Methods of treating cancer using an EZH2 inhibitor and a tricyclic quinolone heterobifunctional degrader of BCL6

Abstract

This disclosure provides methods for treating cancer and other diseases using an EZH2 inhibitor and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof. This disclosure also provides compositions containing the same.

Description

[0001] Docket No. TRLN-013-030W01 / TLS-068WO Methods of treating cancer using an EZH2 inhibitor and a tricyclic quinolone heterobifunctional degrader of BCL6

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U. S. Provisional Application Serial Nos. 63 / 733,924, filed December 13, 2024; 63 / 764,706, filed February 28, 2025; 63 / 794,123, filed April 24, 2025; and 63 / 906,211, filed October 27, 2025, each of which is incorporated by reference in its entirety herein.

[0004] SEQUENCE LISTING

[0005] This application contains a Sequence Listing that has been submitted electronically as an XML file named “TRLN-013-030W01_Sequence_Listing. XML.” The XML file, created on December 9, 2025, is 3 KB in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0006] TECHNICAL FIELD

[0007] This disclosure provides methods for treating cancer and other diseases using an EZH2 inhibitor and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (Laa-1), (Laa-2), (Laa-3), (Laa-4), (Laa-5), or (Laa-6)), Formula (La) (e.g., Formula (La-1), (La-2), (La-3), (La-4), (La-5) or (La-6)), or Formula (Lbb) (e.g., Formula (I-bb-1) or (Lbb-2))), or a pharmaceutically acceptable salt thereof. This disclosure also provides methods for treating cancer and other diseases using a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (Laa) (e.g., Formula (Laa-1), (Laa-2), (Laa-3), (Laa-4), (I-aa-5), or (Laa-6)), Formula (La) (e.g., Formula (La-1), (La-2), (La-3), (La-4), (La-5) or (La-6)), or Formula (Lbb) (e.g., Formula (Lbb-1) or (Lbb-2))), or a pharmaceutically acceptable salt thereof, as a monotherapy. In some cases, the treatment can be maintenance therapy. This disclosure also provides compositions containing the same.

[0008] BACKGROUND

[0009] Cancers such as B-cell lymphomas are treated with a myriad of different agents and strategies based on factors like prior treatment history, patient characteristics, and biology of the disease, and not every patient responds to every treatment. For example, patients with diffuse large B-cell lymphoma (DLBCL) have approximately a 33% relapse / refractory rate with respect to first-line chemotherapy (Wang, Liang, Lin-rong Li, and Ken H. Young. Journal of Hematology & Docket No. TRLN-013-030W01 / TLS-068WO Oncology 13 (2020), doi: 10.1186 / sl3045-020-01011-z). Despite additional therapies available and in development, such as additional chemotherapy regiments, stem cell transplant, CAR-T therapy, and immunotherapy, there remains a need for development of agents to treat cancers like B-cell lymphomas.

[0010] SUMMARY

[0011] Provided herein are methods for treating a relapsed or refractory B-cell lymphoma in a subject in need thereof, the methods comprising administering to the subject:

[0012] (a) a therapeutically effective amount of an EZH2 inhibitor; and

[0013] (b) a therapeutically effective amount of a compound Formula (A):

[0014] R1

[0015]

[0016] Formula (A)

[0017] or a pharmaceutically acceptable salt thereof,

[0018] wherein X3, m3, R1, R6, L, and Ring C are as defined herein; and

[0019] wherein the relapsed or refractory B-cell lymphoma is selected from the group consisting of: a relapsed or refractory large B-cell lymphoma (LBCL), a relapsed or refractory follicular lymphoma (FL), and a relapsed or refractory transformed FL. In some embodiments, a compound of Formula (A) is a compound of Formula (A) (e.g., Formula (A-1)), or a pharmaceutically acceptable salt thereof. In some embodiments, the EZH2 inhibitor is selected from the group consisting of lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, and XNW-5004.

[0020] Also provided herein are methods for treating a relapsed or refractory BCL6+ B-cell lymphoma in a subject in need thereof, the methods comprising i) determining that the subject has a relapsed or refractory BCL6+ B-cell lymphoma; and ii) based on i), administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), or a pharmaceutically acceptable salt thereof). Docket No. TRLN-013-030W01 / TLS-068WO Provided herein are also methods for treating a relapsed or refractory B-cell lymphoma in a subject in need thereof, the methods comprising i) determining that the subject has a relapsed or refractory B-cell lymphoma having an EZH2 dysregulation; and ii) based on i), administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), or a pharmaceutically acceptable salt thereof, wherein the relapsed or refractory B-cell lymphoma is a relapsed or refractory large B-cell lymphoma (LBCL) or relapsed or refractory FL.

[0021] Also provided herein are methods for treating a relapsed or refractory PTCL in a subject in need thereof, the methods comprising administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof).

[0022] Provided also herein are methods for treating a relapsed or refractory BCL6+ PTCL in a subject in need thereof, the methods comprising i) determining that the subject has a relapsed or refractory BCL6+ PTCL; and ii) based on i), administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of Formula (A) (e.g., Formula (A-1)), or a pharmaceutically acceptable salt thereof). Also provided herein are method of treating a CTCL in a subject in need thereof, the methods comprising administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of Formula (A) (e.g., Formula (A-1)), or a pharmaceutically acceptable salt thereof).

[0023] Provided also herein are methods for treating a relapsed or refractory BCL6+ CTCL in a subject in need thereof, the methods comprising i) determining that the subject has a relapsed or refractory BCL6+ CTCL; and ii) based on i), administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of Formula (A) (e.g., Formula (A-1)), or a pharmaceutically acceptable salt thereof).

[0024] Also provided herein are methods for treating a cancer in a subject in need thereof, the methods comprising: (a) determining that the cancer in the subject has an EZH2 dysregulation (e.g., an EZH2 mutation); and (b) administering to the subject: (i) a therapeutically effective amount of an EZH2 inhibitor; and (ii) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), or a pharmaceutically acceptable salt thereof.

[0025] Also provided herein are methods for treating cancer in a subject in need thereof, the methods comprising (a) determining the BCL6 status of the cancer (e.g., by performing an assay Docket No. TRLN-013-030W01 / TLS-068WO or a test, or consulting the subject’s medical record); and (b) administering to the subject a therapeutically effective amount of an EZH2 inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments of any of the methods provided herein, the cancer is BCL6 positive (BCL6+) (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or by a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test).

[0027] Also provided herein are pharmaceutical compositions comprising an EZH2 inhibitor; and a compound of Formula (A) (e.g., Formula (A-1)), or a pharmaceutically acceptable salt thereof.

[0028] To facilitate understanding of the disclosure set forth herein, a number of additional terms are provided. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. In the case of conflict between the present disclosure and any content incorporated by reference, the present disclosure controls.

[0029] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0030] DETAILED DESCRIPTION

[0031] This disclosure provides methods for treating cancer and other diseases using an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof. This disclosure also provides compositions containing an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, as provided herein.

[0032] B-cell lymphoma 6 (BCL6) protein is a transcriptional repressor involved in the formation Docket No. TRLN-013-030W01 / TLS-068WO and maintenance of germinal centers (GCs) within lymphoid follicles. It controls the functions of the GC and coordinates the activities of signaling mediators in the maturation of GC B-cells. There are over 1000 known or putative BCL6 target genes, including MYC, BCL2, genes related to DNA damage response (e.g., A TI TP53 and cell cycle checkpoint control (e.g., CDKN1A, CDKN1B). BCL6 is expressed in the dark zone cells of GCs, where somatic hypermutation is allowed to occur to generate high-affinity B-cell receptors. Overexpression or loss of control of BCL6, for example by translocation, can permit maintenance of the pro-hypermutation functions and abrogation of the antitumor functions of BCL6.

[0033] Upon antigen challenge, germinal centers (GCs) are formed in lymphoid follicles, and B-cells in the dark zone of GCs undergo rapid proliferation and somatic hypermutation, both of their immunoglobulin variable genes to generate high-affinity B-cell receptors, as well as of other genes including BCL6. BCL6 is often considered to be a ‘master regulator’ of the GC reaction. In some cancers, BCL6 can be mutated, translocated, and / or BCL6 expression can be upregulated. See, e.g., Leeman-Neill and Bhagat, Expert Opinion on Therapeutic Targets 22.2 (2018): 143-152, doi: 10.1080 / 14728222.2018.1420782; Mlynarczyk and Melnick. Immunological Reviews 288.1 (2019): 214-239, doi: 10.111 l / imr.12755.

[0034] The BCL6 protein has multiple domains, including a BTB domain, an RD2 domain, and a DNA binding domain. The N-terminal BTB domain is the site of homodimerization of BCL6, and the interface of the monomers forms the “lateral groove”, which is a binding site for endogenous co-repressors of BCL6. such as SMRT, NCOR, and BCOR. See, e.g., Cardenas, Mariano G., et al. Clinical Cancer Research 23.4 (2017): 885-893, doi: 10.1158 / 1078-0432. CCR-16-2071.

[0035] BCL6 dimers bind to specific gene promoter sequences, forming a pocket that accommodates the BCL6 corepressor (BCOR). Together, these proteins contribute to the formation of polycomb repressive complex 1 (PRC1). PRC1 prevents the expression of cell cycle checkpoint and DNA damage response genes that would otherwise interfere with the somatic hypermutation and cell proliferation processes essential to affinity maturation. See, e.g., Cattoretti, Giorgio, et al. Blood (1995): 45-53, doi: 10.1182 / blood. V86.1.45.bloodjoumal86145; Phan, Ryan T., and Riccardo Dalla-Favera. Nature 432.7017 (2004): 635-639, doi: 10.1038 / nature03147; Phan, Ryan T., et al. Nature Immunology 6.10 (2005): 1054-1060, doi: 10.1038 / nil245; Ranuncolo, Stella Maris, etal. Nature Immunology 8.7 (2007): 705-714, doi: 10.1038 / nil478; and Basso, Katia, and Riccardo Dalla-Favera. Immunological Reviews 247.1 (2012): 172-183, doi: 10.111 l / j,1600-065X.2012.01112.x. While affinity maturation is believed to have evolved to fine tune the antibody response to invasive pathogens, simultaneous somatic hypermutation and cell proliferation can be a dangerous scenario for cancer-driving mutations to arise and expand clonally. Aberrant expression of BCL6 due to gene translocations or mutation have been linked to Docket No. TRLN-013-030W01 / TLS-068WO lymphomagenesis (see, e.g., Ye, Bihui H., et al. Nature Genetics 16.2 (1997): 161-170, doi: 10.1038 / ng0697-161; and Wang X, Li Z, Naganuma A, Ye BH. [published correction appears in Proc Natl Acad Sci U S A. 2002 Dec 24;99(26): 17222.]. Proc Natl Acad Sci U S A.

[0036] 2002;99(23):15018-15023. doi:10.1073 / pnas.232581199). The majority of LBCLs and FLs arise from B cells exiting the germinal center (GC) reaction and therefore depend on BCL6 to maintain their growth and survival (see, e.g., Hatzi, Katerina, and Ari Melnick. Trends in Molecular Medicine 20.6 (2014): 343-352, doi: 10.1016 / j.molmed.2014.03.001; and Cardenas, Mariano G., et al. The Journal of Clinical Investigation 126.9 (2016): 3351-3362, doi: 10.1172 / JCI85795).

[0037] Compounds that induce degradation of a target protein are sometimes referred to as heterobifunctional compounds, PROTACs, or degraders. Such compounds generally include a moiety that binds to the target protein and a moiety that binds to a ubiquitin E3 ligase (sometimes referred to as an E3 ligase or simply an E3), these two moieties being optionally separated by a linker. To induce degradation, heterobifunctional compounds are believed to induce formation of a ternary complex between the target protein, the compound, and an E3 ligase. Formation of the ternary complex is then followed by ubiquitination of the target protein and degradation of the ubiquitinated target protein by a proteasome. Several E3 ligases have been used as the partner E3 ligase for heterobifunctional degraders. Herein, the cereblon (CRBN) E3 ligase (also referred to herein as a CRBN protein) is used.

[0038] Heterobifunctional compounds are further described in, for example, International Publication Nos. WO 2021 / 077010; WO 2022 / 221673; WO 2023 / 212147; WO 2023 / 240038; WO 2023 / 244917; WO 2023 / 244918; WO 2024 / 151557; WO 2023 / 114460; McCoull, William, et al., ACS Chemical Biology 13.11 (2018): 3131-3141, doi: 10.1021 / acschembio.8b00698; Chamberlain and Hamann, Nature Chemical Biology 15.10 (2019): 937-944, doi: 10.1038 / s41589-019-0362-y; Li and Song, Journal of Hematology & Oncology 13 (2020), doi: 10.1186 / sl3045-020-00885-3; Wu, et al. Nature Structural & Molecular Biology 27.7 (2020): 605-614, doi: 10.1038 / s41594-020-0438-0; Dong, et al., Journal of Medicinal Chemistry 64.15 (2021): 10606- 10620, doi: 10.1021 / acs.jmedchem.lc00895; Yang, et al., Targeted Oncology 16.1 (2021): 1-12, doi: 10.1007 / sl 1523-020-00782-2.

[0039] Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of polycomb repressive complex 2 (PRC2), which functions to methylate lysine 27 of histone H3 (H3K27) to promote transcriptional silencing. Point mutations of EZH2 in the C-terminal SET domain of EZH2 can confer gain of function of enzyme activity, resulting in increased levels of trimethylated H3K27 (H3K27me3) and thus repressed expression of PRC2 targets. These types of mutations have been observed in cancers such as germinal center B-cell (GCB) large B-cell lymphomas (LBCLs) and follicular lymphomas (FLs). In addition, EZH2 is overexpressed in many B-cell lymphomas. See, Docket No. TRLN-013-030W01 / TLS-068WO e.g., Morschhauser, Franck, et al. Blood Reviews 56 (2022): 100988, doi: 10.1016 / j.blre.2022.100988.

[0040] As part of the PRC2 complex, EZH2 functions to trimethylate lysine residues, both on histone H3 and non-histone targets, such as GATA4 and STAT3. In normal tissues, EZH2 suppresses differentiation by repressing lineage-specifying factors, and expression of EZH2 is believed to be essential to the maintenance of some cancer stem cell populations. In addition, PRC2-independent functions of EZH2 have been implicated in several disease models, including in castration-resistant prostate cancer and breast cancer. See, e.g., Kim, Kimberly H., and Charles WM Roberts. Nature Medicine 22.2 (2016): 128-134, doi: 10.1038 / nm.4036; Duan, Ran, Wenfang Du, andW eijian Guo. Journal of Hematology & Oncology 13.1 (2020), doi: 10.1186 / sl3045-020-00907-0. Although BCL6 and EZH2 are not known to interact directly, they cooperate to recruit a non-canonical PRC1 / BCOR complex that represses differentiation gene expression in GC B-cells, leading to acceleration of B-cell lymphoma development. See, e.g., Beguelin, Wendy, et al. Cancer Cell 30.2 (2016): 197-213, doi: 10.1016 / j.ccell.2016.07.006.

[0041] As is described and exhibited herein, the combination of a BCL6 degrader and an EZH2 inhibitor as described herein demonstrated an unexpected synergy in various models of B-cell lymphomas.

[0042] Methods of Treatment

[0043] Indications

[0044] Provided herein are methods for treating a cancer in a subject in need thereof, the methods comprising administering to the subject:

[0045] (a) a therapeutically effective amount of an EZH2 inhibitor; and

[0046] (b) a therapeutically effective amount of a compound of Formula (A) or Formula (I):

[0047] R1

[0048]

[0049] Formula (A) Docket No. TRLN-013-030W01 / TLS-068WO

[0050] O

[0051]

[0052] Formula (I)

[0053] or a pharmaceutically acceptable salt thereof,

[0054] wherein X3, m3, R1, R6, L, Ring C, TBM, Lc, and X are as defined herein.

[0055] In some embodiments, the cancer is a hematological malignancy.

[0056] In some embodiments, the hematological malignancy is a lymphoma. In some embodiments, the lymphoma is a non-Hodgkin lymphoma.

[0057] In some embodiments, the non-Hodgkin lymphoma is a B-cell lymphoma. In some embodiments, the B-cell lymphoma is a large B-cell lymphoma (LBCL). For example, the large B-cell lymphoma can be DLBCL-NOS. In some embodiments, the B-cell lymphoma is selected from the group consisting of follicular lymphoma (FL) and transformed FL.

[0058] In some embodiments, the non-Hodgkin lymphoma is a T-cell lymphoma. In some embodiments, the T-cell lymphoma is a peripheral T-cell lymphoma (PTCL). For example, the PTCL can be PTCL-NOS. In some embodiments, the PTCL is a nodal T follicular helper cell lymphoma. For example, the nodal T follicular helper cell lymphoma is selected from the group consisting of AITL (also known as nodal T follicular helper cell lymphoma angioimmunoblastic type; angioimmunoblastic T-cell lymphoma; nodal TFH cell lymphoma angioimmunoblastic; or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type; follicular type Tfh cell lymphoma; or nodal Tfh cell lymphoma, follicular type), and nodal T follicular helper cell lymphoma-NOS (also known as follicular helper T-cell lymphoma, NOS; nodal Tfh cell lymphoma, NOS; or Tfh not otherwise specified (NOS)). In some embodiments, the T-cell lymphoma is a CTCL.

[0059] In some embodiments, administering a therapeutically effective amount of an EZH2 inhibitor; and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof is first-line therapy, second-line therapy, or third-line (or beyond) therapy. In some embodiments, the second-line therapy can follow any of the first-line therapies provided herein. In some embodiments, the third-line (or beyond) therapy can follow any of the second-line therapies provided herein. Docket No. TRLN-013-030W01 / TLS-068WO In some embodiments, the hematological malignancy (e.g., the lymphoma) is relapsed or refractory.

[0060] As used herein, a cancer that is “relapsed or refractory” (sometimes denoted “r / r”, “R / R”, or “relapsed / refractory”) means that the cancer has returned or progressed after a period of remission or the cancer progressed or did not sufficiently respond to a treatment (e.g., a standard-of-care (SOC) treatment or a treatment that is not a combination of (i) an EZH2 inhibitor and (ii) a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof. In some embodiments, a cancer that is relapsed or refractory has no satisfactory alternative treatments. In some embodiments, a cancer that is relapsed or refractory has progressed following one or more prior lines of therapy (e.g., systemic therapy) (e.g., at least two prior lines of therapy; at least three prior lines of therapy; etc.). In some embodiments, a subject that has a cancer that is relapsed or refractory has failed at least one prior line of therapy (e.g., systemic therapy) (e.g., at least two prior lines of therapy; at least three prior lines of therapy; etc.).

[0061] LBCL is the most common large B-cell lymphoma and is also the most aggressive. In the US and Western Europe, LBCL accounts for 30 to 58% of all NHL cases (see, e.g., Tilly, H., et al. Annals of Oncology 26 (2015): vll6-vl25, doi: 10.1093 / annonc / mdv304). The annual incidence of LBCL in the US is approximately 5.5 per 100,000 persons and the death rate is 1.6 per 100,000 persons (SEER Cancer Stat Facts: Diffuse Large B-Cell Lymphoma. National Cancer Institute. Bethesda, MD. Available at: https: / / seer.cancer.gov / statfacts / html / dlbcl.html).

[0062] First-line therapy for LBCL is typically combination chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHP (rituximab, cyclophosphamide, doxorubicin, and prednisone) in combination with polatuzumab (see, e.g., Tilly, Herve, et al. New England Journal of Medicine 386.4 (2022): 351-363, doi: 10.1056 / NEJMoa2115304). While these therapies are associated with prolonged remissions and / or cure in >60% of patients, 10 to 15% of patients do not respond and 20 to 25% relapse (see, e.g., Abrisqueta, Pau. Journal of Clinical Medicine 13.7 (2024): 1929, doi: 10.3390 / jcml3071929). Patients who are refractory or who relapse have a poor prognosis (see, e.g., Vaidya, R., and T. E. Witzig. Annals of Oncology 25.11 (2014): 2124-2133, doi: 10.1093 / annonc / mdul09). Chimeric antigen receptor (CAR) T-cell therapies are approved for patients who are refractory to first-line chemoimmunotherapy or who relapse within 12 months; survival benefits have been reported (see, e.g., Bhaskar, Shakthi T., et al. Clinical Hematology International 6.4 (2024): 93, doi: 10.46989 / OOlc.124277; and Trabolsi, Asaad, Artavazd Arumov, and Jonathan H. Schatz. Blood Docket No. TRLN-013-030W01 / TLS-068WO Cancer Journal 14.1 (2024): 27, doi: 10.1038 / s41408-024-00997-w). However, disease burden, medical comorbidities, logistical challenges surrounding the production of an autologous product, and specialized supportive care requirements have limited the use of this modality (see, e.g., Hoffmann, Marc S., et al. Transplantation and Cellular Therapy 29.7 (2023): 440-448, doi: 10.1016 / j.jtct.2023.04.003). Bispecific antibodies to CD20 and CD3 are approved for LBCL in the third-line setting and trials are underway to explore their role in earlier lines of therapy (see, e.g., Trabolsi, Asaad, Artavazd Arumov, and Jonathan H. Schatz. Blood Cancer Journal 14.1 (2024): 27, doi: 10.1038 / s41408-024-00997-w).

[0063] Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) with an incidence rate of 2.2 cases per 100,000 persons and a death rate of 0.4 per 100,000 (SEER Cancer Stat Facts: Follicular Lymphoma. National Cancer Institute. Bethesda, MD. Available at: https: / / seer.cancer.gov / statfacts / html / follicular.html). FL exhibits a wide range of clinical behaviors due to its significant mutational heterogeneity. Asymptomatic patients with low disease burden may be managed through a watch and wait approach. Treatment is typically initiated when patients exhibit constitutional symptoms, evidence of organ compromise, or rapid disease progression. FL is generally considered incurable. Therefore, the typical goal of therapy is a longterm remission or durable disease control with well-tolerated treatment regimens. FL can transform into LBCL at an annualized risk of 2 to 3%, an outcome that is associated with diminished survival (see, e.g., Link, Brian K., et al. Journal of Clinical Oncology 31.26 (2013): 3272-3278, doi: 10.1200 / JC0.2012.48.3990; and Montoto, Silvia, and Jude Fitzgibbon. Journal of Clinical Oncology 29.14 (2011): 1827-1834, doi: 10.1200 / JC0.2010.32.7577).

[0064] Standard first-line therapies for FL include immunotherapy with an anti-CD20 antibody with or without chemotherapy (e.g., bendamustine, CHOP, or CVP [cyclophosphamide, vincristine sulfate, and prednisone]). No single treatment option is considered standard of care in the second-line setting. Options include anti-CD20 antibodies (e.g., rituximab or obinutuzumab) as a single agent or in combination with chemotherapy agents such as bendamustine. Lenalidomide and the radioimmunotherapy 90Y-ibritumomab tiuxetan are also approved for the treatment of R / R FL in the US. In later lines, zanubrutinib, bispecific antibodies, tazemetostat, and CAR-T therapies are approved. As patients progress through successive lines of therapy, they typically exhibit diminishing response rates and shorter disease-free intervals (see, e.g., Link, Brian K., et al. British Journal of Haematology 184.4 (2019): 660-663, doi: 10.1111 / bjh.15149; and Rivas-Delgado, Alfredo, et al. British Journal of Haematology 184.5 (2019): 753-759, doi: 10.1111 / bjh.15708).

[0065] In some cases, a FL can undergo a histologic transformation, wherein the neoplastic B-cell clone evolves to acquire the morphologic and phenotypic features of a more aggressive lymphoma, Docket No. TRLN-013-030W01 / TLS-068WO referred to herein as a “transformed FL” (also referred to as “transformed lymphoma from FL” or “tFL”). While in most cases, the transformation is to a LBCL, the transformation can also result in a Burkitt lymphoma, lymphoblastic lymphoma, acute lymphoblastic leukemia, and Hodgkin lymphoma. See, e.g., Fischer, Thais, et al. Annals of Hematology 97.1 (2018): 17-29, doi: 10.1007 / s00277-017-3151-2. Patients presenting with a transformed FL are often treated with a rituximab-chemotherapy combination, such as R-CHOP or pola-R-CHP. See, e.g., Parry, Erin M., and Jessica Okosun. B / c 146.15 (2025): 1812-1823, doi: 10.1182 / blood.2024026016.

