US 20170209462A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0209462 A1 Bilotti et al. (43) Pub. Date: Jul. 27, 2017 (54) BTK INHIBITOR COMBINATIONS FOR Publication Classification TREATING MULTIPLE MYELOMA (51) Int. Cl. (71) Applicant: Pharmacyclics LLC, Sunnyvale, CA A 6LX 3/573 (2006.01) A69/20 (2006.01) (US) A6IR 9/00 (2006.01) (72) Inventors: Elizabeth Bilotti, Sunnyvale, CA (US); A69/48 (2006.01) Thorsten Graef, Los Altos Hills, CA A 6LX 3/59 (2006.01) (US) A63L/454 (2006.01) (52) U.S. Cl. CPC .......... A61 K3I/573 (2013.01); A61K 3 1/519 (21) Appl. No.: 15/252,385 (2013.01); A61 K3I/454 (2013.01); A61 K 9/0053 (2013.01); A61K 9/48 (2013.01); A61 K (22) Filed: Aug. 31, 2016 9/20 (2013.01) (57) ABSTRACT Disclosed herein are pharmaceutical combinations, dosing Related U.S. Application Data regimen, and methods of administering a combination of a (60) Provisional application No. 62/212.518, filed on Aug. BTK inhibitor (e.g., ibrutinib), an immunomodulatory agent, 31, 2015. and a steroid for the treatment of a hematologic malignancy. US 2017/0209462 A1 Jul. 27, 2017 BTK INHIBITOR COMBINATIONS FOR Subject in need thereof comprising administering pomalido TREATING MULTIPLE MYELOMA mide, ibrutinib, and dexamethasone, wherein pomalido mide, ibrutinib, and dexamethasone are administered con CROSS-REFERENCE TO RELATED currently, simulataneously, and/or co-administered. APPLICATION 0008. In some aspects, provided herein is a method of treating a hematologic malignancy in a subject in need 0001. This application claims the benefit of U.S. Provi thereof, comprising administering to the Subject a therapeu sional Application No. 62/212.518, filed Aug. 31, 2015, tically effective amount of a combination comprising an which is incorporated herein by reference in its entirety. immunomodulatory agent, a BTK inhibitor, and a steroid, BACKGROUND wherein an immunomodulatory agent, a BTK inhibitor, and a steroid are administered concurrently. 0002 Bruton's tyrosine kinase (Btk), a member of the 0009. In some aspects, provided herein is a method of Tec family of non-receptor tyrosine kinases, is a key sig treating a hematologic malignancy in a subject in need naling enzyme expressed in all hematopoietic cells types thereof, comprising administering to the Subject a therapeu except T lymphocytes and natural killer cells. Btk plays an tically effective amount of a combination comprising essential role in the B-cell signaling pathway linking cell pomalidomide, ibrutinib, and dexamethasone following a surface B-cell receptor (BCR) stimulation to downstream dosing regimen wherein the dosing regimen comprises intracellular responses. administering pomalidomide, ibrutinib, and dexamethasone 0003) 1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyra concurrently. Zolo3,4-dipyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one is also known by its IUPAC name as 1-((3R)-3-4-amino-3- DETAILED DESCRIPTION (4-phenoxyphenyl)-1H-pyrazolo 3,4-dipyrimidin-1-yl)pip eridin-1-yl)prop-2-en-1-one or 2-Propen-1-one, 1-(3R)-3- Certain Terminology 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo 3,4-d 0010 Unless defined otherwise, all technical and scien pyrimidin-1-yl)-1-piperidinyl-, and has been given the tific terms used herein have the same meaning as is com USAN name, ibrutinib. The various names given for ibru monly understood by one of skill in the art to which the tinib are used interchangeably herein. Ibrutinib is an inhibi claimed subject matter belongs. It is to be understood that tor of Btk. the foregoing general description and the following detailed description are exemplary and explanatory only and are not SUMMARY restrictive of any Subject matter claimed. In this application, 0004 Disclosed herein are pharmaceutical combinations, the use of the singular includes the plural unless specifically dosing regimens, and methods that comprise a combination stated otherwise. It must be noted that, as used in the of a TEC inhibitor, an immunomodulatory agent, and a specification and the appended claims, the singular forms steroid for the treatment of a hematologic malignancy. Also “a,” “an and “the include plural referents unless the described herein are methods of administrating a combina context clearly dictates otherwise. In this application, the use tion of a TEC inhibitor, an immunomodulatory agent, and a of “or” means “and/or unless stated otherwise. Further steroid for treatment of multiple myeloma. In some more, use of the term “including as well as other forms, instances, the TEC inhibitor is a BTK, ITK, TEC, RLK, or such as “include”, “includes,” and “included,” is not limit BMX inhibitor. In some instances, the BTK inhibitor is ing. ibrutinib. In some instances, the immunomodulatory agent is 0011 AS used herein, ranges and amounts can be pomalidomide. In some instances the steroid is dexametha expressed as “about a particular value or range. About also SO. includes the exact amount. Hence “about 5 uL' means 0005. In some embodiments, provided herein is a phar “about 5 uL and also “5 uL.” Generally, the term “about” maceutical combination that comprises a TEC inhibitor, an includes an amount that would be expected to be within immunomodulatory agent, and a steroid. In some instances, experimental error. The term “about when used before a the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX numerical value indicates that the value may vary within a inhibitor. In some instances, the TEC inhibitor is an ITK reasonable range, such as within +10%, 5% or +1% of the inhibitor. In some instances, the TEC inhibitor is a BTK stated value. inhibitor. In some instances, the BTK inhibitor is ibrutinib. 