Treatment of lymphomas using an EZH2 inhibitor

Abstract

Provided here are methods of treating lymphomas for example, peripheral T-cell lymphomas (PTCLs) (e.g., nodal Tfh cell lymphomas) and / or cutaneous T-cell lymphomas (CTCLs) in a subject, by administering to the subject Compound A, or a pharmaceutically acceptable salt thereof. In some cases, the lymphomas are BCL6 positive. In some cases, the lymphomas are relapsed or refractory. In some cases, the subjects are treatment-naïve (i.e., previously untreated).

Description

[0001] Docket No. TRLN-019-010W01 / TLS-066WO

[0002] TREATMENT OF LYMPHOMAS USING AN EZH2 INHIBITOR

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Application Serial Nos. 63 / 702,925, filed October 3, 2024, and 63 / 765,245, filed February 28, 2025, each of which is incorporated by reference in its entirety herein.

[0005] TECHNICAL FIELD

[0006] This disclosure provides methods for treating lymphomas, for example, peripheral T- cell lymphomas (PTCLs) (e.g., nodal Tfh cell lymphomas) and / or cutaneous T-cell lymphomas (CTCLs) comprising administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some cases, the lymphomas are BCL6 positive. In some cases, the lymphomas are relapsed or refractory. In some cases, the subjects are treatment-naive (i.e., previously untreated).

[0007] BACKGROUND

[0008] Mature natural killer or T-cell lymphomas are a heterogeneous group of aggressive nonHodgkin lymphomas (NHLs) accounting for approximately 5-10% of all NHL in Western countries, with higher incidence in parts of Asia (20-25% of all NHLs). The annual incidence of T-cell lymphoma in the United States (US) is about 1.8 per 100,000 persons and prevalence is estimated at 5.3 per 100,000 persons. See, e.g., International T-Cell Lymphoma Project, Journal of Clinical Oncology 26.25 (2008): 4124-4130, doi: 10.1200 / JCO.2008.16.4558; d'Amore, F., et al. Annals of Onco logy’ 26 (2015): v!08-vl l5, doi: 10.1093 / annonc / mdv201; Ma, Helen, Enrica Marchi, and Owen A. O'Connor. The Lancet Haematology,' 7.10 (2020): e765-e77, doi: 10.1016 / S2352-3026(20)30207-6; Hathuc, Vivian, and Friederike Kreisel. Life 12.3 (2022): 410, doi: 10.3390 / lifel 2030410; Liu, Shuo, et al. Frontiers in Oncology 12 (2022): 863269, doi: 10.3389 / fonc.2022.863269, 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; Teras, Lauren R., et al. CA: A Cancer Journal for Clinicians 66.6 (2016): 443-459, doi: 10.3322 / caac.21357; Marchi, Enrica, and Owen A. O’Connor. CA: A Cancer Journal for Clinicians 70.1 (2020): 47-70, doi: 10.3322 / caac.21589; and Cai, Zhuo Ran, et al. JAMA Oncology 8.11 (2022): 1690-1692, doi : 10.1001 / jamaoncol.2022.3236. Docket No. TRLN-019-010W01 / TLS-066WO

[0009] Classification of T-cell lymphoma subtypes was recently updated by the World Health Organization (WHO, fifth edition) and by the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms. See, e.g., Alaggio, Rita, et al. Leukemia 36.7 (2022): 1720-1748, doi: 10.1038 / s41375-022-01620-2; Campo, Elias, et al. Blood, The Journal of the American Society of Hematology 140.11 (2022): 1229-1253, doi: 10.1182 / blood.2022015851; and Feldman, Andrew L., et al. Virchows Ar chiv 482.1 (2023): 265-279, doi: 10.1007 / s00428- 022-03412-6. Depending on their presentation, mature T-cell lymphomas are sometimes separated into nodal, extranodal, cutaneous, and leukemic types. The most common nodal PTCL subtypes in Western populations are PTCL-NOS (also called herein PTCL, NOS), systemic anaplastic large cell lymphoma (ALCL), and T-follicular helper (Tfh) cell lymphomas, including: angioimmunoblastic T-cell lymphoma (AITL), follicular-type (also known as nodal Tfh cell lymphoma, follicular-type), and not otherwise specified (NOS) (also known as nodal Tfh cell lymphoma, NOS). With the exception of ALK-positive ALCL (ALK+ ALCL) in young patients, where there are more favorable outcomes, 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., 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; 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; 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:

[0010] 10.6004 / jnccn.2022.0015; and Sibon, David. Cancers 14.9 (2022): 2332, doi: 10.3390 / cancers 14092332.

[0011] CTCLs are a group of lymphoproliferative disorders characterized by the localization of malignant lymphocytes to the skin. The most common subtype is mycosis fungoides, which accounts for nearly 50% of CTCLs and has a 5-year OS rate of 80%. Most patients with mycosis fungoides do not present with extracutaneous involvement and have an indolent course. However, approximately 25% of patients present with more advanced stage disease, characterized by measurable tumors, erythroderma, or significant nodal, visceral, or blood involvement, and have more rapidly progressive disease. In the advanced stages, the 5-year Docket No. TRLN-019-010W01 / TLS-066WO survival rate drops to 52%. Sezary syndrome (also called Sezary syndrome herein), an aggressive erythrodermic CTCL with leukemic component, accounts for <5% of all CTCLs and is associated with a more aggressive course and 5-year OS of 11%. See, e.g., Jawed, Sarah I., et al. Journal of the American Academy of Dermatology 70.2 (2014): 205-el, doi: 10.1016 / j.jaad.2013.07.049; Gilson, D., et al. British Journal of Dermatology 180.3 (2019): 496-526, doi: 10.1111 / bjd.17240; Hristov, Alexandra C., Trilokraj Tejasvi, and Ryan A. Wilcox. American Journal of Hematology 98.1 (2023): 193-209, doi: 10.1002 / ajh.26760; Miyashiro, Denis, and Jose Antonio Sanches. Frontiers in Oncology 13 (2023): 1141108, doi: 10.3389 / fonc.2023.1141108; and Scarisbrick, Julia J., et al. Journal of Clinical Oncology 33.32 (2015): 3766-3773, doi: 10.1200 / JC0.2015.61.7142.

[0012] SUMMARY

[0013] Provided herein are methods for treating a relapsed or refractory nodal Tfh cell lymphoma in a subject in need thereof, the methods comprising i) determining that the subject has a relapsed or refractory nodal Tfh cell lymphoma; and ii) based on i), administering a therapeutically effective amount of Compound A:

[0014] Compound A or a pharmaceutically acceptable salt thereof, wherein the relapsed or refractory nodal Tfh cell lymphoma is selected from the group consisting of: nodal Tfh cell lymphoma, follicular-type, and nodal Tfh cell lymphoma, NOS.

[0015] Also provided herein are methods for treating a relapsed or refractory BCL6+ nodal Tfh cell lymphoma in a subject in need thereof, the methods comprising i) determining that the subject has a relapsed or refractory BCL6+ nodal Tfh cell lymphoma; and ii) based on i), administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0016] 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 Docket No. TRLN-019-010W01 / TLS-066WO or refractory BCL6+ PTCL; and ii) based on i), administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0017] Provided herein are methods for treating a cutaneous T cell lymphoma (CTCL) in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0018] Also provided herein are methods for treating a BCL6+ CTCL in a subject, the methods comprising i) determining that the subject has a BCL6+ CTCL; and ii) based on i), administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0019] Also provided herein are methods for treating mycosis fungoides in a subject in need thereof, the methods comprising administering a therapeutically effective amount of an EZH2 inhibitor or an EZH1 / 2 inhibitor to the subject.

[0020] Provided also herein are methods for treating Sezary syndrome in a subject in need thereof, the methods comprising administering a therapeutically effective amount of an EZH2 inhibitor or an EZH1 / 2 inhibitor to the subject.

[0021] Provided herein are methods for treating a BCL6+ peripheral T-cell lymphoma (PTCL) in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment-naive.

[0022] Also provided herein are methods for treating a BCL6+ peripheral T-cell lymphoma (PTCL) in a subject in need thereof, the methods comprising i) determining that the subject has a BCL6+ PTCL; and ii) based on i), administering to the subject a therapeutically effective amount of a compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment-naive.

[0023] Provided also herein are methods for treating a nodal Tfh cell lymphoma in a subject in need thereof, the methods comprising administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; wherein the subject is treatment- naive.

[0024] Provided herein are methods for treating a BCL6+ nodal Tfh cell lymphoma in a subject in need thereof, the methods comprising i) determining that the subject has a BCL6+ nodal Tfh cell lymphoma; and ii) based on i), administering to the subject a therapeutically effective amount of a compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment-naive. Docket No. TRLN-019-010W01 / TLS-066WO

[0025] Additionally provided herein are methods for treating a lymphoma, the methods comprising administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, to a subject having a lymphoma positive for BCL6 expression.

[0026] Also provided herein are methods for treating a lymphoma in a subject in need thereof, the method comprising (a) determining that the lymphoma in the subject is positive for BCL6 expression; and (b) administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0027] 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.

[0028] The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages of the invention will be apparent from the description and from the claims.

[0029] DETAILED DESCRIPTION

[0030] For most subtypes of PTCL, first-line therapy typically includes a combination chemotherapy regimen, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CHOEP (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), or other multidrug regimens. For patients with CD30+ PTCL, brentuximab vedotin in combination with chemotherapy was shown to confer a survival benefit compared to chemotherapy alone. Consolidation of first complete remission with high-dose chemotherapy followed by autologous stem cell transplant. (SCT) may provide a survival benefit in select patients. 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; Horwitz, Steven, et al. The Lancet 393.10168 (2019): 229-240, doi: 10.1016 / S0140- Docket No. TRLN-019-010W01 / TLS-066WO

[0031] 6736(18)32984-2, Wilhelm, Martin, et al. Blood Cancer Journal 6.7 (2016): e452-e452, doi: 10.1038 / bcj .2016.63; and Park, Steven I., et al. Cancer 125.9 (2019): 1507-1517, doi: 10.1002 / cncr.31861.

[0032] Second-line therapies for relapsed or refractory disease remain suboptimal due to modest response rates for most disease subtypes, and durations of response (DOR) are often less than one year. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend a clinical trial as the preferred option for relapsed or refractory T-cell lymphoma (See, e.g., the NATIONAL COMPREHENSIVE CANCER NETWORK® (NCCN) Treatment Guidelines, version 1.2024). 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:

[0033] 10.1001 / jamanetworkopen.2021.9807.

[0034] Certain molecular pathology features have proven useful as predictors of response in PTCL. For example, cell surface expression of CD30 can identify patients appropriate for brentuximab vedotin, and ALK alterations can predict response to crizotinib in the setting of ALCL.

[0035] Early-stage (Stage IA) CTCL with more limited skin involvement (<10% body surface area) is typically treated with skin-directed therapies such as topical high-potency steroids, emollients, and phototherapy. For refractory skin disease or involvement of >10% body surface area, low-dose radiotherapy or electron beam radiotherapy can be used with the goal of symptom control. Immunomodulatory agents, such as low dose methotrexate, interferon, and oral bexarotene may also be used. Patients for whom skin-directed therapies do not provide sufficient disease control, or who have disease not amenable to skin-directed therapy (blood or extracutaneous disease) usually receive systemic treatments, including chemotherapy, brentuximab vedotin, romidepsin, vorinostat, bexarotene, or mogamulizumab. See, e.g., Stuver, Robert, and Shamir Geller. Frontiers in Immunology 14 (2023): 1284045, doi: 10.3389 / fimmu.2023.1284045; Quereux, Gaelle, et al. Archives of Dermatology 144.6 (2008): 727-733, doi: 10.1001 / archderm.144.6.727; Duhovic, Chris, Fiona Child, and E. Mary Wain. Clinical Medicine 12.2 (2012): 160, doi: 10.7861 / clinmedi cine.12-2-160; and Dummer, Reinhard, et al. Journal of Clinical Oncology 30.33 (2012): 4091-4097, doi: 10.1200 / JC0.2011.39.8065.

[0036] Allogenic stem cell transplantation may have a role in a subset of patients with relap sed / refractory CTCL, but it is only recommended for disease that is refractory to multiple Docket No. TRLN-019-010W01 / TLS-066WO primary treatment options. Despite those therapies described above, deep remissions are rare, and clear unmet need remains for novel therapies in the advanced disease setting. See, e.g., Dumont, Maelle, et al. Cancers 12.10 (2020): 2856, doi: 10.3390 / cancersl2102856; Whittaker, Sean, Richard Hoppe, and H. Miles Prince. Blood, The Journal of the American Society of Hematology 127.25 (2016): 3142-3153, doi: 10.1182 / blood-2015-12-611830; Foss, Francine M., and Michael Girardi. Hematology / Oncology Clinics 31.2 (2017): 297-315, doi: 10.1016 / j.hoc.2016.11.008; and the NCCN Clinical Practice Guidelines in Oncology: Primary cutaneous lymphomas, Version 1.2024 (December 21, 2023)

[0037] Epigenetic dysregulation appears to be important to the pathogenesis of T-cell lymphoma. Many T-cell lymphoma subtypes exhibit frequent mutations or overexpression of epigenetic regulators that influence gene expression through chromatin modification. EZH2 is an epigenetic regulator involved in a histone methyltransferase and the catalytic component of polycomb repressive complex 2 (PRC2). The main function of EZH2 is to promote gene repression through the tri-methylation of histone H3 at Lys 27 (H3K27me3), an epigenetic mark that facilitates chromatin compaction and gene silencing. In addition, EZH2 overexpression and gain-of-function mutations have been identified in several cancer types that affect target gene expression, promote tumor growth and accelerate disease progression. EZH2 mutations in T-cell lymphoma are rare; however, EZH2 overexpression has been linked to poor prognosis and an aggressive disease course. See, e.g., Xie, Caiqin, et al. Experimental Hematology & Oncology 9 (2020), doi: 10.1186 / s40164-020-00188-w; Zhang, Ping, and Mingzhi Zhang. Clinical Epigenetics 12.1 (2020): 169, doi: 10.1186 / sl3148-020-00962 -x; 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; Zain, Jasmine, and Avyakta Kallam. Frontiers in Oncology 13 (2023): 1150715, doi: 10.3389 / fonc.2023.1150715; Duan, Ran, Wenfang Du, and Weijian Guo. Journal of Hematology & Oncology 13.1 (2020): 104, doi: 10.1186 / sl3045-020-00937-8; Li, Chen, et al. Clinical Epigenetics 13 (2021), doi: 10.1186 / s 13148-021 -01045- 1 ; and Schumann, Franziska Lea, et al. Biomedicines 9.12 (2021): 1842, doi: 10.3390 / biomedicines9121842.

[0038] Compound A (also known as SHR-2554 and TLN-254) has demonstrated preliminary single-agent activity in T-cell lymphoma in a Chinese study (Study SHR2554-I-101). In addition, three investigational dual EZH1 / 2 inhibitors have also shown preliminary activity in T-cell lymphoma. Valemetostat demonstrated a 48% ORR in patients with relapsed or refractory adult T-cell leukemia / lymphoma and a 43% ORR in 119 patients with relapsed or Docket No. TRLN-019-010W01 / TLS-066WO refractory PTCL HH2853 and tulmimetostat, also investigational EZH1 / 2 inhibitors, demonstrated a 61% ORR in 28 patients, and 43% in 7 patients with PTCL, respectively. See, e.g., Song, Yuqin, et al. The Lancet Haematology 9.7 (2022): e493-e503, doi: 10.1016 / S2352- 3026(22)00134-X; Song, Yuqin, et al. Clinical Cancer Research 30.7 (2024): 1248-1255, doi: 10.1158 / 1078-0432. CCR-23-2582; Horwitz, Steven M., et al. Blood 142 (2023): 302, doi: 10.1182 / blood-2023-179304; Izutsu, Koji, et al. Blood 141.10 (2023): 1159-1168, doi: 10.1182 / blood.2022016862; Drescher, Charles, et al. Journal of Clinical Oncology 41.16_Suppl (2023): 3094-3094, doi: 10.1200 / JC0.2023.41.16_suppl.3094; and Hong, Huangming, et al. Blood 142 (2023): 304, doi: 10.1182 / blood-2023-180372. Compound A is also being studied in clinical trial nos. NCT06733441 and NCT07082803.

[0039] Compound A

[0040] Chemical names of Compound A include N-[(l,2-dihydro-4,6-dimethyl-2-oxo-3- pyridinyl)methyl]-5-ethyl-6-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-2-(l- piperidinylmethyl)-4-benzofurancarboxamide and N-[(4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl]-5-ethyl-6- [ethyl(oxan-4-yl)amino]-2-[(piperidin-l-yl)methyl]- l-benzofuran-4- carboxamide. Additional information about Compound A can be found in U.S. Patent Nos. 10,759,787; 11,155,537; 11,065,239; and 11,390,614; and International Publication Nos. WO 2020 / 063863; WO 2021 / 063340; WO 2023 / 030299; and WO 2023 / 061467.

[0041] The majority of mycosis fungoides and Sezary syndrome are characterized by the so- called T follicular helper (Tfh) phenotype EZH2 inhibitors, including Compound A, have shown higher point estimates of response in Tfh-cell subtypes of PTCL (e.g., AITL and PTCL Tfh). See, e.g., Meyerson, Howard J., et al. Modern Pathology 26.1 (2013): 32-43, doi: 10.1038 / modpathol.2012.124; Bosisio, Francesca M., and Lorenzo Cerroni. The American Journal of Dermatopathology 37.2 (2015): 115-121, doi: 10.1097 / D AD.0000000000000258; Horwitz, Steven M., et al. Blood 142 (2023): 302, doi: 10.1182 / blood-2023-179304; Song, Docket No. TRLN-019-010W01 / TLS-066WO

[0042] Yuqin, et al. The Lancet Haematology 9.7 (2022): e493-e503, doi: 10.1016 / S2352- 3026(22)00134-X; and Song, Yuqin, et al. Clinical Cancer Research 30.7 (2024): 1248-1255, doi: 10.1158 / 1078-0432. CCR-23-2582.

[0043] Methods of Treatment

[0044] Indications

[0045] Provided herein are methods for treating a cancer, such as hematological malignancy (e.g., a lymphoma) comprising administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the subject is treatment naive with respect to the cancer . In some embodiments, the hematological malignancy (e.g., the lymphoma) is relapsed or refractory. In some embodiments, the subject has received one or more lines of therapy for the cancer. In some embodiments, the subject has received chemotherapy, an antibody, an antibody-drug conjugate, autologous stem cell transplant, allogenic stem cell transplant, or two or more thereof. In some embodiments, the subject has received CHOP, CHOEP, brentuximab vedotin, or two or more thereof. In some embodiments, the subject has received a brentuximab vedotin- containing regimen. In some embodiments, the subject has a PTCL and has previously received CHOP, CHOEP, and / or brentuximab vedotin. In some embodiments, the subject has a PTCL and has previously received CHOP. In some embodiments, the subject has a PTCL and has previously received CHOEP. In some embodiments, the subject has a PTCL and has previously received brentuximab vedotin. In some embodiments, the subject has a CTCL with more limited skin involvement (<10% body surface area) and has received one or more skin-directed therapies such as topical high-potency steroids, emollients, and / or phototherapy. In some embodiments, the subject has a CTCL characterized by refractory skin disease, the subject has received low-dose radiotherapy, electron beam radiotherapy, an immunomodulatory agent (e.g., methotrexate, interferon, oral bexarotene, or a combination thereof), or a combination thereof. In some embodiments, skin-directed therapies do not provide sufficient disease control of the CTCL in a subject, or the subject has a CTCL not amenable to skin-directed therapy (e.g., a subject having blood or extracutaneous disease), and the subject has received one or more treatments such as chemotherapy, brentuximab vedotin, romidepsin, vorinostat, bexarotene, and / or mogamulizumab. In some embodiments, the subject has received an autologous stem cell transplantation more than 60 days before the first dose of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has received Docket No. TRLN-019-010W01 / TLS-066WO an allogeneic stem cell transplantation more than 90 days prior to the first dose of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is used in the treatment of a subject who has received one or more lines of therapy for the cancer. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is used in the treatment of a subject who has received two or more lines of therapy for the cancer.

[0046] 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., by 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 30%, greater than or equal to 60%, or greater than or equal to 90%) in an IHC test). In some embodiments, 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 subject is treatment-naive. In some embodiments, the subject has been treated with at least one line of therapy for the PTCL. In some embodiments, the subject has been treated with at least two lines of therapy for the PTCL.

[0047] 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% (e.g., greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 60%, or greater than or equal to 90%) 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 subject is treatment-naive. In some embodiments, the PTCL-NOS has been treated with at Docket No. TRLN-019-010W01 / TLS-066WO least one line of therapy. In some embodiments, the PTCL-NOS has been treated with at least two lines of therapy.

[0048] In some embodiments, the cancer is a Tfh PTCL (also called a nodal T follicular helper cell lymphoma). 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% (e.g., greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 60%, or greater than or equal to 90%) 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 subject is treatment-naive. 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.

[0049] In some embodiments, the cancer is an 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). 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% (e.g., greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 60%, or greater than or equal to 90%) 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 subject is treatment-naive. 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. Docket No. TRLN-019-010W01 / TLS-066WO

[0050] 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 or equal to 1% (e.g., greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 60%, or greater than or equal to 90%) 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 subject is treatment-naive. 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.

[0051] 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% (e.g., greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 60%, or greater than or equal to 90%) 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 Docket No. TRLN-019-010W01 / TLS-066WO cell lymphoma, NOS is relapsed or refractory, BCL6+, and has an EZH2 dysregulation. In some embodiments, the subject is treatment-naive. 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.

[0052] In some embodiments of any of the methods or uses described herein, the cancer is a T-cell or NK-cell lymphoid proliferation or lymphoma (e.g., tumor-like lesions with T-cell predominance (e.g., autoimmune lymphoproliferative syndrome), precursor T-cell neoplasms (e.g., early T-precursor lymphoblastic leukemia / lymphoma or T-lymphoblastic leukemia / lymphomaNOS), mature T-cell and NK-cell neoplasms (e.g., mature T-cell and NK- cell leukemias (e.g., T-prolymphocytic leukemia, T-large granular lymphocytic leukemia, NK- large granular lymphocytic leukemia, adult T-cell leukemia / lymphoma, or aggressive NK-cell leukemia), 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, primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder, mycosis fungoides, Sezary syndrome (also called 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, primary cutaneous CD8- positive aggressive epiderm otropic cytotoxic T-cell lymphoma, or primary cutaneous peripheral T-cell lymphoma NOS), peripheral T-cell lymphoma (PTCL) (e.g., intestinal T-cell and NK-cell lymphoid proliferations and lymphomas (e.g., indolent T-cell lymphoma of the gastrointestinal tract, indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, enteropathy-associated T-cell lymphoma, monomorphic epitheli otropic intestinal T-cell lymphoma, or intestinal T-cell lymphoma NOS), hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, ALK- negative anaplastic large cell lymphoma, or breast implant-associated anaplastic large cell lymphoma), nodal T follicular helper cell lymphoma (also herein called nodal Tfh cell lymphoma or a Tfh PTCL) (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 follicular type Tfh cell lymphoma), or nodal T follicular helper cell lymphoma NOS (also known as follicular helper Docket No. TRLN-019-010W01 / TLS-066WO

[0053] T-cell lymphoma, NOS or follicular helper T-cell lymphoma-NOS or Tfh not otherwise specified (NOS))), other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS (PTCL-NOS)), or EBV-positive T-cell and NK-cell lymphomas (e.g., EBV-positive nodal T- and NK-cell lymphoma or extranodal NK / T-cell lymphoma)))). See, e.g., Alaggio, Rita, et al. Leukemia 36.7 (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; 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; International Publication Nos. WO 2021 / 080950, WO 2021 / 077010, and WO 2022 / 221673.

[0054] In some embodiments of any of the methods or uses described herein, the cancer is a mature T-cell or NK-cell neoplasm (e.g., mature T-cell and NK-cell leukemias (e.g., T- prolymphocytic leukemia, T-large granular lymphocytic leukemia, NK-large granular lymphocytic leukemia, adult T-cell leukemia / lymphoma, or aggressive NK-cell leukemia), 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, primary cutaneous acral CD8-positive 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, primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma, or primary cutaneous peripheral T-cell lymphoma NOS), peripheral T-cell lymphoma (PTCL) (e.g., intestinal T-cell and NK-cell lymphoid proliferations and lymphomas (e.g., indolent T-cell lymphoma of the gastrointestinal tract, indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, or intestinal T-cell lymphoma NOS), hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, or breast implant-associated Docket No. TRLN-019-010W01 / TLS-066WO 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)), other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS), or EBV-positive T-cell and NK-cell lymphomas (e.g., EBV-positive nodal T- and NK-cell lymphoma or extranodal NK / T-cell lymphoma))).

