WO2016123504A1

WO2016123504A1 - Btk inhibitor combinations and multidrug-resistance

Info

Publication number: WO2016123504A1
Application number: PCT/US2016/015697
Authority: WO
Inventors: Zhe-sheng CHEN; Atish PATEL; Hui Zhang
Original assignee: Pharmacyclics Llc
Priority date: 2015-01-30
Filing date: 2016-01-29
Publication date: 2016-08-04

Abstract

Disclosed herein are methods for treating a cancer characterized by an overexpression of an ABC transporter by administration of a combination of a Btk inhibitor and paclitaxel.

Description

BTK INHIBITOR COMBINATIONS AND MULTIPLEDRUG-RESISTANCE

CROSS-REFERENCE

[0001] This application claims the benefit of priority U.S. provisional patent application no. 62/110,301, filed on January 15, 2015, herein incorporated by reference in its entirety.

BACKGROUND OF INVENTION

[0002] Multi-drug resistance is a process that occurs when cancer cells become resistant to an array of anticancer agents. Members of the ABC transporter such as the ATP- Binding Cassette Subfamily B member 1 (ABCBl) and Subfamily C member 10 (ABCCIO) have been implicated to participate in the resistance mechanism. Ibrutinib, an irreversible Bruton's Tyrosine kinase (BTK) and Interleukin-2-inducible kinase (ITK) inhibitor, might be useful for inhibiting ABC transporters such as ABCBl and ABCCIO and thereby ameliorating the resistance mechanism.

SUMMARY OF THE INVENTION

[0003] Disclosed herein, in certain embodiments, is a method of treating a cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a BTK inhibitor and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1 (ABCB l), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCB l . In some embodiments, the ABC-transporter is ABCCIO. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer,

gastroenterological cancer or melanoma. In some embodiments, the cancer is a hematologic cancer. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B- cell malignancy. In some embodiments, the B-cell malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastasized cancer. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, ibrutinib is administered once a day, two times per day, three times per day, four times per day, or five times per day. 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 orally. In some embodiments, ibrutinib and paclitaxel are administered simultaneously, sequentially or intermittently. In some embodiments, the method further comprises administering an additional anticancer agent.

[0004] Disclosed herein, in certain embodiments, is a method of treating a cancer characterized by an overexpression of ATP -binding cassette subfamily B member 1, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a BTK inhibitor and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some embodiments, the ABC-transporter is ATP- binding cassette subfamily B member 1 (ABCBl), ATP -binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer or melanoma. In some embodiments, the cancer is a hematologic cancer. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastasized cancer. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, ibrutinib is administered once a day, two times per day, three times per day, four times per day, or five times per day. 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 orally. In some embodiments, ibrutinib and paclitaxel are administered simultaneously, sequentially or intermittently. In some embodiments, the method further comprises administering an additional anticancer agent.

[0005] Disclosed herein, in certain embodiments, is a method of treating a cancer characterized by an overexpression of ATP -binding cassette subfamily C member 10, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a Btk inhibitor and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP -binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer or melanoma. In some embodiments, the cancer is a hematologic cancer. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastasized cancer. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, ibrutinib is administered once a day, two times per day, three times per day, four times per day, or five times per day. 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 orally. In some embodiments, ibrutinib and paclitaxel are administered simultaneously, sequentially or intermittently. In some embodiments, the method further comprises administering an additional anticancer agent.

[0006] Disclosed herein, in certain embodiments, is a method of treating a paclitaxel- resistant cancer comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a Btk inhibitor and paclitaxel. In some embodiments, the paclitaxel-resistant cancer is characterized by an overexpression of an ABC-transporter. In some embodiments, the ABC-transporter is ATP -binding cassette subfamily B member 1 (ABCB l), ATP -binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP -binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCB l . In some embodiments, the ABC-transporter is ABCCIO. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some

embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer or melanoma. In some embodiments, the cancer is a hematologic cancer. In some

embodiments, the hematologic cancer is a leukemia, a lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's

macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastasized cancer. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, ibrutinib is administered once a day, two times per day, three times per day, four times per day, or five times per day. 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 orally. In some embodiments, ibrutinib and paclitaxel are administered simultaneously, sequentially or intermittently. In some embodiments, the method further comprises administering an additional anticancer agent.

[0007] Disclosed herein, in certain embodiments, is use of a combination comprising a BTK inhibitor and paclitaxel for treatment of a cancer characterized by an overexpression of an ABC transporter. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1 (ABCB l), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCB l . In some embodiments, ABC-transporter is ABCCIO. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer or melanoma. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the cancer is relapsed or refractory cancer. In some embodiments, the cancer is metastasized cancer. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, ibrutinib is administered once a day, two times per day, three times per day, four times per day, or five times per day. 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 orally. In some embodiments, ibrutinib and paclitaxel are administered administered simultaneously, sequentially or intermittently. In some embodiments, an additional anticancer agent is administered.

[0008] Disclosed herein, in certain embodiments, is use of a therapeutically effective amount of a combination comprising a Btk inhibitor and paclitaxel for treatment of a paclitaxel-resistant cancer. In some embodiments, the paclitaxel-resistant cancer is characterized by an overexpression of an ABC-transporter. In some embodiments, ABC- transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer or melanoma. In some embodiments, the cancer is a hematologic cancer. In some embodiments, hematologic cancer is a leukemia, a lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is a metastasized cancer. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, ibrutinib is administered once a day, two times per day, three times per day, four times per day, or five times per day.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] 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:

[0010] Fig. lA-Fig. ID illustrate cytotoxicity assays of ibrutinib alone in the drug-resistant and parental cells. Cell survival percentage was measured after treatment with ibrutinib for 72 h in parental and drug resistant cell lines: KB-3-1 and KB-C2 cells (A), K562 and

K562/A02 cells (B), HEK293/pcDNA3.1 and ABCBl-overexpressing HEK293/ABCB1 cells (C), HEK293/pcDNA3.1 and ABCCIO- overexpressing HEK293/ABCC 10 cells (D). Each point shows the mean ± standard deviation (SD) for independent determinations in triplicate. All these experiments were repeated three times.

[0011] Fig. 2 illustrates ibrutinib which enhances the effect of paclitaxel in ABCBl- overexpressing cells. [0012] Fig. 3 illustrates ibrutinib which enhances the effect of paclitaxel and docetaxel in ABCC10- overexpressing cells.

[0013] Fig. 4 illustrates ibrutinib which sensitizes ABCBl - overexpressing cells to vincristine and colchicine.

[0014] Fig. 5 illustrates ibrutinib which sensitizes ABCC10- overexpressing cells to vincristine.

[0015] Fig. 6A - Fig. 6D illustrate the effect of ibrutinib on the accumulation and efflux of [¾] -paclitaxel in ABCBl- or ABCC10- overexpressing cells. Fig 6A shows that ibrutinib effectively increased the accumulation of [³H] -paclitaxel in B-C2 cells. Columns are the mean of triplicate determinations; bars represent SDs. Fig. 6B shows the effects of ibrutinib on the efflux of [³H]- paclitaxel from KB-3-1 and KB-C2 cells was measured. A time- dependent versus percentage of intracellular [^JH]-paclitaxel was plotted (0, 30, 60 and 120 min). Data shown were means ± SDs for independent determinations in triplicate. Fig. 6C shows that ibrutinib effectively increased the accumulation of [³H]-paclitaxel in

HEK293/ABCC10 cells. Fig. 6D shows the effect of ibrutinib on the efflux of [^JH] -paclitaxel from HE 293/pcDNA3.1 and HEK293/ABCC 10 cells was measured. Three independent experiments were performed.

[0016] Fig. 7A - Fig. 7D illustrate the effect of ibrutinib on ABCB ί and ABCC 10 expression levels, ABCBl ATPase activity, and its docking in the homology model of ABCB L Fig. 7 A shows the effect of ibrutinib on the protein levels of ABCB l was tested by Western blot after the KB-C2 cells were treated with 5 μΜ ibrutinib for 0, 24, 48 and 72 h. The expression level of ABCB l was normalized by β-actin. The differences were statistically not significant (p > 0.05). Fig. 7B shows the effect of ibrutinib on the protein levels of ABCC 10, the expression level of ABCC 10 was normalized by β-actin. Fig. 7C shows the effect of ibrutinib (0-80 uM) on ATP hydrolysis by ABCB l . The mean values are plotted and error bars represent the SD. The experiments were performed at least three independent times. Fig. 7D shows that XP-Glide predicted binding mode of Ibrutinib with homology modeled ABCBl . The docked conformation of ibrutinib as ball and stick model is shown within the large hydrophobic cavity of ABCB 1. Important amino acids are depicted as sticks with the atoms colored as carbon - green, hydrogen - white, nitrogen - blue, oxygen - red, sulfur - yellow, whereas Ibrutinib is shown with the same color scheme as above except carbon atoms are represented in orange. Dotted black line indicates hydrogen-bonding interactions. Molecular surface of homology modeled ABCBl was colored by residue charge (hydrophobic - yellow). [0017] Fig. 8A - Fig. 8D illustrate ibrutinib enhancing the effect of paclitaxel on the growth of an ABCBl-overexpressing KB-C2 cell xenograft model in athymic nude mice. Fig. 8 A shows images of excised KB-C2 tumors tissues from different mice are shown on the 18^th day after treatment (n = 7). Fig. 8B shows changes in tumor volume with time in ABCB l- overexpressing xenograft model are shown. Fig. 8C shows mean weight (n = 7) of the excised KB-C2 tumors from the mice treated with vehicle, ibrutinib, paclitaxel or

combination of ibrutinib and paclitaxel. Error bars represent SD. *: p < 0.05 versus vehicle group; #: p < 0.05 versus the paclitaxel group. Fig. 8D shows the average percentage of body weight change after treatments.

[0018] Fig. 9A - Fig. 9D illustrate ibrutinib enhancing the effect of paclitaxel on the growth of an ABCClO-overexpressing HEK293/ABCC10 cell xenograft model in athymic nude mice. Fig. 9A shows images of excised HEK293/ABCC10 tumors tissues from different mice are shown on the 18^th day after treatment (n = 7). Fig. 9B shows changes in tumor volume with time in ABCCIO- overexpressing xenograft model are shown. Fig. 9C shows the mean weight (n = 7) of the excised HEK293/ABCC10 tumors from the mice treated with vehicle, ibrutinib, paclitaxel or combination of ibrutinib and paclitaxel. Error bars represent SD. *: p < 0.05 versus vehicle group; #: p < 0.05 versus the paclitaxel group. Fig. 9D shows the average percentage of body weight change after treatments.

