embodiments, the ABC-DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof.

[0055] Other exemplary non-Hodgkin lymphomas include T-cell lymphomas, such as precursor T-lymphoblastic lymphoma, peripheral T-cell lymphomas (i.e., cutaneous T-cell lymphomas, adult T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T-cell lymphoma, nasal type, entrepathy-associated intestinal T-cell lymphoma (EATL), anaplastic large cell lymphoma (ALCL), peripheral T-cell lymphoma, unspecified). [0056] In some embodiments, the lymphoma is a relapsed and/or refractory lymphoma, such as a relapsed and/or refractory Hodgkin lymphoma or a relapsed and refractory non- Hodgkin lymphoma. Exemplary relapsed and refractory non-Hodgkin lymphomas include, but are not limited to, relapsed and refractory B-cell lymphomas. Exemplary relapsed and refractory B-cell lymphomas include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (i.e., extranodal marginal zone B-cell lymphoma or mucosa-associated lymphoid tissue (MALT), nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, hairy cell leukemia, primary central nervous system leukemia, and the like. Subtypes of DLBCL include activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma), and germinal center diffuse large B- cell lymphoma (GCB-DLBCL). In some embodiments, ABC-DLBCL is characterized by a CD79B mutation. In some embodiments, ABC-DLBCL is characterized by a CD79A mutation. In some embodiments, the ABC-DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof.

[0057] Other exemplary relapsed and/or refractory non-Hodgkin lymphomas include T- cell lymphomas, such as precursor T-lymphoblastic lymphoma, peripheral T-cell lymphomas (i.e., cutaneous T-cell lymphomas, adult T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T-cell lymphoma, nasal type, entrepathy-associated intestinal T-cell lymphoma (EATL), anaplastic large cell lymphoma (ALCL), peripheral T- cell lymphoma, unspecified).

[0058] In some embodiments, the lymphoma is a treatment naive lymphoma, such as a treatment naive Hodgkin lymphoma or a treatment naive non-Hodgkin lymphoma.

Exemplary treatment naive non-Hodgkin lymphomas include, but are not limited to, treatment naive B-cell lymphomas. Exemplary treatment naive B-cell lymphomas include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (i.e., extranodal marginal zone B-cell lymphoma or mucosa-associated lymphoid tissue (MALT), nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), Burkitt lymphoma, lymphoplasmacytic lymphoma, Waldenstrom macroglobulinemia, hairy cell leukemia, primary central nervous system leukemia, and the like. Subtypes of DLBCL include activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, and germinal center diffuse large B-cell lymphoma (GCB-DLBCL). In some embodiments, ABC-DLBCL is characterized by a CD79B mutation. In some embodiments, ABC-DLBCL is characterized by a CD79A mutation. In some embodiments, the ABC- DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof.

[0059] Other exemplary treatment naive non-Hodgkin lymphomas include T-cell lymphomas, such as precursor T-lymphoblastic lymphoma, peripheral T-cell lymphomas (i.e., cutaneous T-cell lymphomas, adult T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal natural killer/T-cell lymphoma, nasal type, entrepathy-associated intestinal T-cell lymphoma (EATL), anaplastic large cell lymphoma (ALCL), peripheral T- cell lymphoma, unspecified).

[0060] Other lymphomas include, but are not limited to, primary mediastinal B-cell lymphoma (PMBL), Burkitt's lymphoma, immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, mantle cell lymphoma (MCL), B cell prolymphocytic leukemia (B-PLL), lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. The foregoing lymphomas may be relapsed and/or refractory, or treatment naive.

[0061] In some embodiments, the lymphoma is not small lymphocytic lymphoma (SLL). In some embodiments, the lymphoma is not a relapsed and/or refractory small lymphocytic lymphoma (SLL). In some embodiments, the lymphoma is not a treatment naive small lymphocytic lymphoma (SLL).

[0062] In some embodiments, the hematological malignancy is a cancer of the central nervous system (CNS) malignancy. In some embodiments the CNS malignancy is a primary CNS lymphoma. In some embodiments the primary CNS lymphoma is a glioma. In some embodiments the glioma is an astrocytomas, ependymomas, or a oligodendrogliomas. In some embodiments the CNS malignancy is astrocytic tumors such as juvenile pilocytic, subependymal, well differentiated or moderately differentiated anaplastic astrocytoma;

anaplastic astrocytoma; glioblastoma multiforme; ependymal tumors such as myxopapillary and well-differentiated ependymoma, anaplastic ependymoma, ependymoblastoma;

oligodendroglial tumors including well-differentiated oligodendroglioma and anaplastic oligodendroglioma; mixed tumors such as mixed astrocytoma-ependymoma, mixed astrocytoma-oligodendroglioma, mixed astrocytomaependymoma-oligodendroglioma;

medulloblastoma. In some embodiments the CNS malignancy is glioblastoma multiforme. In some embodiments the CNS malignancy is a secondary CNS lymphoma. In some embodiments the secondary CNS lymphoma originates from lung cancer, breast cancer, malignant melanoma, or kidney cancer.

Leukemia

[0063] In some embodiments, methods of the invention may be used to treat leukemia. Exemplary leukemias are acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), and myelodysplastic syndromes (MDS). Preferably, the leukemia is not chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML). In some embodiments, the leukemia is a relapsed and/or refractory leukemia. Exemplary relapsed and refractory leukemias include acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML). In some embodiments, the leukemia is a treatment naive leukemia. Exemplary treatment naive leukemias include, but are not limited to acute lymphocytic leukemia (ALL) and chronic myeloid leukemia (CML).

[0064] Other hematological malignancies that may be treated with the methods of the invention include a myeloma, such as multiple myeloma; plasma cell myeloma; and plasmacytoma. The foregoing cancers may be relapsed and/or refractory, or treatment naive.

[0065] In some embodiments, the leukemia is not a chronic lymphocytic leukemia (CLL). In some embodiments, the leukemia is not a relapsed and/or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the leukemia is not a treatment naive chronic lymphocytic leukemia (CLL).

[0066] In some embodiments, the leukemia is not an acute myeloid leukemia (AML). In some embodiments, the leukemia is not a relapsed and/or refractory acute myeloid leukemia (AML). In some embodiments, the leukemia is not a treatment naive acute myeloid leukemia (AML).

[0067] In some embodiments, the hematological malignancy is not a chronic lymphocytic leukemia (CLL), an acute myeloid leukemia (AML), and/or small lymphocytic lymphoma (SLL). In some embodiments, the hematological malignancy is not a relapsed and/or refractory chronic lymphocytic leukemia (CLL), an acute myeloid leukemia (AML), and/or small lymphocytic lymphoma (SLL).

[0068] In some embodiments, the lymphoma, leukemia, or other hematological malignancy is a Btk-resistant lymphoma, leukemia, or hematological malignancy. For example, the lymphoma, leukemia, or other hematological malignancy contains an acquired resistance to a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib.

[0069] Other exemplary hematological malignancies include, but or not limited to, mucosa-associated lymphoid tissue lymphoma (MALT). Btk Inhibitor Compounds Including Ibrutinib and Pharmaceutically Acceptable Salts Thereof

[0070] The Btk inhibitor compound described herein (i.e. ibrutinib) is selective for Btk and kinases having a cysteine residue in an amino acid sequence position of the tyrosine kinase that is homologous to the amino acid sequence position of cysteine 481 in Btk. The Btk inhibitor compound can form a covalent bond with Cys 481 of Btk (e.g., via a Michael reaction).

[0071] In some embodiments, the Btk inhibitor is a compound of Formula (A) having the structure:

Formula (A);

wherein:

A is N;

Ri is phenyl-O-phenyl or phenyl-S-phenyl;

R₂ and R₃ are independently H;

R4 is L₃-X-L₄-G, wherein,

L₃ is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or

unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;

X is optional, and when present is a bond, -0-, -C(=0)-, -S-, -S(=0)-, -S(=0)₂-, - H-, - R₉-, - HC(O)-, -C(0) H-, - R₉C(0)-, -C(0) R₉-, -S(=0)₂ H-, - HS(=0)₂-, - S(=0)₂ R₉-, -NR₉S(=0)₂-, -OC(0) H-, - HC(0)0-, -OC(0)NR₉-, - R₉C(0)0-, -CH=NO-, -ON=CH-, - RioC(0)NRio-, heteroaryl-, aryl-,

- C(= R_U) R₁₀-, -OC(= R_u)-, or -C(= R_u)0-;

L₄ is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;

or L₃, X and L₄ taken together form a nitrogen containing heterocyclic ring;

wherein,

R6, R-7 and R₈ are independently selected from among H, halogen, CN, OH, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

each R₉ is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;

each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or

two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or

Rio and Rn can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or each Rii is independently selected from H or substituted or unsubstituted alkyl; or a

pharmaceutically acceptable salt thereof. In some embodiments, L₃, X and L₄ taken together form a nitrogen containing heterocyclic ring. In some embodiments, the nitrogen containing

heterocyclic ring is a piperidine group. In some embodiments, G is

. In some embodiments, the compound of Formula (A) is l-[(3R)-3-[4-amino-3-

(4-phenoxyphenyl)pyrazolo[3 ,4-d]pyrimidin- 1 -yljpiperidin- 1 -yl]prop-2-en- 1 -one.

[0072] In some embodiments, the nitrogen containing heterocyclic ring is a piperidine group.

[0073] In some embodiments, G is

[0074] In some embodiments, the compound of Formula (A) is l-[(3R)-3-[4-amino-3-(4- phenoxyphenyl)pyrazolo[3 ,4-d]pyrimidin- 1 -yljpiperidin- 1 -yl]prop-2-en- 1 -one.

[0075] Ibrutinib" or "l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one" or " 1 - { (3R)-3 -[4-amino-3 -(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-<i]pyrimidin- 1 -yljpiperidin- 1 -yl }prop-2-en- 1 -one" or "2- Propen- 1 -one, 1 - [(3R)-3 - [4-amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-<i]pyrimidin- 1 -yl]- 1-piperidinyl-" or ibrutinib or any other suitable name refers to the compound with the following structure:

[0076] A wide variety of pharmaceutically acceptable salts is formed from ibrutinib and includes:

- acid addition salts formed by reacting ibrutinib with an organic acid, which includes aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like;

- acid addition salts formed by reacting ibrutinib with an inorganic acid, which includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.

[0077] The term "pharmaceutically acceptable salts" in reference to ibrutinib refers to a salt of Ibrutinib, which does not cause significant irritation to a mammal to which it is

administered and does not substantially abrogate the biological activity and properties of the compound.

[0078] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition 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, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, and the like. In one aspect, solvates are formed using, but limited to, Class 3 solvent(s). Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of

Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of ibrutinib, or pharmaceutically 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 salts thereof, exist in unsolvated form. In some embodiments, ibrutinib, or pharmaceutically acceptable salts thereof, exist in unsolvated form and are anhydrous.

[0079] In yet other embodiments, ibrutinib, or a pharmaceutically acceptable salt thereof, is prepared in various forms, including but not limited to, amorphous phase, crystalline forms, milled forms and nano-particulate forms. In some embodiments, ibrutinib, or a

pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, ibrutinib, or a pharmaceutically acceptable salt thereof, is amorphous and 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.

[0080] In some embodiments, ibrutinib is prepared as outlined in U.S. Patent no. 7,514,444, the contents of which are herein incorporated by reference in its entirety.

[0081] In some embodiments, the Btk inhibitor is AVL-263 (Avila Therapeutics/Celgene Corporation), AVL-292 (Avila Therapeutics/Celgene Corporation), AVL-291 (Avila

Therapeutics/Celgene Corporation), ACP-196 (Acerta Pharma BV), BMS-488516 (Bristol- Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), or HM71224 (Hanmi Pharmaceutical Company Limited).

