Methods of treatment using an EZH2 modulator

Abstract

This disclosure provides methods of treatment comprising an EZH2 modulator (e.g., tazmetostat). In some embodiments, provided methods of treatment comprise a combination therapy comprising an EZH2 modulator (e.g., tazmetostat) and an additional therapeutic agent.

Description

METHODS OF TREATMENT USING AN EZH2 MODULATORRELATED APPLICATIONS

[0001] This application claims priority to and benefit of PCT Application No. PCT / CN2024 / 076295, filed February 6, 2024, and PCT Application No. PCT / CN2024 / 095035, filed May 23, 2024. the entire contents of each of which are hereby incorporated by reference.TECHNICAL FIELD

[0002] The present disclosure relates to methods of treatment comprising administration of an enhancer-of-zeste-homolog-2 (EZH2) modulator. In some embodiments, the present disclosure relates to combination therapies comprising an EZH2 modulator and one or more additional therapeutic agents.BACKGROUND

[0003] EZH2, a histone methyltransferase, has been associated with various cancers and poor clinical outcomes. For example, EZH2 has been implicated in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), which accounted for approximately 17% and 32%, respectively, of new cases of nonHodgkin’s lymphoma worldwide in 2020. Dysregulation of EZH2 has also been observed in the five most common solid tumors (breast, lung, colorectum, prostate, and stomach).SUMMARY

[0004] Tire present disclosure provides methods of treating a disease or disorder characterized by aberrant, misregulated, or increased EZH2 activity and / or expression (e.g., a cancer) comprising administering to a patient in need thereof a therapeutically effective amount of tazemetostat, or a pharmacally acceptable salt thereof, in combination with one or more additional therapeutic agents. In some embodiments, the present disclosure provides methods of treating a hematological malignancy. In some embodiments, the present disclosure provides methods of treating a solid tumor. In some embodiments, the present disclosure provides methods of treating a cancer selected from lymphoma (e.g., human B cell lymphoma such as diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, or human T cell lymphoma such as peripheral T-cell lymphoma), lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), prostate cancer, and ovarian cancer.

[0005] The present disclosure encompasses the recognition that a combination of certain agents can be beneficial in the treatment of a disease or disorder characterized by aberrant, misregulated, or increased EZH2 activity and / or expression (e.g., a cancer). In some embodiments, a combination of certain agents (e.g., an EZH2 inhibitor and one or more additional therapeutic agents) demonstrates synergy for treating a disease or disorder associated with EZH2 (e.g., a cancer).

[0006] In some embodiments, the present disclosure provides methods of treating a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of tazemetostat, or a pharmaceutically acceptable salt thereof, in combination with amdizalisib (HMPL-689), or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides methods of treating a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of tazemetostat, or a pharmaceutically acceptable salt thereof, in combination with surufatinib, or a pharmaceutically acceptable salt thereof.BRIEF DESCRIPTION OF THE FIGURES

[0007] FIG. 1A is a graph showing the results of an in vitro study of tazemetostat in combination with amdizalisib in a Karpas-422 cell line.

[0008] FIG. IB is a graph showing the results of an in vitro study of tazemetostat in combination with amdizalisib in a Farage cell line.

[0009] FIG. 2 is a graph showing mean tumor volume in a SU-DHL-6 subcutaneous xenograft model following treatment with tazemetostat in combination with amdizalisib.

[0010] FIG. 3 is a Kaplan Meier survival curve of tazemetostat in combination with surufatinib in a human A2780 xenograft tumor model.

[0011] FIG. 4 is a swimming plot of enrolled patients.

[0012] FIG. 5 is a waterfall plot showing the best change in tumor size of target lesions, assessed by investigator. SPD=sum of products of perpendicular diameters.

[0013] FIG. 6 is a graph showing mean concentrations of amdizalisib and tazemetostat in the 20 mg and 30 mg cohorts.DETAILED DESCRIPTIONDefinitions

[0014] As used herein, the term “administering” or “administration” typically refers to administration of a composition to a patient to achieve delivery of an active agent to a site of interest (e.g.. a target site which may, in some embodiments, be a site of disease or damage, and / or a site of responsive processes, cells, tissues, etc.). As will be understood by those skilled in the art, reading the present disclosure, in some embodiments, one or more particular routes of administration may be feasible and / or useful in the practice of the present disclosure. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In someembodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing.

[0015] As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents) . In some embodiments, the tw o or more regimens may be administered simultaneously: in some embodiments, such regimens may be administered sequentially (e.g.. all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, administration of combination therapy may involve administration of one or more agent(s) to a subject receiving the other agent(s) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition.

[0016] As used herein, the term “patient,” means an animal, preferably a mammal, and most preferably a human.

[0017] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease, disorder, or condition or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0018] As used herein, the term “therapeutically effective amount” refers to an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response when administered as part of a therapeutic regimen. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder and / or condition. In some embodiments, a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver atherapeutically effective amount.