[0055] In some embodiments of any of the methods or uses described herein, the cancer is relapsed or refractory (sometimes also referred to as relapsed / refractory).

[0056] In some embodiments of any of the methods or uses described herein, the cancer is a CTCL (e.g., primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, primary cutaneous acral CD8-positive 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, primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma, or primary cutaneous peripheral T-cell lymphoma NOS). In some embodiments, the cancer is a relapsed or refractory CTCL.

[0057] In some embodiments, the cancer is primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder. In some embodiments, the cancer is relapsed or refractory primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder.

[0058] In some embodiments, the cancer is primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder. In some embodiments, the cancer is relapsed or refractory primary cutaneous acral CD8-positive T-cell lymphoproliferative disorder.

[0059] In some embodiments, the cancer is mycosis fungoides. In some embodiments, the cancer is relapsed or refractory mycosis fungoides.

[0060] In some embodiments, the cancer is Sezary syndrome. In some embodiments, the cancer is relapsed or refractory Sezary syndrome.

[0061] In some embodiments, the cancer is primary cutaneous CD30-positive T-cell lymphoproliferative disorder: lymphomatoid papulosis. In some embodiments, the cancer is relapsed or refractory primary cutaneous CD30-positive T-cell lymphoproliferative disorder: lymphomatoid papulosis. Docket No. TRLN-019-010W01 / TLS-066WO

[0062] In some embodiments, the cancer is primary cutaneous CD30-positive T-cell lymphoproliferative disorder: primary cutaneous anaplastic large cell lymphoma. In some embodiments, the cancer is relapsed or refractory primary cutaneous CD30-positive T-cell lymphoproliferative disorder: primary cutaneous anaplastic large cell lymphoma.

[0063] In some embodiments, the cancer is subcutaneous panniculitis-like T-cell lymphoma. In some embodiments, the cancer is relapsed or refractory subcutaneous panniculitis-like T- cell lymphoma.

[0064] In some embodiments, the cancer is primary cutaneous gamma-delta T-cell lymphoma. In some embodiments, the cancer is relapsed or refractory primary cutaneous gamma-delta T- cell lymphoma.

[0065] In some embodiments, the cancer is primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma. In some embodiments, the cancer is relapsed or refractory primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma.

[0066] In some embodiments, the cancer is primary cutaneous peripheral T-cell lymphoma NOS. In some embodiments, the cancer is relapsed or refractory primary cutaneous peripheral T-cell lymphoma NOS.

[0067] In some embodiments of any of the methods or uses described herein, the cancer is a PTCL (e.g., intestinal T-cell and NK-cell lymphoid proliferations and lymphomas (e.g., indolent T-cell lymphoma of the gastrointestinal tract, indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, or intestinal T-cell lymphoma NOS), hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma (ALCL) (e.g., ALK -positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, or breast implant-associated 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)), other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS (PTCL-NOS)), or EBV-positive T-cell and NK-cell lymphomas (e.g., EBV-positive nodal T- and NK-cell lymphoma or extranodal NK / T-cell lymphoma)). In some embodiments, the cancer is a relapsed or refractory PTCL. Docket No. TRLN-019-010W01 / TLS-066WO

[0068] In some embodiments, the cancer is an intestinal T-cell or NK-cell lymphoid proliferation or lymphoma (e.g., indolent T-cell lymphoma of the gastrointestinal tract, indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, enteropathy-associated T- cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, or intestinal T-cell lymphoma NOS). In some embodiments, the cancer is a relapsed or refractory intestinal T-cell or NK-cell lymphoid proliferation or lymphoma (e.g., indolent T-cell lymphoma of the gastrointestinal tract, indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, or intestinal T-cell lymphoma NOS).

[0069] In some embodiments, the cancer is hepatosplenic T-cell lymphoma. In some embodiments, the cancer is relapsed or refractory hepatosplenic T-cell lymphoma.

[0070] In some embodiments, the cancer is anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, or breast implant-associated anaplastic large cell lymphoma). In some embodiments, the cancer is relapsed or refractory anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, or breast implant- associated anaplastic large cell lymphoma).

[0071] In some embodiments, the cancer is ALK-positive anaplastic large cell lymphoma. In some embodiments, the cancer is relapsed or refractory ALK-positive anaplastic large cell lymphoma.

[0072] In some embodiments, the cancer is ALK-negative anaplastic large cell lymphoma. In some embodiments, the cancer is relapsed or refractory ALK-negative anaplastic large cell lymphoma.

[0073] In some embodiments, the cancer is breast implant-associated anaplastic large cell lymphoma. In some embodiments, the cancer is relapsed or refractory breast implant- associated anaplastic large cell lymphoma.

[0074] In some embodiments, the cancer is 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)). In some embodiments, the cancer is relapsed or refractory nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as Docket No. TRLN-019-010W01 / TLS-066WO 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)).

[0075] In some embodiments, the cancer is nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type). In some embodiments, the cancer is relapsed or refractory nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type).

[0076] In some embodiments, the cancer is nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type). In some embodiments, the cancer is relapsed or refractory nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type).

[0077] In some embodiments, the cancer is nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS). In some embodiments, the cancer is relapsed or refractory nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS).

[0078] 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.

[0079] In some embodiments, the cancer is a peripheral T-cell lymphoma NOS (PTCL-NOS). In some embodiments, the cancer is relapsed or refractory peripheral T-cell lymphoma NOS.

[0080] In some embodiments, the cancer is an EBV-positive T-cell and NK-cell lymphoma (e.g., EBV-positive nodal T- and NK-cell lymphoma or extranodal NK / T-cell lymphoma). In some embodiments, the cancer is a relapsed or refractory EBV-positive T-cell and NK-cell lymphoma (e.g., EBV-positive nodal T- and NK-cell lymphoma or extranodal NK / T-cell lymphoma).

[0081] In some embodiments, the cancer is nodal T follicular helper cell lymphoma angioimmunoblastic type, nodal T follicular helper cell lymphoma follicular type, nodal T follicular helper cell lymphoma NOS, peripheral T-cell lymphoma NOS, ALK-positive Docket No. TRLN-019-010W01 / TLS-066WO anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, mycosis fungoides, or Sezary syndrome.

[0082] Accordingly, provided herein is the use of Compound A, or a pharmaceutically acceptable salt thereof, for the treatment of nodal T follicular helper cell lymphoma angioimmunoblastic type, nodal T follicular helper cell lymphoma follicular type, nodal T follicular helper cell lymphoma NOS, peripheral T-cell lymphoma NOS, ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, mycosis fungoides, or Sezary syndrome. Also provided herein is the use of Compound A, or a pharmaceutically acceptable salt thereof, for the treatment of mycosis fungoides or Sezary syndrome.

[0083] Also provided herein is a method for treating a PTCL (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type, nodal T follicular helper cell lymphoma follicular type, nodal T follicular helper cell lymphoma NOS, peripheral T-cell lymphoma NOS, ALK- positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma), or a CTCL (e.g., mycosis fungoides or Sezary syndrome) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0084] Also provided herein is a method for treating a CTCL (e.g., primary cutaneous CD4- positive small or medium T-cell lymphoproliferative disorder, primary cutaneous acral CD8- positive 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, primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma, or primary cutaneous peripheral T-cell lymphoma NOS) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating a mycosis fungoides or Sezary syndrome in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a Docket No. TRLN-019-010W01 / TLS-066WO therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments of any of the methods for treating a CTCL herein, the method does not include administering an immune checkpoint inhibitor (e.g., an anti-PD-Ll antibody or an anti-PD-1 antibody) or a multikinase inhibitor.

[0085] As used herein, “monotherapy”, when referring to Compound A, or a pharmaceutically acceptable salt thereof, means that Compound A, 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). As a person of ordinary skill in the art would understand, monotherapy does not exclude the co-administration of medicaments for the treatment of side effects or general symptoms associated with the cancer or treatment, such as pain, rash, edema, photosensitivity, pruritis, 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”.

[0086] As used herein, “the subject has previously received one or more therapeutic agents or therapies for the cancer” or “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., an anticancer agent or a therapy (e.g., a systemic therapy)) for the cancer other than Compound A, or a pharmaceutically acceptable salt thereof, during a prior treatment cycle. 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 subj ect 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 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. Docket No. TRLN-019-010W01 / TLS-066WO

[0087] As used herein, “the subject is treatment naive with respect to the cancer” or “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.

[0088] As used herein, treatment of a cancer (e.g., a hematological malignancy) can include treatment of a tumor (e.g., a solid or liquid 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), or maintenance therapy (e.g., treatment following response to an additional therapy or therapeutic agent, such as surgery, radiation, chemotherapy, or a line of therapy).

[0089] In some embodiments, administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, is first-line therapy, second-line therapy, or third-line (or beyond) therapy.

[0090] 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 after a period of remission or the cancer did not sufficiently respond to a treatment (e.g., a standard-of-care (SOC) treatment or a treatment that is not a Compound A). Accordingly, a subject that has a cancer that is relapsed or refractory has been treated with 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.). 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.). 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., two or more prior lines of therapy (e.g., systemic therapy); three or more prior lines of therapy (e.g., systemic therapy)).

[0091] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dosage of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg (e.g., 250 mg or 350 mg), twice daily. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dosage of 250 mg twice daily. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dosage of 300 mg twice daily. In some embodiments, Docket No. TRLN-019-010W01 / TLS-066WO

[0092] Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject at a dosage of 350 mg twice daily.

[0093] In some embodiments, the subject is at least 18 years old.

[0094] In some embodiments, the subject has ALCL (e.g., ALK-positive ALCL or ALK- negative ALCL), and the subject has previously received brentuximab vedotin (e.g., ADCETRIS®), or a biosimilar thereof. In some embodiments, the subject has a PTCL (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type, nodal T follicular helper cell lymphoma follicular type, nodal T follicular helper cell lymphoma NOS, peripheral T-cell lymphoma NOS, ALK-positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma) and has received at least one prior therapy (e.g., systemic therapy). In some embodiments, the subject has a PTCL (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type, nodal T follicular helper cell lymphoma follicular type, nodal T follicular helper cell lymphoma NOS, peripheral T-cell lymphoma NOS, ALK-positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma) and has received at least one prior therapy (e.g., systemic therapy) and has relapsed after or not responded to at least one prior therapy (e.g., systemic therapy). In some embodiments, the subject has a CTCL (e.g., mycosis fungoides or Sezary syndrome) and has received at least two prior therapies. In some embodiments, the subject has a CTCL (e.g., mycosis fungoides or Sezary syndrome) and has received at least two prior therapies and has relapsed or not responded to at least two prior therapies.

[0095] In some embodiments, the subject has a PTCL (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type, nodal T follicular helper cell lymphoma follicular type, nodal T follicular helper cell lymphoma NOS, peripheral T-cell lymphoma NOS, ALK-positive anaplastic large cell lymphoma, or ALK-negative anaplastic large cell lymphoma) and at least one measurable lesion which is measurable in 2 perpendicular dimensions on computed tomography based on local radiological read (nodal lesion with any long diameter > 1.5 cm or extranodal lesion with any long diameter > 1.0 cm). In some embodiments, the subject has a CTCL (e.g., mycosis fungoides or Sezary syndrome) and (1) at least one measurable lesion which is measurable in 2 perpendicular dimensions on CT (or MRI) based on local radiological read (nodal lesion with any long diameter > 1.5 cm or extranodal lesion with any long diameter > 1.0 cm); (2) a Modified Severity Weighted Assessment Tool (mSWAT) >0 (see, e.g., Lund, C. C., and N. C. Browder. Surg Gynecol Obstet. Chicago 79.4 (1944): 352-58; Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: Docket No. TRLN-019-010W01 / TLS-066WO

[0096] 10.1182 / blood.2021012057); or (3) atypical T lymphocytes quantifiable by flow cytometry or morphology in the peripheral blood or bone marrow.

[0097] In some embodiments, the subject has an ECOG performance status of 0, 1, or 2 (see, e g., Table B5).

[0098] In some embodiments, the subject has laboratory values of

[0099] • Absolute neutrophil count (ANC) > 1 X 109 / L (no growth factors used within 14 days before testing);

[0100] • Platelet count > 75 X 109 / L (no platelet transfusion within 7 days before testing);

[0101] • Hemoglobin > 8.0 g / dL (no corrective treatment given within 7 days before testing);

[0102] • Adequate coagulation, defined as: prothrombin time (international normalized ratio [INR]) < and aPTT < 1.5 X upper limit of normal (ULN);

[0103] • Adequate renal function, with estimated glomerular filtration (eGFR) rate > 60 mL / min;

[0104] • Serum total bilirubin < 1.5 X ULN (or < 3.0 X ULN with documented tumor / lymphoma involvement of the liver), unless there is documentation that the patient has Gilbert’s syndrome; and

[0105] • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 X ULN; (or N 5.0 X ULN with documented tumor / lymphoma involvement of the liver)

[0106] In some embodiments, the subject has a negative serum / urine pregnancy test result within 72 hours prior to the first dose of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject (if female of childbearing potential) is willing to adopt highly effective contraceptive measures until 6 months after the last dose of Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject (if male, whose partner is a female of childbearing potential) has undergone surgical sterilization or is willing to adopt highly effective contraceptive measures until 3 months after the last dose of Compound A, or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the subject has a life expectancy of at least 12 weeks.

[0108] In some embodiments, any toxicities due to a previous treatment have been resolved (CTCAE Grade < 1) before the first dose of Compound A, or a pharmaceutically acceptable salt thereof. Docket No. TRLN-019-010W01 / TLS-066WO

[0109] In some embodiments, the subject is able to swallow tablets. In some embodiments, the subject has the ability to comply with the dosing schedule of Compound A. In some embodiments, the subject has the ability to comply with laboratory tests.

[0110] In some embodiments, the subject does not have a current or past history of central nervous system (CNS) involvement of lymphoma.

[0111] In some embodiments, the subject does not have a current or past history of CNS disease, (e.g., stroke or epilepsy), other than (a) a history of stroke, wherein the subject has not experienced a stroke or transient ischemic attack in the past 2 years and has no residual neurologic deficits; or (b) a history of epilepsy, wherein the subject has had no seizures in the past 2 years.

[0112] In some embodiments, the subject does not have a history of autologous stem cell transplantation within 60 days or allogeneic stem cell transplantation within 90 days prior to the first dose of Compound A, or a pharmaceutically acceptable salt thereof. Subjects who received allogeneic stem cell transplantation are stable, without signs of graft versus host disease, for at least 2 months off of immunosuppressive therapy.

[0113] In some embodiments, the subject has not had major surgery or severe trauma within 4 weeks prior to the first dose of Compound A, or a pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the subject does not have active infection or unexplained fever > 38.5 °C on the day of the first dose of Compound A, or a pharmaceutically acceptable salt thereof.

[0115] In some embodiments, the subject does not have a known active bacterial, viral (e.g., Epstein Barr virus [EBV], cytomegalovirus [CMV]), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment. If any recent major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics), the date of resolution must be at least 2 weeks prior to first dose of Compound A, or a pharmaceutically acceptable salt thereof.

[0116] In some embodiments, the subject does not have clinically significant cardiovascular disease, including: (1) a history of congestive heart failure (NYHA Class > 2); (2) a history of or current unstable angina; (3) a myocardial infarction in the past year; (4) a history of any supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention; (5) uncontrolled angina pectoris within 6 months prior to screening; (6) coronary / peripheral artery bypass graft within 6 months prior to screening; (7) complete left bundle branch block; or (8) uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg). Docket No. TRLN-019-010W01 / TLS-066WO

[0117] In some embodiments, the subject does not have abnormal electrocardiogram (ECG) findings including:

[0118] (a) evidence of prolongation of QT / QTc interval >470 msec corrected for heartrate using Fridericia’s Formula [QTcF = QT / (RR°33)] for men and women based on the mean value of 3 ECGs;

[0119] (b) diagnosed or suspected long QT syndrome or known family history of long QT syndrome;

[0120] (c) a history of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes;

[0121] (d) uncontrolled arrhythmia (subjects with asymptomatic, controllable atrial fibrillation are acceptable); or

[0122] (e) has had clinically relevant bradycardia of <50 bpm unless the subject has a pacemaker.

[0123] In some embodiments, the subject does not have a history of clinically significant liver disease, including hepatitis (viral and non-viral) and cirrhosis.

[0124] In some embodiments, the subject does not have a history of other malignancy that is one or more of the following:

[0125] (a) a history of curatively treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, or localized prostate cancer are allowed;

[0126] (b) a malignancy that has been treated with curative intent will also be allowed if the malignancy has been in remission without treatment (excluding chronic adjuvant hormonal therapy) for 2 years prior to first dose of Compound A, or a pharmaceutically acceptable salt thereof; without being bound by any particular theory, it is believed that having a history of (a) or (b), above, could affect compliance with the dosing of Compound A or a pharmaceutically acceptable salt thereof, or interpretation of results.

[0127] In some embodiments, the subject does not have chronic hepatitis B or C as defined by positive hepatitis B or C serology; subjects with a negative HBsAg and a positive HBcAb require an undetectable / negative hepatitis B DNA test (e.g., polymerase chain reaction (PCR) test) and must receive hepatitis B prophylaxis until at least 6 months after the last dose of Compound A, or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the subject does not have positive serologic or PCR test results for acute or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Docket No. TRLN-019-010W01 / TLS-066WO

[0129] In some embodiments, a subject whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR.

[0130] In some embodiments, the subject does not have positive serologic test results for human immunodeficiency virus (HIV) infection.

[0131] In some embodiments, the subject has not received prior treatment with an EZH2 inhibitor.

[0132] In some embodiments, the subject does not receive systemic treatment with corticosteroids (>10 mg daily prednisone equivalents). In some embodiments, short-course systemic corticosteroids (for < 7 days) or stable baseline usage of topical steroids (for > 21 days) for CTCL is permitted.

[0133] In some embodiments, the subject does not receive concomitant use of another systemic therapy for PTCL or CTCL. In some embodiments, the subject has had one or more of the following wash-outs from previous treatments:

[0134] (a) at least 4 weeks for systemic anticancer agents (e.g., chemotherapy, immunomodulatory therapy, or monoclonal antibody therapy) or 5 half-lives of the drug, whichever is shorter, to the first dose of Compound A, or a pharmaceutically acceptable salt thereof;

[0135] (b) at least 8 weeks for low-dose (12Gy or less) total skin electron beam therapy (TSEBT);

[0136] (c) at least 2 weeks for local radiation therapy; if the subject received radiotherapy within 4 weeks prior to the first dose of the study drug, subject must have at least one measurable lesion outside of the radiation field. Subjects are permitted who have only one measurable lesion that was previously irradiated but subsequently progressed; and

[0137] (d) at least 1 week for topical retinoids, nitrogen mustard, or imiquimod.

[0138] In some embodiments, the subject is not administered moderate or strong inhibitors or inducers of CYP3A4 or inhibitors of P-gly coprotein from 1 week prior to first dose of Compound A, or a pharmaceutically acceptable salt thereof, through the duration of treatment with Compound A, or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, administration of any proton pump inhibitor (PPI) (e.g., omeprazole of pantoprazole) to the subject is stopped from 1 week prior to the first dose of Compound A, or a pharmaceutically acceptable salt thereof through the duration of treatment with Compound A, or a pharmaceutically acceptable salt thereof. Docket No. TRLN-019-010W01 / TLS-066WO

[0140] In some embodiments, the subject is not administered a substrate of P-gly coprotein with a narrow therapeutic window (e.g., digoxin).

[0141] In some embodiments, the subject is not currently participating in the study of another investigational agent.

[0142] In some embodiments, the subject is not a pregnant or lactating woman.

[0143] In some embodiments, the subject does not have a known or suspected hypersensitivity to Compound A, a pharmaceutically acceptable salt thereof, or any of its excipients.

[0144] In some embodiments, the subject does not have active gastrointestinal inflammation, chronic diarrhea, or a history of gastrectomy, gastric banding, or other cases that may affect absorption of Compound A, or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, administration of Compound A, or a pharmaceutically acceptable salt thereof to a subject may result in one or more adverse events (AEs). In some such embodiments, administration of Compound A, or a pharmaceutically acceptable salt thereof, may be paused for up to 4 weeks (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 2 weeks, 3 weeks, or 4 weeks). In some embodiments, no dose adjustment (e.g., reduction) is made for treatment related toxicities < Grade 2. In some embodiments, no dose interruption is made for treatment related toxicities < Grade 2. In some embodiments, the dose of Compound A, or a pharmaceutically acceptable salt thereof, is adjusted following an AE.

[0146] For example, if the subject was receiving 350 mg of Compound A BID, or a pharmaceutically acceptable salt thereof, a first dose reduction can be to 300 mg BID, and a second dose reduction can be to 250 mg BID. As another example, if the subject was receiving 250 mg of Compound A BID, or a pharmaceutically acceptable salt thereof, a first dose reduction can be to 200 mg BID, and a second dose reduction can be to 150 mg BID.

[0147] In some embodiments, subjects who experience Grade 4 neutropenia, febrile neutropenia, or Grade > 3 thrombocytopenia in the context of clinically significant bleeding are permanently discontinued if they require a second dose reduction for the same toxicity. For other toxicities requiring dose modification, Compound A, or a pharmaceutically acceptable salt thereof, can be permanently discontinued in subjects who require a third dose reduction.

[0148] In some embodiments, the subject experiences neutropenia. If the neutropenia is < Grade 2, then no dose interruption occurs. If the neutropenia is Grade 3, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is interrupted, and symptomatic treatment is performed; once toxicity has resolved to < Grade 1 (or baseline), administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at the same dose level than before the neutropenia. If the neutropenia is Grade 4, then administration of Docket No. TRLN-019-010W01 / TLS-066WO

[0149] Compound A, or a pharmaceutically acceptable salt thereof, is interrupted, and symptomatic treatment is performed; once toxicity has resolved to < Grade 1 (or baseline), administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at a lower dose level than before the neutropenia.

[0150] In some embodiments, the subject experiences febrile neutropenia. If the febrile neutropenia is < Grade 2, then no dose interruption occurs. If the febrile neutropenia is Grade 3, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is interrupted, and symptomatic treatment is performed; once toxicity has resolved to < Grade 1 (or baseline), administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at a lower dose level than before the febrile neutropenia. If the febrile neutropenia is Grade 4, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is interrupted, and symptomatic treatment is performed; once toxicity has resolved to < Grade 1 (or baseline), administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at a lower dose level than before the febrile neutropenia.

[0151] In some embodiments, the subject experiences thrombocytopenia. If the thrombocytopenia is < Grade 2, then no dose interruption occurs. If the thrombocytopenia is Grade 3, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is interrupted, and symptomatic treatment is performed; once toxicity has resolved to < Grade 1 (or baseline), administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at the same dose level as before the thrombocytopenia; however, if the thrombocytopenia occurs in the context of clinically significant bleeding, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at a lower dose level than before the thrombocytopenia. If the thrombocytopenia is Grade 4, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is interrupted, and symptomatic treatment is performed; once toxicity has resolved to < Grade 1 (or baseline), administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at a lower dose level than before the thrombocytopenia; if the thrombocytopenia occurs in the context of clinically significant bleeding, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at a lower dose level than before the thrombocytopenia.

[0152] In some embodiments, the subject experiences anemia. If the anemia is < Grade 2, then no dose interruption occurs. If the anemia is Grade 3, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is interrupted, and symptomatic treatment is performed; once toxicity has resolved to < Grade 1 (or baseline), administration of Compound Docket No. TRLN-019-010W01 / TLS-066WO

[0153] A, or a pharmaceutically acceptable salt thereof, is continued at the same dose level as before the anemia. If the anemia is Grade 4, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is interrupted, and symptomatic treatment is performed; once toxicity has resolved to < Grade 1 (or baseline), administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at a lower dose level than before the anemia.

