WO2016029175A1

WO2016029175A1 - Methods for treating egfr mutant disorders

Info

Publication number: WO2016029175A1
Application number: PCT/US2015/046401
Authority: WO
Inventors: Betty Chang; Taisei Kinoshita
Original assignee: Pharmacyclics Llc
Priority date: 2014-08-21
Filing date: 2015-08-21
Publication date: 2016-02-25

Abstract

Disclosed herein are methods, systems, and kits for patient stratification based on the presence or absence of at least one of a modification at amino acid position 858 in EGFR and a deletion from amino acid position 746 to amino acid position 750 in EGFR. Further described are methods of monitoring a therapeutic regimen, and optimizing a therapeutic regimen. Additional modifications in EGFR include modification at amino acid position 790, modifications in KRAS, and expression level of PTEN.

Description

METHODS FOR TREATING EGFR MUTANT DISORDERS

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisional patent application no. 62/040,390 entitled "METHODS FOR TREATING EGFR MUTANT DISORDERS" filed on August 21, 2014, which is herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cells types except T lymphocytes and natural killer cells. Btk plays an essential role in the B-cell signaling pathway linking cell surface B-cell receptor (BCR) stimulation to downstream intracellular responses.

[0003] 1 -((R)-3 -(4-amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo [3 ,4-d]pyrimidin- 1 -yl)piperidin- 1 - yl)prop-2-en-l-one is also known by its IUPAC name as l-{(3i?)-3-[4-amino-3-(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-JJpyrimidin- 1 -yljpiperidin- 1 -yl}prop-2-en-l -one or 2-Propen- 1-one, l-[(3i?)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-<i]pyrimidin-l-yl]-l- piperidinyl-, and has been given the USAN name, Ibrutinib. The various names given for Ibrutinib are used interchangeably herein.

SUMMARY OF THE INVENTION

[0004] Disclosed herein, in certain embodiments, is a method for selecting an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) administering to the individual a therapeutically effective amount of the BTK inhibitor if there is a presence of at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. Also disclosed herein, in certain embodiments, is a method of monitoring whether an individual receiving a BTK inhibitor for treatment of a solid tumor is responsive or is likely to respond to therapy, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) characterizing the individual as responsive or is likely to respond to therapy with the BTK inhibitor if the individual has at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. Further disclosed herein, in certain embodiments, is a method of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of a solid tumor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) modifying, discontinuing, or continuing the treatment based on the presence or absence of at least one of the modification to an amino acid residue at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. In some embodiments, the modification at amino acid position 858 in EGFR is L858R. In some embodiments, the method further comprises determining the presence or absence of a modification in KRAS. In some embodiments, KRAS does not contain a modification. In some embodiments, the method further comprises determining the expression rate of PTEN relative to a control. In some embodiments, the expression level of PTEN increase by 0.5-fold, 1-fold, 1.5- fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, or more compared to the control. In some embodiments, the control is the expression level of PTEN in an individual who does not have the solid tumor. In some embodiments, the control is the expression level of PTEN in an individual prior to administration of the BTK inhibitor. In some embodiments, the solid tumor is selected from prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer and melanoma. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the solid tumor is a relapsed or refractory solid tumor. In some embodiments, the BTK inhibitor is ibrutinib. 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, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from Erlotinib HC1 (OSI-744), Gefitinib (ZD 1839), lapatinib (GW-572016) Ditosylate, afatinib (BIBW2992), neratinib (HKI-272), canertinib (CI-1033), lapatinib, AG-490 (Tyrphostin B42), CP-724714, dacomitinib (PF299804, PF299), WZ4002, AZD8931 (Sapitinib), CUDC-101, AG- 1478 (Tyrphostin AG- 1478), PD153035 HC1, pelitinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), OSI-420, WZ3146, AST-1306, CO-1686 (AVL-301), varlitinib, icotinib, TAK-285, WHI-P154, desmethyl erlotinib (CP-473420, OSI-774), PD168393, CNX- 2006, tyrphostin 9, AG-18, WZ8040, genistein, chrysophanic acid, and butein. In some embodiments, the additional therapeutic agent is selected from among a chemotherapeutic agent or radiation therapy. In some embodiments, the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, ibrutinib and the additional therapeutic agent are administered simultaneously, sequentially or intermittently.

[0005] Disclosed herein, in certain embodiments, is a method for selecting an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) determining the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR; and (b) to the individual a therapeutically effective amount of ibrutinib if there is an absence of the modification at amino acid position 790 in EGFR. Also disclosed herein, in certain

embodiments, is a method of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of a solid tumor, comprising: (a) determining the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR; and (b) modifying, discontinuing, or continuing the treatment based on the presence or absence of the modification to an amino acid residue at amino acid position 790 in EGFR. In some embodiments, the modification at amino acid position 790 in EGFR is T790M. In some embodiments, the method further comprises determining the presence or absence of a modification to an aromatic residue at amino acid position 858 in EGFR. In some embodiments, the modification at amino acid position 858 in EGFR is L858R. In some embodiments, the method further comprises administering to the individual a therapeutically effective amount of a BTK inhibitor if there is an absence of the modification at amino acid position 790 and at amino acid position 858 in EGFR. In some embodiments, the method further comprises determining the presence or absence of modifications in KRAS. In some embodiments, KRAS contains a modification. In some embodiments, the method further comprises determining the expression level of PTEN relative to a control. In some embodiments, the expression level of PTEN decrease by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5- fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, or more compared to the control. In some embodiments, the control is the expression level of PTEN in an individual who does not have the solid tumor. In some embodiments, the control is the expression level of PTEN in an individual prior to administration of the BTK inhibitor. In some embodiments, the solid tumor is selected from prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer and melanoma. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the solid tumor is a relapsed or refractory solid tumor. In some embodiments, the BTK inhibitor is ibrutinib. 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, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from Erlotinib HC1 (OSI-744), Gefitinib

(ZD 1839), lapatinib (GW-572016) Ditosylate, afatinib (BIBW2992), neratinib (HKI-272), canertinib (CI-1033), lapatinib, AG-490 (Tyrphostin B42), CP-724714, dacomitinib (PF299804, PF299), WZ4002, AZD8931 (Sapitinib), CUDC-101, AG-1478 (Tyrphostin AG- 1478), PD 153035 HC1, pelitinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), OSI- 420, WZ3146, AST-1306, CO-1686 (AVL-301), varlitinib, icotinib, TAK-285, WHI-P154, desmethyl erlotinib (CP-473420, OSI-774), PD 168393, CNX-2006, tyrphostin 9, AG- 18, WZ8040, genistein, chrysophanic acid, and butein. In some embodiments, the additional therapeutic agent is selected from among a chemotherapeutic agent or radiation therapy. In some embodiments, the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fiudarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL- 101 , ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, ibrutinib and the additional therapeutic agent are administered simultaneously, sequentially or intermittently.

[0006] Disclosed herein, in certain embodiments, is a kit for carrying out the method described herein, and comprises one or more reagents for determining the presence or absence of modifications in EGFR and KRAS in the sample. In some embodiments, the kit further comprises one or more reagents for determining the expression level of PTEN.

[0007] Disclosed herein, in certain embodiments, is a system of assessing an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) a digital processing device comprising an operating system configured to perform executable instructions, and an electronic memory; (b) a dataset stored in the electronic memory, wherein the dataset comprises raw data for use in determining one or more modifications in EGFR; and (c) a computer program including instructions executable by the digital processing device to create an application comprising: (i) a first software module configured to analyze the dataset to determine the presence or absence of at least one of a modification to an amino acid residue at amino acid position 8 8 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (ii) a second software module to assign the individual as a candidate for treatment with ibrutinib if there is a presence of at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750. In some embodiments, the modification at amino acid position 858 in EGFR is L858R. In some embodiments, the system further comprises analyzing KRAS to determine the presence or absence of a modification. In some embodiments, KRAS does not contain a modification. In some embodiments, the system further comprises determining the expression level of PTEN relative to a control. In some embodiments, the expression level of PTEN increase by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5- fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, or more compared to the control. In some embodiments, the control is the expression level of PTEN in an individual who does not have the solid tumor. In some embodiments, the control is the expression level of PTEN in an individual prior to administration of the BTK inhibitor. In some embodiments, the solid tumor is selected from prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer and melanoma. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the solid tumor is a relapsed or refractory solid tumor. In some embodiments, the BTK inhibitor is ibrutinib. 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, the system further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from Erlotinib HC1 (OSI-744), Gefitinib (ZD 1839), lapatinib (GW-572016) Ditosylate, afatinib (BIBW2992), neratinib (HKI-272), canertinib (CI-1033), lapatinib, AG-490 (Tyrphostin B42), CP-724714, dacomitinib (PF299804, PF299), WZ4002, AZD8931 (Sapitinib), CUDC-101, AG-1478 (Tyrphostin AG-1478), PD153035 HC1, pelitinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), OSI-420, WZ3146, AST-1306, CO-1686 (AVL-301), varlitinib, icotinib, TAK- 285, WHI-P154, desmethyl erlotinib (CP-473420, OSI-774), PD168393, CNX-2006, tyrphostin 9, AG-18, WZ8040, genistein, chrysophanic acid, and butein. In some embodiments, the additional therapeutic agent is selected from among a chemotherapeutic agent or radiation therapy. In some embodiments, the chemotherapeutic agent is selected from among

chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101 , ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, ibrutinib and the additional therapeutic agent are administered simultaneously, sequentially or intermittently.

[0008] Disclosed herein, in certain embodiments, is a system of assessing an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) a digital processing device comprising an operating system configured to perform executable instructions, and an electronic memory; (b) a dataset stored in the electronic memory, wherein the dataset comprises raw data for use in determining one or more modifications in EGFR; and (c) a computer program including instructions executable by the digital processing device to create an application comprising: (i) a first software module configured to analyze the dataset to determine the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR; and (ii) a second software module to assign the individual as a candidate for treatment with ibrutinib if there is an absence of the modification at amino acid position 790 in EGFR. In some embodiments, the modification at amino acid position 790 in EGFR is T790M. In some embodiments, the system further comprises determining the presence or absence of a modification to an aromatic residue at amino acid position 858 in EGFR. In some embodiments, the modification at amino acid position 858 in EGFR is L858R. In some embodiments, the system further comprises administering to the individual a therapeutically effective amount of ibrutinib if there is an absence of the modification at amino acid position 790 and at amino acid position 858 in EGFR. In some embodiments, the system further comprises analyzing KRAS to determine the presence or absence of a modification. In some embodiments, KRAS does contain a modification. In some embodiments, the system further comprises determining the expression level of PTEN relative to a control. In some embodiments, the expression level of PTEN decrease by 0.5 -fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20- fold, 50-fold, or more compared to the control. In some embodiments, the solid tumor is selected from prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer,

gastroenterological cancer and melanoma. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the solid tumor is a relapsed or refractory solid tumor. In some embodiments, the BTK inhibitor is ibrutinib. 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, the system further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an EGFR inhibitor. In some embodiments, the EGFR inhibitor is selected from Erlotinib HC1 (OSI-744), Gefitinib (ZD 1839), lapatinib (GW-572016) Ditosylate, afatinib (BIBW2992), neratinib (HKI-272), canertinib (CI-1033), lapatinib, AG-490 (Tyrphostin B42), CP-724714, dacomitinib (PF299804, PF299), WZ4002, AZD8931 (Sapitinib), CUDC-101, AG-1478 (Tyrphostin AG-1478), PD153035 HC1, pelitinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), OSI-420, WZ3146, AST-1306, CO-1686 (AVL-301), varlitinib, icotinib, TAK- 285, WHI-P154, desmethyl erlotinib (CP-473420, OSI-774), PD168393, CNX-2006, tyrphostin 9, AG-18, WZ8040, genistein, chrysophanic acid, and butein. In some embodiments, the additional therapeutic agent is selected from among a chemotherapeutic agent or radiation therapy. In some embodiments, the chemotherapeutic agent is selected from among

chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, ibrutinib and the additional therapeutic agent are administered simultaneously, sequentially or intermittently.

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. 1 exemplifies the classification of non-small cell lung cancer cell lines (NSCLC), NCI-H3255, PC9, NCI-H2170, NCI-H2073, NCI-H1975, NCI-H1650, NCI-H460 and A549, according to their sensitivity to treatment with EGFR inhibitors, gefitinib (G), erlotinib (E) or ibrutinib.

[0011] Fig. 2 exemplifies the effect of presence or absence of KRAS mutation on treatment of non-small cell lung cancer cell lines (NSCLC), PC9, H1975, SK-MES1, COR-L105, H2170, H358, H441, H2122 and COR-L23, with ibrutinib.

[0012] Fig. 3 Illustrates a conceptual schematic of an exemplary computer server to be used for processing a system and a method described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0013] Disclosed herein, in certain embodiments, is a method for selecting an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) administering to the individual a therapeutically effective amount of the BTK inhibitor if there is a presence of at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR.

[0014] Disclosed herein, in certain embodiments, is a method of monitoring whether an individual receiving a BTK inhibitor for treatment of a solid tumor is responsive or is likely to respond to therapy, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) characterizing the individual as responsive or is likely to respond to therapy with the BTK inhibitor if the individual has at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. [0015] Disclosed herein, in certain embodiments, is a method of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of a solid tumor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) modifying, discontinuing, or continuing the treatment based on the presence or absence of at least one of the modification to an amino acid residue at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR.

[0016] Disclosed herein, in certain embodiments, is a system of assessing an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) a digital processing device comprising an operating system configured to perform executable instructions, and an electronic memory; (b) a dataset stored in the electronic memory, wherein the dataset comprises raw data for use in determining one or more modifications in EGFR; and (c) a computer program including instructions executable by the digital processing device to create an application comprising: (i) a first software module configured to analyze the dataset to determine the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (ii) a second software module to assign the individual as a candidate for treatment with ibrutinib if there is a presence of at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750.

[0017] Disclosed herein, in certain embodiments, is a system of assessing an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) a digital processing device comprising an operating system configured to perform executable instructions, and an electronic memory; (b) a dataset stored in the electronic memory, wherein the dataset comprises raw data for use in determining one or more modifications in EGFR; and (c) a computer program including instructions executable by the digital processing device to create an application comprising: (i) a first software module configured to analyze the dataset to determine the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR; and (ii) a second software module to assign the individual as a candidate for treatment with ibrutinib if there is an absence of the modification at amino acid position 790 in EGFR.

[0018] Disclosed herein, in certain embodiments, are kits for carrying out the methods described herein, comprising one or more reagents for determining the presence or absence of

modifications in EGFR and KRAS in the sample. In some embodiments, the kit further comprises one or more reagents for determining the expression level of PTEN. Certain Terminology

[0019] 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.

[0020] 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 μί" means "about 5 μί" and also "5 μ " Generally, the term "about" includes an amount that would be expected to be within experimental error.

[0021] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0022] 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).

[0023] "Antibodies" and "immunoglobulins" (Igs) are glycoproteins having the same structural characteristics. The terms are used synonymously. In some instances the antigen specificity of the immunoglobulin is known.

[0024] The term "antibody" is used in the broadest sense and covers fully assembled antibodies, antibody fragments that can bind antigen (e.g., Fab, F(ab')2, Fv, single chain antibodies, diabodies, antibody chimeras, hybrid antibodies, bispecific antibodies, humanized antibodies, and the like), and recombinant peptides comprising the forgoing.

[0025] The terms "monoclonal antibody" and "mAb" as used herein refer to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts.

[0026] "Native antibodies" and "native immunoglobulins" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light and heavy-chain variable domains.

[0027] The term "variable" refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies. Variable regions confer antigen-binding specificity. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions, both in the light chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are celled in the framework (FR) regions. The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a β-pleated-sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the β-pleated-sheet structure. The CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, Kabat et al. (1991) NIH PubL. No. 91 -3242, Vol. I, pages 647-669). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as Fc receptor (FcR) binding, participation of the antibody in antibody-dependent cellular toxicity, initiation of complement dependent cytotoxicity, and mast cell degranulation.