[0082] In some embodiments, the Btk inhibitor is 4-(tert-butyl)-N-(2-methyl-3-(4-methyl- 6-((4-(mo holine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2- yl)phenyl)benzamide (CGI-1746); 7-benzyl-l-(3-(piperidin-l-yl)propyl)-2-(4-(pyridin-4- yl)phenyl)-lH-imidazo[4,5-g]quinoxalin-6(5H)-one (CTA-056); (i?)-N-(3-(6-(4-(l,4- dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2- methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide (GDC-0834); 6- cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{ l-methyl-5-[5-(4-methyl-piperazin-l-yl)- pyridin-2-ylamino]-6-oxo-l,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-l-one (RN- 486); N-[5-[5-(4-acetylpiperazine-l-carbonyl)-4-methoxy-2-methylphenyl]sulfanyl-l,3- thiazol-2-yl]-4-[(3,3-dimethylbutan-2-ylamino)methyl]benzamide (BMS-509744, HY- 11092); or N-(5-((5-(4-Acetylpiperazine-l-carbonyl)-4-methoxy-2- methylphenyl)thio)thiazol-2-yl)-4-(((3-methylbutan-2-yl)amino)methyl)benzam

(HY11066); or a pharmaceutically acceptable salt thereof.

[0083 In some embodiments, the Btk inhibitor is:

; or a pharmaceutically acceptable salt thereof.

[0084] In other embodiments, the Btk inhibitor has the structure:

wherein:

A is a moiety that binds to the active site of a kinase, including a tyrosine kinase, further including a Btk kinase cysteine homolog; Y is an optionally substituted group selected from among alkylene, heteroalkylene, arylene, heteroarylene, heterocycloalkylene, cycloalkylene, alkylenearylene, alkyleneheteroarylene, alkylenecycloalkylene, and alkyleneheterocycloalkylene;

Z is C(=0), OC(=0), HC(=0), NCH₃C(=0), C(=S), S(=0)_x, OS(=0)_x, HS(=0)_x, where x is 1 or 2;

R-7 and R₈ are independently selected from among H, unsubstituted C₁-C₄ alkyl,

substituted Ci-C₄alkyl, unsubstituted Ci-C₄heteroalkyl, substituted Ci- C₄heteroalkyl, unsubstituted C₃-C₆Cycloalkyl, substituted C₃-C₆cycloalkyl, unsubstituted C₂-C₆heterocycloalkyl, and substituted C₂-C₆heterocycloalkyl; or

R₇ and R₈ taken together form a bond; 5 is H, substituted or unsubstituted Ci-C₄alkyl, substituted or unsubstituted Ci- C₄heteroalkyl, Ci-C₆alkoxyalkyl, Ci-C₈alkylaminoalkyl, Ci- C₈hydroxyalkylaminoalkyl, Ci-C₈alkoxyalkylaminoalkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C₂-C₈heterocycloalkyl, substituted or unsubstituted heteroaryl, Ci- C₄alkyl(aryl), Ci-C₄alkyl(heteroaryl), Ci-C₄alkyl(C₃-C₈cycloalkyl), or Ci- C₄alkyl(C₂-C₈heterocycloalkyl); and pharmaceutically active metabolites, or pharmaceutically acceptable solvates,

pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.

[0085] In another embodiment, A is attached to B-La-Ar where B is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

L_a is CH₂, O, NH, NHC(O), NCH3C(0), C(0)NH, C(0)NCH3, or S; Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0086] In yet another embodiment, NH2 or NCH3 is attached to A.

[0087] In a further embodiment, A is a substituted fused biaryl moiety selected from

[0089] In some embodiments Z is C(=0), HC(=0), NCH₃C(=0), or S(=0)₂. In other embodiments, x is 2. In yet other embodiments, Z is C(=0), OC(=0), HC(=0), S(=0)_x, OS(=0)_x, or HS(=0)_x. In some other embodiments, Z is C(=0), HC(=0), or S(=0)₂.

[0090] In some embodiments, R₇ and R₈ are independently selected from among H, unsubstituted C₁-C₄ alkyl, substituted Ci-C₄alkyl, unsubstituted Ci-C₄heteroalkyl, and substituted Ci-C₄heteroalkyl; or R₇ and R₈ taken together form a bond. In yet other embodiments, each of R₇ and R₈ is H; or R₇ and R₈ taken together form a bond.

[0091] In some embodiments, R₆ is H, substituted or unsubstituted Ci-C₄alkyl, substituted or unsubstituted Ci-C₄heteroalkyl, Ci-C₆alkoxyalkyl, Ci-C₈alkylaminoalkyl, Ci- C₈hydroxyalkylaminoalkyl, Ci-C₈alkoxyalkylaminoalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Ci-C₄alkyl(aryl), Ci-C₄alkyl(heteroaryl), Ci- C₄alkyl(C₃-C₈cycloalkyl), or Ci-C₄alkyl(C₂-C₈heterocycloalkyl). In some other

embodiments, R6 is H, substituted or unsubstituted Ci-C₄alkyl, substituted or unsubstituted Ci-C₄heteroalkyl, Ci-C₆alkoxyalkyl, Ci-C₂alkyl-N(Ci-C₃alkyl)₂, Ci-C₄alkyl(aryl), C

C₄alkyl(heteroaryl), Ci-C₄alkyl(C₃-C₈cycloalkyl), or Ci-C₄alkyl(C₂-C₈heterocycloalkyl). In yet other embodiments, R₆ is H, substituted or unsubstituted Ci-C₄alkyl, -CH₂-0-(C₁- C₃alkyl), -CH₂-N(Ci-C₃alkyl)₂, Ci-C₄alkyl(phenyl), or Ci-C₄alkyl(5- or 6-membered heteroaryl). In yet other embodiments, R6 is H, substituted or unsubstituted Ci-C₄alkyl, -CH₂- 0-(Ci-C₃alkyl), -CH₂-(Ci-C₆alkylamino), Ci-C₄alkyl(phenyl), or Ci-C₄alkyl(5- or 6- membered heteroaryl). In some embodiments, R₆ is H, substituted or unsubstituted Ci- C₄alkyl, -CH₂-0-(Ci-C₃alkyl), -CH₂-N(Ci-C₃alkyl)₂, Ci-C₄alkyl(phenyl), or Ci-C₄alkyl(5- or 6-membered heteroaryl containing 1 or 2 N atoms), or Ci-C₄alkyl(5- or 6-membered heterocycloalkyl containing 1 or 2 N atoms).

[0092] In some embodiments, Y is an optionally substituted group selected from among alkylene, heteroalkylene, cycloalkylene, and heterocycloalkylene. In other embodiments, Y is an optionally substituted group selected from among Ci-C₆alkylene, Ci-C₆heteroalkylene, 4-, 5-, 6-, or 7-membered cycloalkylene, and 4-, 5-, 6-, or 7-membered heterocycloalkylene. In yet other embodiments, Y is an optionally substituted group selected from among Ci- C₆alkylene, Ci-C₆heteroalkylene, 5- or 6-membered cycloalkylene, and 5- or 6-membered heterocycloalkylene containing 1 or 2 N atoms. In some other embodiments, Y is a 5- or 6- membered cycloalkylene, or a 5- or 6-membered heterocycloalkylene containing 1 or 2 N atoms. In some embodiments, Y is a 4-, 5-, 6-, or 7-memebered cycloalkylene ring; or Y is a 4-, 5-, 6-, or 7-membered heterocycloalkylene ring.

[0093] In one embodiment is a Btk inhibitor having the structure:

wherein:

Y is a 4-, 5-, 6-membered cycloalkylene ring; each R_a is independently H, halogen, -CF₃, -CN, -N0₂, OH, H₂, -L_a-(substituted or unsubstituted alkyl), -L_a-(substituted or unsubstituted alkenyl), -L_a-(substituted or unsubstituted heteroaryl), or -L_a-(substituted or unsubstituted aryl), wherein L_a is a bond, O, S, -S(=0), -S(=0)₂, H, C(O), CH₂, - HC(0)0, - HC(O), or -C(0) H;

R-₂ is selected from H, lower alkyl, and substituted lower alkyl;

R₆, R₇ and R₈ are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;

Ri₂ is H or lower alkyl; or

Y and Ri₂ taken together form a 4-, 5-, or 6-membered heterocyclic ring; or pharmaceutically acceptable salts thereof.

[0094] In another embodiment, G is R; 8 In a further embodiment, R₆, R₇, and R₈ are H. In yet a further embodiment, R₇ and R₈ are H; and R₆ is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl. In yet another embodiment, R₆ is substituted lower alkyl. In one embodiment, lower alkyl is substituted with a disubstituted amino group. In another embodiment, R₆ and R₈ are H; and R₇ is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl. In one embodiment, R₇ is substituted lower alkyl.

[0095] In another embodiment, lower alkyl is substituted with a disubstituted amino group.

[0096] In yet another embodiment, G is

and R₆ is H. [0097] In another embodiment R₆ is selected from lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl. In a further embodiment, R₆ is substituted lower alkyl. In yet a further embodiment lower alkyl is substituted with a di substituted amino group.

HDAC inhibitor

[0098] In some embodiments, the HDAC inhibitor is a compound of Formula (B):

Formula (B)

wherein:

R¹ is hydrogen or alkyl;

X is -0-, -NR²-, or -S(0)_n where n is 0-2 and R² is hydrogen or alkyl;

Y is alkylene optionally substituted with cycloalkyl, optionally substituted phenyl, alkylthio, alkylsulfinyl, alkysulfonyl, optionally substituted phenylalkylthio, optionally substituted phenylalkylsulfonyl, hydroxy, or optionally substituted phenoxy;

Ar¹ is phenylene or heteroarylene wherein said Ar¹ is optionally substituted with one or two groups independently selected from alkyl, halo, hydroxy, alkoxy, haloalkoxy, or haloalkyl; R³ is hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl; and

Ar² is aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, or heterocycloalkylalkyl.

[0099] In some embodiments, the HDAC inhibitor is 3-[(dimethylamino)methyl]-N-{2- [4-(hydroxycarbamoyl)phenoxy]ethyl}-l-benzofuran-2- carboxamide (i.e. PCI- 24781/abexinostat)

Abexinostat.

[00100] In some embodiments, the HDAC inhibitor is to N-hydroxy-4-{2-[3-(N,N- dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide tosylate, or a solvate thereof. The HDAC inhibitor may be a tosylate salt as disclosed in U.S. Patent Application Publication No. 2014/0249215, the entire contents of which are herein incorporated by reference in its entirety.

[00101] In some aspects, the HDAC inhibitor may be a tosylate salt of abexinostat of formula (I):

[00102] In

some aspects, the HDAC inhibitor is the tosylate salt of abexinostat of formula (II):

[00103] In some embodiments, the HDAC inhibitor is a crystalline form I of N-hydroxy-4- {2-[3-(N,N-dimethylaminomethyl)benzofuran-2-ylcarbonylamino]ethoxy}benzamide tosylate, as disclosed in U.S. Patent Application Publication No. 2014/0249215, the entire contents of which are herein incorporated by reference in its entirety.

[00104] In some embodiments, the HDAC inhibitor is a hydrochloride salt of abexinostat (also referred to herein as "abexinostat HQ."

[00105] In some embodiments, the method further comprises administering a third anticancer therapy. In some embodiments, the third anticancer therapy is selected from among a chemotherapeutic agent or radiation therapy. In some embodiments, the

chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, the third cancer treatment regimen comprises cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, and optionally, rituximab. In some embodiments, the third cancer treatment regimen comprises bendamustine, and rituximab. In some embodiments, the third cancer treatment regimen comprises fludarabine,

cyclophosphamide, and rituximab. In some embodiments, the third cancer treatment regimen comprises cyclophosphamide, vincristine, and prednisone, and optionally, rituximab. In some embodiments, the third cancer treatment regimen comprises etoposide, doxorubicin, vinristine, cyclophosphamide, prednisolone, and optionally, rituximab. In some

embodiments, the second cancer treatment regimen comprises dexamethasone and lenalidomide. It is to be understood that any other known anticancer therapy may be used.

Biomarkers

[00106] In some embodiments, methods of selecting an individual having a hematological malignancy, such as a lymphoma, for therapy with the combination of Btk inhibitor (i.e., ibrutinib) and HDAC inhibitor (i.e., abexinostat) are disclosed. Preferably, the method comprises determining the expression or presence/absence of one or more biomarkers.