[0154] In some embodiments, the subject experiences a non-hematologic toxicity. If the non- hematologic toxicity is < Grade 2, then no dose interruption is required, but it may be considered if the non-hematologic toxicity is Grade 2 and persistent or recurrent that does not resolve with maximal supportive measures to < Grade 1 within 7 days. If the non-hematologic toxicity is Grade 3, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is interrupted, and symptomatic treatment is performed; once toxicity has resolved to

[0155] < Grade 1 (or baseline), administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at the same dose level as before the non-hematologic toxicity. If the non- hematologic toxicity is Grade 4, then administration of Compound A, or a pharmaceutically acceptable salt thereof, is permanently withdrawn, unless the non-hematologic toxicity is clearly unrelated to administration of Compound A, or a pharmaceutically acceptable salt thereof, in which case, administration of Compound A, or a pharmaceutically acceptable salt thereof, is interrupted, and symptomatic treatment is performed; once toxicity has resolved to

[0156] < Grade 1 (or baseline), administration of Compound A, or a pharmaceutically acceptable salt thereof, is continued at a lower dose level than before the non-hematologic toxicity.

[0157] In some embodiments, the subject receives antimicrobial prophylaxis against Pneumocystis jiroveci (e.g., trimethoprim and sulfamethoxazole).

[0158] In some embodiments, the subject receives antiviral prophylaxis against varicella zoster (e.g., acyclovir).

[0159] In some embodiments, a subject with hepatitis B core antibody positivity receives prophylactic medication against hepatitis B (e.g., entecavir or tenofovir) during administration of Compound A, or a pharmaceutically acceptable salt thereof, and for at least 6 months after therapy with Compound A, or a pharmaceutically acceptable salt thereof, is completed.

[0160] In some embodiments, a subject is monitored for CMV and / or EBV infection or reactivation.

[0161] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered to a subject with or without food. Docket No. TRLN-019-010W01 / TLS-066WO

[0162] In some embodiments, the response of a subject to treatment with Compound A, or a pharmaceutically acceptable salt thereof, is assessed using published assessment criteria. For example, if the subject has a cancer that is a PTCL (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type, nodal T follicular helper cell lymphoma follicular type, nodal T follicular helper cell lymphoma NOS, peripheral T-cell lymphoma NOS, ALK-positive anaplastic large cell lymphoma, ALK -negative anaplastic large cell lymphoma), efficacy can be assessed using 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; see also Table B8). As another example, if the subject has a cancer that is a CTCL (e.g., mycosis fungoides or Sezary syndrome), efficacy can be assessed using the Global Response Criterial for CTCL (Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419- 437; doi: 10.1182 / blood.2021012057; see also Table B10).

[0163] A response to treatment with Compound A, or a pharmaceutically acceptable salt thereof, can be determined, independently, on individual and population bases. Exemplary assessments of response of an individual subject to treatment with Compound A, or a pharmaceutically acceptable salt thereof include whether the subject has achieved a complete response, a partial response, or stable disease. The DOR of an individual subject can also be assessed. For a subject having a PTCL, response can be assessed using PET-CT and / or CT and be based on the Lugano 2014 criteria (see, e.g., Table B8); in some such embodiments, a response can be metabolic or radiographic in nature. For a subject having a CTCL, response can be based on the Global Response Criteria (see., e.g., Table B10). For a subject having FL or a large B cell lymphoma (LBCL), response can be assessed using PET-CT and / or CT and be based on the Lugano 2014 criteria (see, e.g., Table B8); in some such embodiments, a response can be metabolic or radiographic in nature..

[0164] Exemplary assessments of response of a population of subjects to treatment with Compound A, or a pharmaceutically acceptable salt thereof, include overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, and duration of response (DOR) (e.g., in the context of pharmacokinetics). In some embodiments, treatment of a population of subjects having PTCL with Compound A, or a pharmaceutically acceptable salt thereof, results in an ORR of about 30% to about 80%. In some embodiments, treatment of a population of subjects having PTCL with Compound A, or a pharmaceutically acceptable salt thereof, results in CR of about 10% to about 40%. In some embodiments, treatment of a population of subjects having a nodal T follicular helper cell lymphoma (e.g., nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell Docket No. TRLN-019-010W01 / TLS-066WO 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)) with Compound A, or a pharmaceutically acceptable salt thereof, results in an ORR of about 40% to about 90%. In some embodiments, treatment of a population of subjects having a 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)) with Compound A, or a pharmaceutically acceptable salt thereof, results in a DOR of about 10 months to about 30 months. In some embodiments, treatment of a population of subjects having an anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, ALK- negative anaplastic large cell lymphoma, or breast implant-associated anaplastic large cell lymphoma) or peripheral T cell lymphoma NOS with Compound A, or a pharmaceutically acceptable salt thereof, results in an ORR of about 10% to about 70%. In some embodiments, treatment of a population of subjects having an anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma, ALK-negative anaplastic large cell lymphoma, or breast implant-associated anaplastic large cell lymphoma) or peripheral T cell lymphoma NOS with Compound A, or a pharmaceutically acceptable salt thereof, results in a DOR of about 1 month to about 8 months. In some embodiments, treatment of a population of subjects having CTCL with Compound A, or a pharmaceutically acceptable salt thereof, results in an ORR of about 10% to about 60%. In some embodiments, treatment of a population of subjects having CTCL with Compound A, or a pharmaceutically acceptable salt thereof, results in a CR of about 5% to about 30%.

[0165] As used herein, a “second primary malignancy” is a newly diagnosed cancer in a subject with cancer who is being administered or has previously been administered one or more doses of Compound A.

[0166] In some embodiments, a subject is monitored for a second primary malignancy during treatment with Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is monitored for a second primary malignancy following cessation of treatment with Compound A, or a pharmaceutically acceptable salt thereof for at least 6 months (e.g., at least 1 year, at least 2 years, at least 3 years, at least 5 years, or at least 10 Docket No. TRLN-019-010W01 / TLS-066WO years). Also provided herein is a method for treating a cutaneous T cell lymphoma in a subject in need thereof, the method comprising (a) administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and (b) monitoring the subject for the development of a second primary malignancy. In some embodiments, the second primary malignancy is myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or T cell lymphoblastic leukemia (T-LBL). In some embodiments, the second primary malignancy is myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or T cell lymphoblastic leukemia (T-LBL), B-cell acute lymphoblastic leukemia (e.g., transformed FL), or lung cancer (e.g., lung squamous cell carcinoma).

[0167] In some embodiments, a subject is monitored for QTc prolongation (e.g., using ECG monitoring, e.g., at Cmax of Compound A, or a pharmaceutically acceptable salt thereof) during treatment with Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, if a subject has a finding of QTc prolongation, the subject is assessed for associated clinical complications (e.g., recent syncope).

[0168] Also provided herein is a method for treating mycosis fungoides in a subject in need thereof, the method comprising administering an EZH2 inhibitor or an EZH1 / 2 inhibitor to the subject. In some embodiments, the EZH2 inhibitor is Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the EZH2 inhibitor or EZH1 / 2 inhibitor is administered as a monotherapy. In some embodiments, the EZH2 inhibitor or EZH1 / 2 inhibitor is administered in combination with an additional therapy or therapeutic agent.

[0169] In some embodiments, provided herein is a method for treating mycosis fungoides in a subject in need thereof, the method comprising administering an EZH2 inhibitor to the subject. In some embodiments, the EZH2 inhibitor is Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the EZH2 inhibitor is administered as a monotherapy. In some embodiments, the EZH2 inhibitor is administered in combination with an additional therapy or therapeutic agent.

[0170] Also provided herein is a method for treating Sezary syndrome in a subject in need thereof, the method comprising administering an EZH2 inhibitor or an EZH1 / 2 inhibitor to the subject. In some embodiments, the EZH2 inhibitor is Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the EZH2 inhibitor or EZH1 / 2 inhibitor is administered as a monotherapy. In some embodiments, the EZH2 inhibitor or EZH1 / 2 inhibitor is administered in combination with an additional therapy or therapeutic agent.

[0171] In some embodiments, provided herein is a method for treating Sezary syndrome in a subject in need thereof, the method comprising administering an EZH2 inhibitor to the subject. Docket No. TRLN-019-010W01 / TLS-066WO

[0172] In some embodiments, the EZH2 inhibitor is Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the EZH2 inhibitor is administered as a monotherapy. In some embodiments, the EZH2 inhibitor is administered in combination with an additional therapy or therapeutic agent.

[0173] In some embodiments, the EZH2 inhibitor or EZH1 / 2 inhibitor is Compound A, or a pharmaceutically acceptable salt thereof, lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI- 0209), EB 1-2511, HH-2853 (epsametostat), HM-97662, XNW-5004, or a combination thereof. In some embodiments, the EZH2 inhibitor or EZH1 / 2 inhibitor is lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide), valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), EBI-2511, HH-2853, HM-97662, XNW-5004, or a combination thereof. In some embodiments, the EZH1 / 2 inhibitor is valemetostat (e.g., valemetostat tosylate), tulmimetostat (CPI-0209), HH-2853, HM-97662, or a combination thereof. In some embodiments, the EZH2 inhibitor is Compound A, lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide), EBI-2511, XNW-5004, or a combination thereof. In some embodiments, the EZH2 inhibitor is lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide), EBI-2511, XNW-5004, or a combination thereof. See, e.g., Vaswani, Rishi G., et al. Journal of Medicinal Chemistry 59.21 (2016): 9928-9941, doi: 10.1021 / acs.jmedchem.6b01315; Kung, Pei-Pei, et al. Journal of Medicinal Chemistry 61.3 (2018): 650-665, doi: 10.1021 / acs.jmedchem.7b01375; Knutson, Sarah K., et al. Molecular Cancer Therapeutics 13.4 (2014): 842-854, doi: 10.1158 / 1535-7163.MCT-13-0773; Yamagishi, Makoto, et al. Cell Reports 29.8 (2019): 2321-2337, doi:

[0174] 10.1016 / j.celrep.2019.10.083; Keller, Patricia J., et al. Cancer Research 84.15 (2024): 2501- 2517, doi: 10.1158 / 0008-5472. CAN-24-0398; Lu, Biao, et al. ACS Medicinal Chemistry Letters 9.2 (2018): 98-102, doi: 10.1021 / acsmedchemlett.7b00437; and Proposed INN: List 130 (WHO Drug Information, Vol. 37, No. 3, 2023).

[0175] Pathologists often rely on diagnostic algorithms that include various IHC markers, such as BCL6, CD20, CD 10, BCL2, MUM1 and Ki-67 to diagnose and classify NHLs based on cell of origin (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 5.4 (2022): 792-793, doi: 10.4103 / crst.crst_247_22 ). Although molecular typing methods provide an alternative, the Docket No. TRLN-019-010W01 / TLS-066WO

[0176] IHC -based Hans algorithm is a common workup for B-cell lymphomas 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 refers to BCL6 positivity for B-cell lymphomas 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 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(l l): 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).

[0177] Additional details of BCL6 and EZH2 biology and chemistry, as well as discussions of the various cancers described herein, are disclosed in, e.g., See, 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 / sl 3148-021 -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. (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 of Hematology 116.24 (2010): 5247-5255, doi: 10.1182 / blood-2010-04- 280149; and Caganova M, Carrisi C, Varano G, et al. [published correction appears m 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 m ' 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. Docket No. TRLN-019-010W01 / TLS-066WO

[0178] Nature 492.7427 (2012): 108-112; doi: 10.1038 / naturel l606; Knutson, Sarah K., et al. Nature Chemical Biology 8.11 (2012): 890-896, doi: 10.1038 / nchembio.l084; 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(l l): 1229-1253. doi: 10.1182 / blood.2022015851; Ondrejka, Sarah L., et al. Virchows Ar chiv 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 H4C 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, 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 / joumal. pone.0098169; Szumera-Cieckiewicz, Anna, et al. International Journal of Laboratory Hematology 42.4 (2020): 453-463, doi: 10.1111 / ijlh.13222; Alaggio, Rita, et al. Leukemia 6.I (2022): 1720- 1748, doi: 10.1038 / s41375-022-01620-2; Sordi, Benedetta, et al. Blood 144 (2024): 4451, doi: 10.1182 / blood-2024-210657).

[0179] Various biomarkers can be used to identify subjects for the methods provided herein and / or to monitor treatment following administration of Compound A. 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, or 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 Docket No. TRLN-019-010W01 / TLS-066WO 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).

[0180] In some embodiments, the hematological malignancy (e.g., the lymphoma) is BCL6 positive (also referred to herein as “BCL6+” or “positive for BCL6 expression” or “BCL6- expressing).

[0181] In some embodiments, the hematological malignancy (e.g., the lymphoma) is BCL6+ as determined by an IHC test. For example, an IHC test can result in an IHC score of 0, 1, 2, or 3. In some such embodiments, a positive BCL6 expression status can be indicated by a score of 1, 2, or 3 (e.g., 2 or 3) (e.g., as determined by a pathologist or an automated system). 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 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.

[0182] 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 Docket No. TRLN-019-010W01 / TLS-066WO collected after the last previous line of therapy and prior to the first dose of Compound A). 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 GI191E / A8 (e.g., Roche / Ventana product number 760-4241), clone LN22 (e.g., Lecia Biosystems product number PA0204), clone GI191E / A8 (e.g., Sigma / Cell Marque product number 227M-98), and clone EP278 (e.g., Sigma / Cell Marque product number 227R-27).

[0183] 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 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 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 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.

[0184] As used herein, “BCL6+” means that a sample from the subject is BCL6-expressing as determined by an appropriate test. 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 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, 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 Docket No. TRLN-019-010W01 / TLS-066WO to 230, or greater than or equal to 270). In some embodiments, the test is an FDA-approved test.

[0185] 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. In some embodiments, a sample from the subject has a percent nuclear positivity score for BCL6 of 0% by IHC.

[0186] In some embodiments, the hematological malignancy (e.g., lymphoma) is BCL6 positive (BCL6+). For example, 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).

[0187] In some embodiments, the hematological malignancy (e.g., lymphoma) is BCL6+ and is a mature B cell neoplasm (e.g., Burkitt lymphoma (BL), large B cell lymphoma (LBCL) (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), primary mediastinal large B cell lymphoma (primary mediastinal LBCL), or high grade B-cell lymphoma NOS), follicular lymphoma (FL), or transformations of indolent B cell lymphomas (e.g., transformed FL)). In some embodiments, 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 20%, greater than or equal to 30%, greater than or equal to 60%, or greater than or equal to 90%), as determined by an IHC test. In some embodiments, 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 20, greater than or equal to 30, greater than or equal to 60, greater than or equal to 90, greater than or equal to 230, greater than or equal to 250, or greater than or equal to 270).

[0188] In some embodiments, the hematological malignancy (e.g., lymphoma) is BCL6+ and is a PTCL or a CTCL. In some embodiments, 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 20%, or greater than or equal to 30%), as determined by an IHC test. In some embodiments, a sample from the subject has an H-score Docket No. TRLN-019-010W01 / TLS-066WO for BCL6 of greater than or equal to 3 (e.g., greater than or equal to 5, greater than or equal to 10, greater than or equal to 20, greater than or equal to 30, greater than or equal to 60, greater than or equal to 90, or greater than or equal to 100).

[0189] In some embodiments, the hematological malignancy (e.g., lymphoma) is BCL6+ and is a Tfh PTCL (also called a nodal T follicular helper cell lymphoma). In some embodiments, 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 20%, greater than or equal to 30%, greater than or equal to 60%, or greater than or equal to 90%), as determined by an IHC test. In some embodiments, 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 20, greater than or equal to 30, greater than or equal to 60, greater than or equal to 90, greater than or equal to 230, greater than or equal to 250, or greater than or equal to 270).

[0190] Provided herein is a method for treating a lymphoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the lymphoma in the subject is BCL6+. In some embodiments, the lymphoma in the subject is negative for BCL6 expression. Also provided herein is a method for treating a lymphoma, the method comprising administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, to a subject having a lymphoma BCL6+. Also provided herein is a method for treating lymphoma in a subject in need thereof, the method comprising (a) determining the BCL6 status of the lymphoma (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 Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating lymphoma in a subject in need thereof, the method comprising: (a) determining that the lymphoma in the subject is BCL6+ (e.g., determining that the lymphoma is BCL6+ by an IHC test); and (b) administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof.

[0191] Also provided herein are methods for treating a lymphoma in a subject in need thereof, the methods comprising: (a) determining the BCL6 status of the lymphoma; and (b) administering to the subject a therapeutically effective amount of Compound A, or a Docket No. TRLN-019-010W01 / TLS-066WO pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof. In some such embodiments, the lymphoma in the subject is BCL6+. In other such embodiments, the lymphoma in the subject is not BCL6+.

[0192] Also provided herein are methods for treating lymphoma, the methods comprising administering to a subject determined to have a lymphoma that is BCL6+ (e.g., a subject determined to have a lymphoma that is BCL6+ by an IHC test) a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments of any of these methods, the BCL6 status of the lymphoma is determined before administration of at least one dose (e.g., two doses, three doses, four doses, five doses, or more) of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof, to the subject (e.g., the BCL6 status of the lymphoma is determined via a biopsy or a blood sample).

[0194] In some embodiments of any of these methods, the BCL6 status of the lymphoma is determined after administration of at least one dose (e.g., two doses, three doses, four doses, five doses, or more) of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof, to the subject (e.g., the BCL6 status of the lymphoma is determined via a biopsy or a blood sample).

[0195] In some embodiments, the subject is treatment naive with respect to the lymphoma. In some embodiments, the subject has received one or more lines of previous therapy for the lymphoma. In some embodiments, the subject has received two or more lines of previous therapy for the lymphoma.

[0196] In some embodiments of any of these methods, Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subj ect as a monotherapy. Some embodiments of these methods include administering to the subject an additional therapy or therapeutic agent.

[0197] In some embodiments, the lymphoma is a Hodgkin lymphoma (e.g., nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)) or a non-Hodgkin lymphoma (e.g., B cell lymphoid proliferations and lymphomas (e.g., mature B cell neoplasms (e.g., Burkitt lymphoma (BL), large B cell lymphoma (LBCL) (e.g., diffuse large B-cell lymphoma not Docket No. TRLN-019-010W01 / TLS-066WO 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), primary mediastinal large B cell lymphoma (primary mediastinal LBCL), or high grade B-cell lymphoma NOS), follicular lymphoma (FL), or transformations of indolent B cell lymphomas (e.g., transformed FL))), T-cell andNK-cell lymphoid proliferations and lymphomas (e.g., mature T-cell andNK- cell neoplasms (e.g., mature T-cell and NK-cell leukemias (e.g., adult T-cell leukemia / lymphoma), 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, 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, or primary cutaneous peripheral T-cell lymphoma NOS), 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 other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS))))).

[0198] 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” is used to refer to the class. Docket No. TRLN-019-010W01 / TLS-066WO

[0199] The EZH2 inhibitor tazemetostat has been studied in combination with rituximab and CHOP in certain populations of LBCLs. See, e.g., Sarkozy, Clementine, et al. EClinicalMedicine 82 (2025), doi: 10.1016 / j.eclinm.2025.103157.

[0200] In some embodiments, the lymphoma is follicular lymphoma (FL) or 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, or HBGCL-NOS). In some embodiments, the lymphoma 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, or HBGCL-NOS). In some embodiments, the lymphoma is FL. In some embodiments, the FL is grade 1-3 a. In some embodiments, the FL is grade 3b. In some embodiments, the lymphoma is BL.

[0201] In some embodiments, the 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 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), 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)))). In some embodiments, the lymphoma is anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma). In some embodiments, the lymphoma is ALK-positive anaplastic large cell lymphoma. In some embodiments, the lymphoma is ALK-negative anaplastic large cell lymphoma. In some embodiments, the lymphoma is 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 Docket No. TRLN-019-010W01 / TLS-066WO helper T-cell lymphoma, NOS)). In some embodiments, the lymphoma is nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T-cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type). In some embodiments, the lymphoma is nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type). In some embodiments, the lymphoma is nodal T follicular helper cell lymphoma NOS (also known as follicular helper T- cell lymphoma, NOS).

[0202] In some embodiments, the lymphoma is a 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, 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, or primary cutaneous peripheral T-cell lymphoma NOS). In some embodiments, the lymphoma is mycosis fungoides. In some embodiments, lymphoma is Sezary syndrome.

[0203] In some embodiments, the 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 gamma-delta T-cell lymphoma). In some embodiments, the PTCL or CTCL is BCL6+ as determined by an H4C test (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 1% in an IHC test). In some embodiments, the PTCL or CTCL is BCL6+ as determined by an H4C test (e.g., indicated by a percent nuclear positivity score for BCL6 of greater than or equal to 30% in an IHC test).

[0204] In some embodiments, the potency and / or efficacy of Compound A, or a pharmaceutically acceptable salt thereof, can be evaluated in an animal model, for example, a Docket No. TRLN-019-010W01 / TLS-066WO xenograft model (e.g., using an established cancer cell line such as DB (ATCC CRL-2289™), H9 (NCI-H82 [H82] (HTB-176™)), HH (ATCC CRL-2105™), HT (ATCC CRL-2260™), HUT78 (ATCC TIB- 161™), KML-1 (JRCB No. JCRB1347), MHHPREB1 (DSMZ ACC 354), MJ ([Gi l] (ATCC CRL-8294™)), OCI-LY7 (DSMZ ACC 688), SUDHL5 (SU-DHL-5 (ATCC CRL-2958™)), SUDHL6 (SU-DHL-6 (ATCC CRL-2959™)), SUDHL10 (SU-DHL- 10 (ATCC CRL-2963™)), and WSU-DLCL2 (DSMZ ACC 575), or a patient-derived xenograft (PDX) model such as 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, CTG-4299, DFBL-13727, DFBL-31357, DFBL- 86381, DFTL-78024, LY0257, LY12962, LY2214, LY2264, LY2318, LY2345, LY3463, LY3604, LY6701, LY6933, LY6934, LY9596, LY9602, ST1735B, ST2761B, ST2902, ST2963, ST359, ST4225, ST5002, ST5380, ST6226, and ST949B, available from sources such as Champions Oncology, Crown Bioscience, and XenoSTART).

[0205] In some embodiments, the potency and / or efficacy of Compound A, or a pharmaceutically acceptable salt thereof can be evaluated in a CDX or PDX model. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is assessed in a CDX mouse model. For example, mice can be implanted with a cell line of interest and a tumor allowed to grow for a period of time, then the mice can be administered Compound A, or a pharmaceutically acceptable salt thereof. The effect of Compound A, or a pharmaceutically acceptable salt thereof, can be determined by measuring tumor growth (or regression). See, e.g., Example B3. An exemplary protocol follows.

[0206] All the procedures related to animal handling, care, and treatment in the efficacy study are performed according to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

[0207] For LBCL and CTCL cell line xenografts (CDX), 6-8 week old NOD SCID, BALB / c or NOG female mice are inoculated subcutaneously on the right flank with 2 x 106or 1 x 107tumor cells in 0.1 mL of 1 : 1 medium / MATRIGEL® for tumor development. Treatments are started and groupings are assigned when the mean tumor volume reaches about 100-300 mm3. Based on the tumor volume, mice are randomly assigned to respective groups such that the average starting tumor size is the same for each treatment group.

[0208] For LBCL, PTCL-NOS, and Burkitt Lymphoma patient derived xenografts (PDX), fresh tumor tissues from tumor bearing mice are harvested and cut into small pieces (e.g., approximately 2-3 mm in diameter). PDX tumor fragments are inoculated subcutaneously at Docket No. TRLN-019-010W01 / TLS-066WO the upper right dorsal flank into NOD SCID mice for tumor development.

[0209] Tumor-bearing mice are treated orally twice daily (BID) with Compound A, or a pharmaceutically acceptable salt thereof (e.g., at a dose of 40 mg / kg, 80 mg / kg, or 160 mg / kg). The mice are treated for a treatment period (e.g., 17 to 28 days), optionally followed by an observation period (e.g., 6 to 32 days).

[0210] The BCL6 and / or EZH2 IHC status of these models is determined. IHC staining for BCL6 and EZH2 is conducted on tumor tissue, or metastatic sites of infiltration, including spleen, lymph node, and kidney sections. Tissues are fixed in 10% neutral buffered formalin for 24 hrs, paraffin embedded, sectioned, and immunohistochemically stained for BCL6 (e.g., using LN22, Leica / 564-L-CE or GI191E / A8 (e.g., Roche / Ventana product number 760-4241 or Sigma / Cell Marque product number 227M-98)) and / or EZH2 (e.g., using D2C9 Cell Signaling Technology #5246) on an automated instrument (e.g., the automated Bond III platform (Leica Biosystems, Inc)), and digitally scanned (e.g., on a Aperio AT2 scanner (Leica Biosystems, Inc)). Positive immunoreactivity is visualized with DAB (brown) and can be defined as greater than or equal to 30% nuclear staining for BCL6 and 60% nuclear staining for EZH2.

