# US 2021/0275530 A1 · Treatment cancers using a combination comprising btk inhibitors

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- Number: US 2021/0275530 A1
- Document ID: US20210275530A1
- Status: Published application
- Kind: A1
- Application number: 16/326,467
- Filed: 2017-08-18
- Published: 2021-09-09
- Earliest claimed: 2016-08-19
- Assignees: BeiGene Switzerland GmbH
- Applicants: BeiGene, Ltd.
- Inventors: Nan Hu; Lai Wang; Jing Song; Tong Zhang; Kang Li; Lusong Luo; Min Wei; Zhiwei Wang; Yunhang Guo
- Web page: https://patentgrep.com/patent/US20210275530A1

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61P 35/00: Antineoplastic agents
- C07K 16/2887: {against CD20}
- A61K 2039/505: {comprising antibodies}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Disclosed herein is a method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a Btk inhibitor, particularly, (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor or a targeted therapy agent. Also, disclosed a pharmaceutical combination comprising a Btk inhibitor, particularly, (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor, or a targeted therapy agent and the use thereof.

## Claims

### Claim 1

A method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a Btk inhibitor, in combination with a therapeutically effective amount of an immune checkpoint inhibitor, or a targeted therapy agent,
wherein the Btk inhibitor is a compound of Formula (I),
or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
A is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms of N, S or O;
each W is independently —(CH2)— or —C(O)—;
L is a bond, CH2, NR12, O, or S;
S/D is a single or double bond, and when a double bond, R5 and R7 are absent;
m is 0, or an integer of 1-4;
n is 0, or an integer of 1-4, wherein when n is more than 1, each R2 may be different;
p is 0, or an integer of 1-2, wherein when p is 0, m is non-zero, and when p is more than 1,
each R6 and each R7 may be different;
R1, R4, R5, R6, and R7 are each independently H, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR13R14, —OR13, —COR13, —CO2R13, —CONR13R14, —C(═NR13)NR14R15, —NR13COR14, —NR13CONR14R15, —NR13CO2R14, —SO2R13, —NR13SO2NR14R15, or —NR13SO2R14, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R16, wherein (R4 and R5), or (R4 and R6), or (R6 and R7), or (R6 and R6 when p is 2), together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R16;
R2 is halogen, alkyl, —S-alkyl, —CN, —NR13R14, —OR13, —COR13, —CO2R13, —CONR13R14, —C(═NR13)NR14R15, —NR13COR14, —NR13CONR14R15, —NR13CO2R14, —SO2R13, —NR13SO2NR14R15, or —NR13SO2R14;
R12 is H or lower alkyl;
R13, R14 and R15 are each independently H, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heteroaryl; wherein (R13 and R14), and/or (R14 and R15) together with the atom(s) to which they are attached, each can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R16;
R16 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, oxo, —CN, —ORa, —NRaRb, —CORa, —CO2Ra, —CONRaRb, —C(═NRa)NRbRc, —NRaCORb, —NRaCONRaRb, —NRaCO2Rb, —SO2Ra, —SO2aryl, —NRaSO2NRbRc, or —NRaSO2Rb, wherein Ra, Rb, and Rc are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, wherein (Ra and Rb), and/or (Rb and Rc) together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings.

### Claim 2 (depends on 1)

The method of claim 1, wherein the targeted therapy agent is an anti-CD20 antibody.

### Claim 3 (depends on 2)

The method of claim 2, wherein the targeted therapy agent is an monoclonal antibody.

### Claim 4 (depends on 2)

The method of claim 2, wherein the targeted therapy agent is selected from rituximab, ibritumomab tiuxetan, tositumonmab, ofatumumab or obinutuzumab.

### Claim 5 (depends on 1)

The method of claim 1, wherein the immune checkpoint inhibitor is an inhibitor of PD-1, PD-PD-L1, PD-L2, TIM-3, Gal-9, CTLA-4, CD80, CD86, A2AR, B7-H3, B7-H4, BTLA, BTLA, HVEM, IDO1, IDO2, TDO, LAG3, VISTA, KIR, 2B4, CD2, CD27, CD28, CD30, CD40, CD90, CD137, CD226, CD276, DR3, GITR, ICOS, LAIR1, LIGHT, MARCO, PS, OX-40, SLAM TIGHT, CTCNI, or a combination thereof.

### Claim 6 (depends on 5)

The method of claim 5, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

### Claim 7 (depends on 6)

The method of claim 6, wherein the immune checkpoint inhibitor is a monoclonal antibody.