Exemplary biomarkers include, but are not limited to, BCL-2, RBI, LRP1B, PIM1, TSC2, TNFRSF11A, SMAD4, PAX5, and CARDll. In some embodiments, modification in one or more biomarker genes selected from BCL-2, RBI, LRP1B, PIM1, TSC2, TNFRSF11A, SMAD4, PAX5, and CARDll indicate that an individual has developed resistance, or is likely to develop resistance to therapy a Btk inhibitor (e.g. ibrutinib). In other cases, an individual's therapeutic regimen is optimized, e.g. modifying, by adding an HDAC inhibitor to the therapy, based on the presence or absence of modifications in the one or more biomarker genes selected from BCL-2, RBI, LRP1B, PIM1, TSC2, TNFRSF11A, SMAD4, PAX5, and CARDll. In some embodiments, the lymphoma is DLBCL. Other exemplary biomarkers include, but are not limited to, ACTG2, LOR, GAPT, CCND2, SELL, GEN1, and HDAC9, and/or modifications in amino acid position 481 of Bruton's Tyrosine Kinase (Btk). Other biomarkers can include cell proliferation and/or apoptosis markers as is known in the art. In some embodiments, the modification comprises a substitution or a deletion of the amino acid at amino acid position 481 in the Btk polypeptide. In some embodiments, the modification is a substitution of cysteine to an amino acid selected from among leucine, isoleucine, valine, alanine, glycine, methionine, serine, threonine, phenylalanine, tryptophan, lysine, arginine, histidine, proline, tyrosine, asparagine, glutamine, aspartic acid and glutamic acid at amino acid position 481 of the Btk polypeptide. In some embodiments, the modification is a substitution of cysteine to an amino acid selected from among serine, methionine, or threonine at amino acid position 481 of the Btk polypeptide. In some embodiments, the modification is a substitution of cysteine to serine at amino acid position 481 of the Btk polypeptide. In some embodiments, the modification comprises a deletion of nucleic acid encoding amino acid position 481 of the Btk polypeptide.

[00107] In another aspect, methods for selecting an individual having a hematological malignancy such as DLBCL for treatment are provided, based on the presence or absence of a modification to an aromatic residue in CD79B and at least one modification at amino acid positions 198 or 265 in MYD88. In some instances, the presence of the modification to an aromatic residue in CD79B and at least one modification at amino acid positions 198 or 265 in MYD88 indicates that the individual is responsive or is likely to respond to therapy with a Btk inhibitor (e.g. ibrutinib). In other instances, an individual's therapeutic regimen is optimized, e.g. by modifying treatment (i.e., by adding HDAC inhibitor to the therapy) based on the presence or absence of the modification to an aromatic residue at amino acid position 196 in CD79B and at least one modification at amino acid positions 198 or 265 in MYD88.

[00108] In some instances, disclosed herein are methods of selecting an individual having a hematological malignancy such as DLBCL for treatment, based on the presence or absence of a modification at amino acid position 15 in ROS1. In some cases, the presence of the modification at amino acid position 15 in ROS1 indicates that the individual has developed resistance or is likely to develop resistance to therapy with a Btk inhibitor (e.g. ibrutinib). In other cases, an individual's therapeutic regimen is optimized, e.g. modifying, by adding an HDAC inhibitor to the therapy, based on the presence or absence of the modification at amino acid position 15 in ROS1.

[00109] Determination of the expression, presence, and/or absence of one or more biomarkers, such as, but not limited to, those recited above can be used to determine whether an individual is resistant to a Btk-inhibitor or will acquire resistance to a Btk inhibitor.

Additionally, determination of the expression, presence, and/or absence of one or more biomarkers can be used to determine whether the hematological malignancy still exists after treatment.

[00110] Determining the expression or presence can be at the protein or nucleic acid level. Thus, the biomarkers include these proteins and the genes encoding these proteins. Where detection is at the protein level, the biomarker protein comprises the full-length polypeptide or any detectable fragment thereof, and can include variants of these protein sequences. Similarly, where detection is at the nucleotide level, the biomarker nucleic acid includes DNA comprising the full-length coding sequence, a fragment of the full-length coding sequence, variants of these sequences, for example naturally occurring variants or splice- variants, or the complement of such a sequence. Biomarker nucleic acids also include RNA, for example, mRNA, comprising the full-length sequence encoding the biomarker protein of interest, a fragment of the full-length RNA sequence of interest, nCRNA (non-coding RNA or miRNA) or variants of these sequences. Biomarker proteins and biomarker nucleic acids also include variants of these sequences. By "fragment" is intended a portion of the polynucleotide or a portion of the amino acid sequence and hence protein encoded thereby. Polynucleotides that are fragments of a biomarker nucleotide sequence generally comprise at least 10, 15, 20, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, or 1,400 contiguous nucleotides, or up to the number of nucleotides present in a full-length biomarker polynucleotide disclosed herein. A fragment of a biomarker polynucleotide will generally encode at least 15, 25, 30, 50, 100, 150, 200, or 250 contiguous amino acids, or up to the total number of amino acids present in a full-length biomarker protein of the invention. "Variant" is intended to mean substantially similar sequences. Generally, variants of a particular biomarker of the invention will have at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%), 96%), 97%), 98%), 99% or more sequence identity to that biomarker as determined by sequence alignment programs known in the art.

[00111] As provided above, any method known in the art can be used in the methods for determining the expression or presence of biomarker described herein. Circulating levels of biomarkers in a blood sample obtained from a candidate subject, can be measured, for example, by ELISA, radioimmunoassay (RIA), electrochemiluminescence (ECL), Western blot, multiplexing technologies, or other similar methods. Cell surface expression of biomarkers can be measured, for example, by flow cytometry, immunohistochemistry, Western Blot, immunoprecipitation, magnetic bead selection, and quantification of cells expressing either of these cell surface markers. Biomarker RNA expression levels could be measured by RT-PCR, Qt-PCR, microarray, Northern blot, or other similar technologies.

[00112] As previously noted, determining the expression or presence of the biomarker of interest at the protein or nucleotide level can be accomplished using any detection method known to those of skill in the art. By "detecting expression" or "detecting the level of is intended determining the expression level or presence of a biomarker protein or gene in the biological sample. Thus, "detecting expression" encompasses instances where a biomarker is determined not to be expressed, expressed at a low level, expressed at a normal level, or overexpressed.

[00113] As provided above, any method known in the art can be used in the methods for determining the expression or presence of biomarker described herein. Circulating levels of biomarkers in a blood sample obtained from a candidate subject, can be measured, for example, by ELISA, radioimmunoassay (RIA), electrochemiluminescence (ECL), Western blot, multiplexing technologies, or other similar methods. Cell surface expression of biomarkers can be measured, for example, by flow cytometry, immunohistochemistry, Western Blot, immunoprecipitation, magnetic bead selection, and quantification of cells expressing either of these cell surface markers. Biomarker RNA expression levels could be measured by RT-PCR, Qt-PCR, microarray, Northern blot, or other similar technologies.

[00114] The biomarkers can be determined from any cells or subpopulation of cells, i.e., lymphocytes, as is known in the art.

[00115] In certain aspects, the expression or presence of these various biomarkers and any clinically useful prognostic markers in a biological sample can be detected at the protein or nucleic acid level, using, for example, immunohistochemistry techniques or nucleic acid- based techniques such as in situ hybridization and RT-PCR. In one embodiments, the expression or presence of one or more biomarkers is carried out by a means for nucleic acid amplification, a means for nucleic acid sequencing, a means utilizing a nucleic acid microarray (DNA and RNA), or a means for in situ hybridization using specifically labeled probes. [00116] In other embodiments, the determining the expression or presence of one or more biomarkers is carried out through gel electrophoresis. In one embodiment, the determination is carried out through transfer to a membrane and hybridization with a specific probe.

[00117] In other embodiments, the determining the expression or presence of one or more biomarkers carried out by a diagnostic imaging technique.

[00118] In still other embodiments, the determining the expression or presence of one or more biomarkers carried out by a detectable solid substrate. In one embodiment, the detectable solid substrate is paramagnetic nanoparticles functionalized with antibodies.

[00119] In another aspect, provided herein are methods for detecting or measuring residual lymphoma following a course of treatment in order to guide continuing or discontinuing treatment or changing from one therapeutic to another comprising determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes in a subject wherein the course of treatment is treatment with ibrutinib and/or abexinostat.

[00120] Methods for detecting expression of the biomarkers described herein, and optionally cytokine markers, within the test and control biological samples comprise any methods that determine the quantity or the presence of these markers either at the nucleic acid or protein level. Such methods are well known in the art and include but are not limited to western blots, northern blots, ELISA, immunoprecipitation, immunofluorescence, flow cytometry, immunohistochemistry, nucleic acid hybridization techniques, nucleic acid reverse transcription methods, and nucleic acid amplification methods. In particular embodiments, expression of a biomarker is detected on a protein level using, for example, antibodies that are directed against specific biomarker proteins. These antibodies can be used in various methods such as Western blot, ELISA, multiplexing technologies,

immunoprecipitation, or immunohistochemistry techniques. In some embodiments, detection of cytokine markers is accomplished by electrochemiluminescence (ECL).

[00121] Any means for specifically identifying and quantifying a biomarker (for example, biomarker, a biomarker of cell survival or proliferation, a biomarker of apoptosis, a biomarker of a Btk-mediated signaling pathway) in the biological sample of a candidate subject is contemplated. Thus, in some embodiments, expression level of a biomarker protein of interest in a biological sample is detected by means of a binding protein capable of interacting specifically with that biomarker protein or a biologically active variant thereof. Preferably, labeled antibodies, binding portions thereof, or other binding partners may be used. The word "label" when used herein refers to a detectable compound or composition that is conjugated directly or indirectly to the antibody so as to generate a "labeled" antibody. The label may be detectable by itself (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable.

[00122] The antibodies for detection of a biomarker protein may be monoclonal or polyclonal in origin, or may be synthetically or recombinantly produced. The amount of complexed protein, for example, the amount of biomarker protein associated with the binding protein, for example, an antibody that specifically binds to the biomarker protein, is determined using standard protein detection methodologies known to those of skill in the art. A detailed review of immunological assay design, theory and protocols can be found in numerous texts in the art (see, for example, Ausubel et al., eds. (1995) Current Protocols in Molecular Biology) (Greene Publishing and Wiley-Interscience, NY)); Coligan et al., eds. (1994) Current Protocols in Immunology (John Wiley & Sons, Inc., New York, N.Y.).

[00123] The choice of marker used to label the antibodies will vary depending upon the application. However, the choice of the marker is readily determinable to one skilled in the art. These labeled antibodies may be used in immunoassays as well as in histological applications to detect the presence of any biomarker or protein of interest. The labeled antibodies may be polyclonal or monoclonal. Further, the antibodies for use in detecting a protein of interest may be labeled with a radioactive atom, an enzyme, a chromophoric or fluorescent moiety, or a colorimetric tag as described elsewhere herein. The choice of tagging label also will depend on the detection limitations desired. Enzyme assays (ELISAs) typically allow detection of a colored product formed by interaction of the enzyme-tagged complex with an enzyme substrate. Radionuclides that can serve as detectable labels include, for example, 1-131, 1-123, 1-125, Y-90, Re-188, Re-186, At-211, Cu-67, Bi-212, and Pd-109. Examples of enzymes that can serve as detectable labels include, but are not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and glucose-6-phosphate dehydrogenase. Chromophoric moieties include, but are not limited to, fluorescein and rhodamine. The antibodies may be conjugated to these labels by methods known in the art. For example, enzymes and chromophoric molecules may be conjugated to the antibodies by means of coupling agents, such as dialdehydes, carbodiimides, dimaleimides, and the like. Alternatively, conjugation may occur through a ligand-receptor pair. Examples of suitable ligand-receptor pairs are biotin-avidin or biotin-streptavidin, and antibody-antigen.