[0019] As used herein, the term “relapsed or refractory” or “R / R” disease, unless specified otherwise, is intended to refer to relapsed and / or refractory disease. ’’Refractory" disease refers to disease which either progressed during therapy, failed to achieve an objective response to prior therapy, or progressed within 6 months after completion of therapy. “Relapsed” disease refers to disease which previously responded to therapy but progressed more than 6 months after completion of therapy.Tazemetostat

[0020] Tazemetostat is an oral small molecule inhibitor of enhancer-of-zeste-homolog-2 (EZH2). EZH2 is a histone methyltransferase (EIMT) that is the catalytic subunit of the polyprotein EIMT complex, called Polycomb Inhibitory Complex 2 (PRC2), responsible for the mono-, di-, and tri-methylation of histone H3 lysine 27 (H3K27). Trimethylation of H3K27 leads to repression of important target gene sets such as differentiation markers, cell cycle regulators, and apoptotic machinery, leading to tumorigenesis. Tazemetostat has been approved in the United States for treatment of (i) adult and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection; (ii) adult patients with relapsed or refractory (R / R) follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation and who have received at least two prior systematic therapies; and (iii) adult patients with R / R FL who have no satisfactory alternative treatment options.

[0021] Tazemetostat has the following structure:

[0022] Tazemetostat is also known as N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-5- (ethyl(tetrahydro-2EI-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[l,l'-biphenyl]-3-carboxamide.

[0023] In some embodiments, tazemetostat is provided and / or utilized as a salt form (e.g., as a pharmaceutically acceptable salt form). In some embodiments, tazemetostat is provided and / or utilized as a 1: 1 hydrobromide salt form. Other pharmaceutically acceptable salts are known in the art. See, e.g., S. M. Berge ct al., J. Pharmaceutical Sciences, 1977, 66, 1-19.Amdizalisib (HMPL-689)

[0024] Amdizalisib (HMPL-689) is a highly potent and selective inhibitor of the pl 105 isoform of phosphatidylinositol 3-kinase (PI3K5), which exerts an anti -tumor effect by blocking the SYK-PI3K-AKT signalling pathway mediated by the B cell receptor in lymphoma cells. Amdizalisib has been the subject of three clinical studies in patients with R / R lymphoma, including R / R follicular lymphoma (FL), marginal zone lymphoma (MZL). and chronic large B-cell lymphoma (DLBCL).

[0025] Amdizalisib has the following structure:

[0026] Amdizalisib is also known as HMPL-689 or (S)-4-amino-6-((l-(3-chloro-6- phenylimidazo[l,2-b]pyridazin-7-yl)ethyl)amino)pyrimidine-5-carbonitrile.

[0027] In some embodiments, amdizalisib is provided and / or utilized as a salt form (e.g., as a pharmacally acceptable salt fonn). Pharmaceutically acceptable salts are known in the art. See, e.g., S. M. Berge et al.. J. Pharmaceutical Sciences. 1977, 66. 1-19.Surufatinib

[0028] Surufatinib is an oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor- 1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Surufatinib has been the subject of multiple clinical trials and is approved in China for treatment of pancreatic and extra-pancreatic neuroendocrine tumors (NETs).

[0029] Surufatinib has the following structure:

[0030] Surufatinib is also known as sulfatinib or N-(2-(dimethylamino)ethyl)-l-(3-((4-((2-methyl-lH- indol-5-yl)oxy)pyrimidin-2-yl)amino)phenyl)methanesulfonamide.

[0031] In some embodiments, surufatinib is provided and / or utilized as a salt form (e.g., as apharmaceutically acceptable salt form). Pharmaceutically acceptable salts are known in the art. See, e.g., S. M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.Description of Exemplary Methods and Uses

[0032] In some embodiments, the present disclosure provides methods of treating a disease or disorder characterized by aberrant, misregulated, or increased EZH2 activity and / or expression (e.g.. a cancer) comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising tazemetostat, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0033] In some embodiments, the present disclosure provides methods of treating a cancer associated with EZH2. In some embodiments, the present disclosure provides methods of treating a hematological malignancy. In some embodiments, the present disclosure provides methods of treating a solid tumor. In some embodiments, the present disclosure provides methods of treating a cancer selected from lymphoma (e.g., human B cell lymphoma such as diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, or human T cell lymphoma such as peripheral T-cell lymphoma), lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), prostate cancer, and ovarian cancer. In some embodiments, the present disclosure provides methods of treating human B cell lymphoma (e.g., follicular lymphoma or diffuse large B cell lymphoma). In some embodiments, the present disclosure provides methods of treating human T cell lymphoma (e.g., peripheral T-cell lymphoma). In some embodiments, the present disclosure provides methods of treating diffuse large B cell lymphoma (DLBCL), e.g., a Grade 3b DLBCL according to the World Health Organization classification of lymphoid neoplasms (as referenced in Swerdlow SH, et al. Blood 2016; 127:2375-90). In some embodiments, the present disclosure provides methods of treating follicular lymphoma (FL), e.g., a Grade l-3aFL or Grade 3b FL according to the World Health Organization classification of lymphoid neoplasms (as referenced in Swerdlow SH. et al. Blood 2016; 127:2375-90). In some embodiments, the present disclosure provides methods of treating mantle cell lymphoma (MCL). In some embodiments, the present disclosure provides methods of treating peripheral T-cell lymphoma (PTCL). In some embodiments, the present disclosure provides methods of treating lung cancer (e.g., small cell lung cancer or non-small cell lung cancer). In some embodiments, the present disclosure provides methods of treating prostate cancer. In some embodiments, the present disclosure provides methods of treating ovarian cancer. In some embodiments, the present disclosure provides methods of treating refractory or relapsed cancer. In some embodiments, the present disclosure provides methods of treating previously untreated cancer.

