Combination therapy for the targeted degradation of BCL6

Abstract

The present disclosure relates to methods of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-cancer agent.

Description

[0001] 137508-06020

[0002] COMBINATION THERAPY FOR THE TARGETED DEGRADATION OF BCL6

[0003] RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Application No. 63 / 725,525, filed on November 26, 2024, U.S. Provisional Application No. 63 / 765,232, filed on February 28, 2025, U.S. Provisional Application No. 63 / 784,761, filed on April 7, 2025, and U.S. Provisional Application No. 63 / 808,753, filed on May 20, 2025. The entire contents of each of the foregoing applications are expressly incorporated herein by reference.

[0005] BACKGROUND

[0006] Bifunctional compounds such as those described in U.S. Patent Application Publications 2015 / 0291562 and 2014 / 0356322 (incorporated herein by reference) function to recruit endogenous proteins to an E3 ubiquitin ligase for degradation. In particular, those bifunctional or proteolysis targeting chimeric (PROTAC) compounds serve as modulators of targeted ubiquitination of a variety of polypeptides and other proteins, which are then degraded and / or otherwise inhibited by the bifunctional compounds. An ongoing need exists in the art for effective treatments for disease associated with (i) aberrant BCL6 expression and / or activity and / or (ii) overexpression or aggregation of B-cell lymphoma 6 protein (BCL6). However, non-specific effects, and the inability to target and modulate BCL6, remain as obstacles to the development of effective treatments. As such, small-molecule therapeutic agents that target BCL6 and that leverage or potentiate E3 ubiquitin ligase (e.g., cereblon’s) substrate specificity would be useful.

[0007] SUMMARY

[0008] In one aspect, this application pertains to a method of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A,

[0009] 1

[0010] MEl\59152596.vl 137508-06020 or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anticancer agent.

[0011] In one aspect, this application pertains to Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject, wherein the method comprises administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-cancer agent.

[0012] In one aspect, this application pertains to a use of Compound A,

[0013] 2

[0014] MEl\59152596.vl 137508-06020 , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject in combination with an additional anti-cancer agent.

[0015] In some embodiments, the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relapsed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma- angioimmunoblastic type (nTFHL-AI), advanced nTFHL- Al, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B- cell (ABC) DLBCL.

[0016] In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL), germinal center B-cell (GCB) DLBCL, or activated B-cell (ABC) DLBCL.

[0017] In some embodiments, the anti-cancer agent is acalabrutinib.

[0018] In some embodiments, the anti-cancer agent is tazemetostat.

[0019] In some embodiments, the anti-cancer agent is venetoclax.

[0020] In some embodiments, the anti-cancer agent is palbociclib.

[0021] In some embodiments, the anti-cancer agent is everolimus.

[0022] In some embodiments, the anti-cancer agent is CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone).

[0023] In some embodiments, the anti-cancer agent is R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone).

[0024] In one aspect, this application pertains to a method of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A,

[0025] 3

[0026] MEl\59152596.vl 137508-06020 or a pharmaceutically acceptable salt thereof, and an effective amount acalabrutinib, wherein the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R)

[0027] NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB)

[0028] DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL. In one aspect, this application pertains to a method of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount tazemetostat, wherein the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R)

[0029] 4

[0030] MEl\59152596.vl 137508-06020

[0031] NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL- Al, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0032] In one aspect, this application pertains to a method of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount venetoclax, wherein the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0033] In one aspect, this application pertains to a method of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A,

[0034] 5

[0035] MEl\59152596.vl 137508-06020 or a pharmaceutically acceptable salt thereof, and an effective amount of palbociclib, wherein the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R)

[0036] NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL- Al, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB)

[0037] DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL. In one aspect, this application pertains to a method of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of everolimus, wherein the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R)

[0038] 6

[0039] MEl\59152596.vl 137508-06020

[0040] NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL- Al, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0041] In one aspect, this application pertains to a method of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of CHOP, wherein the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relapsed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0042] In one aspect, this application pertains to a method of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A,

[0043] 7

[0044] MEl\59152596.vl 137508-06020 or a pharmaceutically acceptable salt thereof, and an effective amount of R-CHOP, wherein the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R)

[0045] NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL- Al, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB)

[0046] DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0047] In one aspect, this application pertains to Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject, wherein the method comprises administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of acalabrutinib, wherein the cancer is non-

[0048] 8

[0049] MEl\59152596.vl 137508-06020

[0050] Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma

[0051] (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive

[0052] DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0053] In one aspect, this application pertains to Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject, wherein the method comprises administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of tazemetostat, wherein the cancer is nonHodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0054] In one aspect, this application pertains to Compound A,

[0055] 9

[0056] MEl\59152596.vl 137508-06020 , or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject, wherein the method comprises administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of venetoclax, wherein the cancer is non- Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R

[0057] NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0058] In one aspect, this application pertains to Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject, wherein the method comprises

[0059] 10

[0060] MEl\59152596.vl 137508-06020 administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of palbociclib, wherein the cancer is nonHodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive

[0061] DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0062] In one aspect, this application pertains to Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject, wherein the method comprises administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of everolimus, wherein the cancer is nonHodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nRFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0063] In one aspect, this application pertains to Compound A,

[0064] 11

[0065] MEl\59152596.vl 137508-06020 , or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject, wherein the method comprises administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of CHOP, wherein the cancer is non- Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R

[0066] NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nRFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0067] In one aspect, this application pertains to Compound A, pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject, wherein the method comprises

[0068] 12

[0069] MEl\59152596.vl 137508-06020 administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of R-CHOP, wherein the cancer is nonHodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nRFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive

[0070] DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL. In one aspect, this application pertains to a use of Compound A, , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject in combination with acalabrutinib, wherein the cancer is nonHodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0071] In one aspect, this application pertains to a use of Compound A,

[0072] 13

[0073] MEl\59152596.vl 137508-06020 , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject in combination with tazemetostat, wherein the cancer is non-

[0074] Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma

[0075] (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0076] In one aspect, this application pertains to a use of Compound A, , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject in combination with venetoclax, wherein the cancer is non-

[0077] 14

[0078] MEl\59152596.vl 137508-06020

[0079] Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0080] In one aspect, this application pertains to a use of Compound A, , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject in combination with palbociclib, wherein the cancer is nonHodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0081] In one aspect, this application pertains to a use of Compound A,

[0082] 15

[0083] MEl\59152596.vl 137508-06020 , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject in combination with everolimus, wherein the cancer is nonHodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0084] In one aspect, this application pertains to a use of Compound A, , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject in combination with CHOP, wherein the cancer is non-Hodgkin's

[0085] 16

[0086] MEl\59152596.vl 137508-06020 lymphoma (NHL), advanced NHL, relapsed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T- follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), highgrade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL. In one aspect, this application pertains to a use of Compound A, , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject in combination with R-CHOP, wherein the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relapsed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T- follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), highgrade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B-cell (ABC) DLBCL.

[0087] BRIEF DESCRIPTION OF THE DRAWINGS

[0088] The accompanying drawings, which are included to provide a further understanding of the present disclosure, are incorporated in and constitute a part of this specification, illustrate aspects of the present disclosure and, together with the detailed description, serve to explain the principles of the present disclosure.

[0089] 17

[0090] MEl\59152596.vl 137508-06020

[0091] FIG. 1 depicts in-vivo efficacy studies of Compound A in combination with acalabrutinib using the OCI-LylO DLBCL (ABC) subcutaneous xenograft model. Compound A in combination with acalabrutinib outperformed either agent alone (Compound A alone = 79% TGI, acalabrutinib = 92% TGI, combination = 123% TGI). Mean tumor volumes are reported ± SEM. TGI= tumor growth inhibition. ** P<0.01, ***P<0.001, one-way ANOVA, Tukey’s multiple comparison’s test.