[00124] In certain embodiments, expression or presence of one or more biomarkers or other proteins of interest within a biological sample, for example, a sample of bodily fluid, is determined by radioimmunoassays or enzyme-linked immunoassays (ELISAs), competitive binding enzyme-linked immunoassays, dot blot (see, for example, Promega Protocols and Applications Guide (2^nd ed.; Promega Corporation (1991), Western blot (see, for example, Sambrook et al. (1989) Molecular Cloning, A Laboratory Manual, Vol. 3, Chapter 18 (Cold Spring Harbor Laboratory Press, Plainview, N. Y.), chromatography, preferably high performance liquid chromatography (HPLC), or other assays known in the art. Thus, the detection assays can involve steps such as, but not limited to, immunoblotting,

immunodiffusion, Immunoelectrophoresis, or immunoprecipitation.

[00125] In certain other embodiments, the methods of the invention are useful for identifying and treating hematological malignancies, including those listed above, that are refractory to (i.e., resistant to, or have become resistant to) first-line oncotherapeutic treatments.

[00126] The expression or presence of one or more of the biomarkers described herein may also be determined at the nucleic acid level. Nucleic acid-based techniques for assessing expression are well known in the art and include, for example, determining the level of biomarker mRNA in a biological sample. Many expression detection methods use isolated RNA. Any RNA isolation technique that does not select against the isolation of mRNA can be utilized for the purification of RNA (see, e.g., Ausubel et al., ed. (1987-1999) Current Protocols in Molecular Biology (John Wiley & Sons, New York). Additionally, large numbers of tissue samples can readily be processed using techniques well known to those of skill in the art, such as, for example, the single-step RNA isolation process disclosed in U.S. Pat. No. 4,843, 155.

[00127] Thus, in some embodiments, the detection of a biomarker or other protein of interest is assayed at the nucleic acid level using nucleic acid probes. The term "nucleic acid probe" refers to any molecule that is capable of selectively binding to a specifically intended target nucleic acid molecule, for example, a nucleotide transcript. Probes can be synthesized by one of skill in the art, or derived from appropriate biological preparations. Probes may be specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are discussed above or that are known in the art. Examples of molecules that can be utilized as probes include, but are not limited to, RNA and DNA.

[00128] For example, isolated mRNA can be used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses and probe arrays. One method for the detection of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that can hybridize to the mRNA encoded by the gene being detected. The nucleic acid probe can be, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least 7, 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to an mRNA or genomic DNA encoding a biomarker, biomarker described herein above.

Hybridization of an mRNA with the probe indicates that the biomarker or other target protein of interest is being expressed.

[00129] In one embodiment, the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose. In an alternative embodiment, the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in a gene chip array. A skilled artisan can readily adapt known mRNA detection methods for use in detecting the level of mRNA encoding the biomarkers or other proteins of interest.

[00130] An alternative method for determining the level of a mRNA of interest in a sample involves the process of nucleic acid amplification, e.g., by RT-PCR (see, for example, U.S. Pat. No. 4,683,202), ligase chain reaction (Barany (1991) Proc. Natl. Acad. Sci. USA 88: 189- 193), self-sustained sequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (Kwoh et al. (1989) Proc. Natl. Acad. Sci. USA 86: 1173-1177), Q-Beta Replicase (Lizardi et al. (1988) Bio/Technology 6: 1197), rolling circle replication (U.S. Pat. No. 5,854,033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. In particular aspects of the invention, biomarker expression is assessed by quantitative fluorogenic RT- PCR (i.e., the TaqMan® System).

[00131] Expression levels of an RNA of interest may be monitored using a membrane blot (such as used in hybridization analysis such as Northern, dot, and the like), or microwells, sample tubes, gels, beads or fibers (or any solid support comprising bound nucleic acids). See U.S. Pat. Nos. 5,770,722, 5,874,219, 5,744,305, 5,677, 195 and 5,445,934. The detection of expression may also comprise using nucleic acid probes in solution.

[00132] In one embodiment of the invention, microarrays are used to determine expression or presence of one or more biomarkers. Microarrays are particularly well suited for this purpose because of the reproducibility between different experiments. DNA microarrays provide one method for the simultaneous measurement of the expression levels of large numbers of genes. Each array consists of a reproducible pattern of capture probes attached to a solid support. Labeled RNA or DNA is hybridized to complementary probes on the array and then detected by laser scanning. Hybridization intensities for each probe on the array are determined and converted to a quantitative value representing relative gene expression levels. See, U.S. Pat. Nos. 6,040,138, 5,800,992 and 6,020,135, 6,033,860, and 6,344,316. High- density oligonucleotide arrays are particularly useful for determining the gene expression profile for a large number of RNA' s in a sample.

[00133] Techniques for the synthesis of these arrays using mechanical synthesis methods are described in, e.g., U.S. Pat. No. 5,384,261. Although a planar array surface is preferred, the array may be fabricated on a surface of virtually any shape or even a multiplicity of surfaces. Arrays may be peptides or nucleic acids on beads, gels, polymeric surfaces, fibers such as fiber optics, glass or any other appropriate substrate, see U.S. Pat. Nos. 5,770,358, 5,789,162, 5,708,153, 6,040,193 and 5,800,992. Arrays may be packaged in such a manner as to allow for diagnostics or other manipulation of an all-inclusive device. See, for example, U.S. Pat. Nos. 5,856, 174 and 5,922,591.

Pharmaceutical Compositions/Formulations

[00134] In some aspects, a composition comprising a therapeutically effective amount of a Btk inhibitor, a HDAC inhibitor, and a pharmaceutically acceptable excipient, for use in the treatment of a hematological malignancy is provided. The hematological malignancy may be a lymphoma. In some aspects, the Btk inhibitor is ibrutinib, and the HDAC inhibitor is abexinostat or a salt thereof. Preferably, the composition is in a separate dosage form. In some aspects, the composition may be in a combined dosage form.

[00135] In some embodiments, a composition comprising a therapeutically effective amount of abexinostat or a salt thereof, a BCL-2 inhibitor, and a pharmaceutically acceptable excipient, for use in the treatment of a hematological malignancy is provided. In some embodiments, the BCL-2 inhibitor is ABT-199. Preferably, the composition is in a separate dosage form. In some embodiments, the composition may be in a combined dosage form.

[00136] In some embodiments, a composition comprising a therapeutically effective amount of abexinostat or a salt thereof, a BCL-2 inhibitor, and a pharmaceutically acceptable excipient, for use in the treatment of a hematological malignancy is provided. In some embodiments, the BCL-2 inhibitor is ABT-199. Preferably, the composition is in a separate dosage form. In some embodiments, the composition may be in a combined dosage form.

[00137] In some embodiments, a composition comprising a therapeutically effective amount of abexinostat or a salt thereof, a BCL-2 inhibitor, a Btk inhibitor, and a pharmaceutically acceptable excipient, for use in the treatment of a hematological malignancy is provided. In some embodiments, the BCL-2 inhibitor is ABT-199. In some embodiments, the Btk inhibitor is ibrutinib. Preferably, the composition is in a separate dosage form. In some embodiments, the composition may be in a combined dosage form.

[00138] Pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used

pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. A summary of pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington 's

Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.

(Lippincott Williams & Wilkinsl999), herein incorporated by reference in their entirety.

[00139] A pharmaceutical composition, as used herein, refers to a mixture of a compound described herein, such as, for example, ibrutinib and abexinostat, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates

administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[00140] In certain embodiments, compositions may also include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[00141] In other embodiments, compositions may also include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[00142] The term "pharmaceutical combination" as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound described herein and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound described herein and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[00143] The pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[00144] Pharmaceutical compositions including a compound described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. [00145] "Antifoaming agents" reduce foaming during processing which can result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing. Exemplary anti-foaming agents include silicon emulsions or sorbitan sesquoleate.

[00146] "Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, antioxidants enhance chemical stability where required.

[00147] In certain embodiments, compositions provided herein may also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury- containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[00148] Formulations described herein may benefit from antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1%) to about 1%> w/v methionine, (c) about 0.1%> to about 2% w/v

monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[00149] "Binders" impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g.,

Methocel^®), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel^®), ethylcellulose (e.g., Ethocel^®), and microcrystalline cellulose (e.g., Avicel^®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac^®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab^®), and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks,

polyvinylpyrrolidone (e.g., Polyvidone^® CL, Kollidon^® CL, Polyplasdone^® XL- 10), larch arabogalactan, Veegum^®, polyethylene glycol, waxes, sodium alginate, and the like.

[00150] A "carrier" or "carrier materials" include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with compounds disclosed herein, such as, compounds of ibrutinib and abexinostat, and the release profile properties of the desired dosage form. Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "Pharmaceutically compatible carrier materials" may include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium

glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate,

polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995); Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andO g Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999).

[00151] "Dispersing agents," and/or "viscosity modulating agents" include materials that control the diffusion and homogeneity of a drug through liquid media or a granulation method or blend method. In some embodiments, these agents also facilitate the effectiveness of a coating or eroding matrix. Exemplary diffusion facilitators/dispersing agents include, e.g., hydrophilic polymers, electrolytes, Tween ^® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone^®), and the carbohydrate-based dispersing agents such as, for example, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,

hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,

hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl

pyrrolidone/vinyl acetate copolymer (S630), 4-(l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68^®, F88^®, and F108^®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908^®, also known as Poloxamine 908^®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)),

polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium

carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium

carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates, chitosans and combinations thereof. Plasticizers such as cellulose or triethyl cellulose can also be used as dispersing agents. Dispersing agents particularly useful in liposomal dispersions and self-emulsifying dispersions are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropyl my ri state.

[00152] Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present compositions.

[00153] The term "diluent" refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution. In certain embodiments, diluents increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling. Such compounds include e.g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel^®; dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;

anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugar, such as Di- Pac^® (Amstar); mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

[00154] The term "disintegrate" includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid. "Disintegration agents or disintegrants" facilitate the breakup or disintegration of a substance. Examples of disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel^®, or sodium starch glycolate such as Promogel^® or Explotab , a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel , Avicel^® PH101, Avicel^® PH102, Avicel^® PH105, Elcema^® P100, Emcocel^®, Vivacel^®, Ming Tia^®, and Solka-Floc^®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol^®), cross-linked

carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked

polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum^® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.

[00155] "Drug absorption" or "absorption" typically refers to the process of movement of drug from site of administration of a drug across a barrier into a blood vessel or the site of action, e.g., a drug moving from the gastrointestinal tract into the portal vein or lymphatic system.

[00156] An "enteric coating" is a substance that remains substantially intact in the stomach but dissolves and releases the drug in the small intestine or colon. Generally, the enteric coating comprises a polymeric material that prevents release 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 sufficiently in the small intestine or colon to release the active agent therein.

[00157] "Erosion facilitators" include materials that control the erosion of a particular material in gastrointestinal fluid. Erosion facilitators are generally known to those of ordinary skill in the art. Exemplary erosion facilitators include, e.g., hydrophilic polymers,

electrolytes, proteins, peptides, and amino acids.

[00158] "Filling agents" include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[00159] "Flavoring agents" and/or "sweeteners" useful in the formulations described herein, include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate

(MagnaSweet^®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet^® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[00160] "Lubricants" and "glidants" are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex^®), higher fatty acids and their alkali- metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet^®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a methoxypolyethylene glycol such as Carbowax™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil^®, a starch such as corn starch, silicone oil, a surfactant, and the like.

[00161] A "measurable serum concentration" or "measurable plasma concentration" describes the blood serum or blood plasma concentration, typically measured in mg, μg, or ng of therapeutic agent per mL, dL, or L of blood serum, absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng/ml or μg/ml.

[00162] "Pharmacodynamics" refers to the factors which determine the biologic response observed relative to the concentration of drug at a site of action.

[00163] "Pharmacokinetics" refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.

[00164] "Plasticizers" are compounds used to soften the microencapsulation material or film coatings to make them less brittle. Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose and triacetin. In some embodiments, plasticizers can also function as dispersing agents or wetting agents. [00165] "Solubilizers" include compounds such as triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS,

dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide and the like.

[00166] "Stabilizers" include compounds such as any antioxidation agents, buffers, acids, preservatives and the like.

[00167] "Steady state," as used herein, is when the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant plasma drug exposure.

[00168] "Suspending agents" include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxy ethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

[00169] "Surfactants" include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic^® (BASF), and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g.,

polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. In some embodiments, surfactants may be included to enhance physical stability or for other purposes.