[0066] Peripheral T-Cell Lymphoma (PTCL) is a rare and heterogenous subgroup of T-cell NHL comprised of over 2 dozen subtypes (see, e.g., Cai, Zhuo Ran, et al. JAMA Oncology 8.11 (2022): 1690-1692, doi: 10.1001 / jamaoncol.2022.3236; Marchi, Enrica, and Owen A. O’Connor. CA: A Cancer Journal for Clinicians 70.1 (2020): 47-70, doi: 10.3322 / caac.21589; Adams, Scott V., Polly A. Newcomb, and Andrei R. Shustov. Journal of Clinical Oncology 34.9 (2016): 963-971, doi: 10.1200 / JC0.2015.63.5540; and Teras, Lauren R., et al. CA: A Cancer Journal for Clinicians 66.6 (2016): 443-459, doi: 10.3322 / caac.21357). The T-follicular helper (Tfh) cell lymphomas are subtypes of PTCL and include AITL, follicular type, and Tfh not otherwise specified (NOS) (see, e.g., Feldman, Andrew L., et al. Virchows Archiv 482.1 (2023): 265-279, doi: 10.1007 / s00428-022-03412-6; Ngu, Henry S., and Kerry J. Savage. American Society of Clinical Oncology Educational Book 43 (2023): e390334, doi: 10.1200 / EDBK 390334; and Epstein-Peterson, Zachary D., and Steven M. Horwitz. Seminars in Hematology. Vol. 58. No. 2. WB Saunders, 2021, doi: 10.1053 / j.seminhematol.2021.02.004). AITL is the most common of these with an incidence of 0.05 per 100,000 persons in the US (see, e.g., Federico, Massimo, et al. Journal of Clinical Oncology 31.2 (2013): 240-246, doi: 10.1200 / JC0.2011.37.3647). The prognosis after a PTCL diagnosis remains poor, with a 70% relapse rate after initial therapy and 2- and 5-year overall survival (OS) rates of 45% and 35%, respectively (see, e.g., Maurer, Matthew J., et al. Journal of Clinical Oncology 35.36 (2017): 4019-4026, doi: 10.1200 / JC0.2017.73.8195; Bellei, Monica, et al. Haematologica 103.7 (2018): 1191, doi: 10.3324 / haematol.2017.186577; Horwitz, Steven M., et al. Journal of the National Comprehensive Cancer Network 20.3 (2022): 285-308, doi: 10.6004 / jnccn.2022.0015; Sibon, David. Cancers 14.9 (2022): 2332, doi: 10.3390 / cancersl4092332; and Ngu, Henry S., and Kerry J. Savage. American Society of Clinical Oncology Educational Book 43 (2023): e390334, doi: 10.1200 / EDBK_390334).

[0067] First-line therapy for PTCL typically consists of a combination chemotherapy regimen, such as CHOP, CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone; also called EPOCH) or other multidrug regimens (see, e.g., Horwitz, Steven M., et al. Journal of the National Comprehensive Cancer Network 20.3 (2022): 285-308, doi: 10.6004 / jnccn.2022.0015). For patients with CD30+ PTCL, brentuximab vedotin in combination Docket No. TRLN-013-030W01 / TLS-068WO with chemotherapy was shown to confer a survival benefit compared to chemotherapy alone (Horwitz S, O'Connor OA, Pro B, et al. [published correction appears in Lancet. 2019 Jan 19;393(10168):228. doi: 10.1016 / S0140-6736(18)33123-4], Lancet. 2019;393(10168):229-240. doi:10.1016 / S0140-6736(18)32984-2). In R / R disease, second-line chemotherapy regimens and hematopoietic stem cell transplantation may also be considered (see, e.g., Du, Jun, et al. JAMA Network Open 4.5 (2021): e219807-e219807, doi: 10.1001 / jamanetworkopen.2021.9807). Other therapies for Tfh PTCL subtypes include belinostat and pralatrexate. However, these agents carry modest response rates (-25%) with durations of response less than one year. National Comprehensive Cancer Network (NCCN) guidelines recommend a clinical trial as the preferred option for R / R T-cell lymphoma (see, e.g., National Comprehensive Cancer Network. NCCN Guidelines: T-cell lymphomas Version 1.2025. 2025. https: / / www.nccn.org / professionals / physician_gls / pdf / t-cell.pdf).

[0068] The World Health Organization (WHO) and the International Consensus Classification (ICC) systems emphasize the identification of the tumor cell of origin (COO) — either germinal center derived B-cells (GCB) or activated B-cell (ABC or non-GCB) — as central to subclassifying B-cell lymphomas (see, e.g., Alaggio, Rita, et al. Leukemia 36.7 (2022): 1720-1748, doi: 10.1038 / s41375-022-01620-2; Campo E, Jaffe ES, Cook JR, et al. [published correction appears in Blood 2023 Jan 26;141(4):437, doi: 10.1182 / blood.2022019016], Blood. 2022;140(ll):1229- 1253, doi:10.1182 / blood.2022015851; and Cho, Junhun. Blood Research 57. SI (2022): 55-61, doi: 10.5045 / br.2022.2022037). COO can be determined through immunohistochemical (IHC) testing.

[0069] Pathologists often rely on diagnostic algorithms that include various IHC markers, such as BCL6, CD20, CD10, BCL2, MUM1 and Ki-67 to diagnose and classify NHLs based on COO (see, e.g., Hans, Christine P., et al. Blood 103.1 (2004): 275-282, doi: 10.1182 / blood-2003-05- 1545; Choi, William WL, et al. Clinical Cancer Research 15.17 (2009): 5494-5502, doi: 10.1158 / 1078-0432. CCR-09-0113; Meyer, Paul N., et al. Journal of Clinical Oncology 29.2 (2011): 200-207, 10.1200 / JC0.2010.30.0368; and Santhosh, Akhil, and Ajay Gogia. Cancer Research, Statistics, and Treatment 5 A (2022): 792-793, doi: 10.4103 / crst.crst_247_22 ). Although molecular typing methods provide an alternative, the IHC -based Hans algorithm is a common workup in clinical practice (see, e.g., Meyer, Paul N., et al. Journal of Clinical Oncology 29.2 (2011): 200-207, 10.1200 / JC0.2010.30.0368; and Abdulla, Maysaa, et al. American Journal of Hematology 95.1 (2020): 57-67, doi: 10.1002 / ajh.25666). Hans defines BCL6 positivity as >30% nuclear staining in tumor cells (see, e.g., Hans, Christine P., et al. Blood 103.1 (2004): 275-282, doi: 10.1182 / blood-2003-05-1545). BCL6 status is also generally part of the diagnostic workup of FL. The ICC recommends BCL6 IHC to help distinguish between Docket No. TRLN-013-030W01 / TLS-068WO FL grade 3a and 3b (see, e.g., Alaggio, Rita, et al. Leukemia 36.7 (2022): 1720-1748, doi: 10.1038 / s41375-022-01620-2; Campo E, Jaffe ES, Cook JR, et al. [published correction appears in Blood. 2023 Jan 26;141(4):437. doi: 10.1182 / blood.2022019016], Blood. 2022; 140(11): 1229- 1253. doi:10.1182 / blood.2022015851; and Fenu, Elena M., et al. EJHaem 4.4 (2023): 1176, doi: 10.1002 / jha2.737). NCCN guidelines for B-cell lymphomas and T-cell lymphomas list BCL6 staining by IHC as important to establishing a diagnosis for LBCL and FL National Comprehensive Cancer Network, (see, e.g., NCCN Guidelines: B-Cell Lymphomas Version 1.2025. 2025. https: / / www.nccn.org / professionals / physician_gls / pdf / b-cell.pdf).

[0070] Additional details of BCL6 and EZH2 biology and chemistry, as well as discussions of the various cancers described herein, are disclosed in, e.g., Cerchietti, Leandro C., et al. Cancer Cell 17.4 (2010): 400-411, doi: 10.1016 / j.ccr.2009.12.050; Pearce, Andrew C., et al. Journal of Biological Chemistry 297.2 (2021), doi: 10.1016 / j.jbc.2021.100928; Li, Chen, et al. Clinical Epigenetics 13 (2021), doi: 10.1186 / s 13148-021 -01045- 1; Straining, Rachael, and William Eighmy. Journal of the Advanced Practitioner in Oncology 13.2 (2022): 158, doi: 10.6004 / jadpro.2022.13.2.7); Drescher, Charles, et al. Journal of Clinical Oncology (2023): 3094-3094, doi: 10.1200 / JC0.2023.41.16_suppl.3094; Hong, Huangming, et al. Blood 142 (2023): 304, doi: 10.1182 / blood-2023-180372; Izutsu, Koji, et al. Blood 141.10 (2023): 1159-1168, doi: 10.1182 / blood.2022016862; Velichutina, Irina, et al. Blood, The Journal of the American Society ofHematology 116.24 (2010): 5247-5255, doi: 10.1182 / blood-2010-04-280149; and Caganova M, Carrisi C, Varano G, et al. [published correction appears in J Clin Invest. 2014 Apr 1; 124(4): 1869], J Clin Invest. 2013;123(12):5009-5022. doi:10.1172 / JCI7062; Baron, Beverly W., et al. Proceedings of the National Academy of Sciences 101.39 (2004): 14198-14203, doi: 10.1073 / pnas.0406138101; Cattoretti, Giorgio, et al. Cancer Cell 7.5 (2005): 445-455, doi: 10.1016 / j.ccr.2005.03.037; Caganova M, Carrisi C, Varano G, et al. [published correction appears in J Clin Invest. 2014 Apr 1; 124(4): 1869]. J Clin Invest. 2013;123(12):5009-5022. doi:10.1172 / JCI7062; McCabe, Michael T., et al. Nature 492.7427 (2012): 108-112; doi: 10.1038 / nature11606; Knutson, Sarah K., et al. Nature Chemical Biology 8.11 (2012): 890-896, doi: 10.1038 / nchembio.1084; Campo E, Jaffe ES, Cook JR, et al. [published correction appears in Blood. 2023 Jan 26;141(4):437. doi: 10.1182 / blood.2022019016], Blood. 2022; 140(11): 1229- 1253. doi: 10.1182 / blood.2022015851; Ondrejka, Sarah L., et al. Virchows Archiv 483.3 (2023): 349-365, doi: 10.1007 / s00428-023-03607-5); de Leval, Laurence, Philippe Gaulard, and Ahmet Dogan. Blood 144.18 (2024): 1855-1872, doi: 10.1182 / blood.2023021786). NCCN guidelines for T-cell lymphomas also list BCL6 staining by IHC as important to establishing a diagnosis for PTCL (see, e.g., National Comprehensive Cancer Network. NCCN Guidelines: T-cell lymphomas Version 1.2025. 2025. https: / / www.nccn.org / professionals / physician_gls / pdf / t-cell.pdf).; Iqbal, Docket No. TRLN-013-030W01 / TLS-068WO Javeed, et al. Leukemia 21.11 (2007): 2332-2343, doi: 10.1038 / sj. leu.2404856; Shustik, Jesse, et al. Haematologica 95.1 (2009): 96, doi: 10.3324 / haematol.2009.007203; Horn, Heike, et al. Blood, The Journal of the American Society of Hematology 121.12 (2013): 2253-2263, doi: 10.1182 / blood-2012-06-435842; Bellas, Carmen, et al. PloS one 9.6 (2014): e98169, doi: 10.1371 / journal. pone.0098169; Szumera-Ciećkiewicz, Anna, et al. International Journal of Laboratory Hematology 42.4 (2020): 453-463, doi: 10.1111 / ijlh.13222; Alaggio, Rita, et al. Leukemia 36.7 (2022): 1720-1748, doi: 10.1038 / s41375-022-01620-2; Sordi, Benedetta, et al. Blood 144 (2024): 4451, doi: 10.1182 / blood-2024-210657; Van Acker, Anna, et al. Cancer Research 85.8_Supplement_l (2025): 1655-1655, doi: 10.1158 / 1538-7445. AM2025-1655; Morschhauser, F., et al. Hematological Oncology 43 (2025): e91_70093, doi: 10.1002 / hon.70093_91; Van Acker, A., et al. Hematological Oncology 43 (2025): e806_70096, doi: 10.1002 / hon.70096_806; Van Acker, A., et al. Hematological Oncology 43 (2025): e430_70094, doi: 10.1002 / hon.70094_430.

[0071] Various biomarkers can be used to identify subjects as being in need of the methods provided herein and / or to monitor treatment following administration of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a- 5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof (e.g., in combination with the EZH2 inhibitor). Such biomarkers include protein expression levels (e.g., BCL6 expression levels), mutation analysis (e.g., EZH2 mutation and / or clonal hematopoiesis (CH)), DNA, RNA, and expression of BCL6 target genes. Exemplary assays used to identify and quantify these biomarkers include immunohistochemistry (IHC), flow cytometry, NanoString, RNA-seq, ctDNA, phased variant enrichment and detection sequencing (PhasED-seq), clonoSEQ, and next-generation sequencing (NGS). Samples from the subject that can be tested include tumor tissues, peripheral blood, and normal tissues. For example, samples can include lymph node biopsies, blood (e.g., whole blood, isolated plasma, peripheral blood, PBMCs), fingernail s / toenails, saliva, buccal swab, and extracted DNA. In some embodiments, a BCL6 expression level can be determined for a sample from a subject. In some embodiments, a BCL6 expression level can be determined by expression profiling (e.g., mRNA expression profiling) (e.g., of a sample of the cancer or from a blood sample). In some embodiments, a BCL6 expression level can be determined by an mRNA-based test, such as RNA sequencing (RNA-seq), reverse transcription polymerase chain reaction (RT-PCR), digital PCR (dPCR), or in-situ hybridization (ISH).

[0072] As used herein, “determining the BCL6 status,” means assessing whether the cancer is BCL6+, e.g., at the mRNA or protein level. In some embodiments, the assessment includes Docket No. TRLN-013-030W01 / TLS-068WO determining the level of BCL6 expression (e.g., BCL6 expression above or below a threshold value). BCL6 expression status can be assessed by a variety of methods (e.g., measuring protein levels, mRNA levels, or both) and can be assessed quantitatively or qualitatively, e.g., using a scale or threshold value accepted by, e.g., a regulatory agency or by a pathologist. In some embodiments, the assessment includes consulting the medical record of a subject (e.g., reviewing or searching (e.g., electronic searching) the medical record of a subject). In some embodiments, the BCL6 expression status is positive (e.g., the sample from the subject is BCL6+). Similarly, “determining that the hematological malignancy (e.g., lymphoma) in the subject is BCL6+” means that the BCL6 status of the hematological malignancy (e.g., lymphoma) is positive for BCL6 expression.

[0073] In some embodiments, a BCL6 status can be determined for a sample from a subject. In some embodiments, the BCL6 status can be determined by expression profiling (e.g., mRNA expression profiling) (e.g., of a sample of the cancer or from a blood sample). In some embodiments, the BCL6 status can be determined by an mRNA-based test, such as RNA sequencing (RNA-seq), reverse transcription polymerase chain reaction (RT-PCR), digital PCR (dPCR), or in-situ hybridization (ISH). In some embodiments, the BCL6 status can be determined by a protein-based test, such as immunohistochemistry (IHC) or liquid chromatography tandem mass spectrometry (LC-MS / MS)). In some embodiments, the BCL6 status can be determined by an IHC test, using any appropriate IHC method and reagents. In some cases, a diagnosis of a mature B-cell neoplasm (e.g., FL or a large B-cell lymphoma (e.g., DLBCL-NOS)) is made by a pathologist using a diagnostic algorithm that includes IHC markers like BCL6, CD20, CD 10, BCL2, MUM1 and / or Ki-67, such as the Hans algorithm. The Hans algorithm includes BCL6 as a determinant of germinal center cell of origin and defines BCL6 positivity as 30% or greater nuclear staining in tumor cells by IHC. See, e.g., Hans, Christine P., et al. Blood 103.1 (2004): 275-282, doi: 10.1182 / blood-2003-05-1545 and Choi, William WL, et al. Clinical Cancer Research 15.17 (2009): 5494-5502, doi: 10.1158 / 1078-0432. CCR-09-0113.

[0074] Accordingly, also provided herein are methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a non-Hodgkin lymphoma (NHL))) in a subject in need thereof, the methods comprising (a) determining the BCL6 status of the cancer (e.g., by performing an assay or a test, or consulting the subject’s medical record); and (b) administering to the subject a therapeutically effective amount of an EZH2 inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb- 2))), or a pharmaceutically acceptable salt thereof. Docket No. TRLN-013-030W01 / TLS-068WO Also provided herein are methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a non-Hodgkin lymphoma (NHL))) in a subject in need thereof, the methods comprising: (a) determining that the cancer in the subject is BCL6+ (e.g., determining that the cancer is BCL6+ by an IHC test (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or by a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test)); and (b) administering to the subject a therapeutically effective amount of an EZH2 inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer in the subject has an EZH2 dysregulation. In some embodiments, the cancer in the subject does not have an EZH2 dysregulation.

[0075] In some embodiments, the hematological malignancy (e.g., the lymphoma) is BCL6 positive (also referred to herein as “BCL6+”, “positive for BCL6 expression”, or “BCL6-expressing”). As used herein, “BCL6+” means that a sample from the subject is BCL6-expressing as determined by an appropriate test. Non-limiting examples of appropriate tests include IHC, mass spectrometry (e.g., liquid chromatography tandem mass spectrometry (LC-MS / MS)), and RNA-seq. The hematological malignancy (e.g., the lymphoma) can be determined to be BCL6+ by an IHC test, and in some embodiments, the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 1% (e.g., greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 40%, or greater than or equal to 50%) for the hematological malignancy (e.g., the lymphoma).

[0076] For example, “BCL6+” can mean that (1) a sample from the subject has a percent nuclear positivity score for BCL6 of greater than or equal to 1% (e.g., greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 15%, greater than or equal to 20%, greater than or equal to 25%, greater than or equal to 30%, greater than or equal to 35%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 55%, greater than or equal to 60%, greater than or equal to 65%, greater than or equal to 70%, greater than or equal to 75%, greater than or equal to 80%, greater than or equal to 85%, or greater than or equal to 90% (e.g., greater than or equal to 1%, greater than or equal to 20%, greater than or equal to 30%, or greater than or equal to 90%), as determined by an IHC test; and / or (2) a sample from the subject has an H-score for BCL6 of greater than or equal to 3 (e.g., greater than or equal to 5, greater than or equal to 10, Docket No. TRLN-013-030W01 / TLS-068WO greater than or equal to 20, greater than or equal to 30, greater than or equal to 60, greater than or equal to 90, greater than or equal to 100, greater than or equal to 130, greater than or equal to 150, greater than or equal to 160, greater than or equal to 190, greater than or equal to 200, greater than or equal to 230, greater than or equal to 250, or greater than or equal to 270 (e.g., greater than or equal to 1, greater than or equal to 20, greater than or equal to 30, greater than or equal to 230, or greater than or equal to 270). In some embodiments, the test is an FDA-approved test.

[0077] In some embodiments, a sample from the subject has a percent nuclear positivity score for BCL6 of 1% to 29% by IHC. In some embodiments, a sample from the subject has a percent nuclear positivity score for BCL6 of 30% to 100% by IHC. For clarity, a percent nuclear positivity score for BCL6 of 1% to 29% by IHC is sometimes referred to by those of skill in the art as “BCL6 negative” or “BCL6 low”, as compared to a percent nuclear positivity score for BCL6 of 30% or greater by IHC that is sometimes referred to as “BCL6 positive” by those of skill in the art (see, e.g., Hans, Christine P., et al. Blood 103.1 (2004): 275-282, doi: 10.1182 / blood-2003-05-1545; and Franco, Renato, et al. Oncotarget 7.37 (2016): 59158, doi: 10.18632 / oncotarget.10993). In some embodiments, a sample from the subject has a percent nuclear positivity score for BCL6 of 0% by IHC.

[0078] In some embodiments, the hematological malignancy (e.g., lymphoma) is BCL6 positive (BCL6+). For example, the lymphoma can be BCL6+ as determined by an IHC test. In some embodiments, the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 25% (e.g., greater than or equal to 30%) for the hematological malignancy (e.g., the lymphoma). In some embodiments, the hematological malignancy (e.g., the lymphoma) has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the hematological malignancy (e.g., the lymphoma) is BCL6+ (e.g., as determined by an IHC test) and has an EZH2 dysregulation (e.g., an EZH2 mutation).

[0079] As another example, an IHC test can result in a percent nuclear positivity score for BCL6 from 0% to 100%. In some such embodiments, BCL6+ status can be indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% (e.g., greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 15%, or greater than or equal to 20%) (e.g., as determined by a pathologist or an automated system). In some embodiments, BCL6+ status can be indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 30% (e.g., greater than or equal to 35%, greater than or equal to 40%, or greater than or equal to 50%) (e.g., as determined by a pathologist or an automated system). See, e.g., Hans, Christine P., et al. Blood 103.1 (2004): 275-282, doi: 10.1182 / blood-2003-05- 1545. In some embodiments, the sample from the subject can have a BCL6 percent nuclear positivity score for BCL6 of greater than or equal to Docket No. TRLN-013-030W01 / TLS-068WO 75% (e.g., greater than or equal to 80%, greater than or equal to 90%, or greater than or equal to 95%) (e.g., as determined by a pathologist or an automated system). As another example, an IHC test can result in an H-score from 0 to 300; in some such embodiments, BCL6+ status can be indicated by an H-score of greater than or equal to 10 (e.g., greater than or equal to 50, greater than or equal to 75, greater than or equal to 100, greater than or equal to 150, greater than or equal to 200). In some embodiments, an H-score is calculated as 3 x percentage of strongly staining nuclei + 2 x percentage of moderately staining nuclei + percentage of weakly staining nuclei.

[0080] For example, a pathologist or an automated system (e.g., the BOND RX system (Leica), the BOND-PRIME system (Leica), the AutoStainer Link 48 system (Agilent), the AutoStainer PLUS system (Agilent), the Dako Omnis system (Agilent), the BenchMark ULTRA system (Roche), or the BenchMark ULTRA PLUS system (Roche)) can determine that a sample of the cancer (e.g., a biopsy sample (e.g., a fresh biopsy sample or an archival biopsy sample)) from the subject subjected to IHC with an appropriate BCL6 antibody is BCL6+. In some embodiments, the sample can be an archival biopsy sample (e.g., an archival biopsy sample collected after the last previous line of therapy and prior to the first dose of an EZH2 inhibitor, the first dose of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, or both). Non-limiting examples of antibodies suitable for an IHC test of BCL6 expression include clone PG-B6p (e.g., Dako / Agilent product number IR625), clone GH91E / A8 (e.g., Roche / Ventana product number 760-4241), clone LN22 (e.g., Leica Biosystems product number PA0204), clone GH91E / A8 (e.g., Sigma / Cell Marque product number 227M-98), and clone EP278 (e.g., Sigma / Cell Marque product number 227R-27). An IHC test can result in a percent nuclear positivity score from 0% to 100%.

[0081] Also provided herein are methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))), the methods comprising administering to a subject determined to have a cancer that is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or by a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test, or determined by consulting the subject’s medical record) a therapeutically effective amount of an EZH2 inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), Docket No. TRLN-013-030W01 / TLS-068WO (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0082] Also provided herein are methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))), the methods comprising administering to a subject who has a record (e.g., a medical record) that indicates that the cancer in the subject is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or by a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test) a therapeutically effective amount of an EZH2 inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb- 2))), or a pharmaceutically acceptable salt thereof.

[0083] Also provided herein are methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))), the methods comprising administering a therapeutically effective amount of an EZH2 inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a- 3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to a subject determined to have a cancer that is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or by a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test).

[0084] In some embodiments, provided herein are methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject that include performing an assay on a sample (e.g., a tumor sample) obtained from the subject to determine that the cancer in the subject is BCL6+, and administering a therapeutically effective amount of an EZH2 inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject having a cancer determined to be BCL6+.

[0085] In some embodiments, provided herein are methods for treating a cancer (e.g., a Docket No. TRLN-013-030W01 / TLS-068WO hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject that include performing an assay on a sample (e.g., a tumor sample) obtained from the subject to determine the BCL6 expression status of the cancer, and administering a therapeutically effective amount of an EZH2 inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject.

[0086] In some embodiments of the methods herein, the cancer (e.g., the hematological malignancy (e.g., the lymphoma (e.g., the NHL))) in the subject is BCL6+. In some embodiments, the cancer in the subject has an EZH2 dysregulation. In some embodiments, the cancer in the subject does not have an EZH2 dysregulation.

[0087] In some embodiments, provided herein are methods for treating a relapsed or refractory B-cell lymphoma in a subject in need thereof, the methods comprising administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, wherein the relapsed or refractory B-cell lymphoma is selected from the group consisting of: a relapsed or refractory large B-cell lymphoma (LBCL), a relapsed or refractory follicular lymphoma (FL), and a relapsed or refractory transformed FL.

[0088] In some embodiments, provided herein are methods for treating a relapsed or refractory BCL6+ B-cell lymphoma in a subject in need thereof, the methods comprising i) determining that the subject has a relapsed or refractory BCL6+ B-cell lymphoma; and ii) based on i), administering to the subj ect: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, provided herein are methods for treating a relapsed or refractory B-cell lymphoma in a subject in need thereof, the methods comprising i) determining that the subject has a relapsed or refractory B-cell lymphoma having an EZH2 dysregulation; and ii) based on i), administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula Docket No. TRLN-013-030W01 / TLS-068WO (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, wherein the relapsed or refractory B-cell lymphoma is a relapsed or refractory large B-cell lymphoma (LBCL) or relapsed or refractory FL.

[0090] In some embodiments, provided herein are methods for treating a relapsed or refractory T-cell lymphoma in a subject in need thereof, the methods comprising administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, provided herein are methods for treating a relapsed or refractory BCL6+ T-cell lymphoma in a subject in need thereof, the methods comprising i) determining that the subject has a relapsed or refractory BCL6+ T-cell lymphoma; and ii) based on i), administering to the subj ect: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof).