[0019] Fig. 10 illustrates the effect of oral ibrutinib administration on the plasma concentration of paclitaxel. Nude mice (n=4) were administered either i.v paclitaxel (18 mg/kg) or i.v paclitaxel in combination with oral administration of ibrutinib (30 mg/kg). Ibrutinib was administered 1 hour prior to administration of paclitaxel as described in materials and methods. Blood was drawn via the retro-orbital route from mice under anesthesia at 0, 60, 120 and 240 min after administration of paclitaxel.

DETAILED DESCRIPTION OF THE INVENTION

Certain Terminology

[0020] 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.

[0021] 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.

[0022] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0023] 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). Overview

[0024] Paclitaxel is originally isolated from Taxus brevifolia that stabilizes microtubule dynamics, thus blocking normal spindle assembly and cell division. Paclitaxel has been successfully used for the treatment of a broad range of cancers, such as for example, lung, breast, ovarian, head and neck cancers and advanced Kaposi's sarcoma, leading to increased patients overall survival rate. In some instances, the occurrence of drug resistance has been a limitation to its clinical success. Innate resistance and acquired resistance during treatment are reported to be mediated by multiple mechanisms such as increased drug efflux, drug inactivation, mutations in the target protein and evasion of drug-induced damage or apoptosis. In one instance, the acquired resistance mechanisms to paclitaxel is mediated by members of the ATP -binding cassette (ABC) transporter, such as for example, ATP -binding cassette subfamily B member 1 (ABCB 1) and C member 10 (ABCCIO). Accumulated evidences from several studies indicated that overexpression of ABCB l or ABCCIO limits the efficacy of paclitaxel.

[0025] The ATP -binding cassette (ABC) transporter family members are transmembrane proteins that are responsible for drug uptake and efflux. There are more than 48 members within the ABC transporter superfamily which can be further divided into seven subfamilies, ABCl, MDR/TAP, MRP, ALD, OABP, GCN20, and White. Several of the ABC transporter members are involved in multidrug resistance (MDR). In some instances, the ABC transporter members involved in MDR include ABCBl, ABCG2 (ATP -binding cassette sub- family G member 2), and multidrug resistance-associated proteins such as MRP1/ABCC1, MRP2/ABCC2, or MRP7/ABCC10.

[0026] The ABCB1 (also known as P-glycoprotein, P-gp, or MDR1), a 170 kDa membrane glycoprotein, is a full length transporter with two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs) (Sharom FJ. "ABC multidrug transporters: structure, function and role in chemoresistance." Pharmacogenomics 9: 105-127 (2008)). The ABCBl can transport a wide range of amphipathic and hydrophobic

compounds, such as anthracyclines, taxanes, epipodophyllotoxin derivatives, vinca alkaloids and derivatives from campthoteca acuminate (Szakacs, et al., "Targeting multidrug resistance in cancer," Nature Reviews Drug Discovery, 5:219-234 (2006); Sharom FJ. "ABC multidrug transporters: structure, function and role in chemoresistance." Pharmacogenomics 9: 105-127 (2008)). Overexpression of ABCBl reduces intracellular drug accumulation and decreases the cytotoxicity of antitumor drugs, thus resulting in multidrug resistance (MDR) and affecting their efficacy (Gottesman et al., "P-glycoprotein and multidrug resistance," Current Opinion in Genetics & Development, 6:610-617 (1996)).

[0027] The ABCCIO (also known as ATP-binding cassette sub-family C member 10 or MRP7), is a member of the MRPs subfamily which is involved in MDR (12). ABCCIO, a 171 kDa membrane protein, consists of three TMDs and two NBDs (Chen et al,

"Characterization of the transport properties of human multidrug resistance protein 7 (MRP7, ABCCIO)," Mol Pharmacol. 63 :351-358 (2003)). In addition to paclitaxel, ABCCIO has been reported to confer resistance to several natural product anticancer drugs including docetaxel, vincristine, vinblastine, vinorelbine, cytarabine, gemcitabine, 2', 3'-dideoxycytidine, 9-(2- phosphonyl methoxyethyl) adenine (PMEA), epothilone B and endogenous substances like estradiol- 17P-D-glucuronide (E₂17pG) and leukotriene C4 (Kathawala et al., "Masitinib antagonizes ATP-binding cassette subfamily C member 10-mediated paclitaxel resistance: a preclinical study," Mol Cancer Ther 13(3):714-723 (2014)). Additional members of the MRP subfamily include ABCCl or MRP1, and ABCC2 or MRP2.

[0028] ABCG2 (also known as ATP-binding cassette sub-family G member 2, BCRP, MXR, ABC-P, or breast cancer resistance protein) is a member of the White subfamily. In some instances, ABCG2 functions as a xenobiotic transporter. In some cases, ABCG2 is involved in multidrug resistance to chemotherapeutic agents such as mitoxantrone and camptothecin analogues.

[0029] Paclitaxel is a cytoskeletal drug that targets tubulin. In some instances, paclitaxel- treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division. In some instances, paclitaxel as described herein also include its derivatives. In some instances, paclitaxel derivatives include those disclosed in WO2000041687;

US6396771; US20050191323, or US20040092428. In some instances, paclitaxel derivatives include glucuronyl paclitaxel as described in Bouvier, et al., "Glucuronyl paclitaxel (Taxol) derivatives as tumor activated prodrugs," Ann Pharm Fr. 63(l):53-62 (2005); or those described in Safavy et al., "Paclitaxel derivatives for targeted therapy of cancer: toward the development of smart taxanes," J. Med. Chem. 42: 4919-4924 (1999).

[0030] Disclosed herein, in certain embodiments, are methods of treating a cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor and paclitaxel. In some embodiments, the TEC inhibitor is a Btk inhibitor or an ITK inhibitor.

[0031] In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, disclosed herein are methods of treating a cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an ITK inhibitor and paclitaxel.

[0032] In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, disclosed herein are methods of treating a cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a Btk inhibitor and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some embodiments, the ABC- transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO.

[0033] In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, disclosed herein are methods of treating a cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising ibrutinib and paclitaxel. In some

embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some embodiments, the ABC- transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO.

[0034] Disclosed herein, in certain embodiments, is a method of treating a paclitaxel- resistant cancer comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor and paclitaxel. In some embodiments, the TEC inhibitor is a Btk inhibitor or an ITK inhibitor.

[0035] In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, disclosed herein is a method of treating a paclitaxel-resistant cancer comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an ITK inhibitor and paclitaxel.

[0036] In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, disclosed herein is a method of treating a paclitaxel-resistant cancer comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a BTK inhibitor and paclitaxel. In some embodiments, the paclitaxel-resistant cancer is characterized by an overexpression of an ABC-transporter. In some embodiments, the ABC- transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO.

[0037] In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, disclosed herein is a method of treating a paclitaxel-resistant cancer comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising ibrutinib and paclitaxel. In some embodiments, the paclitaxel-resistant cancer is characterized by an overexpression of an ABC-transporter. In some embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO.

Btk Inhibitor Compounds and Pharmaceutically Acceptable Salts Thereof [0038] 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).

[0039] 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;

R6, R₇ 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 R₁₁ 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.

[0040] "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:

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] In some embodiments, ibrutinib is prepared as outlined in US Patent no. 7,514,444.

[0046] In some embodiments, the Btk inhibitor is PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (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), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, BGB-3111 (Beigene), KBP-7536 (KBP Biosciences), ACP-196 (Acerta Pharma) or JTE-051 (Japan Tobacco Inc).

[0047] 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); (R)-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.

[0048 In some embodiments, the Btk inhibitor is:

; or a pharmaceutically acceptable salt thereof.

Additional TEC Family Kinase Inhibitors

[0049] BTK is a member of the Tyrosine-protein kinase (TEC) family of kinases. In some embodiments, the TEC family comprises BTK, ITK, TEC, RLK and BMX. In some embodiments, a TEC family kinase inhibitor inhibits the kinase activity of BTK, ITK, TEC, RLK and BMX. In some embodiments, a TEC family kinase inhibitor is a Btk inhibitor, which is disclosed elsewhere herein. In some embodiments, a TEC family kinase inhibitor is an ITK inhibitor. In some embodiments, a TEC family kinase inhibitor is a TEC inhibitor. In some embodiments, a TEC family kinase inhibitor is a RLK inhibitor. In some embodiments, a TEC family kinase inhibitor is a BMK inhibitor.

[0050] In some embodiments, the Itk inhibitor covalently binds to Cysteine 442 of ITK. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2002/0500071, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2005/070420, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2005/079791, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/076228, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/058832, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016610, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016611, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016600, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016615, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2005/026175, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2006/065946, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/027594, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/017455, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2008/025820, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2008/025821, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2008/025822, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2011/017219, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2011/090760, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2009/158571, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2009/051822, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in US 20110281850, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2014/082085, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2014/093383, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in US8759358, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2014/105958, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in US2014/0256704, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in US20140315909, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in US20140303161, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2014/145403, which is incorporated by reference in its entirety.

[0051] In some embodiments, the Itk inhibitor has a structure selected from:

Cancer

[0052] Disclosed herein, in certain embodiments, are methods of treating a cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor (e.g. an ITK inhibitor or a Btk inhibitor such as ibrutinib) and paclitaxel. In some instances, the cancer is a solid tumor. In some cases, the cancer is a hematologic cancer.

[0053] Disclosed herein, in certain embodiments, is a method of treating a solid tumor characterized by an overexpression of an ABC transporter in an individual in need thereof which comprises administering a combination of a TEC inhibitor and paclitaxel. In some embodiments, the solid tumor is a sarcoma or carcinoma. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is a carcinoma.

[0054] In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid

hemangioendothelioma; epithelioid sarcoma; esthesioneuroblastoma; Ewing sarcoma;

extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; giant cell tumor; hemangiopericytoma; infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone;

liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant mesenchymoma; malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma;

myxoinflammatory fibroblastic sarcoma; neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; PNET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cell liposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovial sarcoma; telangiectatic osteosarcoma.

[0055] In some embodiments, the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma. In some embodiments, the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; brain tumor; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer. In some embodiments, the carcinoma is breast cancer. In some embodiments, the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ. In some embodiments, the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal (colon) cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung cancer. In some embodiments, the carcinoma is prostate cancer. In some embodiments, the prostate cancer is adenocarcinoma or small cell carcinoma. In some embodiments, the carcinoma is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the carcinoma is bile duct cancer. In some embodiments, the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.