### Claim 8 (depends on 6)

The method of claim 6, wherein the immune checkpoint inhibitor is selected from nivolumab or pidilizumab.

### Claim 9 (depends on 6)

The method of claim 6, wherein the immune checkpoint inhibitor is a monoclonal antibody or a fragment thereof, comprising a heavy chain variable region (Vh) amino acid sequence of SEQ ID No 24, a light chain variable region (V1) amino acid sequence of SEQ ID No 26, and a IgG4 constant domain amino acid sequence of SEQ ID NO 88.

### Claim 10 (depends on 1)

The method of claim 1, wherein the cancer is hematologic cancer.

### Claim 11 (depends on 10)

The method of claim 10, wherein the hematologic cancer is selected from a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma (NHL), a Hodgkin's lymphoma (HL), or a B-cell malignancy.

### Claim 12 (depends on 11)

The method of claim 11, wherein the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia (WM), Hairy cell leukemia (HCL), Burkitt's-like leukemia (BL), B cell prolymphocytic leukemia (B-PLL), diffuse large B cell lymphoma (DLBCL), germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL), non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB DLBCL), DLBCL with undetermined subtype, primary central nervous system lymphoma (PCNSL), secondary central nervous system lymphoma (SCNSL) of breast or testicular origin, or a combination of two or more thereof.

### Claim 13 (depends on 12)

The method of claim 12, wherein the diffuse large B-cell lymphoma (DLBCL) is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), GCB-DLBCL or Non-GCB DLBCL.

### Claim 14 (depends on 12)

The method of claim 12, wherein the B-cell malignancy is selected form chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), multiple myeloma, or a combination thereof.

### Claim 15 (depends on 12, 13, 14)

The method of any one of claims 12-14, wherein the B-cell malignancy is a relapsed or refractory (R/R) B-cell malignancy.

### Claim 16 (depends on 15)

The method of claim 15, wherein the relapsed or refractory B-cell malignancy is diffuse large B-cell lymphoma (DLBCL).

### Claim 17 (depends on 16)

The method of claim 16, wherein the relapsed or refractory DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), GCB-DLBCL or Non-GCB DLBCL.

### Claim 18 (depends on 15)

The method of claim 15, wherein the relapsed or refractory B-cell malignancy is selected form diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), multiple myeloma, or a combination thereof.

### Claim 19 (depends on 12, 13, 14)

The method of any one of the claims 12-14, wherein the B-cell malignancy is a metastasized B-cell malignancy.

### Claim 20 (depends on 19)

The method of claim 19, wherein the metastasized B-cell malignancy is selected form diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), multiple myeloma, or a combination thereof.

### Claim 21 (depends on 1)

The method of claim 1, wherein the cancer is a sarcoma, or carcinoma.

### Claim 22 (depends on 1, 21)

The method of claim 1 or 21, wherein the cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.

### Claim 23 (depends on 21)

The method of claim 21, wherein the cancer is a relapsed or refractory cancer.

### Claim 24 (depends on 23)

The method of claim 23, wherein the relapsed or refractory cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, or melanoma.

### Claim 25 (depends on 21)

The method of any one of the claim 21, wherein the cancer is a metastasized cancer.

### Claim 26 (depends on 25)

The method of claim 25, wherein the metastasized cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.

### Claim 27 (depends on 1)

The method of claim 1, wherein the BTK inhibitor is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 1)

The method of claim 1, wherein the BTK inhibitor administrated at a dose of 320 mg QD or 160 mg BID.

### Claim 29 (depends on 4)

The method of claim 4, wherein the BTK inhibitor is administrated at a dose of 320 mg QD or 160 mg BID in 28-day cycles, and obinutuzumab is administrated by three loading doses of 1000 mg weekly followed by 1000 mg on day one of cycles 2-6.

### Claim 30 (depends on 9)

The method of claim 9, wherein the immune checkpoint inhibitor is administrated at a dose of 2 mg/kg Q3W to 200 mg/kg Q3W.