[0092] In some embodiments, provided herein are methods for treating a relapsed or refractory PTCL in a subject in need thereof, the methods comprising administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, provided herein are methods for treating a relapsed or refractory BCL6+ PTCL in a subject in need thereof, the methods comprising i) determining that the subject has a relapsed or refractory BCL6+ PTCL; and ii) based on i), administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof. Docket No. TRLN-013-030W01 / TLS-068WO In some embodiments, provided herein are methods for treating a CTCL in a subject in need thereof, the methods comprising administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof

[0094] In some embodiments, provided herein are methods for treating a BCL6+ CTCL in a subject in need thereof, the methods comprising i) determining that the subject has a BCL6+ CTCL; and ii) based on i), administering to the subject: (a) a therapeutically effective amount of an EZH2 inhibitor; and (b) a therapeutically effective amount of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the cancer is a LBCL (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with llq aberrations, or HGBCL-NOS).

[0096] In some embodiments, the cancer is a transformed indolent B-cell lymphoma (e.g., transformed FL or Richter transformation of CLL).

[0097] In some embodiments, the cancer is follicular lymphoma (FL).

[0098] In some embodiments, the cancer is transformed FL.

[0099] In some embodiments, the cancer is BL.

[0100] In some embodiments, the cancer is nodular lymphocyte predominant Hodgkin lymphoma (NLPHL).

[0101] In some embodiments, the cancer is a peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma), nodal T follicular helper cell lymphoma (also referred to herein as nodal Tfh cell lymphoma) (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as nodal T follicular helper cell lymphoma angioimmunoblastic type; angioimmunoblastic T-cell lymphoma; nodal Tfh cell lymphoma angioimmunoblastic; or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, Docket No. TRLN-013-030W01 / TLS-068WO follicular type; follicular type Tfh cell lymphoma; or nodal Tfh cell lymphoma, follicular type), or nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS; nodal Tfh cell lymphoma, NOS; or Tfh not otherwise specified (NOS)))) or a primary cutaneous T-cell lymphoid proliferation or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, Sezary syndrome, or primary cutaneous gamma-delta T-cell lymphoma).

[0102] In some embodiments, the cancer is BCL6+ as determined by an IHC test (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test).

[0103] In some embodiments, the cancer (e.g., the hematological malignancy (e.g., the lymphoma (e.g., the NHL))) in the subject has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the cancer in the subject has wild-type EZH2. In some embodiments, the cancer in the subject does not have an EZH2 dysregulation.

[0104] Also provided herein are methods for treating a hematological malignancy (e.g., a relapsed or refractory hematological malignancy or a lymphoma) in a subject in need thereof, the methods comprising administering to the subject:

[0105] (a) a therapeutically effective amount of an EZH2 inhibitor; and

[0106] (b) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the hematological malignancy (e.g., the lymphoma) has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the hematological malignancy (e.g., the lymphoma) is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or by a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test) and has an EZH2 dysregulation (e.g., an EZH2 mutation).

[0108] In some embodiments, the EZH2 dysregulation comprises an EZH2 mutation. In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, an EZH2 A692X mutation, or a combination thereof. For example, the EZH2 dysregulation can be an EZH2 Y646C mutation, an EZH2 Y646F mutation, an EZH2 Docket No. TRLN-013-030W01 / TLS-068WO Y646H mutation, an EZH2 Y646N mutation, an EZH2 Y646S mutation, an EZH2 Y666N mutation, an EZH2 A682G mutation, an EZH2 A692V mutation, or a combination thereof. In some embodiments, the EZH2 dysregulation comprises an EZH2 mutation selected from the group consisting of an EZH2 Y646X mutation, an EZH2 A682X mutation, and an EZH2 Y692X mutation. For example, the EZH2 dysregulation comprises an EZH2 mutation selected from the group consisting of an EZH2 Y646C mutation, an EZH2 Y646F mutation, an EZH2 Y646H mutation, an EZH2 Y646N mutation, an EZH2 Y646S mutation, an EZH2 A682G mutation, and an EZH2 Y692V mutation.

[0109] In some embodiments, the hematological malignancy (e.g., the lymphoma) in the subject has wild-type EZH2. In some embodiments, the hematological malignancy (e.g., the lymphoma) in the subject does not have an EZH2 dysregulation.

[0110] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose selected from the group consisting of: 50 mg, 100 mg, 150 mg, 160 mg, 240 mg, 250 mg, 300 mg, and 310 mg. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 25 mg, 50 mg, 75 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 25 mg, 50 mg, 75 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg) twice per day.

[0111] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered Docket No. TRLN-013-030W01 / TLS-068WO at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, or 150 mg (e.g., 25 mg, 50 mg, 75 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. For example, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, or 150 mg (e.g., 25 mg, 50 mg, 75 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day. For example, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg twice per day.

[0112] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose selected from the group consisting of: 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg once or twice per day. In some embodiments, the dose is administered once a day. In some embodiments, the dose is administered twice a day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a Docket No. TRLN-013-030W01 / TLS-068WO dose of 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0113] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 25 mg, 50 mg, 75 mg, 100 mg, or 150 mg once or twice per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 25 mg, 50 mg, 75 mg, 100 mg, or 150 mg once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a- 4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 25 mg, 50 mg, 75 mg, 100 mg, or 150 mg twice per day.

[0114] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 25 mg once or twice per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a- 5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 25 mg once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 25 mg twice per day.

[0115] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered Docket No. TRLN-013-030W01 / TLS-068WO at a dose of 30 mg once or twice per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 30 mg once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 30 mg twice per day.

[0116] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg once or twice per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg twice per day.

[0117] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 70 mg once or twice per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 70 mg once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula Docket No. TRLN-013-030W01 / TLS-068WO (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 70 mg twice per day.

[0118] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 75 mg once or twice per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 75 mg once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 75 mg twice per day.

[0119] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg once or twice per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg twice per day.

[0120] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered Docket No. TRLN-013-030W01 / TLS-068WO at a dose of 150 mg once or twice per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg twice per day.

[0121] In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered with food. For example, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, can be administered within 30 minutes of starting a meal. In some embodiments, administration of any acid reducing agent (e.g., antacids, H2 blockers, and proton pump inhibitors (PPIs)) is stopped at least 1 week prior to the first dose of the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, through the duration of treatment with the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0122] Provided herein are methods for treating a hematological malignancy (e.g., a relapsed or refractory hematological malignancy or a lymphoma) in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof. Docket No. TRLN-013-030W01 / TLS-068WO In some embodiments, the hematological malignancy is a lymphoma. In some embodiments, the lymphoma is a non-Hodgkin lymphoma.

[0123] In some embodiments, the non-Hodgkin lymphoma is a B-cell lymphoma. In some embodiments, the B-cell lymphoma is a large B-cell lymphoma (LBCL). For example, the large B-cell lymphoma can be DLBCL-NOS. In some embodiments, the B-cell lymphoma is selected from the group consisting of follicular lymphoma (FL) and transformed FL.

[0124] In some embodiments, the non-Hodgkin lymphoma is a T-cell lymphoma. In some embodiments, the T-cell lymphoma is a peripheral T-cell lymphoma (PTCL). For example, the PTCL can be PTCL-NOS. In some embodiments, the PTCL is a nodal T follicular helper cell lymphoma. For example, the nodal T follicular helper cell lymphoma is selected from the group consisting of AITL, nodal T follicular helper cell lymphoma follicular type, and nodal T follicular helper cell lymphoma-NOS. In some embodiments, the T-cell lymphoma is CTCL.

[0125] As used herein a “nodal T follicular helper cell lymphoma” (also referred to as a “Tfh PTCL” or “Tfh lymphoma” or “nodal Tfh cell lymphoma”, where “Tfh” and “TFH” are used interchangeably) is a T-cell lymphoma that is positive for at least two of the following Tfh cell markers by an IHC assay: CD10, BCL6, PD1 (also known as CD279), CXCL13, and ICOS. See, e.g., National Comprehensive Cancer Network. NCCN Guidelines: T-cell lymphomas Version 1.2025. 2025. https: / / www.nccn.org / professionals / physician_gls / pdf / t-cell.pdf.

[0126] In some embodiments, the hematological malignancy (e.g., the lymphoma) is relapsed or refractory.

[0127] In some embodiments, the hematological malignancy (e.g., the lymphoma) has wild-type EZH2. In some embodiments, the hematological malignancy (e.g., the lymphoma) does not have an EZH2 dysregulation.

[0128] Also provided herein are methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject in need thereof, the methods comprising: (a) determining that the cancer in the subject has an EZH2 dysregulation (e.g., an EZH2 mutation); and (b) administering to the subject: (i) a therapeutically effective amount of an EZH2 inhibitor; and (ii) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the cancer has an EZH2 dysregulation (e.g., an EZH2 mutation). In an aspect of this embodiment, the EZH2 dysregulation is a mutation at residue 27, residue 34, residue 59, residue 141, residue 162, residue 172, residue 197, residue 238, residue 239, residue 246, residue 395, residue 401, residue 452, residue 510, residue 516, residue 556, residue 583, Docket No. TRLN-013-030W01 / TLS-068WO residue 618, residue 644, residue 646, residue 666, residue 682, residue 690, residue 692, residue 716, residue 732, residue 744, residue 745, or a combination thereof, relative to SEQ ID NO. 1. In another aspect of this embodiment, the EZH2 dysregulation is a fusion or translocation. In another aspect of this embodiment, the EZH2 mutation is R27*, R34*, E59*, Q141*, El 62*, V172Cfs*l 1, E197Rfs*12, E238*, E239*, E246*, G395Efs*29, E401Kfs*22, E401*, Y452*, K510Yfs*3, X516_splice, S556*, R583*, X618_splice, S644*, Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, R690G, R690H, A692V, F716Lfs*24, X732_splice, I744Mfs*25, E745Afs*24, EZH2-AUTS2, EZH2-TMEM176B, GALNT11-EZH2, or a combination thereof.

[0130] In some embodiments, the cancer has an EZH2 mutation at a residue selected from the group consisting of residue 646, residue 666, residue 682, and residue 692 (e.g., an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation). In some embodiments, the cancer has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the cancer is a lymphoma (e.g., FL or a large B-cell lymphoma (e.g., DLBCL-NOS)) and has EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V.

[0131] In some embodiments, the cancer has an EZH2 mutation at a residue selected from the group consisting of residue 646, residue 682, and residue 692 (e.g., an EZH2 Y646X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation). In some embodiments, the EZH2 mutation comprises a mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, A682G, and A692V relative to SEQ ID NO: 1. In some embodiments, the cancer is a lymphoma (e.g., FL or a large B-cell lymphoma (e.g., DLBCL-NOS)) and the EZH2 mutation comprises a mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, A682G, and A692V relative to SEQ ID NO: 1.

[0132] In some embodiments, the subject has been identified or diagnosed as having a cancer with an EZH2 dysregulation (e.g., an EZH2 mutation) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for an EZH2 dysregulation (e.g., an EZH2 mutation) (e.g., as determined using a regulatory agency -approved assay or kit). The subject can be a subject with a tumor(s) that is positive for an EZH2 dysregulation (e.g., an EZH2 mutation) (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a medical record indicating that the subject has a tumor that has an EZH2 dysregulation (e.g., an EZH2 mutation).

[0133] In some embodiments, the subject is treatment naive with respect to the cancer (e.g., the hematological malignancy (e.g., the lymphoma (e.g., the NHL))). In some embodiments, the Docket No. TRLN-013-030W01 / TLS-068WO subject has received one or more lines of therapy for the cancer. In some embodiments, the subject has received two or more lines of therapy for the cancer.

[0134] In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has an EZH2 dysregulation (e.g., an EZH2 mutation). In some such embodiments, the method includes administering to a subject determined to have an EZH2 dysregulation (e.g., an EZH2 mutation) a therapeutically effective amount of an EZH2 inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the methods include determining that the subject has an EZH2 dysregulation (e.g., an EZH2 mutation) via an assay performed on a sample obtained from the subject.

[0136] In some embodiments of any of the methods described herein, the subject’s medical record is used to determine whether the subject has an EZH2 dysregulation (e.g., an EZH2 mutation). For example, reference is made to the results of an assay performed on a sample obtained from the subject.

[0137] In some embodiments of any of the methods described herein, an assay is used to determine whether the subject has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the assay can use a sample from a subject and can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR or quantitative real-time RT-PCR). The assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof. Assays can utilize other detection methods known in the art for detecting an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a fresh biopsy sample, or an archival biopsy sample) from the subject.

[0138] In some embodiments, an EZH2 dysregulation (e.g., an EZH2 mutation) can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). See, e.g., Karachaliou, Niki, et \. Annals of Translational Medicine 3.3 (2015), doi: 10.3978 / j.issn.2305-5839.2015.01.16. Liquid biopsy methods can be used to detect total tumor burden and / or the EZH2 dysregulation (e.g., the EZH2 mutation). In some embodiments, the biological sample can include blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, a liquid biopsy Docket No. TRLN-013-030W01 / TLS-068WO can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify an EZH2 dysregulation (e.g., EZH2 mutation).

[0139] The phrases “EZH2 dysregulation” or “dysregulation of EZH2” as used herein refer to: (i) a genetic mutation in an EZH2 gene (e.g., a mutation in an EZH2 gene that results in the expression of an EZH2 protein that includes a deletion of at least one amino acid as compared to a wild type EZH2 protein, a mutation in an EZH2 gene that results in the expression of an EZH2 protein with one or more point mutations as compared to a wild type EZH2 protein, a mutation in an EZH2 gene that results in the expression of an EZH2 protein with at least one inserted amino acid as compared to a wild type EZH2 protein, a gene amplification (e.g., duplication) that results in an increased level of EZH2 protein in a cell, a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of EZH2 protein in a cell, or a partial or full fusion of an EZH2 gene with another partial or full gene), (ii) an alternative spliced version of an EZH2 mRNA that results in an EZH2 protein having an insertion or a deletion of at least one amino acid in the EZH2 protein as compared to the wild type EZH2 protein, (iii) increased expression (e.g., increased levels) of a wild type EZH2 protein in a mammalian cell due to aberrant cell signaling and / or dysregulated signaling (e.g., as compared to a control non-cancerous cell), or (iv) an epigenetic alteration that results in an increased level of an EZH2 protein in the cell.

[0140] A “dysregulated EZH2 protein” as used herein refers to (i) an EZH2 protein having a mutation (e.g., a deletion of at least one amino acid as compared to a wild type EZH2 protein, one or more point mutations as compared to a wild type EZH2 protein, an insertion of at least one amino acid as compared to a wild type EZH2 protein), (ii) an EZH2 protein resulting from a gene duplication event, e.g., of the gene encoding the EZH2 protein (e.g., the wild type EZH2 protein), thus resulting in an increased level and / or activity of the EZH2 protein (e.g., the wild type EZH2 protein) in a cell, or can result from a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that can also result in an increased level and / or activity of the EZH2 protein (e.g., the wild type EZH2 protein) in a cell), (iii) an EZH2 protein resulting from an alternative spliced version of an EZH2 mRNA that results in an EZH2 protein having an insertion or a deletion of at least one amino acid in the EZH2 protein as compared to the wild type EZH2 protein, or (iv) an EZH2 protein resulting from increased expression (e.g., increased levels) of a wild type EZH2 protein in a mammalian cell due to aberrant cell signaling, dysregulated autocrine / paracrine Docket No. TRLN-013-030W01 / TLS-068WO signaling, or epigenetic changes (e.g., as compared to a control non-cancerous cell). In some embodiments, a dysregulated EZH2 protein is a dysregulated human EZH2 protein.

[0141] An exemplary wild type human EZH2 sequence is shown below. This is one of several isoforms of EZH2, and it will be understood that residue numbering may change based on the reference isoform.

[0142] SEQ ID NO: 1 (UniParc ID UPI000006D77C):

[0143] MGQTGKKSEKGP VCWRKRVKSEYMRLRQLKRFRRADEVKSMF S SNRQKILERT EILNQEWKQRRIQPVHILTSVSSLRGTRECSVTSDLDFPTQVIPLKTLNAVASVPIMYSWS PLQQNFMVEDETVLHNIPYMGDEVLDQDGTFIEELIKNYDGKVHGDRECGFINDEIFVEL VNALGQYNDDDDDDDGDDPEEREEKQKDLEDHRDDKESRPPRKFPSDKIFEAISSMFPD KGTAEELKEKYKELTEQQLPGALPPECTPNIDGPNAKSVQREQSLHSFHTLFCRRCFKYD CFLHRKCNYSFHATPNTYKRKNTETALDNKPCGPQCYQHLEGAKEFAAALTAERIKTPP KRPGGRRRGRLPNNSSRPSTPTINVLESKDTDSDREAGTETGGENNDKEEEEKKDETSSS SEANSRCQTPIKMKPNIEPPENVEWSGAEASMFRVLIGTYYDNFCAIARLIGTKTCRQVY EFRVI< ESSIIAPAPAEDVDTPPRI< I< I< RI< HRLWAAHCRI< IQLI< I< DGSSNHVYNYQPCDHP RQPCDSSCPCVIAQNFCEKFCQCSSECQNRFPGCRCKAQCNTKQCPCYLAVRECDPDLC LTCGAADHWDSKNVSCKNCSIQRGSKKHLLLAPSDVAGWGIFIKDPVQKNEFISEYCGE IISQDEADRRGI< VYDI< YMCSFLFNLNNDFVVDATRI< GNI< IRFANHSVNPNCYAI< VMM VNGDHRIGIFAKRAIQTGEELFFDYRYSQADALKYVGIEREMEIP

[0144] A “mutant EZH2 protein” as used herein refers to an EZH2 protein including a substitution, an insertion, a deletion, a truncation and / or a fusion relative to the wild type human EZH2 sequence shown in SEQ ID NO:1. For example, a mutant human EZH2 protein includes a substitution at any amino acid position (relative to SEQ ID NO: 1).

[0145] The term “wild type” or “wild-type” describes a nucleic acid (e.g., an EZH2 gene or a EZH2 mRNA) or protein (e.g., a EZH2 protein) sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein. Although a wild type nucleic acid or protein sequence is the sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein, it is not necessarily the case that a subject that has a disease or disorder related to the reference nucleic acid or protein lacks wild type sequence. For example, a subject with a gene duplication of the reference gene may have the wild type sequence but could still have a disease or disorder related to the reference nucleic acid or protein due to the duplication event. As another example, a subject with a disease or disorder related to the reference nucleic acid or protein may have one allele that encodes wild type protein, and another allele that encodes a mutant protein. Docket No. TRLN-013-030W01 / TLS-068WO The term “wild type EZH2” or “wild-type EZH2” describes a EZH2 nucleic acid (e.g., a EZH2 gene or a EZH2 mRNA) or EZH2 protein that is found in a subject that does not have a disease or disorder associated with EZH2 dysregulation, e.g., a cancer having an EZH2 dysregulation (and optionally also does not have an increased risk of developing a disease or disorder with an EZH2 dysregulation and / or is not suspected of having a disease or disorder with an EZH2 dysregulation), or is found in a cell or tissue from a subject that does not have a disease or disorder associated with EZH2 dysregulation, e.g., a cancer having an EZH2 dysregulation (and optionally also does not have an increased risk of developing a disease or disorder with an EZH2 dysregulation and / or is not suspected of having a disease or disorder with an EZH2 dysregulation). Although a wild type EZH2 nucleic acid or protein sequence is the sequence that is typically found in a subject that does not have a disease or disorder associated with an EZH2 dysregulation, it is not necessarily the case that a subject that has a disease or disorder associated with EZH2 dysregulation lacks the wild type EZH2 sequence. For example, a subject with an EZH2 gene duplication may have the wild type sequence but could still have a disease or disorder associated with an EZH2 dysregulation due to the duplication event. As another example, a subject with a disease or disorder associated with an EZH2 dysregulation may have one allele that encodes wild type EZH2 protein, and another allele that encodes a mutant EZH2 protein.

[0146] An “EZH2 Y646X mutant protein” as used herein refers to an EZH2 protein including substitution of a tyrosine to any other amino acid at the 646thamino acid position relative to SEQ ID NO: 1.

[0147] An “EZH2 Y646C mutant protein” as used herein refers to an EZH2 protein including substitution of a tyrosine to cysteine at the 646thamino acid position relative to SEQ ID NO: 1.

[0148] An “EZH2 Y646F mutant protein” as used herein refers to an EZH2 protein including substitution of a tyrosine to phenylalanine at the 646thamino acid position relative to SEQ ID NO: 1.

[0149] An “EZH2 Y646H mutant protein” as used herein refers to an EZH2 protein including substitution of a tyrosine to histidine at the 646thamino acid position relative to SEQ ID NO: 1.

[0150] An “EZH2 Y646N mutant protein” as used herein refers to an EZH2 protein including substitution of a tyrosine to asparagine at the 646thamino acid position relative to SEQ ID NO: 1.

[0151] An “EZH2 Y646S mutant protein” as used herein refers to an EZH2 protein including substitution of a tyrosine to serine at the 646thamino acid position relative to SEQ ID NO: 1.

[0152] An “EZH2 Y666X mutant protein” as used herein refers to an EZH2 protein including substitution of a tyrosine to any other amino acid at the 666thamino acid position relative to SEQ ID NO: 1. Docket No. TRLN-013-030W01 / TLS-068WO An “EZH2 Y666N mutant protein” as used herein refers to an EZH2 protein including substitution of a tyrosine to asparagine at the 666thamino acid position relative to SEQ ID NO: 1.

[0153] An “EZH2 A682X mutant protein” as used herein refers to an EZH2 protein including substitution of an alanine to any other amino acid at the 682ndamino acid position relative to SEQ ID NO: 1.

[0154] An “EZH2 A682G mutant protein” as used herein refers to an EZH2 protein including substitution of an alanine to glycine at the 682ndamino acid position relative to SEQ ID NO: 1.

[0155] An “EZH2 A692X mutant protein” as used herein refers to an EZH2 protein including substitution of an alanine to any other amino acid at the 692ndamino acid position relative to SEQ ID NO: 1.

[0156] An “EZH2 A692V mutant protein” as used herein refers to an EZH2 protein including substitution of an alanine to valine at the 692ndamino acid position relative to SEQ ID NO: 1.

[0157] As used herein, methods for treating a cancer e.g., the hematological malignancy (e.g., the lymphoma (e.g., the NHL))) can include treatment of a primary tumor (i.e., non-metastatic cancer) (e.g., as first, second, third, or later line of therapy, including, but not limited to, the relapsed / refractory setting), treatment of a metastatic (or secondary) tumor, neoadjuvant therapy (e.g., before treatment with an additional therapy or therapeutic agent, such as surgery, radiation, chemotherapy, or a line of therapy), adjuvant therapy (e.g., following treatment with an additional therapy or therapeutic agent, such as surgery, radiation, chemotherapy, or a line of therapy), maintenance therapy (e.g., treatment following response to an additional therapy or therapeutic agent, such as surgery, radiation, chemotherapy, or a line of therapy), or bridging therapy.

[0158] As used herein, the terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0159] In some embodiments, different phases of a treatment can be distinct. For example, as used herein, a “treatment phase” of a treatment refers to a treatment regimen intended to elicit a response or remission of the disease in the subject. As another example, a “maintenance phase” of a treatment refers to a treatment regimen (sometimes called a “maintenance therapy”) intended to maintain the state of disease achieved in the subject during the treatment phase (e.g., the state of response, remission, or stable disease). In some embodiments, a maintenance phase of a treatment Docket No. TRLN-013-030W01 / TLS-068WO can include one or more of the same therapeutic agents used in the treatment phase. In some such embodiments, the maintenance phase may have fewer therapeutic agents than used in the treatment phase. In some embodiments, a maintenance phase of a treatment can use a lower dose of one or more of the therapeutic agent(s) than used in the treatment phase. In some embodiments, a maintenance phase of a treatment can include one or more different therapeutic agents compared to the therapeutic agent(s) used in the treatment phase. For example, a maintenance phase can include none of the therapeutic agent(s) used in the treatment phase. In some embodiments, the state of the disease achieved in the subject during the treatment phase is a response (e.g., a complete response or a partial response), a remission, or stable disease. As another example, a “bridging phase” of a treatment refers to a treatment regimen (sometimes called a “bridging therapy”) intended to maintain or improve the state of disease achieved in the subject during the treatment phase (e.g., the state of response, remission, or stable disease) until another therapy (e.g., CAR T therapy) is available. It is understood that some therapies (e.g., CAR T therapy) take time to prepare and / or deliver, and in some cases, a bridging phase is needed.

[0160] As used herein “remission” refers to the absence of or a significant reduction of disease signs or symptoms. In some embodiments, remission may be determined by the subject’s physician. In some embodiments, remission can be determined by objective criteria, such as by criteria such as RECIST 1.1, the Lugano 2014 criteria (Cheson, Bruce D., et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JC0.2013.54.8800) or the Global Response Criteria (Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057).

[0161] As used herein, the terms “prevent” or “prevention” refer to prophylactic measures. Beneficial or desired clinical results include, but are not limited to, the delay, arrest, or preclusion of the onset, recurrence or spread, in whole or in part, of a disease or condition, or a symptom thereof, such as any of those provided herein.

[0162] In some embodiments, methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject can include treatment of a primary tumor with a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, and an EZH2 inhibitor. In some embodiments, the subject is treatment naive with respect to the cancer. In some embodiments, the subject has received one or more lines of therapy for the cancer. In some embodiments, the subject has received chemotherapy, cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or Docket No. TRLN-013-030W01 / TLS-068WO antibody-armed cell therapy), or both. In some embodiments, the subject has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R2, R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapy, or two or more thereof. In some embodiments, the subject has received a rituximabcontaining regimen. In some embodiments, the subject has received an obinutuzumab -containing regimen. In some embodiments, the subject has received a mosunetuzumab -containing regimen. In some embodiments, the subject has received a glofitamab-containing regimen. In some embodiments, the subject has received an epcoritamab-containing regimen. In some embodiments, the methods for treating a cancer in a subject include administration of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to a subject who has received one or more lines of therapy for the cancer. In some embodiments, methods for treating a cancer in a subject include administration of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, are to a subject who has received two or more lines of therapy for the cancer.