[0056] In some embodiments, the solid tumor is selected from prostate cancer, pancreatic cancer, breast cancer, colorectal (colon) cancer, lung cancer, gastroenterological cancer and melanoma. In some embodiments, the solid tumor is prostate cancer. In some embodiments, the solid tumor is breast cancer. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is colorectal (colon) cancer. In some embodiments, the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma.

[0057] In some embodiments, described herein are methods of treating a solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor and paclitaxel. In some embodiments, the TEC inhibitor is a Btk inhibitor or an ITK inhibitor.

[0058] In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, disclosed herein are methods of treating a solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an ITK inhibitor and paclitaxel.

[0059] In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, disclosed herein are methods of treating a solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a Btk inhibitor and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some embodiments, the ABC- transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene

Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila

Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol- Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (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), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, BGB-3111 (Beigene), KBP-7536 (KBP Biosciences), ACP-196 (Acerta Pharma) or JTE-051 (Japan Tobacco Inc).

[0060] In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, disclosed herein are methods of treating a solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising ibrutinib and paclitaxel. In some

[0061] Disclosed herein, in certain embodiments, is a method of treating a hematologic cancer characterized by an overexpression of an ABC transporter, which comprises administering a combination of a TEC inhibitor and paclitaxel. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.

[0062] In some embodiments, the hematologic cancer is a T-cell malignancy. In some embodiments, the T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T- cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic K-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal K/T-cell lymphomas, or treatment-related T-cell lymphomas.

[0063] In some embodiments, the hematologic cancer is a B-cell proliferative disorder. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, DLBCL is further divided into subtypes: activated B- cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) 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. In some

embodiments, the cancer is acute or chronic myelogenous (or myeloid) leukemia,

myelodysplastic syndrome, or acute lymphoblastic leukemia.

[0064] In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is activated B-cell diffuse large B-cell lymphoma (ABC- DLBCL). In some embodiments, the cancer is follicular lymphoma (FL). In some

embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is small lymphocytic lymphoma (SLL). In some embodiments, the cancer is non-CLL/SLL lymphoma. In some embodiments, the cancer is high risk CLL or high risk SLL.

[0065] In some embodiments, described herein are methods of treating a hematologic cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor and paclitaxel. In some embodiments, the TEC inhibitor is a Btk inhibitor or an ITK inhibitor.

[0066] In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, disclosed herein are methods of treating a hematologic cancer characterized by an

overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an ITK inhibitor and paclitaxel. [0067] In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, disclosed herein are methods of treating a hematologic cancer characterized by an

overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a Btk inhibitor and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some

embodiments, the ABC-transporter is ATP -binding cassette subfamily B member 1

(ABCB l), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCB l . In some embodiments, the ABC-transporter is ABCCIO. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS- 488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (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), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, BGB-3111 (Beigene), KBP-7536 (KBP Biosciences), ACP-196 (Acerta Pharma) or JTE-051 (Japan Tobacco Inc).

[0068] In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, disclosed herein are methods of treating a hematologic cancer characterized by an

overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising ibrutinib and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some

embodiments, the combination decreases paclitaxel efflux in the subject. In some

embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1

(ABCB l), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCB l . In some embodiments, the ABC-transporter is ABCCIO. Relapsed or Refractory Cancer

[0069] In some embodiments, the solid tumor is a relapsed or refractory solid tumor. In some embodiments, the relapsed or refractory solid tumor is a sarcoma or carcinoma. In some embodiments, the relapsed or refractory solid tumor is a sarcoma. In some embodiments, the relapsed or refractory solid tumor is a carcinoma. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma;

angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;

esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; giant cell tumor;

hemangiopericytoma; infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant

mesenchymoma; malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma;

neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;

P ET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cell liposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovial sarcoma; telangiectatic osteosarcoma. In some embodiments, the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma. In some embodiments, the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; brain tumor; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer. In some embodiments, the carcinoma is breast cancer. In some embodiments, the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ. In some embodiments, the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal (colon) cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung cancer. In some embodiments, the carcinoma is prostate cancer. In some

embodiments, the prostate cancer is adenocarcinoma or small cell carcinoma. In some embodiments, the carcinoma is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the carcinoma is bile duct cancer. In some embodiments, the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.

[0070] In some embodiments, the relapsed or refractory solid tumor is selected from prostate cancer, pancreatic cancer, breast cancer, colorectal (colon) cancer, lung cancer, gastroenterological cancer and melanoma. In some embodiments, the relapsed or refractory solid tumor is prostate cancer. In some embodiments, the relapsed or refractory solid tumor is breast cancer. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma.

[0071] In some embodiments, disclosed herein is a method of treating a relapsed or refractory solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor and paclitaxel. In some embodiments, the TEC inhibitor is a Btk inhibitor or an ITK inhibitor.

[0072] In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, disclosed herein are methods of treating a relapsed or refractory solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an ITK inhibitor and paclitaxel. [0073] In some embodiments, the TEC inhibitor is a BTK inhibitor. In some embodiments, disclosed herein are methods of treating a relapsed or refractory solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a Btk inhibitor and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some

embodiments, the ABC-transporter is ATP -binding cassette subfamily B member 1

[0074] In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, disclosed herein are methods of treating a relapsed or refractory solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising ibrutinib and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some

embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1

(ABCB l), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCB l . In some embodiments, the ABC-transporter is ABCCIO. [0075] In some embodiments, the cancer is a paclitaxel-resistant cancer. In some embodiments, the cancer is a paclitaxel-resistant solid tumor.

[0076] In some embodiments, described herein is a method of treating a paclitaxel-resistant solid tumor comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor and paclitaxel. In some embodiments, the TEC inhibitor is a Btk inhibitor or an ITK inhibitor.

[0077] In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, disclosed herein is a method of treating a paclitaxel-resistant solid tumor comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an ITK inhibitor and paclitaxel.

[0078] In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, disclosed herein is a method of treating a paclitaxel-resistant solid tumor comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a Btk inhibitor and paclitaxel. In some embodiments, the paclitaxel-resistant cancer is characterized by an overexpression of an ABC-transporter. In some embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila

[0079] In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, disclosed herein is a method of treating a paclitaxel-resistant solid tumor comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising ibrutinib and paclitaxel. In some embodiments, the paclitaxel-resistant cancer is characterized by an overexpression of an ABC-transporter. In some embodiments, the ABC- transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO.

[0080] In some embodiments, the hematologic cancer is a relapsed or refractory

hematologic cancer. In some embodiments, the relapsed or refractory hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, T- cell malignancy, or a B-cell malignancy.

[0081] In some embodiments, the relapsed or refractory hematologic cancer is a T-cell malignancy. In some embodiments, the relapsed or refractory T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell

leukemia/lymphoma (ATLL), blastic K-cell lymphoma, enteropathy -type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal K/T-cell lymphomas, or treatment-related T-cell lymphomas.

[0082] In some embodiments, the relapsed or refractory hematologic cancer is a B-cell proliferative disorder. In some embodiments, the relapsed or refractory cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non- CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's

macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the relapsed or refractory DLBCL is further divided into subtypes: activated B- cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) 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. In some

embodiments, the cancer is acute or chronic myelogenous (or myeloid) leukemia,

myelodysplastic syndrome, or acute lymphoblastic leukemia.

[0083] In some embodiments, the cancer is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is relapsed or refractory activated B- cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the cancer is relapsed or refractory follicular lymphoma (FL). In some embodiments, the cancer is relapsed or refractory multiple myeloma. In some embodiments, the cancer is relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is relapsed or refractory small lymphocytic lymphoma (SLL). In some embodiments, the cancer is relapsed or refractory non-CLL/SLL lymphoma. In some embodiments, the cancer is relapsed or refractory high risk CLL or high risk SLL.

[0084] In some embodiments, described herein are methods of treating a relapsed or refractory hematologic cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor and paclitaxel. In some embodiments, the TEC inhibitor is a BTK inhibitor or an ITK inhibitor.

[0085] In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, disclosed herein are methods of treating a relapsed or refractory hematologic cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an ITK inhibitor and paclitaxel.

[0086] In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, disclosed herein are methods of treating a relapsed or refractory hematologic cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a Btk inhibitor and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1 (ABCB l), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCB l . In some embodiments, the ABC-transporter is ABCCIO. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Co oration), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS- 488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (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

[0087] In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, disclosed herein are methods of treating a relapsed or refractory hematologic cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising ibrutinib and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1 (ABCB l), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCB l . In some embodiments, the ABC-transporter is ABCCIO.

[0088] In some embodiments, the hematologic cancer is a paclitaxel-resistant hematologic cancer. In some embodiments, described herein is a method of treating a paclitaxel-resistant hematologic cancer comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor and paclitaxel. In some embodiments, the TEC inhibitor is a Btk inhibitor or an ITK inhibitor.

[0089] In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, disclosed herein is a method of treating a paclitaxel-resistant hematologic cancer comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an ITK inhibitor and paclitaxel.

[0090] In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, disclosed herein is a method of treating a paclitaxel-resistant hematologic cancer comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a BTK inhibitor and paclitaxel. In some embodiments, the paclitaxel-resistant cancer is characterized by an overexpression of an ABC-transporter. In some embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila

[0091] In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, disclosed herein is a method of treating a paclitaxel-resistant hematologic cancer comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising ibrutinib and paclitaxel. In some embodiments, the paclitaxel-resistant cancer is characterized by an overexpression of an ABC-transporter. In some embodiments, the ABC- transporter is ATP-binding cassette subfamily B member 1 (ABCBl), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCBl . In some embodiments, the ABC-transporter is ABCCIO.