[0028] The term "hypervariable region," when used herein, refers to the amino acid residues of an antibody that are responsible for antigen-binding. The hypervariable region comprises amino acid residues from a "complementarily determining region" or "CDR" (i.e., residues 24-34 (LI), 50-56 (L2), and 89-97 (L3) in the light-chain variable domain and 31-35 (HI), 50-65 (H2), and 95-102 (H3) in the heavy-chain variable domain; Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institute of Health, Bethesda, Md.) and/or those residues from a "hypervariable loop" (i.e., residues 26-32 (LI), 50-52 (L2), and 91-96 (L3) in the light-chain variable domain and (HI), 53-55 (H2), and 96-101 (13) in the heavy chain variable domain; Clothia and Lesk, (1987) J. Mol. Biol, 196:901 -917).

"Framework" or "FR" residues are those variable domain residues other than the hypervariable region residues, as herein deemed. [0029] "Antibody fragments" comprise a portion of an intact antibody, preferably the antigen- binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab, F(ab')2, and Fv fragments; diabodies; linear antibodies (Zapata et al. (1995) Protein Eng. 10: 1057-1062); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site, and a residual "Fc" fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab')2 fragment that has two antigen-combining sites and is still capable of cross-linking antigen.

[0030] "Fv" is the minimum antibody fragment that contains a complete antigen recognition and binding site. This region consists of a dimer of one heavy- and one light-chain variable domain in tight, non-covalent association. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer.

Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

[0031] The Fab fragment also contains the constant domain of the light chain and the first constant domain (CHI) of the heavy chain. Fab fragments differ from Fab' fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHI domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. Fab' fragments are produced by reducing the F(ab')2 fragment's heavy chain disulfide bridge. Other chemical couplings of antibody fragments are also known.

[0032] The "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0033] Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of human immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl , and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. Different isotypes have different effector functions. For example, human IgGl and IgG3 isotypes have ADCC (antibody dependent cell-mediated cytotoxicity) activity. Methods of Use

[0034] Disclosed herein, in certain embodiments, are methods for selecting an individual having solid tumor for treatment with a BTK inhibitor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 8 8 and a deletion from amino acid position 746 to amino acid position 750 in EGF ; and (b) administering to the individual a therapeutically effective amount of the BTK inhibitor if there is a presence of at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR.

[0035] Disclosed herein, in certain embodiments, are methods of monitoring whether an individual receiving a BTK inhibitor for treatment of a solid tumor is responsive or is likely to respond to therapy, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) characterizing the individual as responsive or is likely to respond to therapy with the BTK inhibitor if the individual has at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR.

[0036] Disclosed herein, in certain embodiments, are methods of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of a solid tumor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) modifying, discontinuing, or continuing the treatment based on the presence or absence of at least one of the modification to an amino acid residue at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR.

[0037] In some embodiments, the cancer is a solid tumor. 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. 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 myo fibroblastic 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. 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.

[0038] In some embodiments, the cancer is selected from prostate cancer, pancreatic cancer, breast cancer, colorectal (colon) cancer, lung cancer, gastroenterological cancer and melanoma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the cancer is colorectal (colon) cancer. In some embodiments, the cancer is gastroenterological cancer. In some embodiments, the cancer is melanoma.

[0039] In some embodiments, the breast cancer is ductal carcinoma in situ (intraductal carcinoma), lobular carcinoma in situ, invasive (or infiltrating) ductal carcinoma, invasive (or infiltrating) lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma. In some embodiments, the invasive breast carcinoma is further categorized into subtypes. In some embodiments, the subtypes include adenoid cystic (or adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma or mixed carcinoma.

[0040] Disclosed herein, in certain embodiments, are methods for selecting an individual having lung cancer for treatment with a BTK inhibitor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 8 8 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) administering to the individual a therapeutically effective amount of the BTK inhibitor if there is a presence of at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. Also disclosed herein, in certain embodiments, are methods of monitoring whether an individual receiving a BTK inhibitor for treatment of lung cancer is responsive or is likely to respond to therapy, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) characterizing the individual as responsive or is likely to respond to therapy with the BTK inhibitor if the individual has at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. Further disclosed herein, in certain embodiments, are methods of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of lung cancer, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) modifying, discontinuing, or continuing the treatment based on the presence or absence of at least one of the modification to an amino acid residue at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. [0041] Disclosed herein, in certain embodiments, are methods for selecting an individual having non-small cell lung cancer (NSCLC) for treatment with a BTK inhibitor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) administering to the individual a therapeutically effective amount of the BTK inhibitor if there is a presence of at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. Also disclosed herein, in certain embodiments, are methods of monitoring whether an individual receiving a BTK inhibitor for treatment of non-small cell lung cancer (NSCLC) is responsive or is likely to respond to therapy, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) characterizing the individual as responsive or is likely to respond to therapy with the BTK inhibitor if the individual has at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. Further disclosed herein, in certain embodiments, are methods of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of non-small cell lung cancer (NSCLC), comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) modifying, discontinuing, or continuing the treatment based on the presence or absence of at least one of the modification to an amino acid residue at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR.

[0042] Non-small cell lung cancer (NSCLC) is any type of lung cancer other than small cell lung cancer (SCLC). In general, NSCLC originates in the lung epithelial cells. In some cases, NSCLC includes a wide range of histological subtypes, such as for example, adenocarcinoma, bronchioalveolar, squamous, anaplastic and large scale carcinomas. Depending on the staging of NSCLC, different approaches are adopted for treatment. In some instances, NSCLC is insensitive to chemotherapy and radiation. Patients with advanced stage NSCLC exhibit metastatic disease. If left untreated, patients diagnosed with an advanced stage NSCLC are known to have a median survival of 4- 5 months only. Less than 10% of patients diagnosed with an advanced stage NSCLC are known to survive up to one year. In some cases, more than 60% of NSCLCs have been shown to express EGFR. In some cases, inhibitors of EGFR are used for treatment of individuals having NSCLC. [0043] In some embodiments, the cancer is a hematologic cancer. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, or a B-cell malignancy.

[0044] In some embodiments, the 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) and germinal center diffuse large B-cell lymphoma (GCB DLBCL). In some embodiments, ABC-DLBCL is characterized by a CD79B mutation. In some embodiments, ABC-DLBCL is characterized by a CD79A mutation. In some embodiments, the ABC-DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof. In some embodiments, the cancer is acute or chronic myelogenous (or myeloid) leukemia,

myelodysplastic syndrome, or acute lymphoblastic leukemia.

[0045] 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.

[0046] In some embodiments, the cancer is a relapsed or refractory cancer. In some

embodiments, the relapsed or refractory cancer is a solid tumor. 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. 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 myo fibroblastic 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. 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.

[0047] In some embodiments, the relapsed or refractory cancer 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 cancer is prostate cancer. In some embodiments, the relapsed or refractory cancer is breast cancer. In some embodiments, the relapsed or refractory cancer is lung cancer. In some embodiments, the relapsed or refractory cancer is colorectal (colon) cancer. In some embodiments, the relapsed or refractory cancer is gastroenterological cancer. In some embodiments, the relapsed or refractory cancer is melanoma.

[0048] In some embodiments, the relapsed or refractory cancer is a relapsed or refractory breast cancer. In some embodiments, the relapsed or refractory breast cancer is ductal carcinoma in situ (intraductal carcinoma), lobular carcinoma in situ, invasive (or infiltrating) ductal carcinoma, invasive (or infiltrating) lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma. In some embodiments, the invasive breast carcinoma is further categorized into subtypes. In some embodiments, the subtypes include adenoid cystic (or adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma or mixed carcinoma.

[0049] In some embodiments, the relapsed or refractory cancer is a hematologic cancer. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, or a B-cell malignancy.

[0050] In some embodiments, the relapsed or refractory 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, 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) and germinal center diffuse large B-cell lymphoma (GCB DLBCL). In some embodiments, ABC-DLBCL is characterized by a CD79B mutation. In some embodiments, ABC-DLBCL is characterized by a CD79A mutation. In some embodiments, the ABC-DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof. In some embodiments, the cancer is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia.

[0051] 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.

Biomarkers

[0052] Disclosed herein are methods of using biomarkers for stratification of patients, for monitoring the progression of a treatment, or for optimization of a therapeutic regimen. In some embodiments, the biomarkers are evaluated based on the presence or absence of modifications or mutations in the biomarkers, or by expression level. In some embodiments, the biomarkers include EGFR, KRAS and PTEN.

[0053] Epidermal growth factor receptor (EGFR, ErbB-1 , or HERl in humans) is a member of the ErbB family of receptors. Mutations of EGFR generally lead to overexpression or overactivity and have been associated with numerous cancers, including solid tumors such as lung cancer and breast cancer.

[0054] In some embodiments, EGFR contains one or more modifications to the EGFR gene. In some embodiments, mutations or modifications of the EGFR gene comprise base substitution, insertion, deletion, DNA rearrangement, copy number alteration, or a combination thereof. In some embodiments, the EGFR protein comprises one or more modifications. In some embodiments, the modifications in the EGFR protein includes, but is not limited to,

modifications at positions corresponding to amino acid residues 719, 731, 746, 747, 748, 749, 750, 751 , 752, 753, 759, 761 , 762, 768, 769, 770, 773, 779, 790, 792, 810, 826, 833, 835, 847, 851 , 853, 858, 861 , 873, 62, 222, 237, 210, 768, 719, 336, 393, 526, 536, 114, 598, 289, 244, 273, 282, and 786. In some embodiments, the modifications include E746-A750 deletion, E746- S752 deletion, L747-T751 deletion, S752-I759 deletion, L861Q, G719C, L747-P753del, L747- E749 deletion, A750P, V769M, W731 Stop, D761-E762 insertion of glutamic acid, alanine, phenylalanine, and glutamine, S768-D770 duplication, S768I, H773R, G779F, T790M, L792P, L798F, G810S, N826S, L833V, H835L, T847I, V851A, I853T, L858R, G873E, L62R, R222L, A237Y, L210 splice, S768I, G719A, V336 splice, D393Y, C526S, V536M, E114K, G598V, A289T, R244G, T273A, E282A, V786L, and T847K.

[0055] KRAS or V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog is a member of the Ras family. KRAS is a GTPase that is involved in modulating cellular signal transduction pathways. In some instances, KRAS acts as a molecular switch in which when activated, recruits and activates proteins involved in propagating growth factor.

[0056] In some embodiments, KRAS contains one or more modifications to the KRAS gene. In some embodiments, mutations or modifications of the KRAS gene comprise base substitution, insertion, deletion, DNA rearrangement, copy number alteration, or a combination thereof. In some embodiments, the KRAS protein comprises one or more modifications. In some embodiments, the modifications in the KRAS protein includes, but is not limited to,

modifications at positions corresponding to amino acid residues 12, 61 , 146, 22, 68, 164, 176, 158, 118, 24, 18, and 19. In some embodiments, the modifications include G12C, G12V, G12D, G12S, G12A, Q61L, Q61H, A146P, A146T, Q22K, R68S, I24N, R164Q, L19F, A18D, K176Q, T158A, and C1 18S.

[0057] Phosphatase and tensin homolog (PTEN) acts as a tumor suppressor and in some cases, the loss of expression of PTEN is associated with cancer, such as for example lung cancer and breast cancer. In some embodiments, the expression level of PTEN is decreased relative to a control. In some embodiments, the expression level of PTEN is decreased by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7- fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 75-fold, 100- fold, 200-fold, 500-fold, 1000-fold, or more compared to the control. In some embodiments, the expression level of PTEN is increased relative to a control. In some embodiments, the expression level of PTEN is increased by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5- fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 75-fold, 100-fold, 200-fold, 500-fold, 1000-fold, or more compared to the control.

[0058] In some embodiments, the control is the expression level of PTEN in an individual who does not have the solid tumor. In some embodiments, the control is the expression level of PTEN in an individual prior to administration of the BTK inhibitor. In some embodiments, the BTK inhibitor is selected from among ibrutinib (PCI-32765), PCI-45292, PCI-45466, AVL- 101/CC-lOl (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), R 486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited) and LFM-A13. In some embodiments, the BTK inhibitor is ibrutinib.

[0059] In some embodiments, an individual having a solid tumor for treatment with a BTK inhibitor is administered a therapeutically effective amount of the BTK inhibitor when there is the presence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR. In some embodiments, an individual having a solid tumor for treatment with a BTK inhibitor is administered a therapeutically effective amount of the BTK inhibitor when there is the presence a modification at amino acid position 858. In some embodiments, the modification is L858R. In some embodiments, an individual having a solid tumor for treatment with a BTK inhibitor is administered a therapeutically effective amount of the BTK inhibitor when there is the presence of a deletion from amino acid position 746 to amino acid position 750 in EGFR. In some embodiments, the presence of absence of modification is determined in KRAS. In some embodiments, KRAS does not contain a modification. In some embodiments, the expression rate of PTEN is determined relative to a control. In some embodiments, the expression level of PTEN increase by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5- fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15- fold, 20-fold, 50-fold, or more compared to the control.

[0060] In some embodiments, described herein, is a method for selecting an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR, and one or more additional biomarkers; and (b) administering to the individual a therapeutically effective amount of the BTK inhibitor if there is a presence of at least one of the modification at amino acid position 8 8 and the deletion from amino acid position 746 to amino acid position 750 in EGFR, and at one or more additional biomarkers. [0061] In some embodiment, the one or more additional biomarkers include a mutation or modification in BTK. In some embodiments, the modification is a mutation at amino acid position 481 in BTK. In some embodiments, the mutation is C481S in BTK. In some embodiments, the C481 mutation in BTK is accompanied with additional mutations in BTK. In some embodiments, the additional mutations in BTK include substitutions at amino acid positions LI 1 , K12, S14, K19, F25, K27, R28, R33, Y39, Y40, E41, 161 , V64, R82, Q103, V113, S 1 15, T117, Q127, C154, C155, T184, P189, P190, Y223, W251, R288, L295, G302, R307, D308, V319, Y334, L358, Y361, H362, H364, N365, S366, L369, 1370M, R372, L408, G414, Y418, 1429, K430, E445, G462, Y476, M477, C502, C506, A508, M509, L512, L518, R520, D521, A523, R525, N526, V535, L542, R544, Y551 , F559, R562, W563, E567, S578, W581, A582, F583, M587, E589, S592, G594, Y598, A607, G613, Y617, P619, A622, V626, M630, C633, R641 , F644, L647, L652, V1065, and Al 185. In some embodiments, the additional modifications is selected from among Ll lP, K12R, S 14F, K19E, F25S, K27R, R28H, R28C, R28P, T33P, Y3S9, Y40C, Y40N, E41K, 16 IN, V64F, V64D, R82K, Q103QSFSSVR, V113D, S115F, T117P, Q127H, C154S, C 155G, T184P, P189A, Y223F, W251L, R288W, R288Q, L295P, G302E, R307K, R307G, R307T, D308E, V319A, Y334S, L358F, Y361C, H362Q, H364P, N365Y, S366F, L369F, I370M, R372G, L408P, G414R, Y418H, I429N, K430E, E445D, G462D, G462V, Y476D, M477R, C502F, C502W, C506Y, C506R, A508D, M509I, M509V, L512P, L512Q, L518R, R520Q, D521G, D521H, D521N, A523E, R525G, R525P, R525Q, N526K, V535F, L542P, R544G, R544K, Y551F, F559S, R562W, R562P, W563L, E567K, S578Y, W581R, A582V, F583S, M587L, E589D, E589K, E589G, S592P, G594E, Y598C, A607D, G613D, Y617E, P619A, P619S, A622P, V626G, M630I, M630K, M630T, C633Y, R641C, F644L, F644S, L647P, L652P, V1065I, and Al 185V.

[0062] In some embodiments, the one or more additional biomarkers include a mutation in PLCy2. In some embodiments, the mutation in PLCy2 is a mutation at amino acid residue 665, 707, or a combination thereof. In some embodiments, the mutation is R665W and S707F.