[0163] In some embodiments, methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject can include treatment of a metastatic tumor with an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is treatment naive with respect to the metastatic tumor. In some embodiments, the subject has received one or more lines of therapy for the metastatic tumor. In some embodiments, the subject has received chemotherapy, cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy), or both. In some embodiments, the subject has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R2, R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapy, or two or more thereof. In some embodiments, the subject has received a rituximabcontaining regimen. In some embodiments, the subject has received an obinutuzumab -containing regimen. In some embodiments, the subject has received a mosunetuzumab -containing regimen. In some embodiments, the subject has received a glofitamab-containing regimen. In some embodiments, the subject has received an epcoritamab-containing regimen. In some embodiments, Docket No. TRLN-013-030W01 / TLS-068WO methods for treating a cancer in a subject include administration of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to subject who has received one or more lines of therapy for the cancer. In some embodiments, methods for treating a cancer in a subject include administration of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to a subject who has received two or more lines of therapy for the cancer.

[0164] In some embodiments, methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject can include administration of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, as adjuvant therapy. In some embodiments, the subject has received chemotherapy, cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy), or both. In some embodiments, the subject has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R2, R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapy, or two or more thereof. In some embodiments, the subject has received a rituximab -containing regimen. In some embodiments, the subject has received an obinutuzumab-containing regimen. In some embodiments, the subject has received a mosunetuzumab-containing regimen. In some embodiments, the subject has received a glofitamab-containing regimen. In some embodiments, the subject has received an epcoritamab -containing regimen. In some embodiments, methods for treating a cancer in a subject include administration of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof as adjuvant therapy to a subject who has received one or more lines of therapy for the cancer. In some embodiments, methods for treating a cancer in a subject include administration of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), Docket No. TRLN-013-030W01 / TLS-068WO (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, as adjuvant therapy to a subject who has received two or more lines of therapy for the cancer. In some embodiments, the adjuvant therapy follows surgery (e.g., surgical resection, such as partial surgical resection or complete, total, or full surgical resection). In some embodiments, the adjuvant therapy follows radiation therapy. In some embodiments, the adjuvant therapy follows chemotherapy.

[0165] In some embodiments, methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject can include administration of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, as maintenance therapy. In some embodiments, the subject has received chemotherapy, cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy), a stem cell transplant, or a combination thereof, in a treatment phase. In some embodiments, the subject has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R2, R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapy, or two or more thereof, in a treatment phase. In some embodiments, the subject has received a rituximabcontaining regimen in a treatment phase. In some embodiments, the subject has received an obinutuzumab-containing regimen in a treatment phase. In some embodiments, the subject has received a mosunetuzumab -containing regimen in a treatment phase. In some embodiments, the subject has received a glofitamab-containing regimen in a treatment phase. In some embodiments, the subject has received an epcoritamab -containing regimen in a treatment phase. In some embodiments, the subject has received a stem cell transplant in a treatment phase. In some embodiments, the subject has received a cell-based therapy (e.g., CAR T therapy) in a treatment phase. In some embodiments, methods for treating a cancer in a subject include administration of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, as maintenance therapy to a subject who has received one or more lines of therapy for the cancer. In some embodiments, methods for treating a cancer in a subject include administration of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I- Docket No. TRLN-013-030W01 / TLS-068WO bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, as maintenance therapy to a subject who has received two or more lines of therapy for the cancer.

[0166] In some embodiments, methods for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject can include administration of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, as bridging therapy. In some embodiments, the subject has received chemotherapy, cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy), a stem cell transplant, or a combination thereof, in a treatment phase. In some embodiments, the subject has received R-CHOP, G-CHOP, R-EPOCH, CVP, CVAD, R2, R-CODOX-M, R-IVAC, DA-EPOCH-R, cell-based therapy, or two or more thereof, in a treatment phase. In some embodiments, the subject has received a rituximabcontaining regimen in a treatment phase. In some embodiments, the subject has received an obinutuzumab-containing regimen in a treatment phase. In some embodiments, the subject has received a mosunetuzumab -containing regimen in a treatment phase. In some embodiments, the subject has received a glofitamab-containing regimen in a treatment phase. In some embodiments, the subject has received an epcoritamab -containing regimen in a treatment phase. In some embodiments, the subject has received a stem cell transplant in a treatment phase. In some embodiments, the subject has received a cell-based therapy (e.g., CAR T therapy) in a treatment phase. In some embodiments, methods for treating a cancer in a subject include administration of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, as bridging therapy to a subject who has received one or more lines of therapy for the cancer. In some embodiments, methods for treating a cancer in a subject include administration of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, as bridging therapy to a subject who has received two or more lines of therapy for the cancer.

[0167] As used herein, “monotherapy”, when referring to a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I- Docket No. TRLN-013-030W01 / TLS-068WO aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, means that the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is the only therapeutic agent or therapy (e.g., anticancer agent or therapy) administered to the subject during the treatment cycle (e.g., no additional targeted therapeutics, anticancer agents, chemotherapeutics, or checkpoint inhibitors are administered to the subject during the treatment cycle). Monotherapy does not exclude the co-administration of medicaments (including, for example, over the counter or prescription medications, vitamins, and / or herbal supplements) for the treatment of side effects (e.g., adverse events), concurrent illnesses, or general symptoms associated with the cancer or treatment, such as pain, rash, edema, photosensitivity, pruritus, skin discoloration, hair brittleness, hair loss, brittle nails, cracked nails, discolored nails, swollen cuticles, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms, including nausea, diarrhea, and lack of appetite. These types of medicaments are sometimes referred to as “supportive care” or “supportive therapy”. In some embodiments, transfusion with blood products and / or administration of granulocyte colony-stimulating factor (G-CSF) is considered to be supportive care.

[0168] In some embodiments, when an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, are administered to the subject, and this combination is the only therapy (e.g., anticancer agent or therapy) administered to the subject during the treatment cycle (e.g., no additional targeted therapeutics, anticancer agents, chemotherapeutics, or checkpoint inhibitors are administered to the subject during the treatment cycle). Such a combination is referred to herein as a “BCL6 / EZH2 combination therapy”. This combination therapy does not exclude the coadministration of medicaments for the treatment of side effects or general symptoms associated with the cancer or treatment, such as pain, rash, edema, photosensitivity, pruritus, skin discoloration, hair brittleness, hair loss, brittle nails, cracked nails, discolored nails, swollen cuticles, fatigue, weight loss, general malaise, shortness of breath, infection, anemia, or gastrointestinal symptoms, including nausea, diarrhea, and lack of appetite. For example, a subject receiving a “BCL6 / EZH2 combination therapy” of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I- Docket No. TRLN-013-030W01 / TLS-068WO aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a- 5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, could receive anti-nausea medication, but not, e.g., CHOP or rituximab.

[0169] As used herein, “the subject has received one or more lines of therapy for the cancer” means that the subject has been previously administered one or more therapeutic agents or therapies (e.g., anticancer agent or therapy (e.g., systemic therapies)) for the cancer other than a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, during a prior treatment cycle. In some embodiments, at least one of the one or more therapeutic agents or therapies was administered systemically. In some embodiments, the subject cannot tolerate the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not respond to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject did not adequately respond to one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, the subject has stopped responding to the one or more therapeutic agents or therapies previously administered for the cancer. In some embodiments, a lack of response, an inadequate response, or a discontinued response can be determined by objective criteria (e.g., tumor volume, or by criteria such as RECIST 1.1, the Lugano 2014 criteria (Cheson, Bruce D., et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JC0.2013.54.8800) or the Global Response Criteria (Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057)). In some embodiments, a lack of response, an inadequate response, or a discontinued response can be determined by the subject’s physician.

[0170] As used herein, “the subject is treatment naive with respect to the cancer”, “the subject is treatment-naive”, or that the subject was “previously untreated” for the cancer means that the subject has not been previously administered one or more therapeutic agents or therapies for the cancer. Treatment of a subject who is treatment naive with respect to the cancer is often referred to as “first-line” therapy.

[0171] For any of the solid tumors described herein, the solid tumors can be primary tumors or metastatic (or secondary) tumors. As used herein, “primary” tumors are those located at the site where the tumor began to grow (i.e., where it originated). As used herein, “metastatic” (or “secondary”) tumors are those that have spread to other parts of body from the original tumor site. In some embodiments, the metastatic or secondary tumors are the same type Docket No. TRLN-013-030W01 / TLS-068WO of cancer as the primary tumor. In some embodiments, the metastatic or secondary tumors are not genetically identical to the primary tumor.

[0172] In some embodiments of any of the methods or uses described here, the cancer is a hematological cancer (e.g., lymphoma (e.g., non-Hodgkin lymphoma (e.g., B-cell lymphoid proliferations and lymphomas (e.g., mature B-cell neoplasms (also called herein B-cell lymphomas) (e.g., large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), or primary mediastinal large B-cell lymphoma (primary mediastinal LBCL)), follicular lymphoma (FL), or transformations of indolent B-cell lymphomas (e.g., transformed FL or Richter transformation of CLL)))), T-cell and NK-cell lymphoid proliferations and lymphomas (e.g., mature T-cell and NK-cell neoplasms (e.g., primary cutaneous T-cell lymphoid proliferations and lymphomas (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, or Sezary syndrome), or peripheral T-cell lymphoma (PTCL) (e.g., nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type), or nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS)), or other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS)))))).

[0173] In some embodiments, the cancer is a mature B-cell neoplasm (e.g., chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Burkitt lymphoma (BL), large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), T-cell / histiocyte-rich large B-cell lymphoma, diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary large B-cell lymphoma of immune-privileged sites (primary LBCL of immune-privileged sites), intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL), HGBCL with 11q aberrations, or high grade B-cell lymphoma NOS (HGBCL-NOS)), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or transformations of indolent B-cell lymphomas (e.g., transformed FL or Richter transformation of CLL)), a peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK -positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma), nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as Docket No. TRLN-013-030W01 / TLS-068WO follicular helper T-cell lymphoma, follicular type), or nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS))), a primary cutaneous T-cell lymphoid proliferation or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, Sezary syndrome, or primary cutaneous gamma-delta T-cell lymphoma), nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), diffuse histiocytic lymphoma (DHL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), or early T-precursor lymphoblastic leukemia. In some embodiments, the cancer is a mature B-cell neoplasm (e.g., BL, large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with 11q aberrations, or HGBCL-NOS), FL, MCL, MZL, or transformations of indolent B-cell lymphomas (e.g., transformed FL or Richter transformation of CLL)), a peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma), nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type), or nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS))), a primary cutaneous T-cell lymphoid proliferation or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, Sezary syndrome, or primary cutaneous gamma-delta T-cell lymphoma), or ALL (e.g., B-ALL). In some embodiments, the cancer is a mature B-cell neoplasm (e.g., a large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with llq aberrations, or HGBCL-NOS), FL, or transformations of indolent B-cell lymphomas (e.g., transformed FL or Richter transformation of CLL)). In some embodiments, the cancer is a mature B-cell neoplasm (e.g., large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with llq aberrations, or HGBCL-NOS), FL, MCL, MZL, or transformations of indolent B-cell lymphomas (e.g., Docket No. TRLN-013-030W01 / TLS-068WO transformed FL or Richter transformation of CLL)), or ALL (e.g., B-ALL). In some embodiments, the cancer is a peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma), nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type), or nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS))). See, e.g., Leeman-Neill and Bhagat, Expert Opinion on Therapeutic Targets 22.2 (2018): 143-152, doi: 10.1080 / 14728222.2018.1420782; Mlynarczyk and Melnick. Immunological Reviews 288.1 (2019): 214-239, doi: 10.1111 / imr.12755; Hurtz, Christian, et al., Journal of Experimental Medicine 208.11 (2011): 2163-2174, doi: 10.1084 / jem.20110304; Deb, Dhruba, et al. Cancer Research 77.11 (2017): 3070-3081, doi: 10.1158 / 0008-5472. CAN-15-3052; Cardenas, Mariano G., et al., Clinical Cancer Research 23.4 (2017): 885-893, doi: 10.1158 / 1078-0432. CCR- 16-2071; Walker, Sarah R., et al., Oncogene 34.9 (2015): 1073-1082, doi: 10.1038 / onc.2014.61; Alaggio, Rita, et

[0174]

[0175] Leukemia 36.1 (2022): 1720-1748, doi: 10.1038 / s41375-022-01620-2; Paik, Jin Ho, et al. Human Pathology 131 (2023): 47-60, doi: 10.1016 / j. humpath.2022.12.003; and International Publication Nos. WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673.

[0176] In The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms, Alaggio and colleagues noted that a group of lymphomas previously known as “diffuse large B-cell lymphomas” (DLBCLs) had been renamed to “large B-cell lymphomas” (LBCLs), as not all diseases in the class had a detectable diffuse growth pattern. See, e.g., Alaggio, Rita, et al. Leukemia 36.7 (2022): 1720-1748, doi: 10.1038 / s41375-022-01620-2. However, in clinical and / or regulatory practice, the term “diffuse large B-cell lymphomas” (DLBCLs) may still be in common use to refer to large B-cell lymphomas, and in some cases, DLBCL-NOS is referred to as “DLBCL”. As used herein, “DLBCL-NOS” is used to refer to the specific subclass, and “large B-cell lymphoma” (LBCL) is used to refer to the class.

[0177] In some embodiments, the cancer is a non-Hodgkin lymphoma (NHL). In some embodiments, the non-Hodgkin lymphoma is a mature B-cell neoplasm. In some embodiments, the mature B-cell neoplasm is a large B-cell lymphoma (LBCL). In some embodiments, the large B-cell lymphoma is DLBCL-NOS. In some embodiments, the mature B-cell neoplasm is FL. In some embodiments, the FL is grade l-3a. In some embodiments, the FL is grade 3b. In some embodiments, the non-Hodgkin lymphoma is a T-cell lymphoma. In some embodiments, the cancer is relapsed or refractory. In some embodiments, the cancer is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, a percent Docket No. TRLN-013-030W01 / TLS-068WO nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In some embodiments, the cancer is relapsed or refractory and BCL6+. In some embodiments, the cancer has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the cancer has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the cancer is BCL6+ and has an EZH2 dysregulation. In some embodiments, the cancer is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the cancer has been treated with at least one line of therapy. In some embodiments, the cancer has been treated with at least two lines of therapy.

[0178] In some embodiments, the cancer is a non-Hodgkin lymphoma, for example, any of the non-Hodgkin lymphomas described herein. In some embodiments, the non-Hodgkin lymphoma is relapsed or refractory. In some embodiments, the non-Hodgkin lymphoma is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In some embodiments, the non-Hodgkin lymphoma is relapsed or refractory and BCL6+. In some embodiments, the non-Hodgkin lymphoma has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the non-Hodgkin lymphoma has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the non-Hodgkin lymphoma is BCL6+ and has an EZH2 dysregulation. In some embodiments, the non-Hodgkin lymphoma is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the non-Hodgkin lymphoma is previously untreated. In some embodiments, the non-Hodgkin lymphoma has been treated with at least one line of therapy. In some embodiments, the non-Hodgkin lymphoma has been treated with at least two lines of therapy.

[0179] Provided herein are methods for treating a non-Hodgkin lymphoma in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a Docket No. TRLN-013-030W01 / TLS-068WO pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0180] In some embodiments, the cancer is a mature B-cell neoplasm, for example, any of the mature B-cell neoplasms described herein. In some embodiments, the mature B-cell neoplasm is relapsed or refractory. In some embodiments, the mature B-cell neoplasm is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In some embodiments, the mature B-cell neoplasm is relapsed or refractory and BCL6+. In some embodiments, the mature B-cell neoplasm has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the mature B-cell neoplasm has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the mature B-cell neoplasm is BCL6+ and has an EZH2 dysregulation. In some embodiments, the mature B-cell neoplasm is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some Docket No. TRLN-013-030W01 / TLS-068WO embodiments, the mature B-cell neoplasm is previously untreated. In some embodiments, the mature B-cell neoplasm has been treated with at least one line of therapy. In some embodiments, the mature B-cell neoplasm has been treated with at least two lines of therapy.

[0181] In some embodiments, provided herein are methods for treating a mature B-cell neoplasm in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0182] In some embodiments, the cancer is a large B-cell lymphoma (LBCL), for example, any of the large B-cell lymphomas described herein. In some embodiments, the large B-cell lymphoma (LBCL) is relapsed or refractory. In some embodiments, the large B-cell lymphoma is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In Docket No. TRLN-013-030W01 / TLS-068WO some embodiments, the large B-cell lymphoma (LBCL) is relapsed or refractory and BCL6+. In some embodiments, the large B-cell lymphoma (LBCL) has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the large B-cell lymphoma (LBCL) has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the large B-cell lymphoma (LBCL) is BCL6+ and has an EZH2 dysregulation. In some embodiments, the large B-cell lymphoma (LBCL) is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the LBCL is previously untreated. In some embodiments, the large B-cell lymphoma (LBCL) has been treated with at least one line of therapy. In some embodiments, the large B-cell lymphoma (LBCL) has been treated with at least two lines of therapy.

[0183] In some embodiments, provided herein are methods for treating a LBCL in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 Docket No. TRLN-013-030W01 / TLS-068WO mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0184] In some embodiments, the cancer is a FL. In some embodiments, the FL is grade l-3a. In some embodiments, the FL is grade 3b (sometimes called follicular large B-cell lymphoma (FLBCL)). In some embodiments, the FL is relapsed or refractory. In some embodiments, the FL is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test)). In some embodiments, the FL is relapsed or refractory and BCL6+. In some embodiments, the FL has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the FL has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the FL is BCL6+ and has an EZH2 dysregulation. In some embodiments, the FL is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the FL is previously untreated. In some embodiments, the FL has been treated with at least one line of therapy. In some embodiments, the FL has been treated with at least two lines of therapy.

[0185] In some embodiments, provided herein are methods for treating a FL in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, Docket No. TRLN-013-030W01 / TLS-068WO 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0186] In some embodiments, the cancer is a transformed FL. In some embodiments, the transformed FL is relapsed or refractory. In some embodiments, the transformed FL is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In some embodiments, the transformed FL is relapsed or refractory and BCL6+. In some embodiments, the transformed FL has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the transformed FL has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the transformed FL is BCL6+ and has an EZH2 dysregulation. In some embodiments, the transformed FL is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the transformed FL is previously untreated. In some embodiments, the transformed FL has been treated with at least one line of therapy. In some embodiments, the transformed FL has been treated with at least two lines of therapy.

[0187] Provided herein are methods for treating a transformed FL in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a Docket No. TRLN-013-030W01 / TLS-068WO pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0188] In some embodiments, the cancer is a DLBCL-NOS. In some embodiments, the DLBCL-NOS is relapsed or refractory. In some embodiments, the DLBCL-NOS is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test)). In some embodiments, the DLBCL-NOS is relapsed or refractory and BCL6+. In some embodiments, the DLBCL-NOS has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the DLBCL-NOS has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the DLBCL-NOS is BCL6+ and has an EZH2 dysregulation. In some embodiments, the DLBCL-NOS is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the DLBCL-NOS is previously untreated. In some embodiments, the DLBCL-NOS has been treated with at least one line of therapy. In some embodiments, the DLBCL-NOS has been treated with at least two lines of therapy.

[0189] Provided herein are methods for treating a DLBCL-NOS in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I- Docket No. TRLN-013-030W01 / TLS-068WO aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a- 5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0190] In some embodiments, the cancer is a T-cell lymphoma. In some embodiments, the PTCL is relapsed or refractory. In some embodiments, the T-cell lymphoma is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In some embodiments, the T-cell lymphoma is relapsed or refractory and BCL6+. In some embodiments, the T-cell lymphoma has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the T-cell lymphoma has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the T-cell lymphoma is BCL6+ and has an EZH2 dysregulation. In some embodiments, the T-cell lymphoma is relapsed or refractory, Docket No. TRLN-013-030W01 / TLS-068WO BCL6+, and has an EZH2 dysregulation. In some embodiments, the T-cell lymphoma is previously untreated. In some embodiments, the T-cell lymphoma has been treated with at least one line of therapy. In some embodiments, the T-cell lymphoma has been treated with at least two lines of therapy.

[0191] Also provided herein are methods for treating a T-cell lymphoma in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0192] In some embodiments, the cancer is a PTCL. In some embodiments, the PTCL is relapsed or refractory. In some embodiments, the PTCL is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In some embodiments, Docket No. TRLN-013-030W01 / TLS-068WO the PTCL is relapsed or refractory and BCL6+. In some embodiments, the PTCL has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the PTCL has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the PTCL is BCL6+ and has an EZH2 dysregulation. In some embodiments, the PTCL is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the PTCL is previously untreated. In some embodiments, the PTCL has been treated with at least one line of therapy. In some embodiments, the PTCL has been treated with at least two lines of therapy.

[0193] Also provided herein are methods for treating a PTCL in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a- 5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day. Docket No. TRLN-013-030W01 / TLS-068WO In some embodiments, the cancer is a PTCL-NOS. In some embodiments, the PTCL-NOS is relapsed or refractory. In some embodiments, the PTCL-NOS is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test)). In some embodiments, the PTCL-NOS is relapsed or refractory and BCL6+. In some embodiments, the PTCL-NOS has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the PTCL-NOS has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the PTCL-NOS is BCL6+ and has an EZH2 dysregulation. In some embodiments, the PTCL-NOS is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the PTCL-NOS is previously untreated. In some embodiments, the PTCL-NOS has been treated with at least one line of therapy. In some embodiments, the PTCL-NOS has been treated with at least two lines of therapy.

[0194] Provided herein are methods for treating a PTCL-NOS in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a- 5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Docket No. TRLN-013-030W01 / TLS-068WO Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0195] In some embodiments, the cancer is a Tfh PTCL. In some embodiments, the Tfh PTCL is relapsed or refractory. In some embodiments, the Tfh PTCL is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In some embodiments, the Tfh PTCL is relapsed or refractory and BCL6+. In some embodiments, the Tfh PTCL has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the Tfh PTCL has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the Tfh PTCL is BCL6+ and has an EZH2 dysregulation. In some embodiments, the Tfh PTCL is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the Tfh PTCL is previously untreated. In some embodiments, the Tfh PTCL has been treated with at least one line of therapy. In some embodiments, the Tfh PTCL has been treated with at least two lines of therapy.

[0196] Provided herein are methods for treating a Tfh PTCL in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I- Docket No. TRLN-013-030W01 / TLS-068WO bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0197] In some embodiments, the cancer is an AITL. In some embodiments, the AITL is relapsed or refractory. In some embodiments, the AITL is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In some embodiments, the AITL is relapsed or refractory and BCL6+. In some embodiments, the AITL has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the AITL has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the AITL is BCL6+ and has an EZH2 dysregulation. In some embodiments, the AITL is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the AITL is previously untreated. In some embodiments, the AITL has been treated with at least one line of therapy. In some embodiments, the AITL has been treated with at least two lines of therapy.

[0198] Provided herein are methods for treating an AITL in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I- Docket No. TRLN-013-030W01 / TLS-068WO aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0199] In some embodiments, the cancer is a nodal T follicular helper cell lymphoma follicular type. In some embodiments, the nodal T follicular helper cell lymphoma follicular type is relapsed or refractory. In some embodiments, the nodal T follicular helper cell lymphoma follicular type is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In some embodiments, the nodal T follicular helper cell lymphoma follicular type is relapsed or refractory and BCL6+. In some embodiments, the nodal T follicular helper cell lymphoma follicular type has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the nodal T follicular helper cell lymphoma follicular type has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the nodal T follicular helper cell lymphoma follicular type is BCL6+ and has an EZH2 dysregulation. In some embodiments, the nodal T follicular helper cell lymphoma follicular type is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the Docket No. TRLN-013-030W01 / TLS-068WO nodal T follicular helper cell lymphoma follicular type is previously untreated. In some embodiments, the nodal T follicular helper cell lymphoma follicular type has been treated with at least one line of therapy. In some embodiments, the nodal T follicular helper cell lymphoma follicular type has been treated with at least two lines of therapy.

[0200] In some embodiments, provided herein are methods for treating a nodal T follicular helper cell lymphoma follicular type in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0201] In some embodiments, the cancer is a nodal T follicular helper cell lymphoma-NOS. In some embodiments, the nodal T follicular helper cell lymphoma-NOS is relapsed or refractory. In some embodiments, the nodal T follicular helper cell lymphoma-NOS is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or a Docket No. TRLN-013-030W01 / TLS-068WO percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). In some embodiments, the nodal T follicular helper cell lymphoma-NOS is relapsed or refractory and BCL6+. In some embodiments, the nodal T follicular helper cell lymphoma-NOS has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, or an EZH2 A692X mutation. In some embodiments, the nodal T follicular helper cell lymphoma-NOS has an EZH2 mutation selected from the group consisting of Y646C, Y646F, Y646H, Y646N, Y646S, Y666N, A682G, and A692V. In some embodiments, the nodal T follicular helper cell lymphoma-NOS is BCL6+ and has an EZH2 dysregulation. In some embodiments, the nodal T follicular helper cell lymphoma-NOS is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the nodal T follicular helper cell lymphoma-NOS is previously untreated. In some embodiments, the nodal T follicular helper cell lymphoma-NOS has been treated with at least one line of therapy. In some embodiments, the nodal T follicular helper cell lymphoma-NOS has been treated with at least two lines of therapy.