[0092] FIG. 2 depicts in-vivo efficacy studies of Compound A in combination with tazemetostat using the SU-DHL-6 DLBCL (HGBCL) subcutaneous xenograft model. Mean tumor volumes are reported ± SEM. Dosing holidays are indicated by small black arrows. ** P<0.01, ****P<0.0001, One-way ANOVA, Tukey’s multiple comparison’s test.

[0093] FIG. 3 depicts in-vivo efficacy studies of Compound A in combination with tazemetostat using the OCI-Lyl DLBCL (GCB) subcutaneous xenograft model. Mean tumor volumes are reported ± SEM. * P<0.05, ****P<0.0001, One-way ANOVA, Tukey’s multiple comparison’s test.

[0094] FIG. 4 depicts in-vivo efficacy studies of Compound A in combination with venetoclax using the OCI-Lyl DLBCL (GCB) subcutaneous xenograft model. Mean tumor volumes are reported ± SEM.

[0095] FIG. 5 depicts in-vivo efficacy studies of Compound A in combination with venetoclax using the SU-DHL-6 DLBCL (HGBCL) subcutaneous xenograft model. Mean tumor volumes are reported ± SEM. Dosing holidays are indicated by small black arrows.

[0096] FIG. 6 depicts in-vivo efficacy studies of Compound A in combination with palbociclib using the SU-DHL-6 DLBCL (HGBCL) subcutaneous xenograft model. Mean tumor volumes are reported ± SEM. One-way ANOVA, Tukey’s multiple comparison’s test, * p< 05, ***p<0.001. Dosing holidays are indicated by small black arrows.

[0097] FIG. 7 depicts in-vivo efficacy studies of Compound A in combination with everolimus using the SU-DHL-6 DLBCL (HGBCL) subcutaneous xenograft model. Mean tumor volumes are reported ± SEM. One-way ANOVA, Tukey’s multiple comparison’s test, * p< 05.

[0098] FIG. 8 depicts in-vivo efficacy studies of Compound A in combination with everolimus using the OCI-Lyl DLBCL (GCB) subcutaneous xenograft model. Mean tumor volumes are reported ± SEM.

[0099] FIG. 9 depicts in-vivo efficacy studies of Compound A in combination with CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone) or R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone) using the SU-DHL-4 subcutaneous xenograft model. Mean tumor volumes are reported ±

[0100] 18

[0101] MEl\59152596.vl 137508-06020

[0102] SEM. For mice sacrificed because their tumor reached ethical limits, the value was extended., * / ?<0.05; ****p<0.0001, One-way ANOVA, Tukey’s multiple comparison’s test.

[0103] FIG. 10 depicts tumor lysate levels of EZH2, MYC, BCL2, and BCL6 proteins in Vehicle, Compound A, Tazemetostat, or Tazemetostat / Compound A combo treated mice, 24- hours post-last dose in the SU-DHL-6 DLBCL (HGBCL) subcutaneous xenograft model. ** p< 01, ****p<0.0001, One-way ANOVA, Tukey’s multiple comparison’s test.

[0104] FIG. 11 depicts body weight change over time during the efficacy studies shown in FIG. 1.

[0105] FIG. 12 depicts body weight change over time during the efficacy studies shown in FIG. 2.

[0106] FIG. 13 depicts body weight change over time during the efficacy studies shown in FIG. 4.

[0107] FIG. 14 depicts body weight change over time during the efficacy studies shown in FIG. 9.

[0108] FIG. 15 depicts tumor lysate levels of BCL6 proteins in Vehicle, Compound A, acalabrutinib, or acalabrutinib / Compound A combo treated mice, 24-hours post-last dose in the OCI-LylO DLBCL (ABC) subcutaneous xenograft model. ****p<0.0001, One-way ANOVA, Tukey’s multiple comparison’s test.

[0109] FIG. 16 depicts tumor lysate levels of BCL6 proteins in Vehicle, Compound A, venetoclax, or venetoclax / Compound A combo treated mice, 24-hours post-last dose in the OCI-Lyl DLBCL (GCB) subcutaneous xenograft model. ****p<0.0001, One-way ANOVA, Tukey’s multiple comparison’s test.

[0110] FIG. 17 depicts tumor lysate levels of BCL6 proteins in Vehicle, Compound A, palbociclib, or palbociclib / Compound A combo treated mice, 24-hours post-last dose in the SU-DHL-6 DLBCL (HGBCL) subcutaneous xenograft model. ****p<0.0001, One-way ANOVA, Tukey’s multiple comparison’s test.

[0111] FIG. 18 depicts tumor lysate levels of BCL6 proteins in Vehicle, Compound A, everolimus, or everolimus / Compound A combo treated mice, 24-hours post-last dose in the SU-DHL-6 DLBCL (HGBCL) subcutaneous xenograft model. ****p<0.0001, One-way ANOVA, Tukey’s multiple comparison’s test.

[0112] DETAILED DESCRIPTION

[0113] The present disclosure provides a method of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A,

[0114] 19

[0115] MEl\59152596.vl 137508-06020 or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anticancer agent.

[0116] The present disclosure relates to Compound A, , or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject, wherein the method comprises administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-cancer agent.

[0117] The present disclosure relates to a use of Compound A,

[0118] 20

[0119] MEl\59152596.vl 137508-06020 , or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cancer, wherein the medicament is administered to a subject in combination with an additional anti-cancer agent.

[0120] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and the additional anti-cancer agent are administered simultaneously.

[0121] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and the additional anti-cancer agent are administered separately.

[0122] In some embodiments, the administration of the additional anti-cancer agent occurs before the administration of Compound A, or a pharmaceutically acceptable salt thereof.

[0123] In some embodiments, the administration of the additional anti-cancer agent occurs at least 30 minutes before the administration of Compound A, or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the administration of the additional anti-cancer agent occurs after the administration of Compound A, or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the administration of the additional anti-cancer agent occurs at least 30 minutes after the administration of Compound A, or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the cancer is associated with (i) aberrant BCL6 expression and / or activity and / or (ii) overexpression or aggregation of BCL6.

[0127] In some embodiments, the cancer is lymphoma.

[0128] In some embodiments, the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relapsed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma- angioimmunoblastic type (nTFHL-AI), advanced nTFHL- Al, R / R nTFHL-AI, advanced B-cell

[0129] 21

[0130] MEl\59152596.vl 137508-06020

[0131] NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, or activated B- cell (ABC) DLBCL.

[0132] In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL), germinal center B-cell (GCB) DLBCL, or activated B-cell (ABC) DLBCL.

[0133] In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

[0134] In some embodiments, the cancer is germinal center B-cell (GCB) DLBCL.

[0135] In some embodiments, the cancer is activated B-cell (ABC) DLBCL.

[0136] In some embodiments, the anti-cancer agent is a BTK inhibitor.

[0137] In some embodiments, the anti-cancer agent is acalabrutinib or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the anti-cancer agent is acalabrutinib.

[0139] In some embodiments, the anti-cancer agent is acalabrutinib maleate.

[0140] In some embodiments, acalabrutinib is administered to the subject once a day.

[0141] In some embodiments, acalabrutinib is administered to the subject about once every 12 hours.

[0142] In some embodiments, about 50 mg to about 250 mg acalabrutinib is administered to the subject daily.

[0143] In some embodiments, about 50 mg to about 200 mg acalabrutinib is administered to the subject daily.

[0144] In some embodiments, 100 mg acalabrutinib is administered to the subject daily.

[0145] In some embodiments, 200 mg acalabrutinib is administered to the subject daily.