Metastasized Cancer

[0092] In some embodiments, the solid tumor is a metastasized solid tumor. In some embodiments, the metastasized solid tumor is a sarcoma or carcinoma. In some embodiments, the metastasized solid tumor is a sarcoma. In some embodiments, the metastasized solid tumor is a carcinoma. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;

P ET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cell liposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovial sarcoma; telangiectatic osteosarcoma. In some embodiments, the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma. In some embodiments, the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; brain tumor; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer. In some embodiments, the carcinoma is breast cancer. In some embodiments, the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ. In some embodiments, the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is

adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal (colon) cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung cancer. In some embodiments, the carcinoma is prostate cancer. In some

[0093] In some embodiments, the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma. In some embodiments, the metastasized solid tumor is breast cancer. In some embodiments, the metastasized solid tumor is lung cancer. In some embodiments, the metastasized solid tumor is ovarian cancer. In some embodiments, the metastasized solid tumor is prostate cancer. In some embodiments, the metastasized solid tumor is genitourinary tract cancer. In some embodiments, the metastasized solid tumor is osteosarcoma. In some embodiments, the metastasized solid tumor is leiomyosarcoma. In some embodiments, the metastasized solid tumor is malignant fibrous histiocytoma. In some embodiments, the metastasized solid tumor is alveolar soft part sarcoma. In some

embodiments, the metastasized solid tumor is Ewing's bone sarcomas. In some embodiments, the metastasized solid tumor is melanoma. In some embodiments, the metastasized solid tumor is head and neck cancer. In some embodiments, the metastasized solid tumor is kidney cancer. In some embodiments, the metastasized solid tumor is colorectal cancer. In some embodiments, the metastasized solid tumor is pancreatic cancer. In some embodiments, the metastasized solid tumor is neuroblastoma.

[0094] In some embodiments, the metastasized solid tumor is a cancer that has

metastasized into the central nervous system (CNS) from another location. In some embodiments, the metastasized cancer into the CNS is referred to as brain metastases. In some embodiments, exemplary sources of solid tumor brain metastases includes, but is not limited to, breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.

[0095] In some embodiments, described herein are methods of treating a metastasized solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor and paclitaxel. In some embodiments, the TEC inhibitor is a BTK inhibitor or an ITK inhibitor.

[0096] In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, disclosed herein are methods of treating a metastasized solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an ITK inhibitor and paclitaxel.

[0097] In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, disclosed herein are methods of treating a metastasized solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a Btk inhibitor and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some

embodiments, the ABC-transporter is ATP -binding cassette subfamily B member 1

[0098] In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, disclosed herein are methods of treating a metastasized solid tumor characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising ibrutinib and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some

embodiments, the ABC-transporter is ATP -binding cassette subfamily B member 1

(ABCB l), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO). In some embodiments, the ABC-transporter is ABCB l . In some embodiments, the ABC-transporter is ABCCIO.

[0099] In some embodiments, the hematologic cancer is a metastasized hematologic cancer. In some embodiments, the metastasized hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.

[00100] In some embodiments, the metastasized hematologic cancer is a T-cell malignancy. In some embodiments, the T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic K-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal K/T-cell lymphomas, or treatment-related T- cell lymphomas.

[00101] In some embodiments, the metastasized hematologic cancer is a B-cell proliferative disorder. In some embodiments, the metastasized hematologic cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the metastasized hematologic cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, DLBCL is further divided into subtypes: activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) 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. In some embodiments, the cancer is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia.

[00102] In some embodiments, the metastasized hematologic cancer is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the metastasized hematologic cancer is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the metastasized hematologic cancer is follicular lymphoma (FL). In some embodiments, the metastasized hematologic cancer is multiple myeloma. In some embodiments, the

metastasized hematologic cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the metastasized hematologic cancer is small lymphocytic lymphoma (SLL). In some embodiments, the metastasized hematologic cancer is non-CLL/SLL lymphoma. In some embodiments, the metastasized hematologic cancer is high risk CLL or high risk SLL.

[00103] In some embodiments, described herein are methods of treating a metastasized hematologic cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor and paclitaxel. In some embodiments, the TEC inhibitor is a BTK inhibitor or an ITK inhibitor.

[00104] In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, disclosed herein are methods of treating a metastasized hematologic cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising an ITK inhibitor and paclitaxel.

[00105] In some embodiments, the TEC inhibitor is a BTK inhibitor. In some embodiments, disclosed herein are methods of treating a metastasized hematologic cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a BTK inhibitor and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some

embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1

[00106] In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, disclosed herein are methods of treating a metastasized hematologic cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising ibrutinib and paclitaxel. In some embodiments, the combination sensitizes the cancer to paclitaxel. In some embodiments, the combination decreases paclitaxel efflux in the subject. In some

embodiments, the ABC-transporter is ATP-binding cassette subfamily B member 1

Additional Therapeutic Agents

[00107] Disclosed herein, in certain embodiments, are methods of treating a cancer characterized by an overexpression of an ABC transporter, comprising administering to a subject in need thereof a therapeutically effective amount of a combination comprising a TEC inhibitor (e.g. an ITK inhibitor or a Btk inhibitor such as ibrutinib), paclitaxel, and an additional agent.

[00108] In some embodiments, the additional therapeutic agent is a chemotherapeutic agent, a steroid, an immunotherapeutic agent, a targeted therapy, or a combination thereof. In some embodiments, the additional therapeutic agent is a B cell receptor pathway inhibitor. In some embodiments, the B cell receptor pathway inhibitor is a CD79A inhibitor, a CD79B inhibitor, a CD 19 inhibitor, a Lyn inhibitor, a Syk inhibitor, a PI3K inhibitor, a Blnk inhibitor, a PLCy inhibitor, a ΡίΧβ inhibitor, or a combination thereof. In some embodiments, the additional therapeutic agent is an antibody, B cell receptor signaling inhibitor, a PI3K inhibitor, an IAP inhibitor, an mTOR inhibitor, a radioimmunotherapeutic, a DNA damaging agent, a proteosome inhibitor, a histone deacetylase inhibitor, a protein kinase inhibitor, a hedgehog inhibitor, an Hsp90 inhibitor, a telomerase inhibitor, a Jakl/2 inhibitor, a protease inhibitor, a PKC inhibitor, a PARP inhibitor, or a combination thereof.

[00109] In some embodiments, the additional therapeutic agent comprises an agent selected from: an inhibitor of LYN, SYK, JAK, PI3K, PLCy, MAPK, MEK or NFKB.

[00110] In some embodiments, the additional therapeutic agent comprises an agent selected from: bendamustine, bortezomib, lenalidomide, idelalisib (GS-1 101), vorinostat, everolimus, panobinostat, temsirolimus, romidepsin, vorinostat, fludarabine, cyclophosphamide, mitoxantrone, pentostatine, prednisone, etopside, procarbazine, and thalidomide.

[00111] In some embodiments, the additional therapeutic agent is rituximab. In some embodiments, rituximab is further administered as a maintenance therapy.

[00112] In some embodiments the additional therapeutic agent is bendamustine. In some embodiments, bortezomib is administered in combination with rituximab.

[00113] In some embodiments, the additional therapeutic agent is bortezomib. In some embodiments, bendamustine is administered in combination with rituximab.

[00114] In some embodiments, the additional therapeutic agent is lenalidomide. In some embodiments, lenalidomide is administered in combination with rituximab.

[00115] In some embodiments, the additional therapeutic agent is a multi-agent therapeutic regimen. In some embodiments the additional therapeutic agent comprises the HyperCVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and cytarabine). In some embodiments, the HyperCVAD regimen is

administered in combination with rituximab.

[00116] In some embodiments the additional therapeutic agent comprises the R-CHOP regiment (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). [00117] In some embodiments the additional therapeutic agent comprises bortezomib and rituximab.

[00118] In some embodiments the additional therapeutic agent comprises cladribine and rituximab.

[00119] In some embodiments the additional therapeutic agent comprises the FCR regimen (FCR (fludarabine, cyclophosphamide, rituximab).

[00120] In some embodiments the additional therapeutic agent comprises the FCMR regimen (fludarabine, cyclophosphamide, mitoxantrone, rituximab).

[00121] In some embodiments the additional therapeutic agent comprises the FMR regimen (fludarabine, mitoxantrone, rituximab).

[00122] In some embodiments the additional therapeutic agent comprises the PCR regimen (pentostatin, cyclophosphamide, rituximab).

[00123] In some embodiments the additional therapeutic agent comprises the PEPC regimen

(prednisone, etoposide, procarbazine, cyclophosphamide).

[00124] In some embodiments the additional therapeutic agent comprises

radioimmunotherapy with ⁹⁰Y-ibritumomab tiuxetan or ¹³¹I-tositumomab.

[00125] In some embodiments, the additional therapeutic agent is an autologous stem cell transplant.

[00126] In some embodiments, the additional therapeutic agent is selected from: nitrogen mustards such as for example, bendamustine, chlorambucil, chlormethine,

cyclophosphamide, ifosfamide, melphalan, prednimustine, trofosfamide; alkyl sulfonates like busulfan, mannosulfan, treosulfan; ethylene imines like carboquone, thiotepa, triaziquone; nitrosoureas like carmustine, fotemustine, lomustine, nimustine, ranimustine, semustine, streptozocin; Epoxides such as for example, etoglucid; other alkylating agents such as for example dacarbazine, mitobronitol, pipobroman, temozolomide; folic acid analogues such as for example methotrexate, permetrexed, pralatrexate, raltitrexed; purine analogs such as for example cladribine, clofarabine, fludarabine, mercaptopurine, nelarabine, tioguanine;

pyrimidine analogs such as for example azacitidine, capecitabine, carmofur, cytarabine, decitabine, fluorouracil, gemcitabine, tegafur; vinca alkaloids such as for example vinblastine, vincristine, vindesine, vinflunine, vinorelbine; podophyllotoxin derivatives such as for example etoposide, teniposide; colchicine derivatives such as for example

demecolcine; taxanes such as for example docetaxel, paclitaxel, paclitaxel poliglumex; other plant alkaloids and natural products such as for example trabectedin; actinomycines such as for example dactinomycin; antracyclines such as for example aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pirarubicin, valrubicin, zorubincin; other cytotoxic antibiotics such as for example bleomycin, ixabepilone, mitomycin, plicamycin; platinum compounds such as for example carboplatin, cisplatin, oxaliplatin, satraplatin; methylhydrazines such as for example procarbazine; sensitizers such as for example aminolevulinic acid, efaproxiral, methyl aminolevulinate, porfimer sodium, temoporfin; protein kinase inhibitors such as for example dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib, temsirolimus; other

antineoplastic agents such as for example alitretinoin, altretamine, amzacrine, anagrelide, arsenic trioxide, asparaginase, bexarotene, bortezomib, celecoxib, denileukin diftitox, estramustine, hydroxycarbamide, irinotecan, lonidamine, masoprocol, miltefosein, mitoguazone, mitotane, oblimersen, pegaspargase, pentostatin, romidepsin, sitimagene ceradenovec, tiazofurine, topotecan, tretinoin, vorinostat; estrogens such as for example diethylstilbenol, ethinylestradiol, fosfestrol, polyestradiol phosphate; progestogens such as for example gestonorone, medroxyprogesterone, megestrol; gonadotropin releasing hormone analogs such as for example buserelin, goserelin, leuprorelin, triptorelin; anti -estrogens such as for example fulvestrant, tamoxifen, toremifene; anti-androgens such as for example bicalutamide, flutamide, nilutamide, , enzyme inhibitors, aminoglutethimide, anastrozole, exemestane, formestane, letrozole, vorozole; other hormone antagonists such as for example abarelix, degarelix; immunostimulants such as for example histamine dihydrochloride, mifamurtide, pidotimod, plerixafor, roquinimex, thymopentin; immunosuppressants such as for example everolimus, gusperimus, leflunomide, mycophenolic acid, sirolimus; calcineurin inhibitors such as for example ciclosporin, tacrolimus; other immunosuppressants such as for example azathioprine, lenalidomide, methotrexate, thalidomide; and radiopharmaceuticals such as for example, iobenguane.