0012. The section headings used herein are for organiza In some instances, the immunomodulatory agent is tional purposes only and are not to be construed as limiting pomalidomide. In some instances, the steroid is dexametha the subject matter described. Sone. In some instances, the pharmaceutical combination is 0013 As used herein, the terms “individual(s)', 'subject administered for the treatment of a hematologic malignancy. (s)' and “patient(s) mean any mammal. In some embodi In some instances, the hematologic malignancy is multiple ments, the mammal is a human. In some embodiments, the myeloma. mammal is a non-human. None of the terms require or are 0006. In some instances, provided herein is a dosing limited to situations characterized by the Supervision (e.g., regimen for the treatment of a hematologic malignancy in a constant or intermittent) of a health care worker (e.g., a Subject in need thereof comprising administering an immu doctor, a registered nurse, a nurse practitioner, a physician’s nomodulatory agent, a BTK inhibitor, and a steroid, wherein assistant, an orderly or a hospice worker). the immunomodulatory agent, the Btk inhibitor, and the 0014. The terms “co-administration,” “simultaneous steroid are administered concurrently, simulataneously, and/ administration,” “concurrently,” or the like, and any gram or co-administered. matical version thereof, as used herein, are meant to encom 0007. In some instances, provided herein is a dosing pass administration of the selected therapeutic agents to a regimen for the treatment of a hematologic malignancy in a single patient, and are intended to include treatment regi US 2017/0209462 A1 Jul. 27, 2017 mens in which the agents are administered by the same or tially homogeneous population of antibodies, i.e., the indi different route of administration or at the same or different vidual antibodies comprising the population are identical time; however, all agents (i.e., all three agents) are admin except for possible naturally occurring mutations that may istered during the same cycle (even though the administra be present in minor amounts. tion of the agents is begun, initiated, or occurs on different 0020 “Antibody fragments’ comprise a portion of an days of that cycle). In some embodiments, “co-administra intact antibody, preferably the antigen-binding or variable tion,” “simultaneously,” and concurrently are interchange region of the intact antibody. Examples of antibody frag able. In some embodiments, the patients have not been ments include Fab, Fab, F(ab')2, and Fv fragments: diabod administered Btk inhibitor, such as ibrutinib, prior to initia ies; linear antibodies (Zapata et al. (1995) Protein Eng. tion of the dosing regimen disclosed herein. 10:1057-1062); single-chain antibody molecules; and mul 0015 The terms “effective amount” or “therapeutically tispecific antibodies formed from antibody fragments. effective amount, as used herein, refer to a sufficient Papain digestion of antibodies produces two identical anti amount of an agent or a compound, or a combination or two gen-binding fragments, called “Fab' fragments, each with a or more agents or compounds, or a sufficient amount of an single antigen-binding site, and a residual "Fo' fragment, individual agent or compound in a combination of two or whose name reflects its ability to crystallize readily. Pepsin more agents or compounds, being administered which will treatment yields an F(ab')2 fragment that has two antigen relieve to some extent one or more of the symptoms of the combining sites and is still capable of cross-linking antigen. disease or condition being treated. The result can be reduc 0021 “Fv is the minimum antibody fragment that con tion and/or alleviation of the signs, symptoms, or causes of tains a complete antigen recognition and binding site. This a disease, or any other desired alteration of a biological region consists of a dimer of one heavy- and one light-chain system. For example, an “effective amount” for therapeutic variable domain in tight, non-covalent association. It is in uses is the amount of the composition including a compound this configuration that the three CDRs of each variable as disclosed herein required to provide a clinically signifi domain interact to define an antigen-binding site on the cant decrease in disease symptoms without undue adverse surface of the V-V, dimer.