[0202] Provided herein are methods for treating a nodal T follicular helper cell lymphoma-NOS in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) once per day. In some embodiments, the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a Docket No. TRLN-013-030W01 / TLS-068WO pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, or 150 mg) twice per day.

[0203] In some embodiments, the cancer is a non-Hodgkin lymphoma (e.g., a mature B-cell neoplasm (e.g., chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Burkitt lymphoma (BL), large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary large B-cell lymphoma of immune-privileged sites (primary LBCL of immune-privileged sites), intravascular large B-cell lymphoma (IVLBCL), primary mediastinal large B-cell lymphoma (primary mediastinal LBCL), HGBCL with 11q aberrations, or high grade B-cell lymphoma NOS (HGBCL-NOS)), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or transformations of indolent B-cell lymphomas (e.g., transformed FL or Richter transformation of CLL)), a peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma), nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type), or nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS))), or a primary cutaneous T-cell lymphoid proliferation or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, Sezary syndrome, or primary cutaneous gamma-delta T-cell lymphoma)). In some embodiments, the non-Hodgkin lymphoma is B-cell non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is CD20-positive. In some embodiments, the non-Hodgkin lymphoma is CD20-positive B-cell non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is a T-cell lymphoma.

[0204] In some embodiments, the subject is treatment-naive for the non-Hodgkin lymphoma. In some embodiments, the subject has previously received chemotherapy. In some embodiments, the subject has been previously treated with an anti-CD20 therapy (e.g., rituximab or obinutuzumab) as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has been previously treated with rituximab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has been previously treated with obinutuzumab as a monotherapy or in combination with an Docket No. TRLN-013-030W01 / TLS-068WO additional therapy or therapeutic agent. In some embodiments, the subject has previously been treated with R-CHOP (RITUXAN® (rituximab), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), or G-CHOP (GAZYVA® (obinutuzumab)), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone). A less intensive and / or dose reduced regimen of CHOP is sometimes called “mini”-CHOP (and, consequently, mini-R-CHOP or mini-G-CHOP for those combinations). In some cases, the subject has previously been treated with etoposide and R-CHOP (called R-EPOCH). In some cases, the subject has been previously treated with R-CHOP combined with lenalidomide, venetoclax, ibrutinib, acalabrutinib, obinutuzumab, polatuzumab, pembrolizumab, durvalumab, or mosunetuzumab. In some embodiments, the subject has been previously treated with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP). In some embodiments, the subject has been previously treated with rituximab and bendamustine (BR). In some embodiments, the subject has been previously treated with rituximab, bendamustine, and polatuzumab vedotin (pola-BR). In some embodiments, the subject has been previously treated with cyclophosphamide, vincristine, and prednisone (CVP), with or without rituximab or obinutuzumab. In some embodiments, the subject has been previously treated with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE). In some embodiments, the subject has been previously treated with a lenalidomide-containing regimen (e.g., rituximab and lenalidomide (R2) or R2+ brentuximab vedotin). In some embodiments, the subject has been previously treated with an anti -CD 19 therapy (e.g., tafasitamab (e.g., MONJUVI® (tafasitamab-cxix), or a biosimilar thereof) and lenalidomide. In some embodiments, the subject has previously been treated with a cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy). In some embodiments, the subject has been previously treated with a CD 19 targeted CAR T therapy (e.g., axicabtagene ciloleucel (e.g., YESCARTA® (axicabtagene ciloleucel), or a biosimilar thereof), lisocabtagene maraleucel (e.g., BREYANZI® (lisocabtagene maraleucel), or a biosimilar thereof), or tisagenlecleucel (e.g., KYMRIAH® (tisagenlecleucel), or a biosimilar thereof)). In some embodiments, the subject has been previously treated with an antibody-drug conjugate (e.g., polatuzumab vedotin, zilovertamab vedotin, or loncastuximab tesirine). In some embodiments, the subject has been previously treated with an XPO1 inhibitor (e.g., selinexor). In some embodiments, the subject has been previously treated with an anti-IL6 receptor therapy (e.g., tocilizumab). In some embodiments, the subject has been previously treated with a BTK inhibitor (e.g., zanubrutinib), optionally in combination with obinutuzumab. In some embodiments, the subject has been previously treated with golcadomide. In some embodiments, the subject has been previously treated with an EZH2 inhibitor (e.g., tazemetostat, or any of the EZH2 inhibitors described herein). Docket No. TRLN-013-030W01 / TLS-068WO In some embodiments, the subject has received one or more lines of therapy. In some embodiments, the subject has received two or more lines of therapy. In some embodiments, the non-Hodgkin lymphoma is non-progressing (including stable disease) non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is relapsed or refractory non-Hodgkin lymphoma. In some embodiments, the subject relapsed after, or is refractory to, a rituximabcontaining regimen. In some embodiments, the subject relapsed after, or is refractory to, an obinutuzumab-containing regimen.

[0205] In some embodiments, treatment effect can be measured by progression-free survival (PFS), event-free survival (EFS), overall survival (OS), time to treatment failure, response rate (e.g., overall response rate, complete response, partial response, or a combination thereof), duration of response, or a combination thereof.

[0206] In some embodiments, the cancer is a large B-cell lymphoma (LBCL) (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with llq aberrations, or HGBCL-NOS). In some embodiments, the large B-cell lymphoma (e.g., DLBCL-NOS) is characterized by BCL2 translocation, BCL6 translocation, a CD79B mutation (e.g., H225Y, A205D, Y196del, Y196F, Y196D, Y207X, Y196N, A205fs, Y196S, Y196H, A205fs, T206fs, H194_E197delinsQ, E197G, K219T, E192fs, or Y196C), an EZH2 mutation (e.g., a Y646F, Y646N, A682G, or A692V mutation), a MYC translocation, a MYD88 mutation (e.g., a L265P mutation), a NOTCH1 mutation (e.g., Q2394X, Q2501X, Q2459X, Y2490X, G2427fs, Q2444X, P2514fs, orP2517S), a. NOTCH 2 mutation (e.g., Q2285K, S2136fs, Q2361X, P2288fs, L2415fs, G2410fs, Q2409X, S2388X, I2304fs, Q2364X, Q2360fs, S2395X, E2261fs, M2267fs, Q2285fs, R2400X, P2303fs, Q2285fs, A2273fs, K2133fs, Q2389X, E2399X, E2290X, Q2325X, Y2340X, Y2392X, or E2411fs), a TP53 mutation (e.g., R181C, E336A, R248W, P98fs, P152L, R280I, S149fs, P151H, G245D, Y236D, S127F, A161T, D148fs, M246I, Y126C, H179R, A159P, C238G, L93fs, Y220C, R283fs, G244D, G245S, E171X, R209X, T155_R156dup, E271K, R306X, G105D, L93fs, G262V, W53X, G244V, H214Y, R282W, R337C, Q331fs, R273G, R273C, C176Y, S215R, R213Q, I195T, G245R, I232T, R175H, Y126D, R273H, R196X, Y205C, C141Y, C229X, Y126N, P278S, P151S, Y236H, R282G, Y103X, V216M, G244S, G266E, V173A, V173fs, I254S, T125M, R342X, P152fs, Y205D, V274L, L257P, C135Y, C176R, Y234N, R248Q, G244R, Y234H, R248G, M237I, R213X, E258D, V173M, L252_I254del, L252I, Y234C, or C176F), 17p deletion, 18q gain, or a combination thereof. In some embodiments, the large B-cell lymphoma (e.g., DLBCL-NOS) has a BCL6 rearrangement, a NOTCH2 mutation (e.g., Q2285K, S2136fs, Q2361X, P2288fs, L2415fs, Docket No. TRLN-013-030W01 / TLS-068WO G2410fs, Q2409X, S2388X, I2304fs, Q2364X, Q2360fs, S2395X, E2261fs, M2267fs, Q2285fs, R2400X, P2303fs, Q2285fs, A2273fs, K2133fs, Q2389X, E2399X, E2290X, Q2325X, Y2340X, Y2392X, E2411fs), or a combination thereof. In some embodiments, the large B-cell lymphoma (e.g., DLBCL-NOS) is large B-cell lymphoma having a germinal center B-cell (GCB) cell of origin. In some embodiments, the large B-cell lymphoma (e.g., DLBCL-NOS) is a BN2-type large B-cell lymphoma (e.g., having a BCL6 rearrangement and / or a NOTCH2 mutation). In some embodiments, the large B-cell lymphoma (e.g., DLBCL-NOS) is an EZB-type large B-cell lymphoma (e.g., having an EZH2 mutation and / or a BCL2 translocation). In some embodiments, the large B-cell lymphoma (e.g., DLBCL-NOS) is a Cl genetic cluster large B-cell lymphoma (e.g., having a BCL6 rearrangement and / or a NOTCH 2 mutation). See, e.g., Schmitz, Roland, et al. New England Journal of Medicine 378.15 (2018): 1396-1407, doi: 10.1056 / NEJMoal801445; Chapuy, Bjoem, et al. Nature Medicine 24.5 (2018): 679-690, doi: 10.1038 / s41591 -018-0016-8 for additional description of these classifications.

[0207] In some embodiments, the cancer is a FL. In some embodiments, the FL is grade l-3a. In some embodiments, the FL is grade 3b. In some embodiments, the FL has a BCL2 translocation (e.g., a t(14; 18) translocation). In some embodiments, the FL has an EZH2 mutation (e.g., aY646F, Y646N, A682G, or A692V mutation). See, e.g., Kridel, Robert, Laurie H. Sehn, and Randy D. Gascoyne. The Journal of Clinical Investigation 122.10 (2012): 3424-3431, doi: 10.1172 / JCI63186.

[0208] In some embodiments, the cancer is a B-ALL. In some embodiments, the B-ALL has an MLL rearrangement (e.g., an MLL-Af4 fusion, an MLL-Af6 fusion, an MLL-Af9 fusion, an MLL-ENL fusion, or an MLL-PTD fusion), is pre-B-cell receptor positive (Pre-BCR+), has the Philadelphia chromosome, is Philadelphia chromosome-like, is dependent on Ras signaling, has a BCL2 amplification, has a JAK2 mutation (with or without high cytokine receptor-like factor 2 (CRLF2) expression), or a combination thereof. See, e.g., Knight, Thomas, and Julie Anne Elizabeth Irving. Frontiers in Oncology 4 (2014): 160, doi: 10.3389 / fonc.2014.00160; Geng, Huimin, et al. Cancer Cell 27.3 (2015): 409-425, doi: 10.1016 / j.ccell.2015.02.003; Jain, Nitin, et a\. Blood, 129.5 (2017): 572-581, doi: 10.1182 / blood-2016-07-726588; andHurtz, Christian, etal. Genes & Development 33 (2019): 1265-1279, doi: 10.1101 / gad.327593.119. In some embodiments, a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is used in the treatment of subj ect having a B-ALL. In some embodiments, the B-ALL is a relapsed or refractory B-ALL after two or more lines of therapy. Docket No. TRLN-013-030W01 / TLS-068WO In some embodiments, the subject has previously been treated with one or more lines of therapy, such as chemotherapy, radiation, a multi-kinase inhibitor, or a combination thereof. In some embodiments, the subject has previously been treated with surgery.

[0209] In some embodiments, the cancer is a large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with 11 q aberrations, or HGBCL-NOS). In some embodiments, the subj ect has not been previously treated for the large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with llq aberrations, or HGBCL-NOS).

[0210] As used herein, a “multispecific antibody or antigen binding fragment thereof’ is an antibody or antigen binding fragment thereof that binds to two or more (e.g., three, four, or more) different human antigens. Non-limiting examples of multispecific antibodies or antigen binding fragments thereof include bispecific, trispecific, and tetraspecific antibodies or antigen binding fragments thereof. A multispecific antibody or antigen binding fragment thereof can take many different antibody or antibody fragment formats, such as a traditional antibody including 2 Fab domains and 1 Fc domain, a tandem scFv, and four scFvs connected by a Fc domain. See, e.g., Arvedson, Tara, et al. Annual Review of Cancer Biology 6.1 (2022): 17-34, doi: 10.1146 / annurev-cancerbio-070620- 104325. When referring to an “antigen binding fragment” of a multispecific antibody, the antigen binding fragment binds to each of the specified human antigens. In some embodiments, a multispecific antibody can bind to at least one antigen on an immune cell (e.g., a T-cell, an NK cell, a macrophage, or a myeloid cell); in some such embodiments, the multispecific antibody can be called an “immune engager”. In some embodiments, a multispecific antibody includes an Fc portion that interacts with an Fc receptor, for example, on the surface of a macrophage, NK cell, or dendritic cell. A multispecific T-cell recruiting antibody or an antigen binding fragment thereof is a type of multispecific antibody (and can also be considered to be an immune engager). Other immune engagers include, for example, myeloid cell engagers such as DR-0201 (SAR-448501) andLTZ-301.

[0211] As used herein, a “multispecific T-cell recruiting antibody or antigen binding fragment thereof’ is an antibody or antigen binding fragment thereof that binds to at least one antigen on T-cells (often CD3) and at least one antigen on a tumor cell. In some embodiments, the antigen on the tumor cell is CD19, CD20, or both. A bispecific T-cell recruiting antibody is a type of Docket No. TRLN-013-030W01 / TLS-068WO multispecific T-cell recruiting antibody. Another multispecific T-cell recruiting antibody is EVOLVE-205, which binds to CD2, CD3, and CD20. See, e.g., An, Xingyue, et al. Cancer Research 85.8_Supplement_l (2025): 2137-2137, doi: 10.1158 / 1538-7445. AM2025-2137. A multispecific T-cell recruiting antibody or an antigen binding fragment thereof can take many different antibody or antibody fragment formats, such as a traditional antibody including 2 Fab domains and 1 Fc domain, a tandem scFv (also sometimes referred to as a bispecific T-cell engager or a BiTE®), and four scFvs connected by a Fc domain. See, e.g., Arvedson, Tara, et al. Annual Review of Cancer Biology 6.1 (2022): 17-34, doi: 10.1146 / annurev-cancerbio-070620-104325.

[0212] As used herein, a “bispecific antibody or antigen binding fragment thereof’ is an antibody or antigen binding fragment thereof that binds to two different human antigens. A bispecific antibody or antigen binding fragment thereof can take many different antibody or antibody fragment formats, such as a traditional antibody including 2 Fab domains and 1 Fc domain, a tandem scFv, and four scFvs connected by a Fc domain. See, e.g., Arvedson, Tara, et al. Annual Review of Cancer Biology 6.1 (2022): 17-34, doi: 10.1146 / annurev-cancerbio-070620-104325. When referring to an “antigen binding fragment” of a bispecific antibody, the antigen binding fragment binds to both of the two human antigens. One example of a bispecific antibody is zeripatamig (TG-1801), which binds to CD19 and CD47. See, e.g., Hawkes, Eliza, et al. Blood (2022) 140 (Supplement 1): 6599-6601, doi: 10.1182 / blood-2022-169171. In some embodiments, a bispecific antibody includes an Fc portion that interacts with an Fc receptor, for example, on the surface of a macrophage, NK cell, or dendritic cell. A bispecific T-cell recruiting antibody or an antigen binding fragment thereof is a type of bispecific antibody.

[0213] As used herein, a “bispecific T-cell recruiting antibody or antigen binding fragment thereof’ is an antibody or antigen binding fragment thereof that binds to an antigen on T-cells (often CD3) and an antigen on a tumor cell. In some embodiments, the antigen on the tumor cell is CD19, CD20, or both. A bispecific T-cell recruiting antibody or an antigen binding fragment thereof can take many different antibody or antibody fragment formats, such as a traditional antibody including 2 Fab domains and 1 Fc domain, a tandem scFv (also sometimes referred to as a bispecific T-cell engager or a BiTE®), and four scFvs connected by a Fc domain. See, e.g., Arvedson, Tara, et al. Annual Review of Cancer Biology 6.1 (2022): 17-34, doi: 10.1146 / annurev-cancerbio-070620- 104325. In some embodiments, a bispecific T-cell recruiting antibody or an antigen binding fragment thereof is a bispecific T-cell engager.

[0214] In some embodiments, a bispecific T-cell recruiting antibody is an anti-CD19 and anti-CD3 bispecific antibody or antigen binding fragment thereof (e.g., BLINCYTO® (blinatumomab), surovatamig (AZD-0486), or a biosimilar thereof). In some embodiments, a bispecific T-cell Docket No. TRLN-013-030W01 / TLS-068WO recruiting antibody is an anti-CD19 and anti-CD3 bispecific T-cell engager (e.g., BLINCYTO® (blinatumomab), or a biosimilar thereof).

[0215] In some embodiments, a bispecific T-cell recruiting antibody is an anti-CD20 and anti-CD3 bispecific antibody or antigen binding fragment thereof (e.g., epcoritamab (e.g., epcoritamab-bysp (EPKINLY™), or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab-axgb (LUNSUMIO™), or a biosimilar thereof), plamotamab, odronextamab (e.g., ORDSPONO™), biosimilars thereof, or a combination thereof). In some embodiments, bispecific T-cell recruiting antibody is an anti-CD20 and anti-CD3 bispecific T-cell engager.

[0216] In some embodiments, the subject having a large B-cell lymphoma has previously received chemotherapy. In some embodiments, the subject has been previously treated with rituximab or obinutuzumab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has been previously treated with rituximab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has been previously treated with obinutuzumab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has previously been treated with lenalidomide in combination with rituximab or obinutuzumab. In some embodiments, the subject has been previously treated with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP). In some embodiments, the subject has been previously treated with rituximab and bendamustine (BR). In some embodiments, the subject has been previously treated with rituximab, bendamustine, and polatuzumab vedotin (pola-BR). In some embodiments, the subject has previously been treated with cyclophosphamide, vincristine and prednisone (CVP), optionally in combination with rituximab or obinutuzumab. In some embodiments, the subject has been previously treated with rituximab, ifosfamide, carboplatin, and etoposide (R-ICE). In some embodiments, the subject has been previously treated with a lenalidomide-containing regimen (e.g., rituximab and lenalidomide (R2) or R2+ brentuximab vedotin). In some embodiments, the subject has been previously treated with an anti-CD 19 therapy (e.g., tafasitamab (e.g., MONJUVI® (tafasitamab-cxix), or a biosimilar thereof) and lenalidomide. In some embodiments, the subject has previously been treated with R-CHOP (RITUXAN® (rituximab), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone), or G-CHOP (GAZYVA® (obinutuzumab)), cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone). A less intensive and / or dose reduced regimen of CHOP is sometimes called “mini”-CHOP (and, consequently, mini-R-CHOP or mini-G-CHOP for those combinations). In some cases, the subject has previously been treated with etoposide and R-CHOP (called R-EPOCH). In some cases, the subject has been previously treated with R-CHOP combined with lenalidomide, Docket No. TRLN-013-030W01 / TLS-068WO venetoclax, ibrutinib, acalabrutinib, obinutuzumab, polatuzumab, pembrolizumab, durvalumab, or mosunetuzumab. In some embodiments, the subject has been previously treated with a rituximabcontaining regimen. In some embodiments, the subject has been previously treated with an obinutuzumab-containing regimen. In some embodiments, the subject has been previously treated with a mosunetuzumab-containing regimen. In some embodiments, the subject has been previously treated with a glofitamab-containing regimen. In some embodiments, the subject has been previously treated with an epcoritamab -containing regimen. In some embodiments, the subject has previously been treated with a cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy). In some embodiments, the subject has been previously treated with a CD19 targeted CAR T therapy (e.g., axicabtagene ciloleucel (e.g., YESCARTA® (axicabtagene ciloleucel), or a biosimilar thereof) or lisocabtagene maraleucel (e.g., BREYANZI® (lisocabtagene maraleucel), or a biosimilar thereof)). In some embodiments, the subject has been previously treated with an antibody-drug conjugate (e.g., polatuzumab vedotin, zilovertamab vedotin, or loncastuximab tesirine). In some embodiments, the subject has been previously treated with an XPO1 inhibitor (e.g., selinexor).

[0217] In some embodiments, the subject having a large B-cell lymphoma has received one or more lines of therapy. In some embodiments, the subject has been previously treated with rituximab combined with chemotherapy (e.g., R-CHOP, mini-R-CHOP, Pola-R-CHP, R-EPOCH, or R-CVP) as first-line therapy. In some embodiments, the subject has been previously treated with rituximab combined with chemotherapy (e.g., R-CHOP, mini-R-CHOP, Pola-R-CHP, R-EPOCH, or R-CVP), an anti-CD20 and anti-CD3 bispecific antibody (e.g., epcoritamab (e.g., epcoritamab-bysp (EPKINLY™), or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab -axgb (LUNSUMIO™), or a biosimilar thereof)), optionally combined with polatuzumab vedotin (e.g., mosunetuzumab and polatuzumab vedotin) as first-line therapy. In some embodiments, the subject has been previously treated with rituximab combined with chemotherapy (e.g., R-CHOP, Pola-R-CHP, R-EPOCH, or R-CVP), an anti-CD20 and anti-CD3 bispecific antibody (e.g., epcoritamab (e.g., epcoritamab-bysp (EPKINLY™), or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab -axgb (LUNSUMIO™), or a biosimilar thereof), plamotamab, odronextamab (e.g., ORDSPONO™, or a biosimilar thereof)), optionally combined with polatuzumab vedotin (e.g., mosunetuzumab + polatuzumab vedotin), or a chemotherapy-containing regimen (e.g., epcoritamab + R-CHOP, glofitamab + Pola-R-CHP, or odronextamab + CHOP) as first-line therapy. In some embodiments, the subject has received two or more lines of therapy. In some embodiments, the subject has been Docket No. TRLN-013-030W01 / TLS-068WO previously treated with a CD-19 targeted CAR T therapy (e.g., axicabtagene ciloleucel (e.g., YESCARTA® (axicabtagene ciloleucel), or a biosimilar thereof) or lisocabtagene maraleucel (e.g., BREYANZI® (lisocabtagene maraleucel), or a biosimilar thereof)), rituximab combined with chemotherapy (e.g, R-CHOP, mini-R-CHOP, Pola-R-CHP, R-EPOCH, R-CVP, R-ICE, BR, or pola-BR), or tafasitamab-lenalidomide as second-line therapy. In some embodiments, the subject has been previously treated with a CD-19 targeted CAR T therapy (e.g., axicabtagene ciloleucel (e.g., YESCARTA® (axicabtagene ciloleucel), or a biosimilar thereof) or lisocabtagene maraleucel (e.g., BREYANZI® (lisocabtagene maraleucel), or a biosimilar thereof)), rituximab combined with chemotherapy (e.g, R-CHOP, mini-R-CHOP, Pola-R-CHP, R-EPOCH, R-CVP, R-ICE, BR, or pola-BR), tafasitamab-lenalidomide, or an anti-CD20 and anti-CD3 bispecific antibody (e.g., epcoritamab (e.g., epcoritamab-bysp (EPKINLY™), or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab-axgb (LUNSUMIO™), or a biosimilar thereof), plamotamab, odronextamab (e.g., ORDSPONO™, or a biosimilar thereof)), optionally combined with polatuzumab vedotin (e.g., mosunetuzumab + polatuzumab vedotin), or a chemotherapy-containing regimen (e.g., epcoritamab + R-CHOP, glofitamab + Pola-R-CHP, or odronextamab + CHOP) as second-line therapy. In some embodiments, these second-line therapies are administered to a subject ineligible for autologous stem cell transplant (ASCT). In some embodiments, the large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with 11q aberrations, or HGBCL-NOS) is non-progressing (including stable disease) LBCL. In some embodiments, the large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with llq aberrations, or HGBCL-NOS), is relapsed or refractory LBCL. In some embodiments, the subject relapsed after, or is refractory to, a rituximab -containing regimen. In some embodiments, the subject relapsed after, or is refractory to, an obinutuzumab-containing regimen.

[0218] In some embodiments, the cancer is a large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with llq aberrations, or HGBCL-NOS). In some embodiments, the large B-cell lymphoma (e.g., diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell Docket No. TRLN-013-030W01 / TLS-068WO lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with 11 q aberrations, or HGBCL-NOS) that is a relapsed or refractory LBCL after two or more lines of therapy. In some embodiments, the subject with the large B-cell lymphoma is ineligible for autologous stem cell transplant (ASCT).

[0219] In some embodiments, the cancer is a FL. In some embodiments, the subject has not been previously treated for the FL. In some embodiments, the FL is grade l-3a. In some embodiments, the FL is grade 3b.

[0220] In some embodiments, the subject having a FL has previously received chemotherapy. In some embodiments, the subject has been previously treated with rituximab or obinutuzumab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has been previously treated with rituximab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has been previously treated with obinutuzumab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has previously been treated with rituximab or obinutuzumab monotherapy. In some embodiments, the subject has previously been treated with bendamustine in combination with rituximab or obinutuzumab. In some embodiments, the subject has previously been treated with lenalidomide in combination with rituximab or obinutuzumab (the combination of lenalidomide with rituximab is sometimes called “R2”). In some embodiments, the subject has previously been treated with cyclophosphamide, vincristine and prednisone (CVP), optionally in combination with rituximab or obinutuzumab. In some embodiments, the subject has previously been treated with R-CHOP or G-CHOP. In some embodiments, the subject has previously been treated with a cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy). In some embodiments, the subject has been previously treated with a CD19 targeted CAR T therapy (e.g., axicabtagene ciloleucel (e.g., YESCARTA® (axicabtagene ciloleucel), or a biosimilar thereof) or lisocabtagene maraleucel (e.g., BREYANZI® (lisocabtagene maraleucel), or a biosimilar thereof)). In some embodiments, the subject has received an anti-IL6 receptor therapy (e.g., tocilizumab). In some embodiments, the subject has received a BTK inhibitor (e.g., zanubrutinib), optionally in combination with obinutuzumab.