[0211] The body weight of each animal is measured and recorded twice weekly throughout the study. The measurement of tumor size is conducted twice weekly with a caliper and recorded. The tumor volume (mm3) is estimated using the formula: TV=a x b2 / 2, where “a” and “b” are long and short diameters of a tumor, respectively. The tumor volume is plotted as a function of time.

[0212] For systemic models of AITL, fresh splenocytes from tumor bearing stock animals are isolated and NOG mice are inoculated intravenously through tail vein with 1 * 106live cells in 0.1 mL of PBS solution for tumor development. The randomization and treatment is initiated when the mean flow cytometry hCD45+% reaches approximately 0.5%-5%. Tumor growth is monitored weekly using peripheral blood hCD45% levels and at end of the study using hCD45% levels in the spleen, kidney, and lymph nodes.

[0213] In some cases, treatment of a lymphoma or a model of a lymphoma (e.g., a PDX or CDX model) with Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof, can result in a regression (e.g., greater than or equal to 50% regression) of the lymphoma or the model of the lymphoma. See, e.g., Gao, H. and Williams, A. Mol & Cell One 2018;5(2);el 162895, doi: 10.1080 / 23723556.2016.1162895; and Gao, H. et al., Nature Medicine 2015;21(11); 1318-1325, doi: 10.1038 / nm.3954. In some cases, treatment of a Docket No. TRLN-019-010W01 / TLS-066WO lymphoma or a model of a lymphoma (e.g., a PDX or CDX model) with Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof, as a monotherapy can result in a regression (e.g., greater than or equal to 50% regression) of the lymphoma or the model of the lymphoma. 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). In some embodiments, the PDX model is positive for MYC expression as determined by an IHC test (e.g., indicated by a percent nuclear positivity score for MYC of greater than or equal to 30% in an IHC test). 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) and positive for MYC expression as determined by an IHC test (e.g., indicated by a percent nuclear positivity score for MYC of greater than or equal to 30% in an IHC test).

[0214] Provided herein is use of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the treatment of a lymphoma that is BCL6+ (e.g., as determined by an IHC test).

[0215] Provided herein is use of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament for the treatment of a lymphoma that is BCL6+ (e.g., as determined by an IHC test).

[0216] Provided herein is use of Compound A, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a lymphoma that is BCL6+ (e.g., as determined by an IHC test).

[0217] Provided herein is Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament in the treatment of a lymphoma that is BCL6+ (e.g., as determined by an IHC test).

[0218] Provided herein is Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a lymphoma, for example, any of the lymphomas provided herein. Also provided is Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a lymphoma that is BCL6+ in a subject identified or diagnosed as having a lymphoma that is BCL6+ through a step of performing a test (e.g., an IHC test) on a sample (e.g., a tumor sample) obtained from the subject to determine whether the lymphoma in the subject that is BCL6+ (e.g., as determined by an IHC test). Docket No. TRLN-019-010W01 / TLS-066WO

[0219] Combinations

[0220] In any of the indications described herein, Compound A, or a pharmaceutically acceptable salt thereof, can be used as a monotherapy. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of Compound A, or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of Compound A, or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor.

[0221] In some embodiments, a subject in need thereof can be administered one or more doses of Compound A, or a pharmaceutically acceptable salt thereof, for a period of time and undergo one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of Compound A, or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy.

[0222] In some embodiments of any the methods described herein, Compound A, or a pharmaceutically acceptable salt thereof, is administered in combination with a therapeutically effective amount of at least one additional therapeutic (e.g., chemotherapeutic) agent.

[0223] In some embodiments, the additional therapy or therapeutic agent is an ALK inhibitor or degrader, a dihydrofolate reductase (DHFR) inhibitor or degrader, an epigenetic modifier (a histone deacetylase (HD AC) inhibitor or degrader or a BCL6 inhibitor or degrader), a retinoid, anti-CD30 therapy, anti-C-C motif chemokine receptor 4 (CCR4) therapy, chemotherapy, or a combination thereof. In some embodiments, the cancer is a PTCL, and the additional therapy or therapeutic agent is an ALK inhibitor or degrader, a dihydrofolate reductase (DHFR) inhibitor or degrader, an epigenetic modifier (e.g., a histone deacetylase (HD AC) inhibitor or degrader), anti-CD30 therapy, chemotherapy, or a combination thereof. In some embodiments, the cancer is a CTCL, and the additional therapy or therapeutic agent is a histone deacetylase (HDAC) inhibitor or degrader, a retinoid, an anti-CD30 antibody or antibody-drug conjugate, anti-CCR4 therapy, chemotherapy, or a combination thereof.

[0224] In some embodiments, the additional therapy or therapeutic agent is an ALK inhibitor or degrader. In some embodiments, the ALK inhibitor or degrader is alectinib (e.g., alectinib hydrochloride), brigatinib, ceritinib, crizotinib, ensartinib (e.g., ensartinib hydrochloride), envonalkib (e.g., envonalkib citrate) (TQ-B-3139), dirozalkib (dexitinib), fidrisertib, iruplinalkib, lorlatinib, neladalkib, TGRX-326, TQ-B-3101, or a combination thereof. In some Docket No. TRLN-019-010W01 / TLS-066WO embodiments, the ALK inhibitor is crizotinib. In some embodiments, the cancer is a PTCL (e.g., a relapsed or refractory PTCL), and the additional therapy or therapeutic agent is crizotinib.

[0225] In some embodiments, the additional therapy or therapeutic agent is a DHFR inhibitor or degrader. In some embodiments, the DHFR inhibitor or degrader is aminopterin, edatrexate, methotrexate, pemetrexed (e.g., pemetrexed disodium), piritrexim, pralatrexate, tetroxoprim, trimetrexate glucuronate, AA-243, TNP-351, or a combination thereof. In some embodiments, the DHFR inhibitor is pralatrexate. In some embodiments, the cancer is a PTCL (e.g., a relapsed or refractory PTCL), and the additional therapy or therapeutic agent is pralatrexate.

[0226] In some embodiments, the additional therapy or therapeutic agent is an HD AC inhibitor or degrader. In some embodiments, the HD AC inhibitor or degrader is abexinostat, belinostat, entinostat, fimepinostat, givinostat (e.g., givinostat hydrochloride monohydrate), mocetinostat, nanatinostat, panobinostat (e.g., panobinostat lactate), pracinostat, purinostat, quisinostat, remetinostat, resminostat, rocilinostat, romidepsin, selisistat, tacedinaline, tucidinostat, vorinostat, (S)-HDAC-42, CKD-506, EVP-0334, KA-2507, or a combination thereof. In some embodiments, the HDAC inhibitor is belinostat, romidepsin, or vorinostat. In some embodiments, the cancer is a PTCL (e.g., a relapsed or refractory PTCL), and the additional therapy or therapeutic agent is belinostat. In some embodiments, the cancer is a CTCL (e.g., a relapsed or refractory CTCL), and the additional therapy or therapeutic agent is romidepsin. In some embodiments, the cancer is a CTCL (e.g., a relapsed or refractory CTCL), and the additional therapy or therapeutic agent is vorinostat.

[0227] In some embodiments, the additional therapy or therapeutic agent is a BCL6 inhibitor or degrader. Exemplary BCL6 degraders are described in, e.g., International Publication Nos. WO 2023 / 240038; WO 2023 / 244917; WO 2023 / 244918; WO 2025 / 049964, WO 2025 / 050016; and WO 2025 / 049968.

[0228] In some embodiments, the additional therapy or therapeutic agent is a retinoid. In some embodiments, the retinoid is bexarotene, fenretinide, or a combination thereof. In some embodiments, the retinoid is bexarotene. In some embodiments, the cancer is a CTCL (e.g., a relapsed or refractory CTCL), and the additional therapy or therapeutic agent is bexarotene.

[0229] In some embodiments, the additional therapy or therapeutic agent is anti-CD30 therapy. In some embodiments, the anti-CD30 therapy is acimtamig, brentuximab, brentuximab vedotin (e.g., ADCETRIS®), iratumumab, a biosimilar of any thereof, or a combination thereof. In some embodiments, the anti-CD30 therapy is a bispecific antibody or antigen-binding fragment thereof (e.g., acimtamig), or a biosimilar thereof. In some embodiments, the anti-CD30 therapy Docket No. TRLN-019-010W01 / TLS-066WO is an antibody-drug conjugate (e.g., brentuximab vedotin (e.g., ADCETRIS®), or a biosimilar thereof). In some embodiments, the cancer is a PTCL (e.g., a relapsed or refractory PTCL), and the additional therapy or therapeutic agent is brentuximab vedotin (e.g., ADCETRIS®), or a biosimilar thereof. In some embodiments, the cancer is a CTCL (e.g., a relapsed or refractory CTCL), and the additional therapy or therapeutic agent is brentuximab vedotin (e.g., ADCETRIS®), or a biosimilar thereof.

[0230] In some embodiments, the additional therapy or therapeutic agent is anti-CCR4 therapy. In some embodiments, the anti-CCR4 therapy is mogamulizumab (e.g., mogamulizumab - kpkc), or a biosimilar thereof. In some embodiments, the cancer is a CTCL (e.g., a relapsed or refractory CTCL), and the additional therapy or therapeutic agent is mogamulizumab (e.g., mogamulizumab-kpkc), or a biosimilar thereof.

[0231] In some embodiments, the additional therapy is chemotherapy. In some embodiments, the chemotherapy is CHOP or CHOEP. In some embodiments, the chemotherapy includes one or more of etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone.

[0232] In some embodiments, provided herein are methods for treating a BCL6+ peripheral T- cell lymphoma (PTCL) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment-naive. In some embodiments, the BCL6+ PTCL is selected from the group consisting of: nodal Tfh cell lymphoma; PTCL-NOS; ALK-positive anaplastic large-cell lymphoma; and ALK -negative anaplastic large-cell lymphoma. In some embodiments, the BCL6+ PTCL is a nodal Tfh cell lymphoma. In some embodiments, the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular-type; and nodal Tfh cell lymphoma, NOS. In some embodiments, the nodal Tfh cell lymphoma is AITL. In some embodiments, the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type. In some embodiments, the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0233] Also provided herein are methods for treating a BCL6+ peripheral T-cell lymphoma (PTCL) in a subject in need thereof, the method comprising i) determining that the subject has a BCL6+ PTCL; and ii) based on i), administering to the subject a therapeutically effective amount of a compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment-naive. In some embodiments, the BCL6+ PTCL is selected from the group consisting of: nodal Tfh cell lymphoma; PTCL-NOS; ALK-positive anaplastic large-cell lymphoma; and ALK- Docket No. TRLN-019-010W01 / TLS-066WO negative anaplastic large-cell lymphoma. In some embodiments, the BCL6+ PTCL is a nodal Tfh cell lymphoma. In some embodiments, the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular-type; and nodal Tfh cell lymphoma, NOS. In some embodiments, the nodal Tfh cell lymphoma is AITL. In some embodiments, the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type. In some embodiments, the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS. In some embodiments, determining that the subject has a BCL6+ PTCL comprises identifying that an IHC test on a sample of the PTCL exhibits 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%, or greater than or equal to 35%).

[0234] Provided herein are also methods for treating a BCL6+ nodal Tfh cell lymphoma in a subject in need thereof, the methods comprising i) determining that the subject has a BCL6+ nodal Tfh cell lymphoma; and ii) based on i), administering to the subject a therapeutically effective amount of a compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment-naive. In some embodiments, the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular-type; and nodal Tfh cell lymphoma, NOS. In some embodiments, the nodal Tfh cell lymphoma is AITL. In some embodiments, the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type. In some embodiments, the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS. In some embodiments, determining that the subject has a BCL6+ PTCL comprises identifying that an IHC test on a sample of the nodal Tfh cell lymphoma exhibits a percent nuclear positivity score for BCL6 of greater than or equal to or equal to 1% (e.g., greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 35%, greater than or equal to 60%, or greater than or equal to 90%)

[0235] Provided also herein are methods for treating a nodal Tfh cell lymphoma in a subject in need thereof, the methods comprising administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; wherein the subject is treatment- naive. In some embodiments, the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular-type; and nodal Tfh cell lymphoma, NOS. In some embodiments, the nodal Tfh cell lymphoma is AITL. In some embodiments, the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type. In some embodiments, Docket No. TRLN-019-010W01 / TLS-066WO the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS. In some embodiments, the nodal Tfh cell lymphoma is BCL6+.

[0236] These additional therapeutic agents may be administered with one or more doses of Compound A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising Compound A, or a pharmaceutically acceptable salt thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and / or on the same or different administration schedules according to standard pharmaceutical practice. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered as separate dosages simultaneously, separately, or sequentially in any order, in jointly therapeutically effective amounts, e.g., in daily or intermittent dosages. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage. When administered simultaneously, the two agents can be administered as a single dosage form (e.g., a fixed dosage form) or as separate dosages (e.g., non-fixed dosage forms).

[0237] 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.

[0238] 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 disease, disorder, or condition to be treated and / or prevented.

[0239] In some embodiments, the subject is a pediatric subject.

[0240] The term “pediatric subject” as used herein refers to a subject under the age of 21 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 month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 Docket No. TRLN-019-010W01 / TLS-066WO years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph ’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. 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 21 years of age (up to, but not including, the twenty-second 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 22 years of age.

[0241] The term “preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.

[0242] 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).

[0243] The phrase “therapeutically effective amount” means an amount of 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 described herein. The amount of Compound A, or a pharmaceutically acceptable salt thereof, that will correspond to such an amount will vary depending upon factors such as the disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment.

[0244] Pharmaceutical Compositions and Administration

[0245] General

[0246] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition that includes the compound, or a Docket No. TRLN-019-010W01 / TLS-066WO pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

[0247] In some embodiments, the compounds can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as a-, P-, and y- cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing Compound A described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient can be prepared. The contemplated compositions can contain 0.001%- 100% of a compound provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms can be found, for example, in Remington: The Science and Practice of Pharmacy, 22ndEdition (Pharmaceutical Press, London, UK. 2012).

[0248] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition that includes Compound A (e.g., about 25% to about 35% by weight, or about 27% to about 31% by weight), microcrystalline cellulose (e.g., about 10% to about 20% by weight, or about 15% by weight to about 17% by weight), lactose monohydrate (e.g., about 40% by weight to about 55% by weight, or about 45% by weigh to about 50% by weight), croscarmellose sodium (e.g., about 2% by weight to about 6% by weight, or about 3% to about 5% by weight), hypromellose (e.g., about 1% by weight to about 2% by weight), magnesium stearate (e.g., about 0.5% by weight to about 1.5% by weight), and silicon dioxide (e.g., about 0.5% by weight to about 1.5% by weight). In some embodiments, the pharmaceutical composition that includes Compound A is a coated tablet. Docket No. TRLN-019-010W01 / TLS-066WO

[0249] Routes of Administration and Composition Components

[0250] In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition thereof, can be administered to a subject in need thereof orally.

[0251] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and / or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0252] In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition can contain, along with Compound A, or pharmaceutically acceptable salt thereof, as provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives, or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEGs, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more compounds provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

[0253] Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth Docket No. TRLN-019-010W01 / TLS-066WO or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

[0254] In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP / NF standard is usually sufficient.

[0255] Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

[0256] In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

[0257] Dosages

[0258] The dosages can be varied depending on factors such as the requirement of the subject, and the severity of the condition being treated.

[0259] In some embodiments, Compound A is administered at a dosage of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg. For example, in some embodiments, Compound A is administered at a dosage of 250 mg, 300 mg, or 350 mg. In some embodiments, Compound A is administered at a dosage of 250 mg. In some embodiments, Compound A is administered at a dosage of 300 mg. In some embodiments, Compound A is administered at a dosage of 350 mg.

[0260] Regimens

[0261] The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses). In some embodiments, Compound A is administered once daily (QD). In some embodiments, Compound A is administered twice daily (BID).

[0262] In some embodiments, the period of administration of Compound A is for one or more cycles of 28 days. In some embodiments, administration of Compound A is administered in Docket No. TRLN-019-010W01 / TLS-066WO cycles of 28 days until disease progression is observed, an unacceptable toxicity is experienced by the subject, or the subject withdraws from treatment.

[0263] In some embodiments, Compound A is administered at a dosage of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, or 450 mg once or twice daily. For example, in some embodiments, Compound A is administered at a dosage of 250 mg, 300 mg, or 350 mg twice daily. In some embodiments, Compound A is administered at a dosage of 250 mg twice daily. In some embodiments, Compound A is administered at a dosage of 300 mg twice daily. In some embodiments, Compound A is administered at a dosage of 350 mg twice daily.

[0264] The term “acceptable” with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0265] “API” refers to an active pharmaceutical ingredient.

[0266] The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed , Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed. Rowe el al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed:, Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed. Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0267] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an Docket No. TRLN-019-010W01 / TLS-066WO alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as di cyclohexylamine, A-methyl-D- glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The term “pharmacologically acceptable salts” is not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein form with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine, and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts can be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0268] The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and / or thickening agents. The pharmaceutical composition facilitates administration of the compound to a subject. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0269] EXAMPLES

[0270] Example Bl

[0271] Clinical Study Protocol

[0272] Overall Study Design

[0273] This is a Phase lb, open-label, randomized, dose optimization study of two doses in patients with relapsed or refractory PTCL (Cohort 1), with study objectives of assessing the anti -tumor activity, safety, and PK of Compound A at 250 mg BID and 350 mg BID. Cohort 1 will enroll approximately 40 patients (20 patients per treatment arm). Cohort 2 of the study will evaluate 10 patients with relapsed or refractory CTCL treated with Compound A 350 mg BID to assess initial anti-tumor activity, safety, and PK in this population arm.

[0274] A Safety Review Committee (SRC) will monitor patient safety during the study. Docket No. TRLN-019-010W01 / TLS-066WO

[0275] The study will consist of a screening period, treatment period, and a follow-up period. All patients will undergo assessments throughout the study.

[0276] After signing an informed consent form (ICF), patients will undergo screening assessments to determine study eligibility over a 28-day screening period. The baseline tumor evaluation will be performed within 28 days before the first dose. The results of imaging performed at the study site before signing the ICF (but within the screening period) that meet relevant quality and technical requirements may be used as the screening tumor evaluation. A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen in paraffin block (preferred) or unstained, freshly cut, serial sections (on slides) from an FFPE tumor specimen or fresh biopsy tissue fixed in formalin solution, or archived tumor tissue samples (collected following most recent therapy prior to study enrolment) will be collected at screening for assessing expression of EZH2 and BCL6 and banked for future research.

[0277] For Cohort 1, a patient is randomized when the Investigator or designee has obtained written consent, has confirmed all eligibility criteria have been met and all screening procedures have been completed; randomization can occur within 14 days of baseline. Eligible patients will be randomized 1 : 1 to one of the two treatment arms

[0278] • Arm 1 : Compound A 350 mg BID PO

[0279] • Arm 2: Compound A 250 mg BID PO

[0280] Randomization will be stratified by T-cell lymphoma subtype with the following two strata:

[0281] • PTCL TFH subtypes (nodal TFH cell lymphoma angioimmunoblastic, follicular helper T-cell lymphoma angioimmunoblastic type; nodal TFH cell lymphoma follicular type, follicular helper T -cell lymphoma follicular type; nodal TFH cell lymphoma NOS, follicular helper T-cell lymphoma NOS)

[0282] • PTCL non-TFH subtypes (PTCL NOS; anaplastic large-cell lymphoma, ALK positive; anaplastic large-cell lymphoma, ALK negative)

[0283] Compound A will be administered until disease progression as assessed locally by investigator, unacceptable toxicity, or other reasons for treatment discontinuation. Patients with CTCL with concern over progression of skin disease should continue treatment until biopsy (if deemed warranted by the Investigator) to confirm progression; this work up should be performed and discussed with the Sponsor (or designee) before a study disposition decision is made. Docket No. TRLN-019-010W01 / TLS-066WO

[0284] Each treatment cycle will last for 28 days. The treatment cycle starts from the date of the first dose. If treatment is interrupted due to a missed dose, an adverse event (AE), or for other reason, then the time of the scheduled dose and the reason for a missed dose should be documented in detail. The dosing regimen should not be adjusted, and the missed dose should be skipped. Thereafter Compound A should be administered according to the dosing regimen. Compound A may be given with or without food, as there is little or no effect of food on the pharmacokinetics (PK) of Compound A.

[0285] On-treatment radiographic evaluations will consist of PET-CT performed on Cycle 3 Day 1, Cycle 5 Day 1, and Cycle 7 Day 1 and then every 3 cycles (or any time that progressive disease needs to be confirmed). A diagnostic CT of the Chest / Abdomen / Pelvis (C / A / P) with contrast evaluation will also be performed at baseline. The time window for imaging examination is 7 days prior to the start of Cycle 3, 5, 7, and every 3 cycles thereafter. For patients who stop treatment for reasons other than PD, response evaluation should still be carried out according to the specified times for radiographic evaluation, if possible.

[0286] An end of treatment visit should be carried out within 5 days of the treatment discontinuation and / or withdrawal from study. If response evaluation and safety are within 28 days and 7 days respectively of end of treatment, they need not be repeated upon treatment discontinuation and / or withdrawal from study.

[0287] All patients will be followed 30 days (± 5 days) post last treatment with Compound A and will be contacted by phone or in-person every 3 months (± 7 days) thereafter to determine survival status.

[0288] Study Duration

[0289] For each patient enrolled, study participation will require: Docket No. TRLN-019-010W01 / TLS-066WO

[0290] End of Study Definition

[0291] Patients will be regarded as having completed the study if complete data are available from the long-term follow-up period. The end of the study is defined as the date on which the last patient completes the last visit (includes follow-up visit) or the required number of deaths for the final analysis of OS has been observed.

[0292] Eligibility Criteria

[0293] Inclusion Criteria

[0294] To be eligible for participation in this study, patients must meet all the following:

[0295] Age

[0296] 1. At least 18 years of age at the time of signing the ICF.

[0297] Type of Patient and Disease Characteristics

[0298] 2. Cohort 1: PTCL that has relapsed after, or not responded to at least one prior systemic treatment regimen. Patients with ALCL should have received prior brentuximab vedotin treatment. Eligible subtypes per 2022 WHO classification (Alaggio, Rita, et al. Leukemia 36.7 (2022): 1720-1748, doi: 10.1038 / s41375- 022-01620-2) or ICC 2022 (Campo, Elias, et al. Blood, The Journal of the American Society of Hematology 140.11 (2022): 1229-1253, doi: 10.1182 / blood.2022015851):

[0299] • Nodal TFH cell lymphoma angioimmunoblastic; Follicular helper T-cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma)

[0300] • Nodal TFH cell lymphoma, follicular type; Follicular helper T-cell lymphoma, follicular type

[0301] • Nodal TFH cell lymphoma, NOS; Follicular helper T-cell lymphoma, NOS

[0302] • PTCL, NOS

[0303] • Anaplastic large-cell lymphoma, ALK positive

[0304] • Anaplastic large-cell lymphoma, ALK negative; or

[0305] Cohort 2: CTCL subtypes: Sezary syndrome or Mycosis fungoides (IB or above) which has relapsed after, or not responded to at least two prior systemic treatments. Docket No. TRLN-019-010W01 / TLS-066WO

[0306] Diagnosis should be confirmed by the local pathologist and enrollment based on local histological diagnosis. Any T-cell lymphoid malignancies not listed above are excluded.