[0146] In some embodiments, the anti-cancer agent is an EZH2 inhibitor.

[0147] In some embodiments, the anti-cancer agent is tazemetostat or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the anti-cancer agent is tazemetostat.

[0149] In some embodiments, the anti-cancer agent is tazemetostat hydrobromide.

[0150] In some embodiments, tazemetostat is administered to the subject twice a day.

[0151] In some embodiments, 400 mg tazemetostat is administered to the subject daily.

[0152] In some embodiments, 600 mg tazemetostat is administered to the subject daily.

[0153] In some embodiments, 800 mg tazemetostat is administered to the subject daily.

[0154] In some embodiments, 1200 mg tazemetostat is administered to the subject daily.

[0155] In some embodiments, 1600 mg tazemetostat is administered to the subject daily.

[0156] 22

[0157] MEl\59152596.vl 137508-06020

[0158] In some embodiments, about 200 mg to about 2000 mg tazemetostat is administered to the subject daily.

[0159] In some embodiments, about 200 mg to about 1600 mg tazemetostat is administered to the subject daily.

[0160] In some embodiments, about 100 mg to about 1000 mg tazemetostat is administered to the subject twice a day.

[0161] In some embodiments, about 100 mg to about 800 mg tazemetostat is administered to the subject twice a day.

[0162] In some embodiments, 200 mg tazemetostat is administered to the subject twice a day.

[0163] In some embodiments, 400 mg tazemetostat is administered to the subject twice a day.

[0164] In some embodiments, 600 mg tazemetostat is administered to the subject twice a day.

[0165] In some embodiments, 800 mg tazemetostat is administered to the subject twice a day.

[0166] In some embodiments, the tazemetostat is administered to the subject in a first dose of 400 mg, followed by a second dose of 200 mg 12 hours later, daily.

[0167] In some embodiments, the anti-cancer agent is a CDK4 and / or CDK6 inhibitor.

[0168] In some embodiments, the anti-cancer agent is palbociclib or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the anti-cancer agent is palbociclib.

[0170] In some embodiments, 125 palbociclib is administered to the subject once a day for 21 days followed by 7 days off treatment.

[0171] In some embodiments, 100 palbociclib is administered to the subject once a day for 21 days followed by 7 days off treatment.

[0172] In some embodiments, 75 palbociclib is administered to the subject once a day for 21 days followed by 7 days off treatment.

[0173] In some embodiments, the anti-cancer agent is a mTOR inhibitor.

[0174] In some embodiments, the anti-cancer agent is everolimus or a pharmaceutically acceptable salt thereof.

[0175] In some embodiments, the anti-cancer agent is everolimus.

[0176] In some embodiments, 2.5 mg everolimus is administered to the subject once a day.

[0177] In some embodiments, 5 mg everolimus is administered to the subject once a day.

[0178] In some embodiments, 7.5 mg everolimus is administered to the subject once a day.

[0179] In some embodiments, 10 mg everolimus is administered to the subject once a day.

[0180] In some embodiments, 15 mg everolimus is administered to the subject once a day.

[0181] 23

[0182] MEl\59152596.vl 137508-06020

[0183] In some embodiments, 20 mg everolimus is administered to the subject once a day. In some embodiments, the anti-cancer agent is a BCL2 inhibitor.

[0184] In some embodiments, the anti-cancer agent is venetoclax or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the anti-cancer agent is venetoclax.

[0186] In some embodiments, venetoclax is administered to the subject once a day.

[0187] In some embodiments, about 10 mg to about 800 mg venetoclax is administered to the subject daily.

[0188] In some embodiments, about 200 mg to about 500 mg venetoclax is administered to the subject daily.

[0189] In some embodiments, 400 mg venetoclax is administered to the subject daily.

[0190] In some embodiments, venetoclax is administered according to a ramp-up dosing schedule.

[0191] In some embodiments, the ramp-up dosing schedule comprises: i. 20 mg venetoclax administered to the subject daily on days 1-7; ii. 50 mg venetoclax administered to the subject daily on days 8-14; iii. 100 mg venetoclax administered to the subject daily on days 15-21; iv. 200 mg venetoclax administered to the subject daily on days 22-28; and v. 400 mg venetoclax administered to the subject daily on day 29 and thereafter.

[0192] In some embodiments, the ramp-up dosing schedule comprises: i. about 10 mg to about 30 mg venetoclax administered to the subject daily on days 1-7; ii. about 25 mg to about 75 mg venetoclax administered to the subject daily on days 8-14; iii. about 50 mg to about 125 mg venetoclax administered to the subject daily on days 15- 21; iv. about 100 mg to about 250 mg venetoclax administered to the subject daily on days 22- 28; and v. about 200 mg to about 500 mg venetoclax administered to the subject daily on day 29 and thereafter.

[0193] In some embodiments, the ramp-up dosing schedule comprises: i. about 10 mg to about 20 mg venetoclax administered to the subject daily on days 1-7; ii. about 25 mg to about 50 mg venetoclax administered to the subject daily on days 8-14; iii. about 50 mg to about 100 mg venetoclax administered to the subject daily on days 15-

[0194] 21;

[0195] 24

[0196] MEl\59152596.vl 137508-06020 iv. about 100 mg to about 200 mg venetoclax administered to the subject daily on days 22- 28; and v. about 200 mg to about 400 mg venetoclax administered to the subject daily on day 29 and thereafter.

[0197] In some embodiments, the ramp-up dosing schedule comprises: i. 100 mg venetoclax administered to the subject daily on day 1; ii. 200 mg venetoclax administered to the subject daily on day 2; iii. 400 mg venetoclax administered to the subject daily on day 3; and iv. 400 mg venetoclax administered to the subject daily on day 4 and thereafter.

[0198] In some embodiments, the ramp-up dosing schedule comprises: i. 100 mg venetoclax administered to the subject daily on day 1; ii. 200 mg venetoclax administered to the subject daily on day 2; iii. 400 mg venetoclax administered to the subject daily on day 3; and iv. 600 mg venetoclax administered to the subject daily on day 4 and thereafter.

[0199] In some embodiments, the ramp-up dosing schedule comprises: i. about 50 to about 125 mg venetoclax administered to the subject daily on day 1; ii. about 100 to about 250 mg venetoclax administered to the subject daily on day 2; iii. about 200 to about 500 mg venetoclax administered to the subject daily on day 3; and iv. about 200 to about 500 mg venetoclax administered to the subject daily on day 4 and thereafter.

[0200] In some embodiments, the ramp-up dosing schedule comprises: i. about 50 to about 125 mg venetoclax administered to the subject daily on day 1; ii. about 100 to about 250 mg venetoclax administered to the subject daily on day 2; iii. about 200 to about 500 mg venetoclax administered to the subject daily on day 3; and iv. about 300 to about 800 mg venetoclax administered to the subject daily on day 4 and thereafter.

[0201] In some embodiments, the anti-cancer agent is CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone), or pharmaceutically acceptable salts thereof.

[0202] In some embodiments, the anti-cancer agent is R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone), or pharmaceutically acceptable salts thereof.

[0203] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered orally to the subject.

[0204] 25

[0205] MEl\59152596.vl 137508-06020

[0206] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject once a day, twice a day, three times a day, or four times a day.

[0207] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject once a day.

[0208] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject twice a day.

[0209] In some embodiments, about 1 mg to about 500 mg Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject daily.

[0210] In some embodiments, about 1 mg to about 250 mg Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject daily.

[0211] In some embodiments, about 1 mg to about 100 mg Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject twice a day.

[0212] In some embodiments, about 3 mg to about 90 mg Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject twice a day.