[0034] In some embodiments, provided methods comprise administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or apharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the present disclosure provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments, the present disclosure provides a method of treating lymphoma comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the lymphoma is previously untreated lymphoma. In some embodiments, the lymphoma is refractory or relapsed lymphoma.

[0037] In some embodiments, the present disclosure provides a method of treating relapsed or refractory (R / R) lymphoma comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has failed prior standard treatment. In some embodiments, the patient has had no standard treatment. In some embodiments, the patient had progressed on prior standard treatment. In some embodiments, the patient is refractory to prior standard treatment.

[0038] In some embodiments, the present disclosure provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the DLBCL is previously untreated DLBCL. In some embodiments, the DLBCL is refractory or relapsed DLBCL.

[0039] In some embodiments, the present disclosure provides a method of treating relapsed or refractory (R / R) diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is suffering from Grade 3b DLBCL. In some embodiments, the patient has undergone at least two prior lines of standard therapy (e.g., alkylator / anthracycline / anti-CD20-based therapy). In some embodiments, the patient is considered unable to benefit from intensive treatment with autologous hematopoietic stem cell transplantation (ASCT). In some embodiments, the patient is considered unable to benefit from intensive treatment with ASCT if the patient meets at least one of the criteria defined in Example 1 herein.

[0040] In some embodiments, the present disclosure provides a method of treating follicular lymphoma (FL) comprising administering to a patient in need thereof a therapeutically effective amount ofa combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the FL is previously untreated FL. In some embodiments, the FL is refractory or relapsed FL.

[0041] In some embodiments, the present disclosure provides a method of treating relapsed or refractory (R / R) follicular lymphoma (FL) comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient is suffering from Grade 3b FL. In some embodiments, the patient is suffering from Grade l-3a FL. In some embodiments, the patient has undergone at least two prior lines of standard therapy (e.g., alkylator / anthracycline / anti-CD20-based therapy). In some embodiments, the patient is considered unable to benefit from intensive treatment with autologous hematopoietic stem cell transplantation (ASCT). In some embodiments, tire patient is considered unable to benefit from intensive treatment with ASCT if the patient meets at least one of the criteria defined in Example 1 herein. In some embodiments, the patient has undergone at least two systemic prior therapies, including at least one anti- CD20-based regimen. In some embodiments, a patient has undergone one anti-CD20-based regimen.

[0042] In some embodiments, the present disclosure provides a method of treating mantle cell lymphoma (MCL) comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the MCL is previously untreated MCL. In some embodiments, the MCL is refractory or relapsed MCL.

[0043] In some embodiments, the present disclosure provides a method of treating relapsed or refractory (R / R) mantle cell lymphoma (MCL) comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has undergone one prior line of systemic standard chemotherapy containing a CD20 monoclonal antibody. In some embodiments, the patient has previously received a Bruton’s tyrosine kinase (BTK) inhibitor.

[0044] In some embodiments, the present disclosure provides a method of treating peripheral T-cell lymphoma (PTCL) comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the PTCL is previously untreated PTCL. In some embodiments, the PTCL is refractory or relapsed PTCL.

[0045] In some embodiments, the present disclosure provides a method of treating relapsed or refractory (R / R) peripheral T-cell lymphoma (PTCL) comprising administering to a patient in need thereofa therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has undergone at least one prior standard systemic therapy. In some embodiments, the patient has not undergone an effective standard therapy.

[0046] In some embodiments, a patient has a life expectancy of greater than or equal to 12 weeks. In some embodiments, a patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. In some embodiments, a patient exhibits adequate bone marrow function (e.g., an absolute neutrophil count > 1.5 x 109 / L, hemoglobin > 9.0 g / dL, and platelets > 75 x 109 / L). In some embodiments, a patient exhibits adequate renal function (e.g., creatinine clearance > 40 mL / min). In some embodiments, a patient exhibits adequate hepatic function (e.g., serum total bilirubin < 1.5 x upper limit of normal (ULN), except for unconjugated bilirubinemia of Gilbert's syndrome, and / or alkaline phosphatase (ALP, in the absence of bone disease), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN (< 5 x ULN if the subject has liver metastases).