[00127] In some embodiments, the additional therapeutic agent is selected from: interferons, interleukins, tumor necrosis factors, growth factors, or the like.

[00128] In some embodiments, the additional therapeutic agent is selected from: ancestim, filgrastim, lenograstim, molgramostim, pegfilgrastim, sargramostim; interferons such as for example interferon alfa natural, interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, interferon alfa-nl, interferon beta natural, interferon beta-la, interferon beta-lb, interferon gamma, peginterferon alfa-2a, peginterferon alfa-2b; Interleukins such as for example aldesleukin, oprelvekin; other immunostimulants such as for example BCG vaccine, glatiramer acetate, histamine dihydrochloride, immunocyanin, lentinan, melanoma vaccine, mifamurtide, pegademase, pidotimod, plerixafor, poly I:C, poly ICLC, roquinimex, tasonermin, thymopentin; Immunosuppressants such as for example abatacept, abetimus, alefacept, antilymphocyte immunoglobulin (horse), antithymocyte immunoglobulin (rabbit), eculizumab, efalizumab, everolimus, gusperimus, leflunomide, muromab-CD3,

mycophenolic acid, natalizumab, sirolimus; TNF alpha inhibitors such as for example adalimumab, afelimomab, certolizumab pegol, etanercept, golimumab, infliximab; interleukin inhibitors such as for example anakinra, basiliximab, canakinumab, daclizumab,

mepolizumab, rilonacept, tocilizumab, ustekinumab; calcineurin inhibitors such as for example ciclosporin, tacrolimus; other immunosuppressants such as for example

azathioprine, lenalidomide, methotrexate, thalidomide.

[00129] In some embodiments, the additional therapeutic agent is selected from:

adalimumab, alemtuzumab, basiliximab, bevacizumab, cetuximab, certolizumab pegol, daclizumab, eculizumab, efalizumab, gemtuzumab, ibritumomab tiuxetan, infliximab, muromonab-CD3, natalizumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab, or the like, or a combination thereof.

[00130] In some embodiments, the additional therapeutic agent is selected from: monoclonal antibodies such as for example alemtuzumab, bevacizumab, catumaxomab, cetuximab, edrecolomab, gemtuzumab, panitumumab, rituximab, trastuzumab; immunosuppressants, eculizumab, efalizumab, muromab-CD3, natalizumab; TNF alpha inhibitors such as for example adalimumab, afelimomab, certolizumab pegol, golimumab, infliximab; interleukin inhibitors, basiliximab, canakinumab, daclizumab, mepolizumab, tocilizumab, ustekinumab; radiopharmaceuticals, ibritumomab tiuxetan, tositumomab; others monoclonal antibodies such as for example abagovomab, adecatumumab, alemtuzumab, anti-CD30 monoclonal antibody Xmab2513, anti-MET monoclonal antibody MetMab, apolizumab, apomab, arcitumomab, basiliximab, bispecific antibody 2B1, blinatumomab, brentuximab vedotin, capromab pendetide, cixutumumab, claudiximab, conatumumab, dacetuzumab, denosumab, eculizumab, epratuzumab, epratuzumab, ertumaxomab, etaracizumab, figitumumab, fresolimumab, galiximab, ganitumab, gemtuzumab ozogamicin, glembatumumab, ibritumomab, inotuzumab ozogamicin, ipilimumab, lexatumumab, lintuzumab, lintuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab, monoclonal antibody CC49, necitumumab, nimotuzumab, oregovomab, pertuzumab, ramacurimab, ranibizumab, siplizumab, sonepcizumab, tanezumab, tositumomab, trastuzumab, tremelimumab, tucotuzumab celmoleukin, veltuzumab, visilizumab, volociximab, zalutumumab.

[00131] In some embodiments, the additional therapeutic agent is selected from: agents that affect the tumor micro-environment such as cellular signaling network (e.g. phosphatidylinositol 3-kinase (PI3K) signaling pathway, signaling from the B-cell receptor and the IgE receptor). In some embodiments, the additional therapeutic agent is a PI3K signaling inhibitor or a syc kinase inhibitor. In one embodiment, the syk inhibitor is R788. In another embodiment is a PKCy inhibitor such as by way of example only, enzastaurin.

[00132] Examples of agents that affect the tumor micro-environment include PI3K signaling inhibitor, syc kinase inhibitor, protein kinase inhibitors such as for example dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazonanib, sorafenib, sunitinib, temsirolimus; Other Angiogenesis Inhibitors such as for example GT-111, JI- 101, R1530; other kinase inhibitors such as for example AC220, AC480, ACE-041, AMG 900, AP24534, Arry-614, AT7519, AT9283, AV-951, axitinib, AZD1152, AZD7762, AZD8055, AZD8931, bafetinib, BAY 73-4506, BGJ398, BGT226, BI 811283, BI6727, BIBF 1120, BIBW 2992, BMS-690154, BMS-777607, BMS-863233, BSK-461364, CAL-101, CEP-11981, CYC116, DCC-2036, dinaciclib, dovitinib lactate, E7050, EMD 1214063, ENMD-2076, fostamatinib disodium, GSK2256098, GSK690693, INCB 18424, INNO-406, JNJ-26483327, JX-594, KX2-391, linifanib, LY2603618, MGCD265, MK-0457, MK1496, MLN8054, MLN8237, MP470, NMS-1116354, NMS-1286937, ON 01919.Na, OSI-027, OSI-930, Btk inhibitor, PF- 00562271, PF-02341066, PF-03814735, PF-04217903, PF-04554878, PF-04691502, PF- 3758309, PHA-739358, PLC3397, progenipoietin, R547, R763, ramucirumab, regorafenib, R05185426, SAR103168, SCH 727965, SGI-1176, SGX523, SNS-314, TAK-593, TAK- 901, TKI258, TLN-232, TTP607, XL147, XL228, XL281R05126766, XL418, XL765.

[00133] In some embodiments, the additional therapeutic agent is selected from: inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352,

PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or

LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).

[00134] In some embodiments, the additional therapeutic agent is selected from: adriamycin, dactinomycin, bleomycin, vinblastine, cisplatin, acivicin; aclarubicin; acodazole

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

hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium;

bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin;

carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine;

gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II, or rlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-1 a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate;

melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;

nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

[00135] In some embodiments, the additional therapeutic agent is selected from: 20-epi-l, 25 dihy droxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox;

amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;

andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;

azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists;

benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;

calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine;

carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4;

combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;

cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;

didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;

epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists;

etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin

hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin;

gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-such as for example growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;

kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon;

leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A;

marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;

mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N- acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine;

napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;

nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;

ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate;

phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B 1 ; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense

oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D;

spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide;

tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin;

thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine;

triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;

tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

[00136] In some embodiments, the additional therapeutic agent is selected from: alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, ete.), or triazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[00137] In some embodiments, the additional therapeutic agent is selected from: nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, ete.). Examples of antimetabolites include, but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

[00138] In some embodiments, the additional therapeutic agent is selected from: agents which act by arresting cells in the G2-M phases due to stabilized microtubules, e.g.,

Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC- 376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC-639829,

Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1, Spongi statin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B ), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS- 310705), 21 -hydroxy epothilone D (also known as Desoxyepothilone F and dEpoF), 26- fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651 ), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138

(Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A),

Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969), T- 138067 (Tularik, also known as T-67, TL- 138067 and TI- 138067), COBRA- 1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), HI 6 (Kansas State University), Oncocidin Al (also known as BTO-956 and DIME), DDE- 313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU

(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T- 138026 (Tularik), Monsatrol, lnanocine (also known as NSC-698666), 3-lAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607), RPR- 115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and Z- Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA- 110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC- 12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi).

Pharmaceutical Compositions/Formulations

[00139] Disclosed herein, in certain embodiments, are compositions for treating a cancer in an individual in need thereof comprising a TEC inhibitor (e.g., an ITK inhibitor, a Btk inhibitor, e.g. a covalent Btk inhibitor,) and paclitaxel or a paclitaxel derivative. Disclosed herein, in certain embodiments, are compositions for treating a cancer in an individual in need thereof comprising a covalent Btk inhibitor (e.g., an irreversible covalent Btk inhibitor, e.g., ibrutinib) and paclitaxel or a paclitaxel derivative.

[00140] In some embodiments, the covalent Btk inhibitor is a compound of Formula (A). In some embodiments, the covalent Btk inhibitor is (R)-l-(3-(4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one (i.e. PCI-32765/ibrutinib). In some embodiments, the CDK4 inhibitor is palbociclib.

[00141] Pharmaceutical compositions of covalent Btk inhibitors (e.g., an irreversible covalent Btk inhibitor, e.g., ibrutinib) and/or CDK4 inhibitors are 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. A summary of pharmaceutical compositions described herein is 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).

[00142] A pharmaceutical composition, as used herein, refers to a mixture of a covalent Btk inhibitor (e.g., an irreversible covalent Btk inhibitor, e.g., ibrutinib) and/or a CDK4 inhibitor (e.g., a selective CDK4 inhibitor; e.g., palbociclib) with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.

[00143] Pharmaceutical compositions are optionally 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. [00144] 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.

[00145] 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.

[00146] 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.

[00147] The pharmaceutical formulations described herein are administered by any suitable administration route, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.