### Claim 31

A pharmaceutical combination for use in the prevention, delay of progression or treatment of cancer, comprising a Btk inhibitor, and a targeted therapy agent, wherein the Btk inhibitor is a compound of Formula (I),
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
A is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms of N, S or O;
each W is independently —(CH2)— or —C(O)—;
L is a bond, CH2, NR12, O, or S;
S/D is a single or double bond, and when a double bond, R5 and R7 are absent;
m is 0, or an integer of 1-4;
n is 0, or an integer of 1-4, wherein when n is more than 1, each R2 may be different;
p is 0, or an integer of 1-2, wherein when p is 0, m is non-zero, and when p is more than 1,
each R6 and each R7 may be different;
R1, R4, R5, R6, and R7 are each independently H, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR13R14, —OR13, —COR13, —CO2R13, —CONR13R14, —C(═NR13)NR14R15, —NR13COR14, —NR13CONR14R15, —NR13CO2R14, —SO2R13, —NR13SO2NR14R15, or —NR13SO2R14, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R16, wherein (R4 and R5), or (R4 and R6), or (R6 and R7), or (R6 and R6 when p is 2), together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R16;
R2 is halogen, alkyl, —S-alkyl, —CN, —NR13R14, —OR13, —COR13, —CO2R13, —CONR13R14, —C(═NR13)NR14R15, —NR13COR14, —NR13CONR14R15, —NR13CO2R14, —SO2R13, —NR13SO2NR14R15, or —NR13SO2R14;
R12 is H or lower alkyl;
R13, R14 and R15 are each independently H, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heteroaryl; wherein (R13 and R14), and/or (R14 and R15) together with the atom(s) to which they are attached, each can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R16;
R16 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, oxo, —CN, —ORa, —NRaRb, —CORa, —CO2Ra, —CONRaRb, —C(═NRa)NRbRc, —NRaCORb, —NRaCONRaRb, —NRaCO2Rb, —SO2Ra, —SO2aryl, —NRaSO2NRbRc, or —NRaSO2Rb, wherein Ra, Rb, and Rc are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, wherein (Ra and Rb), and/or (Rb and Rc) together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings.

### Claim 32 (depends on 31)

The pharmaceutical combination of claim 31, wherein the targeted therapy agent is an anti-CD20 antibody.

### Claim 33 (depends on 32)

The pharmaceutical combination of claim 32, wherein the targeted therapy agent is an monoclonal antibody.

### Claim 34 (depends on 32)

The pharmaceutical combination of claim 32, wherein the targeted therapy agent is is selected from rituximab, ibritumomab tiuxetan, tositumonmab, ofatumumab or obinutuzumab.

### Claim 35

A pharmaceutical combination for use in the prevention, delay of progression or treatment of cancer, comprising a Btk inhibitor, and an immune checkpoint inhibitor, wherein the Btk inhibitor is a compound of Formula (I),
a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
A is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms of N, S or O;
each W is independently —(CH2)— or —C(O)—;
L is a bond, CH2, NR12, O, or S;
S/D is a single or double bond, and when a double bond, R5 and R7 are absent;
m is 0, or an integer of 1-4;
n is 0, or an integer of 1-4, wherein when n is more than 1, each R2 may be different;
p is 0, or an integer of 1-2, wherein when p is 0, m is non-zero, and when p is more than 1, each R6 and each R7 may be different;
R1, R4, R5, R6, and a R7 are each independently H, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR13R14, —OR13, COR13, —CO2R13, —CONR13R14, —C(═NR13)NR14R15, —NR13COR14, —NR13CONR14R15, —NR13CO2R14, —SO2R13, —NR13SO2NR14R15, or —NR13SO2R14, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R16, wherein (R4 and R5), or (R4 and R6), or (R6 and R7), or (R6 and R6 when p is 2), together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R16;
R2 is halogen, alkyl, —S-alkyl, —CN, —NR13R14, —OR13, —COR13, —CO2R13, —CONR13R14, —C(═NR13)NR14R15, —NR13COR14, —NR13COR14, —NR13CONR14R15, —NR13CO2R14, —SO2R13, —NR13SO2NR14R15,
or —NR13SO2R14;
R12 is H or lower alkyl;
R13, R14 and R15 are each independently H, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heteroaryl; wherein (R13 and R14), and/or (R14 and R15) together with the atom(s) to which they are attached, each can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R16;
R16 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, oxo, —CN, —ORa, —NRaRb, —CORa, —CO2Ra, —CONRaRb, —C(═NRa)NRbRc, —NRaCORb, —NRaCONRaRb, —NRaCO2Rb, —SO2Ra, —SO2aryl, —NRaSO2NRbRc, or —NRaSO2Rb, wherein Ra, Rb, and Rc are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, wherein (Ra and Rb), and/or (Rb and Rc) together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings.