[0063] In some embodiments, the one or more additional biomarkers include cytogenetic abnormalities such as del(17pl3.1), del(13ql4.3), del(l lq22.3), del(l lq23), unmutated IgVH together with ZAP-70+ and/or CD38+, trisomy 12, t(l I ; 14)(ql3;q32), t(14; 19)(q32;ql3), t(2; 14)(pl3;q32), del(13ql4), +(12q21), del(6q21), ATM del, p53 del, t(15; 17);

t(8;21)(q22;q22), t(6;9), inv(16)(pl3q22), del(16q); inv(16), t(16; 16), del(l lq), t(9; l l), t(l l;19), t(l ;22), del(5q), +8, +21 , +22, del(7q), del(9q), abnormal l lq23, -5, -7, abnormal 3q, complex karyotype, t(14;19), t(3 : 14), t(l l ;14), t(2;8)(pl l;q24), t(l ;8)(p36;q24), t(8:9)(q24;pl3), t(9; 14)(pl3;q32), t(3 : 14)(q27;q32), or a combination thereof. [0064] In some embodiments, described herein, is a method of monitoring whether an individual receiving a BTK inhibitor for treatment of a solid tumor is responsive or is likely to respond to therapy, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) characterizing the individual as responsive or is likely to respond to therapy with the BTK inhibitor if the individual has at least one of the modification at amino acid position 8 8 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. In some embodiments, the individual is characterized as responsive or is likely to respond to therapy with the BTK inhibitor if the individual has a modification at position 858. In some embodiments, the modification is L858R. In some embodiments, the individual is characterized as responsive or is likely to respond to therapy with the BTK inhibitor if the individual has a deletion from amino acid position 746 to amino acid position 750 in EGFR. In some embodiments, the presence of absence of modification is also determined in KRAS. In some embodiments, KRAS does not contain a modification. In some embodiments, the expression rate of PTEN is also determined relative to a control. In some embodiments, the expression level of PTEN increase by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5- fold, 10-fold, 15 -fold, 20-fold, 50-fold, or more compared to the control.

[0065] In some embodiments, described herein, is a method of monitoring whether an individual receiving a BTK inhibitor for treatment of a solid tumor is responsive or is likely to respond to therapy, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR, and one or more additional biomarkers; and (b) characterizing the individual as responsive or is likely to respond to therapy with the BTK inhibitor if the individual has at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR, and at one or more biomarkers.

[0066] In some embodiments, the one or more additional biomarkers include a mutation or modification in BTK. In some embodiments, the modification is a mutation at amino acid position 481 in BTK. In some embodiments, the mutation is C481S in BTK. In some embodiments, the C481 mutation in BTK is accompanied with additional mutations in BTK. In some embodiments, the additional mutations in BTK include substitutions at amino acid positions LI 1 , K12, S14, K19, F25, K27, R28, R33, Y39, Y40, E41, 161 , V64, R82, Q103, V113, S I 15, T117, Q127, C154, C155, T184, P189, P190, Y223, W251, R288, L295, G302, R307, D308, V319, Y334, L358, Y361, H362, H364, N365, S366, L369, 1370M, R372, L408, G414, Y418, 1429, K430, E445, G462, Y476, M477, C502, C506, A508, M509, L512, L518, R520, D521, A523, R525, N526, V535, L542, R544, Y551 , F559, R562, W563, E567, S578, W581, A582, F583, M587, E589, S592, G594, Y598, A607, G613, Y617, P619, A622, V626, M630, C633, R641 , F644, L647, L652, V1065, and Al 185. In some embodiments, the additional modifications is selected from among Ll lP, K12R, S 14F, K19E, F25S, 27R, R28H, R28C, R28P, T33P, Y3S9, Y40C, Y40N, E41K, 16 IN, V64F, V64D, R82K, Q103QSFSSVR, V113D, S115F, T117P, Q127H, C154S, C 155G, T184P, P189A, Y223F, W251L, R288W, R288Q, L295P, G302E, R307K, R307G, R307T, D308E, V319A, Y334S, L358F, Y361C, H362Q, H364P, N365Y, S366F, L369F, I370M, R372G, L408P, G414R, Y418H, I429N, K430E, E445D, G462D, G462V, Y476D, M477R, C502F, C502W, C506Y, C506R, A508D, M509I, M509V, L512P, L512Q, L518R, R520Q, D521G, D521H, D521N, A523E, R525G, R525P, R525Q, N526K, V535F, L542P, R544G, R544K, Y551F, F559S, R562W, R562P, W563L, E567K, S578Y, W581R, A582V, F583S, M587L, E589D, E589K, E589G, S592P, G594E, Y598C, A607D, G613D, Y617E, P619A, P619S, A622P, V626G, M630I, M630K, M630T, C633Y, R641C, F644L, F644S, L647P, L652P, V1065I, and Al 185V.

[0067] In some embodiments, the one or more additional biomarkers include a mutation in PLCy2. In some embodiments, the mutation in PLCy2 is a mutation at amino acid residue 665, 707, or a combination thereof. In some embodiments, the mutation is R665W and S707F.

[0068] In some embodiments, the one or more additional biomarkers include cytogenetic abnormalities such as del(17pl3.1), del(13ql4.3), del(l lq22.3), del(l lq23), unmutated IgVH together with ZAP-70+ and/or CD38+, trisomy 12, t(l I ; 14)(ql3;q32), t(14; 19)(q32;ql3), t(2; 14)(pl3;q32), del(13ql4), +(12q21), del(6q21), ATM del, p53 del, t(15; 17);

t(8;21)(q22;q22), t(6;9), inv(16)( l3q22), del(16q); inv(16), t(16; 16), del(l lq), t(9; l l), t(l l;19), t(l ;22), del(5q), +8, +21 , +22, del(7q), del(9q), abnormal l lq23, -5, -7, abnormal 3q, complex karyotype, t(14;19), t(3 : 14), t(l l ; 14), t(2;8)(pl l;q24), t(l ;8)(p36;q24), t(8:9)(q24;pl3), t(9; 14)(pl3;q32), t(3 : 14)(q27;q32), or a combination thereof.

[0069] In some embodiments, described herein, is a method of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of a solid tumor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (b) modifying, discontinuing, or continuing the treatment based on the presence or absence of at least one of the modification to an amino acid residue at amino acid position 8 8 and the deletion from amino acid position 746 to amino acid position 750 in EGFR. In some

embodiments, the modification is L858R. In some embodiments, the presence of absence of modification is also determined in KRAS. In some embodiments, KRAS does not contain a modification. In some embodiments, the expression rate of PTEN is also determined relative to a control. In some embodiments, the expression level of PTEN increase by 0.5-fold, 1-fold, 1.5- fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50-fold, or more compared to the control.

[0070] In some embodiments, described herein, is a method of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of a solid tumor, comprising: (a) determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR, and one or more additional biomarkers; and (b) modifying, discontinuing, or continuing the treatment based on the presence or absence of at least one of the modification to an amino acid residue at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR, and one or more additional biomarkers.

[0071] In some embodiments, the one or more additional biomarkers include a mutation or modification in BTK. In some embodiments, the modification is a mutation at amino acid position 481 in BTK. In some embodiments, the mutation is C481S in BTK. In some embodiments, the C481 mutation in BTK is accompanied with additional mutations in BTK. In some embodiments, the additional mutations in BTK include substitutions at amino acid positions LI 1 , K12, S14, K19, F25, K27, R28, R33, Y39, Y40, E41, 161 , V64, R82, Q103, V113, S 1 15, T117, Q127, C154, C155, T184, P189, P190, Y223, W251, R288, L295, G302, R307, D308, V319, Y334, L358, Y361, H362, H364, N365, S366, L369, 1370M, R372, L408, G414, Y418, 1429, K430, E445, G462, Y476, M477, C502, C506, A508, M509, L512, L518, R520, D521, A523, R525, N526, V535, L542, R544, Y551 , F559, R562, W563, E567, S578, W581, A582, F583, M587, E589, S592, G594, Y598, A607, G613, Y617, P619, A622, V626, M630, C633, R641 , F644, L647, L652, V1065, and Al 185. In some embodiments, the additional modifications is selected from among LI IP, K12R, S 14F, K19E, F25S, K27R, R28H, R28C, R28P, T33P, Y3S9, Y40C, Y40N, E41K, 16 IN, V64F, V64D, R82K, Q103QSFSSVR, V113D, S115F, T117P, Q127H, C154S, C 155G, T184P, P189A, Y223F, W251L, R288W, R288Q, L295P, G302E, R307K, R307G, R307T, D308E, V319A, Y334S, L358F, Y361C, H362Q, H364P, N365Y, S366F, L369F, I370M, R372G, L408P, G414R, Y418H, I429N, K430E, E445D, G462D, G462V, Y476D, M477R, C502F, C502W, C506Y, C506R, A508D, M509I, M509V, L512P, L512Q, L518R, R520Q, D521G, D521H, D521N, A523E, R525G, R525P, R525Q, N526K, V535F, L542P, R544G, R544K, Y551F, F559S, R562W, R562P, W563L, E567K, S578Y, W581R, A582V, F583S, M587L, E589D, E589K, E589G, S592P, G594E, Y598C, A607D, G613D, Y617E, P619A, P619S, A622P, V626G, M630I, M630K, M630T, C633Y, R641C, F644L, F644S, L647P, L652P, V1065L and Al 185V. [0072] In some embodiments, the one or more additional biomarkers include a mutation in PLCy2. In some embodiments, the mutation in PLCy2 is a mutation at amino acid residue 665, 707, or a combination thereof. In some embodiments, the mutation is R665W and S707F.

[0073] In some embodiments, the one or more additional biomarkers include cytogenetic abnormalities such as del(17pl3.1), del(13ql4.3), del(l lq22.3), del(l lq23), unmutated IgVH together with ZAP-70+ and/or CD38+, trisomy 12, t(l I ; 14)(ql3;q32), t(14; 19)(q32;ql3), t(2; 14)(pl3;q32), del(13ql4), +(12q21), del(6q21), ATM del, p53 del, t(15; 17);

t(8;21)(q22;q22), t(6;9), inv(16)( l3q22), del(16q); inv(16), t(16; 16), del(l lq), t(9; l l), t(l l;19), t(l ;22), del(5q), +8, +21 , +22, del(7q), del(9q), abnormal l lq23, -5, -7, abnormal 3q, complex karyotype, t(14;19), t(3 : 14), t(l l ;14), t(2;8)(pl l;q24), t(l ;8)(p36;q24), t(8:9)(q24;pl3), t(9; 14)(pl3;q32), t(3 : 14)(q27;q32), or a combination thereof.

[0074] In some embodiments, described herein, is a method of selecting an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) determining the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR; and (b) administering to the individual a therapeutically effective amount of ibrutinib if there is an absence of the modification at amino acid position 790 in EGFR. In some embodiments, the modification at amino acid position 790 is T790M. In some embodiments, the method further comprises determining the presence or absence of a modification to an aromatic residue at amino acid position 858 in EGFR. In some embodiments, the modification at amino acid position 858 in EGFR is L858R. In some embodiments, the method further comprises administering to the individual a therapeutically effective amount of a BTK inhibitor if there is an absence of the modification at amino acid position 790 and at amino acid position 858 in EGFR. In some embodiments, the method further comprises determining the presence or absence of modifications in KRAS. In some embodiments, KRAS contains one or more modifications. In some embodiments, the method further comprises determining the expression level of PTEN relative to a control. In some embodiments, the expression level of PTEN decrease by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20- fold, 50-fold, or more compared to the control.

[0075] In some embodiments, described herein, is a method of selecting an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) determining the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR, and one or more additional biomarkers; and (b) administering to the individual a therapeutically effective amount of ibrutinib if there is an absence of the modification at amino acid position 790 in EGFR, and one or more additional biomarkers. [0076] In some embodiment, the one or more additional biomarkers include a mutation or modification in BTK. In some embodiments, the modification is a mutation at amino acid position 481 in BTK. In some embodiments, the mutation is C481S in BTK. In some embodiments, the C481 mutation in BTK is accompanied with additional mutations in BTK. In some embodiments, the additional mutations in BTK include substitutions at amino acid positions LI 1 , K12, S14, K19, F25, K27, R28, R33, Y39, Y40, E41, 161 , V64, R82, Q103, V113, S 1 15, T117, Q127, C154, C155, T184, P189, P190, Y223, W251, R288, L295, G302, R307, D308, V319, Y334, L358, Y361, H362, H364, N365, S366, L369, 1370M, R372, L408, G414, Y418, 1429, K430, E445, G462, Y476, M477, C502, C506, A508, M509, L512, L518, R520, D521, A523, R525, N526, V535, L542, R544, Y551 , F559, R562, W563, E567, S578, W581, A582, F583, M587, E589, S592, G594, Y598, A607, G613, Y617, P619, A622, V626, M630, C633, R641 , F644, L647, L652, V1065, and Al 185. In some embodiments, the additional modifications is selected from among Ll lP, K12R, S 14F, K19E, F25S, K27R, R28H, R28C, R28P, T33P, Y3S9, Y40C, Y40N, E41K, 16 IN, V64F, V64D, R82K, Q103QSFSSVR, V113D, S115F, T117P, Q127H, C154S, C 155G, T184P, P189A, Y223F, W251L, R288W, R288Q, L295P, G302E, R307K, R307G, R307T, D308E, V319A, Y334S, L358F, Y361C, H362Q, H364P, N365Y, S366F, L369F, I370M, R372G, L408P, G414R, Y418H, I429N, K430E, E445D, G462D, G462V, Y476D, M477R, C502F, C502W, C506Y, C506R, A508D, M509I, M509V, L512P, L512Q, L518R, R520Q, D521G, D521H, D521N, A523E, R525G, R525P, R525Q, N526K, V535F, L542P, R544G, R544K, Y551F, F559S, R562W, R562P, W563L, E567K, S578Y, W581R, A582V, F583S, M587L, E589D, E589K, E589G, S592P, G594E, Y598C, A607D, G613D, Y617E, P619A, P619S, A622P, V626G, M630I, M630K, M630T, C633Y, R641C, F644L, F644S, L647P, L652P, V1065I, and Al 185V.

[0077] In some embodiments, the one or more additional biomarkers include a mutation in PLCy2. In some embodiments, the mutation in PLCy2 is a mutation at amino acid residue 665, 707, or a combination thereof. In some embodiments, the mutation is R665W and S707F.

[0078] In some embodiments, the one or more additional biomarkers include cytogenetic abnormalities such as del(17pl3.1), del(13ql4.3), del(l lq22.3), del(l lq23), unmutated IgVH together with ZAP-70+ and/or CD38+, trisomy 12, t(l I ; 14)(ql3;q32), t(14; 19)(q32;ql3), t(2; 14)(pl3;q32), del(13ql4), +(12q21), del(6q21), ATM del, p53 del, t(15; 17);

t(8;21)(q22;q22), t(6;9), inv(16)(pl3q22), del(16q); inv(16), t(16; 16), del(l lq), t(9; l l), t(l l;19), t(l ;22), del(5q), +8, +21 , +22, del(7q), del(9q), abnormal l lq23, -5, -7, abnormal 3q, complex karyotype, t(14;19), t(3 : 14), t(l l ;14), t(2;8)(pl l;q24), t(l ;8)(p36;q24), t(8:9)(q24;pl3), t(9; 14)(pl3;q32), t(3 : 14)(q27;q32), or a combination thereof. [0079] In some embodiments, described herein, is a method of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of a solid tumor, comprising: (a) determining the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR; and (b) modifying, discontinuing, or continuing the treatment based on the presence or absence of the modification to an amino acid residue at amino acid position 790 in EGFR. In some embodiments, the modification at amino acid position 790 is T790M. In some

embodiments, the method further comprises determining the presence or absence of a modification to an aromatic residue at amino acid position 858 in EGFR. In some embodiments, the modification at amino acid position 858 in EGFR is L858R. In some embodiments, the method further comprises administering to the individual a therapeutically effective amount of a BTK inhibitor if there is an absence of the modification at amino acid position 790 and at amino acid position 858 in EGFR. In some embodiments, the method further comprises determining the presence or absence of modifications in KRAS. In some embodiments, KRAS contains one or more modifications. In some embodiments, the method further comprises determining the expression level of PTEN relative to a control. In some embodiments, the expression level of PTEN decrease by 0.5-fold, 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5- fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15- fold, 20-fold, 50-fold, or more compared to the control.