[00148] The pharmaceutical compositions described herein are 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 an individual 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. In some embodiments, the compositions are formulated into capsules. In some embodiments, the compositions are formulated into solutions (for example, for IV

administration).

[00149] The pharmaceutical solid dosage forms described herein optionally 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.

[00150] 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 compositions. In some embodiments, the compositions are formulated into particles (for example for administration by capsule) and some or all of the particles are coated. In some embodiments, the compositions are formulated into particles (for example for administration by capsule) and some or all of the particles are microencapsulated. In some embodiments, the compositions are formulated into particles (for example for administration by capsule) and some or all of the particles are not microencapsulated and are uncoated.

[00151] 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.

[00152] "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.

[00153] "Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, antioxidants enhance chemical stability where required.

[00154] 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.

[00155] "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.

[00156] 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 An anticancer agent, 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).

[00157] "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.

[00158] Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present compositions.

[00159] 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.

[00160] 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^® PHlOl, 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.

[00161] "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. [00162] 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.

[00163] "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.

[00164] "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.

[00165] "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.

[00166] "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.

[00167] 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.

[00168] "Pharmacodynamics" refers to the factors which determine the biologic response observed relative to the concentration of drug at a site of action.

[00169] "Pharmacokinetics" refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.

[00170] "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.

[00171] "Solubilizers" include compounds such as triacetin, triethyl 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.

[00172] "Stabilizers" include compounds such as any antioxidation agents, buffers, acids, preservatives and the like.

[00173] "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.

[00174] "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.

[00175] "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.

[00176] "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.

[00177] "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

[00178] 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. In some embodiments, the composition is formulated for administration in a combined dosage form. In some embodiments, the composition is formulated for administration in a separate dosage forms. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. The terms "individual(s)",

"subject(s)" and "patient(s)" are used interchangeably herein, and 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).

[00179] Moreover, the pharmaceutical compositions described herein, which include ibrutinib and/or an anticancer agent 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.

[00180] 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.

[00181] 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.

[00182] 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.

[00183] 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.

[00184] In some embodiments, solid dosage forms, e.g., tablets, effervescent tablets, and capsules, are prepared by mixing particles of ibrutinib and/or an anticancer agent, 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 an anticancer agent, 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.

[00185] 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.

[00186] 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 an anticancer agent. In another embodiment, some or all of the particles of ibrutinib and/or an anticancer agent, are not microencapsulated and are uncoated.

[00187] 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.

[00188] 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.

[00189] In order to release the compound of ibrutinib and/or an anticancer agent, 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.

[00190] 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.

[00191] 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.

[00192] 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. [00193] 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.

[00194] 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.

[00195] 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.

[00196] 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.

[00197] 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.

[00198] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[00199] 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.

[00200] 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.

[00201] 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.

[00202] 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.

[00203] In various embodiments, the particles of ibrutinib and/or an anticancer agent, 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. [00204] 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.

[00205] Materials useful for the microencapsulation described herein include materials compatible with ibrutinib and/or an anticancer agent, which sufficiently isolate the compound of any of ibrutinib or an anticancer agent, from other non-compatible excipients. Materials compatible with compounds of any of ibrutinib or an anticancer agent, are those that delay the release of the compounds of any of ibrutinib or an anticancer agent, in vivo.

[00206] 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^® L100, 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 HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

[00207] 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.

[00208] Microencapsulated compounds of any of ibrutinib or an anticancer agent 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.

[00209] In one embodiment, the particles of compounds of any of ibrutinib or an anticancer agent 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).

[00210] In other embodiments, the solid dosage formulations of the compounds of any of ibrutinib and/or an anticancer agent 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.

[00211] In other embodiments, a powder including the formulations with a compound of any of ibrutinib and/or an anticancer agent, 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. [00212] 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.

[00213] 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.

[00214] 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:

[00215] Shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7; [00216] 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;

[00217] 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 μιη. 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 (ELF), 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.

[00218] 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.

[00219] 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.

[00220] In other embodiments, the formulations described herein, which include ibrutinib and/or an anticancer agent, 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.

[00221] In some embodiments, pharmaceutical formulations are provided that include particles of ibrutinib and/or an anticancer agent, 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.

[00222] 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. [00223] 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.

[00224] 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.

[00225] 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., FIPC, FIPC-SL, and FIPC-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^®).

[00226] 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.

[00227] 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. [00228] 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.

[00229] 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.

[00230] 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, phosphatidylcholine, 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.

[00231] 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.

[00232] 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

[00233] Intranasal formulations are known in the art and are described in, for example, U.S. Pat. Nos. 4,476,1 16, 5,116,817 and 6,391,452, each of which is specifically incorporated by reference. Formulations that include ibrutinib and/or An anticancer agent, 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.

[00234] 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

[00235] 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 An anticancer agent, 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

[00236] 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.

[00237] 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 An anticancer agent; (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.

[00238] 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 An anticancer agent. 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

[00239] Formulations that include a compound of ibrutinib and/or an anticancer agent, 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.

[00240] 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.

[00241] 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

[00242] 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.

[00243] 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.

[00244] 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.

[00245] In some embodiments, the pharmaceutical compositions are formulated such that the amount of the covalent Btk inhibitor (e.g., an irreversible covalent Btk inhibitor, e.g., ibrutinib) in each unit dosage form is about 140 mg per. Kits/Article of Manufacture

[00246] 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.

[00247] 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.

[00248] For example, the container(s) include ibrutinib, optionally in a composition or in combination with paclitaxel or a paclitaxel derivative as disclosed herein. Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.

[00249] 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.

[00250] 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.

[00251] 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

[00252] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

Example 1

Materials

[00253] [³H]-paclitaxel (37.9 Ci/ mmol) was purchased from Moravek Biochemicals, Inc. (Brea, CA). Dulbecco Modified Eagle Medium (DMEM), fetal bovine serum (FBS), trypsin 0.25% and penicillin/streptomycin were products of Hyclone, Thermo Scientific (Logan, UT). Antibody C-219 against ABCB l was purchased from Signet Laboratories Inc (Dedham, MA). Antibodies D-19 against ABCCIO and β-actin were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). Ibrutinib was a gift from Johnson & Johnson Services, Inc. (New Brunswick, NJ). Paclitaxel, docetaxel, vincristine, vinblastine, colchicine and cisplatin were purchased from Tocris Bioscience (Ellisville, MO). Cepharanthine was a gift from by

Kakenshoyaku Co. (Tokyo, Japan). 3-(4, 5-Dimethylthiazol-yl)-2,5-diphenyltetrazolium bromide (MTT), Dimethyl sulfoxide, verapamil and other chemicals were obtained from Sigma Chemical (St. Louis, MO).

Cell lines and cell culture

[00254] Human epidermal carcinoma cell line KB-3-1 and colchicine-selected ABCBl- overexpressing cell line KB-C2, the human leukemia cell line K562 and doxorubicin-selected ABCBl - overexpressing derivative cell line K562/A02 were used in the study. Human embryonic kidney cell line HEK293 transfected with empty vector pcDNA3.1 and ABCB l, ABCCIO stable gene-transfected cell lines, HEK293/ABCB 1 and HEK293/ABCC 10 were used in all experiments. Cell lines used in this study were thawed from early passage stocks and were passaged for less than 6 months. All the cells were cultured under 37°C, 5% C0₂ in DMEM supplemented with 10% heat-inactivated FBS and 1% penicillin/streptomycin. All in vitro experiments were conducted at 60% to 80% cell confluence.

Experimental Animals

[00255] Male athymic NCR (nu/nu) nude mice (19-24 g, age 5-6 weeks) were purchased from Taconic Farms (NCRNU-M, Homozygous, Albino color) and were used for the ABCB 1- and ABCC10- overexpressing tumor xenograft model. All animals were treated with sterilized food and water and were maintained at the St. John' s University Animal Facility. All experiments were carried out in accordance with the guidelines on animal care and experiments of laboratory animals which were approved by the Institutional Animal Care & Use Committee (IACUC) at St. John' s University and the research was conducted in compliance with the Animal Welfare Act and other federal statutes.

MTT cytotoxicity assay

[00256] MTT assay was conducted to measure the sensitivity of the cells to anticancer drugs as previously described in Patel et al. "PD 173074, a selective FGFR inhibitor, reverses ABCB l -mediated drug resistance in cancer cells," Cancer Chemother Pharmacol . 72: 189- 199 (2013). The drug concentrations required to inhibit the cell growth by 50% (IC₅₀) were calculated from survival curves.

Immunoblot analysis

[00257] Equal amounts of cell lysate (60 μg) from various treatments with ibrutinib were resolved by SDS-PAGE and transferred onto polyvinylidene fluoride membranes through electrophoresis. The membrane was then blocked in TBST buffer (10 mmol/L Tris-HCL, 150 mmol/L NaCl, and 0.1% Tween20 pH 8.0) with 5% non-fat milk for 2 h at room temperature. ABCB l was determined from C-219 mouse monoclonal antibody and ABCC IO was determined by D-19 monoclonal antibody, β-actin was used as in internal loading control.

[³H]-paclitaxel accumulation assay

[00258] The cells were trypsinized and four aliquots (5 ^χ 10⁶ cells) were suspended in the medium, and then pre-incubated the cells with or without ibrutinib (1, 5 μΜ) or other reversal agents for 1 h at 37°C. Subsequently, these cells were treated 0.1 μΜ [³H]-paclitaxel and incubated further for another 2 h at 37°C. Then the suspended cells were pelleted at 4°C and were washed twice with 10 ml ice-cold PBS. The cells were lysed in 1% SDS, and radioactivity was measured using a liquid scintillation counter. Each sample was placed in scintillation fluid and radioactivity was measured using a Packard TRI-CARB 1900CA liquid scintillation analyzer from Packard Instrument Company Inc. (Downers Grove, Illinois, USA).

[³H]-paclitaxel efflux assay

[00259] For the efflux study, the cells were pre-treated with ibrutinib for 1 h. The

radioactive substrate [³H]-paclitaxel was then added to the cells and further incubated for 2 h after which the cells were washed in ice-cold PBS and supplemented with fresh medium with or without ibrutinib at 37°C. After 0, 30, 60 or 120 min, the aliquots of cells were removed and immediately washed twice with 10 ml of ice-cold PBS. The cells were collected and lysed for the detection of radioactivity. Each sample was placed in scintillation fluid and radioactivity was measured.

ABCB1 ATPase assay

[00260] The vanadate-sensitive ATPase activity of ABCBl in crude membranes of High- five insect cells, in the presence of concentrations of ibrutinib ranging from 0 to 80 μΜ was measured.