[0221] In some embodiments, the subject having a FL has received one or more lines of therapy. In some embodiments, the subject has been previously treated with rituximab monotherapy, rituximab combined with chemotherapy (e.g., R-CHOP, BR, rituximab + chlorambucil, R-CVP, fludarabine + cyclophosphamide + rituximab (FCR)), or obinutuzumab combined with Docket No. TRLN-013-030W01 / TLS-068WO chemotherapy (e.g., G-CHOP, G-CVP, or obinutuzumab + bendamustine) as first-line therapy. In some embodiments, the subject has received rituximab or obinutuzumab as maintenance therapy after first-line therapy (e.g., any of the first-line therapies provided herein). In some embodiments, the subject has been previously treated with rituximab monotherapy, rituximab combined with chemotherapy (e.g., R-CHOP, BR, rituximab + chlorambucil, R-CVP, fludarabine + cyclophosphamide + rituximab (FCR)), obinutuzumab combined with chemotherapy (e.g., G-CHOP, G-CVP, or obinutuzumab + bendamustine), or an anti-CD20 and anti-CD3 bispecific antibody (e.g., epcoritamab (e.g., epcoritamab-bysp (EPKINLY™), or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab-axgb (LUNSUMIO™), or a biosimilar thereof), plamotamab, odronextamab (e.g., ORDSPONO™, or a biosimilar thereof)), as monotherapy or optionally combined with lenalidomide (e.g., mosunetuzumab + lenalidomide or odronextamab + lenalidomide) or R2(e.g., epcoritamab + R2) as first-line therapy. In some embodiments, the subject has been previously treated with rituximab monotherapy, rituximab combined with chemotherapy (e.g., R-CHOP, BR, rituximab + chlorambucil, R-CVP, fludarabine + cyclophosphamide + rituximab (FCR)), obinutuzumab combined with chemotherapy (e.g., G-CHOP, G-CVP, or obinutuzumab + bendamustine), an anti-CD20 and anti-CD3 bispecific antibody (e.g., epcoritamab (e.g., epcoritamab-bysp (EPKINLY™), or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab-axgb (LUNSUMIO™), or a biosimilar thereof), plamotamab, odronextamab (e.g., ORDSPONO™, or a biosimilar thereof)), as monotherapy or optionally combined with lenalidomide (e.g., mosunetuzumab + lenalidomide), R2(e.g., epcoritamab + R2), or chemotherapy (e.g., odronextamab + CHOP or odronextamab + CVP), or an anti-CD19 and anti-CD3 bispecific antibody (e.g., surovatamig (AZD0486)) optionally combined with rituximab as first-line therapy. In some embodiments, the subject has received two or more lines of therapy. In some embodiments, the subject has been previously treated with rituximab monotherapy, rituximab combined with chemotherapy (e.g., R-CHOP, BR, rituximab + chlorambucil, R-CVP, or R2), obinutuzumab combined with chemotherapy (e.g., G-CHOP, G-CVP, or obinutuzumab + bendamustine), tafasitamab + R2, bendamustine monotherapy, or tazemetostat as second-line therapy. In some embodiments, the subject has received rituximab or obinutuzumab as maintenance therapy after second-line therapy (e.g., any of the second-line therapies provided herein). In some embodiments, the subject has been previously treated with rituximab monotherapy, rituximab combined with chemotherapy (e.g., R-CHOP, BR, rituximab + chlorambucil, R-CVP, or R2), obinutuzumab combined with chemotherapy (e.g., G-CHOP, G-CVP, or obinutuzumab + bendamustine), tafasitamab with or without R2, bendamustine Docket No. TRLN-013-030W01 / TLS-068WO monotherapy, tazemetostat with or without R2, or an anti-CD20 and anti-CD3 bispecific antibody (e.g., epcoritamab (e.g., epcoritamab-bysp (EPKINLY™), or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab-axgb (LUNSUMIO™), or a biosimilar thereof), plamotamab, odronextamab (e.g., ORDSPONO™, or a biosimilar thereof)), as monotherapy or optionally combined with lenalidomide (e.g., mosunetuzumab + lenalidomide or odronextamab + lenalidomide) or R2(e.g., epcoritamab + R2) as second-line therapy. In some embodiments, the subject has been previously treated with rituximab monotherapy, rituximab combined with chemotherapy (e.g., R-CHOP, BR, rituximab + chlorambucil, R-CVP, or R2), obinutuzumab combined with chemotherapy (e.g., G-CHOP, G-CVP, or obinutuzumab + bendamustine), tafasitamab with or without R2, bendamustine monotherapy, tazemetostat with or without R2, an anti-CD20 and anti-CD3 bispecific antibody (e.g., epcoritamab (e.g., epcoritamab-bysp (EPKINLY™), or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab-axgb (LUNSUMIO™), or a biosimilar thereof), plamotamab, odronextamab (e.g., ORDSPONO™, or a biosimilar thereof)), as monotherapy or optionally combined with lenalidomide (e.g., mosunetuzumab + lenalidomide or odronextamab + lenalidomide) or R2(e.g., epcoritamab + R2), a BTK inhibitor (e.g., Zanubrutinib) combined with anti-CD20 therapy (e.g., obinutuzumab), a CD 19 targeted CAR T therapy (e.g., axicabtagene ciloleucel (e.g., YESCARTA® (axicabtagene ciloleucel), or a biosimilar thereof) or lisocabtagene maraleucel (e.g., BREYANZI® (lisocabtagene maraleucel), or a biosimilar thereof)), or rituximab combined with golcadomide as second-line therapy.

[0222] In some embodiments, the non-Hodgkin lymphoma is non-progressing (including stable disease) FL. In some embodiments, the FL is relapsed or refractory FL. In some embodiments, the FL is a relapsed or refractory FL, and the subject has previously received a rituximab-containing regimen. In some embodiments, the FL is relapsed or refractory FL, and the subject has previously received an obinutuzumab-containing regimen. In some embodiments, the FL is a relapsed or refractory FL after two or more lines of therapy.

[0223] In some embodiments, the cancer is a BL. In some embodiments, the subject has not been previously treated for the BL. In some embodiments, the subject has previously received chemotherapy. In some embodiments, the subject has been previously treated with rituximab or obinutuzumab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has been previously treated with rituximab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has been previously treated with obinutuzumab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has previously been Docket No. TRLN-013-030W01 / TLS-068WO treated with rituximab or obinutuzumab monotherapy. In some embodiments, the subject has previously been treated with bendamustine in combination with rituximab or obinutuzumab. In some embodiments, the subject has previously been treated with R-CHOP or G-CHOP. In some embodiments, the subject has previously been treated with rituximab, cyclophosphamide, vincristine, doxorubicin, and methotrexate (R-CODOX-M). In some embodiments, the subject has previously been treated with rituximab, ifosfamide, etoposide, and cytarabine (R-IVAC). In some embodiments, the subject has previously been treated with rituximab with dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH-R). In some embodiments, the subject has received one or more lines of therapy. In some embodiments, the subject has received two or more lines of therapy. In some embodiments, the subject has previously been treated with a cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy). In some embodiments, the BL is non-progressing (including stable disease) BL. In some embodiments, the BL is relapsed or refractory BL. In some embodiments, the BL is relapsed or refractory BL, and the subject has previously received a rituximab-containing regimen. In some embodiments, the BL is relapsed or refractory BL, and the subject has previously received an obinutuzumab-containing regimen. In some embodiments, the BL is a relapsed or refractory BL after two or more lines of therapy.

[0224] In some embodiments, the cancer is a T-cell lymphoma. In some embodiments, the T-cell lymphoma is a peripheral T-cell lymphoma (PTCL) (e.g., anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma), nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type), or nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS))) or a primary cutaneous T-cell lymphoid proliferation or lymphoma (cutaneous T-cell lymphoma (CTCL)) (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, Sezary syndrome, or primary cutaneous gammadelta T-cell lymphoma) In some embodiments, the subject has not been previously treated for the PTCL or CTCL. In some embodiments, the subject has previously received chemotherapy. In some embodiments, the subject has been previously treated with rituximab or obinutuzumab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has been previously treated with rituximab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject Docket No. TRLN-013-030W01 / TLS-068WO has been previously treated with obinutuzumab as a monotherapy or in combination with an additional therapy or therapeutic agent. In some embodiments, the subject has previously been treated with rituximab or obinutuzumab monotherapy. In some embodiments, the subject has previously been treated with bendamustine in combination with rituximab or obinutuzumab. In some embodiments, the subject has previously been treated with lenalidomide in combination with rituximab or obinutuzumab (the combination with rituximab is sometimes called “R2”). In some embodiments, the subject has previously been treated with cyclophosphamide, vincristine and prednisone (CVP), optionally in combination with rituximab or obinutuzumab (R-CVP or G-CVP, respectively). In some embodiments, the subject has previously been treated with R-CHOP or G-CHOP. In some embodiments, the subject has received one or more lines of therapy. In some embodiments, the subject has received two or more lines of therapy. In some embodiments, the subject has previously been treated with a cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy). In some embodiments, the PTCL or CTCL is non-progressing (including stable disease) PTCL or CTCL. In some embodiments, the PTCL or CTCL is relapsed or refractory PTCL or CTCL. In some embodiments, the PTCL or CTCL is relapsed or refractory PTCL or CTCL, and the subject has previously received a rituximab-containing regimen. In some embodiments, the PTCL or CTCL is relapsed or refractory PTCL or CTCL, and the subject has previously received an obinutuzumab-containing regimen. In some embodiments, the PTCL or CTCL is a relapsed or refractory PTCL or CTCL after two or more lines of therapy.

[0225] In some embodiments, the cancer is B-ALL. In some embodiments, the B-ALL is Philadelphia chromosome positive B-ALL. In some embodiments, the B-ALL is Philadelphia chromosome negative B-ALL. In some embodiments, the subject has previously received chemotherapy. In some embodiments, the subject has previously been treated with at least one cycle of induction, consolidation, intensification, and optional maintenance. In some cases, induction therapy can include an anthracycline, vincristine, a corticosteroid, and cyclophosphamide. In some embodiments, the anthracycline is doxorubicin. In some embodiments, the corticosteroid is dexamethasone. In some cases, the combination of doxorubicin, vincristine, dexamethasone, and cyclophosphamide is known as CVD. In some embodiments, induction therapy can further include a tyrosine kinase inhibitor (e.g., a BCR-ABL inhibitor for subjects with this fusion). In some embodiments, induction therapy can further include asparaginase (e.g., for pediatric subjects). In some cases, consolidation therapy can include methotrexate, cytarabine, vincristine, 6-mercaptopurine, 6-thioguanine, cyclophosphamide, and etoposide. In some embodiments, consolidation therapy can further include a tyrosine kinase inhibitor (e.g., a BCR-ABL inhibitor for subjects with this fusion). In some embodiments, Docket No. TRLN-013-030W01 / TLS-068WO consolidation therapy can further include asparaginase (e.g., for pediatric subjects). In some cases, intensification therapy can include an anthracycline, vincristine, a corticosteroid, and cyclophosphamide. In some embodiments, intensification therapy can further include a tyrosine kinase inhibitor (e.g., a BCR-ABL inhibitor for subjects with this fusion). In some embodiments, intensification therapy can further include asparaginase (e.g., for pediatric subjects). Typically, pediatric and young adult regimens include higher cumulative doses of asparaginase and vincristine but can have lower cumulative doses of anthracycline and cyclophosphamide compared to adult regimens. In any of these cycle phases, an anti-CD20 immunotherapy (e.g., rituximab) can be added for subjects expressing the CD20 protein on the cells. See, e.g., Muffly, Lori, and Emily Curran. Hematology 2014, the American Society of Hematology Education Program Book 2019.1 (2019): 17-23, doi: 10.1182 / hematology.2019000009. In some embodiments, the subject has received one or more lines of therapy. In some embodiments, the subject has received two or more lines of therapy. In some embodiments, the B-ALL is relapsed or refractory B-ALL. In some embodiments, the B-ALL is a relapsed or refractory B-ALL after two or more lines of therapy.

[0226] It will be understood that when employed as pharmaceuticals, the compounds of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein. Similarly, it will be understood that when employed as a pharmaceutical, an EZH2 inhibitor, can be administered in the form of a pharmaceutically acceptable salt or a pharmaceutical composition as described herein.

[0227] Also provided herein is an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, for use in treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject in need thereof. Provided herein is use of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, for the treatment of cancer, for example, any of the cancers provided herein. Also provided herein is use of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a- Docket No. TRLN-013-030W01 / TLS-068WO 3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) that is BCL6+ (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test, by a percent nuclear positivity score of greater than or equal to 20% in an IHC test, by a percent nuclear positivity score for BCL6 of greater than or equal to 25% in an IHC test, or by a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test) Provided also herein is an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject in need thereof. Provided herein is use of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of cancer, for example, any of the cancers provided herein.

[0228] Also provided herein is a pharmaceutical composition for treating a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))) in a subject in need thereof, which comprises an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier. Also provided herein is use of such a pharmaceutical composition for the treatment of cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))). Provided also herein is use of such a pharmaceutical composition for the manufacture of a medicament for the treatment of cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))).

[0229] Also provided herein are methods for treating a subject having a cancer (e.g., a hematological malignancy (e.g., a lymphoma (e.g., a NHL))), wherein the methods comprise:

[0230] (a) administering one or more doses of a first anticancer agent to the subject; and

[0231] (b) after (a), administering a therapeutically effective amount of an EZH2 inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula Docket No. TRLN-013-030W01 / TLS-068WO (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, a first anticancer agent includes any of the previous lines of therapy described herein (e.g., any of the first-line or second-line therapies provided herein). In some embodiments, a first anticancer agent includes a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))) (but not an EZH2 inhibitor). In some embodiments, a first anticancer agent includes an EZH2 inhibitor, (but not a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof).

[0233] In some embodiments of any the methods described herein, a therapeutically effective amount of an EZH2 inhibitor, and the therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapy) agents.

[0234] In some embodiments, the additional therapeutic agent is chemotherapy, anti-CD20 therapy, cell-based therapy (e.g., adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy or a combination thereof).

[0235] In some embodiments, the additional therapy or therapeutic agent is chemotherapy. In some embodiments, the chemotherapy is CVD, hyperCVD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone), CHOP, R-CHOP, G-CHOP, EPOCH, R-EPOCH, Pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone), R-CODOX-M, R-IVAC, DA-EPOCH-R, CVP, R-CVP, G-CVP, CVD (cyclophosphamide, vincristine, dacarbazine, including mini-CVD), cyclophosphamide, bendamustine with rituximab or obinutuzumab, methotrexate-cytarabine, vincristine (with or without steroids (e.g., dexamethasone)), nelarabine, a hypomethylating agent (e.g., azacitidine and / or decitabine), CALGB8811, or pediatric-inspired multi-agent chemotherapy (e.g., GRAALL-2003, COG Docket No. TRLN-013-030W01 / TLS-068WO AALL-0434, CCG-1961, CALGB 10403, or the DFCI regimen). In some embodiments, the chemotherapy is cyclophosphamide.

[0236] In some embodiments, the anti-CD20 therapy is divozilimab, epcoritamab (e.g., epcoritamab-bysp, or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), ibritumomab tiuxetan (e.g., ZEVALIN® (ibritumomab tiuxetan), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab-axgb, or a biosimilar thereof), obinutuzumab (e.g., GAZYVA® (obinutuzumab), or a biosimilar thereof), ocrelizumab (e.g., OCREVUS® (ocrelizumab), or a biosimilar thereof), odronextamab, ofatumumab (e.g., ARZERRA® (ofatumumab), or a biosimilar thereof), plamotamab, rituximab (e.g., RITUXAN® (rituximab), or a biosimilar thereof (e.g., rituximab -abbs, rituximab-arrx, rituximab-pvvr, ACELLBIA® (rituximab), HALPRYZA® (rituximab), HANLIKON® (rituximab), RIXATHON® (rituximab), REDITUX™ (rituximab), Retuxira (rituximab), BI-695500, GB-241, Mabion-CD20, RTXM-83, SAIT-101), ublituximab (e.g., ublituximab-xiiy, or a biosimilar thereof), veltuzumab, zuberitamab, MIL-62, SCT-400, TQB-2303, biosimilars thereof, or a combination thereof. In some embodiments, the anti-CD20 therapy is a bispecific antibody or antigen-binding fragment thereof (e.g., epcoritamab (e.g., epcoritamab-bysp, or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab-axgb, or a biosimilar thereof), plamotamab, odronextamab, biosimilars thereof, or a combination thereof. In some embodiments, the anti-CD20 therapy is an anti-CD20 and anti-CD3 bispecific antibody or antigen-binding fragment thereof (e.g., epcoritamab (e.g., epcoritamab-bysp, or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab-axgb, or a biosimilar thereof), plamotamab, odronextamab, biosimilars thereof, or a combination thereof. In some embodiments, the anti-CD20 therapy is an antibody-drug conjugate (e.g., ibritumomab tiuxetan (e.g., ZEVALIN® (ibritumomab tiuxetan), or a biosimilar thereof). In some embodiments, the anti-CD20 therapy is rituximab. In some embodiments, the anti-CD20 therapy is obinutuzumab. In some embodiments, the anti-CD20 therapy is mosunetuzumab. In some embodiments, the anti-CD20 therapy is epcoritamab.

[0237] In some embodiments, the cell-based therapy is adoptive cell therapy (e.g., CAR T therapy, cytokine-induced killer cells (CIKs), natural killer cells (e.g., CAR-modified NK cells)) or antibody-armed cell therapy. In some embodiments, the cell-based therapy is actalycabtagene autoleucel, axicabtagene ciloleucel (e.g., YESCARTA® (axicabtagene ciloleucel), or a biosimilar thereof), brexucabtagene autoleucel (e.g., TECARTUS® (brexucabtagene autoleucel), or a biosimilar thereof), cemacabtagene ansegedleucel, inaticabtagene autoleucel, lisocabtagene maraleucel (e.g., BREYANZI® (lisocabtagene maraleucel), or a biosimilar thereof), obecabtagene Docket No. TRLN-013-030W01 / TLS-068WO autoleucel, rapcabtagene autoleucel, relmacabtagene autoleucel (e.g., CARTEYVA® (relmacabtagene autoleucel), or a biosimilar thereof), tisagenlecleucel (e.g., KYMRIAH® (tisagenlecleucel), or a biosimilar thereof), varnimcabtagene autoleucel (e.g., IMN-003A, or a biosimilar thereof), zamtocabtagene autoleucel, BZ-019, CD19CAR CTL, CTL-119, TAK-007, XLCART-001, biosimilars thereof, or a combination thereof. In some embodiments, the cell-based therapy is a CD 19 targeted cell-based therapy (e.g., actalycabtagene autoleucel, axicabtagene ciloleucel (e.g., YESCARTA® (axicabtagene ciloleucel), or a biosimilar thereof), brexucabtagene autoleucel (e.g., TECARTUS® (brexucabtagene autoleucel), or a biosimilar thereof), cemacabtagene ansegedleucel, inaticabtagene autoleucel, lisocabtagene maraleucel (e.g., BREYANZI® (lisocabtagene maraleucel), or a biosimilar thereof), obecabtagene autoleucel, rapcabtagene autoleucel, relmacabtagene autoleucel (e.g., CARTEYVA® (relmacabtagene autoleucel), or a biosimilar thereof), tisagenlecleucel (e.g., KYMRIAH® (tisagenlecleucel), or a biosimilar thereof), varnimcabtagene autoleucel (e.g., IMN-003A, or a biosimilar thereof), zamtocabtagene autoleucel, BZ-019, CD19CAR CTL, CTL-119, TAK-007, XLCART-001, biosimilars thereof, or a combination thereof.) In some embodiments, the cell-based therapy is a CD20 targeted cell-based therapy (e.g., zamtocabtagene autoleucel).

[0238] Also provided herein are methods for inhibiting cell proliferation, in vitro or in vivo, the methods comprising contacting a cell with an effective amount of an EZH2 inhibitor, and an effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0239] Further provided herein are methods for increasing cell death, in vitro or in vivo, the methods comprising contacting a cell with an effective amount of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof. Also provided herein are methods for increasing tumor cell death in a subject. The methods comprise administering to the subject an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death. Docket No. TRLN-013-030W01 / TLS-068WO As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system, an in vivo system, or an ex vivo system. For example, “contacting” a cell with a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))) and an EZH2 inhibitor, includes the administration of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))) and an EZH2 inhibitor, to the cell, in vitro or in vivo, including, for example, introducing a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))) and an EZH2 inhibitor, into a sample containing cells (e.g., grown in culture or derived from a subject), an organoid, or an organism (e.g., an animal (e.g., an animal bearing a tumor), or a human). A cell viability assay can be used to measure the effect of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, on cell death in combination with an EZH2 inhibitor,. For example, cells expressing BCL6 protein and EZH2 protein (e.g, A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI-1, RL, SUDHL-4, SUDHL-5, SUDHL-6, SUDHL-8, SUDHL-10, VAL, or WSUDLCL2 cells) can be incubated (e.g., for 72 hours or for 120 hours) in a 7x7 dose matrix at various concentrations (e.g., half-log diluted from 316 nM to 1 nM, or as described in Example B2) of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, then exposed to a detection reagent (e.g., a CELLTITER-GLO® Cell Viability Assay kit) to determine cell viability. The combination activity can be assessed by the Bliss independence model: negative values indicate antagonism, positive values indicate synergy, and a value of zero indicates additive activity. All Bliss scores in the dose matrix can be added up to give a “Bliss sum” value to reflect the overall synergy activity of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula Docket No. TRLN-013-030W01 / TLS-068WO (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, in each cell line, where a positive value is indicative of synergy, a value of zero is indicative of additive activity, and a negative value is indicative of antagonism. Another way to evaluate synergy is via the “maximum synergistic area” (MSA), which is the Bliss sum of the 3×3 grid with the greatest Bliss sum in the dose matrix, where a positive value is indicative of synergy, a value of zero is indicative of additive activity, and a negative value is indicative of antagonism. In some embodiments, the cell lines tested include one or more cell lines bearing an EZH2 mutation (e.g., DB, OCI-Lyl, Pfeiffer, RL, SUDHL-4, SUDHL-6, SUDHL-10, and / or WSUDLCL2). In some embodiments, a cell line that is not dependent on BCL6 and / or that does not have significant expression of BCL6 can be used as a control (e.g., Toledo, H929, MM. IS, OPM2). As shown herein, the combination of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, surprisingly show synergy, both for EZH2 wild type and EZH2 mutant cell lines.

[0240] As another example, the potency and / or efficacy of an EZH2 inhibitor, and a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for example, a xenograft model (e.g., using an established cancer cell line such as OCI-Lyl or a patient-derived xenograft (PDX) model). See, e.g., Guo, Weikai, et al., Journal of Medicinal Chemistry 63.2 (2020): 676-695, doi: 10.1021 / acs.jmedchem.9b01618.

[0241] In some cases, treatment of a cancer or a model of a cancer (e.g., a PDX or CDX model) with a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, and an EZH2 inhibitor, can result in a regression (e.g., greater than or equal to 50% regression) of the cancer or the model of the cancer (e.g., a CDX or PDX model). In some such embodiments, the PDX model is BCL6+ as determined by an IHC test (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test). Nonlimiting examples of cell lines that can be used for a CDX study include A3 / KAW, A4 / FUK, DB, DOHH2, Farage, HT, Karpas 422, KML1, MHHPREB1, NUDHL1, OCI-Ly1, OCI-Ly3, OCI-Ly7, OCI-Ly18, OCI-Ly19, Pfeiffer, RI-1, RL, SC-1, Docket No. TRLN-013-030W01 / TLS-068WO SUDHL-4, SUDHL-5, SUDHL-6, SUDHL-8, SUDHL-10, VAL, or WSUDLCL2 cells. Nonlimiting examples of PDX models that can be used in a PDX study include CTG-3064, CTG-3766, CTG-3793, CTG-3794, CTG-3795, CTG-3797, CTG-3799, CTG-3800, CTG-3801, CTG-3802, CTG-3803, CTG-3804, CTG-3805, CTG-3830, CTG-3879, CTG-3905, DFBL-31357, DFBL-86381, DFTL-78024, LY0257, LY12962, LY2214, LY2264, LY2318, LY2345, LY3463, LY3604, LY6701, LY6933, LY6934, LY9596, LY9602, ST1735B, ST2761B, ST2902, ST2963, ST3497, ST359, ST4225, ST5002, ST5380, ST6226, or ST949B. Exemplary sources for these cell lines and PDX models include ATCC, DSMZ, JCRB, Crown Biosciences, XenoSTART, Champions Oncology, and the CPDM Center of Patient Derived Models (DFCI).