[0213] In some embodiments, the methods, compounds, or uses of the application further comprise a dosing holiday, wherein the dosing holiday comprises one, two, three, four, five, or more days where Compound A, or a pharmaceutically acceptable salt thereof, is not administered to the subject.

[0214] Definitions

[0215] Bruton’s Tyrosine Kinase (BTK) is a non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, BTK phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK.

[0216] BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. It plays an important role in the function of immune cells of innate as well as in adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense.

[0217] 26

[0218] MEl\59152596.vl 137508-06020

[0219] Another key role for BTK is the regulation of TLR9 activation in splenic B-cells. Within the TLR pathway, BTK induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK also plays also a critical role in transcription regulation as it is involved in the signaling pathway linking TLR8 and TLR9. As a result, BTK activity induces the activity of NF-kappa-B, which is itself involved in regulating the expression of hundreds of genes. Other transcriptional targets of BTK include ARID3A, NF AT and GTF2I BTK is required for the formation of functional ARID3A DNA-binding complexes; whilst BTK’s transient phosphorylation of GTF21 causes it to translocate to the nucleus to bind regulatory enhancer elements to modulate gene expression.

[0220] Acalabrutinib, or 4-{8-Amino-3-[(25)-l-(2-butynoyl)-2-pyrrolidinyl]imidazo[l,5- a]pyrazin-l-yl}-A-(2-pyridinyl)benzamide (also referred to as ACP-196) is a BTK inhibitor, having the structure:

[0221] Acalabrutinib and pharmaceutically acceptable salts thereof are described in U.S.

[0222] Patent Nos. 7,459,554, 9,290,504, 9,758,524, 9,796,721, 10,167,291, 10,239,883, 10,272,083, and 11,771,696. The contents of each of the foregoing references are incorporated herein by reference in their entirety. In some embodiments, acalabrutinib is administered as acalabrutinib maleate hydrate.

[0223] EZH2 is a histone methyltransferase that is the catalytic subunit of the PRC2 complex which catalyzes the mono- through tri-methylation of lysine 27 on histone H3 (H3-K27). Histone H3-K27 trimethylation is a mechanism for suppressing transcription of specific genes that are proximal to the site of histone modification. This trimethylation is known to be a cancer marker with altered expression in cancer, such as prostate cancer (see, e.g., U.S. Patent Application Publication No. 2003 / 0175736; incorporated herein by reference in its entirety). Other studies provided evidence for a functional link between dysregulated EZH2 expression, transcriptional repression, and neoplastic transformation.

[0224] 27

[0225] MEl\59152596.vl 137508-06020

[0226] Tazemetostat, or N-[(4,6-Dimethyl-2-oxo-U / -pyridin-3-yl)methyl]-3-[ethyl(oxan-4- yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide is a selective EZH2 inhibitor having the structure:

[0227] Tazemetostat and pharmaceutically acceptable salts thereof are described in U.S.

[0228] Patent Nos. 8,410,088, 8,691,507, 8,765,732, 8,895,245, 9,090,562, 9,175,331, 9,333,217, 9,334,527, 9,394,283, 9,549,931, 9,688,665, 9,855,275, 9,889,138, 9,949,999, 10,155,002, 10,245,269, 10,369,155, 10,420,775, 10,786,511, 10,821,113, 11,052,093, and 11,491,163.

[0229] The contents of each of the foregoing references are incorporated herein by reference in their entirety. In some embodiments, tazemetostat is administered as tazemetostat hydrobromide.

[0230] B-cell lymphoma 2 protein (BCL-2) is an important regulator of programmed cell death (apoptosis).

[0231] Venetoclax, or 4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-l-cyclohexen-l-yl]methyl}- l-piperazinyl)-V-({3-nitro-4-[(tetrahydro-2J / -pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2- (U / -pyrrolo[2,3-Z>]pyridin-5-yloxy)benzamide is a BCL-2 inhibitor having the structure:

[0232] Venetoclax and pharmaceutically acceptable salts thereof are described in U.S. Patent Nos. 8,546,399, 8,722,657, 9,174,982, 9,539,251, 10,730,873, 10,993,942, 11,110,087, 11,369,599, 11,413,282, and 11,590,128. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0233] 28

[0234] MEl\59152596.vl 137508-06020

[0235] Cyclin-dependent kinases 4 and 6 are serine / threonine protein kindase which are involved in the regulation of the cell cycle.

[0236] Palbociclib, or 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-l-yl)pyridin-2- yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one, is a CDK4 / 6 inhibitor having the structure:

[0237] Palbociclib and pharmaceutically acceptable salts thereof are described in U.S. Patent Nos. 10,723,730 and 11,065,250. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0238] The mammalian target of rapamycin (mTOR) is a human kinase which regulates a number of cellular functions such as cell growth, proliferation, motility, and survival.

[0239] Everolimus, or (6R,7E,9R,10R,12S,14R,15E,17E,19E,21S,23R,26S,27S,34aR)-9,27- dihydroxy-3-((S)-l-((lS,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl)propan-2-yl)- 10,21-dimethoxy-6,8,12,14,20,26-hexamethyl- 9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-3H-23,27-epoxypyrido[2,l- c][l]oxa[4]azacyclohentriacontine-l,5, 11,28,29(414,614,3 U4)-pentaone, is a mTOR inhibitor having the structure:

[0240] Everolimus and pharmaceutically acceptable salts thereof are described in U.S. Patent Nos. 8,410,131 and 9,006,224. The contents of each of the foregoing references are incorporated herein by reference in their entirety.

[0241] Cyclophosphamide, or 2-(bis(2-chloroethyl)amino)-l,3,2-oxazaphosphinane 2-oxide, is a DNA-cross linking compound having the structure:

[0242] 29

[0243] MEl\59152596.vl 137508-06020

[0244] Doxorubicin, or (8S,10S)-10-(((2R,4S,5R,6S)-4-amino-5-hydroxy-6- methyltetrahydro-2H-pyran-2-yl)oxy)-6, 8, l l-trihydroxy-8-(2-hydroxyacetyl)-l -methoxy- 7,8,9, 10-tetrahydrotetracene-5, 12-dione, is a DNA intercalator having the structure:

[0245] Vincristine, or methyl (3aR,3alR,4R,5S,5aR,10bR)-4-acetoxy-3a-ethyl-9- ((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-l,4,5,6,7,8,9,10-octahydro-2H-3,7- methano[l]azacycloundecino[5,4-b]indol-9-yl)-6-formyl-5-hydroxy-8-methoxy- 3a,3al,4,5,5a,6,l l,12-octahydro-lH-indolizino[8,l-cd]carbazole-5-carboxylate is an in hibitor of the tubulin protein having the structure:

[0246] Vincristine sulfate is the sulfate salt of vincristine.

[0247] Prednisone, or (8S,9S,10R,13S,14S,17R)-17-hydroxy-17-(2-hydroxyacetyl)-10,13- dimethyl-7,8,9,10,12,13,14,15,16,17-decahydro-3H-cyclopenta[a]phenanthrene-3,l l(6H)- dione, is a steroid having the structure:

[0248] MEl\59152596.vl 137508-06020

[0249] Rituximab is a genetically engineered chimeric murine / human monoclonal IgGl kappa antibody directed against the CD20 antigen and having an approximate molecular weight of 145 kD and a binding affinity for the CD20 antigen of approximately 8.0 nM. In some embodiments, Rituximab is commercially available under the trade name RITUXAN®. RITUXAN® is produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium that may contain the antibiotic gentamicin (not detectable in the final product). Rituximab is indicated in adult patients with Non-Hodgkin’s Lymphoma (NHL), pediatric patients aged 6 months and older with mature B-cell NHL and mature B-cell acute leukemia (B-AL), and adult patients with Chronic Lymphocytic Leukemia (CLL) (previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC).