[0307] 3. Measurable disease as follows:

[0308] Cohort 1: PTCL: At least one measurable lesion which is measurable in 2 perpendicular dimensions on computed tomography based on local radiological read (nodal lesion with any long diameter > 1.5 cm or extranodal lesion with any long diameter > 1.0 cm); or

[0309] Cohort 2: CTCL (Sezary syndrome or Mycosis fungoides): at least one of the following:

[0310] • At least one measurable lesion which is measurable in 2 perpendicular dimensions on CT (or MRI) based on local radiological read (nodal lesion with any long diameter > 1.5 cm or extranodal lesion with any long diameter > 1.0 cm)

[0311] • Modified Severity Weighted Assessment Tool (mSWAT) >0 (Lund, C. C., and N. C. Browder. Surg Gynecol Obstet. Chicago 79.4 (1944): 352- 58; Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057)

[0312] • Atypical T lymphocytes quantifiable by flow cytometry or morphology in the peripheral blood or bone marrow

[0313] 4. Agreement to provide tumor samples as follows:

[0314] • For patients with more than one bi-dimensionally measurable lesion (>1.5 cm in the largest dimension for nodal lesions, or >1.0 cm in its largest dimension for extranodal lesions by CT scan or MRI), agreement to undergo biopsy from a safely accessible site per investigator determination (e.g. lymph node or skin). Biopsies obtained per clinical standard of care at any time between the last dose of last prior anticancer therapy and the first dose of Compound A may be acceptable. In either case, an FFPE block, or 15 unstained freshly cut, serial sections (on slides) from tumor lesion, or fresh biopsy tissue fixed in formalin solution should be provided. Docket No. TRLN-019-010W01 / TLS-066WO

[0315] • Patients unable to undergo biopsy procedures may be eligible for study enrollment after confirming with the Sponsor (or designee). In such cases archival tumor tissue samples (paraffin blocks or at least 15 unstained slides) should be made available to the Sponsor.

[0316] • If less than the required amount of tissue / slides is available, the patient may be eligible for study enrollment after confirming with the Sponsor (or designee).

[0317] Diagnostic Assessments

[0318] 5. ECOG performance status of 0, 1, or 2.

[0319] 6. Adequate organ function as evidenced by the following laboratory values:

[0320] • Absolute neutrophil count (ANC) > 1 x 109 / L (no growth factors used within 14 days before testing)

[0321] • Platelet count > 75 * 109 / L (no platelet transfusion within 7 days before testing)

[0322] • Hemoglobin > 8.0 g / dL (no corrective treatment given within 7 days before testing).

[0323] • Adequate coagulation, defined as: prothrombin time (international normalized ratio [INR]) < and aPTT < 1.5 x upper limit of normal (ULN)

[0324] • Adequate renal function, with estimated glomerular filtration (eGFR) rate > 60 mL / min

[0325] • Serum total bilirubin < 1.5 x ULN (or < 3.0 x ULN with documented tumor / lymphoma involvement of the liver), unless there is documentation that the patient has Gilbert’s syndrome

[0326] • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN; (or < 5.0 x ULN with documented tumor / lymphoma involvement of the liver)

[0327] 7. Patients who do not meet criteria for hematologic function because of extensive marrow involvement of lymphoma may be eligible after discussion with and confirmation by the Sponsor (or designee).

[0328] Contraception

[0329] 8. Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Docket No. TRLN-019-010W01 / TLS-066WO

[0330] 9. Female patients of childbearing potential must have a negative serum / urine pregnancy test result within 72 hours prior to the first dose and be willing to adopt highly effective contraceptive measures from the signing of ICF to 6 months after the last dose of the study drug.

[0331] 10. Male patients whose partners are females of childbearing potential must have undergone surgical sterilization or be willing to adopt highly effective contraceptive measures from the signing of ICF to 3 months after the last dose of the study drug.

[0332] Other

[0333] 11. Life expectancy of at least 12 weeks.

[0334] 12. Toxicities due to the previous treatment must have been resolved (CTCAE Grade < 1) before the first dose, unless as judged by the investigator and agreed by the Sponsor (or designee), the AEs do not pose any safety risk.

[0335] 13. Able to swallow tablets and willingness and ability to comply with the visit schedule, dosing schedule, laboratory tests, and other clinical study procedures.

[0336] 14. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

[0337] Exclusion Criteria

[0338] The patients must be excluded from participating in the study if they meet any of the following:

[0339] Medical Conditions

[0340] 1. Other T-cell lymphoma subtypes not listed in the inclusion criteria.

[0341] 2. Current or past history of central nervous system (CNS) involvement of lymphoma, or current or past history of CNS disease, such as stroke, epilepsy, other than:

[0342] (a) A history of stroke who have not experienced a stroke or transient ischemic attack in the past 2 years and have no residual neurologic deficits as judged by the investigator are allowed.

[0343] (b) A history of epilepsy who have had no seizures in the past 2 years.

[0344] 3. History of autologous stem cell transplantation within 60 days or allogeneic stem cell transplantation within 90 days prior to the signing of ICF. Patients who received allogeneic stem cell transplantation should be stable, without Docket No. TRLN-019-010W01 / TLS-066WO signs of graft versus host disease, for at least 2 months off of immunosuppressive therapy.

[0345] 4. Major surgery or severe trauma within 4 weeks prior to the first dose of the study drug.

[0346] 5. Active infection or unexplained fever > 38.5 °C during the screening period or Cycle 1 Day 1 (C1D1) prior to dosing.

[0347] 6. Known active bacterial, viral (e.g. Epstein Barr virus [EBV], cytomegalovirus [CMV]), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment. If any recent major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics), date of resolution must be at least 2 weeks prior to first dose of the study drug.

[0348] 7. Clinically significant cardiovascular disease, including: (1) history of congestive heart failure (NYHA Class > 2); (2) history of or current unstable angina; (3) myocardial infarction in the past year; (4) history of any supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention; (5) Uncontrolled angina pectoris within 6 months prior to screening; (6) Coronary / peripheral artery bypass graft within 6 months prior to screening; (7) Complete left bundle branch block; (8) Uncontrolled hypertension (resting systolic blood pressure >180 mmHG or diastolic blood pressure >110 mmHg).

[0349] 8. Abnormal electrocardiogram (ECG) findings including:

[0350] (a) Evidence of prolongation of QT / QTc interval >470 msec corrected for heartrate using Fridericia’s Formula [QTcF = QT / (RR0 33)] for men and women based on the mean value of all 3 screening ECGs.

[0351] (b) Diagnosed or suspected long QT syndrome or known family history of long QT syndrome.

[0352] (c) History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes.

[0353] (d) Uncontrolled arrhythmia (patients with asymptomatic, controllable atrial fibrillation may be enrolled).

[0354] (e) Has clinically relevant bradycardia of <50 bpm unless the patient has a pacemaker. Docket No. TRLN-019-010W01 / TLS-066WO

[0355] 9. History of clinically significant liver disease, including hepatitis (viral and non- viral) and cirrhosis.

[0356] 10. History of other malignancy that could affect compliance with the protocol or interpretation of results:

[0357] (a) History of curatively treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, or localized prostate cancer are allowed.

[0358] (b) A malignancy that has been treated with curative intent will also be allowed if the malignancy has been in remission without treatment (excluding chronic adjuvant hormonal therapy) for 2 years prior to first dose of the study drug.

[0359] Virology Assessments

[0360] 11. Patients with chronic hepatitis B or C as defined by positive hepatitis B or C serology: Patients with a negative HBsAg and a positive HBcAb require an undetectable / negative hepatitis B DNA test (e.g., polymerase chain reaction [PCR] test) to be enrolled and must receive hepatitis B prophylaxis until at least 6 months after completion of study drug(s).

[0361] 12. Positive serologic or PCR test results for acute or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

[0362] Patients whose HBV infection status cannot be determined by serologic test results must be negative for HBV by PCR to be eligible for study participation.

[0363] 13. Positive serologic test results for human immunodeficiency virus (HIV) infection.

[0364] Prior / Concomitant Therapy

[0365] 14. Prior treatment with an EZH2 inhibitor.

[0366] 15. Concomitant systemic treatment with corticosteroids (>10 mg daily prednisone equivalents).

[0367] Note-. Short-course systemic corticosteroids (for < 7 days) or stable baseline usage of topical steroids (for > 21 days) for CTCL is permitted.

[0368] 16. Concomitant use of another systemic therapy for PTCL or CTCL. Patients must have the following wash-out from previous treatments:

[0369] (a) At least 4 weeks for systemic anticancer agents (e.g., chemotherapy, immunomodulatory therapy, or monoclonal antibody therapy) or 5 halflives of the drug, whichever is shorter, to the first dose of the study drug. Docket No. TRLN-019-010W01 / TLS-066WO

[0370] (b) At least 8 weeks for low-dose (12Gy or less) total skin electron beam therapy (TSEBT).

[0371] (c) At least 2 weeks for local radiation therapy; If patient received radiotherapy within 4 weeks prior to the first dose of the study drug, patient must have at least one measurable lesion outside of the radiation field. Patients who have only one measurable lesion that was previously irradiated but subsequently progressed is eligible.

[0372] (d) At least 1 week for topical retinoids, nitrogen mustard, or imiquimod.

[0373] 17. Use of moderate or strong inhibitors or inducers of CYP3A4 and inhibitors of P-glycoprotein from 1 week prior to first dose of the study drug through the duration of study participation. See Table Bl and Table B2 for exemplary inhibitors and inducers of CYP3A4; non-systemic (e.g., topical creams, eye drops, mouthwashes, etc.) applications of these agents are permissible.

[0374] 18. Use of proton pump inhibitors (PPI, e.g., omeprazole, pantoprazole) from 1 week prior to enrollment through the duration of study participation.

[0375] 19. Use of substrates of P-glycoprotein with narrow therapeutic window (e.g., digoxin).

[0376] Prior / Concurrent Clinical Study Experience

[0377] 20. Patients currently participating in the study of another investigational agent.

[0378] Other Exclusions

[0379] 21. Pregnant or lactating women.

[0380] 22. Known or suspected hypersensitivity to Compound A or any of its excipients.

[0381] 23. Unable to swallow tablets.

[0382] 24. Active gastrointestinal inflammation, chronic diarrhea, or history of gastrectomy, gastric banding, or other cases that may affect drug absorption.

[0383] Table Bl. Inhibitors of CYP3A4 Docket No. TRLN-019-010W01 / TLS-066WO

[0384] Abbreviations: AUC-area under the concentration versus time curve; CYP3A4 -cytochrome P450 3A4.aIncreases the AUC of the substrate by > 5-fold.bIncreases the AUC of the substrate by 2- to 5-fold.

[0385] Table B2. Inducers of CYP3A4

[0386] Abbreviations: AUC-area under the concentration versus time curve; CYP3A4 -cytochrome P450 3A4.aDecreases the AUC of the substrate by > 80%.bDecreases the AUC of the substrate by 50-80%.

[0387] Measures to Minimize Bias: Randomization and Blinding

[0388] At screening, a unique patient number will be assigned to a patient upon signing of the ICF.

[0389] Within 14 days of dosing, eligible patients in Cohort 1 will be randomized 1 : 1 to one of two treatment arms: Compound A 350 mg BID PO or Compound A 250 mg BID PO.

[0390] Randomization for Cohort 1 will be stratified by T-cell lymphoma subtype with the following two strata:

[0391] • PTCL TFH subtypes (nodal TFH cell lymphoma angioimmunoblastic, follicular helper T-cell lymphoma angioimmunoblastic type; nodal TFH cell lymphoma follicular type, follicular helper T-cell lymphoma follicular type; nodal TFH cell lymphoma NOS, follicular helper T-cell lymphoma NOS) Docket No. TRLN-019-010W01 / TLS-066WO

[0392] PTCL non-TFH subtypes (PTCL NOS; anaplastic large-cell lymphoma, ALK positive; anaplastic large-cell lymphoma, ALK negative)

[0393] This is an open-label study (all patients in both Cohorts will receive Compound A). For Cohort 1, the specific dose of study drug will be assigned by a central study randomization code that will be established prior to the first study patient screened. Patients found eligible for study treatment will be assigned to the next available slot (dose level) on the randomization list. The site study pharmacist will dispense the appropriate number of study drug bottles in accordance with the assigned dose level before each patient visit. The study site staff will record the dose level the patient was assigned on the applicable electronic Case Report Form (eCRF). Potential bias will be reduced by using central randomization. Patients in Cohort 2 will receive the same dose of 350 mg BID.

[0394] Dose Modification, Toxicity Management and Guidelines

[0395] After treatment interruption or delay due to toxicity, a dose reduction may be necessary upon treatment resumption. During the trial, Compound A may be held for up to 4 weeks to allow for AE resolution. No dose reduction is generally recommended for treatment related toxicities < Grade 2. However, Investigators should always use their best professional judgement when determining the clinical appropriateness of study drug intervention. The investigator should consult with the Sponsor (or designee) before any dose modifications are implemented if time allows. Please refer to the Guidance for the Investigator section of the IB for additional information regarding potential risks of treatment. Dose modification guidance is based on the nature and severity of the toxicity and is summarized in Table B3 using the following dose levels:

[0396] Treatment 350 mg BID

[0397] • First Reduction: 300 mg BID PO

[0398] • Second Reduction: 250 mg BID PO

[0399] Treatment 250 mg BID

[0400] • First Reduction: 200 mg BID PO

[0401] • Second Reduction: 150 mg BID PO

[0402] Patients who experience Grade 4 neutropenia, febrile neutropenia, or Grade > 3 thrombocytopenia in the context of clinically significant bleeding should be permanently Docket No. TRLN-019-010W01 / TLS-066WO discontinued if they require a second dose reduction for the same toxicity. For other toxicities requiring dose modification, Compound A should be permanently discontinued in patients who require a third dose reduction. During the study, Compound A can be held for up to 4 weeks to allow for resolution of an AE.

[0403] Table B3. Toxicity Management Docket No. TRLN-019-010W01 / TLS-066WO

[0404] Antimicrobial Prophylactic Measures

[0405] As per institutional guidelines:

[0406] Patients are recommended to receive antimicrobial prophylaxis against Pneumocystis jiroveci (e.g., trimethoprim / sulfamethoxazole).

[0407] Patients are recommended to receive antiviral prophylaxis against varicella zoster (e.g., acyclovir).

[0408] Patients with hepatitis B core antibody positivity are recommended to receive prophylactic medication against hepatitis B (e.g., entecavir or tenofovir) during therapy and for at least 6 months after therapy is completed.

[0409] Patients are recommended to be monitored for CMV and EB V infection or reactivation, as clinically appropriate.

[0410] Concomitant Medication

[0411] H2 antagonists (e.g., ranitidine, famotidine, or cimetidine) may be used only if they are taken 2 hours after the dose of Compound A and 10 hours prior to the next dose.

[0412] Chewable antacids (e.g. aluminum hydroxide / magnesium hydroxide / simethicone (e.g., MAALOX® or calcium carbonate (e.g., TUMS®)) may be used only if they are taken 2 hours before or after the dose of Compound A.

[0413] Concomitant medications necessary for the health and well-being of the patient and that do not interfere with study assessments are permitted during the study at the Investigator’s Docket No. TRLN-019-010W01 / TLS-066WO discretion. All treatments that the investigator considers necessary for a patient’s welfare may be administered at the discretion of the Investigator in keeping with the community standards of medical care. This includes the use of appropriate medications for the treatment of AEs and / or concurrent illnesses under the direction of the Investigator. All medications should be recorded in the source and on the appropriate electronic case report forms (eCRFs).

[0414] Prohibited Medications

[0415] Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the ongoing study. The following therapies / procedures are excluded for all patients during the study:

[0416] • Any investigational agent other than Compound A

[0417] • Moderate or strong inhibitors of CYP3A4, as they could alter the metabolism of Compound A. This restriction includes herbal products such as St. John’s wort (See, e g., Table Bl)

[0418] • Grapefruit or grapefruit juice, Seville oranges, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days before the first dose of Compound A until the End of Treatment (EOT)ZEarly Termination (ET) visit

[0419] • Systemic treatment with corticosteroids (>10 mg daily prednisone equivalents). Note: Short-course systemic corticosteroids (for < 7 days) or stable baseline usage of topical steroids (for > 21 days) for CTCL is permitted. Steroid regimens utilized for acute adverse events that exceed these limitations should be discussed with the Sponsor (or designee).

[0420] • Concomitant use of other therapies for PTCL or CTCL including:

[0421] (a) Systemic anticancer agents (e.g., chemotherapy, immunomodulatory therapy, or monoclonal antibody therapy), including other EZH2 inhibitors

[0422] (b) Low-dose (12Gy or less) TSEBT

[0423] (c) Local radiation therapy

[0424] (d) Topical retinoids, nitrogen mustard, or imiquimod

[0425] • Live, attenuated vaccines

[0426] • Systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, and thalidomide) Docket No. TRLN-019-010W01 / TLS-066WO

[0427] Botanical medicines with claimed anti-tumor effects (e.g. herbal supplements or traditional Eastern medicine or unapproved proprietary medicines)

[0428] PPIs (e.g. omeprazole, pantoprazole, etc.)

[0429] Study Stopping Rules

[0430] Toxicity for the assessment of safety will be defined as follows (grades are according to CTCAE v5):

[0431] • Neutropenic fever

[0432] • Any Grade >3 non-hematologic toxicity, except: o Grade >3 nausea / vomiting or diarrhea <72 hours with adequate supportive care o Grade >3 fatigue <1 week o A laboratory abnormality that is asymptomatic and resolves within 72 hours o A laboratory abnormality that represents < 1 Grade severity change from baseline (e.g. a Grade 3 laboratory in a patient with a Grade 2 baseline)

[0433] • AST and / or ALT > 3 x ULN (or baseline in patients with abnormal baseline values) associated with > 2 x ULN (or baseline in patients with abnormal baseline values) hyperbilirubinemia and < 2 x ULN alkaline phosphatase

[0434] • Grade >3 thrombocytopenia with an associated hemorrhagic event

[0435] • Grade 4 thrombocytopenia or neutropenia >7 days and unresponsive to supportive care

[0436] All of the above will be considered as toxicity unless it is clearly due to disease progression, pre-existing concurrent medical conditions, or extraneous causes. Events of the same nature that occur in a single patient will be considered based upon the event which had the greatest severity and strongest causality.

[0437] Discontinuation of Study Patients

[0438] A patient may be discontinued from the study drug for any of the following reasons:

[0439] • Treatment failure (e.g., disease progression as defined by progression criteria)

[0440] • Unacceptable toxicity

[0441] • Intercurrent illness compromising ability to fulfill protocol requirements

[0442] • Pregnancy Docket No. TRLN-019-010W01 / TLS-066WO

[0443] • Requirement for alternative treatment in the opinion of the Investigator, unless such treatment is temporary (e.g., local radiation or surgery for disease that does not meet the definition of PD)

[0444] • Death

[0445] • Lost to follow-up

[0446] • Significant non-compliance with study drug

[0447] • Protocol deviation (e.g., use of prohibited medication and procedures requiring study drug discontinuation)

[0448] • Physician decision

[0449] • Site terminated by Sponsor

[0450] • Study terminated by Sponsor

[0451] • Withdrawal of consent by patient

[0452] The reasons for patients discontinuing the study drug, based on the judgment of the Investigator and / or the Sponsor, will be recorded in the eCRF. If the study drug is definitively discontinued (after Day 1), the patient will be encouraged to remain in the study and undergo Early Termination (ET) visit and will be followed up for response rate.

[0453] At the time a patient discontinues treatment, all safety data normally required by the EOT visit will be obtained if possible. Patients discontinuing treatment will be followed for long-term follow-up.

[0454] Efficacy Assessments

[0455] Response Evaluation

[0456] The Investigator will assess response for Cohort 1, PTCL subtypes, according to the Lugano 2014 Criteria and for Cohort 2, CTCL, based on the Global Response Criteria for CTCL (Cheson, Bruce D., et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JC0.2013.54.8800; Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057). Definitions of response for both criteria are described herein; see, e.g., Table B8 and Table B10.

[0457] Safety Assessments

[0458] Adverse Events Docket No. TRLN-019-010W01 / TLS-066WO

[0459] The Investigator is responsible for capturing all adverse events (AEs) in the patient’s medical record and in the electronic data capture (EDC) that are observed or reported during the study, regardless of their relationship to the study drug or their clinical significance.

[0460] An AE is defined as any untoward medical occurrence in a patient enrolled into this study, regardless of its causal relationship with the study drug. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug. If a new, primary malignancy is diagnosed, it will also be considered (and thus, reported as) an AE. Patients will be instructed to contact the Investigator at any time if any symptoms develop.

[0461] A treatment-emergent adverse event (TEAE) is defined as any event not present before exposure to the study drug or any event already present that worsens in either intensity or frequency after exposure to the study drug.

[0462] Anticipated day-to-day fluctuations of pre-existing diseases or conditions present or detected at the start of the study that do not worsen would not be considered AEs. Laboratory results of disease / disorders being studied, medical / surgical procedures are not an AE but rather the condi tion / event that leads to it are defined as an AE.

[0463] Serious Adverse Events

[0464] A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose:

[0465] • Results in death

[0466] • Is immediately life-threatening

[0467] • Requires inpatient hospitalization or prolongation of existing hospitalization

[0468] • Results in persistent or significant disability / incapacity

[0469] • Is a congenital anomaly / birth defect

[0470] • Is an important medical event

[0471] Important medical events that may not result in death, be life threatening, or require hospitalization may be considered SAEs when, based upon appropriate medical judgment, they may jeopardize the patient or may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. Docket No. TRLN-019-010W01 / TLS-066WO

[0472] Any hospital admission with at least one overnight stay will be considered an inpatient hospitalization. An emergency room visit (included extended visit and / or observation period that may have a duration exceeding 24 hours) without hospital admission will not be recorded as an SAE under this criterion, nor will hospitalization for a procedure that is scheduled or planned. However, unexpected complications and / or prolongation of hospitalization that occur during elective surgery should be recorded as AEs and assessed for seriousness. Admission to the hospital for social or situational reasons (i.e. no place to stay, live too far from hospital for visits) will not be considered inpatient hospitalizations unless concurrent medical event or circumstance meets additional criteria.

[0473] In the event of an accidental or intentional overdose by a patient, the site staff must immediately inform the Sponsor (or designee). The overdose in and of itself is not considered an adverse event. The appropriate eCRF completion must reflect this information. In the event the overdose is associated with an adverse event, the events should be linked to clearly indicate that the event occurred in the setting of an acute overdose.

[0474] Assessment of Severity

[0475] The severity / intensity of AEs will be graded based upon the patient’s symptoms according to the current active minor version of the CTCAE v5; available at the National Cancer Institute website for the Cancer Therapy Evaluation Program (CTEP) under “Common Terminology Criteria for Adverse Events (CTCAE)”

[0476] Adverse events that are not defined in CTCAE should be evaluated for severity / intensity according to the following grading scale:

[0477] • Grade 1 = Mild - transient or mild discomfort; no limitation in activity; no medical intervention / therapy required

[0478] • Grade 2 = Moderate - mild to moderate limitation in activity, some assistance may be needed; no or minimal medical intervention / therapy required

[0479] • Grade 3 = Severe - marked limitation in activity, some assistance usually required; medical intervention / therapy required, hospitalization is possible

[0480] • Grade 4 = Life-threatening - An event that puts the patient at immediate or potential risk of death, requires hospitalization or which drastically impact’s a patient’s well being

[0481] • Grade 5 = Death - the event results in death Docket No. TRLN-019-010W01 / TLS-066WO

[0482] The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as severe headache). This criterion is not the same as “serious”, which is based on patient / event outcome or action criteria associated with events that pose a threat to a patient’s life or functioning.

[0483] Seriousness, not severity, serves as a guide for defining regulatory obligations.

[0484] Events considered life-threatening are diseases or conditions where the likelihood of death is high unless the course of the disease or condition is interrupted. These are not events where, had they occurred in a more severe fashion, could have been life-threatening.

[0485] Changes in the severity / intensity of an AE should be documented to allow an assessment of the duration of the event at each grade of severity / intensity. Adverse events characterized as intermittent do not require documentation of onset or duration of each episode.

[0486] Clinical Safety Laboratory Assessments

[0487] All protocol-required laboratory assessments, as defined in Table B4, must be conducted in accordance with the laboratory manual. The laboratory tests will be performed by the local laboratory, unless otherwise specified, at the visits as designated. Fasting is not required, unless otherwise specified in Table B4.

[0488] The laboratory reports must be filed with the source documents (including reference ranges), unless the laboratory reports are transferred electronically.

[0489] The Investigator must review the laboratory reports, document this review, and record any clinically relevant changes occurring during the study. Abnormal laboratories will be classified according to the NCI CTCAE, v5.

[0490] If a laboratory finding is abnormal but not clinically significant (NCS) at baseline, postbaseline laboratory abnormalities will be reported as an AE only if there is worsening compared to baseline. In most cases, clinically significant abnormal laboratory findings are those that are not associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the patient’s condition.

[0491] All laboratory tests with values considered clinically significantly abnormal during participation in the study should be repeated until the values return to normal or baseline or are no longer deemed significant by the Investigator or treating physician. If such values do not return to normal / baseline within a period judged reasonable by the Investigator, the etiology should be identified, and the Sponsor (or designee) notified. Additional laboratory tests may Docket No. TRLN-019-010W01 / TLS-066WO be performed at any time during the study as determined necessary by the Investigator or required by local regulations.