[00170] "Viscosity enhancing agents" include, e.g., methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.

[00171] "Wetting agents" include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts and the like.

Dosage Forms

[00172] The compositions described herein can be formulated for administration to a subject via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably.

Moreover, the pharmaceutical compositions described herein, which include ibrutinib and/or abexinostat can be formulated into any suitable dosage form, including but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a patient to be treated, solid oral dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[00173] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum

tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents may be added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. [00174] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc,

polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[00175] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[00176] In some embodiments, the solid dosage forms disclosed herein may be in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet.

Additionally, pharmaceutical formulations described herein may be administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.

[00177] In some embodiments, solid dosage forms, e.g., tablets, effervescent tablets, and capsules, are prepared by mixing particles of ibrutinib and/or Abexinostat, with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend compositions as homogeneous, it is meant that the particles of ibrutinib and/or

Abexinostat, are dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. The individual unit dosages may also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.

[00178] Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.

[00179] The pharmaceutical solid dosage forms described herein can include a compound described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington 's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of ibrutinib and/or Abexinostat. In another embodiment, some or all of the particles of ibrutinib and/or Abexinostat, are not microencapsulated and are uncoated.

[00180] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate,

carrageenan, monoglyceride, diglyceride, pregelatinized starch,

hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.

[00181] Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC),

hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[00182] In order to release the compound of ibrutinib and/or Abexinostat, from a solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel^®, or sodium starch glycolate such as Promogel^® or Explotab^®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel^®, Avicel^® PH101, Avicel^®PH102, Avicel^® PH105, Elcema^® P100, Emcocel^®, Vivacel^®, Ming Tia^®, and Solka-Floc^®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol^®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked

polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum^® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.

[00183] Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel^®), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel^®), ethylcellulose (e.g., Ethocel^®), and microcrystalline cellulose (e.g., Avicel^®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac^®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab^®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone^® CL, Kollidon^® CL, Polyplasdone^® XL- 10, and Povidone^® K-12), larch arabogalactan, Veegum^®, polyethylene glycol, waxes, sodium alginate, and the like.

[00184] In general, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common.

[00185] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet^®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl

palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.

[00186] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides

(including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.

[00187] The term "non water-soluble diluent" represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (e.g., having a density of about 0.45 g/cm³, e.g. Avicel, powdered cellulose), and talc.

[00188] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10^®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.

[00189] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic^® (BASF), and the like.

[00190] Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl

pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose,

hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan

monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

[00191] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[00192] It should be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.

[00193] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, a plasticizer is generally a high boiling point solid or liquid.

Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[00194] Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above. In various embodiments, compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide a delayed release of ibrutinib or the second agent, from the formulation. In other embodiments, the film coating aids in patient compliance (e.g., Opadry^® coatings or sugar coating). Film coatings including Opadry^® typically range from about 1% to about 3% of the tablet weight. In other embodiments, the compressed tablets include one or more excipients.

[00195] A capsule may be prepared, for example, by placing the bulk blend of the formulation of ibrutinib or the second agent, described above, inside of a capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in a soft gelatin capsule. In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, wherein the capsule may be swallowed whole or the capsule may be opened and the contents sprinkled on food prior to eating. In some embodiments, the therapeutic dose is split into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the formulation is delivered in a capsule form.

[00196] In various embodiments, the particles of ibrutinib and/or abexinostat, and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[00197] In another aspect, dosage forms may include microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the

microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[00198] Materials useful for the microencapsulation described herein include materials compatible with ibrutinib and/or abexinostat, which sufficiently isolate the compound of any of ibrutinib or abexinostat, from other non-compatible excipients. Materials compatible with compounds of any of ibrutinib or abexinostat, are those that delay the release of the compounds of any of ibrutinib or abexinostat, in vivo.

[00199] Exemplary microencapsulation materials useful for delaying the release of the formulations including compounds described herein, include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel^® or Nisso HPC, low- substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat^®, Metolose SR, Methocel^®-E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel^®-A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and

Metolose^®, Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel^®, Aqualon^®-EC, Surelease^®, Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol^®, carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon^®-CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR^®, monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit^® EPO, Eudragit^® L30D-55, Eudragit^® FS 30D Eudragit^® L100-55, Eudragit^® LlOO, Eudragit^® S100, Eudragit^® RD100, Eudragit^® E100, Eudragit^® L12.5, Eudragit^® S12.5, Eudragit^® E30D, and Eudragit^® E 40D, cellulose acetate phthalate, sepifilms such as mixtures of FIPMC and stearic acid, cyclodextrins, and mixtures of these materials.

[00200] In still other embodiments, plasticizers such as polyethylene glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulating material useful for delaying the release of the pharmaceutical compositions is from the USP or the National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is methocel.

[00201] Microencapsulated compounds of any of ibrutinib or abexinostat, may be formulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath. In addition to these, several chemical techniques, e.g., complex coacervation, solvent evaporation, polymer-polymer

incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used. Furthermore, other methods such as roller compaction, extrusion/spheronization, coacervation, or nanoparticle coating may also be used.

[00202] In one embodiment, the particles of compounds of any of ibrutinib or abexinostat, are microencapsulated prior to being formulated into one of the above forms. In still another embodiment, some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Remington 's Pharmaceutical Sciences, 20th Edition (2000).

[00203] In other embodiments, the solid dosage formulations of the compounds of any of ibrutinib and/or abexinostat, are plasticized (coated) with one or more layers. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[00204] In other embodiments, a powder including the formulations with a compound of any of ibrutinib and/or abexinostat, described herein, may be formulated to include one or more pharmaceutical excipients and flavors. Such a powder may be prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units.

[00205] In still other embodiments, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid. When salts of the compositions described herein are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing "effervescence." Examples of effervescent salts include, e.g., the following ingredients: sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[00206] In some embodiments, the solid dosage forms described herein can be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to affect release in the small intestine of the gastrointestinal tract. The enteric coated dosage form may be a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated. The enteric coated oral dosage form may also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.

[00207] The term "delayed release" as used herein refers to the delivery so that the release can be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations. In some embodiments the method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments the polymers described herein are anionic carboxylic polymers. In other embodiments, the polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to:

Shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7;

Acrylic polymers. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution. Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series E, L, S, RL, RS and E (Rohm Pharma) are available as solubilized in organic solvent, aqueous dispersion, or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting. The Eudragit series E dissolve in the stomach. The Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine;

Cellulose Derivatives. Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves in pH >6. Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles <1 μπι. Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). The performance can vary based on the degree and type of

substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable. The performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules, or as fine powders for aqueous dispersions; Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH >5, and it is much less permeable to water vapor and gastric fluids. [00208] In some embodiments, the coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.

[00209] Colorants, detackifiers, surfactants, antifoaming agents, lubricants (e.g., carnuba wax or PEG) may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.

[00210] In other embodiments, the formulations described herein, which include ibrutinib and/or abexinostat, are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. Many other types of controlled release systems known to those of ordinary skill in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, e.g., polymer-based systems, such as polylactic and polyglycolic acid, plyanhydrides and polycaprolactone; porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides;

hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, e.g.,

Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2^nd Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014 and 6,932,983.

[00211] In some embodiments, pharmaceutical formulations are provided that include particles of ibrutinib and/or abexinostat, described herein and at least one dispersing agent or suspending agent for oral administration to a subject. The formulations may be a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained. [00212] Liquid formulation dosage forms for oral administration can be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2^nd Ed., pp. 754-757 (2002). In addition the liquid dosage forms may include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersions can further include a crystalline inhibitor.

[00213] The aqueous suspensions and dispersions described herein can remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. The homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition. In one embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute. In another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds. In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion.

[00214] Examples of disintegrating agents for use in the aqueous suspensions and dispersions include, but are not limited to, a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel^®, or sodium starch glycolate such as Promogel^® or Explotab^®; a cellulose such as a wood product,

methylcrystalline cellulose, e.g., Avicel^®, Avicel^® PH101, Avicel^®PH102, Avicel^® PH105, Elcema^® PI 00, Emcocel^®, Vivacel^®, Ming Tia^®, and Solka-Floc^®, methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium

carboxymethylcellulose (Ac-Di-Sol^®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crospovidone; a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a clay such as Veegum^® HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth; sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation- exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination starch; and the like. [00215] In some embodiments, the dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween ^® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone^®), and the carbohydrate-based dispersing agents such as, for example, hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC- L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone^®, e.g., S-630), 4-(l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68^®, F88^®, and F108^®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908^®, also known as Poloxamine 908^®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)). In other embodiments, the dispersing agent is selected from a group not comprising one of the following agents: hydrophilic polymers; electrolytes; Tween ^® 60 or 80; PEG;

polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat^® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium; methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulose phthalate; hydroxypropylmethyl- cellulose acetate stearate; non-crystalline cellulose; magnesium aluminum silicate;

triethanolamine; polyvinyl alcohol (PVA); 4-(l, l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68^®, F88^®, and F108^®, which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic 908^®, also known as Poloxamine 908^®).

[00216] Wetting agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, cetyl alcohol, glycerol monostearate, poly oxy ethylene sorbitan fatty acid esters (e.g., the commercially available Tweens^® such as e.g., Tween 20^® and Tween 80^® (ICI Specialty Chemicals)), and

polyethylene glycols (e.g., Carbowaxs 3350^® and 1450^®, and Carbopol 934^® (Union

Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphotidylcholine and the like.

[00217] Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

[00218] Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methyl cellulose, xanthan gum,

carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Plasdon^® S-630, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof. The concentration of the viscosity enhancing agent will depend upon the agent selected and the viscosity desired.

[00219] Examples of sweetening agents suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,

monoammonium glyrrhizinate (MagnaSweet^®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet^® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate- mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla- mint, and mixtures thereof. In one embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.001% to about 1.0% the volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.005% to about 0.5% the volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.01% to about 1.0% the volume of the aqueous dispersion.

[00220] In addition to the additives listed above, the liquid formulations can also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[00221] In some embodiments, the pharmaceutical formulations described herein can be self-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation. An advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. Additionally, water or the aqueous phase can be added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient. Thus, the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. SEDDS may provide improvements in the bioavailability of hydrophobic active ingredients. Methods of producing self-emulsifying dosage forms are known in the art and include, but are not limited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, each of which is specifically incorporated by reference.

[00222] It is to be appreciated that there is overlap between the above-listed additives used in the aqueous dispersions or suspensions described herein, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in formulations described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired. Intranasal Formulations

[00223] Intranasal formulations are known in the art and are described in, for example, U.S. Pat. Nos. 4,476, 116, 5,116,817 and 6,391,452, each of which is specifically incorporated by reference. Formulations that include ibrutinib and/or abexinostat, which are prepared according to these and other techniques well-known in the art are prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, Ansel, H. C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably these compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of these can be found in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, a standard reference in the field. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents may also be present. The nasal dosage form should be isotonic with nasal secretions.

[00224] For administration by inhalation described herein may be in a form as an aerosol, a mist or a powder. Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluorom ethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch.

Buccal Formulations

[00225] Buccal formulations may be administered using a variety of formulations known in the art. For example, such formulations include, but are not limited to, U.S. Pat. Nos.

4,229,447, 4,596,795, 4,755,386, and 5,739, 136, each of which is specifically incorporated by reference. In addition, the buccal dosage forms described herein can further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa. The buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherein the delivery is provided essentially throughout. Buccal drug delivery, as will be appreciated by those skilled in the art, avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver. With regard to the bioerodible (hydrolysable) polymeric carrier, it will be appreciated that virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with ibrutinib and/or abexinostat, and any other components that may be present in the buccal dosage unit. Generally, the polymeric carrier comprises hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as "carbomers" (Carbopol^®, which may be obtained from B.F. Goodrich, is one such polymer). Other components may also be incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, or gels formulated in a conventional manner.

Transdermal Formulations

[00226] Transdermal formulations described herein may be administered using a variety of devices which have been described in the art. For example, such devices include, but are not limited to, U.S. Pat. Nos. 3,598, 122, 3,598, 123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144, each of which is specifically incorporated by reference in its entirety.