[0047] In some embodiments, a patient has not previously received an EZH2 inhibitor. In some embodiments, a patient has not previously received a PI3K inhibitor. In some embodiments, a patient is not suffering brain metastases or leptomeningeal invasion. In some embodiments, a patient is not suffering from thrombocytopenia, neutropenia, or anemia of Grade >3 (per CTCAE 5.0 criteria). In some embodiments, a patient does not have any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS / AML / MPN) or any abnormalities associated with MDS (e.g., del 5q, chr 7 abn) or MPN (e.g., JAK2 V617F). In some embodiments, a patient does not have a history of T-cell lymphoblastic lymphoma (T-LBL) or T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, a patient is not taking strong or moderate inducers or strong inhibitors of cytochrome P450 3A4 (CYP3A42). In some embodiments, a patient is not suffering from toxicity from prior anticancer therapy which has not recovered to < Grade 1. In some embodiments, a patient has not been administered a cytotoxic chemotherapy in the last 21 days; a non-cytotoxic chemotherapeutic agent in the last 14 days; nitrosuria in the last 6 weeks; a monoclonal antibody in the last 28 days; local radiotherapy in the last 14 days; radioisotope therapy in the last 6 weeks; 50% pelvic or total body radiotherapy in the last 12 weeks; high-dose autologous stem cell transplantation in the last 60 days; or high-dose allogeneic stem cell transplantation in the last 90 days.

[0048] In some embodiments, provided methods comprise administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat. or a pharmaceutically acceptable salt thereof; and (ii) surufatinib, or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the present disclosure provides a method of treating small cell lung cancer comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat. or a pharmaceutically acceptable salt thereof; and (ii)surufatinib, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the present disclosure provides a method of treating non-small cell lung cancer comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) surufatinib, or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the present disclosure provides a method of treating prostate cancer comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) surufatinib, or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, the present disclosure provides a method of treating ovarian cancer comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising (i) tazemetostat. or a pharmaceutically acceptable salt thereof; and (ii) surufatinib. or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, provided combination therapies are administered according to a regimen demonstrated to achieve a particular effect. In some embodiments, certain parameters may be evaluated to determine if a particular effect is achieved. For example, certain measures of, e.g., objective response rate (ORR), complete response (CR) rate, disease control rate (DCR), duration of response (DOR), time to response (TTR), progression-free survival (PFS). treatment-emergent adverse events (TEAEs), peak concentration (Cmax), trough concentration (Cmm), time to peak concentration (Tmax), elimination half-life (ti / 2), area under the plasma concentration-time curve (AUCo-t), apparent clearance (CL / F), apparent volume of distribution (Vz / F) and accumulation ratio (AR), changes in plasma levels of cytokines and chemokines (such as CCL3, CCL17, CCL22, CXCL13, etc.), and changes in expression of H3K27me3 in blood samples can be obtained. Any one or more of parameters such as these may be useful for determining, e.g., efficacy, safety, and / or tolerability of a combination therapy provided herein (e.g., tazemetostat in combination with amdizalisib or surufatinib).

[0054] In some embodiments, the present disclosure encompasses the recognition that provided combination therapies can achieve a synergistic effect in the treatment of patients suffering from a disease or disorder associated with EZH2 (such as a cancer described herein). For example, in some embodiments, administration of provided combination therapies achieves a particular effect (e.g., efficacy, safety, and / or tolerability) that is better than that achieved with the administration of each component of the combination therapy alone. In some embodiments, administration of provided combination therapies achieves a particular effect (e.g., efficacy, safety; and / or tolerability) that is better than the additive effect achieved with administration of each component of the combination therapy alone.Dosing

[0055] In some embodiments, provided methods comprise administering to a patient in need thereof a therapeutically effective amount of tazemetostat, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0056] It will be appreciated that reference to an amount of a compound herein (e.g., tazemetostat) means the amount of that compound in free base form. Accordingly, a compound may be provided and / or utilized as, e.g., a salt form of the compound such that the amount of the salt (or other form) is an amount that corresponds to the “free base equivalent” of the compound.

[0057] In some embodiments, provided methods comprise administering to a patient in need thereof about 200 mg to about 800 mg tazemetostat, or a pharmaceutically acceptable salt thereof, twice daily (BID). In some embodiments, provided methods comprise administering to a patient in need thereof about 800 mg tazemetostat, or a pharmaceutically acceptable salt thereof, twice daily (BID). In some embodiments, provided methods comprise administering to a patient in need thereof about 600 mg tazemetostat, or a pharmaceutically acceptable salt thereof, twice daily (BID). In some embodiments, provided methods comprise administering to a patient in need thereof about 400 mg tazemetostat, or a pharmaceutically acceptable salt thereof, twice daily (BID). In some embodiments, provided methods comprise administering to a patient in need thereof about 200 mg tazemetostat, or a pharmaceutically acceptable salt thereof, twice daily (BID).

[0058] In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of tazemetostat, or a pharmaceutically acceptable salt thereof, of about 400 mg to about 1600 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of tazemetostat, or a pharmaceutically acceptable salt thereof, of about 1600 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of tazemetostat, or a pharmaceutically acceptable salt thereof, of about 1200 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of tazemetostat, or a pharmaceutically acceptable salt thereof, of about 800 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of tazemetostat, or a pharmaceutically acceptable salt thereof, of about 400 mg.