[0492] Table B4. Clinical Safety Laboratory Tests Docket No. TRLN-019-010W01 / TLS-066WO

[0493] Electrocardiograms

[0494] 12-lead ECGs will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and [QTc] intervals. QTc interval must be corrected using the Fridericia’s method. Correction formula: QTc=QT / RR0 33.

[0495] An ECG should be performed in triplicate during screening and on Day 1 of Cycles 1- 6 (taken at least 10 min apart and initiated 90 minutes post dose) and the mean value of the 3 QTcF results is used as the QTcF value for that visit. At other study visits, if the QTc interval increases by > 30 msec compared to baseline or if any one of the measured QTc interval has an absolute value > 480 msec, then 2 additional reflex ECG examinations are required, to complete a triplicate ECG capture (at least 10 min apart).

[0496] During the treatment period an echogram may be conducted if clinically indicated (e.g. abnormal ECG findings).

[0497] Eastern Cooperative Oncology Group Performance Status

[0498] The ECOG Performance Status will be used to assess patient’s performance status (Table B5). The ECOG performance status should be assessed by the same study personnel at each visit, if possible.

[0499] Table B5. Eastern Cooperative Oncology Group Performance Status

[0500] Pharmacokinetics

[0501] Blood samples to determine the plasma concentrations of Compound A will be collected at the timepoints described in Table B6. The time of day (24-hour clock) and date of each sample collection will be recorded along with the actual time of the most recent study Docket No. TRLN-019-010W01 / TLS-066WO drug administration. The timings of sample collection may be amended during the study conduct on the basis of emerging data in order to allow optimal characterization of the PK profile of Compound A.

[0502] Plasma concentrations of Compound A will be quantified by a validated bioanalytical method. Plasma samples of Compound A may also be screened for exploratory metabolite identification, with the use of non-validated methods. If such analyses are conducted, they will be reported separately.

[0503] Table B6. Pharmacokinetic Blood Collection Biomarkers and Biospecimens

[0504] Tumor tissue, peripheral blood, and normal tissue samples will be collected at timepoints specified in Table B7. All unused biospecimens will be kept for up to 20 years after the study is over and the data have been published. Docket No. TRLN-019-010W01 / TLS-066WO

[0505] Table B7. Specimen Collection

[0506] Tumor Specimens:

[0507] • Archived tumor tissue (collected following most recent therapy prior to enrollment into this study); or

[0508] • Fresh biopsy embedded in a paraffin block; or

[0509] • 15 unstained slides

[0510] Specimens collected in support of patient screening will be sent to central pathology for analysis within 60 days of enrollment. Biopsies at screening may not need to be performed if: Docket No. TRLN-019-010W01 / TLS-066WO

[0511] • Either the site investigator or person performing the biopsy judges that no tumor is accessible for biopsy; or

[0512] • Biopsy poses too great of a risk to the patients; or

[0513] • If the only tumor accessible for biopsy is also the only lesion that can be used for response evaluation, then the patient may be exempt from biopsy after discussion with the Sponsor

[0514] The tumor tissue analyses will include but are not limited to the below:

[0515] • EZH2 expression by IHC at a central laboratory

[0516] • BCL6 expression by IHC at a central laboratory

[0517] DNA will be extracted from tumor specimens and banked centrally for potential future NGS.

[0518] If BCL6 IHC is not available from the local pathology report, and adequate tissue remains after the above specimens are sent for central testing and banking, BCL6 IHC testing should be performed locally, and results provided within 3 -months of enrollment. If available from local testing, NGS results regarding tumor variants should also be reported.

[0519] Peripheral Blood:

[0520] Patients with Sezary syndrome or blood involvement by lymphoma will have flow cytometry performed locally to be factored into the response endpoint (Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057).

[0521] Peripheral blood will be sent for central flow analysis.

[0522] Peripheral blood will be collected and banked for future correlative studies.

[0523] Peripheral blood will be sent for assessment of histone H3 lysine 27 trimethylation (H3K27me3).

[0524] Normal Tissue

[0525] Normal tissue will be collected from one of the below:

[0526] • Fingernails / toenails

[0527] • Saliva

[0528] • Buccal swab

[0529] • Peripheral blood (granulocytes)

[0530] DNA will be extracted and banked for potential NGS testing. Docket No. TRLN-019-010W01 / TLS-066WO

[0531] Statistical Consideration

[0532] Sample size Determination

[0533] This study is designed to evaluate the anti-tumor activity, safety, and tolerability of two dose levels of Compound A in patients with PTCL and explore anti-tumor activity, safety, and PK in a population of patients with CTCL. The observed ORR in patients with PTCL was approximately 60% (17 / 28) in the 350 mg dose cohort in a similar patient population from a previous study conducted in China.

[0534] For Cohort 1, assuming an inferior dose is 40% or lower, with 20 patients per treatment arm, the design will have approximately 83% probability to select the correct dose when the selected dose is observed to have at least 15% higher ORR (Simon, R., R. E. Wittes, and S. S. Ellenberg. Cancer Treatment Reports 69.12 (1985): 1375-1381). In addition, with 20 patients per treatment arm, the maximum width of the 95% confidence interval for the ORR estimate is 0.456. If 10 of the 20 patients achieve a CR or PR, the ORR will be 50% with a 95% confidence interval of (27.2%, 72.8%).

[0535] For Cohort 2, a sample size of 10 will have 83% power to detect a difference between a null hypothesis ORR of 20% and an alternative ORR of 60% using an exact binomial test with a nominal 5% one-sided significance level.

[0536] Population for Analyses

[0537] For purposes of analysis, the following populations are defined:

[0538] Statistical Methods

[0539] General

[0540] The statistical analyses for this study will be descriptive and presented by dose, by disease subtype, and by dose and disease subtype for Cohort 1 and by disease subtype for Docket No. TRLN-019-010W01 / TLS-066WO

[0541] Cohort 2. Statistical inference will be performed at the nominal 2-sided 5% alpha level without multiplicity adjustment. Point estimates will be accompanied by 95% confidence intervals.

[0542] Data collected will be presented using summary tables, data listings, and figures. For continuous variables, descriptive summaries will include the mean, median, standard deviation, the first and third quartiles, minimum, and maximum. For categorical variables, the number and percentage of patients in each category will be presented.

[0543] A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. The SAP will include a more technical and detailed description of all statistical analyses to be performed for the clinical study report.

[0544] Anti-Tumor Activity Analysis

[0545] For patients with PTCL in Cohort 1, ORR is defined as the proportion of patients achieving a best response of CR or PR based on Investigator assessment as per 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; see also Table B8). For patients with CTCL (Sezary syndrome and mycosis fungoides) in Cohort 2, ORR is defined as the proportion of patients achieving a best response of CR or PR based on the Global Assessment Scale for CTCL (Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419- 437; doi: 10.1182 / blood.2021012057). ORR will be estimated along with the 95% Clopper- Pearson confidence intervals based on the Response Evaluable Population. A sensitivity analysis will be performed using the Safety Analysis Population.

[0546] DOR is the time from the date of first documentation of objective response (CR or PR) to the date of the first documentation of disease progression (progressive or relapsed disease) based on Investigator assessments or to death due to any cause, whichever occurs first. DOR will be summarized for responders only. The Kaplan-Meier method may be used to analyze the DOR.

[0547] Exploratory endpoints of PFS and OS will be analyzed using the Kaplan-Meier method. PFS is defined as the time from randomization until first documented instance of disease progression or death from any cause, whichever comes first. Patients who are alive without disease progression will be censored at the time of last disease assessment. PFS rates at 3, 6, 9, and 12 months will be estimated using the Kaplan -Mei er method and accompanied by 95% confidence intervals. Estimates of median PFS and PFS rates at other timepoints will also be provided. Docket No. TRLN-019-010W01 / TLS-066WO

[0548] OS is defined as the time from randomization to death from any cause. Patients who are alive will be censored at the last known alive date. OS will be summarized similarly as the PFS endpoint using the Kaplan-Meier method.

[0549] Safety and Tolerability Analysis

[0550] Patient incidence of TEAEs will be tabulated by MedDRA system organ class and preferred term. Summary tables of TEAEs that are fatal (Grade 5), serious, treatment-related, Grade 3 or 4, TEAEs leading to treatment discontinuation, reduction or interruption will be provided.

[0551] Treatment exposure will be summarized to include treatment duration, cumulative dose, dose intensity, and relative dose intensity. Dose modifications will also be summarized by frequency and reason.

[0552] Laboratory values outside the normal reference ranges that are deemed clinically significant will be identified and summarized. Summary tables of change from baseline and maximum shift in toxicity grade from baseline for selected parameters will be provided.

[0553] Other Analyses

[0554] Biomarkers will be evaluated and summarized descriptively. Exploratory analyses correlating biomarker levels with safety and anti-tumor activity endpoints will be performed.

[0555] Plasma concentrations will be analyzed by noncompartmental PK methods and PK parameters, Cmax, Tmax, AUCo-t, half-life, CL / F, Vz / F, and accumulation index will be calculated if feasible.

[0556] Individual and mean plasma concentration versus time curves will be presented for both linear and semi-log scales. Descriptive statistics (arithmetic and geometric means, standard deviation [SD], coefficient of variation [CV%], minimum [Min], maximum [Max], and median) of the plasma concentrations versus time will be presented as well for the PK parameters.

[0557] Details will be specified in the statistical analysis plan (SAP).

[0558] Interim Analysis

[0559] An interim analysis in Cohort 1 will be performed after 20 patients have been randomized and treated for cycle 1 (10 patients in each treatment arm). A benefit-risk analysis of safety, tolerability, efficacy, and PK data will be reviewed by the SRC. The lower dose arm may be discontinued at the discretion of the SRC if the safety and tolerability of the higher Docket No. TRLN-019-010W01 / TLS-066WO dose are acceptable and there are no responders in the lower dose arm. Futility of the lower dose will also be continuously monitored using a Bayesian beta binomial model.

[0560] Cohort 2 will not have a formal interim analysis, however the benefit-risk of the regimen will be continuously monitored using a Bayesian beta binomial model.

[0561] Response Evaluation Criteria

[0562] PTCL Assessments - Lugano 2014 Criteria

[0563] Table B8. Response Evaluation Criteria for Lymphoma (Lugano 2014 Criteria) Docket No. TRLN-019-010W01 / TLS-066WO

[0564] Source: *Lugano 2014 criteria (Cheson, Bruce D., et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JC0.2013.54.8800)

[0565] Abbreviations: CMR, complete metabolic response; CRR, complete radiographic response; CT, computed tomography; FDG,18F -fluorodeoxy glucose; LDi: longest transverse diameter; PD, progressive disease; Docket No. TRLN-019-010W01 / TLS-066WO

[0566] PET, positron emission tomography; PMR, partial metabolic response; PPD: cross product of the longest transverse diameter and perpendicular diameter; PRR, partial radiographic response; SPD: sum of the product of the perpendicular diameters; SDi: shortest axis perpendicular to LDi

[0567] Imaging Guidelines

[0568] Imaging will be evaluated as outlined in Table B9 including PET-CT and contrast- enhanced CT C / A / P, and any other sites of known lesions. For patients with PTCL that is18F- fluorodeoxyglucose (FDG)-avid, the Lugano Classification as outlined in Table B8 will be used for response assessment. For patients with disease measurable by FDG-PET / CT, repeat CT C / A / P is optional. For patients with non-FDG-avid PTCL, a CT-based response will be performed as outlined in Table B8. For patients with contrast media allergy or CrCl below the institutional limit, non-contract CT may be used for the chest while plain MRI or CT (MRI preferred) may be used for the neck, abdomen, pelvis, and other sites of known lesions. The same method of evaluation should be used each time for the same site in a patient (unless contraindications arise subsequently). Patients with no abnormalities on baseline CT do not need repeat CT C / A / P unless clinically indicated. For patients with lymphoma subtypes (e.g. certain patients with CTCL) that are not typically measurable on CT scan, monitoring by CT scans is optional as long as there are no abnormalities at baseline imaging.

[0569] Patients with potential for CNS involvement of lymphoma should undergo contrast- enhanced MRI of the head at baseline to rule out CNS involvement. If MRI is contraindicated, contrast-enhanced CT may be used instead; for patients with contrast media allergy or contraindications, plain MRI or CT (MRI preferred) may be used instead.

[0570] Table B9. Imaging Guidelines

[0571] *The time window for imaging examination is -7 days from the start of the Cycle.

[0572] Abbreviations: C / A / P, chest / abdomen / pelvic; CT, computed tomography; PET, positron emission tomography.

[0573] 1The results of CT / MRI, PET-CT performed at the study site before the signing of ICF may be used for tumor evaluation in the screening period as long as they meet the requirements of the protocol. Docket No. TRLN-019-010W01 / TLS-066WO

[0574] CTCL Assessments

[0575] For CTCL, patients with mycosis fungoides or Sezary syndrome, the global response score as described by Olsen, et al 2022 will be used as shown in Table BIO (Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057). This assessment includes the assessment of skin (Table Bll), blood (Table B13), lymph nodes (Table B14), and viscera (Table B15). The assessment of skin is performed by the mSWAT (provided in Table Bll).

[0576] Global Response Criteria (Mycosis Fungoides and Sezary Syndrome)

[0577] Table B10. Global Response Criteria for Mycosis Fungoides and Sezary Syndrome

[0578] Source: Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057

[0579] Abbreviations: CR, complete response, NI, not involved; PD, progressive disease, PR, partial response, SD, stable disease

[0580] This table assumes that (1) all patients at baseline have measurable skin disease and (2) in patients with PCL and no extracutaneous disease at baseline, any new nodal or visceral involvement constitutes PD in those compartments. NI, noninvolved; SD, stable disease.

[0581] *This assumes that the response (CR, PR, SD, PD, or relapse) has been maintained for at least 4 weeks in any involved category. Docket No. TRLN-019-010W01 / TLS-066WO

[0582] Response in Skin

[0583] Table Bll. Response in skin for Patients with CTCL

[0584] Abbreviations: CR, complete response, CTCL, Cutaneous T-cell lymphoma; MF, Mycosis Fungoides; PD, progressive disease, PR, partial response, SD, stable disease, SS, Sezary Syndrome.

[0585] *A biopsy of normal appearing skin is unnecessary to assign a CR. However, a skin biopsy should be performed of a representative area of the skin if there is any question of residual disease (persistent erythema or pigmentary change) where otherwise a CR would exist. If histologic changes are suspicious or suggestive of PCL, the response should be considered a PR only. f Whichever criterion occurs first.

[0586] {One form of assessment of skin disease should be used throughout a given clinical trial. For a global response score and a designation of Very Good PR, a comparison of total body skin assessment based on mSWAT assessment (Table B12) or sum of the product of perpendicular tumor measurements (SLAT score is one example) at baseline is necessary. Regional or lesional skin scoring may also have CR, PR, SD and PD response but may not be representative of the response of skin disease on the entire body skin surface and cannot be used to assess global response.

[0587] §For patients with limited T1 stage disease, there is a potential for a >25% increase in patch / plaque skin score to lead to a PD despite an insignificant change in total skin lymphoma. This is of particular concern in studies where global response is the primary endpoint and skin the primary determinant of that response. In these cases, study design may elect to add additional requirements for PD in patients with T1 disease at BL, including a T1 to T2 change in skin classification in addition to the >25% increase in skin score

[0588] Modified Severity Weighted Assessment Tool (mSWAT)

[0589] The mSWAT score (Table Bll) assess the total skin involvement in CTCL by the summation of the product of the approximate body surface area (BSA) covered by 1 of 3 types of skin lesions (patch, plaque or tumor) multiplied by the weighing factor of 1, 2 or 4, respectively. The percent BSAs per body area in the table are from Lund and Browder (Lund, C. C., and N. C. Browder. Surg Gynecol Obstet. Chicago 79.4 (1944): 352-58). In Lund and Browder, A, B, and C designate the body regions of head, thigh, and leg, respectively, for which they provided adjustments in BSA for children aged 1 to 5 years. Docket No. TRLN-019-010W01 / TLS-O66WO

[0590] Abbreviation: BSA, body surface area. Response in Blood (Mycosis Fungoides and Sezary Syndrome)

[0591] Source: Olsen, Elise A., et al. Blood, The Journal of the American Society of Hematology 140.5 (2022): 419-437; doi: 10.1182 / blood.2021012057

[0592] Abbreviations: B, blood; Bo, absence of significant blood involvement; Bi, low blood tumor burden; B2, high blood tumor burden

[0593] *As determined by absolute numbers of neoplastic cells / mL by flow cytometry.

[0594] ’i'Thc absolute number of CD4+CD26" and / or CD4+CD7" lymphocytes may be used to assess blood involvement in clinical trials. In the case where more than one aberrant population of lymphocytes is recorded, the population with the highest absolute number at baseline should determine the B classification and the highest absolute number at each assessment should be used to determine the number of aberrant lymphocytes for response purposes.

[0595] {There is no PR in those with Bi disease at baseline as the difference within the range of neoplastic cells that define Bi is not considered significant and should not affect determination of global objective response.

[0596] §Whichever occurs first. Docket No. TRLN-019-010W01 / TLS-066WO

[0597] AThe determination of what constitutes a significantly high count of neoplastic cells above 1000 neoplastic cells / mL and what should be used here to help define PD in Mycosis Fungoides / Sezary syndrome blood involvement is at present arbitrary and based on expert opinion. Response in Lymph Nodes (CTCL)

[0598] Table B14. Response in Lymph Nodes for Patients with CTCL

[0599] Modified from Cheson, Bruce D., et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JC0.2013.54.8800

[0600] Abbreviations: CR, complete responses, FDG, fluorodeoxy glucose; LDi, longest diameter; LN, lymph node; 5PS, 5-point scale; PD, progressive disease; PR, partial response; SD, stable disease; SDi, short axis (longest perpendicular diameter to the LDi); SPD, sum of the products of the perpendicular diameters for multiple lesions *5PS: 1 = no FDG uptake > background; 2 = FDG uptake < mediastinum; 3 = FDG uptake > mediastinum but < liver; 4 = FDG uptake moderately > liver; 5 = FDG uptake markedly > liver and / or new lesions.

[0601] ■(Target LNs are those >1.5 cm with representative abnormal node positive pathologically for lymphoma. In MF / SS, this is currently the LN classification of N3.

[0602] Docket No. TRLN-019-010W01 / TLS-066WO

[0603] Response in Viscera

[0604] Table B15. Response in Viscera for Patients with CTCL

[0605] Based on Cheson, Bruce D., et al. Journal of Clinical Oncology 32.27 (2014): 3059-3067; doi: 10.1200 / JC0.2013.54.8800

[0606] Abbreviations: FDG, fluorodeoxy glucose; LDi, longest diameter; LN, lymph node; 5PS, 5 -point scale; PD, progressive disease; SDi, short axis (longest perpendicular diameter to the LDi); SPD, sum of the products of the perpendicular diameters for multiple lesions

[0607] *5PS: 1 = no FDG uptake > background; 2 = FDG uptake < mediastinum; 3 = FDG uptake > mediastinum but < liver; 4 = FDG uptake moderately > liver; 5 = FDG uptake markedly > liver and / or new lesions.

[0608] Example B2

[0609] Measurement of cellular proliferation

[0610] In white, flat-bottom 384-well tissue culture treated microplates, CTCL and LBCL cells were seeded at previously determined seeding densities such that the well would be approximately 80% confluent at the end of the assay. Immediately after seeding, compounds were dispensed into the treatment plates using a Tecan D300e compound printer in 9-point DRC format, 10-micromolar top concentration, in triplicate. Treatment plates were then transferred to a 37 °C, 5% CO2 humidified incubator for 120 hours unless otherwise stated. After the completion of treatment, CELLTITER-GLO® 2.0 reagent (Promega) was added directly to each well. The plates were covered to protect from light and incubated on an orbital shaker at room temperature for 10 minutes. Assay plates were then read on a BMG Labtech Docket No. TRLN-019-010W01 / TLS-066WO

[0611] PHERAstar FSX microplate reader. Data were analyzed by calculating the ratio of signal from treated wells relative to negative control -treated wells. The replicates were averaged and a variable slope (3 -parameter), non-linear regression curve was fitted for each compound of interest. IC50 values, as a geometric mean of multiple runs, if applicable, are reported in Table B16 with two significant figures.

[0612] BCL6 status was determined by Western blot. Cell pellets from LBCL and CTCL cell lines were collected and resuspended in cell lysis buffer with protease and phosphatase inhibitors. Twenty pg of protein were loaded onto a Novex 4-12% Bis-Tris Gel and transferred using a Trans-Blot Turbo transfer system. The membrane was incubated with anti-BCL6 (1 :1000, D412V Cell Signaling Technology) and Anti-P-Actin (1 :20,000, A5316 Sigma- Aldrich) antibodies overnight at 4 °C and image data was acquired on Odyssey Infrared Imaging System. Alternatively, the lysate was run using the JESS Automated Western Blot System with anti-BCL6 (1 :50, D412V Cell Signaling Technology) and Anti-Vinculin (1 :4000, E1E9V Cell Signaling Technology). Band density was analyzed and quantified on LICOR Empiria Studio software or Compass for Simple Western compared to a positive and negative control.

[0613] Table B16.

[0614] Example B3

[0615] PDX and CDX Models I

[0616] All the procedures related to animal handling, care, and treatment in the efficacy study were performed according to guidelines approved by the Institutional Animal Care and Use Docket No. TRLN-019-010W01 / TLS-066WO

[0617] Committee (IACUC) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

[0618] For LBCL and CTCL cell line xenografts (CDX), 6-8 week old female mice were inoculated subcutaneously on the right flank with tumor cells in 0.1 mL of 1 : 1 medium / Matrigel for tumor development. Treatments started and groupings (3-8 mice per group) were assigned when the mean tumor volume reached about 100-300 mm3. Based on the tumor volume, mice were randomly assigned to groups such that the average starting tumor size was the same for each treatment group.

[0619] For LBCL, CTCL, and Burkitt Lymphoma patient derived xenografts (PDX), fresh tumor tissues from tumor bearing mice were harvested and cut into small pieces (approximately 2-3 mm in diameter). PDX tumor fragments were inoculated subcutaneously at the upper right dorsal flank into immunodeficient mice for tumor development (3-8 mice per group).

[0620] Tumor-bearing mice were treated orally twice daily (BID) with Compound A, or a pharmaceutically acceptable salt thereof, at a dose of 40 mg / kg, 80 mg / kg, or 160 mg / kg. The treatment period was 17, 21, or 28 days, optionally followed by an observation period of 6, 15, 21, or 32 days.

[0621] The BCL6 status of these models is shown in Table B17, either as positivity by Western blot (CDX; see Example B2) or as percent nuclear staining greater than or equal to 30% (PDX). IHC staining for BCL6 was conducted on tumor tissue, or metastatic sites of infiltration, including spleen, lymph node, and kidney sections.

[0622] For IHC, tissues were fixed in 10% neutral buffered formalin for 24 hrs, paraffin embedded, sectioned, and immunohistochemically stained for BCL6 (LN22, Leica / 564-L-CE) and EZH2 (D2C9 Cell Signaling Technology #5246) on the automated Bond III platform (Leica Biosystems, Inc), and digitally scanned on a Aperio AT2 scanner (Leica Biosystems, Inc). Positive immunoreactivity was visualized with DAB (brown).

[0623] The body weight of each animal was measured and recorded twice weekly throughout the study. The measurement of tumor size was conducted twice weekly with a caliper and recorded. The tumor volume (mm3) was estimated using the formula: TV=a x b2 / 2, where “a” and “b” are long and short diameters of a tumor, respectively.

[0624] In the CDX models, Models E, K, L, B, and C showed slowing of tumor growth when administered Compound A. No regressions were observed.

[0625] In the PDX models, S (all three dose levels), and V showed slowing of tumor growth when administered Compound A. Models M, N, O, P, Q, R, and T showed regressions when administered Compound A. Docket No. TRLN-019-010W01 / TLS-066WO

[0626] For systemic models of AITL, fresh splenocytes from tumor bearing stock animals were isolated and NOG mice were inoculated intravenously through the tail vein with P I O6live cells in 0.1 mL of PBS solution for tumor development. Randomization and treatment was initiated when the mean flow cytometry hCD45+% reached approximately 0.5%-5%. Tumor growth was monitored weekly using peripheral blood hCD45% levels and at end of the study using hCD45% levels in the spleen, kidney, and lymph nodes. In both AITL Models U and W, peripheral blood engraftment was decreased when administered Compound A, and Compound A was tolerated as demonstrated by body weight similar to vehicle. In Model U, engraftment in the spleen and kidney was reduced when administered Compound A (not measured in Model W). Administration of Compound A also increased survival time in Model

[0627] W (data not reported for Model U).