Docking

[00261] Ibrutinib structure was built and prepared using protocols for ligand preparation described in Guo et al., "Beta-elemene, a compound derived from rhizoma zedoariae, reverses multidrug resistance mediated by the ABCBl transporter," Oncology Reports 31 :858-866 (2014). The output file containing at the most 100 unique conformers of ibrutinib was used as an input for docking simulations into transmembrane binding site of homology - modeled human ABCB 1. Homology human ABCB 1 model was prepared using recently refined mouse ABCBl crystal structure as the template. Docking grid was refined by selecting important residues for drug interaction. All docking calculations were done using the "Extra Precision" (XP) mode of Glide docking program v6.0 (Schrodinger, LLC, New York, NY, 2013) retaining the default settings. The top-scoring pose of ibrutinib docked ABCBl complex structure was then used for graphical analysis. All computations were carried out on a Dell Precision 490n dual processor with Linux OS (Ubuntu 12.04 LTS). Nude mouse xenograft model

[00262] The ABCBl - overexpressing KB-C2 model and ABCC10- overexpressing

HEK293/ABCC 10 model were designed as follows. Briefly, KB-C2 (1.2 ^χ 10⁷) and

HEK293/ABCC 10 (1.2 x 10⁷) cells were subcutaneously injected under the armpits. The mice were randomized into four groups when the tumors reached a mean diameter of 5 mm (n = 7) and treated with one of the following regimens: (a) vehicle (autoclaved water) (q3d ^χ 7), (b) ibrutinib (30 mg/kg, p.o., q3d x 7), (c) paclitaxel (18 mg/kg, i.p., q3d x 7), and (d) ibrutinib (30 mg/kg, p.o., q3d x 7, given 1 h before giving paclitaxel) + paclitaxel (18 mg/kg, i.p., q3d 7) in ABCB l- or ABCCIO- overexpressing models. Tumor volume was measured using calipers and body weights were recorded. The body weight of the animals was monitored every 3rd day to adjust the drug dosage and to access treatment related toxicities as well as disease progression. The two perpendicular diameters of tumors (termed A and B) were recorded every 3rd day and tumor volume (V) was estimated according to the following formula:

Statistical analysis

[00263] All experiments were repeated at least three times and the differences were determined using the two-tailed student's t-test and statistical significance was determined at p < 0.05.

HPLC analysis of paclitaxel in plasma samples

[00264] Quantification of paclitaxel was conducted using isocratic Shimadzu LC-20AB liquid chromatograph equipped with the Shimadzu SIL-20A HT autosampler and LC-20AB pump connected to a Dgu-20A3 degasser (Shimadzu, Columbia, MD). The column used was a reversed-phase, Phenomenex Luna C18 column (2504.6 mm i.d., 51m; Phenomenex, Torrance, CA) with an ODS guard column (4 mm³ mm; Phenomenex). The injection volume was 20 μΐ, and the mobile phase used for the separation of paclitaxel in plasma and tissue homogenate samples consisted of acetonitrile water (53 :47, v/v) delivered at 1.0 ml/min flow rate. For paclitaxel detection, Shimadzu UV SPD-20A (Shimadzu, Columbia, MD) detector set at 227 nm was used. Data acquisition and analysis was achieved using LC Solution software version 1.22 SP1 (Shimadzu, Columbia, MD). All samples were analyzed in duplicate. Under these chromatographic conditions, the total run time was 15 min with a retention time of 12 min for paclitaxel. Standard curves for paclitaxel in plasma and tissue homogenates were prepared in the ranges of 25-5000 ng/ml.

Extraction of paclitaxel from plasma

[00265] Simple one-step protein precipitation with acetonitrile was used for sample preparation. Paclitaxel was extracted from plasma and tissue homogenate samples by precipitation with acetonitrile in 1 : 1 and 1 :2 ratios (v/v), respectively. Samples were then vortexed for 1.0 min followed by centrifugation for 10 min at 10,000 rpm. The supernatant was transferred to insert vials from which 20 μΐ was injected onto the HPLC column. Samples with concentrations higher than the calibration range limit were appropriately diluted to fit within the working calibration curve.

Ibrutinib significantly sensitizes ABCB1- and ABCC10- overexpressing cells to paclitaxel. [00266] MTT assay was performed to examine the cytotoxicity of ibrutinib on the cell lines used in our study before determining the potential reversal effect of ibrutinib on paclitaxel resistance. As shown in Fig. 1, more than 85% of the cells were viable at the concentration of ibrutinib up to 5 μΜ. Hence the concentrations of 1, 2.5 and 5 μΜ were chosen to investigate the effect of ibrutinib on enhancing the sensitivity of paclitaxel. The results showed that nontoxic concentrations of ibrutinib significantly increased the effect of paclitaxel in ABCBl - overexpressing KB-C2, K562/A02 cells and transfected HEK293/ABCB 1 cells in a dose- dependent manner, and this effect is comparable to the well-known inhibitor of ABCB1, verapamil (Fig. 2). Further results demonstrated that ibrutinib significantly sensitized ABCC10- overexpressing HEK293/ABCC 10 cells to paclitaxel and docetaxel (Fig. 3).

However, ibrutinib showed no enhanced effect of paclitaxel in the parental cells KB-3-1, K562 and HEK293/pcDNA3.1, which do not express ABCBl or ABCCIO. Ibrutinib also significantly increased the response of KB-C2, K562/A02 and HEK293/ABCB 1 cells to vincristine and colchicine, which are substrates of ABCB l (Fig. 4). Similarly, ibrutinib increased the sensitivity of HEK293/ABCC10 cells to vincristine, which is a substrate of ABCCIO (Fig. 5). In addition, ibrutinib did not significantly alter the IC₅₀ values of cisplatin, which is not a substrate of ABCBl or ABCCIO in any of the cell lines. These results suggested that ibrutinib significantly enhanced the sensitivity of paclitaxel in MDR cells overexpressing ABCBl and ABCCIO.

Ibrutinib significantly increases the accumulation of [³H]-paclitaxel in MDR cells overexpressing ABCBl and ABCCIO.

[00267] In order to understand the potential mechanism of the reversing effect of ibrutinib to paclitaxel resistance in MDR cells, the intracellular accumulation of [³H]-paclitaxel in ABCBl - overexpressing KB-C2 cells and ABCCIO- overexpressing HEK293/ABCC10 cells was tested. The results illustrated that [³H] -paclitaxel accumulation was significantly higher in the parental KB-3-1 cells than in the resistant KB-C2 cells. Ibrutinib at 1 and 5 μΜ significantly increased the intracellular level of [³H]-paclitaxel in KB-C2 cells without affecting the sensitive KB-3-1 cells (Fig. 6A). Similarly, in the presence of 1 and 5 μΜ of ibrutinib, a significant increase in the intracellular accumulation of [³H]-paclitaxel was observed in HEK293/ABCC10 cells. This effect of ibrutinib at 5 μΜ was similar to that of cepharanthine at the same concentration. However, ibrutinib did not alter the intracellular accumulation in the parental HEK293/pcDNA3.1 cells (Fig. 6B). These results indicated that ibrutinib was able to increase the accumulation of [³H] -paclitaxel in the cells overexpressing ABCBl or ABCCIO. Ibrutinib significantly decreases efflux of [³H]-paclitaxel in MDR cells overexpressing ABCBl and ABCCIO.

[00268] To determine whether ibrutinib can directly inhibit the efflux activity of ABCBl and ABCCIO, thus leading to the increased intracellular accumulation of [³H]-paclitaxel, we examined the efflux of [³H]-paclitaxel in the presence or absence of ibrutinib at different time points in the MDR cells. The results indicated that in the absence of ibrutinib, KB-C2 and HEK293/ABCC10 efflux more [³H]-paclitaxel out of the cells comparing with their paired sensitive cells KB-3-1 and HEK293/pcDNA3.1 at different time point, respectively.

However, the efflux activities of ABCBl and ABCCIO were significantly inhibited by the treatment of 5.0 μΜ of ibrutinib at 0, 30, 60 and 120 min, thus inducing an obvious increased accumulation of [³H]-paclitaxel in the MDR cells but not in the parental sensitive cells (Fig. 6C, D). These results further validated the efficacy of ibrutinib to inhibit the drug efflux function of ABCBl and ABCCIO.

Ibrutinib does not significantly alter the protein expression level of ABCBl or ABCCIO in the MDR cells.

[00269] The reversal effect of ibrutinib might act by either inhibiting the function of the protein or decreasing the expression level of the protein. In order to ascertain whether ibrutinib affect the protein expression level of ABCBl and ABCCIO, the MDR cells were treated with 5 μΜ of ibrutinib for 24, 48 and 72h, respectively. Immunoblot analysis confirmed that ibrutinib did not significantly alter the protein expression level of ABCBl or ABCCIO in the MDR cells (Fig. 7A, B). These findings indicated that the reversal of paclitaxel resistance by ibrutinib was not the result of a decrease in ABCBl or ABCCIO protein expression.

Ibrutinib stimulates the ATPase activity of ABCBl.

[00270] The drug efflux process by ABC transporters utilizes the energy from hydrolysis of ATP and substrates or modulators that interact with this transporter might stimulate or inhibit ATPase activity. To assess the effect of ibrutinib on the ATPase activity of ABCBl, ABCBl -mediated ATP hydrolysis with different concentrations of ibrutinib (0-80 μΜ) was tested. Ibrutinib stimulated the ATPase activity of ABCBl in a concentration dependent manner, with a maximal stimulation of 3.05-fold of the basal activity. Fig. 7C demonstrates that the concentration of ibrutinib required to obtain 50% stimulation is 0.641 μΜ. The result indicated that ibrutinib interacts with ABCBl transporter in a substrate manner.

Ibrutinib Docking Analysis with Human ABCBl Homology Model [00271] In the absence of the crystal structure of human ABCBl, a homology model based on the updated crystal structure of ABCB l from mice was developed. To understand the molecular interactions of ibrutinib with human ABCB l, docking studies were performed within the drug-binding cavity of homology-modeled human ABCB l . The top docking score was found to be -9.6 kcal/mol and this pose was chosen for discussion of the binding interactions within the large binding site in ABCB 1. The figure of ibrutinib and nearby residues was shown in Fig. 7D.