[0059] In some embodiments, tazemetostat is administered orally. In some embodiments, tazemetostat is administered with or without food.

[0060] In some embodiments, provided methods comprise administering to a patient in need thereof about 5 mg to about 40 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof about 5 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments,provided methods comprise administering to a patient in need thereof about 10 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof about 20 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof about 30 mg amdizalisib, or a pharmacally acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof about 40 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD).

[0061] In some embodiments, provided methods comprise administering to a patient in need thereof about 2.5 mg to about 10 mg amdizalisib, or a pharmaceutically acceptable salt thereof, twice daily (BID). In some embodiments, provided methods comprise administering to a patient in need thereof about 2.5 mg amdizalisib, or a pharmaceutically acceptable salt thereof, twice daily (BID). In some embodiments, provided methods comprise administering to a patient in need thereof about 5 mg amdizalisib, or a pharmaceutically acceptable salt thereof, twice daily (BID). In some embodiments, provided methods comprise administering to a patient in need thereof about 7.5 mg amdizalisib, or a pharmaceutically acceptable salt thereof, twice daily (BID). In some embodiments, provided methods comprise administering to a patient in need thereof about 10 mg amdizalisib. or a pharmacally acceptable salt thereof, twice daily (BID).

[0062] In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of amdizalisib, or a pharmaceutically acceptable salt thereof, of about 5 mg to about 40 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of amdizalisib, or a pharmaceutically acceptable salt thereof, of about 5 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of amdizalisib, or a pharmacally acceptable salt thereof, of about 10 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of amdizalisib. or a pharmacally acceptable salt thereof, of about 15 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of amdizalisib, or a pharmaceutically acceptable salt thereof, of about 20 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of amdizalisib. or a pharmacally acceptable salt thereof, of about 30 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of amdizalisib, or a pharmaceutically acceptable salt thereof, of about 40 mg.

[0063] In some embodiments, amdizalisib is administered orally.

[0064] In some embodiments, provided methods comprise administering to a patient in need thereof (i) about 200 mg to about 800 mg tazcmctostat, or a pharmaceutically acceptable salt thereof, twice daily (BID); and (ii) about 5 mg to about 40 mg amdizalisib, or a pharmaceutically acceptable salt thereof, oncedaily (QD) or about 2.5 mg to about 10 mg amdizalisib, or a pharmaceutically acceptable salt thereof, twice daily (BID). In some embodiments, provided methods comprise administering to a patient in need thereof (i) about 800 mg tazemetostat, or a pharmaceutically acceptable salt thereof, twice daily (BID); and (ii) about 20 mg to about 30 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof (i) about 800 mg tazemetostat, or a pharmaceutically acceptable salt thereof, twice daily (BID); and (ii) about 20 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof (i) about 800 mg tazemetostat, or a pharmaceutically acceptable salt thereof, twice daily (BID); and (ii) about 30 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, a first dose of tazemetostat is taken at approximately the same time as a dose of amdizalisib; and a second dose of tazemetostat is taken alone (e.g., approximately 12 hours after the first dose).

[0065] In some embodiments, provided methods comprise administering to a patient in need thereof about 50 mg to about 400 mg sumfatinib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof about 50 mg sumfatinib, or a pharmacally acceptable salt thereof, once daily (QD) . In some embodiments, provided methods comprise administering to a patient in need thereof about 100 mg sumfatinib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof about 200 mg sumfatinib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof about 250 mg sumfatinib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof about 300 mg sumfatinib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof about 350 mg sumfatinib, or a pharmaceutically acceptable salt thereof, once daily (QD). In some embodiments, provided methods comprise administering to a patient in need thereof about 400 mg sumfatinib, or a pharmaceutically acceptable salt thereof, once daily (QD).

[0066] In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of sumfatinib. or a pharmacally acceptable salt thereof, of about 50 mg to about 400 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of sumfatinib, or a pharmaceutically acceptable salt thereof, of about 50 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of sumfatinib, or a pharmaceutically acceptable salt thereof, of about 100 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of sumfatinib, or apharmaceutically acceptable salt thereof, of about 200 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of surufatinib, or a pharmaceutically acceptable salt thereof, of about 250 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of surufatinib, or a pharmaceutically acceptable salt thereof, of about 300 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of surufatinib, or a pharmaceutically acceptable salt thereof, of about 350 mg. In some embodiments, provided methods comprise administering to a patient in need thereof a total daily dose of surufatinib, or a pharmaceutically acceptable salt thereof, of about 400 mg.

[0067] In some embodiments, surufatinib is administered orally.

[0068] In some embodiments, provided methods comprise administering to a patient in need thereof (i) about 200 mg to about 800 mg tazemetostat. or a pharmacally acceptable salt thereof, twice daily (BID): and (ii) about 50 mg to about 400 mg surufatinib. or a pharmaceutically acceptable salt thereof, once daily (QD).