[00227] The transdermal dosage forms described herein may incorporate certain pharmaceutically acceptable excipients which are conventional in the art. In one

embodiments, the transdermal formulations described herein include at least three

components: (1) a formulation of a compound of ibrutinib and abexinostat; (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, transdermal formulations can include additional components such as, but not limited to, gelling agents, creams and ointment bases, and the like. In some embodiments, the transdermal formulation can further include a woven or non-woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin. In other embodiments, the transdermal formulations described herein can maintain a saturated or supersaturated state to promote diffusion into the skin.

[00228] Formulations suitable for transdermal administration of compounds described herein may employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Still further, transdermal delivery of the compounds described herein can be accomplished by means of iontophoretic patches and the like.

Additionally, transdermal patches can provide controlled delivery of ibrutinib and

abexinostat. The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. An absorption enhancer or carrier can include absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

Injectable Formulations

[00229] Formulations that include a compound of ibrutinib and/or abexinostat, suitable for intramuscular, subcutaneous, or intravenous injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Formulations suitable for subcutaneous injection may also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin.

[00230] For intravenous injections, compounds described herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. For other parenteral injections, appropriate formulations may include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.

[00231] Parenteral injections may involve bolus injection or continuous infusion.

Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The pharmaceutical composition described herein may be in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

Other Formulations

[00232] In certain embodiments, delivery systems for pharmaceutical compounds may be employed, such as, for example, liposomes and emulsions. In certain embodiments, compositions provided herein can also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer),

poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

[00233] In some embodiments, the compounds described herein may be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[00234] The compounds described herein may also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

Dosing

[00235] In some embodiments, the amount of Btk inhibitor is administered from about 10 mg/day up to, and including, 1000 mg/day. In some embodiments, the amount of Btk inhibitor administered is from about 100 mg/day to about 1000 mg/day. In some

embodiments, the amount of Btk inhibitor administered is from about 40 mg/day to 900 mg/day, about 40 mg/day to 840 mg/day, about 80 mg/day to 600 mg/day, about 100 mg/day to 500 mg/day, or about 140 mg/day to 420 mg/day. In some embodiments, the amount of Btk inhibitor that is administered per day is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 180 mg, about 220 mg, about 260 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 560 mg, or about 840 mg. In some embodiments, the amount of Btk inhibitor administered is less than 10 mg/day. In some embodiments, the amount of Btk inhibitor administered is 560 mg/day. The Btk inhibitor may be ibrutinib.

[00236] In some embodiments, the Btk inhibitor is administered once per day, twice per day, three times per day, once daily, every other day, once a week, twice a week, three times a week, every other week, three times a month, once a month, or intermittently.

[00237] In some embodiments, ibrutinib is administered once per day, twice per day, three times per day, once daily, every other day, once a week, twice a week, three times a week, every other week, three times a month, once a month, or intermittently. In some

embodiments, ibrutinib is administered once per day. In some embodiments, ibrutinib is administered as a maintenance therapy. [00238] In some embodiments, the Btk inhibitor is administered via oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes. In some embodiments, the Btk inhibitor is administered orally.

[00239] In other embodiments, the amount of ibrutinib that is administered in combination with abexinostat is from about 140 mg/day up to and including 560 mg/day. In some embodiments, the amount of ibrutinib is about 140 mg/day, about 280 mg/day, about 420 mg/day, and/or about 560 mg/day.

[00240] In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is from about 10 mg to about 200 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is from about 20 mg to about 100 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is from about 40 mg to about 80 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is about 40 mg, 60 mg, and/or 80 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is less than about 10 mg or greater than about 200 mg. In some embodiments, the amount of HDAC inhibitor that is given to the patient per administration is from about 10 mg/day to about 200 mg/day. The HDAC inhibitor may be abexinostat or a salt thereof.

[00241] In some embodiments, the HDAC inhibitor is administered in cycles consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 28 days of consecutive administration of the HDAC inhibitor followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 28 with no administration of the HDAC inhibitor. In some embodiments, the HDAC inhibitor is administered in cycles consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 of consecutive administration of HDAC inhibitor followed by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days with no administration of the HDAC inhibitor.

[00242] In some embodiments, the HDAC inhibitor is not administered on consecutive days, i.e., the HDAC inhibitor may be administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and/or day 28, and administered on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and/or day 28.

[00243] In some embodiments, the HDAC inhibitor is administered once per day, twice per day, three times per day, once daily, every other day, once a week, twice a week, three times a week, every other week, three times a month, once a month, or intermittently. [00244] In some embodiments, the HDAC inhibitor is administered on 7 consecutive days of daily administration of HDAC inhibitor followed by 7 consecutive says of no

administration of HDAC inhibitor. In some embodiments, the 7 consecutive days of daily administration of HDAC inhibitor comprises daily administration of about 40 mg to about 80 mg of HDAC inhibitor. In some embodiments, the daily administration of about 40 mg to about 80 mg of HDAC inhibitor comprises twice daily administration of about 40 mg to about 80 mg of HDAC inhibitor. In some embodiments, the twice daily administration of about 40 mg to about 80 mg of HDAC inhibitor comprises administration of each dosage (or each administration) about 4-6 hours apart.

[00245] An exemplary dosing regimen includes twice daily administration of about a 40 mg, about 60 mg, or about 80 mg tablet or capsule of abexinostat. The first dosage of about a 40 mg, about 60 mg, or about 80 mg is administered at a first time, and the second dosage of about a 40 mg, about 60 mg, or about 80 mg is administered at a second time, wherein the second time is about 4-6 hours after the first time. The foregoing twice daily administration of abexinostat can continue for 7 consecutive days, which can then be followed by 7 consecutive days of no abexinostat administration. Meanwhile, ibrutinib (at a dosage of 560 mg) can be administered daily, and its administration is continued even during the 7 consecutive day period when abexinostat is not administered. In some embodiments, the administration of abexinostat can be initiated at a dosage of, for example, 80 mg per administration (with administrations being, for example, twice a day). That administration can be changed to, for example, 40 mg the next day (per administration). Accordingly, the dosage of abexinostat can be de-escalated. For example, the dosage of abexinostat may start at 80 mg, and may be lowered for subsequent administrations. In some embodiments, the HDAC inhibitor may be administered for 14 consecutive days, followed by 7 consecutive days of no administration of the HDAC inhibitor. In some embodiments, less than about 40 mg of HDAC may be administered per administration, or greater than 80 mg of HDAC inhibitor may be administered per administration. In some embodiments, 20 mg of HDAC inhibitor may be administered.

[00246] In some embodiments, ibrutinib is administered once per day, twice per day, or three times per day. In some embodiments, ibrutinib is administered once per day. In some embodiments, abexinostat is administered once per day, twice per day, or three times per day. In some embodiments, abexinostat is administered once per day. In some embodiments, ibrutinib and abexinostat are co-administered (e.g., in a single dosage form), once per day. In some embodiments, ibrutinib and abexinostat are administered as a maintenance therapy. [00247] In some embodiments, a HDAC inhibitor (i.e., abexinostat or a salt thereof) and a BCL-2 inhibitor (i.e., ABT-199) are co-administered. The HDAC inhibitor may be administered as disclosed herein. In some embodiments, the BCL-2 inhibitor is administered orally. In some embodiments, the BCL-2 inhibitor is administered daily. In some

embodiments, the BCL-2 inhibitor is administered at a dosage of about 10 mg to about 1000 mg per day. In some embodiments, the BCL-2 inhibitor is administered at a dosage of about 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or about 500 mg. In some embodiments, the BCL-2 inhibitor is not administered daily, or is administered as needed. In some embodiments, the HDAC inhibitor (i.e., abexinostat or a salt thereof), the BCL-2 inhibitor (i.e., ABT-199), and the Btk inhibitor (i.e., ibrutinib) are co-administered. For example, each of the three compounds may be administered in a cycle (at the same or different time during the cycle).

[00248] In some embodiments, the compositions disclosed herein are administered for prophylactic, therapeutic, or maintenance treatment. In some embodiments, the compositions disclosed herein are administered for therapeutic applications. In some embodiments, the compositions disclosed herein are administered for therapeutic applications. In some embodiments, the compositions disclosed herein are administered as a maintenance therapy, for example for a patient in remission.

[00249] In some embodiments, it may be determined that it would be beneficial to the patient to at the onset administer both Btk inhibitor and HDAC inhibitor, rather than try Btk inhibitor prior to administration of the combination of Btk inhibitor and HDAC inhibitor. For example, in some instance, it may be determined (i.e., by analyzing biomarker expression, presence, or absence) that the individual is at risk for developing resistance to Btk inhibitor such as ibrutinib. In these instance, it may be optimal to administer both Btk inhibitor and HDAC inhibitor at the onset, rather than administer a course of Btk inhibitor alone.

[00250] In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compounds may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday may be from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[00251] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[00252] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, the severity of the disease, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, or from about 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00253] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[00254] 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 condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[00255] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

Kits/Article of Manufacture

[00256] Disclosed herein, in certain embodiments, are kits and articles of manufacture for use with one or more methods described herein. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[00257] The articles of manufacture provided herein contain packaging materials.

Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.

[00258] For example, the container(s) include ibrutinib, optionally in a composition or in combination with abexinostat as disclosed herein. Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.

[00259] A kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[00260] In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

EXAMPLES

[00261] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

[00262] Example 1. Abexinostat increased ibrutinib sensitivity in GCB-DLBCL cell lines

[00263] GCB-DLBCL cell lines HT, SUDHL4, SUDHL6, SUDHL10, WSU- HL, SUDHL5, LY8, and SUDHL8 were used for this experiment.

[00264] FIGS. 1-8 illustrate graphical representations of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the growth of GCB-DLBCL cell lines.

Abexinostat was administered at a concentration of 0 nM (represented by a square) and a concentration of 200 nM (represented by a triangle). As is shown, addition of abexinostat enhanced ibrutinib sensitivity in the HT, SUDHL4, SUDHL6, SUDHL10, WSU-NHL, SUDHL5, LY8, and SUDHL8 cell lines. Additionally, ibrutinib and abexinostat displayed synergistic growth suppression in these cell lines.

[00265] FIG. 9 is a chart showing the EC50 (μΜ) of ibrutinib alone, or in combination with abexinostat, in GCB-DLBCL cell lines. As is shown, the EC50 of ibrutinib is lowered with the addition of abexinostat. [00266] Example 2. Abexinostat increased ibrutinib sensitivity in follicular lymphoma cell lines

[00267] Follicular lymphoma cell lines SC-1, WSU-FSCCL, NFS 1.0 C-l, and DoHH2 were used for this experiment.

[00268] FIGS. 10-13 illustrate graphical representations of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the growth of follicular lymphoma cell lines. As is shown, addition of abexinostat enhanced ibrutinib sensitivity in these cell lines.

Additionally, ibrutinib and abexinostat displayed synergistic growth suppression in these cell lines.

[00269] FIG. 14 is a chart showing the EC50 (μΜ) of ibrutinib alone, or in combination with abexinostat, in follicular lymphoma cell lines. As is shown, the EC50 of ibrutinib is lowered with the addition of abexinostat.

[00270] Example 3. Relative HDAC gene expression

[00271] Different follicular lymphoma (FL) cell lines were used for this experiment. The human FL cell lines used were: SC-1, WSU-FSCCL, DoHH2, and HF-1.

[00272] FIG. 15 is a graphical representation of relative gene expression of HDAC 1, HDAC2, HDAC3, HDAC4, HDAC 5, HDAC6, HDAC7, HDAC 8, HDAC9, HDAC10, and HDAC 11 in human FL cell lines.

[00273] Example 4. Abexinostat enhanced ibrutinib sensitivity in mantle cell lines

[00274] Different mantle cell lymphoma lines were used for this experiment. The mantle cell lines included: JEKO-1, MAVER-1, and JVM-2.