[0628] Additional details of these experiments are shown in Table B17.

[0629] Docket No. TRLN-019-010W01 / TLS-066WO

[0630] Table B17

[0631] Notes:

[0632] (1) sc= subcutaneous; iv = intravenous; ND = not determined

[0633] Docket No. TRLN-019-010W01 / TLS-066WO

[0634] Example B4

[0635] PDX and CDX Models II

[0636] All the procedures related to animal handling, care, and treatment in the efficacy studies were performed according to guidelines approved by the Institutional Animal Care and Use Committee (IACUC) following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

[0637] For LBCL cell line xenografts (CDX), 6-8 week-old female mice were inoculated subcutaneously on the right flank with tumor cells in 0.1 mL of 1 : 1 medium / Matrigel for tumor development. Treatments started and groupings (3-8 mice per group) were assigned when the mean tumor volume reached about 100-300 mm3. Based on the tumor volume, mice were randomly assigned to groups such that the average starting tumor size was the same for each treatment group.

[0638] For LBCL, FL, and PTCL patient derived xenografts (PDX), fresh tumor tissues from tumor bearing mice were harvested and cut into small pieces (approximately 2-3 mm in diameter). PDX tumor fragments were inoculated subcutaneously at the upper right dorsal flank into immunodeficient mice for tumor development (3-8 mice per group).

[0639] Tumor-bearing mice were treated with Compound A BID at 160 mg / kg. The treatment period was 17, 20, 21, or 27 days. For efficacy calculations, a percent tumor growth inhibition (%TGI) value was calculated and reported for each treatment group (T) versus control (C) using initial (i) and final (f) tumor measurements using the following formula: %T / C = Tf / Cf. If the vehicle reached terminal tumor growth prior to the end of study, control and treatment groups were compared for the last day of vehicle treatment. If end-of-study tumor volume was less than the initial tumor volume on Day 0, percent tumor regression (%TR) was determined using the following formula: %TR = 1 - Tf / Ti x 100.

[0640] The BCL6 status of these models is shown in Table Bl 8, either as positivity by Western blot (CDX; see Example B2) or as percent nuclear staining greater than or equal to 30% (PDX). IHC staining for BCL6 was conducted on tumor tissue, or metastatic sites of infiltration, including spleen, lymph node, and kidney sections.

[0641] For IHC, tissues were fixed in 10% neutral buffered formalin for 24 hrs, paraffin embedded, sectioned, and immunohistochemically stained for BCL6 (LN22, Leica / 564-L-CE) on the automated Bond III platform (Leica Biosystems, Inc), and digitally scanned on a Aperio AT2 scanner (Leica Biosystems, Inc). Positive immunoreactivity was visualized with DAB (brown).

[0642] In the CDX studies, treatment with Compound A resulted in 50% (1 / 2) of 50% < %T / C < 70% compared to the average tumor starting size.

[0643] In the PDX studies, treatment with Compound A resulted in 17% (6 / 36) regressions of at least 50% compared to the average tumor starting size. Treatment with Compound A resulted in Docket No. TRLN-019-010W01 / TLS-066WO

[0644] 64% (23 / 36) of 50% < %T / C < 70% (or better response) compared to the average tumor starting size. Model 37, an ALK+ ALCL, showed complete regression.

[0645] Additional details and results of these experiments are shown in Table B18.

[0646] Table B18. Docket No. TRLN-019-010W01 / TLS-066WO

[0647] Notes:

[0648] (1) “A”: >50% TR; “B”: 0% < %TR < 50%; “C”: 0 %< %T / C < 50%; “D”: 50% < %T / C

[0649] < 70%; “E”: %T / C > 70%

[0650] (2) ND = not determined; sc = subcutaneous

[0651] EXEMPLARY EMBODIMENTS

[0652] P01 Embodiments

[0653] Embodiment 1. A method for treating a cutaneous T cell lymphoma (CTCL) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0654] Embodiment 2. The method of Embodiment 1, wherein the CTCL is selected from the group consisting of primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, primary cutaneous acral CD8-positive 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, primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma, and primary cutaneous peripheral T-cell lymphoma NOS.

[0655] Embodiment 3. The method of Embodiment 1 or 2, wherein the CTCL is mycosis fungoides.

[0656] Embodiment 4. The method of Embodiment 1 or 2, wherein the CTCL is Sezary syndrome. Docket No. TRLN-019-010W01 / TLS-066WO

[0657] Embodiment 5. The method of Embodiment 1 or 2, wherein the CTCL is primary cutaneous gamma-delta T-cell lymphoma.

[0658] Embodiment 6. The method of Embodiment 1 or 2, wherein the CTCL is primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma.

[0659] Embodiment 7. The method of Embodiment 1 or 2, wherein the CTCL is primary cutaneous peripheral T-cell lymphoma NOS.

[0660] Embodiment 8. The method of any one of Embodiments 1-7, wherein the subject does not have a history of autologous stem cell transplantation within 60 days or allogeneic stem cell transplantation within 90 days prior to the first dose of Compound A, or a pharmaceutically acceptable salt thereof.

[0661] Embodiment 9. The method of any one of Embodiments 1-8, wherein the subject does not have a current or past history of central nervous system (CNS) involvement of the CTCL.

[0662] Embodiment 10. The method of any one of Embodiments 1-9, wherein the subject does not have a current or past history of CNS disease other than:

[0663] (a) a history of stroke, wherein the subject has not experienced a stroke or transient ischemic attack in the past 2 years and has no residual neurologic deficits; or

[0664] (b) a history of epilepsy, wherein the subject has had no seizures in the past 2 years.

[0665] Embodiment 11. The method of any one of Embodiments 1-10, wherein the subject does not have clinically significant cardiovascular disease.

[0666] Embodiment 12. The method of any one of Embodiments 1-11, wherein the subject does not have abnormal electrocardiogram (ECG) findings.

[0667] Embodiment 13. The method of any one of Embodiments 1-12, wherein the subject does not have a QTc interval >470 msec, corrected using Fridericia’s Formula.

[0668] Embodiment 14. The method of any one of Embodiments 1-13, wherein administration of any proton pump inhibitor (PPI) (e.g., omeprazole or pantoprazole) is stopped 1 Docket No. TRLN-019-010W01 / TLS-066WO week prior to the first dose of Compound A, or a pharmaceutically acceptable salt thereof, through the duration of treatment with Compound A, or a pharmaceutically acceptable salt thereof.

[0669] Embodiment 15. The method of any one of Embodiments 1-11, wherein the subject has an ECOG score of 0, 1, or 2 prior to administration of the first dose of Compound A, or a pharmaceutically acceptable salt thereof.

[0670] Embodiment 16. The method of any one of Embodiments 1-15, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0671] Embodiment 17. The method of Embodiment 16, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0672] Embodiment 18. The method of Embodiment 16, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

[0673] Embodiment 19. The method of any one of Embodiments 1-18, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy.

[0674] Embodiment 20. The method of any one of Embodiments 1-18, comprising administering an additional therapy or therapeutic agent to the subject.

[0675] Embodiment 21. A method for treating mycosis fungoides in a subject in need thereof, the method comprising administering a therapeutically effective amount of an EZH2 inhibitor or an EZH1 / 2 inhibitor to the subject.

[0676] Embodiment 22. The method of Embodiment 21, wherein the EZH2 or EZH1 / 2 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.

[0677] Embodiment 23. The method of Embodiment 21, wherein the EZH2 inhibitor is selected from the group consisting of lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide), EBI-2511, and XNW-5004. Docket No. TRLN-019-010W01 / TLS-066WO

[0678] Embodiment 24. The method of Embodiment 21, wherein the EZH2 inhibitor is Compound A, or a pharmaceutically acceptable salt thereof.

[0679] Embodiment 25. The method of Embodiment 24, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0680] Embodiment 26. The method of Embodiment 24, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0681] Embodiment 27. The method of Embodiment 24, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

[0682] Embodiment 28. A method for treating Sezary syndrome in a subject in need thereof, the method comprising administering a therapeutically effective amount of an EZH2 inhibitor or an EZH1 / 2 inhibitor to the subject.

[0683] Embodiment 29. The method of Embodiment 28, wherein the EZH2 or EZH1 / 2 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.

[0684] Embodiment 30. The method of Embodiment 28, wherein the EZH2 inhibitor is selected from the group consisting of lirametostat, mevrometostat, tazemetostat (e.g., tazemetostat hydrobromide), EBI-2511, and XNW-5004.

[0685] Embodiment 31. The method of Embodiment 28, wherein the EZH2 inhibitor is Compound A, or a pharmaceutically acceptable salt thereof.

[0686] Embodiment 32. The method of Embodiment 31, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day. Docket No. TRLN-019-010W01 / TLS-066WO

[0687] Embodiment 33. The method of Embodiment 31, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0688] Embodiment 34. The method of Embodiment 31, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

[0689] Embodiment 35. A method for treating a lymphoma, the method comprising administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, to a subject having a BCL6+ lymphoma.

[0690] Embodiment 36. The method of Embodiment 35, wherein the lymphoma is a Hodgkin lymphoma (e.g., nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)) or a non-Hodgkin lymphoma (e.g., B cell lymphoid proliferations and lymphomas (e.g., mature B cell neoplasms (e.g., 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), primary mediastinal large B cell lymphoma (primary mediastinal LBCL), or high grade B-cell lymphoma NOS), follicular lymphoma (FL), or transformations of indolent B cell lymphomas (e.g., transformed FL))), T-cell and NK-cell lymphoid proliferations and lymphomas (e.g., mature T-cell and NK-cell neoplasms (e.g., mature T-cell and NK-cell leukemias (e.g., adult T-cell leukemia / lymphoma), 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, 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, or primary cutaneous peripheral T-cell lymphoma NOS), 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 Docket No. TRLN-019-010W01 / TLS-066WO

[0691] NOS (also known as follicular helper T-cell lymphoma, NOS)), or other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS))))).

[0692] Embodiment 37. The method of Embodiment 36, wherein the lymphoma is FL or 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, or HBGCL-NOS).

[0693] Embodiment 38. The method of Embodiment 37, wherein the lymphoma 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, or HBGCL-NOS).

[0694] Embodiment 39. The method of Embodiment 37, wherein the lymphoma is FL.

[0695] Embodiment 40. The method of Embodiment 36, wherein the lymphoma is BL.

[0696] Embodiment 41. The method of Embodiment 36, wherein the 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))).

[0697] Embodiment 42. The method of Embodiment 41, wherein the lymphoma is anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma).

[0698] Embodiment 43. The method of Embodiment 42, wherein the lymphoma is ALK- positive anaplastic large cell lymphoma. Docket No. TRLN-019-010W01 / TLS-066WO

[0699] Embodiment 44. The method of Embodiment 42, wherein the lymphoma is ALK- negative anaplastic large cell lymphoma.

[0700] Embodiment 45. The method of Embodiment 41, wherein the lymphoma is 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)).

[0701] Embodiment 46. The method of Embodiment 45, wherein the lymphoma is nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T- cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type).

[0702] Embodiment 47. The method of Embodiment 45, wherein the lymphoma is nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type).

[0703] Embodiment 48. The method of Embodiment 45, wherein the lymphoma is nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS).

[0704] Embodiment 49. The method of Embodiment 36, wherein the lymphoma is a 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, 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, or primary cutaneous peripheral T- cell lymphoma NOS).

[0705] Embodiment 50. The method of Embodiment 49, wherein the lymphoma is mycosis fungoides. Docket No. TRLN-019-010W01 / TLS-066WO

[0706] Embodiment 51. The method of Embodiment 49, wherein the lymphoma is Sezary syndrome.

[0707] Embodiment 52. The method of any one of Embodiments 35-51, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0708] Embodiment 53. The method of Embodiment 52, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0709] Embodiment 54. The method of Embodiment 52, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

[0710] Embodiment 55. A method for treating a lymphoma in a subject in need thereof, the method comprising:

[0711] (a) determining that the lymphoma in the subject is BCL6+; and

[0712] (b) administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0713] Embodiment 56. The method of Embodiment 55, wherein the lymphoma is a Hodgkin lymphoma (e.g., nodular lymphocyte predominant Hodgkin lymphoma (NLPHL)) or a non-Hodgkin lymphoma (e.g., B cell lymphoid proliferations and lymphomas (e.g., mature B cell neoplasms (e.g., 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), primary mediastinal large B cell lymphoma (primary mediastinal LBCL), or high grade B-cell lymphoma NOS), follicular lymphoma (FL), or transformations of indolent B cell lymphomas (e.g., transformed FL))), T-cell and NK-cell lymphoid proliferations and lymphomas (e.g., mature T-cell and NK-cell neoplasms (e.g., mature T-cell and NK-cell leukemias (e.g., adult T-cell leukemia / lymphoma), 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, Sezary syndrome, primary cutaneous CD30-positive T-cell lymphoproliferative disorder: lymphomatoid papulosis, primary cutaneous CD30-positive T-cell Docket No. TRLN-019-010W01 / TLS-066WO lymphoproliferative disorder: primary cutaneous anaplastic large cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, primary cutaneous gamma-delta T-cell lymphoma, or primary cutaneous peripheral T-cell lymphoma NOS), 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 other peripheral T-cell lymphomas (e.g., peripheral T-cell lymphoma NOS))))).

[0714] Embodiment 57. The method of Embodiment 56, wherein the lymphoma is FL or 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, or HBGCL-NOS).

[0715] Embodiment 58. The method of Embodiment 57, wherein the lymphoma 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, or HBGCL-NOS).

[0716] Embodiment 59. The method of Embodiment 58, wherein the lymphoma is FL.

[0717] Embodiment 60. The method of Embodiment 56, wherein the lymphoma is BL.

[0718] Embodiment 61. The method of Embodiment 56, wherein the 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 Docket No. TRLN-019-010W01 / TLS-066WO nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS))).

[0719] Embodiment 62. The method of Embodiment 61, wherein the lymphoma is anaplastic large cell lymphoma (ALCL) (e.g., ALK-positive anaplastic large cell lymphoma or ALK-negative anaplastic large cell lymphoma).

[0720] Embodiment 63. The method of Embodiment 62, wherein the lymphoma is ALK- positive anaplastic large cell lymphoma.

[0721] Embodiment 64. The method of Embodiment 62, wherein the lymphoma is ALK- negative anaplastic large cell lymphoma.

[0722] Embodiment 65. The method of Embodiment 61, wherein the lymphoma is 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)).

[0723] Embodiment 66. The method of Embodiment 65, wherein the lymphoma is nodal T follicular helper cell lymphoma angioimmunoblastic type (also known as angioimmunoblastic T- cell lymphoma (AITL) or follicular helper T-cell lymphoma, angioimmunoblastic type).

[0724] Embodiment 67. The method of Embodiment 65, wherein the lymphoma is nodal T follicular helper cell lymphoma follicular type (also known as follicular helper T-cell lymphoma, follicular type).

[0725] Embodiment 68. The method of Embodiment 65, wherein the lymphoma is nodal T follicular helper cell lymphoma NOS (also known as follicular helper T-cell lymphoma, NOS).

[0726] Embodiment 69. The method of Embodiment 56, wherein the lymphoma is a 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, Sezary syndrome, primary cutaneous CD30-positive T-cell Docket No. TRLN-019-010W01 / TLS-066WO 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, or primary cutaneous peripheral T-cell lymphoma NOS).

[0727] Embodiment 70. The method of Embodiment 69, wherein the lymphoma is mycosis fungoides.

[0728] Embodiment 71. The method of Embodiment 69, wherein the lymphoma is Sezary syndrome.

[0729] Embodiment 72. The method of any one of Embodiments 55-71, wherein determining that the lymphoma in the subject is BCL6+ comprises consulting the subject’s medical record.

[0730] Embodiment 73. The method of any one of Embodiments 55-71, wherein determining that the lymphoma in the subject is BCL6+ comprises using immunohistochemistry (IHC) or RNA expression analysis.

[0731] Embodiment 74. The method of Embodiment 73, wherein the lymphoma is determined to be BCL6+ using an IHC test.

[0732] Embodiment 75. The method of Embodiment 74, wherein the IHC test is performed on a tumor sample from the subject.

[0733] Embodiment 76. The method of Embodiment 75, wherein the IHC test on the tumor sample from the subject is BCL6+ as indicated by a percent nuclear positivity score for BCL6 expression of greater than or equal to 1% in the IHC test.

[0734] Embodiment 77. The method of Embodiment 75, wherein the IHC test on the tumor sample from the subject is BCL6+ as indicated by a percent nuclear positivity score for BCL6 expression of greater than or equal to 5% in the IHC test. Docket No. TRLN-019-010W01 / TLS-066WO

[0735] Embodiment 78. The method of Embodiment 75, wherein the IHC test on the tumor sample from the subject is BCL6+ as indicated by a percent nuclear positivity score for BCL6 expression of greater than or equal to 10% in the IHC test.

[0736] Embodiment 79. The method of Embodiment 75, wherein the IHC test on the tumor sample from the subject is BCL6+ as indicated by a percent nuclear positivity score for BCL6 expression of greater than or equal to 20% in the IHC test.

[0737] Embodiment 80. The method of Embodiment 75, wherein the IHC test on the tumor sample from the subject is BCL6+ as indicated by a percent nuclear positivity score for BCL6 expression of greater than or equal to 30% in the IHC test.

[0738] Embodiment 81. The method of any one of Embodiments 55-80, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0739] Embodiment 82. The method of Embodiment 81, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0740] Embodiment 83. The method of Embodiment 81, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

[0741] Embodiment 84. A method for treating a cutaneous T cell lymphoma in a subject in need thereof, the method comprising:

[0742] (a) administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and

[0743] (b) monitoring the subject for the development of a second primary malignancy.

[0744] Embodiment 85. The method of Embodiment 84, wherein the second primary malignancy is myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or T cell lymphoblastic leukemia (T-LBL).

[0745] P02 Embodiments Docket No. TRLN-019-010W01 / TLS-066WO

[0746] Embodiment 1. A method for treating a relapsed or refractory nodal Tfh cell lymphoma in a subject in need thereof, the method comprising i) determining that the subject has a relapsed or refractory nodal Tfh cell lymphoma; and ii) based on i), administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the relapsed or refractory nodal Tfh cell lymphoma is selected from the group consisting of: nodal Tfh cell lymphoma, follicular-type, and nodal Tfh cell lymphoma, NOS.

[0747] Embodiment 2. The method of Embodiment 1, wherein the relapsed or refractory nodal Tfh cell lymphoma is BCL6 positive (BCL6+).

[0748] Embodiment 3. The method of Embodiment 1 or 2, wherein the relapsed or refractory nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

[0749] Embodiment 4. The method of Embodiment 1 or 2, wherein the relapsed or refractory nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0750] Embodiment 5. A method for treating a relapsed or refractory BCL6+ nodal Tfh cell lymphoma in a subject in need thereof, the method comprising i) determining that the subject has a relapsed or refractory BCL6+ nodal Tfh cell lymphoma; and ii) based on i), administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0751] Embodiment 6. The method of Embodiment 5, wherein the relapsed or refractory BCL6+ nodal Tfh cell lymphoma is selected from the group consisting of: nodal Tfh cell lymphoma, angioimmunoblastic-type (AITL); nodal Tfh cell lymphoma, follicular-type, and nodal Tfh cell lymphoma, NOS.

[0752] Embodiment 7. The method of Embodiment 5 or 6, wherein the relapsed or refractory BCL6+ nodal Tfh cell lymphoma is AITL.

[0753] Embodiment 8. The method of Embodiment 5 or 6, wherein the relapsed or refractory BCL6+ nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

[0754] Embodiment 9. The method of Embodiment 5 or 6, wherein the relapsed or refractory BCL6+ nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0755] Embodiment 10. The method of any one of Embodiments 5-9, wherein determining that the subject has a relapsed or refractory BCL6+ nodal Tfh cell lymphoma comprises evaluating a percent nuclear positivity for BCL6 in a sample from the subject by an IHC test.

[0756] Embodiment 11. The method of Embodiment 10, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 25% for the nodal Tfh cell lymphoma.

[0757] Embodiment 12. The method of Embodiment 11, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 30% for the nodal Tfh cell lymphoma. Docket No. TRLN-019-010W01 / TLS-066WO

[0758] Embodiment 13. A method for treating a relapsed or refractory BCL6+ PTCL in a subject in need thereof, the method comprising i) determining that the subject has a relapsed or refractory BCL6+ PTCL; and ii) based on i), administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0759] Embodiment 14. The method of Embodiment 13, wherein the relapsed or refractory BCL6+ PTCL is selected from the group consisting of: nodal Tfh cell lymphoma; PTCL-NOS; ALK-positive anaplastic large-cell lymphoma; and ALK-negative anaplastic large-cell lymphoma.

[0760] Embodiment 15. The method of Embodiment 14, wherein the relapsed or refractory BCL6+ PTCL is a nodal Tfh cell lymphoma.

[0761] Embodiment 16. The method of Embodiment 15, wherein the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular- type; and nodal Tfh cell lymphoma, NOS.

[0762] Embodiment 17. The method of Embodiment 16, wherein the nodal Tfh cell lymphoma is AITL.

[0763] Embodiment 18. The method of Embodiment 16, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

[0764] Embodiment 19. The method of Embodiment 16, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0765] Embodiment 20. The method of any one of Embodiments 13-19, wherein determining that the subject has a relapsed or refractory BCL6+ PTCL comprises identifying that an IHC test on a sample of the relapsed or refractory PTCL exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 20%.

[0766] Embodiment 21. The method of Embodiment 20, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 25% for the PTCL.

[0767] Embodiment 22. The method of Embodiment 21, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 30% for the PTCL.

[0768] Embodiment 23. The method of any one of Embodiments 1-22, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0769] Embodiment 24. The method of Embodiment 23, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0770] Embodiment 25. The method of Embodiment 23, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 300 mg twice per day.

[0771] Embodiment 26. The method of Embodiment 23, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day. Docket No. TRLN-019-010W01 / TLS-066WO

[0772] Embodiment 27. The method of any one of Embodiments 1-26, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy.

[0773] Embodiment 28. The method of any one of Embodiments 1-26, comprising administering an additional therapy or therapeutic agent to the subject.

[0774] Embodiment 29. The method of Embodiment 28, wherein the additional therapy or therapeutic agent is an ALK inhibitor or degrader, a dihydrofolate reductase (DHFR) inhibitor or degrader, an epigenetic modifier (e.g., a histone deacetylase (HDAC) inhibitor or degrader or a BCL6 inhibitor or degrader), a retinoid, anti-CD30 therapy, anti-C-C motif chemokine receptor 4 (CCR4) therapy, chemotherapy, or a combination thereof.

[0775] Embodiment 30. A method for treating a cutaneous T cell lymphoma (CTCL) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0776] Embodiment 31. The method of Embodiment 30, wherein the CTCL is selected from the group consisting of primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, primary cutaneous acral CD8-positive 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, primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma, and primary cutaneous peripheral T-cell lymphoma NOS.

[0777] Embodiment 32. The method of Embodiment 30 or 31, wherein the CTCL is mycosis fungoides.

[0778] Embodiment 33. The method of Embodiment 30 or 31, wherein the CTCL is Sezary syndrome.

[0779] Embodiment 34. The method of Embodiment 30 or 31, wherein the CTCL is primary cutaneous gamma-delta T-cell lymphoma.

[0780] Embodiment 35. The method of Embodiment 30 or 31, wherein the CTCL is primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma.

[0781] Embodiment 36. The method of Embodiment 30 or 31, wherein the CTCL is primary cutaneous peripheral T-cell lymphoma NOS.

[0782] Embodiment 37. The method of any one of Embodiments 30-36, wherein the CTCL is BCL6 positive (BCL6+). Docket No. TRLN-019-010W01 / TLS-066WO

[0783] Embodiment 38. A method for treating a BCL6+ CTCL in a subject, the method comprising i) determining that the subject has a BCL6+ CTCL; and ii) based on i), administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

[0784] Embodiment 39. The method of Embodiment 38, wherein the BCL6+ CTCL is selected from the group consisting of primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, primary cutaneous acral CD8-positive 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, primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma, and primary cutaneous peripheral T-cell lymphoma NOS.