[0069] In some embodiments, a provided combination therapy is administered to a patient in need thereof according to a dosing regimen for a 28-day cycle. In some embodiments, a provided combination therapy is administered to a patient in need thereof according to a dosing regimen for two 28-day cycles. In some embodiments, a provided combination therapy is administered to a patient in need thereof according to a dosing regimen for three, four, five, or more 28-day cycles. In some embodiments, a 28-day cycle includes or is followed by a dose holiday for one or more of the agents comprising the combination therapy. As used herein, a “dose holiday” refers to a period of time wherein the agent is not administered to the patient. In some embodiments, a 28-day cycle includes a dose holiday (e.g., an agent is administered for three weeks, followed by a one-week dose holiday). In some embodiments, a 28-day cycle is followed by a dose holiday (e.g., an agent is administered for four weeks, followed by a one-week dose holiday). In some embodiments, a provided combination therapy is administered to a patient in need thereof according to a dosing regimen until symptoms of disease are no longer measurable. In some embodiments, a provided combination therapy is administered to a patient in need thereof according to a dosing regimen for the duration of the patient’s life.Unit Dosage Forms

[0070] In some embodiments, provided combination therapies are administered as one or more unit dosage forms. As used herein, a “unit dosage form” refers to a physically discrete unit of an active agent (e.g., a therapeutic agent) for administration to a patient. Typically, each such unit contains a predetermined quantity of active agent. It will be appreciated that the total amount of a therapeutic composition or agent administered to a patient may involve administration of multiple unit dosage fonns.

[0071] In some embodiments, tazemetostat is administered to a patient in a unit dosage form. In some embodiments, a unit dosage form is a capsule or tablet. In some embodiments, a unit dosage form comprises about 200 mg tazemetostat, or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, amdizalisib is administered to a patient in a unit dosage form. In some embodiments, a unit dosage form is a capsule or tablet. In some embodiments, a unit dosage fonn comprises about 5 mg to about 40 mg amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage fomr comprises about 5 mg amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage form comprises about 10 mg amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage form comprises about 20 mg amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage fonn comprises about 30 mg amdizalisib, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage form comprises about 40 mg amdizalisib. or a pharmaceutically acceptable salt thereof.

[0073] In some embodiments, surufatinib is administered to a patient in a unit dosage form. In some embodiments, a unit dosage form is a capsule or tablet. In some embodiments, a unit dosage form comprises about 50 mg to about 400 mg surufatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage form comprises about 50 mg surufatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage form comprises about 100 mg surufatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage form comprises about 200 mg surufatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage form comprises about 300 mg surufatinib, or a pharmaceutically acceptable salt thereof. In some embodiments, a unit dosage form comprises about 400 mg surufatinib, or a pharmaceutically acceptable salt thereof.Pharmaceutically Acceptable Compositions

[0074] In some embodiments, provided methods comprise administering one or more compositions comprising one or more therapeutic agents (e.g., tazemetostat, amdizalisib, or surufatinib). In some embodiments, provided combination therapies comprise administering (i) a composition comprising tazemetostat, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle; and (ii) a composition comprising an additional therapeutic agent (e.g., amdizalisib or surufatinib). and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, provided compositions are formulated for oral administration.

[0075] In some embodiments, provided methods comprise administering a composition comprising tazemetostat, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, provided methods comprise administering a composition comprising amdizalisib, or a pharmacally acceptable salt thereof, and a pharmacally acceptablecarrier, adjuvant, or vehicle. In some embodiments, provided methods comprise administering a composition comprising surufatinib. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0076] Tire term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is fonnulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, 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 carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0077] Compositions may be administered orally parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. Tire tenn "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic. intralesional and intracranial injection or infusion techniques. Preferably, tire compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0078] Pharmaceutically acceptable compositions for use in provided methods may be orally administered in any orally acceptable dosage fomr including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In tire case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0079] Liquid dosage forms for oral administration include, but arc not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the activecompounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, gemr, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0080] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier 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, 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 may also comprise buffering agents.

[0081] Solid compositions of a similar type may 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 tire like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may 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 polethylene glycols and the like.

[0082] The compound can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.EXEMPLIFICATIONExample 1: A Phase II Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Tazemetostat in Combination With HMPL-689 in Patients With Relapsed / Refractory Lymphoma

[0083] Preclinical studies demonstrated synergistic antitumor effects of tazemetostat in combination with HMPL-689 in vitro and in vivo. To further explore the clinical efficacy and safety of tazemetostat in combination with HMPL-689, a Phase II study was conducted to evaluate the safety, tolerability and preliminary anti-tumor efficacy of tazemetostat in combination with HMPL-689 in patients with relapsed / refractory (R / R) lymphoma.Target Population

[0084] Patients with histologically confirmed R / R lymphoma who had progressive disease or are refractory after the prior standard systemic therapy or had no standard therapy.Study Drug

[0085] Dose Escalation Phase (Phase Ila):

[0086] Tazemetostat: 800 mg twice daily (BID. approximately 12 hours apart) orally (with or without food) continuously.

[0087] HMPL -689: The starting dose was 20 mg once daily (QD) orally over 30 minutes with a 24 ± 4 hour interval between doses, with possible escalation to 30 mg QD based on the dose escalation rules.

[0088] Dose Expansion Phase (Phase lib): Recommended Phase II dose (RP2D).