[0080] In some embodiments, described herein, is a method of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of a solid tumor, comprising: (a) determining the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR, and one or more additional biomarkers; and (b) modifying, discontinuing, or continuing the treatment based on the presence or absence of the modification to an amino acid residue at amino acid position 790 in EGFR, and in one or more additional biomarkers.

[0081] In some embodiments, the one or more additional biomarkers include a mutation or modification in BTK. In some embodiments, the modification is a mutation at amino acid position 481 in BTK. In some embodiments, the mutation is C481S in BTK. In some embodiments, the C481 mutation in BTK is accompanied with additional mutations in BTK. In some embodiments, the additional mutations in BTK include substitutions at amino acid positions LI 1 , K12, S14, K19, F25, K27, R28, R33, Y39, Y40, E41, 161 , V64, R82, Q103, V113, S 1 15, T117, Q127, C154, C155, T184, P189, P190, Y223, W251, R288, L295, G302, R307, D308, V319, Y334, L358, Y361, H362, H364, N365, S366, L369, 1370M, R372, L408, G414, Y418, 1429, K430, E445, G462, Y476, M477, C502, C506, A508, M509, L512, L518, R520, D521, A523, R525, N526, V535, L542, R544, Y551 , F559, R562, W563, E567, S578, W581, A582, F583, M587, E589, S592, G594, Y598, A607, G613, Y617, P619, A622, V626, M630, C633, R641 , F644, L647, L652, V1065, and Al 185. In some embodiments, the additional modifications is selected from among LI IP, K12R, S 14F, K19E, F25S, K27R, R28H, R28C, R28P, T33P, Y3S9, Y40C, Y40N, E41K, 16 IN, V64F, V64D, R82K, Q103QSFSSVR, V113D, S115F, T117P, Q127H, C154S, C 155G, T184P, P189A, Y223F, W251L, R288W, R288Q, L295P, G302E, R307K, R307G, R307T, D308E, V319A, Y334S, L358F, Y361C, H362Q, H364P, N365Y, S366F, L369F, I370M, R372G, L408P, G414R, Y418H, I429N, K430E, E445D, G462D, G462V, Y476D, M477R, C502F, C502W, C506Y, C506R, A508D, M509I, M509V, L512P, L512Q, L518R, R520Q, D521G, D521H, D521N, A523E, R525G, R525P, R525Q, N526K, V535F, L542P, R544G, R544K, Y551F, F559S, R562W, R562P, W563L, E567K, S578Y, W581R, A582V, F583S, M587L, E589D, E589K, E589G, S592P, G594E, Y598C, A607D, G613D, Y617E, P619A, P619S, A622P, V626G, M630I, M630K, M630T, C633Y, R641C, F644L, F644S, L647P, L652P, V1065I, and Al 185V.

[0082] In some embodiments, the one or more additional biomarkers include a mutation in PLCy2. In some embodiments, the mutation in PLCy2 is a mutation at amino acid residue 665, 707, or a combination thereof. In some embodiments, the mutation is R665W and S707F.

[0083] In some embodiments, the one or more additional biomarkers include cytogenetic abnormalities such as del(17pl3.1), del(13ql4.3), del(l lq22.3), del(l lq23), unmutated IgVH together with ZAP-70+ and/or CD38+, trisomy 12, t(l I ; 14)(ql3;q32), t(14; 19)(q32;ql3), t(2; 14)(pl3;q32), del(13ql4), +(12q21), del(6q21), ATM del, p53 del, t(15; 17);

[0084] Disclosed herein, in certain embodiments, are methods of treating a solid tumor in an individual in need thereof, by modulating the tumor microenvironment or by modulating the tumor infiltrating cells. In some embodiments, the tumor infiltrating cells include tumor infiltrating B cells, tumor infiltrating macrophages/monocytes such as MDSC and CD1 lb/Grl ⁺ subpopulations, tumor infiltrating dendritic cells, and mast cells.

[0085] Disclosed herein, in certain embodiments, are methods of treating a solid tumor in a subject in need thereof by modulating the Thl :Th2 biomarker ratio in the subject, comprising administering to the subject a therapeutically effective amount of a BTK inhibitor such as ibrutinib. In some embodiments, ibrutinib is administered in combination with an additional therapeutic agent such as an EGFR inhibitor. In some embodiments, the BTK inhibitor or in combination with an EGFR inhibitor decreases the Th2 response in the subject and increases the Thl response in the subject. In some embodiments, the Btk inhibitor (e.g., ibrutinib) functions to suppress the Thl response while enhancing the Th2 response. In some embodiments, the Btk inhibitor (e.g., ibrutinib) functions to decrease the number of Th2 polarized T cells in a subject. In some embodiments, the Btk inhibitor (e.g., ibrutinib) functions to increase the number of Thl polarized T cells in a subject. In some embodiments, the Btk inhibitor (e.g., ibrutinib) functions to increase the number of activated CD8+ cytotoxic T cells in a subject. In some embodiments, the Btk inhibitor (e.g., ibrutinib) functions to increase the ratio of Thl polarized T cells to Th2 polarized T cells in a subject. In some embodiments, the Btk inhibitor (e.g., ibrutinib) functions to increase IFN-γ expression in a subject.

[0086] In some embodiments, the Btk inhibitor (e.g., ibrutinib) increases a Thl immune response against the cancer compared to no treatment with the Btk inhibitor (e.g., ibrutinib). In some embodiments, the Btk inhibitor (e.g., ibrutinib) decreases a Th2 immune response against the cancer compared to no treatment with the Btk inhibitor (e.g., ibrutinib). In some

embodiments, the Btk inhibitor (e.g., ibrutinib) alters the ratio of Thl -Th2 immune response against the cancer compared to no treatment with the Btk inhibitor (e.g., ibrutinib). In some embodiments, the Btk inhibitor (e.g., ibrutinib) increases the ratio of Thl-Th2 immune response against the cancer compared to no treatment with the Btk inhibitor (e.g., ibrutinib). In some embodiments, the Btk inhibitor (e.g., ibrutinib) increases the population of Thl cells by about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater compared to no treatment with the Btk inhibitor (e.g., ibrutinib). In some embodiments, the Btk inhibitor (e.g., ibrutinib) decreases the population of Th2 cells by about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater compared to no treatment with the Btk inhibitor (e.g., ibrutinib). In some embodiments, the Btk inhibitor (e.g., ibrutinib) increases the expression of one or more Thl related markers. In some embodiments, the Btk inhibitor (e.g., ibrutinib) increases the expression of one or more Thl related markers by about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater compared to no treatment with the Btk inhibitor (e.g., ibrutinib). In some embodiments, the one or more Thl related marker includes CCR1, CD4, CD26, CD94, CD1 19, CD183, CD195, CD212, GM-CSF, Granzyme B, IFN- , IFN-γ, IL-2, IL-12, IL-15, IL-18R, IL-23, IL-27, IL-27R, Lymphotoxin, perforin, t-bet, Tim-3, TNF- , TRANCE, sCD40L, or any combination thereof. In some embodiments, the one or more Thl related markers includes IFN-γ, IL-2, IL-12 or any combination thereof. In some embodiments, the Btk inhibitor (e.g., ibrutinib) decreases the expression of Th2 related markers. In some embodiments, the Btk inhibitor (e.g., ibrutinib) decreases the expression of Th2 related markers by about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater compared to no treatment with the Btk inhibitor (e.g., ibrutinib). In some embodiments, the one or more Th2 related markers includes CCR3, CCR4, CCR7, CCR8, CD4, CD30, CD81, CD184, CD278, c-maf, CRTH2, Gata-3, GM- CSF, IFN jR, IgD, IL-1R, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-15, ST2L/T1 , Tim- 1, or any combination thereof. In some embodiments, the one or more Thl related markers includes IL-4, IL-10, IL-13, or any combination thereof.

[0087] In some embodiments, the combination of ibrutinib and an EGFR inhibitor increases a Thl immune response against the cancer compared to no treatment with this combination. In some embodiments, the combination of ibrutinib and an EGFR inhibitor decreases a Th2 immune response against the cancer compared to no treatment with this combination. In some embodiments, the combination of ibrutinib and an EGFR inhibitor alters the ratio of Thl-Th2 immune response against the cancer compared to no treatment with this combination. In some embodiments, the combination of ibrutinib and an EGFR inhibitor increases the ratio of Thl - Th2 immune response against the cancer compared to no treatment with this combination. In some embodiments, the combination of ibrutinib and an EGFR inhibitor increases the population of Thl cells by about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater compared to no treatment with this combination. In some embodiments, the combination of ibrutinib and an EGFR inhibitor decreases the population of Th2 cells by about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater compared to no treatment with this combination. In some embodiments, the combination of ibrutinib and an EGFR inhibitor increases the expression of one or more Thl related markers. In some embodiments, the combination of ibrutinib and an EGFR inhibitor increases the expression of one or more Thl related markers by about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%), 80%, 90% or greater compared to no treatment with this combination. In some embodiments, the one or more Thl related marker includes CCR1, CD4, CD26, CD94, CD1 19, CD183, CD195, CD212, GM-CSF, Granzyme B, IFN-oc, IFN-γ, IL-2, IL-12, IL-15, IL-18R, IL- 23, IL-27, IL-27R, Lymphotoxin, perforin, t-bet, Tim-3, TNF-a, TRANCE, sCD40L, or any combination thereof. In some embodiments, the one or more Thl related markers includes IFN- γ, IL-2, IL-12 or any combination thereof. In some embodiments, the Btk inhibitor (e.g., ibrutinib) decreases the expression of Th2 related markers. In some embodiments, the combination of ibrutinib and an EGFR inhibitor decreases the expression of Th2 related markers by about 1 %, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater compared to no treatment with this combination. In some embodiments, the one or more Th2 related markers includes CCR3, CCR4, CCR7, CCR8, CD4, CD30, CD81, CD184, CD278, c- maf, CRTH2, Gata-3, GM-CSF, IFN jR, IgD, IL-1R, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL- 15, ST2L/T1, Tim-1 , or any combination thereof. In some embodiments, the one or more Thl related markers includes IL-4, IL-10, IL-13, or any combination thereof. TEC Family Kinase Inhibitors

[0088] 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 covalent TEC family kinase inhibitor inhibits the kinase activity of BTK, ITK, TEC, RLK and BMX. In some embodiments, a covalent TEC family kinase inhibitor is a BTK inhibitor. In some embodiments, a covalent TEC family kinase inhibitor is an ITK inhibitor. In some embodiments, a covalent TEC family kinase inhibitor is a TEC inhibitor. In some embodiments, a covalent TEC family kinase inhibitor is a RLK inhibitor. In some

embodiments, a covalent TEC family kinase inhibitor is a BMK inhibitor.

BTK Inhibitor Compounds Including Ibrutinib, and Pharmaceutically Acceptable Salts Thereof

[0089] 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).

[0090] 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-, -NH-, -

NR₉-, -NHC(O)-, -C(0)NH-, -NR₉C(0)-, -C(0)NR₉-, -S(=0)₂NH-, -NHS(=0)₂-, -S(=0)₂NR₉-, - NR₉S(=0)₂-, -OC(0)NH-, -NHC(0)0-, -OC(0)NR₉-, -NR₉C(0)0-, -CH=NO-, -ON=CH-, - NRioC(0)NRio-, heteroaryl-, aryl-, -NR₁₀C(= R₁₁) R₁₀-, - R₁₀C(= R_n)-, -C(=NRn)NR₁₀-, - OC(=NRii)-, or -C(=NR_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;

G is

, wherein,

Re, R7 and Rg 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 Rn 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

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

[0091] "Ibrutinib" or "l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l- yl)piperidin- l-yl)prop-2-en- 1 -one" or "1 - {(3i?)-3-[4-amino-3-(4-phenoxyphenyl)- 1H- pyrazolo[3,4-JJpyrimidin-l-yl]piperidin-l-yl}prop-2-en-l-one" or "2-Propen- 1 -one, l -[(3i?)-3- [4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-JJpyrimidin-l-yl]-l-piperidinyl-" or any other suitable name refers to the compound with the following structure:

[0092] A wide variety of pharmaceutically acceptable salts is formed from Ibrutinib and includes:

[0093] - 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;

[0094] - 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] In some embodiments, Ibrutinib is prepared as outlined in US Patent no. 7,514,444.

[0099] In some embodiments, the Btk inhibitor is 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) and LFM-A13.

[00100] In some embodiments, the BTK inhibitor is 4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6- ((4-(morpholine-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- { 1 -methyl-5-[5-(4-methyl-piperazin- 1 -yl)-pyridin-2-ylamino]-6-oxo- 1 ,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- 1 1092); or N-(5-((5-(4-Acetylpiperazine-l- carbonyl)-4-methoxy-2-methylphenyl)thio)thiazol-2-yl)-4-(((3-methylbutan-2- yl)amino)methyl)benzamide (HY11066); or a pharmaceutically acceptable salt thereof. bodiments, the BTK inhibitor is:

-37-

pharmaceutically acceptable salt thereof.

ITK Inhibitors

[00102] 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 ΓΤΚ 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 13/177657, which is incorporated by reference in its entirety.

and H

Diagnostic and Therapeutic Methods

Diagnostic Methods

[00104] Methods for determining the expression or presence of biomarkers such as EGFR, KRAS, and PTEN are well known in the art. Circulating levels of biomarkers in a blood sample obtained from a candidate subject are measured, for example, by ELISA,

radioimmunoassay (RIA), electrochemiluminescence (ECL), Western blot, multiplexing technologies, or other similar methods. Cell surface expression of biomarkers are measured, for example, by flow cytometry, immunohistochemistry, Western Blot, immunoprecipitation, magnetic bead selection, and quantification of cells expressing either of these cell surface markers. Biomarker RNA expression levels could be measured by RT-PCR, Qt-PCR, microarray, Northern blot, or other similar technologies.

[00105] As disclosed herein, determining the expression or presence of the biomarker of interest at the protein or nucleotide level are accomplished using any detection method known to those of skill in the art. By "detecting expression" or "detecting the level of is intended determining the expression level or presence of a biomarker protein or gene in the biological sample. Thus, "detecting expression" encompasses instances where a biomarker is determined not to be expressed, not to be detectably expressed, expressed at a low level, expressed at a normal level, or overexpressed.

[00106] In certain aspects of the method provided herein, the one or more subpopulation of lymphocytes are isolated, detected or measured. In certain embodiments, the one or more subpopulation of lymphocytes are isolated, detected or measured using immunophenotyping techniques. In other embodiments, the one or more subpopulation of lymphocytes are isolated, detected or measured using fluorescence activated cell sorting (FACS) techniques.

[00107] In certain aspects, the expression or presence of these various biomarkers and any clinically useful prognostic markers in a biological sample are detected at the protein or nucleic acid level, using, for example, immunohistochemistry techniques or nucleic acid- based techniques such as in situ hybridization and T-PC . In one embodiments, the expression or presence of one or more biomarkers is carried out by a means for nucleic acid amplification, a means for nucleic acid sequencing, a means utilizing a nucleic acid microarray (DNA and RNA), or a means for in situ hybridization using specifically labeled probes.

[00108] In other embodiments, the determining the expression or presence of one or more biomarkers is carried out through gel electrophoresis. In one embodiment, the determination is carried out through transfer to a membrane and hybridization with a specific probe.

[00109] In other embodiments, the determining the expression or presence of one or more biomarkers carried out by a diagnostic imaging technique.