[0242] In some embodiments of any of the methods herein, an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, are administered simultaneously, separately or sequentially, wherein the amounts of an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, are together effective in treating the cancer. In some embodiments, an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, are administered simultaneously as separate pharmaceutical compositions. In some embodiments, an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, are administered as separate pharmaceutical compositions sequentially in any order, in jointly therapeutically effective amounts, e.g., in daily or intermittent dosages, in the same or different dosage forms. In some embodiments, an EZH2 inhibitor, and the compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof, are administered simultaneously as a combined dosage. Docket No. TRLN-013-030W01 / TLS-068WO In addition to EZH2, the PRC2 includes two non-catalytic subunits, embryonic ectoderm development (EED) and suppressor of zeste 12 protein homolog (SUZ12). Functions of EED include stabilization of the PRC2 and enhancement of histone methyltransferase activity. See, e.g., Bao, Qichao, et al. Drug Discovery Today (2024): 103986, doi: 10.1016 / j.drudis.2024.103986. As used herein, an “EED inhibitor” is a compound that binds to EED and reduces the abundance and / or stability of PRC2 (e.g., as determined by Western blot) and / or decreases the histone methyltransferase activity of PRC2 (e.g., as determined by a methyltransferase assay, such as the one described in Example A of International Publication No. WO 2019 / 152419, or as determined by a cell viability assay, such as the one described in Example B of International Publication No. WO 2019 / 152419).

[0243] Accordingly, provided herein are methods for treating a cancer in a subject in need thereof, the methods comprising administering to the subject: a therapeutically effective amount of an EED inhibitor; and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer in the subject has an EZH2 dysregulation (e.g., an EZH2 mutation). In some embodiments, the cancer in the subject has wild-type EZH2. In some embodiments, the cancer in the subject does not have an EZH2 dysregulation.

[0244] Also provided herein are methods for treating a hematological malignancy (e.g., a relapsed or refractory hematological malignancy or a lymphoma) in a subject in need thereof, the methods comprising administering to the subject:

[0245] (a) a therapeutically effective amount of an EED inhibitor; and

[0246] (b) a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb-2))), or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the cancer in the subject is BCL6+. Accordingly, also provided herein is are methods of treating a cancer in a subject in need thereof, the methods comprising: i) determining that the cancer in the subj ect is BCL6+; and ii) based on i), administering to the subj ect a therapeutically effective amount of an EED inhibitor, and a therapeutically effective amount of a compound of Formula (A) (e.g., Formula (A-1)), Formula (I) (e.g., Formula (I-aa) (e.g., Formula (I-aa-1), (I-aa-2), (I-aa-3), (I-aa-4), (I-aa-5), or (I-aa-6)), Formula (I-a) (e.g., Formula (I-a-1), (I-a-2), (I-a-3), (I-a-4), (I-a-5) or (I-a-6)), or Formula (I-bb) (e.g., Formula (I-bb-1) or (I-bb- Docket No. TRLN-013-030W01 / TLS-068WO 2))), or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer in the subject has an EZH2 dysregulation. In some embodiments, the cancer in the subject does not have an EZH2 dysregulation.

[0248] Exemplary EED inhibitors are described in, for example, International Publication Nos. WO 2016 / 103155, WO 2019 / 120276, WO 2019 / 152419, WO 2020 / 156479, WO 2020 / 190754, WO 2021 / 011713, WO 2021 / 032004, WO 2021 / 083380, WO 2022 / 212746, WO 2022 / 171166, WO 2023 / 016511 WO 2023 / 143576, and WO 2024 / 059607.

[0249] In some embodiments, the EED inhibitor is Compound 1002:

[0250]

[0251] Compound 1002

[0252] or a pharmaceutically acceptable salt thereof.

[0253] Compound 1002 is also known as ORIC-944 with a chemical name of 8-(4-((dimethylamino)methyl)-2-methylphenyl)-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)imidazo[1,2-c]pyrimidine-2-carbonitrile. See, e.g., Daemen, Anneleen, et al. Cancer Research 84.6_Supplement (2024): 6586-6586, doi: 10.1158 / 1538-7445. AM2024-6586 and the associated presentation slides made available on ORIC Pharmaceuticals’ website at https: / / oricpharma.eom / wp-content / uploads / 2024 / 04 / AACR2024_ORIC-944_Minisymposium.pdf.

[0254] In some embodiments, the EED inhibitor is Compound 1002, or a pharmaceutically acceptable salt thereof, pociredir, APG-5918, BR-1733, HJM-353, or MAK-683.

[0255] As used herein, the terms “subject,” “individual,” or “patient,” are used interchangeably, and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the Docket No. TRLN-013-030W01 / TLS-068WO disease, disorder, or condition to be treated and / or prevented.

[0256] In some embodiments, the subject is a pediatric subject.

[0257] The term “pediatric subject” as used herein refers to a subject under the age of 17 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first 27 days of life); infants (28 days up to 23 months); children (two years of age to 11 years of age); and adolescents (12 years of age to younger than 17 years (up to, but not including, the seventeenth birthday)). See 21 C. F. R.

[0258] 201.57(c)(9)(iv)(A); Regulatory Considerations Guidance atFN 1; and Guidance - Pediatric Drug Development: Regulatory Considerations — Complying With the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act, U. S. Food & Drug Administration (May 17, 2023). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 16 years of age (up to, but not including, the seventeenth birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 17 years of age.

[0259] In some embodiments, the subject is a geriatric subject.

[0260] The term “geriatric subject” as used herein refers to a subject 65 years of age or older. See 21 C. F. R. 201.57(c)(9)(v)(A). In some embodiments, a geriatric subject is 70 years of age or older. In some embodiments, a geriatric subject is 75 years of age or older.

[0261] The term “regulatory agency” refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U. S. Food and Drug Administration (FDA).

[0262] The phrase “therapeutically effective amount” means an amount of a compound that, when administered to a subject in need thereof is sufficient to (i) treat a disease, disorder, or condition, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, disorder, or condition, or (iii) delay the onset of one or more symptoms of the particular disease, disorder, or condition as described herein. The amount of the compound that will correspond to such an amount may vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, the use or identity of Docket No. TRLN-013-030W01 / TLS-068WO prior treatments, as well as whether the compound is administered in combination with another agent (e.g., another therapeutic agent or a supportive care agent).

[0263] The phrase “effective amount” means an amount of a compound that, when administered to a cell, in vitro or in vivo, is sufficient to reduce proliferation of the cell or to kill the cell. The amount of the compound that will correspond to such an amount will vary depending upon factors such as the particular compound and genetics of the cell to be treated, as well as whether the compound is administered in combination with another agent (e.g., another therapeutic agent or a supportive care agent).

[0264] Compound Embodiments

[0265] Provided herein are compounds of Formula (A):

[0266] / R1

[0267]

[0268] Formula (A)

[0269] or pharmaceutically acceptable salts thereof, wherein:

[0270] m3 is 1;

[0271] X3is C1-3alkylene; and

[0272] R1is -H;

[0273] R6is -F or -Cl;

[0274] L is selected from the group consisting of:

[0275] -LA4a-LA1-LA4b-bb;

[0276] -LA4a-LA3- / > / >;

[0277] -LA4a-LA3-LA4b-M>; and

[0278] -LA4a-LA1-LA4b-LA3- / > / >, wherein bb represents the point of attachment to Ring C;

[0279] LA1is selected from the group consisting of: -CH2-, -CHRL-, and -C(RL)2-;

[0280] each RLis an independently selected C1-3 alkyl; Docket No. TRLN-013-030W01 / TLS-068WO LA3is selected from the group consisting of -C=O and -O-;

[0281] LA4ais a 5-15 membered heterocyclylene optionally substituted with 1-2 substituents, each substituent an independently selected C1-3 alkyl; and

[0282] LA4bis a 5-7 membered heterocyclylene optionally substituted with 1-2 substituents independently selected from the group consisting of halo and C1-3 alkyl;

[0283] z N

[0284] N

[0285] z N

[0286] N

[0287] Ring C

[0288]

[0289] is

[0290] cl is 0, 1 or 2;

[0291] each RYis -F;

[0292] RaNis -H or C1-3alkyl; and

[0293] yy represents the point of attachment to L.

[0294] In some embodiments of Formula (A), L is -LA4a-LA1-LA4b- / > / >, wherein bb represents the point of attachment to Ring C.

[0295] In some embodiments of Formula (A), LA4ais a 5-11 membered heterocyclylene optionally substituted with 1-2 substituents independently selected from the group consisting of C1-3 alkyl. For example, LA4acan be a 6 membered heterocyclylene optionally substituted with 1-2 substituents independently selected from the group consisting of C1-3 alkyl. In some embodiments, LA4ais piperidinylene optionally substituted with 1-2 substituents independently selected from the group consisting of C1-3 alkyl.

[0296] In some embodiments of Formula (A), LA4bis a 6 membered heterocyclylene optionally substituted with 1-2 substituents independently selected from the group consisting of halo and Ci-3 alkyl. For example, LA4bis piperidinylene optionally substituted with 1-2 substituents independently selected from the group consisting of -F and -CH3.

[0297] In some embodiments of Formula (A), LA1is -CH2-.

[0298] In some embodiments of Formula (A), L is selected from the group consisting of the moieties delineated in Table LI, wherein bb represents the point of attachment to Ring C.

[0299] Table LI Docket No. TRLN-013-030W01 / TLS-068WO

[0300]

[0301] In some embodiments of Formula (A), X3is -CH2-.

[0302] In some embodiments of Formula (A), R6is -Cl.

[0303] In some embodiments of Formula (A), Ring

[0304]

[0305] C is embodiments, cl is 0 or 1. For example, cl can be 1.

[0306] In some embodiments of Formula (A), Ring C is selected from the group consisting of:

[0307]

[0308] . In some embodiments, cl is 0.

[0309] In some embodiments of Formula (A), RaNis -CH3.

[0310] In some embodiments of Formula (A), Ring C is selected from the group consisting of:

[0311]

[0312] Docket No. TRLN-013-030W01 / TLS-068WO

[0313]

[0314] In some embodiments, the compounds of Formula (A) are compounds of Formula (A-l):

[0315]

[0316] Formula (A-l)

[0317] or a pharmaceutically acceptable salt thereof, wherein:

[0318] m3 is 1;

[0319] X3is C1-3 alkylene;

[0320] R1is H;

[0321] R6is -F or -Cl;

[0322] LA1is CH2, CHMe, or CMe2;

[0323] Z1and Z2are independently selected from the group consisting of: CH, CRa4, and N; Z3and Z4are independently selected from the group consisting of: CH, CRa5, and N, provided that at least one of Z1and Z2is N; at least one of Z3and Z4is N; and when Z2is N, then Z3is CH or CRa5;

[0324] m4 and m5 are independently selected from the group consisting of: 0, 1, and 2; each Ra4is an independently selected C1-3 alkyl;

[0325] each Ra5is independently selected from the group consisting of: -F and C1-3 alkyl; and Docket No. TRLN-013-030W01 / TLS-068WO

[0326]

[0327] In some embodiments of Formula (A-l), LA1is -CH2-.

[0328] In some embodiments of Formula (A-l), X3is -CH2-.

[0329] In some embodiments of Formula (A-l), R6is -Cl.

[0330] In some embodiments of Formula (A-l), Ring C is selected from the group consisting of:

[0331]

[0332] In some embodiments of Formula (A-l), Ring

[0333]

[0334] C is

[0335] In some embodiments of Formula (A-l), Z1is N; and Z2is CH or CRa4. For example, Z1is N; Z2is CH or CRa4; and Z3is N.

[0336] i —xz4-l- 1 / / xx” z2"|_A1 \ J ’bb

[0337] In some embodiments of Formula (A-l), the

[0338]

[0339] m4^R(Ra5)ms moiety is selected from the group consisting of the moieties delineated in Table L2, wherein bb represents the point of attachment to Ring C.

[0340] Table L2

[0341]

[0342] Docket No. TRLN-013-030W01 / TLS-068WO

[0343]

[0344] In some embodiments, a compound of Formula (A) is selected from the group consisting of Compound Nos 397, 397a, 412, 412a, 449, 449a, 469, 469a, 505, 505a, 507, 507a, 516, 516a, 522, 522a, 522b, 525, 525a, 525b, 531, 531a, 533, 533a, and 575, 575a, 575b as depicted in Table Cl, or a pharmaceutically acceptable salt thereof. In some embodiments, a compound of Formula (A) is selected from the group consisting of Compound Nos. 397a, 412a, 449a, 469a, 505a, 507a, 516a, 522a, 522b, 525a, 525b, 531a, 533a, and 575b as depicted in Table Cl, or a pharmaceutically acceptable salt thereof.

[0345] Also provided herein are compounds of Formula (I):

[0346]

[0347] Formula (I)

[0348] or pharmaceutically acceptable salts thereof, wherein:

[0349] TBM is (T1):

[0350] R3R3

[0351] R6R2HN-^ TA I1')ml

[0352] A2) 'm2,

[0353] X1

[0354]

[0355] (Tl)

[0356] X1is selected from the group consisting of N and CR2;

[0357] X2is CH;

[0358] each R2is independently selected from the group consisting of: H, halo, cyano, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, -OH, and -NRdRe;

[0359] m3 is 0 or 1;

[0360] X3is C1-3 alkylene optionally substituted with 1-3 Rc;

[0361] R1is selected from the group consisting of: H and C3-6 cycloalkyl; Docket No. TRLN-013-030W01 / TLS-068WO

[0362] ml is 2; each A1is independently CH2, CHR4, or CR4R4;

[0363] m2 is 1; A2is -O-;

[0364] one R3is selected from the group consisting of:

[0365] (i) C3-6 cycloalkyl optionally substituted with 1-3 Rg, and

[0366] (ii) C1-3 alkyl optionally substituted with 1-3 -F; and

[0367] the other R3is H;

[0368] each R4is independently selected from the group consisting of: H, Ra, and Rb;

[0369] Xais selected from the group consisting of: N, CH, and CF;

[0370] Xbis selected from the group consisting of N and CRxl;

[0371] R6and Rxlare each independently selected from the group consisting of: H, halo, C1-2 alkyl, C1-2 haloalkyl, C1-2 alkoxy, CN, and -C=CH;

[0372] L is — (LA)ni~, wherein LAand nl are defined according to (AA) or (BB):

[0373] (AA)

[0374] nl is an integer from 1 to 15; and

[0375] each LAis independently selected from the group consisting of: LA1, LA3, and LA4, provided that 1-3 occurrences of LAis LA4;

[0376] (BB)

[0377] nl is an integer from 0 to 20; and

[0378] each LAis independently selected from the group consisting of: LA1and LA3;

[0379] each LA1is independently selected from the group consisting of: -CH2-, -CHRL-, and - C(RL)2-;

[0380] each LA3is independently selected from the group consisting of: -N(Rd)-, -N(Rb)-, -O-, -S(0)o-2-, and C(=O);

[0381] each LA4is independently selected from the group consisting of:

[0382] (a) C3-15 cycloalkylene or 3-15 membered heterocyclylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb; and Docket No. TRLN-013-030W01 / TLS-068WO (b) Ce-15 arylene or 5-15 membered heteroarylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of: Raand Rb;

[0383] provided that L does not contain any O-O, N-0, N-N, N-S(0)o, or 0-S(0)o-2 bonds;

[0384] wherein each RLis independently selected from the group consisting of: halo, cyano, -OH, -C1-6 alkoxy, -C1-6 haloalkoxy, -NRdRe, C(=0)N(Rf)2, S(0)o-2(Ci-6 alkyl), S(0)o-2(Ci-6 haloalkyl), S(O)i-2N(Rf)2, -Rb, and C1-6 alkyl optionally substituted with 1-6 Rc;

[0385] d(RY)

[0386] Ring C is selected from the group consisting of:

[0387]

[0388]

[0389] cl is 0, 1, 2, or 3;

[0390] each RYis independently selected from the group consisting of: Raand Rb;

[0391] RaNis H or C1-6 alkyl optionally substituted with 1-3 Rc;

[0392] Y1and Y2are independently N, CH, or CRY;

[0393] yy represents the point of attachment to L;

[0394] X is CH, C, orN;

[0395] the is a single bond or a double bond;

[0396] Lcis selected from the group consisting of: a bond, -CH2-, -CHRa-, -C(Ra)2-, -C(=O)-, -N(Rd)-, and O, provided that when X is N, then Lcis other than O; and

[0397] further provided that when Ring C is attached to -Lc- via a ring nitrogen, then X is CH, and Lcis a bond;

[0398] each Rais independently selected from the group consisting of:

[0399] (a) halo;

[0400] (b) cyano;

[0401] (c) -OH; Docket No. TRLN-013-030W01 / TLS-068WO (d) oxo;

[0402] (e) Ci-6 alkoxy optionally substituted with 1-6 Rc;

[0403] (f) -NRdRe;

[0404] (g) C(=O)Ci-6 alkyl;

[0405] (h) C(=O)Ci-6haloalkyl;

[0406] (i) C(=O)OH;

[0407] (j) C(=O)OCi-6alkyl;

[0408] (k) C(=O)OCi-6haloalkyl;

[0409] (l) C(=O)N(Rf)2;

[0410] (m) S(0)o-2(Ci-6 alkyl);

[0411] (n) S(0)o-2(Ci-6 haloalkyl);

[0412] (o) S(O)i-2N(Rf)2; and

[0413] (p) Ci-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc;

[0414] each Rbis independently selected from the group consisting of: -(Lb)b-Rbland -Rbl, wherein:

[0415] each b is independently 1, 2, or 3;

[0416] each -Lbis independently selected from the group consisting of: -O-, -N(H)-, -N(CI-3 alkyl)-, -S(0)o-2-, C(=O), and C1-3 alkylene; and

[0417] each Rblis independently selected from the group consisting of: C3-10 cycloalkyl, 4-10 membered heterocyclyl, Ce-io aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg;

[0418] each Rcis independently selected from the group consisting of: halo, cyano, -OH, -C1-6 alkoxy, -C1-6 haloalkoxy, -NRdRe, C(=O)Ci-6 alkyl, C(=O)Ci-6 haloalkyl, C(=O)OCi-6 alkyl, C(=O)OCi-6haloalkyl, C(=O)OH, C(=O)N(R')2, S(0)o-2(Ci-6 alkyl), S(0)o-2(Ci-6 haloalkyl), and S(O)i-2N(Rf)2;

[0419] each Rdand Reis independently selected from the group consisting of: H, C(=O)Ci-6 alkyl, C(=O)Ci-6haloalkyl, C(=O)OCi-6 alkyl, C(=O)OCi-6 haloalkyl, C(=O)N(Rf)2, S(O)i-2(Ci-6 alkyl), S(O)i-2(Ci-6 haloalkyl), S(O)i-2N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rb;

[0420] each Rfis independently selected from the group consisting of: H and C1-6 alkyl optionally substituted with 1-3 Rb;

[0421] each Rgis independently selected from the group consisting of: Rb, oxo, C1-3 alkyl, and Ci-3 haloalkyl; and Docket No. TRLN-013-030W01 / TLS-068WO each Rhis independently selected from the group consisting of: halo, cyano, -OH, -(C0-3 alkylene)-Ci-6 alkoxy, -(C0-3 alkylene)-Ci-6 haloalkoxy, -(C0-3 alkylene)-NH2, -(C0-3 alkylene)-N(H)(Ci-3 alkyl), and -(C0-3 alkylene)-N(Ci-3 alkyl)?.

[0422] In some embodiments of Formula (I), Ring C is selected from the group consisting of:

[0423] z N

[0424] N

[0425] RaN

[0426]

[0427] and. In some embodiments, cl is 0 or 1; and RYis selected from the group consisting of halo (e.g., -F) and C1-3 alkyl optionally substituted with 1-3 F, and RaNis C1-3 alkyl.

[0428] In some embodiments of Formula (I), Ring C is selected from the group consisting of:

[0429] ✓ N

[0430] N

[0431] aN✓ N

[0432] R N

[0433]

[0434] and; cl is 0 or 1; and RYis selected from the group consisting of halo (e.g., -F) and C1-3 alkyl optionally substituted with 1-3 F, and RaNis C1-3 alkyl.

[0435] / N N

[0436] In some embodiments of Formula (I), Ring C is

[0437]

[0438] Rald(Ra)

[0439] z N

[0440] N

[0441] yy

[0442]

[0443] . In some embodiments, cl is 0. In some embodiments, cl is 1; and RYis halo (e.g., -F). In some embodiments, RaNis C1-3 alkyl (e.g., methyl).

[0444] N

[0445] z N z N N

[0446] RaNIn some embodiments of Formula (I), Ring C

[0447]

[0448] is (eg., In some embodiments, cl is 0. In some embodiments, cl is 1; and RYis halo (e.g., -F). In some embodiments, RaNis C1-3 alkyl (e.g., methyl). Docket No. TRLN-013-030W01 / TLS-068WO d(Ra) d(Ra)

[0449] In some embodiments of Formula (I), Ring C is

[0450]

[0451] yyor yy. In some embodiments, cl is 0. In some embodiments, cl is 1; and RYis halo (e.g., -F).

[0452] In some embodiments of Formula (I), Ring C is

[0453]

[0454]

[0455] . In some embodiments, cl is 0. In some embodiments, cl is 1; and RYis halo (e g-, -F).

[0456] In some embodiments of Formula (I), cl is 0. In some embodiments, cl is 1; and RYis halo (e.g., -F). In some embodiments, RaNis C1-3 alkyl (e.g., methyl).

[0457] In some embodiments of Formula (I), X is CH.

[0458] In some embodiments of Formula (I), Lcis a bond.

[0459] In some embodiments of Formula (I), the

[0460]

[0461] moiety is selected from the group consisting of the moieties delineated in Table CM-lb:

[0462]

[0463]

[0464] Docket No. TRLN-013-030W01 / TLS-068WO

[0465]

[0466]

[0467] the group consisting of the moieties delineated in Table CM-la:

[0468] 5 Table CM-la

[0469]

[0470]

[0471] Docket No. TRLN-013-030W01 / TLS-068WO

[0472] In some embodiments of Formula (I),

[0473]

[0474] moiety is

[0475] In some embodiments,

[0476]

[0477] moiety is

[0478] In some embodiments of Formula (I), -(A')mi- is -C(R4R4)-CH2-* (e.g., -CF2-CH2-*), wherein * represents the point of attachment to -(A2)m2-.

[0479] In some embodiments of Formula (I), one R3is C3-6 cycloalkyl; and the other R3is H. In some embodiments, one R3is cyclopropyl; and the other R3is H.

[0480] In some embodiments of Formula (I), one R3is cyclopropyl; the other R3is H; and -(A¹)m1- is -CF2-CH2-*, wherein * represents the point of attachment to -(A2)m2-.

[0481] In some embodiments of Formula (I), X2is CH.

[0482] In some embodiments of Formula (I), X1is CH.

[0483] In some embodiments of Formula (I), the carbon atom to which each R3is attached has fS')-stereochemical configuration.

[0484] In some embodiments of Formula (I), Xais N; and Xbis CH.

[0485] In some embodiments of Formula (I), Xais CH; and Xbis CH.

[0486] In some embodiments of Formula (I), R6is halo (e.g., -F, -Cl, -Br) or CN. For example, R6can be -Cl, -F, or CN.

[0487] In some embodiments of Formula (I), R6is halo (e.g., -F, -Cl, -Br). In some embodiments, R6is -F. In some embodiments, R6is -Cl. In some embodiments, R6is -Br.

[0488] In some embodiments of Formula (I), R6is CN.

[0489] In some embodiments of Formula (I), each R2is H. Docket No. TRLN-013-030W01 / TLS-068WO In some embodiments of Formula (I), m3 is 1; and X3is C1-3 alkylene (e.g., methylene, ethylene, or isopropylene).

[0490] In some embodiments of Formula (I), m3 is 0.

[0491] In some embodiments of Formula (I), R1is H.

[0492] In some embodiments of Formula (I), m3 is 1; X3is C1-3 alkylene optionally substituted with 1-3 Rc; and R1is H. In some embodiments, m3 is 1; X3is C1-3 alkylene; and R1is H.

[0493] In some embodiments of Formula (I), -(X3)m3-R1is methyl, ethyl, or isopropyl (e.g., methyl).

[0494] In some embodiments of Formula (I), TBM is (Tl-a). For example, TBM can be

[0495] O.

[0496] o

[0497] N'H

[0498]

[0499] (Tl-a-A)

[0500] In some embodiments of (Tl-a), m3 is 1; X3is C1-3 alkylene; and R1is H.

[0501] In some embodiments of (Tl-a), -(X3)m3-R1is methyl, ethyl, or isopropyl. For example, -(X3)m3-R1can be methyl.

[0502] In some embodiments of (Tl-a), Xais CH. In some embodiments, Xais N.

[0503] In some embodiments of (Tl-a), R6is -F or -Cl.

[0504] In some embodiments of (Tl-a), Xais N or CH; R6is -F or -Cl; m3 is 1; X3is C1-3 alkylene; and R1is H.

[0505] In some embodiments of Formula (I), L is -(LA)n1-, wherein LAand nl are defined according to (AA). In some embodiments, nl is an integer from 1 to 5. In some embodiments, nl is an integer from 2 to 4 (e.g., 2 or 3). Docket No. TRLN-013-030W01 / TLS-068WO In some embodiments of Formula (I), L is selected from the group consisting of: -LA4-LAI-LA4- / > / >; -LA4-LA4- / > / >; -LA4-LA1-LA1-LA4- / , / ,; -LA4-LA3-LA4- / > / >; and -LA4-LA1-LA4-LA3-w,, wherein bb represents the point of attachment to Ring C.