[0250] RITUXAN® is a sterile, preservative-free, clear, colorless solution for intravenous infusion. RITUXAN® is supplied at a concentration of 10 mg / mL in either 100 mg / 10 mL or 500 mg / 50 mL single-dose vials. Each mL of solution contains 10 mg rituximab, 0.7 mg polysorbate 80, 9 mg sodium chloride, 7.35 mg sodium citrate dihydrate, and water for injection, USP. The pH of the solution is 6.5.

[0251] Compound A of the present disclosure refers to 2-((6-((5-chloro-2-(4-((lr,3r)-3-(4-(2- (2,6-dioxopiperidin-3-yl)-4-fluoro-l-oxoisoindolin-5-yl)piperidin-l- yl)cyclobutoxy)piperidin- 1 -yl)pyrimidin-4-yl)amino)- 1 -isopropyl-2-oxo- 1 ,2- dihydroquinolin-3-yl)oxy)-N-methylacetamide, which has the following structure: (Compound A).

[0252] In some embodiments, Compound A can be prepared as described in US Patent No.

[0253] 11,986,532 B2, which is incorporated herein by reference in its entirety.

[0254] 31

[0255] MEl\59152596.vl 137508-06020

[0256] The term “pharmaceutical composition” or “pharmaceutical formulation” refers to one or more active pharmaceutical ingredients (APIs) combined with one or more inactive ingredients (e.g., “carrier”, “diluent”, “vehicle”, or “excipient”). The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism, such as a human or other mammals. In some embodiments, a pharmaceutical composition refers to Compound A, or a pharmaceutically acceptable salt thereof, combined with one or more carriers, diluents, vehicles, excipients, or a combination thereof. In some embodiments, a pharmaceutical composition refers to Compound A, or a pharmaceutically acceptable salt thereof, combined one or more additional anti-cancer agents and one or more carriers, diluents, vehicles, excipients, or a combination thereof.

[0257] The term “pharmaceutically acceptable”, “carrier”, “diluent”, “vehicle”, or “excipient” refers to a material (or materials) that may be included with a particular pharmaceutical agent to form a pharmaceutical composition, and may be solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropyl methylcellulose, methylmethacrylate and the like.

[0258] The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of “treating” as defined immediately above. For example, the terms “treat”, “treating” and “treatment” can refer to a method of alleviating or abrogating a particular disorder and / or one or more of its attendant symptoms.

[0259] As used herein, “subject” means a human or animal (in the case of an animal, the subject can be a mammal). In one aspect, the subject is a human.

[0260] The term “about” is used herein to mean approximately, in the region of, roughly or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%, a variance of 10%, a variance of 5%, a variance of 3%, or a variance of 1%.

[0261] Methods of ubiquitinating / degrading a target protein in a cell

[0262] 32

[0263] MEl\59152596.vl 137508-06020

[0264] The present disclosure provides a method of ubiquitinating / degrading a target protein in a cell.

[0265] In some embodiments, the method comprises administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-cancer agent.

[0266] In some embodiments, the E3 ubiquitin ligase binding moiety is coupled to the protein targeting moiety via a linker moiety, and wherein the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase, preferably an E3 ubiquitin ligase) and the protein targeting moiety recognizes the target protein such that degradation of the target protein will occur when the target protein is placed in proximity to the ubiquitin ligase, thus resulting in degradation / inhibition of the effects of the target protein and the control of protein levels. The control of protein levels afforded by the present disclosure provides treatment of a disease state or condition, which is modulated through the target protein by lowering the level of that protein in the cells of a patient.

[0267] In some embodiments, the present disclosure is directed to a method of treating a patient in need for a disease state or condition modulated through a protein where the degradation of that protein (e.g. BCL6) will produce a therapeutic effect in that patient, the method comprising administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-cancer agent. The disease state or condition may be a disease caused by overexpression of a protein, which leads to a disease state and / or condition.

[0268] Methods of Treatment

[0269] The description provides therapeutic compositions as described herein for effectuating the degradation of a protein of interest (e.g. BCL6) for the treatment or amelioration of a disease, e.g. cancer.

[0270] In some embodiments, the method comprises administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-cancer agent wherein Compound A is a bifunctional compound comprising an E3 ubiquitin ligase binding moiety and a protein targeting moiety linked via a linker moiety.

[0271] In some embodiments, the E3 ubiquitin ligase binding moiety is coupled to the protein targeting moiety via a linker moiety, and wherein the E3 ubiquitin ligase binding moiety recognizes a ubiquitin pathway protein (e.g., an ubiquitin ligase, preferably an E3 ubiquitin

[0272] 33

[0273] MEl\59152596.vl 137508-06020 ligase) and the protein targeting moiety recognizes the target protein such that degradation of the target protein will occur when the target protein is placed in proximity to the ubiquitin ligase, thus resulting in degradation / inhibition of the effects of the target protein and the control of protein levels. The control of protein levels afforded by the present disclosure provides treatment of a disease state or condition, which is modulated through the target protein by lowering the level of that protein in the cells of a patient. In certain embodiments, the method comprises administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-cancer agent.

[0274] In additional embodiments, the description provides methods for treating or ameliorating a disease, disorder, or symptom thereof in a subject or a patient, e.g., an animal such as a human, comprising administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-cancer agent , wherein the composition is effective for treating or ameliorating the disease or disorder or symptom thereof in the subject.

[0275] In any aspect or embodiment described herein, the disease or disorder is associated with aberrant BCL6 expression and or activity.

[0276] In any aspect or embodiment described herein, the disease or disorder is a cancer associated with aberrant BCL6 expression and or activity.

[0277] In any aspect or embodiment described herein, the disease or disorder is associated with BCL6 accumulation and aggregation.

[0278] In any aspect or embodiment described herein, the disease or disorder is a cancer associated with BCL6 accumulation and aggregation.

[0279] In another aspect, the description provides methods for identifying the effects of the degradation of the protein of interest (e.g. BCL6) in a biological system using Compound A.

[0280] In another embodiment, the present disclosure is directed to a method of treating a human patient in need for a disease state or condition modulated through a protein (e.g. BCL6) where the degradation of that BCL6 protein will produce a therapeutic effect in the patient, the method comprising administering to the subject an effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anti-cancer agent. The disease state or condition may be a disease caused by a microbial agent or other exogenous agent such as a virus, bacteria, fungus, protozoa or other microbe or may be a disease state, which is caused by overexpression of a protein, which leads to a disease state and / or condition.

[0281] 34

[0282] MEl\59152596.vl 137508-06020

[0283] The term “disease state or condition” is used to describe any disease state or condition wherein protein dysregulation (i.e., the amount of protein expressed in a patient is elevated) occurs and where degradation of one or more proteins in a patient may provide beneficial therapy or relief of symptoms to a patient in need thereof. In certain instances, the disease state or condition may be cured.

[0284] The term “neoplasia” or “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors.

[0285] Exemplary cancers which may be treated by Compound A in combination with at least one additional anti-cancer agent include non-Hodgkin's lymphoma (NHL), advanced NHL, relapsed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL- Al, also referred to as angioimmunoblastic T- cell lymphoma or AITL), advanced nTFHL- Al, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B- cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, aggressive DLBCL, high-grade (HG) DLBCL, and activated B-cell (ABC) DLBCL.

[0286] The term “pharmaceutically acceptable salt” is used throughout the specification to describe, where applicable, a salt form of one or more of the compounds described herein which are presented to increase the solubility of the compound in the gastric juices of the patient's gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids and bases well

[0287] 35

[0288] MEl\59152596.vl 137508-06020 known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralization salts of the phosphates according to the present disclosure.