[00110] In still other embodiments, the determining the expression or presence of one or more biomarkers carried out by a detectable solid substrate. In one embodiment, the detectable solid substrate is paramagnetic nanoparticles functionalized with antibodies.

[00111] In another aspect, provided herein are methods for detecting or measuring residual lymphoma following a course of treatment in order to guide continuing or discontinuing treatment or changing from one therapeutic regimen to another comprising determining the expression or presence of one or more biomarkers from one or more subpopulation of lymphocytes in a subject wherein the course of treatment is treatment with a Btk inhibitor (e.g., ibrutinib).

[00112] Methods for detecting expression of the biomarkers described herein, within the test and control biological samples comprise any methods that determine the quantity or the presence of these markers either at the nucleic acid or protein level. Such methods are well known in the art and include but are not limited to western blots, northern blots, ELISA, immunoprecipitation, immunofluorescence, flow cytometry, immunohistochemistry, nucleic acid hybridization techniques, nucleic acid reverse transcription methods, and nucleic acid amplification methods. In particular embodiments, expression of a biomarker is detected on a protein level using, for example, antibodies that are directed against specific biomarker proteins. These antibodies are used in various methods such as Western blot, ELISA, multiplexing technologies,

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

[00113] Any means for specifically identifying and quantifying a biomarker (for example, biomarker, a biomarker of cell survival or proliferation, a biomarker of apoptosis, a biomarker of a Btk-mediated signaling pathway) in the biological sample of a candidate subject is contemplated. Thus, in some embodiments, expression level of a biomarker protein of interest in a biological sample is detected by means of a binding protein capable of interacting specifically with that biomarker protein or a biologically active variant thereof. In some embodiments, labeled antibodies, binding portions thereof, or other binding partners are used. The word "label" when used herein refers to a detectable compound or composition that is conjugated directly or indirectly to the antibody so as to generate a "labeled" antibody. In some embodiments, the label is detectable by itself (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, catalyzes chemical alteration of a substrate compound or composition that is detectable.

[00114] The antibodies for detection of a biomarker protein are either monoclonal or polyclonal in origin, or are synthetically or recombinantly produced. The amount of complexed protein, for example, the amount of biomarker protein associated with the binding protein, for example, an antibody that specifically binds to the biomarker protein, is determined using standard protein detection methodologies known to those of skill in the art. A detailed review of immunological assay design, theory and protocols are found in numerous texts in the art (see, for example, Ausubel et al., eds. (1995) Current Protocols in Molecular Biology) (Greene Publishing and Wiley-lnterscience, NY)); Coligan et al, eds. (1994) Current Protocols in Immunology (John Wiley & Sons, Inc., New York, N.Y.).

[00115] The choice of marker used to label the antibodies will vary depending upon the application. However, the choice of the marker is readily determinable to one skilled in the art. These labeled antibodies are used in immunoassays as well as in histological applications to detect the presence of any biomarker or protein of interest. The labeled antibodies are either polyclonal or monoclonal. Further, the antibodies for use in detecting a protein of interest are labeled with a radioactive atom, an enzyme, a chromophoric or fluorescent moiety, or a colorimetric tag as described elsewhere herein. The choice of tagging label also will depend on the detection limitations desired. Enzyme assays (ELISAs) typically allow detection of a colored product formed by interaction of the enzyme -tagged complex with an enzyme substrate.

Radionuclides that serve as detectable labels include, for example, 1-131 , 1 -123, 1-125, Y-90, Re-188, Re-186, At-211 , Cu-67, Bi-212, and Pd-109. Examples of enzymes that serve as detectable labels include, but are not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and glucose-6-phosphate dehydrogenase. Chromophoric moieties include, but are not limited to, fluorescein and rhodamine. The antibodies are conjugated to these labels by methods known in the art. For example, enzymes and chromophoric molecules are conjugated to the antibodies by means of coupling agents, such as dialdehydes, carbodiimides, dimaleimides, and the like. Alternatively, conjugation occurs through a ligand-receptor pair. Examples of suitable ligand-receptor pairs are biotin-avidin or biotin-streptavidin, and antibody- antigen.

[00116] In certain embodiments, expression or presence of one or more biomarkers or other proteins of interest within a biological sample, for example, a sample of bodily fluid, is determined by radioimmunoassays or enzyme-linked immunoassays (ELISAs), competitive binding enzyme-linked immunoassays, dot blot (see, for example, Promega Protocols and Applications Guide, Promega Corporation (1991), Western blot (see, for example, Sambrook et al. (1989) Molecular Cloning, A Laboratory Manual, Vol. 3, Chapter 18 (Cold Spring Harbor Laboratory Press, Plainview, N.Y.), chromatography such as high performance liquid chromatography (HPLC), or other assays known in the art. Thus, the detection assays involve steps such as, but not limited to, immunoblotting, immunodiffusion, Immunoelectrophoresis, or immunoprecipitation.

[00117] In certain other embodiments, the methods of the invention are useful for identifying and treating cancer, including those listed above, that are refractory to (i.e., resistant to, or have become resistant to) first-line oncotherapeutic treatments.

[00118] In some embodiments, the expression or presence of one or more of the biomarkers described herein are also determined at the nucleic acid level. Nucleic acid-based techniques for assessing expression are well known in the art and include, for example, determining the level of biomarker mRNA in a biological sample. Many expression detection methods use isolated RNA. Any RNA isolation technique that does not select against the isolation of mRNA is utilized for the purification of RNA (see, e.g., Ausubel et al, ed. (1987-1999) Current Protocols in

Molecular Biology (John Wiley & Sons, New York). Additionally, large numbers of tissue samples are readily processed using techniques well known to those of skill in the art, such as, for example, the single-step RNA isolation process disclosed in U.S. Pat. No. 4,843, 155.

[00119] Thus, in some embodiments, the detection of a biomarker or other protein of interest is assayed at the nucleic acid level using nucleic acid probes. The term "nucleic acid probe" refers to any molecule that is capable of selectively binding to a specifically intended target nucleic acid molecule, for example, a nucleotide transcript. Probes are synthesized by one of skill in the art, or derived from appropriate biological preparations. Probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are discussed above or that are known in the art. Examples of molecules that are utilized as probes include, but are not limited to, RNA and DNA.

[00120] For example, isolated mRNA are used in hybridization or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses and probe arrays. One method for the detection of mRNA levels involves contacting the isolated mRNA with a nucleic acid molecule (probe) that hybridize to the mRNA encoded by the gene being detected. The nucleic acid probe comprises of, for example, a full-length cDNA, or a portion thereof, such as an oligonucleotide of at least 7, 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to an mRNA or genomic DNA encoding a biomarker, biomarker described herein above.

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

[00121] In one embodiment, the mRNA is immobilized on a solid surface and contacted with a probe, for example by running the isolated mRNA on an agarose gel and transferring the mRNA from the gel to a membrane, such as nitrocellulose. In an alternative embodiment, the probe(s) are immobilized on a solid surface and the mRNA is contacted with the probe(s), for example, in a gene chip array. A skilled artisan readily adapts known mRNA detection methods for use in detecting the level of mRNA encoding the biomarkers or other proteins of interest.

[00122] An alternative method for determining the level of an mRNA of interest in a sample involves the process of nucleic acid amplification, e.g., by RT-PCR (see, for example, U.S. Pat. No. 4,683,202), ligase chain reaction (Barany (1991) Proc. Natl. Acad. Sci. USA 88: 189 193), self-sustained sequence replication (Guatelli et al. (1990) Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (Kwoh et al. (1989) Proc. Natl. Acad. Sci. USA 86: 1173-1 177), Q-Beta Replicase (Lizardi et al. (1988) Bio/Technology 6: 1197), rolling circle replication (U.S. Pat. No. 5,854,033) or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers. In particular aspects of the invention, biomarker expression is assessed by quantitative fluorogenic RT-PCR (i.e., the TaqManO System).

[00123] Expression levels of an RNA of interest are monitored using a membrane blot (such as used in hybridization analysis such as Northern, dot, and the like), or microwells, sample tubes, gels, beads or fibers (or any solid support comprising bound nucleic acids). See U.S. Pat. Nos. 5,770,722, 5,874,219, 5,744,305, 5,677,195 and 5,445,934, which are incorporated herein by reference. The detection of expression also comprises using nucleic acid probes in solution.

[00124] In one embodiment of the invention, microarrays are used to determine expression or presence of one or more biomarkers. Microarrays are particularly well suited for this purpose because of the reproducibility between different experiments. DNA microarrays provide one method for the simultaneous measurement of the expression levels of large numbers of genes. Each array consists of a reproducible pattern of capture probes attached to a solid support. Labeled RNA or DNA is hybridized to complementary probes on the array and then detected by laser scanning Hybridization intensities for each probe on the array are determined and converted to a quantitative value representing relative gene expression levels. See, U.S. Pat. Nos. 6,040,138, 5,800,992 and 6,020, 135, 6,033,860, and 6,344,316, which are incorporated herein by reference. High-density oligonucleotide arrays are particularly useful for determining the gene expression profile for a large number of RNA's in a sample.

[00125] Techniques for the synthesis of these arrays using mechanical synthesis methods are described in, e.g., U.S. Pat. No. 5,384,261 , incorporated herein by reference in its entirety. In some embodiments, an array is fabricated on a surface of virtually any shape or even a multiplicity of surfaces. In some embodiments, an array is a planar array surface. In some embodiments, arrays include peptides or nucleic acids on beads, gels, polymeric surfaces, fibers such as fiber optics, glass or any other appropriate substrate, see U.S. Pat. Nos.

5,770,358, 5,789, 162, 5,708, 153, 6,040,193 and 5,800,992, each of which is hereby incorporated in its entirety for all purposes. In some embodiments, arrays are packaged in such a manner as to allow for diagnostics or other manipulation of an all-inclusive device.

Samples

[00126] In some embodiments, the sample for use in the methods is obtained from cells of a solid tumor cell line. In some embodiments, the sample is obtained from cells of prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer and melanoma. In some embodiments, the sample is obtained from cells of lung cancer. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the sample is obtained from cells of non-small cell lung cancer.

[00127] In some embodiments, the cell lines include leukemia cell lines: CCRF-CEM, HL- 60(TB), K-562, MOLT-4, RPMI-8226, SR, P388, and P388/ADR; NSCLC cell lines:

A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460, NCI- H522, and LXFL 529; Small Cell Lung Cancer cell lines: DMS 1 14 and SHP-77; colon cancer cell lines: COLO 205, HCC-2998, HCT-116, HCT-15, HT29, KM 12, SW-620, DLD-1, and KM20L2; CNS cell lines: SF-268, SF-295, SF-539, SNB-19, SNB-75, U251 , SNB-78, and XF 498; melanoma cell lines: LOX IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-2, SK- MEL-28, SK-MEL-5, UACC-257, UACC-62, RPMI-7951 , and M19-MEL; ovarian cancer cell lines: IGR-OV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, NCI/ADR-RES, and SK-OV- 3; renal cancer cell lines: 786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, UO-31, RXF-631 , and SN12K1 ; prostate cancer cell lines: PC-3 and DU-145; breast cancer cell lines: MCF7, MDA-MB-231/ATCC, MDA-MB-468, HS 578T, BT-549, and T-47D. In some embodiments, the cell lines are cell lines included in the NCI 60 panel cell lines.

[00128] In some embodiments, the cell lines that are sensitive to treatment with a BTK inhibitor include PC9, COR-L105, H1975, H2170, and SK-MES1. In some embodiments, the PC9 cells contain a deletion in EGFR from amino acid position 746-750. In some embodiments, the cell lines that are insensitive to treatment with a BTK inhibitor include H1975, H1650, H460, and A549.

[00129] In some embodiments, the sample for use in the methods is from any tissue or fluid from a patient. Samples include, but are not limited, to whole blood, dissociated bone marrow, bone marrow aspirate, pleural fluid, peritoneal fluid, central spinal fluid, abdominal fluid, pancreatic fluid, cerebrospinal fluid, brain fluid, ascites, pericardial fluid, urine, saliva, bronchial lavage, sweat, tears, ear flow, sputum, hydrocele fluid, semen, vaginal flow, milk, amniotic fluid, and secretions of respiratory, intestinal or genitourinary tract. In some embodiments, the sample is a sample obtained from a solid tumor, such as from a biopsy, or a tumor tissue sample. In some embodiments, the sample is a blood serum sample. In some embodiments, the sample is from a fluid or tissue that is part of, or associated with, the lymphatic system or circulatory system. In some embodiments, the sample is a blood sample that is a venous, arterial, peripheral, tissue, cord blood sample. In some embodiments, the sample is a blood cell sample containing one or more peripheral blood mononuclear cells (PBMCs). In some embodiments, the sample contains one or more circulating tumor cells (CTCs). In some embodiments, the sample contains one or more disseminated tumor cells (DTC, e.g., in a bone marrow aspirate sample).

[00130] In some embodiments, the samples are obtained from the individual by any suitable means of obtaining the sample using well-known and routine clinical methods. Procedures for obtaining fluid samples from an individual are well known. For example, procedures for drawing and processing whole blood and lymph are well-known and can be employed to obtain a sample for use in the methods provided. Typically, for collection of a blood sample, an anticoagulation agent (e.g., EDTA, or citrate and heparin or CPD (citrate, phosphate, dextrose) or comparable substances) is added to the sample to prevent coagulation of the blood. In some examples, the blood sample is collected in a collection tube that contains an amount of EDTA to prevent coagulation of the blood sample.

[00131] In some embodiments, the collection of a sample from the individual is performed at regular intervals, such as, for example, one day, two days, three days, four days, five days, six days, one week, two weeks, weeks, four weeks, one month, two months, three months, four months, five months, six months, one year, daily, weekly, bimonthly, quarterly, biyearly or yearly.

[00132] In some embodiments, the collection of a sample is performed at a predetermined time or at regular intervals relative to treatment with a combination of a TEC inhibitor and an additional therapeutic agent. In some embodiments, the TEC inhibitor is a BT inhibitor, an ITK inhibitor, a TEC inhibitor, a RLK inhibitor, or a BMX inhibitor. In some embodiments, the TEC inhibitor is an ITK inhibitor. In some embodiments, the TEC inhibitor is a BTK inhibitor. In some embodiments, the BTK inhibitor is selected from among ibrutinib (PCI-32765), 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), R 486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited) and LFM-A13. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the additional therapeutic agent is an EGFR inhibitor. In some embodiments, the EGFR inhibitor is Erlotinib HCl (OSI-744), Gefitinib (ZD 1839), lapatinib (GW-572016) Ditosylate, afatinib (BIBW2992), neratinib (HKI-272), canertinib (CI-1033), lapatinib, AG-490 (Tyrphostin B42), CP-724714, dacomitinib (PF299804, PF299), WZ4002, AZD8931 (Sapitinib), CUDC-101, AG-1478 (Tyrphostin AG-1478), PD153035 HCl, pelitinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), OSI-420, WZ3146, AST-1306, CO-1686 (AVL-301), varlitinib, icotinib, TAK- 285, WHI-P154, desmethyl erlotinib (CP-473420, OSI-774), PD168393, CNX-2006, tyrphostin 9, AG-18, WZ8040, genistein, chrysophanic acid, or butein.

Combination Therapy

[00133] In some embodiments, a TEC inhibitor is administered in combination with an additional therapeutic agent for the treatment of a solid tumor. In some embodiments, the TEC inhibitor is a BTK inhibitor, an ITK inhibitor, a TEC inhibitor, a RLK inhibitor, or a BMX inhibitor. In certain embodiments, an ITK inhibitor is administered in combination with an additional therapeutic agent for the treatment of a cancer. In certain embodiments, a BTK inhibitor (e.g. ibrutinib) is administered in combination with an additional therapeutic agent for the treatment of a cancer. In some embodiments, the additional therapeutic agent is an inhibitor of EGFR. In some embodiments, the additional therapeutic agent is an inhibitor of HER2, HER4, LYN, SYK, JAK, PI3K, PLCy, MAPK, HDAC, NF_KB, or MEK. In some embodiments, the additional therapeutic agent is selected from a chemotherapeutic agent, a biologic agent, radiation therapy, bone marrow transplant or surgery.