[0089] In both phases, it was recommended to take the drugs at the same time every day, with tire first dose of two drugs taken together and tire second dose of tazemetostat alone. If a dose was missed (i.e., not taken within 4 hours of the scheduled dosing time), the dose should not be taken. Dose administration was resumed at the next scheduled dose. If a subject vomits after administration, the subject should not take an additional dose. Dose administration was resumed at the next scheduled dose. Study treatment was administered in 28-day cycles until the patient experienced: progressive disease (PD), intolerable toxicity, or meeting other protocol-specified criteria for ending study treatment, whichever occurs first.Study Objectives

[0090] Primary Objectives:

[0091] Dose Escalation Phase (Phase Ila): To evaluate the safety, tolerability, and determine the maximum tolerated dose (MTD) and / or RP2D of tazemetostat in combination with HMPL-689 in patients with R / R lymphoma.

[0092] Dose Expansion Phase (Phase lib): To evaluate the efficacy of tazemetostat in combination with HMPL-689 in patients with lymphoma.

[0093] Secondary' Objectives:

[0094] Dose Escalation Phase (Phase Ila): To assess the preliminary efficacy of tazemetostat in combination with HMPL-689.

[0095] Dose Expansion Phase (Phase lib): To evaluate tazemetostat safety and tolerability in combination with HMPL-689 in patients with R / R lymphoma

[0096] Phase Ila and lib: To evaluate the pharmacokinetics (PK) profile of tazemetostat combined with HMPL-689 in patients with R / R lymphoma

[0097] Exploratory' Objectives:

[0098] To explore the biomarker changes associated with the target of this combination therapy.

[0099] To evaluate the effect of tumor gene mutations on the antitumor activity of the study drug.Study Endpoints

[0100] Primary Endpoints:

[0101] Dose Escalation Phase (Phase Ila): Dose limiting toxicity (DLT); RP2D and / or MTD.

[0102] Dose Expansion Phase (Phase lib): Primary' efficacy endpoint was objective response rate (ORR). Secondary' efficacy endpoints were complete response (CR) rate, disease control rate (DCR), duration of response (DOR), time to response (TTR), and progression-free survival (PFS).

[0103] Secondary Endpoints:

[0104] Dose Escalation Phase (Phase Ila): ORR, CR rate, DCR, DOR, TTR, and PFS.

[0105] Dose Expansion Phase (Phase lib): Incidence, severity, and causality to study drag of treatment-emergent adverse events (TEAEs) as determined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCLCTCAE 5.0).

[0106] Phase Ila and lib: To evaluate the PK profile of Tazemetostat (including its metabolite EPZ- 6930, N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)-4-methyl-4'-(morpholinomethyl)-5- ((tetrahydro-2H-pyran-4-yl)amino)-| 1.1 '-biphenyl |-3-carboxamidc): to evaluate the PK profile of HMPL- 689; and to preliminarily evaluate the relationship between efficacy, safety, tolerability, and PK.

[0107] Exploratory Endpoints:

[0108] Changes in plasma levels of cytokines and chcmokincs such as CCL3, CCL17, CCL22, CXCL13, etc.; and changes in expression of H3K27me3 in blood samples before and after treatment.

[0109] To explore the effect of tumor gene mutation on drug efficacy in different samples and explore the effect of tumor gene mutation on drug resistance mechanisms.Study Overview

[0110] A phase II clinical study of tazemetostat combined with HMPL-689 in patients with R / R lymphoma. The study included 2 phases: a dose escalation phase (phase Ila) and a dose expansion phase (phase lib).

[0111] Dose Escalation Phase (Phase Ila):

[0112] It was planned to enroll approx. 6-20 patients with R / R lymphoma who have failed standard treatment or have no standard treatment. Enrolled patients received tazemetostat (fixed dose, 800 mg BID orally) combined with HMPL-689 treatment (dose escalation). It was planned to set two HMPL-689 dose groups: 20 mg and 30 mg, QD orally. Dose escalation was performed according to the "3 + 3" strategy: first. 3 DLT-evaluable patients were enrolled in the 20 mg dose group:• If 3 DLT evaluable patients did not experience DLT during the DLT evaluation window (Cycle 1, Days 1-28), dose escalation proceeded to the next dose group.• If 1 of the 3 DLT-evaluable patients experienced a DLT, 3 additional patients (up to 6 evaluable patients) were required in the same dose group; and if the additional 3 patients did not experience a DLT, the dose was escalated to the next dose group. If 1 or more of the additional 3 DLT-evaluable patients (2 or more evaluable patients in total) experienced a DLT, dose escalation was stopped.• Dose escalation was stopped if 2 out of 3 DLT-evaluable patients experienced a DLT.• At the end of escalation, 1-2 dose groups were selected, with 3-7 patients added in each group to 10 patients. RP2D was determined based on the further safety and preliminary efficacy.