[0289] Throughout the present disclosure, amounts (e.g., dosage amounts) of compounds disclosed herein (e.g., Compound A, acalabrutinib, tazemetostat, venetoclax, palbociclib, everolimus, cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, prednisone) refer to the amount of the free form (i.e., “free base”) of the compound recited in the method. The term “corresponding amount” as used herein refers to the amount of a pharmaceutically acceptable salt of a compound required to obtain the equivalent amount of the free form of that compound recited in the method. It would be clear to one of skill in the art how to calculate the “corresponding amount” of the salt of a compound, such as the corresponding amount of the pharmaceutically acceptable salt of tazemetostat, taking into account the difference in molecular weight between the free form of a compound and a salt form. For example, about 200 mg of tazemetostat would correspond to about 228 mg tazemetostat hydrobromide, and 100 mg of acalabrutinib would correspond to 129 mg of acalabrutinib maleate hydrate.

[0290] As used herein, reference to an amount of a compound administered “daily” refers to the total amount of that compound administered over the course of the day, irrespective of how that dose is divided. Reference to an amount of a compound administered “once a day,” “twice a day”, etc. refer to the amount of that compound administered in each dose. For example, a dosing regimen of 100 mg in the morning, and another 100 mg dose in the evening can be described as “200 mg daily” and “100 mg twice a day.”

[0291] EXAMPLES

[0292] Abbreviations used:

[0293] Example 1. Mouse Xenograft Models

[0294] Female CB17SCID mice aged 6-9 weeks were injected with OCI-Lyl, OCI-LylO, or SU-DHL-6 cells (~1 x 107cells, prepared in Matrigel™). Approximately one month after injection, mice were subsequently dosed with vehicle, Compound A, and / or a combination

[0295] 36

[0296] MEl\59152596.vl 137508-06020 partner (acalabrutinib, tazemetostat, or venetoclax). Tumor volumes were measured as indicated in FIGs 1-5.

[0297] Compound A was administered QD, PO in 40% 2-hydroxypropyl-beta-cyclodextrin in 10 mM citrate (pH = 3.0). Acalabrutinib was administered BID, PO in 0.5% hydroxypropyl methyl cellulose / 0.2% Tween 80. Tazemetostat was administered BID, PO in 40% 2- hydroxypropyl-beta-cyclodextrin in 10 mM citrate (pH = 3.0). Venetoclax was administered QD, PO in 40% 2-hydroxypropyl-beta-cyclodextrin in 10 mM citrate (pH = 3.0).

[0298] Each treatment arm included eight or ten mice. In mice that were administered Compound A and a combination partner, Compound A and the combination partner were coadministered.

[0299] Tumor growth inhibition (TGI) was calculated as follows, where tumor volume is in mm3:

[0300] For the SU-DHL-6 model, protein lysates were harvested from tumor samples in Vehicle, Compound A, Tazemetostat (Taz) or Compound A plus Taz treated mice, 24-hours post-last dose.

[0301] Findings

[0302] Evidence of combinatorial effects between Compound A and acalabrutinib was observed in an OCI-LylO mouse xenograft model (FIG 1). Tumor regression was observed in 10 out of 10 mice treated with Compound A in combination with acalabrutinib. The combination of Compound A with acalabrutinib induced significantly greater TGI than either single agent treatment. Body weights were maintained with monotherapy and combination treatments (FIG. 11)

[0303] Evidence of combinatorial effects between Compound A and tazemetostat was observed in a SU-DHL-6 mouse xenograft model (FIG 2) and in an OCI-Ly 1 mouse xenograft model (FIG 3). Tumor regression was observed in 10 out of 10 mice treated with Compound A in combination with tazemetostat in the SU-DHL-6 mouse xenograft model. The combination of Compound A with tazemetostat was also significantly better than either single agent treatment in both models. In the SU-DHL-6 mouse xenograft model, MYC, EZH2 and BCL2 protein levels were increased 56%, 66% and 12%, respectively, with Compound A alone vs vehicle, but were decreased 75%, 80% and 96% vs vehicle, with greater BCL6 degradation (65% vs 87%) when Compound A was administered in combination with tazemetostat. Without

[0304] 37

[0305] MEl\59152596.vl 137508-06020 wishing to be bound by theory, the reduction of MYC, EZH2, and BCL2 coupled with the enhanced BCL6 degradation with the combination of Compound A and tazemetostat may be responsible for the enhanced anti-tumor activity. Body weights were maintained with monotherapy and combination treatments (FIG. 12)

[0306] Evidence of combinatorial effects between Compound A and venetoclax was observed in an OCI-Lyl mouse xenograft model (FIG 4) and in an SU-DHL-6 mouse xenograft model (FIG 5). Tumor regression was observed in 10 out of 10 mice treated with Compound A in combination with venetoclax in the OCI-Lyl model. Body weights were maintained with monotherapy and combination treatments (FIG. 13)

[0307] As shown in FIG 10, Compound A plus Taz combination demonstrates a synergistic reduction of four proteins known to support lymphoma cell growth (MYC, EZH2, BCL2, and BCL6). MYC, EZH2, and BCL2 protein levels were increased by 56%, 66%, and 12%, respectively, with Compound A alone vs vehicle, but were decreased by 75%, 80%, and 96%, respectively, with Compound A plus tazemetostat vs vehicle. BCL6 degradation was greater with Compound A combined with tazemetostat vs Compound A alone (87% vs 65%).

[0308] Example 2. Mouse Xenograft Models

[0309] Female CB17SCID mice aged 6-9 weeks were injected with OCI-Lyl or SU-DHL-6 cells (~1 x 107cells, prepared in Matrigel™). Approximately one month after injection, mice were subsequently dosed with vehicle, Compound A, and / or a combination partner (palbociclib or emerolimus). Tumor volumes were measured as indicated in FIGs 6-8.

[0310] Compound A was administered QD, PO in 40% 2-hydroxypropyl-beta-cyclodextrin in 10 mM citrate (pH = 3.0). Everolimus was administered QD, PO in 10% DMSO, 90% (2% Tween80, PEG400). Palbociclib was administered QD, PO in 50mmol sodium lactate (pH=4.0).

[0311] Each treatment arm included eight or ten mice. In mice that were administered Compound A and a combination partner, Compound A and the combination partner were coadministered.

[0312] Tumor growth inhibition (TGI) was calculated as follows, where tumor volume is in mm3:

[0313] (T umor volume, compound, DayX) - (T umor volume, compound, Day 0)

[0314] TGI (%) = [!-J- - ’ - - ’ - - ] x 100

[0315] (T umor volume, vehicle, DayX) - (T umor volume, vehicle, Day 0)

[0316] Findings

[0317] 38

[0318] MEl\59152596.vl 137508-06020

[0319] An in-vivo efficacy study was performed in a cell line-derive xerograph (CDX) model of high-grade B-cell lymphoma (HGBCL) to test antitumor activity of Compound A in combination with palbociclib. Mice bearing subcutaneous tumors from the cell line SU-DHL- 6 were orally (po) administered vehicle, compound A at 30 mg / kg daily (qd), palbociclib at 45 mg / kg daily (qd) or the combination of Compound A and palbociclib for 22 days. Each treatment arm consisted of 8 mice. The results are shown in FIG 6. The combination of Compound A with palbociclib induced significantly greater TGI than either single agent treatment. Furthermore, tumor regression was observed in 8 out of 8 mice treated with Compound A in combination with palbociclib (FIG 6).

[0320] To test antitumor activity of Compound A in combination with everolimus, mice bearing subcutaneous tumors from the cell line SU-DHL-6 were orally (po) administered vehicle, compound A at 30 mg / kg daily (qd), everolimus at 2 mg / kg daily (qd) or the combination of Compound A and everolimus for 22 days. Each treatment arm consisted of 8 mice. The combination of Compound A with everolimus induced significantly greater TGI than single agent Compound A, and greater TGI than single agent everolimus (FIG 7).