### Claim 36 (depends on 35)

The pharmaceutical combination of claim 35, wherein the immune checkpoint inhibitor is an inhibitor of PD-1, PD-L1, PD-L2 TIM-3, Gal-9, CTLA-4, CD80, CD86, A2AR, B7-H3, B7-H4, BTLA, BTLA, HVEM, IDO1, IDO2, TDO, LAG3, VISTA, KIR, 2B4, CD2, CD27, CD28, CD30, CD40, CD90, CD137, CD226, CD276, DR3, GITR, ICOS, LAIR1, LIGHT, MARCO, PS, OX-40, SLAM TIGHT, CTCNI, or a combination thereof.

### Claim 37 (depends on 35)

The pharmaceutical combination of claim 35, wherein the immune checkpoint inhibitor is an inhibitor of PD-1.

### Claim 38 (depends on 37)

The pharmaceutical combination of claim 37, wherein the immune checkpoint inhibitor is a monoclonal antibody.

### Claim 39 (depends on 37)

The pharmaceutical combination of claim 37, wherein the immune checkpoint inhibitor is an antibody selected from nivolumab, or pidilizumab.

### Claim 40 (depends on 37)

The pharmaceutical combination of claim 37, wherein the immune checkpoint inhibitor is a monoclonal antibody or a fragment thereof, comprising a heavy chain variable region (Vh) amino acid sequence of SEQ ID No 24, a light chain variable region (V1) amino acid sequence of SEQ ID No 26, and a IgG4 constant domain amino acid sequence of SEQ ID NO 88.

### Claim 41 (depends on 31, 35)

The pharmaceutical combination of claim 31 or 35, wherein the cancer is hematologic cancer.

### Claim 42 (depends on 41)

The pharmaceutical combination of claim 41, wherein the hematologic cancer is selected from a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma (NHL), a Hodgkin's lymphoma (HL), or a B-cell malignancy.

### Claim 43 (depends on 42)

The pharmaceutical combination of claim 42, wherein the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia (WM), Hairy cell leukemia (HCL), Burkitt's-like leukemia (BL), B cell prolymphocytic leukemia (B-PLL), diffuse large B cell lymphoma (DLBCL), germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL), non-germinal center B-cell diffuse large B-cell lymphoma (non-GCB DLBCL), DLBCL with undetermined subtype, primary central nervous system lymphoma (PCNSL), secondary central nervous system lymphoma (SCNSL) of breast or testicular origin, or a combination of two or more thereof.

### Claim 44 (depends on 43)

The pharmaceutical combination of claim 43, wherein the DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), GCB-DLBCL or Non-GCB DLBCL.

### Claim 45 (depends on 44)

The pharmaceutical combination of claim 44, wherein the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), multiple myeloma, or a combination thereof.

### Claim 46 (depends on 43, 44)

The pharmaceutical combination of any one of claims 43-44, wherein the B-cell malignancy is a relapsed or refractory B-cell malignancy.

### Claim 47 (depends on 46)

The pharmaceutical combination of claim 46, wherein the relapsed or refractory B-cell malignancy is diffuse large B-cell lymphoma (DLBCL).

### Claim 48 (depends on 47)

The pharmaceutical combination of claim 47, wherein the relapsed or refractory DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), GCB-DLBCL or Non-GCB DLBCL.

### Claim 49 (depends on 45)

The pharmaceutical combination of claim 45, wherein the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), multiple myeloma, or a combination thereof, or a combination thereof.

### Claim 50 (depends on 43, 44, 45)

The pharmaceutical combination of any one of claims 43-45, wherein the B-cell malignancy is a metastasized B-cell malignancy.

### Claim 51 (depends on 50)

The pharmaceutical combination of claim 50, wherein the metastasized B-cell malignancy is diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), multiple myeloma, or a combination thereof.

### Claim 52 (depends on 31, 35)

The pharmaceutical combination of claim 31 or 35, wherein the cancer is a sarcoma, or carcinoma.

### Claim 53 (depends on 31, 35, 52)

The pharmaceutical combination of any one of claim 31, 35 or 52, wherein the cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma.

### Claim 54 (depends on 52)

The pharmaceutical combination of claim 52, wherein the cancer is a relapsed or refractory (R/R) cancer.

### Claim 55 (depends on 54)

The pharmaceutical combination of claim 54, wherein the relapsed or refractory cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer or melanoma.

### Claim 56 (depends on 52)

The pharmaceutical combination of claim 52, wherein the cancer is a metastasized cancer.

### Claim 57 (depends on 56)

The pharmaceutical combination of claim 56, wherein the metastasized cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, or melanoma.

### Claim 58 (depends on 31, 35)

The pharmaceutical combination of claim 31 or 35, wherein the BTK inhibitor is (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-a]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt thereof.