[0506] In some embodiments of Formula (I), L is -LA4-LAI-LA4- / > / >. In some embodiments, L is -LA4-LA1-LA4- / > / >, and LA1is -CH2-, -CHMe-, -CMe2-, or -CH(OH)-. In some embodiments, L is -LA4-LA1-LA4- / > / >, and LA1is -CH2-, -CHMe-, or -CMe2-. In some embodiments, L is -LA4-LA1-LA4-bb, and LA1is -CH(OH)-.

[0507] In some embodiments of Formula (I), L is -LA4-LA3-LA4- / > / >. In some embodiments, LA3is -C(=O).

[0508] In some embodiments of Formula (I), L is -LA4-LA3-LA4- / > / >, and LA3is C(=O). In some embodiments, L is -LA4-LA3-LA4- / > / >, and LA3is O, NH, orN(Ci-3 alkyl). In some embodiments, L is -LA4-LA3-LA4- / > / >, and L is -LA4-LA3-LA4-M>, and LA3is S(O)2.

[0509] In some embodiments of Formula (I), L is -LA4-LA1-LA4-LA3- / > / >, and LA3is C(=O).

[0510] In some embodiments of Formula (I), L is -LA4-LA1-LA4-LA3- / > / >, and LA3is O.

[0511] In some embodiments of Formula (I), L is -LA4-LA1-LA1-LA4- / > / >, and one or both of LA1is CH2.

[0512] In some embodiments of Formula (I), L is -LA4-LA1-LA4-LA3- / > / >. In some embodiments, L is -LA4-LAI-LA4-O- / > / >.

[0513] In some embodiments of Formula (I), each LA4is independently C3-10 cycloalkylene or 4-12 membered heterocyclylene, each of which is optionally substituted with 1-6 Ra. In some embodiments, each LA4is independently 4-12 (e.g., 4-10) membered heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, each Rapresent on LA4is independently selected from the group consisting of: -F; CN; C1-3 alkoxy; OH; C1-3 alkyl substituted with OH; and C1-3 alkyl optionally substituted with 1-3 F. In some embodiments, each Rapresent on LA4is independently selected from the group consisting of: -F, CN, C1-3 alkoxy, OH, and C1-3 alkyl optionally substituted with 1-3 F.

[0514] In some embodiments of Formula (I), each LA4is independently monocyclic 4-6 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, each LA4contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, each Rapresent on LA4is independently selected from the group consisting of: -F; CN; C1-3 alkoxy; OH; C1-3 alkyl substituted with OH; and C1-3 alkyl optionally substituted with 1-3 F. In some embodiments, each Rapresent on LA4is independently selected from the group consisting of: -F, CN, C1-3 alkoxy, OH, and C1-3 alkyl optionally substituted with 1-3 F. Docket No. TRLN-013-030W01 / TLS-068WO In some embodiments of Formula (I), one LA4is monocyclic 4-6 membered nitrogencontaining heterocyclylene optionally substituted with 1-3 Ra; and the other LA4is bicyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, each LA4contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, each Rapresent on LA4is independently selected from the group consisting of: -F; CN; C1-3 alkoxy; OH; C1-3 alkyl substituted with OH; and C1-3 alkyl optionally substituted with 1-3 F. In some embodiments, each Rapresent on LA4is independently selected from the group consisting of: -F, CN, C1-3 alkoxy, OH, and C1-3 alkyl optionally substituted with 1-3 F.

[0515] In some embodiments of Formula (I), one LA4is monocyclic 4-6 membered nitrogencontaining heterocyclylene optionally substituted with 1-3 Ra; and the other LA4is bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, each LA4contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, each Rapresent on LA4is independently selected from the group consisting of: -F, CN, C1-3 alkoxy, OH, and C1-3 alkyl optionally substituted with 1-3 F.

[0516] In some embodiments of Formula (I), L is selected from the group consisting of:

[0517] -LA4-LA1-LA4-M>;

[0518] -LA4-LA1-LA1-LA4- / > / >;

[0519] -LA4-LA4- / > / >;

[0520] -LA4-C(=O)-LA4- / > / >; and

[0521] -LA4-LA1-LA4-C(=O)- / > / >,

[0522] wherein bb represents the point of attachment to Ring C; and

[0523] LA1is -CH2-, -CHMe-, -CMe2-, or -CH(OH)-;

[0524] each LA4is independently a 4-12 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra, wherein:

[0525] each Rapresent on LA4is independently selected from the group consisting of: -F; CN; C1-3 alkoxy; OH; C1-3 alkyl substituted with OH; and C1-3 alkyl optionally substituted with 1-3 F.

[0526] In some embodiments of Formula (I), L is selected from the group consisting of:

[0527] -LA4-LA1-LA4-M>;

[0528] -LA4-LAI-LAI-LA4- / > / >;

[0529] -LA4-LA4- / > / >;

[0530] -LA4-C(=O)-LA4- / > / >; and

[0531] _LA4-LA1-LA4-C(=O)-M,,

[0532] wherein bb represents the point of attachment to Ring C; and Docket No. TRLN-013-030W01 / TLS-068WO LA1is CH2, CHMe, or CMe2;

[0533] each LA4is independently a 4-12 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra, wherein:

[0534] each Rapresent on LA4is independently selected from the group consisting of: -F, CN, C1-3 alkoxy, OH, and C1-3 alkyl optionally substituted with 1-3 F.

[0535] In some embodiments of Formula (I), L is LA4-LAI-LA4- / > / >. wherein:

[0536] bb represents the point of attachment to Ring C;

[0537] LA1is -CH2-, -CHMe-, -CMe2-, or -CH(OH)-;

[0538] each LA4is independently 4-12 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra; and

[0539] each Rapresent on LA4is independently selected from the group consisting of: -F; CN; C1-3 alkoxy; OH; C1-3 alkyl substituted with OH; and C1-3 alkyl optionally substituted with 1-3 F.

[0540] In some embodiments of Formula (I), L is LA4-LA1-LA4- / > / >, wherein:

[0541] bb represents the point of attachment to Ring C;

[0542] LA1is CH2, CHMe, or CMe2;

[0543] each LA4is independently a 4-12 membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra, wherein:

[0544] each Rapresent on LA4is independently selected from the group consisting of: -F, CN, C1-3 alkoxy, OH, and C1-3 alkyl optionally substituted with 1-3 F.

[0545] In some embodiments of Formula (I), L is selected from the group consisting of:

[0546] -LA4-LA3- / > / >;

[0547] -I / 3-!?4-* / ,;

[0548] -LA4-LA1- / > / >(e.g., -LA4-CH2-);

[0549] -LA4-LA1- / > / >; and

[0550] -L4-L,-L3-W),

[0551] wherein bb represents the point of attachment to Ring C.

[0552] In some embodiments of Formula (I), L is selected from the group consisting of:

[0553] -LA4-LA3- / > / >;

[0554] -I / 3-!?4-* / ,;

[0555] -

[0556]

[0557] LA4-LA1- / , / ,(e.g., -LA4-CH2-);

[0558] -LA4-LA1- / > / >; and Docket No. TRLN-013-030W01 / TLS-068WO -LA4-LA1-LA3-w,,

[0559] wherein bb represents the point of attachment to Ring C.

[0560] In some embodiments of Formula (I), L is selected from the group consisting of:

[0561] -LA4-LA3- / > / >;

[0562] -LA4-LA1- / > / >; and

[0563] -LA4-LA1-LA3- / > / >,

[0564] wherein bb represents the point of attachment to Ring C.

[0565] In some embodiments of Formula (I), L is -LA4-LA3- / > / >. In some embodiments, LA3is -NH- or -N(CI-3 alkyl)- (e.g., -NH-). In some embodiments, LA4contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, each Rapresent on LA4is independently selected from the group consisting of: -F, CN, C1-3 alkoxy, OH, and C1-3 alkyl optionally substituted with 1-3 F.

[0566] In some embodiments of Formula (I), LA4is 4-12 membered heterocyclylene optionally substituted with 1-6 Ra. In some embodiments, LA4contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, each Rapresent on LA4is independently selected from the group consisting of: -F, CN, C1-3 alkoxy, OH, and C1-3 alkyl optionally substituted with 1-3 F.

[0567] In some embodiments of Formula (I), LA4is 4-12 (e.g., 6-10) membered nitrogencontaining heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, LA4is bicyclic spirocyclic 6-12 (e.g., 6-10) membered nitrogen-containing heterocyclylene optionally substituted with 1-3 Ra. In some embodiments, LA4contains 1-2 ring nitrogen atoms and no additional ring heteroatoms. In some embodiments, each Rapresent on LA4is independently selected from the group consisting of: -F, CN, C1-3 alkoxy, OH, and C1-3 alkyl optionally substituted with 1-3 F.

[0568] In some embodiments of Formula (I), L is selected from the group consisting of the moieties delineated in Table L, wherein bb represents the point of attachment to Ring C.

[0569] Table L

[0570]

[0571] Docket No. TRLN-013-030W01 / TLS-068WO OH

[0572] vCAQ,. |

[0573] rxxT^NXX> X^ 'XXN'zZXX i

[0574] V'Nx / kz X^N>_z XN\ / J

[0575] / bb \ / bb OH

[0576] |Z^ 'Z^NX^S|

[0577] VN^ X^x7 rrr \ ^NXxJ k^N^y

[0578] X / bb X / bb V'-xv ^^My»

[0579] vcrQ... \T rry>

[0580] ~^ybbyOnx

[0581] bb

[0582] (ZZSSIZ^NXX‘] YN^O ^NyMvCTOy 'sxz'l^x /

[0583] ' 7bbV0-X>+- ^O^C"-^

[0584] fz^NXXYz'^ V XNn^*m\ VNo^yn-% o Xz'N'xX'^X, X-z'N's /

[0585] 7 bb X 7 bb X / bb

[0586] L. N^y Xx1'1"^ \x'l'lx /

[0587] X / b v

[0588] Qb ■ X / bbN^ < / Nv X 7bb y z—

[0589] v" J A^NV

[0590] X 7bb V XN^..>-"<xNv 7bb V^x / X x / ^x / x ' bb x \JO

[0591] }H ‘ / bb \ / bb x^Nx / ^ \ / Nx /

[0592] X / bb

[0593] [ / ZXy^N’x^ [ZZXT^NX^ [ZXXY^NX^SI V^N^ J L N^y V^x / x^x / \ / bb \ / bb X / bb

[0594] |Z^N'ZASVZ^ |z^NX^YXXs|

[0595] X / bb X / bb vNx> < / Ny ' 'bb r m4*Y^N'Z^YZ^ v"sA <-Ny V^Xz^X X.z'N’s /

[0596] X 7bb X / bb v XU% kJy F 7 bb

[0597] YN5^^ yOX 'v

[0598]

[0599] / bb. Docket No. TRLN-013-030W01 / TLS-068WO X OH \ OH

[0600] X f bb X f bb ' 'bb

[0601] rpA

[0602] X YNQ^n >^X

[0603] fbb XNy f bb yN^ "■'k-'NyM

[0604] V-C / Oy vCZ-Oy y XCACy f bb 1 — N l | |

[0605] XZN\ / KT(X KT -Qi, fbb fbb fbb

[0606] VNXA- <_NVrr n VN^x / X ^'s X ' f bb v X"-Jr X <-Nv z'N'V / bb X X f bb yOCOyw v.co \

[0607] Y" nXArFn ^NybbNcrp

[0608] \Ff bb V X X / XFr< / NV f bb

[0609] lrS^Nrh-n V' ^"sxz\ V X

[0610] X f bb Y xN^'% >

[0611] f bb \ f F

[0612] -zzZXNzZ> Xj V \Nr~^V\"^ <, NV' / zL / \ _bk J fbb X fbb Y "" ybb

[0613] nnn

[0614] v \H^< <^Ny fOkD„ YNrX>^C% 'C <x^

[0615] XNy VNx / >»

[0616] fbb X fbb v X CCOy f bb Y XNXA My f bbV" OCNOywYX^''''''XN'XX>

[0617] VNXYX N / k /

[0618] X f bb y XCCOyvcco+- f bb

[0619] VNCX " CN^“xCCQ‘-\bbvn" W “

[0620] KO I i

[0621] f bbt-x oy / „ bb r \

[0622]

[0623] f bb Docket No. TRLN-013-030W01 / TLS-068WO |Z^NXXV

[0624] yXXs|

[0625] N. _ J rj^ i

[0626] X 1 / bb v^S ^Voo OH OH

[0627] H0X'XXXNX^izZ^| HOX^|Z^N'Z^XZ^

[0628] kA / vU

[0629] X | f bb X f bb \ f bb OH

[0630] |ZXXV^NX^

[0631] Xxcrn V^xX

[0632] f bb X | f bb X 1 f bb OH OH OH OH VNx> AA /

[0633] ' 1 'bb

[0634] OH

[0635] V-N^ J \ zN\ / X zN^ J \> ZN'K / \ / bb \ fbb HO

[0636] « V

[0637] V)

[0638] — fbb r \ - J / bb v y L1’^ / J / bb

[0639] rN\ J rr^

[0640] ' / f bb YN^> V ^NyM / ^N'xxyx>X / x. /

[0641] \ X^N y x V NNC'" J / 7 / bb f bb f bb

[0642] z^x / ^N^Xj^X

[0643] VNX^' / ^Nx / i r"^ L /

[0644] / P S " Z-.

[0645] ' f bb 'UX &

[0646] &..

[0647] NI < N y

[0648] y »> Vbb vd^ X XC^. H5pN^OyMVOX L r bb

[0649] vO'©y.. X X ly

[0650] \ fbb x \ nx fbb VNrTVj"^ XNy X TiX YNrXV> i M^-NyhhX f bb \ 7bb i^^N'zZXyz\ l''Y,NXXYX'X|xcr-^ XZ \ / VNx / xzNx /

[0651]

[0652] X f bb X fbb Docket No. TRLN-013-030W01 / TLS-068WO \ _ J L EhL / X^N _ J Q ■ \ / bb X / bb ^ ■O Z v — Y„

[0653] VZNCA'"X?^> ^ ■o.AX ^s^Nsy XH

[0654] zJ« / bb ^N0 / ^^ " QN^bb vNC^“''xn Q ■

[0655] \^N

[0656] ^bb

[0657] Examples when L is -LA4-LA4- / > / > p

[0658] |— h / h / \l— 16b

[0659] ^'N'sxzJ

[0660] bb L \> Q

[0661] — Y 'b■ r"

[0662] NNZZ~~

[0663] 1 1 ZN

[0664] \ / =Z\-zN^ A h

[0665] r 1 ^T 1 \ V / N_ j / ohbh

[0666] Example when L is -LA4-LA1-LA1-LA4- / > / >

[0667] ^ T^NAW>

[0668] vCr

[0669] Examples when L is -LA4-LA3-LA4- / > / >

[0670] v r~~k

[0671] \OX ly J

[0672] / bb 'bb

[0673]

[0674] Docket No. TRLN-013-030W01 / TLS-068WO o 0

[0675] Q ■ X ^N. J L N. i VzN^^J l^N^y o \ fbb

[0676] X fbb ^X Q0b

[0677] z^

[0678] >°

[0679] Z j —

[0680] $

[0681] z

[0682] ’* &•

[0683] O...

Claims

Docket No. TRLN-013-030W01 / TLS-068WO WHAT IS CLAIMED IS:

1. A method for treating a relapsed or refractory non-Hodgkin lymphoma in a subject in need thereof, the method comprising administering to the subject:(a) a therapeutically effective amount of an EZH2 inhibitor selected from the group consisting of lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, and XNW-5004; and(b) a therapeutically effective amount of Compound 412a:or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the method comprises administering to the subject a therapeutically effective amount of Compound 412a, or a pharmaceutically acceptable salt thereof, in a treatment phase.

3. The method of any one of claims 1-2, wherein the method comprises administering to the subject a therapeutically effective amount of an EZH2 inhibitor selected from the group consisting of lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, and XNW-5004, in a treatment phase.

4. The method of any one of claims 1-3, wherein the method comprises administering to the subject the therapeutically effective amount of Compound 412a, or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount of the EZH2 inhibitor, in a treatment phase.

5. The method of any one of claims 1-4, wherein the method comprises administering to the subject a therapeutically effective amount of Compound 412a, or a pharmaceutically acceptable salt thereof, in a maintenance phase.

6. The method of any one of claims 1-5, wherein the method comprises administering to the subject a therapeutically effective amount of an EZH2 inhibitor selected from the group consisting of lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide),Docket No. TRLN-013-030W01 / TLS-068WO valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, and XNW-5004, in a maintenance phase.

7. The method of any one of claims 1-6, wherein the method comprises administering to the subject the therapeutically effective amount of Compound 412a, or a pharmaceutically acceptable salt thereof, and the therapeutically effective amount of the EZH2 inhibitor, in a maintenance phase.

8. The method of any one of claims 1-7, wherein the subject has been previously treated with chemotherapy.

9. The method of claim 8, wherein the chemotherapy comprises CHOP, EPOCH, R-CHOP, mini-R-CHOP, Pola-R-CHP, R-EPOCH, R-CVP, R-ICE, BR, or pola-BR.

10. The method of any one of claims 8-9, wherein the chemotherapy is first-line therapy or second-line therapy.

11. The method of any one of claims 1-10, wherein the subject has been previously treated with a multispecific antibody, or an antigen-binding fragment thereof (e.g., a multispecific T-cell recruiting antibody, or an antigen-binding fragment thereof (e.g., a bispecific T-cell recruiting antibody, or an antigen-binding fragment thereof), or a bispecific antibody, or an antigen-binding fragment thereof), or CAR T therapy.

12. The method of claim 11, wherein the subject has been previously treated with an anti-CD20 and anti-CD3 bispecific antibody, or an antigen-binding fragment thereof.

13. The method of claim 12, wherein the anti-CD20 and anti-CD3 bispecific antibody is epcoritamab (e.g., epcoritamab-bysp (EPKINLY™), or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), mosunetuzumab (e.g., mosunetuzumab-axgb (LUNSUMIO™), or a biosimilar thereof), plamotamab, or odronextamab (e.g., ORDSPONO™, or a biosimilar thereof).

14. The method of claim 13, wherein the anti-CD20 and anti-CD3 bispecific antibody is epcoritamab (e.g., epcoritamab-bysp (EPKINLY™), or a biosimilar thereof), glofitamab (e.g., COLUMVI® (glofitamab), or a biosimilar thereof), or mosunetuzumab (e.g., mosunetuzumab-axgb (LUNSUMIO™), or a biosimilar thereof).

15. The method of claim 11, wherein the subject has been previously treated with an anti-CD19 and anti-CD3 bispecific antibody or an antigen-binding fragment thereof.

16. The method of claim 15, wherein the anti-CD19 and anti-CD3 bispecific antibody is surovatamig.

17. The method of any one of claims 11-16, wherein the multispecific antibody or antigen-binding fragment thereof (e.g., a multispecific T-cell recruiting antibody, or an antigenbinding fragment thereof (e.g., a bispecific T-cell recruiting antibody, or an antigen-bindingDocket No. TRLN-013-030W01 / TLS-068WO fragment thereof), or a bispecific antibody, or an antigen-binding fragment thereof) or CAR T therapy is first-line therapy or second-line therapy.

18. The method of any one of claims 1-17, wherein the relapsed or refractory nonHodgkin lymphoma is a mature B-cell neoplasm.

19. The method of claim 18, wherein the mature B-cell neoplasm is a large B-cell lymphoma (LBCL).

20. The method of claim 19, wherein the LBCL is selected from the group consisting of diffuse large B-cell lymphoma not otherwise specified (DLBCL-NOS), diffuse large B-cell lymphoma / high grade B-cell lymphoma (HGBCL) (e.g., HGBCL with MYC and / or BCL2 rearrangements (HGBCL-MYC / BCL-2)), primary LBCL of immune-privileged sites, primary mediastinal LBCL, HGBCL with 11q aberrations, and HGBCL-NOS.

21. The method of claim 20, wherein the LBCL is DLBCL-NOS.

22. The method of claim 18, wherein the mature B-cell neoplasm is a FL (e.g., grade l-3a or FLBCL) or transformed FL.

23. The method of any one of claims 1-17, wherein the relapsed or refractory nonHodgkin lymphoma is a T-cell lymphoma.

24. The method of claim 23, wherein the relapsed or refractory T-cell lymphoma is a peripheral T-cell lymphoma (PTCL).

25. The method of claim 24, wherein the PTCL is selected from the group consisting of anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma), nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type), nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type), and nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS)).

26. The method of claim 25, wherein the PTCL is a nodal T follicular helper cell lymphoma.

27. The method of claim 26, wherein the PTCL is AITL.

28. The method of claim 26, wherein the PTCL is nodal T follicular helper cell lymphoma follicular type.

29. The method of claim 26, wherein the PTCL is nodal T follicular helper cell lymphoma NOS.

30. The method of claim 23, wherein the relapsed or refractory T-cell lymphoma is a cutaneous T-cell lymphoma (CTCL).Docket No. TRLN-013-030W01 / TLS-068WO 31. The method of claim 30, wherein the CTCL is selected from the group consisting of primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, mycosis fungoides, Sezary syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disorder: lymphomatoid papulosis, primary cutaneous CD30-positive T-cell lymphoproliferative disorder: primary cutaneous anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous gamma-delta T-cell lymphoma, and primary cutaneous peripheral T-cell lymphoma NOS.

32. The method of claim 31, wherein the CTCL is mycosis fungoides or Sezary syndrome.

33. The method of any one of claims 1-32, wherein the relapsed or refractory nonHodgkin lymphoma is BCL6+.

34. The method of claim 33, wherein the relapsed or refractory non -Hodgkin lymphoma is BCL6+ with a percent nuclear positivity score for BCL6 in an IHC test of greater than or equal to 1%.

35. The method of claim 34, wherein the relapsed or refractory non-Hodgkin lymphoma is BCL6+ with a percent nuclear positivity score for BCL6 in an IHC test of greater than or equal to 20%.

36. The method of claim 35, wherein the relapsed or refractory non-Hodgkin lymphoma is BCL6+ with a percent nuclear positivity score for BCL6 in an IHC test of greater than or equal to 30%.

37. The method of any one of claims 1-36, wherein the non-Hodgkin lymphoma has an EZH2 dysregulation.

38. The method of claim 37, wherein the EZH2 dysregulation is an EZH2 Y646X mutation, an EZH2 Y666X mutation, an EZH2 A682X mutation, an EZH2 A692X mutation, or a combination thereof.

39. The method of claim 38, wherein the EZH2 dysregulation is an EZH2 Y646C mutation, an EZH2 Y646F mutation, an EZH2 Y646H mutation, an EZH2 Y646N mutation, an EZH2 Y646S mutation, an EZH2 Y666N mutation, an EZH2 A682G mutation, an EZH2 A692V mutation, or a combination thereof.

40. The method of any one of claims 1-39, wherein Compound 412a, or a pharmaceutically acceptable salt thereof, is administered at a dose selected from the group consisting of: 25 mg, 30 mg, 50 mg, 70 mg, 75 mg, 100 mg, and 150 mg, wherein the dose is administered once or twice per day.Docket No. TRLN-013-030W01 / TLS-068WO 41. The method of any one of claims 1-40, wherein Compound 412a, or a pharmaceutically acceptable salt thereof, is administered at a dose of 30 mg, wherein the dose is administered once or twice per day.

42. The method of any one of claims 1-40, wherein Compound 412a, or a pharmaceutically acceptable salt thereof, is administered at a dose of 50 mg, wherein the dose is administered once or twice per day.

43. The method of any one of claims 1-40, wherein Compound 412a, or a pharmaceutically acceptable salt thereof, is administered at a dose of 70 mg, wherein the dose is administered once or twice per day.

44. The method of any one of claims 1-40, wherein Compound 412a, or a pharmaceutically acceptable salt thereof, is administered at a dose of 100 mg, wherein the dose is administered once or twice per day.

45. The method of any one of claims 1-40, wherein Compound 412a, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, wherein the dose is administered once or twice per day.

46. The method of any one of claims 40-45, wherein the dose is administered once per day.

47. The method of any one of claims 40-45, wherein the dose is administered twice per day.

48. The method of any one of claims 1-47, wherein Compound 412a, or a pharmaceutically acceptable salt thereof, is administered with food.

49. The method of any one of claims 1-48, wherein EZH2 inhibitor is administered at a dose of about 100 mg to 400 mg (e.g., about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg), wherein the dose is administered once or twice per day.

50. The method of claim 49, wherein the dose is administered once per day.

51. The method of claim 49, wherein the dose is administered twice per day.

52. The method of any one of claims 1-51, wherein non-Hodgkin lymphoma is a mantle cell lymphoma (MCL).

53. The method of any one of claims 1-51, wherein the non-Hodgkin lymphoma is a marginal zone lymphoma (MZL).

54. The method of any one of claims 1-51, wherein the non-Hodgkin lymphoma is a chronic lymphocytic leukemia (CLL).

55. The method of any one of claims 1-51, wherein the non-Hodgkin lymphoma is a Richter transformation of CLL.Docket No. TRLN-013-030W01 / TLS-068WO56. The method of any one of claims 1-51, wherein the non -Hodgkin lymphoma is asmall lymphocytic lymphoma (SLL).

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