[0321] An in-vivo efficacy study was performed in a cell line-derive xerograph (CDX) model of diffuse large B-cell lymphoma - germinal center B cell (DLBCL-GCB) to test antitumor activity of Compound A in combination with everolimus. Mice bearing subcutaneous tumors from the cell line OCI-Ly-1 were orally (po) administered vehicle, compound A at 3 mg / kg daily (qd), everolimus at 2 mg / kg daily (qd) or the combination of Compound A and everolimus for 22 days. Each treatment arm consisted of 10 mice. The combination of Compound A with everolimus induced greater TGI (80%) than either single agent treatment (65% or 70%) (FIG 8).

[0322] Example 3. Mouse Xenograft Models

[0323] Female CB17SCID mice aged 7-9 weeks were injected with SU-DHL-4 cells (~1 x 107cells, prepared in Matrigel™). Approximately one month after injection, mice were subsequently dosed with vehicle, control, Compound A, and / or a combination partner(s) (CHOP or R-CHOP). Tumor volumes were measured as indicated in FIG 9.

[0324] Compound A at 6 mg / kg or 30 mg / kg was administered orally (PO) once daily (QD) for 28 days in 40% 2-hydroxypropyl-beta-cyclodextrin in 10 mM citrate (pH = 3.0); rituximab at 3 mg / kg was administered intravenously (IV) on days 1, 8, 15, and 22; CHOP at 30:2.475:0.375:0.15 mg / kg was given IV on day 1 (prednisone was dosed PO, QD on days 1- 5); and R-CHOP followed these same dosing methods. The Compound A 6 mg / kg dose was

[0325] 39

[0326] MEl\59152596.vl 137508-06020 used for all combinations. Control groups included mice that received an immunoglobulin G1 (IgGl) IV on days 1, 8, 15, and 22 or mice treated with a vehicle PO QD.

[0327] Tumor growth inhibition (TGI) was calculated as follows, where tumor volume is in mm3:

[0328] Findings

[0329] Compound A combined with R-CHOP drives tumor repressions and has a significantly stronger tumor growth inhibition compared to any single agent (R-CHOP, CHOP, rituximab, or Compound A) alone (FIG. 9). Compound A combined with R-CHOP induced complete regressions and had significantly higher TGI compared with rituximab, CHOP, R-CHOP, or Compound A alone. Compound A induced complete regressions in 4 / 10 mice when combined with rituximab, in 6 / 10 mice when combined with CHOP, and in 10 / 10 mice when combined with R-CHOP. Body weights were maintained with monotherapy and combination treatments (FIG. 14).

[0330] EQUIVALENTS

[0331] While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

[0332] 40

[0333] MEl\59152596.vl

Claims

137508-06020CLAIMSWhat is claimed is:

1. A method of treating cancer in a subject, comprising administering to the subject an effective amount of Compound A,or a pharmaceutically acceptable salt thereof, and an effective amount of an additional anticancer agent.

2. The method of claim 1, wherein Compound A, or a pharmaceutically acceptable salt thereof, and the additional anti-cancer agent are administered simultaneously.

3. The method of claim 1, wherein Compound A, or a pharmaceutically acceptable salt thereof, and the additional anti-cancer agent are administered separately.

4. The method of claim 1 or 3, wherein the administration of the additional anti-cancer agent occurs before the administration of Compound A, or a pharmaceutically acceptable salt thereof.

5. The method of any one of claims 1, 3, and 4, wherein the administration of the additional anti-cancer agent occurs at least 30 minutes before the administration of Compound A, or a pharmaceutically acceptable salt thereof.41MEl\59152596.vl137508-060206. The method of claim 1 or 3, wherein the administration of the additional anti-cancer agent occurs after the administration of Compound A, or a pharmaceutically acceptable salt thereof.

7. The method of any one of claims 1, 3, and 6, wherein the administration of the additional anti-cancer agent occurs at least 30 minutes after the administration of Compound A, or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1 to 7, wherein the cancer is associated with (i) aberrant BCL6 expression and / or activity and / or (ii) overexpression or aggregation of BCL6.

9. The method of any one of claims 1 to 8, wherein the cancer is lymphoma.

10. The method of any one of claims 1 to 8, wherein the cancer is non-Hodgkin's lymphoma (NHL), advanced NHL, relap sed / refractory (R / R) NHL, advanced R / R NHL, nodal T-follicular helper cell lymphoma (nTFHL), advanced nTFHL, R / R nTFHL, nodal T-follicular helper cell lymphoma-angioimmunoblastic type (nTFHL-AI), advanced nTFHL-AI, R / R nTFHL-AI, advanced B-cell NHL, R / R B-cell NHL, B-cell lymphoma (BCL), high-grade (HG) BCL, activated BCL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Burkitt lymphoma, germinal center B-cell (GCB) DLBCL, high-grade (HG) DLBCL, or activated B- cell (ABC) DLBCL.

11. The method of any one of claims 1 to 8, wherein the cancer is diffuse large B-cell lymphoma (DLBCL), germinal center B-cell (GCB) DLBCL, or activated B-cell (ABC) DLBCL.

12. The method of any one of claims 1 to 11, wherein the anti-cancer agent is a BTK inhibitor.

13. The method of any one of claims 1 to 12, wherein the anti-cancer agent is acalabrutinib or a pharmaceutically acceptable salt thereof.

14. The method of any one of claims 1 to 13, wherein the anti-cancer agent is acalabrutinib.42MEl\59152596.vl137508-0602015. The method of any one of claims 1 to 14, wherein the anti-cancer agent is acalabrutinib maleate.

16. The method of any one of claims 1 to 15, wherein acalabrutinib is administered to the subject once a day.

17. The method of any one of claims 1 to 15, wherein acalabrutinib is administered to the subject about once every 12 hours.

18. The method of any one of claims 1 to 15, wherein about 50 mg to about 250 mg acalabrutinib is administered to the subject daily.

19. The method of any one of claims 1 to 15, wherein about 50 mg to about 200 mg acalabrutinib is administered to the subject daily 1 to 18.

20. The method of any one of claims 1 to 15, wherein 100 mg acalabrutinib is administered to the subject daily.

21. The method of any one of claims 1 to 15, wherein 200 mg acalabrutinib is administered to the subject daily.

22. The method of any one of claims 1 to 11, wherein the anti-cancer agent is an EZH2 inhibitor.

23. The method of any one of claims 1 to 11 and 22, wherein the anti-cancer agent is tazemetostat or a pharmaceutically acceptable salt thereof.

24. The method of any one of claims 1 to 11, 22, and 23, wherein the anti-cancer agent is tazemetostat.

25. The method of any one of claims 1 to 11 and 22 to 24, wherein the anti-cancer agent is tazemetostat hydrobromide.43MEl\59152596.vl137508-0602026. The method of any one of claims 1 to 11 and 22 to 25, wherein tazemetostat is administered to the subject twice a day.

27. The method of any one of claims 1 to 11 and 22 to 25, wherein 400 mg tazemetostat is administered to the subject daily.

28. The method of any one of claims 1 to 11 and 22 to 25, wherein 600 mg tazemetostat is administered to the subject daily.

29. The method of any one of claims 1 to 11 and 22 to 25, wherein 800 mg tazemetostat is administered to the subject daily.

30. The method of any one of claims 1 to 11 and 22 to 25, wherein 1200 mg tazemetostat is administered to the subject daily.

31. The method of any one of claims 1 to 11 and 22 to 25, wherein 1600 mg tazemetostat is administered to the subject daily.