[0785] Embodiment 40. The method of Embodiment 38 or 39, wherein the BCL6+ CTCL is mycosis fungoides.

[0786] Embodiment 41. The method of Embodiment 38 or 39, wherein the BCL6+ CTCL is

[0787] Sezary syndrome.

[0788] Embodiment 42. The method of Embodiment 38 or 39, wherein the BCL6+ CTCL is primary cutaneous gamma-delta T-cell lymphoma.

[0789] Embodiment 43. The method of Embodiment 38 or 39, wherein the BCL6+ CTCL is primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma.

[0790] Embodiment 44. The method of Embodiment 38 or 39, wherein the CTCL is primary cutaneous peripheral T-cell lymphoma NOS.

[0791] Embodiment 45. The method of any one of Embodiments 38-44, wherein determining that the subject has a BCL6+ CTCL comprises evaluating a percent nuclear positivity for BCL6 in a sample from the subject by H4C.

[0792] Embodiment 46. The method of Embodiment 45, wherein the H4C test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 25% for the CTCL.

[0793] Embodiment 47. The method of Embodiment 46, wherein the H4C test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 30% for the CTCL.

[0794] Embodiment 48. The method of any one of Embodiments 30-47, wherein Compound

[0795] A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0796] Embodiment 49. The method of Embodiment 48, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day. Docket No. TRLN-019-010W01 / TLS-066WO

[0797] Embodiment 50. The method of Embodiment 48, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 300 mg twice per day.

[0798] Embodiment 51. The method of Embodiment 48, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

[0799] Embodiment 52. The method of any one of Embodiments 30-51, wherein Compound

[0800] A, or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy.

[0801] Embodiment 53. The method of any one of Embodiments 30-52, comprising administering an additional therapy or therapeutic agent to the subject.

[0802] Embodiment 54. The method of Embodiment 53, wherein the additional therapy or therapeutic agent is an ALK inhibitor or degrader, a dihydrofolate reductase (DHFR) inhibitor or degrader, an epigenetic modifier (e.g., a histone deacetylase (HDAC) inhibitor or degrader or a BCL6 inhibitor or degrader), a retinoid, anti-CD30 therapy, anti-C-C motif chemokine receptor 4 (CCR4) therapy, chemotherapy, or a combination thereof

[0803] Embodiment 55. A method for treating a BCL6+ peripheral T-cell lymphoma (PTCL) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment- naive.

[0804] Embodiment 56. The method of Embodiment 55, wherein the BCL6+ PTCL is selected from the group consisting of: nodal Tfh cell lymphoma; PTCL-NOS; ALK-positive anaplastic large-cell lymphoma; and ALK-negative anaplastic large-cell lymphoma.

[0805] Embodiment 57. The method of Embodiment 55 or 56, wherein the BCL6+ PTCL is a nodal Tfh cell lymphoma.

[0806] Embodiment 58. The method of Embodiment 57, wherein the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular- type; and nodal Tfh cell lymphoma, NOS.

[0807] Embodiment 59. The method of Embodiment 58, wherein the nodal Tfh cell lymphoma is AITL.

[0808] Embodiment 60. The method of Embodiment 58, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

[0809] Embodiment 61. The method of Embodiment 58, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0810] Embodiment 62. A method for treating a BCL6+ peripheral T-cell lymphoma (PTCL) in a subject in need thereof, the method comprising i) determining that the subject has a BCL6+ PTCL; and ii) based on i), administering to the subject a therapeutically effective amount of a Docket No. TRLN-019-010W01 / TLS-066WO compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment-naive.

[0811] Embodiment 63. The method of Embodiment 62, wherein the BCL6+ PTCL is selected from the group consisting of: a nodal Tfh cell lymphoma; PTCL-NOS; ALK-positive anaplastic large-cell lymphoma; and ALK-negative anaplastic large-cell lymphoma.

[0812] Embodiment 64. The method of Embodiment 62 or 63, wherein the BCL6+ PTCL is a nodal Tfh cell lymphoma.

[0813] Embodiment 65. The method of Embodiment 64, wherein the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular- type; and nodal Tfh cell lymphoma, NOS.

[0814] Embodiment 66. The method of Embodiment 65, wherein the nodal Tfh cell lymphoma is AITL.

[0815] Embodiment 67. The method of Embodiment 65, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

[0816] Embodiment 68. The method of Embodiment 65, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0817] Embodiment 69. The method of any one of Embodiments 62-68, wherein determining that the subj ect has a BCL6+ PTCL comprises identifying that an IHC test on a sample of the PTCL exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 20%.

[0818] Embodiment 70. The method of Embodiment 69, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 25% for the PTCL.

[0819] Embodiment 71. The method of Embodiment 70, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 30% for the PTCL.

[0820] Embodiment 72. A method for treating a nodal Tfh cell lymphoma in a subject in need thereof, the method comprising administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; wherein the subject is treatment- naive.

[0821] Embodiment 73. The method of Embodiment 72, wherein the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular- type, and nodal Tfh cell lymphoma, NOS.

[0822] Embodiment 74. The method of Embodiment 72 or 73, wherein the nodal Tfh cell lymphoma AITL.

[0823] Embodiment 75. The method of Embodiment 72 or 73, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type. Docket No. TRLN-019-010W01 / TLS-066WO

[0824] Embodiment 76. The method of Embodiment 72 or 73, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0825] Embodiment 77. The method of any one of Embodiments 72-76, wherein the nodal Tfh cell lymphoma is BCL6 positive (BCL6+).

[0826] Embodiment 78. A method for treating a BCL6+ nodal Tfh cell lymphoma in a subject in need thereof, the method comprising i) determining that the subject has a BCL6+ nodal Tfh cell lymphoma; and ii) based on i), administering to the subject a therapeutically effective amount of a compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment-naive.

[0827] Embodiment 79. The method of Embodiment 78, wherein the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular- type; and nodal Tfh cell lymphoma, NOS.

[0828] Embodiment 80. The method of Embodiment 79, wherein the nodal Tfh cell lymphoma is AITL.

[0829] Embodiment 81. The method of Embodiment 79, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

[0830] Embodiment 82. The method of Embodiment 79, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0831] Embodiment 83. The method of any one of Embodiments 78-82, wherein determining that the subject has a BCL6+ nodal Tfh cell lymphoma comprises identifying that an IHC test on a sample of the nodal Tfh cell lymphoma exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 20%.

[0832] Embodiment 84. The method of Embodiment 83, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 25% for the nodal Tfh cell lymphoma.

[0833] Embodiment 85. The method of Embodiment 84, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 30% for the nodal Tfh cell lymphoma.

[0834] Embodiment 86. The method of any one of Embodiments 55-85, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0835] Embodiment 87. The method of Embodiment 86, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0836] Embodiment 88. The method of Embodiment 86, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 300 mg twice per day. Docket No. TRLN-019-010W01 / TLS-066WO

[0837] Embodiment 89. The method of Embodiment 86, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

[0838] Exemplary Embodiment Set A

[0839] Embodiment 1. Compound A, or a pharmaceutically acceptable salt thereof, for use in treating a relapsed or refractory nodal Tfh cell lymphoma in a subject in need thereof, wherein the relapsed or refractory nodal Tfh cell lymphoma is selected from the group consisting of: nodal Tfh cell lymphoma, follicular-type, and nodal Tfh cell lymphoma, NOS.

[0840] Embodiment 2. The compound for use of Embodiment 1, wherein the relapsed or refractory nodal Tfh cell lymphoma is BCL6 positive (BCL6+).

[0841] Embodiment 3. The compound for use of Embodiment 1, wherein the relapsed or refractory nodal Tfh cell lymphoma has a percent nuclear positivity score for BCL6 of 1% to 29% by IHC.

[0842] Embodiment 4. The compound for use of Embodiment 1, wherein the relapsed or refractory nodal Tfh cell lymphoma has a percent nuclear positivity score for BCL6 of 30% to 100% by IHC.

[0843] Embodiment 5. The compound for use of Embodiment 1, wherein the relapsed or refractory nodal Tfh cell lymphoma has a percent nuclear positivity score for BCL6 of 0% by IHC.

[0844] Embodiment 6. The compound for use of any one of Embodiments 1-5, wherein the relapsed or refractory nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

[0845] Embodiment 7. The compound for use of any one of Embodiments 1-5, wherein the relapsed or refractory nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0846] Embodiment s. The compound for use of any one of Embodiments 1-7, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0847] Embodiment 9. The compound for use of Embodiment 8, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0848] Embodiment 10. The compound for use of Embodiment 8, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 300 mg twice per day.

[0849] Embodiment 11. The compound for use of Embodiment 8, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day. Docket No. TRLN-019-010W01 / TLS-066WO

[0850] Exemplary Embodiments Set B

[0851] Embodiment 1. Compound A, or a pharmaceutically acceptable salt thereof, for use in treating a relapsed or refractory BCL6+ PTCL in a subject in need thereof, wherein the use is predicated upon determining that the subject has a relapsed or refractory BCL6+ PTCL.

[0852] Embodiment 2. The compound for use of Embodiment 1, wherein determining that the subject has a relapsed or refractory BCL6+ PTCL comprises evaluating a percent nuclear positivity for BCL6 in a sample from the subject by IHC.

[0853] Embodiment 3. The compound for use of Embodiment 2, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of:

[0854] (a) greater than or equal to 1% for the PTCL;

[0855] (b) greater than or equal to 20% for the PTCL;

[0856] (c) greater than or equal to 25% for the PTCL; or

[0857] (d) greater than or equal to 30% for the PTCL.

[0858] Embodiment 4. Compound A, or a pharmaceutically acceptable salt thereof for use in treating a relapsed or refractory PTCL in a subject identified as having a relapsed or refractory BCL6+ PTCL.

[0859] Embodiment 5. The compound for use of any one of Embodiments 1-4, wherein the relapsed or refractory BCL6+ PTCL is selected from the group consisting of: nodal Tfh cell lymphoma; PTCL-NOS; ALK-positive anaplastic large-cell lymphoma; and ALK-negative anaplastic large-cell lymphoma.

[0860] Embodiment 6. The compound for use of Embodiment 5, wherein the relapsed or refractory BCL6+ PTCL is a nodal Tfh cell lymphoma.

[0861] Embodiment 7. The compound for use of Embodiment 6, wherein the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular- type; and nodal Tfh cell lymphoma, NOS.

[0862] Embodiment 8. The compound for use of Embodiment 7, wherein the nodal Tfh cell lymphoma is AITL.

[0863] Embodiment 9. The compound for use of Embodiment 7, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

[0864] Embodiment 10. The compound for use of Embodiment 7, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0865] Embodiment 11. The compound for use of any one of Embodiments 1-10, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day. Docket No. TRLN-019-010W01 / TLS-066WO

[0866] Embodiment 12. The compound for use of Embodiment 11, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0867] Embodiment 13. The compound for use of Embodiment 11, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 300 mg twice per day.

[0868] Embodiment 14. The compound for use of Embodiment 11, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

[0869] Embodiment 15. The compound for use of any one of Embodiments 1-14, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy.

[0870] Embodiment 16. The compound for use of any one of Embodiments 1-15, comprising administering an additional therapy or therapeutic agent to the subject.

[0871] Embodiment 17. The compound for use of Embodiment 16, wherein the additional therapy or therapeutic agent is an ALK inhibitor or degrader, a dihydrofolate reductase (DHFR) inhibitor or degrader, an epigenetic modifier (e.g., a histone deacetylase (HDAC) inhibitor or degrader or a BCL6 inhibitor or degrader), a retinoid, anti-CD30 therapy, anti-C-C motif chemokine receptor 4 (CCR4) therapy, chemotherapy, or a combination thereof.

[0872] Exemplary Embodiments Set C

[0873] Embodiment 1. Compound A, or a pharmaceutically acceptable salt thereof, for use in treating a cutaneous T cell lymphoma (CTCL) in a subject in need thereof.

[0874] Embodiment 2. The compound for use of Embodiment 1, wherein the CTCL is selected from the group consisting of primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, primary cutaneous acral CD8-positive 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, primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma, and primary cutaneous peripheral T-cell lymphoma NOS.

[0875] Embodiment 3. The compound for use of Embodiment 1 or 2, wherein the CTCL is mycosis fungoides.

[0876] Embodiment 4. The compound for use of Embodiment 1 or 2, wherein the CTCL is

[0877] Sezary syndrome.

[0878] Embodiment 5. The compound for use of Embodiment 1 or 2, wherein the CTCL is primary cutaneous gamma-delta T-cell lymphoma. Docket No. TRLN-019-010W01 / TLS-066WO

[0879] Embodiment 6. The compound for use of Embodiment 1 or 2, wherein the CTCL is primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma.

[0880] Embodiment 7. The compound for use of Embodiment 1 or 2, wherein the CTCL is primary cutaneous peripheral T-cell lymphoma NOS.

[0881] Embodiment 8. The compound for use of any one of Embodiments 1-7, wherein the CTCL is BCL6 positive (BCL6+).

[0882] Embodiment 9. The compound for use of any one of Embodiments 1-7, wherein the CTCL has a percent nuclear positivity score for BCL6 of 1% to 29% by IHC.

[0883] Embodiment 10. The compound for use of any one of Embodiments 1-7, wherein the CTCL has a percent nuclear positivity score for BCL6 of 30% to 100% by IHC.

[0884] Embodiment 11. The compound for use of any one of Embodiments 1-7, wherein the CTCL has a percent nuclear positivity score for BCL6 of 0% by IHC.

[0885] Embodiment 12. The compound for use of any one of Embodiments 1-7, wherein the use is predicated upon determining that the subject has a CTCL that is BCL6 positive (BCL6+).

[0886] Embodiment 13. The compound for use of Embodiment 12, wherein determining that the subject has a BCL6+ CTCL comprises evaluating a percent nuclear positivity for BCL6 in a sample from the subject by IHC.

[0887] Embodiment 14. The compound for use of Embodiment 13 wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of:

[0888] (a) greater than or equal to 1% for the CTCL;

[0889] (b) greater than or equal to 20% for the CTCL;

[0890] (c) greater than or equal to 25% for the CTCL; or

[0891] (d) greater than or equal to 30% for the CTCL.

[0892] Embodiment 15. The compound for use of any one of Embodiments 1-14, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0893] Embodiment 16. The compound for use of Embodiment 15, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0894] Embodiment 17. The compound for use of Embodiment 15, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 300 mg twice per day.

[0895] Embodiment 18. The compound for use of Embodiment 15, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

[0896] Embodiment 19. The compound for use of any one of Embodiments 1-18, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy. Docket No. TRLN-019-010W01 / TLS-066WO

[0897] Embodiment 20. The compound for use of any one of Embodiments 1-19, wherein the subject does not receive an immune checkpoint inhibitor or a multikinase inhibitor.

[0898] Exemplary Embodiments Set D

[0899] Embodiment 1. Compound A for use for treating a BCL6+ peripheral T-cell lymphoma (PTCL) in a subject in need thereof, in combination with CHOP or CHOEP; wherein the subject is treatment-naive.

[0900] Embodiment 2. The compound for use of Embodiment 1, wherein the BCL6+ PTCL is selected from the group consisting of: nodal Tfh cell lymphoma; PTCL-NOS; ALK-positive anaplastic large-cell lymphoma; and ALK-negative anaplastic large-cell lymphoma.

[0901] Embodiment 3. The compound for use of Embodiment 1 or 2, wherein the BCL6+ PTCL is a nodal Tfh cell lymphoma.

[0902] Embodiment 4. The compound for use of Embodiment 3, wherein the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular- type; and nodal Tfh cell lymphoma, NOS.

[0903] Embodiment 5. The compound for use of Embodiment 4, wherein the nodal Tfh cell lymphoma is AITL.

[0904] Embodiment 6. The compound for use of Embodiment 4, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

[0905] Embodiment 7. The compound for use of Embodiment 4, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

[0906] Embodiment s. The compound for use of any one of Embodiments 1-7, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0907] Embodiment 9. The compound for use of Embodiment 8, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0908] Embodiment 10. The compound for use of Embodiment 9, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 300 mg twice per day.

[0909] Embodiment 11. The compound for use of Embodiment 10, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

[0910] Exemplary Embodiments Set E

[0911] Embodiment 1. Compound A, or a pharmaceutically acceptable salt thereof, for use in treating a BCL6+ peripheral T-cell lymphoma (PTCL) in a subject in need thereof, wherein the Docket No. TRLN-019-010W01 / TLS-066WO use is predicated upon determining that the subject has a BCL6+ PTCL, in combination with CHOP or CHOEP; wherein the subject is treatment-naive.

[0912] Embodiment 2. The compound for use of Embodiment 1, wherein determining that the subject has a BCL6+ PTCL comprises evaluating a percent nuclear positivity for BCL6 in a sample from the subject by IHC.

[0913] Embodiment 3. The compound for use of Embodiment 2, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of:

[0914] (a) greater than or equal to 1% for the PTCL;

[0915] (b) greater than or equal to 20% for the PTCL;

[0916] (c) greater than or equal to 25% for the PTCL; or

[0917] (d) greater than or equal to 30% for the PTCL.

[0918] Embodiment 4. Compound A, or a pharmaceutically acceptable salt thereof, for use in treating a peripheral T-cell lymphoma (PTCL) in a subject in a subject identifies as having a BCL6+ PTCL, in combination with CHOP or CHOEP; wherein the subject is treatment-naive

[0919] Embodiment s. The compound for use of any one of Embodiments 1-4, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

[0920] Embodiment 6. The compound for use of Embodiment 5, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 250 mg twice per day.

[0921] Embodiment 7. The compound for use of Embodiment 6, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 300 mg twice per day.

[0922] Embodiment 8. The compound for use of Embodiment 7, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 350 mg twice per day.

Claims

Docket No. TRLN-019-010W01 / TLS-066WOWHAT IS CLAIMED IS:

1. A method for treating a relapsed or refractory nodal Tfh cell lymphoma in a subject in need thereof, the method comprising i) determining that the subject has a relapsed or refractory nodal Tfh cell lymphoma; and ii) based on i), administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, wherein the relapsed or refractory nodal Tfh cell lymphoma is selected from the group consisting of: nodal Tfh cell lymphoma, follicular-type, and nodal Tfh cell lymphoma, NOS.

2. The method of claim 1, wherein the relapsed or refractory nodal Tfh cell lymphoma is BCL6 positive (BCL6+).

3. The method of claim 1, wherein the relapsed or refractory nodal Tfh cell lymphoma has a percent nuclear positivity score for BCL6 of 1% to 29% by IHC.

4. The method of claim 1, wherein the relapsed or refractory nodal Tfh cell lymphoma has a percent nuclear positivity score for BCL6 of 30% to 100% by IHC.

5. The method of claim 1, wherein the relapsed or refractory nodal Tfh cell lymphoma has a percent nuclear positivity score for BCL6 of 0% by IHC.

6. A method for treating a relapsed or refractory BCL6+ PTCL in a subject in need thereof, the method comprising i) determining that the subject has a relapsed or refractory BCL6+ PTCL; and ii) based on i), administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

7. The method of claim 6, wherein the relapsed or refractory BCL6+ PTCL is selected from the group consisting of: nodal Tfh cell lymphoma; PTCL-NOS; ALK-positive anaplastic large-cell lymphoma; and ALK-negative anaplastic large-cell lymphoma.

8. The method of claim 7, wherein the relapsed or refractory BCL6+ PTCL is a nodal Tfh cell lymphoma.

9. The method of claim 8, wherein the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular-type; and nodal Tfh cell lymphoma, NOS.

10. The method of claim 9, wherein the nodal Tfh cell lymphoma is AITL.

11. The method of claim 9, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

12. The method of claim 9, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.Docket No. TRLN-019-010W01 / TLS-066WO13. The method of any one of claims 6-12, wherein determining that the subject has a relapsed or refractory BCL6+ PTCL comprises identifying that an IHC test on a sample of the relapsed or refractory PTCL exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 1%.

14. The method of claim 13, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 20% for the PTCL.

15. The method of claim 14, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 30% for the PTCL.

16. The method of any one of claims 1-15, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

17. The method of claim 16, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of:(a) 250 mg twice per day;(b) 300 mg twice per day; or(c) 350 mg twice per day.

18. The method of any one of claims 1-17, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy.

19. A method for treating a cutaneous T cell lymphoma (CTCL) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein the CTCL is selected from the group consisting of primary cutaneous CD4-positive small or medium T-cell lymphoproliferative disorder, primary cutaneous acral CD8-positive 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, primary cutaneous CD8-positive aggressive epiderm otropic cytotoxic T-cell lymphoma, and primary cutaneous peripheral T-cell lymphoma NOS.

21. The method of claim 19 or 20, wherein the CTCL is mycosis fungoides.

22. The method of claim 19 or 20, wherein the CTCL is Sezary syndrome.

23. The method of claim 19 or 20, wherein the CTCL is primary cutaneous gammadelta T-cell lymphoma.Docket No. TRLN-019-010W01 / TLS-066WO24. The method of claim 19 or 20, wherein the CTCL is primary cutaneous CD8- positive aggressive epidermotropic cytotoxic T-cell lymphoma.

25. The method of claim 19 or 20, wherein the CTCL is primary cutaneous peripheral T-cell lymphoma NOS.

26. The method of any one of claims 19-25, wherein the CTCL is BCL6 positive (BCL6+).

27. The method of any one of claims 19-25, wherein the CTCL has a percent nuclear positivity score for BCL6 of 1% to 29% by IHC.

28. The method of any one of claims 19-25, wherein the CTCL has a percent nuclear positivity score for BCL6 of 30% to 100% by IHC.

29. The method of any one of claims 19-25, wherein the CTCL has a percent nuclear positivity score for BCL6 of 0% by IHC.

30. A method for treating a BCL6+ CTCL in a subject, the method comprising i) determining that the subject has a BCL6+ CTCL; and ii) based on i), administering a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein determining that the subject has a BCL6+ CTCL comprises evaluating a percent nuclear positivity for BCL6 in a sample from the subject by IHC.

32. The method of claim 31, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 1% for the CTCL.

33. The method of claim 32, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 20% for the CTCL.

34. The method of claim 33, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 30% for the CTCL.

35. The method of any one of claims 19-35, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

36. The method of claim 35, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of:(a) 250 mg twice per day;(b) 300 mg twice per day; or(c) 350 mg twice per day.

37. The method of any one of claims 19-36, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered to the subject as a monotherapy.Docket No. TRLN-019-010W01 / TLS-066WO38. A method for treating a BCL6+ peripheral T-cell lymphoma (PTCL) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment-naive.

39. The method of claim 38, wherein the BCL6+ PTCL is selected from the group consisting of: nodal Tfh cell lymphoma; PTCL-NOS; ALK-positive anaplastic large-cell lymphoma; and ALK-negative anaplastic large-cell lymphoma.

40. The method of claim 38 or 39, wherein the BCL6+ PTCL is a nodal Tfh cell lymphoma.

41. The method of claim 40, wherein the nodal Tfh cell lymphoma is selected from the group consisting of: AITL; nodal Tfh cell lymphoma, follicular-type; and nodal Tfh cell lymphoma, NOS.

42. The method of claim 41, wherein the nodal Tfh cell lymphoma is AITL.

43. The method of claim 41, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, follicular-type.

44. The method of claim 41, wherein the nodal Tfh cell lymphoma is nodal Tfh cell lymphoma, NOS.

45. A method for treating a BCL6+ peripheral T-cell lymphoma (PTCL) in a subject in need thereof, the method comprising i) determining that the subject has a BCL6+ PTCL; and ii) based on i), administering to the subject a therapeutically effective amount of a compound of Compound A, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of CHOP or CHOEP; wherein the subject is treatment-naive.

46. The method of claim 45, wherein determining that the subject has a BCL6+ PTCL comprises identifying that an IHC test on a sample of the PTCL exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 1%.

47. The method of claim 46, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 20% for the PTCL.

48. The method of claim 47, wherein the IHC test exhibits a percent nuclear positivity score for BCL6 of greater than or equal to 30% for the PTCL.

49. The method of any one of claims 38-48, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, or 400 mg twice per day.

50. The method of claim 49, wherein Compound A, or a pharmaceutically acceptable salt thereof, is administered at a dose of:Docket No. TRLN-019-010W01 / TLS-066WO(a) 250 mg twice per day;(b) 300 mg twice per day; or(c) 350 mg twice per day.

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