[00134] In some embodiments, the additional therapeutic agent is an inhibitor of EGFR. In some embodiments, the EGFR inhibitor includes, but is not limited to, Erlotinib HCl (OSI-744), Gefitinib (ZD1839), lapatinib (GW-572016) Ditosylate, afatinib (BIBW2992), neratinib (HKI- 272), canertinib (CI- 1033), lapatinib, AG-490 (Tyrphostin B42), CP-724714, dacomitinib (PF299804, PF299), WZ4002, AZD8931 (Sapitinib), CUDC-101, AG-1478 (Tyrphostin AG- 1478), PD 153035 HCl, pelitinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), OSI-420, WZ3146, AST-1306, CO-1686 (AVL-301), varlitinib, icotinib, TAK-285, WHI-P154, desmethyl erlotinib (CP-473420, OSI-774), PD 168393, CNX-2006, tyrphostin 9, AG- 18, WZ8040, genistein, chrysophanic acid, and butein.

[00135] In some embodiments, the additional therapeutic agent is selected from among a chemotherapeutic agent, a biologic agent, radiation therapy, bone marrow transplant or surgery. In some embodiments, the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.

Pharmaceutical Compositions/Formulations

[00136] In some embodiments, pharmaceutical compositions 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. Any of the well-known techniques, carriers, and excipients can be used as suitable and as understood in the art. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and

Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference in their entirety. [00137] A pharmaceutical composition, as used herein, refers to a mixture of a compound described herein, such as, for example, ibrutinib, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. In practicing the methods of treatment or use provided herein, therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated. Preferably, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[00138] In certain embodiments, compositions 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.

[00139] In other embodiments, compositions 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.

[00140] 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.

[00141] The pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[00142] In some embodiments, pharmaceutical compositions including a compound described herein are 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.

[00143] "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.

[00144] "Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain embodiments, antioxidants enhance chemical stability where required.

[00145] In certain embodiments, compositions provided herein 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.

[00146] In some embodiments, formulations described herein 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.

[00147] "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.

[00148] 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 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" 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 and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999).

[00149] "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 4M, 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 myristate.

[00150] Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present compositions.

[00151] 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. [00152] The term "disintegrate" includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid. "Disintegration agents or disintegrants" facilitate the breakup or disintegration of a substance. Examples of disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel^®, or sodium starch glycolate such as Promogel^® or Explotab^®, a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel^®, Avicel^® PH101, Avicel^® PH102, Avicel^® PH105, Elcema^® P100, Emcocel^®, Vivacel^®, Ming Tia^®, and Solka-Floc^®,

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

[00153] "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.

[00154] 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.

[00155] "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.

[00156] "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.

[00157] "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.

[00158] "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 fumarate, 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.

[00159] 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.

[00160] "Pharmacodynamics" refers to the factors which determine the biologic response observed relative to the concentration of drug at a site of action.

[00161] "Pharmacokinetics" refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.

[00162] "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.

[00163] "Solubilizers" include compounds such as triacetin, triethylcitrate, 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.

[00164] "Stabilizers" include compounds such as any antioxidation agents, buffers, acids, preservatives and the like.

[00165] "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.

[00166] "Suspending agents" include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone 12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone 30, 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, 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.

[00167] "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 alkyl ethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. In some embodiments, surfactants are included to enhance physical stability or for other purposes.

[00168] "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.

[00169] "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

[00170] The compositions described herein can be formulated for administration to a subject via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes. As used herein, the term "subject" is used to mean an animal, preferably a mammal, including a human or non-human. As used herein, the terms patient and subject are used interchangeably.

[00171] Moreover, the pharmaceutical compositions described herein, which include ibrutinib 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.

[00172] 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. In some embodiments, disintegrating agents are added, such as the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[00173] Dragee cores are provided with suitable coatings. For this purpose, in some embodiments, concentrated sugar solutions are used, which, in particular embodiments, optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[00174] 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 some embodiments, in soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid

polyethylene glycols. In addition, in some embodiments, stabilizers are added. All formulations for oral administration should be in dosages suitable for such administration.

[00175] In some embodiments, the solid dosage forms disclosed herein are 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, in some embodiments,

pharmaceutical formulations described herein are 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.

[00176] In some embodiments, solid dosage forms, e.g., tablets, effervescent tablets, and capsules, are prepared by mixing particles of ibrutinib, 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 are dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. In some embodiments, the individual unit dosages also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.

[00177] 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.

[00178] 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. In another embodiment, some or all of the particles of ibrutinib, are not microencapsulated and are uncoated.

[00179] 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.

[00180] 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.

[00181] In order to release the compound of ibrutinib, 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.

[00182] 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.

[00183] 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.

[00184] 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.

[00185] 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.

[00186] 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/cm , e.g. Avicel, powdered cellulose), and talc.

[00187] 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.

[00188] 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.

[00189] Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,

polyvinylpyrrolidone 17, 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, hydroxypropylmethylcellulose, 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.

[00190] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[00191] 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.

[00192] 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.

[00193] 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.

[00194] In some embodiments, a capsule is 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 can be swallowed whole or the capsule can 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.

[00195] In various embodiments, the particles of ibrutinib, 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. [00196] In another aspect, in some embodiments, dosage forms 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.

[00197] Materials useful for the microencapsulation described herein include materials compatible with ibrutinib, which sufficiently isolate the compound of any of ibrutinib, from other non-compatible excipients. Materials compatible with compounds of any of ibrutinib, are those that delay the release of the compounds of any of ibrutinib, in vivo.

[00198] 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 ollicoat 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^® S 12.5, Eudragit^® NE30D, and Eudragit^® NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

[00199] 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. [00200] In some embodiments, microencapsulated compounds of any of ibrutinib, are 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, in some embodiments, other methods such as roller compaction, extrusion/spheronization, coacervation, or nanoparticle coating are used.

[00201] In one embodiment, the particles of compounds of any of ibrutinib, 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).

[00202] In other embodiments, the solid dosage formulations of the compounds of any of ibrutinib, 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.

[00203] In other embodiments, a powder including the formulations with a compound of any of ibrutinib, described herein, is formulated to include one or more pharmaceutical excipients and flavors. In some embodiments, such a powder is 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.

[00204] 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.

[00205] 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. In some embodiments, the enteric coated dosage form is 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. In some embodiments, the enteric coated oral dosage form is a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.

[00206] 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:

[00207] Shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7;

[00208] 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 NE (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; [00209] 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 psuedo latex with particles <1 μηι. Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). The performance can vary based on the degree and type of substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable. The performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules, or as fine powders for aqueous dispersions; Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH >5, and it is much less permeable to water vapor and gastric fluids.

[00210] 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.

[00211] In some embodiments, colorants, detackifiers, surfactants, antifoaming agents, lubricants (e.g., carnuba wax or PEG) are added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.

[00212] In other embodiments, the formulations described herein, which include ibrutinib, 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.

[00213] In some embodiments, pharmaceutical formulations are provided that include particles of ibrutinib, described herein and at least one dispersing agent or suspending agent for oral administration to a subject. In some embodiments, the formulations are a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.

[00214] 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, in some embodiments, the liquid dosage forms 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.

[00215] 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.

[00216] 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^® 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.

[00217] 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 4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,

hydroxypropylmethyl-cellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone^®, e.g., S-630), 4-(l , l ,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68^®, F88^®, and F108^®, which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908^®, also known as Poloxamine 908^®, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)). In other embodiments, the dispersing agent is selected from a group not comprising one of the following agents: hydrophilic polymers; electrolytes; Tween ^® 60 or 80; PEG; polyvinylpyrrolidone (PVP);

hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC 4M, 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 , 1 ,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^®).

[00218] 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, polyoxyethylene 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.

[00219] 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.

[00220] 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.

[00221] 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 glyrrfiizinate (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.

[00222] 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 -butyl eneglycol,

dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[00223] 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. In some embodiments, SEDDS 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.

[00224] 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

[00225] Intranasal formulations are known in the art and are described in, for example, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391 ,452, each of which is specifically incorporated by reference. Formulations that include ibrutinib, 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. In some embodiments, 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 are also present. The nasal dosage form should be isotonic with nasal secretions.

[00226] In some embodiments, for administration by inhalation described herein, the pharmaceutical compositions are 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., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In some embodiments, in the case of a pressurized aerosol, the dosage unit is determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch. Buccal Formulations

[00227] In some embodiments, buccal formulations are 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 any other components that are 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 can be obtained from B.F. Goodrich, is one such polymer). In some embodiments, other components are also incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. In some embodiments, for buccal or sublingual administration, the compositions are in the form of tablets, lozenges, or gels formulated in a conventional manner.

Transdermal Formulations

[00228] In some embodiments, transdermal formulations described herein are 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 ,21 1 , 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.

[00229] In some embodiments, the transdermal dosage forms described herein 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; (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.

[00230] In some embodiments, formulations suitable for transdermal administration of compounds described herein 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. In some embodiments, such patches are 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. 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

[00231] In some embodiments, formulations that include a compound of ibrutinib, suitable for intramuscular, subcutaneous, or intravenous injection 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. In some embodiments, formulations suitable for subcutaneous injection 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. In some embodiments, it is also 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.

[00232] In some embodiments, for intravenous injections, compounds described herein are 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. In some embodiments, for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.

[00233] In some embodiments, parenteral injections involve bolus injection or continuous infusion. In some embodiments, formulations for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the pharmaceutical composition described herein is in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contains 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, in some embodiments, suspensions of the active compounds are 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. In some embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, in some embodiments, the suspension also contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in some embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g. , sterile pyrogen-free water, before use.

Other Formulations

[00234] In certain embodiments, delivery systems for pharmaceutical compounds are 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), polymethylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

[00235] In some embodiments, the compounds described herein are 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.

[00236] In some embodiments, the compounds described herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

Dosing and Treatment Regiments

[00237] In some embodiments, the amount of a TEC inhibitor that is administered from 10 mg/day up to, and including, 1000 mg/day. In some embodiments, the amount of a TEC inhibitor that is administered is from about 40 mg/day to 70 mg/day. In some embodiments, the amount of a TEC inhibitor that is administered per day is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg.

[00238] In some embodiments, the amount of an ITK inhibitor that is administered from 10 mg/day up to, and including, 1000 mg/day. In some embodiments, the amount of an ITK inhibitor that is administered is from about 40 mg/day to 70 mg/day. In some embodiments, the amount of an ITK inhibitor that is administered per day is about 10 mg, about 1 1 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg.

[00239] In some embodiments, the amount of a BTK inhibitor that is administered from 10 mg/day up to, and including, 1000 mg/day. In some embodiments, the amount of a BTK inhibitor that is administered is from about 40 mg/day to 70 mg/day. In some embodiments, the amount of a BTK inhibitor that is administered per day is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 1 10 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg.

[00240] In some embodiments, the amount of ibrutinib that is administered from 10 mg/day up to, and including, 1000 mg/day. In some embodiments, the amount of Ibrutinib that is administered is from about 40 mg/day to 70 mg/day. In some embodiments, the amount of Ibrutinib that is administered per day is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg. In some embodiments, the amount of Ibrutinib that is administered is about 40 mg/day. In some embodiments, the amount of Ibrutinib that is administered is about 50 mg/day. In some embodiments, the amount of Ibrutinib that is administered is about 60 mg/day. In some embodiments, the amount of Ibrutinib that is administered is about 70 mg/day.

[00241] In some embodiments, Ibrutinib is administered once per day, twice per day, or three times per day. In some embodiments, Ibrutinib is administered once per day. In some embodiments, Ibrutinib is administered as a maintenance therapy.

[00242] In some embodiments, the compositions disclosed herein are administered for prophylactic, therapeutic, or maintenance treatment. In some embodiments, the compositions disclosed herein are administered for therapeutic applications. In some embodiments, the compositions disclosed herein are administered for therapeutic applications. In some embodiments, the compositions disclosed herein are administered as a maintenance therapy, for example for a patient in remission.

[00243] In some embodiments, in the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compounds is given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. In some embodiments, the dose reduction during a drug holiday is from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[00244] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long- term basis upon any recurrence of symptoms.

[00245] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, the severity of the disease, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, or from about 1-1500 mg per day. In some embodiments, the desired dose is conveniently presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00246] In some embodiments, the pharmaceutical composition described herein is in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. In some embodiments, the unit dosage is in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single- dose non-reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, in some embodiments, formulations for parenteral injection are presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[00247] The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. In some embodiments, such dosages are altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. [00248] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. In some embodiments, the dosage is varied within this range depending upon the dosage form employed and the route of administration utilized.

Digital Processing Device

[00249] Disclosed herein, in certain embodiments, are systems of assessing an individual having a solid tumor for treatment with a BT inhibitor, comprising: (a) a digital processing device comprising an operating system configured to perform executable instructions, and an electronic memory; (b) a dataset stored in the electronic memory, wherein the dataset comprises raw data for use in determining one or more modifications in EGFR; and (c) a computer program including instructions executable by the digital processing device to create an application comprising: (i) a first software module configured to analyze the dataset to determine the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and (ii) a second software module to assign the individual as a candidate for treatment with ibrutinib if there is a presence of at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750.

[00250] Disclosed herein, in certain embodiments, are systems of assessing an individual having a solid tumor for treatment with a BTK inhibitor, comprising: (a) a digital processing device comprising an operating system configured to perform executable instructions, and an electronic memory; (b) a dataset stored in the electronic memory, wherein the dataset comprises raw data for use in determining one or more modifications in EGFR; and (c) a computer program including instructions executable by the digital processing device to create an application comprising: (i) a first software module configured to analyze the dataset to determine the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR; and (ii) a second software module to assign the individual as a candidate for treatment with ibrutinib if there is an absence of the modification at amino acid position 790 in EGFR.

[00251] In some embodiments, the systems and methods described herein include a digital processing device, or use of the same. In further embodiments, the digital processing device includes one or more hardware central processing units (CPU) that carry out the device's functions. In still further embodiments, the digital processing device further comprises an operating system configured to perform executable instructions. In some embodiments, the digital processing device is optionally connected to a computer network. In further

embodiments, the digital processing device is optionally connected to the Internet such that it accesses the World Wide Web. In still further embodiments, the digital processing device is optionally connected to a cloud computing infrastructure. In other embodiments, the digital processing device is optionally connected to an intranet. In other embodiments, the digital processing device is optionally connected to a data storage device.

[00252] In accordance with the description herein, suitable digital processing devices include, by way of non-limiting examples, server computers, desktop computers, laptop computers, notebook computers, sub-notebook computers, netbook computers, netpad computers, set-top computers, media streaming devices, handheld computers, Internet appliances, mobile smartphones, tablet computers, personal digital assistants, video game consoles, and vehicles. Those of skill in the art will recognize that many smartphones are suitable for use in the system described herein. Those of skill in the art will also recognize that select televisions, video players, and digital music players with optional computer network connectivity are suitable for use in the system described herein. Suitable tablet computers include those with booklet, slate, and convertible configurations, known to those of skill in the art.

[00253] In some embodiments, the digital processing device includes an operating system configured to perform executable instructions. The operating system is, for example, software, including programs and data, which manages the device's hardware and provides services for execution of applications. Those of skill in the art will recognize that suitable server operating systems include, by way of non-limiting examples, FreeBSD, OpenBSD, NetBSD^®, Linux, Apple^® Mac OS X Server^®, Oracle^® Solaris^®, Windows Server^®, and Novell^® NetWare^®. Those of skill in the art will recognize that suitable personal computer operating systems include, by way of non-limiting examples, Microsoft^® Windows^®, Apple^® Mac OS X^®, UNIX^®, and UNIX- like operating systems such as GNU/Linux^®. In some embodiments, the operating system is provided by cloud computing. Those of skill in the art will also recognize that suitable mobile smart phone operating systems include, by way of non-limiting examples, Nokia^® Symbian^® OS, Apple^® iOS^®, Research In Motion^® BlackBerry OS^®, Google^® Android^®, Microsoft^® Windows Phone^® OS, Microsoft^® Windows Mobile^® OS, Linux^®, and Palm^® WebOS^®. Those of skill in the art will also recognize that suitable media streaming device operating systems include, by way of non-limiting examples, Apple TV^®, Roku^®, Boxee^®, Google TV^®, Google Chromecast^®, Amazon Fire^®, and Samsung^® HomeSync^®. Those of skill in the art will also recognize that suitable video game console operating systems include, by way of non-limiting examples, Sony^® PS3^®, Sony^® PS4^®, Microsoft^® Xbox 360^®, Microsoft Xbox One, Nintendo^® Wii^®, Nintendo^® Wii U^®, and Ouya^®.