32. The method of any one of claims 1 to 11 and 22 to 25, wherein about 200 mg to about 2000 mg tazemetostat is administered to the subject daily.

33. The method of any one of claims 1 to 11 and 22 to 25, wherein about 200 mg to about 1600 mg tazemetostat is administered to the subject daily.

34. The method of any one of claims 1 to 11 and 22 to 25, wherein about 100 mg to about 1000 mg tazemetostat is administered to the subject twice a day.

35. The method of any one of claims 1 to 11 and 22 to 25, wherein about 100 mg to about 800 mg tazemetostat is administered to the subject twice a day.

36. The method of any one of claims 1 to 11 and 22 to 25, wherein 200 mg tazemetostat is administered to the subject twice a day.44MEl\59152596.vl137508-0602037. The method of any one of claims 1 to 11 and 22 to 25, wherein 400 mg tazemetostat is administered to the subject twice a day.

38. The method of any one of claims 1 to 11 and 22 to 25, wherein 600 mg tazemetostat is administered to the subject twice a day.

39. The method of any one of claims 1 to 11 and 22 to 25, wherein 800 mg tazemetostat is administered to the subject twice a day.

40. The method of any one of claims 1 to 11 and 22 to 25, wherein the tazemetostat is administered to the subject in a first dose of 400 mg, followed by a second dose of 200 mg 12 hours later, daily.

41. The method of any one of claims 1 to 11, wherein the anti-cancer agent is a BCL2 inhibitor.

42. The method of any one of claims 1 to 11 and 41, wherein the anti-cancer agent is venetoclax or a pharmaceutically acceptable salt thereof.

43. The method of any one of claims 1 to 11, 41 and 42, wherein the anti -cancer agent is venetoclax.

44. The method of any one of claims 1 to 11 and 41 to 43, wherein venetoclax is administered to the subject once a day.

45. The method of any one of claims 1 to 11 and 41 to 44, wherein about 10 mg to about 800 mg venetoclax is administered to the subject daily.

46. The method of any one of claims 1 to 11 and 41 to 44, wherein about 200 mg to about 500 mg venetoclax is administered to the subject daily.

47. The method of any one of claims 1 to 11 and 41 to 44, wherein 400 mg venetoclax is administered to the subject daily.45MEl\59152596.vl137508-0602048. The method of any one of claims 1 to 11 and 41 to 44, wherein venetoclax is administered according to a ramp-up dosing schedule.

49. The method of claim 48, wherein the ramp-up dosing schedule comprises: i. 20 mg venetoclax administered to the subject daily on days 1-7; ii. 50 mg venetoclax administered to the subject daily on days 8-14; iii. 100 mg venetoclax administered to the subject daily on days 15-21; iv. 200 mg venetoclax administered to the subject daily on days 22-28; and v. 400 mg venetoclax administered to the subject daily on day 29 and thereafter.

50. The method of claim 48, wherein the ramp-up dosing schedule comprises: i. about 10 mg to about 30 mg venetoclax administered to the subject daily on days 1- 7; ii. about 25 mg to about 75 mg venetoclax administered to the subject daily on days 8- 14; iii. about 50 mg to about 125 mg venetoclax administered to the subject daily on days 15-21; iv. about 100 mg to about 250 mg venetoclax administered to the subject daily on days 22-28; and v. about 200 mg to about 500 mg venetoclax administered to the subject daily on day 29 and thereafter.

51. The method of claim 48, wherein the ramp-up dosing schedule comprises: i. about 10 mg to about 20 mg venetoclax administered to the subject daily on days 1- 7; ii. about 25 mg to about 50 mg venetoclax administered to the subject daily on days 8- 14; iii. about 50 mg to about 100 mg venetoclax administered to the subject daily on days 15-21; iv. about 100 mg to about 200 mg venetoclax administered to the subject daily on days 22-28; and v. about 200 mg to about 400 mg venetoclax administered to the subject daily on day 29 and thereafter.46MEl\59152596.vl137508-0602052. The method of claim 48, wherein the ramp-up dosing schedule comprises: i. 100 mg venetoclax administered to the subject daily on day 1; ii. 200 mg venetoclax administered to the subject daily on day 2; iii. 400 mg venetoclax administered to the subject daily on day 3; and iv. 400 mg venetoclax administered to the subject daily on day 4 and thereafter.

53. The method of claim 48, wherein the ramp-up dosing schedule comprises: i. 100 mg venetoclax administered to the subject daily on day 1; ii. 200 mg venetoclax administered to the subject daily on day 2; iii. 400 mg venetoclax administered to the subject daily on day 3; and iv. 600 mg venetoclax administered to the subject daily on day 4 and thereafter.

54. The method of claim 48, wherein the ramp-up dosing schedule comprises: i. about 50 to about 125 mg venetoclax administered to the subject daily on day 1; ii. about 100 to about 250 mg venetoclax administered to the subject daily on day 2; iii. about 200 to about 500 mg venetoclax administered to the subject daily on day 3; and iv. about 200 to about 500 mg venetoclax administered to the subject daily on day 4 and thereafter.

55. The method of claim 48, wherein the ramp-up dosing schedule comprises: i. about 50 to about 125 mg venetoclax administered to the subject daily on day 1; ii. about 100 to about 250 mg venetoclax administered to the subject daily on day 2; iii. about 200 to about 500 mg venetoclax administered to the subject daily on day 3; and iv. about 300 to about 800 mg venetoclax administered to the subject daily on day 4 and thereafter.

56. The method of any one of claims 1 to 11, wherein the anti-cancer agent is a CDK4 and / or CDK6 inhibitor.

57. The method of any one of claims 1 to 11 and 56, wherein the anti-cancer agent is palbociclib or a pharmaceutically acceptable salt thereof.47MEl\59152596.vl137508-0602058. The method of any one of claims 1 to 11, 56, and 57, wherein the anti-cancer agent is palbociclib.

59. The method of any one of claims 1 to 11, wherein the anti-cancer agent is a mTOR inhibitor.

60. The method of any one of claims 1 to 11 and 59, wherein the anti-cancer agent is everolimus or a pharmaceutically acceptable salt thereof.

61. The method of any one of claims 1 to 11, 59, and 60, wherein the anti-cancer agent is everolimus.

62. The method of any of claims 1 to 11, wherein the anti-cancer agent is cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone, or pharmaceutically acceptable salts thereof.

63. The method of any of claims 1 to 11 and 62, wherein the anti-cancer agent is cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone.

64. The method of any of claims 1 to 11, wherein the anti-cancer agent is rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone, or pharmaceutically acceptable salts thereof.

65. The method of any of claims 1 to 11 and 64, wherein the anti-cancer agent is rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine sulfate, and prednisone.

66. The method of any one of claims 1 to 65, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered orally to the subject.

67. The method of any one of claims 1 to 66, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject once a day, twice a day, three times a day, or four times a day.48MEl\59152596.vl137508-0602068. The method of any one of claims 1 to 66, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject once a day.

69. The method of any one of claims 1 to 66, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject twice a day.

70. The method of any one of claims 1 to 66, wherein about 1 mg to about 500 mg Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject daily.

71. The method of any one of claims 1 to 66, wherein about 1 mg to about 250 mg Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject daily.

72. The method of any one of claims 1 to 66, wherein about 1 mg to about 100 mg Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject twice a day.

73. The method of any one of claims 1 to 66, wherein about 3 mg to about 90 mg Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject twice a day.

74. The method of any one of claims 1 to 73, further comprising a dosing holiday, wherein the dosing holiday comprises one, two, three, four, five, or more days where Compound A, or a pharmaceutically acceptable salt thereof, is not administered to the subject.49MEl\59152596.vl

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