[00275] FIGS. 16A, 16C, and 16E illustrate graphical representations of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the growth of three mantle cell lymphoma cell lines. Abexinostat was administered at (3) different concentrations: 12.5nM (shown in green), 25nM (shown in blue), and 50nM (shown in red) in each cell line. As is shown, addition of abexinostat enhanced ibrutinib sensitivity in the JEKO-1, MAVER-1, and JVM-2 cell lines. Additionally, ibrutinib and abexinostat displayed synergistic growth suppression in these cell lines.

[00276] FIGS. 16B, 16D, and 16F illustrate a graphical representation of the combination index (CI) for the combination of ibrutinib and abexinostat in the JEKO-1 cell line (FIG. 16B), the MAVER-1 cell line (FIG. 16D), and the JVM-2 cell line (FIG, 16F). CI is a quantitative description of the interaction property of the combination of the two drugs. In general, the combination is described as synergistic (CI<1), additive (CI=1), or antagonistic (CI>1). FIGS. 16A, 16C, and 16E illustrate graphical representations of the effect of ibrutinib, or the combination of ibrutinib and abexinostat, on the growth of the JEKO-1 cell line (FIG. 16B), the MAVER-1 cell line (FIG. 16D), and the JVM-2 cell line (FIG. 16F). As shown herein, the combination of ibrutinib and abexinostat showed synergism in the JEKO-1, MAVER-1, and JVM-2 mantle cell lines.

[00277] Example 5. Synergistic growth suppression of ibrutinib and abexinostat in mantle cell lines.

[00278] Different mantle cell lymphoma cell lines were used for this experiment. The mantle cell lines included: JEKO-1, MAVER-1, and JVM-2.

[00279] The CellTiter-Glo® Luminescent Cell Viability assay was performed according to manufacturer's instructions. Briefly, cells were seeded at 8,000-10,000 cells/well in a 96- well plate in the presence of ibrutinib and abexinostat, either individually or in combination, for 3 days. The mantle cell lines tested were JEKO-1 (FIGS. 17A-B); MAVER-1 (FIGS. 17C-D); and JVM-2 (FIGS. 17E-F). Ibrutinib concentrations were from 5μΜ and diluted from that concentration. Abexinostat concentrations were from .1 μΜ and diluted from that concentration. The number of viable cells in culture was determined by the quantification of ATP present, which was proportional to the luminal signal detected. Synergy scores and isobolograms were calculated by the Chance Analyzer (Horizon CombinatoRx). As shown herein, based on the isobologram (FIGS. 17B, 17D, and 17F), and based on the data points and the lines falling on the left side of the diagonal line, ibrutinib had synergy with abexinostat in each of the JEKO-1, MAVER-1, and JVM-2 mantle cell lymphoma cell lines.

[00280] Example 6. ABT-199 enhanced abexinostat sensitivity in follicular lymphoma cell lines

[00281] Follicular lymphoma cell lines SC-1, WSU-FSCCL, and F S1.0 were used for this experiment.

[00282] FIGS. 18A-18C illustrate graphical representations of the effect of abexinostat (PCI-24781), or the combination of abexinostat and ABT-199, in SC-1 (FIG. 18A); WSU- FSCCL (FIG. 18B); and FS1.0 c-1 cell lines. Two different concentrations of ABT-199 were used in each cell line in addition to a vehicle (OnM of ABT-199 and shown as upside- down triangle): FIG. 18A: 56nM (shown as a square) and 167nM (shown as a triangle); FIG. 18B: 167nM (shown as a square) and 500 nM (shown as a triangle); FIG. 18C: 167nM (shown as a square) and 500 nM (shown as a triangle). As is shown herein, ABT-199 increased abexinostat sensitivity in these follicular lymphoma cell lines.

[00283] FIG. 18D shows the EC50 of abexinostat, either alone or in combination with ABT-199, in SC-1, WSU-FSCCL, and FSl .OC-1 (mouse) follicular lymphoma cell lines. As is shown, addition of ABT-199 lowered the EC50 of abexinostat in each of the follicular lymphoma cell lines.

[00284] Example 7. ABT-199 enhanced sensitivity of the combination of ibrutinib and abexinostat or the combination of ibrutinib and ABT-199 in GCB-DLBCL cell lines.

[00285] GCB-DLBCL cell lines SUDHL4, SUDHL10, DLCL-2, and SUDHL6 were used for this experiment.

[00286] FIGS. 19A-B illustrate graphical representations of ibrutinib alone (represented by a square) or in the following combinations: (1) ibrutinib and ABT-199 (represented by a triangle); (2) ibrutinib and abexinostat (represented by an upside-down triangle); or (3) ibrutinib, ABT-199, and abexinostat (represented by a diamond) in the SUDHL4 GCB- DLBCL cell line. Two different concentrations of ABT-199 were used: 30nM (FIG. 19A); and 100 nM (FIG. 19B). The abexinostat concentration used for these experiments was 500nM. As shown herein, the ibrutinib sensitivity was increased following the addition of ABT-199 and abexinostat.

[00287] FIGS. 19C-D illustrate graphical representations of ibrutinib alone (represented by a square) or in the following combinations: (1) ibrutinib and ABT-199 (represented by a triangle); (2) ibrutinib and abexinostat (represented by an upside-down triangle); or (3) ibrutinib, ABT-199, and abexinostat (represented by a diamond) in the SUDHL10 GCB- DLBCL cell line. Two different concentrations of ABT-199 were used: ΙΟηΜ (FIG. 19C); and ΙΟΟηΜ (FIG. 19D). The abexinostat concentration used for these experiments was 500nM. As shown herein, the ibrutinib sensitivity was increased following the addition of ABT-199 and abexinostat.

[00288] FIGS. 19E-F illustrate graphical representations of ibrutinib alone (represented by a square) or in the following combinations: (1) ibrutinib and ABT-199 (represented by a triangle); (2) ibrutinib and abexinostat (represented by an upside-down triangle); or (3) ibrutinib, ABT-199, and abexinostat (represented by a diamond) in the DLCL-2 GCB- DLBCL cell line. Two different concentrations of ABT-199 were used: ΙΟηΜ (FIG. 19E); and 30nM (FIG. 19F). The abexinostat concentration used for these experiments was 500nM. As shown herein, ibrutinib sensitivity was increased following the addition of ABT-199 and abexinostat.

[00289] FIG. 19G illustrates a graphical representation of ibrutinib alone (represented by a square) or in the following combinations: (1) ibrutinib and ABT-199 (represented by a triangle); (2) ibrutinib and abexinostat (represented by an upside-down triangle); or (3) ibrutinib, ABT-199, and abexinostat (represented by a diamond) in the SUDHL6 cell line. 30nM of ABT-199 and 167nM of abexinostat were used in these experiments. As shown herein, the ibrutinib sensitivity was increased following the addition of ABT-199 and abexinostat.

[00290] The examples and embodiments described herein are illustrative and various modifications or changes suggested to persons skilled in the art are to be included within this disclosure. As will be appreciated by those skilled in the art, the specific components listed in the above examples may be replaced with other functionally equivalent components, e.g., diluents, binders, lubricants, fillers, and the like.

Claims

What is claimed is:

1. A method of treating a lymphoma comprising co-administering to an individual in need thereof a Btk inhibitor and an HDAC inhibitor compound.

2. A method of treating a lymphoma comprising co-administering to an individual in need thereof ibrutinib and abexinostat or a salt thereof.

3. The method of claim 2, wherein the co-administration provides a synergistic therapeutic effect compared to administration of ibrutinib or abexinostat or a salt thereof alone.

4. The method of any one of claims 2-3, wherein the salt of abexinostat is abexinostat HC1.

5. The method of any one of claims 2-3 wherein the salt of abexinostat is abexinostat tosylate.

6. The method of any one of claims 2-6, wherein the lymphoma is relapsed and/or refractory.

7. The method of any one of claims 2-6, wherein the lymphoma is a non-Hodgkin's lymphoma.

8. The method of any one of claims 2-6, wherein the lymphoma is a Hodgkin lymphoma.

9. The method of claim 7, wherein the non-Hodgkin's lymphoma is a B-cell lymphoma.

10. The method of claim 9, wherein the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL).

11. The method of claim 10, wherein the DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL).

12. The method of claim 11, wherein the ABC-DLBCL is characterized by a mutation in MYD88.

13. The method of claim 12, wherein the mutation is at position 265 of MYD88.

14. The method of claim 13, wherein the mutation is an L265P mutation.

15. The method of claim 11, wherein the B-cell lymphoma is follicular lymphoma.

16. The method of claim 11, wherein the B-cell lymphoma is mantle cell lymphoma.

17. The method of claim 11, wherein the B-cell lymphoma is marginal zone B-cell

oma.

The method of claim 11, wherein the B-cell lymphoma is Burkitt lymphoma.

19. The method of claim 11, wherein the B-cell lymphoma is Waldenstrom macroglobulinemia.

20. The method of claim 11, wherein the B-cell lymphoma is germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL).

21. The method of claim 7, wherein the non-Hodgkin's lymphoma is a T-cell lymphoma.

22. The method of claim 21, wherein the T-cell lymphoma is a peripheral T-cell lymphoma.

23. The method of any one of claims 2-22, wherein ibrutinib is administered orally.

24. The method of any one of claims 2-23, wherein abexinostat or a salt thereof is administered orally.

25. The method of any one of claims 2-24, wherein ibrutinib is administered daily.

26. The method of any one of claims 2-25, wherein ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day.

27. The method of claim 26, wherein ibrutinib is administered at a dosage of about 560 mg/day.

28. The method of any one of claims 2-27, wherein abexinostat or a salt thereof is administered in cycles consisting of 7 days of consecutive administration of abexinostat or a salt thereof followed by 7 consecutive days with no administration of abexinostat or a salt thereof.

29. The method of claim 28, wherein the cycles of 7 consecutive days of daily

administration of abexinostat or a salt thereof comprises daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof.

30. The method of claim 29, wherein the daily administration of about 40 mg to about 80 mg of abexinostat or salt thereof comprises twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof.

31. The method of claim 30, wherein the twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises administration of each dosage about 4- 6 hours apart.

32. A composition comprising a therapeutically effective amount of ibrutinib, abexinostat or a salt thereof, and a pharmaceutically acceptable excipient, for use in the treatment of a lymphoma.

33. The composition of claim 32, wherein the composition provides a synergistic therapeutic effect compared to administration of ibrutinib or the abexinostat or a salt thereof alone.

34. The composition of claim 33, wherein the salt of abexinostat is abexinostat HC1.

35. The composition of claim 33, wherein the salt of abexinostat is abexinostat tosylate.

36. The composition of any one of claims 32-35, wherein the composition is in a combined dosage form.

37. The composition of any one of claims 32-35, wherein the composition is in a separate dosage form.

38. The composition of any one of claims 32-35, wherein the composition is in the form of a capsule.

39. The composition of any one of claims 32-35, wherein the composition is in the form of a tablet.

40. The composition of any one of claims 32-39, further comprising zinc.

41. The composition of any one of claims 32-40, wherein the lymphoma is relapsed and/or refractory.

42. The composition of any one of claims 32-41, wherein the lymphoma is a non- Hodgkin's lymphoma.

43. The composition of any one of claims 32-40, wherein the lymphoma is a Hodgkin lymphoma.

44. The composition of claim 42, wherein the non-Hodgkin's lymphoma is a B-cell lymphoma.

45. The composition of claim 44, wherein the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL).

46. The composition of claim 45, wherein the DLBCL is activated B-cell diffuse large B- cell lymphoma (ABC-DLBCL).

47. The composition of claim 46, wherein the ABC-DLBCL is characterized by a mutation in MYD88.

48. The composition of claim 47, wherein the mutation is at position 265 of MYD88.

49. The composition of claim 48, wherein the mutation is an L265P mutation.

50. The composition of claim 44, wherein the B-cell lymphoma is follicular lymphoma.

51. The composition of claim 44, wherein the B-cell lymphoma is mantle cell lymphoma.

52. The composition of claim 44, wherein the B-cell lymphoma is marginal zone B-cell lymphi oma.

53. The composition of claim 44, wherein the B-cell lymphoma Burkitt lymphoma.

54. The composition of claim 44, wherein the B-cell lymphoma is Waldenstrom macroglobulinemia.

55. The composition of claim 42, wherein the non-Hodgkin's lymphoma is a T-cell lymphoma.

56. The composition of claim 44, wherein the B-cell lymphoma is germinal center B cell diffuse large B-cell lymphoma (GCB-DLBCL).