[00254] In some embodiments, the device includes a storage and/or memory device. The storage and/or memory device is one or more physical apparatuses used to store data or programs on a temporary or permanent basis. In some embodiments, the device is volatile memory and requires power to maintain stored information. In some embodiments, the device is non- volatile memory and retains stored information when the digital processing device is not powered. In further embodiments, the non-volatile memory comprises flash memory. In some embodiments, the non-volatile memory comprises dynamic random-access memory (DRAM). In some embodiments, the non-volatile memory comprises ferroelectric random access memory (FRAM). In some embodiments, the non-volatile memory comprises phase -change random access memory (PRAM). In other embodiments, the device is a storage device including, by way of non-limiting examples, CD-ROMs, DVDs, flash memory devices, magnetic disk drives, magnetic tapes drives, optical disk drives, and cloud computing based storage. In further embodiments, the storage and/or memory device is a combination of devices such as those disclosed herein.

[00255] In some embodiments, the digital processing device includes a display to send visual information to a user. In some embodiments, the display is a cathode ray tube (CRT). In some embodiments, the display is a liquid crystal display (LCD). In further embodiments, the display is a thin film transistor liquid crystal display (TFT -LCD). In some embodiments, the display is an organic light emitting diode (OLED) display. In various further embodiments, on OLED display is a passive -matrix OLED (PMOLED) or active-matrix OLED (AMOLED) display. In some embodiments, the display is a plasma display. In other embodiments, the display is a video projector. In still further embodiments, the display is a combination of devices such as those disclosed herein.

[00256] In some embodiments, the digital processing device includes an input device to receive information from a user. In some embodiments, the input device is a keyboard. In some embodiments, the input device is a pointing device including, by way of non-limiting examples, a mouse, trackball, track pad, joystick, game controller, or stylus. In some embodiments, the input device is a touch screen or a multi-touch screen. In other embodiments, the input device is a microphone to capture voice or other sound input. In other embodiments, the input device is a video camera or other sensor to capture motion or visual input. In further embodiments, the input device is a Kinect™, Leap Motion™, or the like. In still further embodiments, the input device is a combination of devices such as those disclosed herein.

Non-transitory computer readable storage medium

[00257] In some embodiments, the systems and methods disclosed herein include one or more non-transitory computer readable storage media encoded with a program including instructions executable by the operating system of an optionally networked digital processing device. In further embodiments, a computer readable storage medium is a tangible component of a digital processing device. In still further embodiments, a computer readable storage medium is optionally removable from a digital processing device. In some embodiments, a computer readable storage medium includes, by way of non-limiting examples, CD-ROMs, DVDs, flash memory devices, solid state memory, magnetic disk drives, magnetic tape drives, optical disk drives, cloud computing systems and services, and the like. In some cases, the program and instructions are permanently, substantially permanently, semi-permanently, or non-transitorily encoded on the media.

Computer program

[00258] In some embodiments, the systems and methods disclosed herein include at least one computer program, or use of the same. A computer program includes a sequence of instructions, executable in the digital processing device's CPU, written to perform a specified task. In some embodiments, computer readable instructions are implemented as program modules, such as functions, objects, Application Programming Interfaces (APIs), data structures, and the like, that perform particular tasks or implement particular abstract data types. In light of the disclosure provided herein, those of skill in the art will recognize that a computer program, in certain embodiments, is written in various versions of various languages.

[00259] In some embodiments, the functionality of the computer readable instructions are combined or distributed as desired in various environments. In some embodiments, a computer program comprises one sequence of instructions. In some embodiments, a computer program comprises a plurality of sequences of instructions. In some embodiments, a computer program is provided from one location. In other embodiments, a computer program is provided from a plurality of locations. In various embodiments, a computer program includes one or more software modules. In various embodiments, a computer program includes, in part or in whole, one or more web applications, one or more mobile applications, one or more standalone applications, one or more web browser plug-ins, extensions, add-ins, or add-ons, or

combinations thereof.

Web application

[00260] In some embodiments, a computer program includes a web application. In light of the disclosure provided herein, those of skill in the art will recognize that a web application, in various embodiments, utilizes one or more software frameworks and one or more database systems. In some embodiments, a web application is created upon a software framework such as Microsoft^® .NET or Ruby on Rails (RoR). In some embodiments, a web application utilizes one or more database systems including, by way of non-limiting examples, relational, non-relational, object oriented, associative, and XML database systems. In further embodiments, suitable relational database systems include, by way of non-limiting examples, Microsoft^® SQL Server, mySQL™, and Oracle^®. Those of skill in the art will also recognize that a web application, in various embodiments, is written in one or more versions of one or more languages. In some embodiments, a web application is written in one or more markup languages, presentation definition languages, client-side scripting languages, server-side coding languages, database query languages, or combinations thereof. In some embodiments, a web application is written to some extent in a markup language such as Hypertext Markup Language (HTML), Extensible Hypertext Markup Language (XHTML), or extensible Markup Language (XML). In some embodiments, a web application is written to some extent in a presentation definition language such as Cascading Style Sheets (CSS). In some embodiments, a web application is written to some extent in a client-side scripting language such as Asynchronous Javascript and XML (AJAX), Flash^® Actionscript, Javascript, or Silverlight^®. In some embodiments, a web application is written to some extent in a server-side coding language such as Active Server Pages (ASP), ColdFusion^®, Perl, Java™, JavaServer Pages (JSP), Hypertext Preprocessor (PHP), Python™, Ruby, Tel, Smalltalk, WebDNA^®, or Groovy. In some embodiments, a web application is written to some extent in a database query language such as Structured Query Language (SQL). In some embodiments, a web application integrates enterprise server products such as IBM^® Lotus Domino^®. In some embodiments, a web application includes a media player element. In various further embodiments, a media player element utilizes one or more of many suitable multimedia technologies including, by way of non-limiting examples, Adobe^® Flash^®, HTML 5, Apple^® QuickTime^®, Microsoft^® Silverlight^®, Java™, and Unity^®.

Mobile application

[00261] In some embodiments, a computer program includes a mobile application provided to a mobile digital processing device. In some embodiments, the mobile application is provided to a mobile digital processing device at the time it is manufactured. In other embodiments, the mobile application is provided to a mobile digital processing device via the computer network described herein.

[00262] In view of the disclosure provided herein, a mobile application is created by techniques known to those of skill in the art using hardware, languages, and development environments known to the art. Those of skill in the art will recognize that mobile applications are written in several languages. Suitable programming languages include, by way of non-limiting examples, C, C++, C#, Objective-C, Java™, Javascript, Pascal, Object Pascal, Python™, Ruby, VB.NET, WML, and XHTML/HTML with or without CSS, or combinations thereof.

[00263] Suitable mobile application development environments are available from several sources. Commercially available development environments include, by way of non-limiting examples, AirplaySDK, alcheMo, Appcelerator^®, Celsius, Bedrock, Flash Lite, .NET Compact Framework, Rhomobile, and WorkLight Mobile Platform. Other development environments are available without cost including, by way of non-limiting examples, Lazarus, MobiFlex, MoSync, and Phonegap. Also, mobile device manufacturers distribute software developer kits including, by way of non-limiting examples, iPhone and iPad (iOS) SDK, Android™ SDK, BlackBerry^® SDK, BREW SDK, Palm^® OS SDK, Symbian SDK, webOS SDK, and Windows^® Mobile SDK.

[00264] Those of skill in the art will recognize that several commercial forums are available for distribution of mobile applications including, by way of non-limiting examples, Apple^® App Store, Android™ Market, BlackBerry^® App World, App Store for Palm devices, App Catalog for webOS, Windows^® Marketplace for Mobile, Ovi Store for Nokia^® devices, Samsung^® Apps, and Nintendo^® DSi Shop.

Standalone application

[00265] In some embodiments, a computer program includes a standalone application, which is a program that is run as an independent computer process, not an add-on to an existing process, e.g., not a plug-in. Those of skill in the art will recognize that standalone applications are often compiled. A compiler is a computer program(s) that transforms source code written in a programming language into binary object code such as assembly language or machine code. Suitable compiled programming languages include, by way of non-limiting examples, C, C++, Objective-C, COBOL, Delphi, Eiffel, Java™, Lisp, Python™, Visual Basic, and VB .NET, or combinations thereof. Compilation is often performed, at least in part, to create an executable program. In some embodiments, a computer program includes one or more executable complied applications. Web browser plug-in

[00266] In some embodiments, the computer program includes a web browser plug-in. In computing, a plug-in is one or more software components that add specific functionality to a larger software application. Makers of software applications support plug-ins to enable third- party developers to create abilities which extend an application, to support easily adding new features, and to reduce the size of an application. When supported, plug-ins enable customizing the functionality of a software application. For example, plug-ins are commonly used in web browsers to play video, generate interactivity, scan for viruses, and display particular file types. Those of skill in the art will be familiar with several web browser plug-ins including, Adobe^® Flash^® Player, Microsoft^® Silverlight^®, and Apple^® QuickTime^®. In some embodiments, the toolbar comprises one or more web browser extensions, add-ins, or add-ons. In some embodiments, the toolbar comprises one or more explorer bars, tool bands, or desk bands.

[00267] In view of the disclosure provided herein, those of skill in the art will recognize that several plug-in frameworks are available that enable development of plug-ins in various programming languages, including, by way of non-limiting examples, C++, Delphi, Java™, PHP, Python™, and VB .NET, or combinations thereof.

[00268] Web browsers (also called Internet browsers) are software applications, designed for use with network-connected digital processing devices, for retrieving, presenting, and traversing information resources on the World Wide Web. Suitable web browsers include, by way of non- limiting examples, Microsoft^® Internet Explorer^®, Mozilla^® Firefox^®, Google^® Chrome, Apple^® Safari^®, Opera Software^® Opera^®, and KDE Konqueror. In some embodiments, the web browser is a mobile web browser. Mobile web browsers (also called mircrobrowsers, mini-browsers, and wireless browsers) are designed for use on mobile digital processing devices including, by way of non-limiting examples, handheld computers, tablet computers, netbook computers, subnotebook computers, smartphones, music players, personal digital assistants (PDAs), and handheld video game systems. Suitable mobile web browsers include, by way of non-limiting examples, Google^® Android^® browser, RIM BlackBerry^® Browser, Apple^® Safari^®, Palm^® Blazer, Palm^® WebOS^® Browser, Mozilla^® Firefox^® for mobile, Microsoft^® Internet Explorer^® Mobile, Amazon^® Kindle^® Basic Web, Nokia^® Browser, Opera Software^® Opera^® Mobile, and Sony^® PSP™ browser.

Software modules

[00269] In some embodiments, the systems and methods disclosed herein include software, server, and/or database modules, or use of the same. In view of the disclosure provided herein, software modules are created by techniques known to those of skill in the art using machines, software, and languages known to the art. The software modules disclosed herein are implemented in a multitude of ways. In various embodiments, a software module comprises a file, a section of code, a programming object, a programming structure, or combinations thereof. In further various embodiments, a software module comprises a plurality of files, a plurality of sections of code, a plurality of programming objects, a plurality of programming structures, or combinations thereof. In various embodiments, the one or more software modules comprise, by way of non-limiting examples, a web application, a mobile application, and a standalone application. In some embodiments, software modules are in one computer program or application. In other embodiments, software modules are in more than one computer program or application. In some embodiments, software modules are hosted on one machine. In other embodiments, software modules are hosted on more than one machine. In further embodiments, software modules are hosted on cloud computing platforms. In some embodiments, software modules are hosted on one or more machines in one location. In other embodiments, software modules are hosted on one or more machines in more than one location.

Databases

[00270] In some embodiments, the methods and systems disclosed herein include one or more databases, or use of the same. In view of the disclosure provided herein, those of skill in the art will recognize that many databases are suitable for storage and retrieval of analytical information described elsewhere herein. In various embodiments, suitable databases include, by way of non-limiting examples, relational databases, non-relational databases, object oriented databases, object databases, entity-relationship model databases, associative databases, and XML databases. In some embodiments, a database is internet-based. In further embodiments, a database is web-based. In still further embodiments, a database is cloud computing-based. In other embodiments, a database is based on one or more local computer storage devices.

Services

[00271] Disclosed herein in certain embodiments, are methods and systems performed as a service. In some embodiments, a service provider obtains a solid tumor samples that a customer wishes to analyze. In some embodiments, the service provider then encodes each solid tumor sample to be analyzed by any of the methods described herein, performs the analysis and provides a report to the customer. In some embodiments, the customer also performs the analysis and provides the results to the service provider for decoding. In some embodiments, the service provider then provides the decoded results to the customer. In some embodiments, the customer also encodes the solid tumor samples, analyzes the samples and decodes the results by interacting with software installed locally (at the customer's location) or remotely (e.g. on a server reachable through a network). In some embodiments, the software generates a report and transmit the report to the costumer. Exemplary customers include clinical laboratories, hospitals, and the like. In some embodiments, a customer or party is any suitable customer or party with a need or desire to use the methods, systems, compositions, and kits of the invention.

Server

[00272] In some embodiments, the methods provided herein are processed on a server or a computer server (Fig. 3). In some embodiments, the server 401 includes a central processing unit (CPU, also "processor") 405 which is a single core processor, a multi core processor, or plurality of processors for parallel processing. In some embodiments, a processor used as part of a control assembly is a microprocessor. In some embodiments, the server 401 also includes memory 410 (e.g. random access memory, read-only memory, flash memory); electronic storage unit 415 (e.g. hard disk); communications interface 420 (e.g. network adaptor) for

communicating with one or more other systems; and peripheral devices 425 which includes cache, other memory, data storage, and/or electronic display adaptors. The memory 410, storage unit 415, interface 420, and peripheral devices 425 are in communication with the processor 405 through a communications bus (solid lines), such as a motherboard. In some embodiments, the storage unit 415 is a data storage unit for storing data. The server 401 is operatively coupled to a computer network ("network") 430 with the aid of the communications interface 420. In some embodiments, a processor with the aid of additional hardware is also operatively coupled to a network. In some embodiments, the network 430 is the Internet, an intranet and/or an extranet, an intranet and/or extranet that is in communication with the Internet, a telecommunication or data network. In some embodiments, the network 430 with the aid of the server 401,

implements a peer-to-peer network, which enables devices coupled to the server 401 to behave as a client or a server. In some embodiments, the server is capable of transmitting and receiving computer-readable instructions (e.g., device/system operation protocols or parameters) or data (e.g., sensor measurements, raw data obtained from detecting metabolites, analysis of raw data obtained from detecting metabolites, interpretation of raw data obtained from detecting metabolites, etc.) via electronic signals transported through the network 430. Moreover, in some embodiments, a network is used, for example, to transmit or receive data across an international border.

[00273] In some embodiments, the server 401 is in communication with one or more output devices 435 such as a display or printer, and/or with one or more input devices 440 such as, for example, a keyboard, mouse, or joystick. In some embodiments, the display is a touch screen display, in which case it functions as both a display device and an input device. In some embodiments, different and/or additional input devices are present such an enunciator, a speaker, or a microphone. In some embodiments, the server uses any one of a variety of operating systems, such as for example, any one of several versions of Windows®, or of MacOS®, or of Unix®, or of Linux®.