[00272] The docking pose indicated the importance of hydrophobic and electrostatic interactions within the large drug-binding cavity of ABCBl . The two-benzene group (D- and E-ring) forms hydrophobic contacts with side chains of residues Ile306, Leu339, Phe343 and Gln990. The pyrazole and pyrimidine ring (B- and C-ring) bind to the hydrophobic pocket formed by the side chains of residue Tyr310, Phe728, Ala729, Phe732 and Phe983.

Moreover, the piperidine (A-ring) is stabilized by hydrophobic contact with Met69, Phe335, Phe336, Ile340, Tyr953 and Phe983. In addition, N₃ atom of C-ring formed a hydrogen bonding interaction with side chain amide 'NET of Gln725 (-N · H₂N-Gln725, 1.78 A). The carbonyl oxygen atom in Gln725 also formed a hydrogen bond with the amino group in C- ring (-NH-H · OC-Gln725, 2.07 A).

Ibrutinib significantly potentiates the anticancer activity of paclitaxel in ABCBl- and ABCC10- expressing cell xenograft model

[00273] An established KB-C2 cell xenograft model in nude mice was used to evaluate the efficacy of ibrutinib on paclitaxel induced anti-tumor activity. After serious of pilot studies, a dose of 30 mg/kg of ibrutinib and a dose of 18 mg/kg of paclitaxel was chosen for further studies. As shown in Fig. 8A, there was no significant difference in tumor size between groups treated with normal saline and ibrutinib. The group treated with paclitaxel (18 mg/kg i.p.) mildly reduced the growth rate of tumors compared to normal saline control group. However, the group treated with ibrutinib (30 mg/kg p.o.) in combination with paclitaxel (18 mg/kg i.p.) produced a significant inhibition of tumor growth compared with groups treated with normal saline, paclitaxel, or ibrutinib alone (Fig. 8A, B). The mean values of the weight of tumors removed from sacrificed mice were analyzed in Fig. 8C. In addition, there was no significant difference in body weight or in phenotypic changes between the treatment groups after the course of therapy (Fig. 8D). These results indicated that ibrutinib in combination with paclitaxel does not increase the incidence of toxicity; but improves the anti-tumor efficacy of paclitaxel in KB-C2 cell xenograft model. Similarly, a HEK293/ABCC 10 cell xenograft model was established in nude mice that was used to evaluate the efficacy of ibrutinib on the paclitaxel induced anti-tumor activity. The results demonstrated that the combination of ibrutinib and paclitaxel produced a significant inhibition of tumor growth compared with animals treated with paclitaxel, normal saline, or ibrutinib alone (P < 0.05; Fig. 9A, B, C). Furthermore, at the selected doses, no mortality or apparent decrease in body weight was observed in all the groups, indicating that the combination regimen did not increase the incidence of toxic side effects (Fig. 9D). In an effort to understand the pharmacokinetic implications of ibrutinib on systemic distribution of paclitaxel, a group of mice were administered paclitaxel (18 mg/kg) intravenously with or without oral

administration of ibrutinib (30 mg/kg). As seen in Fig. 5, the paclitaxel concentration increased gradually with time over a period of 240 min. However the administration of ibrutinib had no effect on the paclitaxel concentration. There was no significant difference in the plasma concentration of paclitaxel over a period of 240 min in the mice receiving paclitaxel alone and the mice receiving ibrutinib in combination with paclitaxel.

Discussion

[00274] Ibrutinib was initially subjected to cytotoxicity assays to determine its toxicity. With the data obtained relatively non-toxic concentrations of 1, 2.5 and 5 μΜ were used to study its potential to reverse paclitaxel resistance. As demonstrated in Fig. 2, ibrutinib significantly potentiated the cytotoxicity of paclitaxel in KB-C2, HEK293/ABCB 1 and K562/A02 cells in a concentration dependent manner. Further studies showed that ibrutinib significantly enhanced the cytotoxicity of paclitaxel in HEK293/ABCC10 cells. In addition, ibrutinib could also potentiate the cytotoxicity of other substrates of ABCB l or ABCCIO but not cisplatin, which is not a substrate of these two transporters. However, ibrutinib showed no significant effect to the parental KB-3-1 and HEK293/pcDNA3.1 cells. These findings indicated that ibrutinib may antagonize ABCB l - and ABCC IO- mediated paclitaxel resistance. This effect was due to a significant increase in the intracellular accumulation of [³H] -paclitaxel in the resistant cells when incubated with ibrutinib. [³H]-paclitaxel efflux experiments showed that ibrutinib significantly reduced the rapid efflux of the [³H] -paclitaxel in KB-C2 and HEK293/ABCC 10 cells in a time-dependent manner (Fig. 6).

[00275] Possibly, the effect of ibrutinib on ABCB l- and ABCC IO- mediated paclitaxel resistance can be obtained either by antagonizing the function of the transporters or lowering the protein expression levels. Accordingly, Western blot was used to analyze the expression level of ABCB l and ABCCIO, after incubating the cells with ibrutinib for 24, 48 and 72 h. Western blot results illustrated that ibrutinib did not alter the expression level of ABCB l or ABCCIO when incubated for 72 h. This excludes the probability that the effect of ibrutinib on paclitaxel resistance was due to alteration in the protein expression.

[00276] Because the ABC transporters pump the substrates drug out of the cells utilizing energy derived from ATP hydrolysis, the profile of drug-stimulated ATPase activity in the ABCBl- expressing membrane is considered to reflect the interaction of transporter pumps with drug substrates. Thus ATPase assay was performed to test the interaction of ibrutinib and ABCB 1 transporter. Ibrutinib was found to stimulate ATPase activity in a concentration- dependent manner indicating that ibrutinib may be a substrate and therefore a competitive inhibitor of ABCBl . In addition, a docking analysis was performed to study the binding conformation of ibrutinib within the large cavity of the transmembrane region of ABCB 1.

[00277] To examine whether ibrutinib can also reverse ABCB l and ABCCIO- mediated paclitaxel resistance in vivo, the effect of ibrutinib on the toxicity of paclitaxel in the nude mouse xenograft model was studied. Consistent with in vitro experiments, the results obtained from in vivo studies showed that combination of paclitaxel with ibrutinib obviously enhances the anticancer activity of paclitaxel in the ABCBl- and ABCCIO- overexpressing xenograft model. In addition the combination of ibritunib with paclitaxel did not alter the plasma paclitaxel concentration, thereby ensuring that the combination does not adversely redistribute the paclitaxel concentration in vivo.

[00278] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. Use of a combination comprising a Btk inhibitor and paclitaxel for treatment of a cancer characterized by an overexpression of an ABC transporter.

2. The use of claim 1, wherein the combination sensitizes the cancer to paclitaxel.

3. The use of claim 1, wherein the combination decreases paclitaxel efflux in the subject.

4. The use of claim 1, wherein the ABC-transporter is ATP -binding cassette subfamily B member 1 (ABCB 1), ATP-binding cassette sub-family G member 2 (ABCG2), ATP- binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette sub-family C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO).

5. The use of claim 4, wherein the ABC-transporter is ABCBl .

6. The use of claim 4, wherein the ABC-transporter is ABCCIO.

7. The use of any one of the claims 1-6, wherein the cancer is a solid tumor.

8. The use of claim 7, wherein the solid tumor is prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer or melanoma.

9. The use of any one of the claims 1-6, wherein the cancer is a hematologic cancer.

10. The use of claim 9, wherein the hematologic cancer is a leukemia, a lymphoma, a T- cell malignancy, or a B-cell malignancy.

11. The use of claim 10, wherein the hematologic cancer is a B-cell malignancy.

12. The use of claim 11, wherein the B-cell malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

13. The use of any one of the claims 1-12, wherein the cancer is a relapsed or refractory cancer.

14. The use of any one of the claims 1-13, wherein the cancer is a metastasized cancer.

15. The use of any one of the claims 1-14, wherein the Btk inhibitor is ibrutinib.

16. The use of claim 15, wherein ibrutinib is administered once a day, two times per day, three times per day, four times per day, or five times per day.

17. The use of claim 15 or 16, wherein ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day.

18. The use of any one of the claims 15 -17, wherein ibrutinib is administered orally.

19. The use of any one of the claims 15 -18, wherein ibrutinib and paclitaxel are

administered simultaneously, sequentially or intermittently.

20. The use of any one of the claims 1-19, further comprising administering an additional anticancer agent.

21. The use of any one of the claims 35 -37, wherein ibrutinib is administered orally.

22. The use of any one of the claims 35 -38, wherein ibrutinib and paclitaxel are

administered simultaneously, sequentially or intermittently.

23. The use of any one of the claims 21-39, further comprising administering an

additional anticancer agent.

24. Use of a therapeutically effective amount of a combination comprising a BTK

inhibitor and paclitaxel for treatment of a paclitaxel-resistant cancer.

25. The use of claim 24, wherein the paclitaxel-resistant cancer is characterized by an overexpression of an ABC-transporter.

26. The use of claim 25, wherein the ABC-transporter is ATP-binding cassette subfamily B member 1 (ABCB l), ATP-binding cassette sub-family G member 2 (ABCG2), ATP-binding cassette sub-family C member 1 (ABCCl), ATP-binding cassette subfamily C member 2 (ABCC2), or ATP-binding cassette sub-family C member 10 (ABCCIO).

27. The use of claim 26, wherein the ABC-transporter is ABCB 1.

28. The use of claim 26, wherein the ABC-transporter is ABCCIO.

29. The use of any one of claims 24-28, wherein the combination sensitizes the cancer to paclitaxel.

30. The use of any one of claims 24-29, wherein the combination decreases paclitaxel efflux in the subject.

31. The use of any one of the claims 24-30, wherein the cancer is a solid tumor.

32. The use of claim 31, wherein the solid tumor is prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer or melanoma.

33. The use of any one of claims 24-30, wherein the cancer is a hematologic cancer.

34. The use of claim 33, wherein the hematologic cancer is a leukemia, a lymphoma, a T- cell malignancy, or a B-cell malignancy.

35. The use of claim 33, wherein the hematologic cancer is a B-cell malignancy.

36. The use of claim 34, wherein the B-cell malignancy is acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.

37. The use of any one of the claims 24-36, wherein the cancer is a relapsed or refractory cancer.

38. The use of any one of the claims 24-36, wherein the cancer is a metastasized cancer.

39. The use of any one of the claims 24-38, wherein the BTK inhibitor is ibrutinib.

40. The use of claim 39, wherein ibrutinib is administered once a day, two times per day, three times per day, four times per day, or five times per day.