57. The composition of claim 55, wherein the T-cell lymphoma is a peripheral T-cell lymphoma.

58. The composition of any one of claims 35-57, wherein the combination of ibrutinib and abexinostat is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of abexinostat alone.

59. The composition of any one of claims 32-58, wherein the combination of ibrutinib and abexinostat is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% more efficacious than administration of ibrutinib alone.

60. A method of reducing the development or preventing the development of ibrutinib resistance in an individual in need thereof having a lymphoma comprising administering to the individual a combination comprising ibrutinib and abexinostat or a salt thereof.

61. The method of claim 60, wherein the combination provides a synergistic therapeutic effect compared to administration of ibrutinib or abexinostat or a salt thereof alone.

62. The method of any one of claims 60-61, wherein the salt of abexinostat is abexinostat HC1.

63. The method of claim 60-61, wherein the salt of abexinostat is a tosylate salt.

64. The method of any one of claims 60-63, wherein the lymphoma is relapsed and/or refractory.

65. The method of any one of claims 60-64, wherein the lymphoma is a non-Hodgkin's lymphoma.

66. The method of any one of claims 60-64, wherein the lymphoma is a Hodgkin lymphoma.

67. The method of claim 65, wherein the non-Hodgkin's lymphoma is a B-cell lymphoma.

68. The method of claim 67, wherein the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL).

69. The method of claim 68, wherein the DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC -DLBCL).

70. The method of claim 69, wherein the ABC-DLBCL is characterized by a mutation in MYD88.

71. The method of claim 70, wherein the mutation is at position 265 of MYD88.

72. The method of claim 71, wherein the mutation is an L265P mutation.

73. The method of claim 67, wherein the B-cell lymphoma is follicular lymphoma.

74. The method of claim 67, wherein the B-cell lymphoma is mantle cell lymphoma.

75. The method of claim 67, wherein the B-cell lymphoma is marginal zone B-cell lymphoma.

76. The method of claim 67, wherein the B-cell lymphoma is Burkitt lymphoma.

77. The method of claim 67, wherein the B-cell lymphoma is Waldenstrom

macroglobulinemia.

78. The method of claim 65, wherein the non-Hodgkin's lymphoma is a T-cell lymphoma.

79. The method of claim 78, wherein the T-cell lymphoma is a peripheral T-cell lymphoma.

80. The method of any one of claims 60-79, wherein ibrutinib is administered orally.

81. The method of any one of claims 60-80, wherein abexinostat or a salt thereof is administered orally.

82. The method of any one of claims 60-81, wherein ibrutinib is administered daily.

83. The method of any one of claims 60-82, wherein ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day.

84. The method of claim 83, wherein ibrutinib is administered at a dosage of about 560 mg/day.

85. The method of any one of claims 60-84, wherein abexinostat or a salt thereof is administered in cycles consisting of 7 days of consecutive administration of abexinostat or a salt thereof followed by 7 consecutive days with no administration of abexinostat or a salt thereof.

86. A method of treating a Btk inhibitor-resistant lymphoma comprising administering to an individual in need thereof a combination comprising Btk inhibitor and HDAC inhibitor.

87. The method of claim 86, wherein the Btk inhibitor is ibrutinib.

88. The method of any one of claims 86-87, wherein the HDAC inhibitor is abexinostat or a salt thereof.

89. The method of claim 88, wherein the combination provides a synergistic therapeutic effect compared to administration of ibrutinib or abexinostat or a salt thereof alone.

90. The method of any one of claims 88-89, wherein the salt of abexinostat is abexinostat HC1.

91. The method of any one of claims 88-89, wherein the salt of abexinostat is abexinostat tosylate.

92. The method of any one of claims 86-91, wherein the lymphoma is relapsed and/or refractory.

93. The method of any one of claims 86-91, wherein the lymphoma is a non-Hodgkin's lymphoma.

94. The method of any one of claims 86-91, wherein the lymphoma is a Hodgkin lymphoma.

95. The method of claim 93, wherein the non-Hodgkin's lymphoma is a B-cell lymphoma.

96. The method of claim 95, wherein the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL).

97. The method of claim 96, wherein the DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL).

98. The method of claim 97, wherein the ABC-DLBCL is characterized by a mutation in MYD88.

99. The method of claim 98, wherein the mutation is at position 265 of MYD88.

100. The method of claim 99, wherein the mutation is an L265P mutation.

101. The method of claim 95, wherein the B-cell lymphoma is follicular lymphoma.

102. The method of claim 95, wherein the B-cell lymphoma is mantle cell lymphoma.

103. The method of claim 95, wherein the B-cell lymphoma is marginal zone B-cell lymphoma.

104. The method of claim 95, wherein the B-cell lymphoma is Burkitt lymphoma.

105. The method of claim 95, wherein the B-cell lymphoma is Waldenstrom

macroglobulinemia.

106. The method of claim 95, wherein the B-cell lymphoma is germinal center B-cell diffuse large B-cell lymphoma (GCB -DLBCL).

107. The method of claim 93, wherein the non-Hodgkin's lymphoma is a T-cell lymphoma.

108. The method of claim 107, wherein the T-cell lymphoma is a peripheral T-cell lymphoma.

109. The method of any one of claims 87-109, wherein ibrutinib is administered orally.

110. The method of any one of claims 88-109, wherein abexinostat or a salt thereof is administered orally.

111. The method of any one of claims 87-109, wherein ibrutinib is administered daily.

112. The method of any one of claims 87-111, wherein ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day.

113. The method of claim 112, wherein ibrutinib is administered at a dosage of about 560 mg/day.

114. The method of any one of claims 88-113, wherein abexinostat or a salt thereof is administered in cycles consisting of 7 days of consecutive administration of abexinostat or a salt thereof followed by 7 consecutive days with no administration of abexinostat or a salt thereof.

115. The method of claim 114, wherein the cycles of 7 consecutive days of daily administration of abexinostat or a salt thereof comprises daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof.

116. The method of claim 115, wherein the daily administration of about 40 mg to about 80 mg of abexinostat or salt thereof comprises twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof.

117. The method of claim 116, wherein the twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises administration of each dosage about 4- 6 hours apart.

118. The method of any one of claims 1-117, wherein the lymphoma is not a small lymphocytic lymphoma (SLL).

119. A method of treating a diffuse large B-cell lymphoma (DLBCL) comprising co-administering to an individual in need thereof a Btk inhibitor and an HDAC inhibitor compound.

120. A method of treating a follicular lymphoma comprising

co-administering to an individual in need thereof a Btk inhibitor and an HDAC inhibitor compound.

121. A method of treating a T-cell lymphoma comprising co-administering to an individual in need thereof a Btk inhibitor and an HDAC inhibitor compound.

122. A method of treating a hematological malignancy co-administering to an individual in need thereof abexinostat or a salt thereof and a BCL-2 inhibitor.

123. The method of claim 122, wherein abexinostat or a salt thereof and the BCL-2

inhibitor are co-administered simultaneously, sequentially, or intermittently.

124. The method of any one of claims 122-123, wherein the co-administration provides a synergistic therapeutic effect compared to the administration of abexinostat or a salt thereof or the BCL-2 inhibitor alone.

125. The method of claim 124, wherein the BCL-2 inhibitor is ABT-199.

126. The method of any one of claims 122-125, further comprising co-administering a Btk inhibitor.

127. The method of claim 126, wherein abexinostat or a salt thereof, the BCL-2 inhibitor, and the Btk inhibitor are co-administered simultaneously, sequentially, or intermittently.

128. The method of any one of claims 126-127, wherein the co-administration of

abexinostat or a salt thereof, the BCL-2 inhibitor, and the Btk inhibitor provides a synergistic therapeutic effect compared to one or more of the following: the

administration of the Btk inhibitor alone, the abexinostat or a salt thereof alone, the combination of the Btk inhibitor and the BCL-2 inhibitor, the combination of abexinostat or a salt thereof and the BCL-2 inhibitor, and/or the combination of the Btk inhibitor and abexinostat or a salt thereof.

129. The method of any one of claims 122-128, wherein the Btk inhibitor is ibrutinib.

130. The method of any one of claims 122-129, wherein the salt of abexinostat is

abexinostat HC1, abexinostat tosylate, or a combination thereof.

131. The method of any one of claims 122-130, wherein the hematological malignancy is a relapsed or refractory hematological malignancy.

132. The method of any one of claims 122-130, wherein the hematological malignancy is a treatment naive hematological malignancy.

133. The method of any one of claims 122-130, wherein the hematological malignancy is a lymphoma.

134. The method of claim 133, wherein the lymphoma is a non-Hodgkin lymphoma.

135. The method of claim 133, wherein the lymphoma is a Hodgkin lymphoma.

136. The method of claim 134, wherein the non-Hodgkin's lymphoma is a B-cell

lymphoma.

137. The method of claim 136, wherein the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL).

138. The method of claim 137, wherein the DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC -DLBCL).

139. The method of claim 138, wherein the ABC-DLBCL is characterized by a mutation in MYD88.

140. The method of claim 139, wherein the mutation is at position 265 of MYD88.

141. The method of claim 140, wherein the mutation is an L265P mutation.

142. The method of claim 136, wherein the B-cell lymphoma is follicular lymphoma.

143. The method of claim 136, wherein the B-cell lymphoma is mantle cell lymphoma.

144. The method of claim 136, wherein the B-cell lymphoma is marginal zone B-cell lymphoma.

145. The method of claim 136, wherein the B-cell lymphoma is Burkitt lymphoma.

146. The method of claim 136, wherein the B-cell lymphoma is Waldenstrom

macroglobulinemia.

147. The method of claim 136, wherein the B-cell lymphoma is germinal B-cell diffuse large B-cell lymphoma (GCB-DLBCL).

148. The method of claim 134, wherein the non-Hodgkin's lymphoma is a T-cell

lymphoma.

149. The method of claim 134, wherein the non-Hodgkin's lymphoma is a peripheral T- cell lymphoma.

150. The method of claim 134, wherein the non-Hodgkin's lymphoma is a cutaneous T- cell lymphoma.

151. The method of any one of claims 129-150, wherein ibrutinib is administered orally.

152. The method of any one of claims 129-151, wherein abexinostat or a salt thereof is administered orally.

153. The method of any one of claims 129-152, wherein ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day.

154. The method of claim 153, wherein abexinostat or a salt thereof is administered in cycles consisting of 7 consecutive days of daily administration of abexinostat or a salt thereof followed by 7 consecutive days with no administration of abexinostat or a salt thereof.

155. The method of claim 154, wherein the cycles of 7 consecutive days of daily

administration of abexinostat or a salt thereof comprises the daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof.

156. The method of claim 155, wherein the daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof.

157. The method of claim 156, wherein the twice daily administration of about 40 mg to about 80 mg of abexinostat or a salt thereof comprises administration of each dosage about 4-6 hours apart.

158. A method of treating a CNS malignancy in an individual in need thereof comprising administering to an individual in need thereof abexinostat or a salt thereof.

159. The method of claim 158, wherein the abexinostat or a salt thereof is abexinostat HCl.

160. The method of claim 158, wherein the abexinostat or a salt thereof is abexinostat tosylate.

161. The method of claim 158, wherein the abexinostat or a salt thereof is a combination of abexinostat HCl and abexinostat tosylate.

162. The method of any one of claims 158-161, wherein the CNS malignancy is a primary CNS lymphoma.

163. The method of any one of claims 158-161, wherein the CNS malignancy is a

secondary CNS lymphoma.

164. A method of treating a cutaneous T-cell lymphoma in an individual in need thereof comprising administering to an individual in need thereof abexinostat or a salt thereof.

165. The method of claim 164, wherein the abexinostat or a salt thereof is abexinostat HCl.

166. The method of claim 164, wherein the abexinostat or salt thereof is abexinostat

tosylate.

167. The method of any one of claims 164, wherein the abexinostat or a salt thereof is a combination of abexinostat HCl and abexinostat tosylate.