[00274] In some embodiments, the storage unit 415 stores files or data associated with the operation of a device, systems or methods described herein.

[00275] In some embodiments, the server communicates with one or more remote computer systems through the network 430. In some embodiments, the one or more remote computer systems include, for example, personal computers, laptops, tablets, telephones, Smart phones, or personal digital assistants.

[00276] In some embodiments, a control assembly includes a single server 401. In other situations, the system includes multiple servers in communication with one another through an intranet, extranet and/or the Internet.

[00277] In some embodiments, the server 401 is adapted to store device operation parameters, protocols, methods described herein, and other information of potential relevance. In some embodiments, such information is stored on the storage unit 415 or the server 401 and such data is transmitted through a network.

Kits/Article of Manufacture

[00278] 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.

[00279] 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.

[00280] For example, the container(s) include Ibrutinib, optionally in a composition or in combination with EGFR inhibitors as disclosed herein. Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.

[00281] 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. [00282] 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.

[00283] 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

[00284] These examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.

EXAMPLE 1: Use of non-small cell lung cancer cell line (NSCLC) as in vitro surrogates for in vivo drug sensitivity

[00285] Human tumor-derived non-small-cell lung cancer (NSCLC) cell lines, H3255, PC9, NCI H2170, NCIH2073, NCI-H1975, NCI-H1650, and NCI-H460, were shown to have varying degrees of sensitivity to gefitinib and erlotinib inhibitors, marked as "G" and "E" respectively in Fig. 1. The NSCLC cell lines were classified into hypersensitive, sensitive and insensitive, based on their response to the gelfitinib and erlotinib inhibitors. The NSCLC cell lines were treated in vitro with gefitinib and erlotinib such that the in vitro concentrations used in the tissue culture roughly correlated with the plasma concentrations of these drugs in patients treated with standard doses of the same agents. The standard doses in patients were, for example, 250 mg per day for gefitinib and 150 mg a day for erlotinib. [00286] The IC50, for treatment with gefitinib or erlotinib, was, for example, between 0.1 nM and 100 nM for the hypersensitive cell lines. Exemplary hypersensitive NSCLC cell lines were H3255 and PC9. The IC₅₀ for exemplary hypersensitive NSCLC cell lines, H3255 and PC9, were 1 nM and 4 nM respectively. The exemplary hypersensitive NSCLC cell line, H3255, was found to contain EGFR tyrosine kinase domain mutations, for example, L858R. The exemplary hypersensitive NSCLC cell line, PC9 was also found to contain EGFR tyrosine kinase domain mutations, for example, Δ(Ε746-Α750).

[00287] The IC50, for treatment with gefitinib or erlotinib, was, for example, between 100 nM and 1 μΜ for the sensitive cell lines. Exemplary sensitive NSCLC cell lines were NCI-H2170 and NCI-H2073. The IC₅₀ for the exemplary sensitive NSCLC cell lines, NCI-H2170 and NCI- H2073, were 200 nM and 250 nM respectively. The sensitive NSCLC cell lines were wild type and were not found to contain genetic mutations.

[00288] The IC50, for treatment with gefitinib or erlotinib, was, for example, between 1 μΜ and higher for the insensitive cell lines. Exemplary insensitive NSCLC cell lines were NCI-H1975, NCI-H1650, and NCI-H460. The IC₅₀ for exemplary insensitive NSCLC cell lines, NCI-H1975, NCI-H1650, and NCI-H460 were 12 μΜ, 9 μΜ, and 20 μΜ, respectively. The exemplary insensitive NSCLC cell line, NCI-H1975, was found to contain EGFR tyrosine kinase domain mutations, for example, L858R and Δ(Ε746-Α750) . The exemplary insensitive NSCLC cell line, NCI-H1975, was found to also contain additional mutations, for example, T790M . The exemplary insensitive NSCLC cell line, NCI-H1650, was found to contain EGFR tyrosine kinase domain mutations, for example, L858R and Δ(Ε746-Α750). The exemplary insensitive NSCLC cell line, NCI-H1650, was found to also contain additional mutations, for example, phosphatase and tensin homologue (PTEN) loss. The exemplary insensitive NSCLC cell line, NCI-H460, was found to contain KRAS mutations.

[00289] NSCLC cells lines A549 and H460 were treated with ibrutinib. Ibrutinib did not induce cell death in the A549 and H460 cell lines. The NSCLC cell line A549 was classified as insensitive to ibrutinib. The NSCLC cell line A549 was found to contain KRAS mutations.

[00290] Exemplary NSCLC hypersensitive cells line PC9 was also treated with ibrutinib. The

PC9 cell line, was found to contain EGFR tyrosine kinase domain mutations, for

example, Δ(Ε746-Α750). The PC9 cell contained wild type KRAS and PTEN. The PC9 cell line was found to be sensitive to ibrutinib treatment, as indicated in Fig. 1.

EXAMPLE 2: Screening of twenty five non-small cell lung cancer cell line (NSCLC) identified five exemplary NSCLC cell lines that were sensitive to ibrutinib treatment

[00291] Five exemplary NSCLC cell lines, PC9, H1975, SK-MES1, COR-L105, and H2170 were found to lack the KRAS mutation, as illustrated in Fig. 2. The five exemplary NSCLC cell lines were treated with ibrutinib at concentrations ranging between 0 μΜ and 1.5 μΜ. The five exemplary NSCLC cell lines showed EC50 values, for ibrutinib treatment with above mentioned concentrations, of 18.7 nM (PC9), 89.0 nM (HI 975), 44.8 nM (SK-MES1), 67.5 nM (COR- L105), and 137.6 nM (H2170). Among the other NSCLC cell lines that were treated with ibrutinib, more than 50% were found to contain KRAS mutations. Some examples, among the other cell lines, that exhibited EC50 values of 1 μΜ or higher, were H358, H441, H2122, COR- L23, DV90, and A549.

[00292] 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. A method for selecting an individual having a solid tumor for treatment with a BTK inhibitor, comprising:

a. determining the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and

b. administering to the individual a therapeutically effective amount of the BTK inhibitor if there is a presence of at least one of the modification at amino acid position 8 8 and the deletion from amino acid position 746 to amino acid position 750 in EGFR.

2. A method of monitoring whether an individual receiving a BTK inhibitor for treatment of a solid tumor is responsive or is likely to respond to therapy, comprising:

b. characterizing the individual as responsive or is likely to respond to therapy with the BTK inhibitor if the individual has at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR.

3. A method of optimizing the therapy of an individual receiving a BTK inhibitor for treatment of a solid tumor, comprising:

b. modifying, discontinuing, or continuing the treatment based on the presence or absence of at least one of the modification to an amino acid residue at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750 in EGFR.

4. The method of any one of claims 1 -3, wherein the modification at amino acid position 858 in EGFR is L858R.

5. The method of any one of claims 1-3, further comprising determining the presence or absence of a modification in KRAS.

6. The method of claim 5, wherein KRAS does not contain a modification.

7. The method of any one of claims 1 -3, further comprising determining the expression rate of PTEN relative to a control.

8. The method of claim 7, wherein the expression level of PTEN increase by 0.5-fold, 1- fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50- fold, or more compared to the control.

9. The method of claim 7 or 8, wherein the control is the expression level of PTEN in an individual who does not have the solid tumor.

10. The method of claim 7 or 8, wherein the control is the expression level of PTEN in an individual prior to administration of the BTK inhibitor.

11. A method for selecting an individual having a solid tumor for treatment with a BTK inhibitor, comprising:

a. determining the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR; and

b. administering to the individual a therapeutically effective amount of ibrutinib if there is an absence of the modification at amino acid position 790 in EGFR.

12. A method of optimizing the therapy of an individual receiving a BTK inhibitor for

treatment of a solid tumor, comprising:

b. modifying, discontinuing, or continuing the treatment based on the presence or absence of the modification to an amino acid residue at amino acid position 790 in EGFR.

13. The method of claim 11 or 12, wherein the modification at amino acid position 790 in EGFR is T790M.

14. The method of any one of claims 11-13, further comprising determining the presence or absence of a modification to an aromatic residue at amino acid position 858 in EGFR.

15. The method of claim 14, wherein the modification at amino acid position 858 in EGFR is L858R.

16. The method of any one of claims 11-15, further comprising administering to the

individual a therapeutically effective amount of a BTK inhibitor if there is an absence of the modification at amino acid position 790 and at amino acid position 858 in EGFR.

17. The method of any one of claims 11-16, further comprising determining the presence or absence of modifications in KRAS.

18. The method of claim 17, wherein KRAS contains a modification.

19. The method of any one of claims 11-18, further comprising determining the expression level of PTEN relative to a control.

20. The method of claim 19, wherein the expression level of PTEN decrease by 0.5-fold, 1- fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50- fold, or more compared to the control.

21. The method of claim 19 or 20, wherein the control is the expression level of PTEN in an individual who does not have the solid tumor.

22. The method of claim 19 or 20, wherein the control is the expression level of PTEN in an individual prior to administration of the BTK inhibitor.

23. The method of any one of claims 1 -22, wherein the solid tumor is selected from prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer and melanoma.

24. The method of claim 23, wherein the lung cancer is non- small cell lung cancer.

25. The method of any one of the proceeding claims, wherein the solid tumor is a relapsed or refractory solid tumor.

26. The method of any one of claims 1 -25, wherein the BTK inhibitor is ibrutinib.

27. The method of claim 26, wherein ibrutinib is administered at a dosage of about 40

mg/day to about 1000 mg/day.

28. The method of claim 26 or 27, wherein ibrutinib is administered orally.

29. The method of any one of claims 1 -28, wherein the method further comprises

administering an additional therapeutic agent.

30. The method of claim 29, wherein the additional therapeutic agent is an EGFR inhibitor.

31. The method of claim 30, wherein the EGFR inhibitor is selected from Erlotinib HC1 (OSI-744), Gefitinib (ZD 1839), lapatinib (GW-572016) Ditosylate, afatinib

(BIBW2992), neratinib (HKI-272), canertinib (CI- 1033), lapatinib, AG-490 (Tyrphostin B42), CP-724714, dacomitinib (PF299804, PF299), WZ4002, AZD8931 (Sapitinib), CUDC-101, AG-1478 (Tyrphostin AG-1478), PD153035 HC1, pelitinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), OSI-420, WZ3146, AST-1306, CO- 1686 (AVL-301), varlitinib, icotinib, TAK-285, WHI-P154, desmethyl erlotinib (CP- 473420, OSI-774), PD168393, CNX-2006, tyrphostin 9, AG-18, WZ8040, genistein, chrysophanic acid, and butein.

32. The method of claim 29, wherein the additional therapeutic agent is selected from among a chemotherapeutic agent or radiation therapy.

33. The method of claim 32, wherein the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.

34. The method of any one of the proceeding claims, wherein ibrutinib and the additional therapeutic agent are administered simultaneously, sequentially or intermittently.

35. A kit for carrying out the method of any one of the proceeding claims, comprising one or more reagents for determining the presence or absence of modifications in EGFR and KRAS in the sample.

36. The kit of claim 35, further comprising one or more reagents for determining the

expression level of PTEN.

37. A system of assessing an individual having a solid tumor for treatment with a BTK

inhibitor, comprising:

a. a digital processing device comprising an operating system configured to perform executable instructions, and an electronic memory;

b. a dataset stored in the electronic memory, wherein the dataset comprises raw data for use in determining one or more modifications in EGFR; and

c. a computer program including instructions executable by the digital processing device to create an application comprising:

i. a first software module configured to analyze the dataset to determine the presence or absence of at least one of a modification to an amino acid residue at amino acid position 858 and a deletion from amino acid position 746 to amino acid position 750 in EGFR; and ii. a second software module to assign the individual as a candidate for treatment with ibrutinib if there is a presence of at least one of the modification at amino acid position 858 and the deletion from amino acid position 746 to amino acid position 750.

38. The system of claim 37, wherein the modification at amino acid position 858 in EGFR is L858R.

39. The system of claim 37, further comprising analyzing KRAS to determine the presence or absence of a modification.

40. The system of claim 39, wherein KRAS does not contain a modification.

41. The system of any one of claims 37-40, further comprising determining the expression level of PTEN relative to a control.

42. The system of claim 41, wherein the expression level of PTEN increase by 0.5 -fold, 1- fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50- fold, or more compared to the control.

43. The system of claim 41 or 42, wherein the control is the expression level of PTEN in an individual who does not have the solid tumor.

44. The system of claim 41 or 42, wherein the control is the expression level of PTEN in an individual prior to administration of the BTK inhibitor.

45. A system of assessing an individual having a solid tumor for treatment with a BTK

inhibitor, comprising:

i. a first software module configured to analyze the dataset to determine the presence or absence of a modification to an amino acid residue at amino acid position 790 in EGFR; and

ii. a second software module to assign the individual as a candidate for treatment with ibrutinib if there is an absence of the modification at amino acid position 790 in EGFR.

46. The system of claim 45, wherein the modification at amino acid position 790 in EGFR is T790M.

47. The system of claim 45 or 46, further comprising determining the presence or absence of a modification to an aromatic residue at amino acid position 858 in EGFR.

48. The system of claim 47, wherein the modification at amino acid position 858 in EGFR is L858R.

49. The method of claim 46, further comprising administering to the individual a

therapeutically effective amount of ibrutinib if there is an absence of the modification at amino acid position 790 and at amino acid position 8 8 in EGFR.

50. The system of any one of claims 45-49, further comprising analyzing KRAS to

determine the presence or absence of a modification.

1. The system of claim 0, wherein KRAS does contain a modification.

52. The system of any one of claims 45-51 , further comprising determining the expression level of PTEN relative to a control.

53. The system of claim 52, wherein the expression level of PTEN decrease by 0.5-fold, 1- fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 6.5-fold, 7-fold, 7.5-fold, 8-fold, 8.5-fold, 9-fold, 9.5-fold, 10-fold, 15-fold, 20-fold, 50- fold, or more compared to the control.

54. The system of any one of claims 37-53, wherein the solid tumor is selected from prostate cancer, pancreatic cancer, breast cancer, colon cancer, lung cancer, gastroenterological cancer and melanoma.

55. The system of claim 54, wherein the lung cancer is non-small cell lung cancer.

56. The system of any one of claims 37-55, wherein the solid tumor is a relapsed or

refractory solid tumor.

57. The system of any one of claims 37-56, wherein the BTK inhibitor is ibrutinib.

58. The system of claim 57, wherein ibrutinib is administered at a dosage of about 40

mg/day to about 1000 mg/day.

59. The system of claim 57 or 58, wherein ibrutinib is administered orally.

60. The system of any one of claims 37-59, further comprising administering an additional therapeutic agent.

61. The system of claim 60, wherein the additional therapeutic agent is an EGFR inhibitor.

62. The system of claim 61, wherein the EGFR inhibitor is selected from Erlotinib HC1 (OSI-744), Gefitinib (ZD 1839), lapatinib (GW-572016) Ditosylate, afatinib

(BIBW2992), neratinib (HKI-272), canertinib (CI- 1033), lapatinib, AG-490 (Tyrphostin B42), CP-724714, dacomitinib (PF299804, PF299), WZ4002, AZD8931 (Sapitinib), CUDC-101, AG-1478 (Tyrphostin AG-1478), PD153035 HC1, pelitinib (EKB-569), AEE788 (NVP-AEE788), AC480 (BMS-599626), OSI-420, WZ3146, AST-1306, CO- 1686 (AVL-301), varlitinib, icotinib, TAK-285, WHI-P1 4, desmethyl erlotinib (CP- 473420, OSI-774), PD168393, CNX-2006, tyrphostin 9, AG-18, WZ8040, genistein, chrysophanic acid, and butein.

63. The system of claim 60, wherein the additional therapeutic agent is selected from among a chemotherapeutic agent or radiation therapy.

64. The system of claim 63, wherein the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.

5. The system of any one of the proceeding claims, wherein ibrutinib and the additional therapeutic agent are administered simultaneously, sequentially or intermittently.