[0113] DLT was defined as a patient who experienced, in the judgment of the investigator, the following toxicities possibly related to or related to tazemetostat and / or HMPL-689 within 28 days of the first dose (DLT evaluation window):1. Non-hcmatological adverse events (AEs) of Grade > 3, except:• Grade 3 fatigue relieved to < Grade 2 after treatment;• Any nausea / vomiting, diarrhea, and constipation of Grade > 3 relieved to Grade < 2 within 7 days with appropriate supportive care:• Grade 3 rash;• Any electrolyte imbalance of Grade > 3 relieved to Grade < 2 within 7 days with appropriate supportive care: and• Alanine aminotransferase / aspartate aminotransferase / alkaline phosphatase / indirect bilirubin elevation of Grade 3 relieved to < Grade 2 within one week of treatment.2. Hematological AEs of Grade > 3:• Grade 4 neutropenia lasting > 7 days despite receiving the granulocyte-colony stimulating factor (G-CSF) support treatment;• Grade 3 neutropenia lasting > 14 days despite receiving the G-CSF support treatment;• Febrile neutropenia lasting > 48 hours despite receiving the G-CSF support treatment [absolute neutrophil count (ANC) < 1.0 X 10A9 / L with body temperature reaching 38.3 °C (axillary temperature) or persisting > 38 °C (axillary’ temperature) for more than one hour];• Grade 3 thrombocytopenia with bleeding (except transient controllable epistaxis, mild gingival bleeding or normal menstruation) requiring platelet transfusion;• Grade 4 thrombocytopenia;• Grade 3 or 4 anemia requiring transfusion;3. Other drug -related AEs leading to permanent discontinuation as judged by the investigator.

[0114] DLT evaluable patients were defined as those who met both of the following criteria during theDLT assessment window:• Complete the safety assessment required by DLT assessment per protocol: and• Tire total dose of HMPL-689 and tazemetostat received during DLT assessment is no less than 70% of the planned dose.

[0115] MTD was defined as the maximum dose at which < 33% of patients experience DLT during the DLT observation period.

[0116] In case of DLT during DLT evaluation window, patients can receive subsequent study drug treatment or dose reduction or discontinuation, according to the dose modification principle defined in protocol.

[0117] The investigator must notify the Sponsor immediately of any unexpected Grade > 3 AE or laboratory abnormality. Prior to a patient enrolled in a higher-dose level, all AEs of Grade > 2 at the current dose level must be checked.

[0118] If the patients in 30 mg QD HMPL-689 cohort do not reach the MTD criteria within the DLT evaluation window, a Drug Safety Monitoring Committee (SRC) consisting of the Principal Investigator or other designated investigators, the Sponsor's Clinical Project Leader, Medical Monitor, Safety Reporting Liaison, and PK Scientist, was required to decide whether to continue to perform the dose escalation at higher dose levels, or to determine the RP2D, based on the PK, safety tolerability, and preliminary efficacy of the combination treatment.

[0119] Dose Expansion Phase (Phase Tib):

[0120] Multiple expansion cohorts were set up according to different tumor types, and about 15-20 patients were enrolled in each cohort to further observe the anti-tumor effect of tazemetostat combined with HMPL-689 in different pathological types of R / R lymphoma. All cohorts included patients who hadprogressed on or were refractory to standard therapy.

[0121] Cohort 1: Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) Grade 3b, rclapscd / refractory after at least 2 prior lines of standard therapy, including alkylator / anthracycline (unless anthracycline-based chemotherapy is contraindicated) / anti-CD20-based therapy (R-CHOP or equivalent), and must be considered unable to benefit from intensive treatment with autologous hematopoietic stem cell transplantation (ASCT, defined as meeting at least 1 of the following criteria):• Relapsed / refractory after previous ASCT• Failure to achieve at least a partial response to standard salvage regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide [R-ICE] or rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP])• Intensive therapy is not suitable due to age or significant comorbidities• Ineligibility for intensive therapy due to failure to mobilize an acceptable number of hematopoietic stem cells• Refusal of intensive treatment and / or ASCT

[0122] Cohort 2: FL, pathological Grade 1 to 3a:• Cohort 2A: R / R FL with at least 2 prior systemic therapies, including at least one anti-CD20-based regimen• Cohort 2B: R / R FL previously treated with one anti-CD20-based regimen

[0123] Cohort 2A was initiated firstly, and the decision on whether to start cohort 2B is made after efficacy evaluation.

[0124] Cohort 3: Mantle cell lymphoma (MCL): relapsed and refractory MCL, with prior therapies including:• (A) Received one line of systemic standard chemotherapy containing CD20 monoclonal antibody• (B) Progressive disease or intolerance after treatment with Bruton's tyrosine kinase (BTK) inhibitors

[0125] Cohort 4: Peripheral T-cell lymphoma (PTCL): Patients with histologically confirmed R / R PTCL who have failed or could not tolerate at least one prior standard systemic therapy and / or for whom had no effective standard therapy.

[0126] All patients enrolled received continuous treatment with tazemetostat in combination with HMPL-689 in 28-day cycles until PD (as assessed by the investigator), intolerable toxicity, or other protocol-specified criteria for study treatment discontinuation are met. whichever occurs first.

[0127] Tumor assessments were performed using the Lugano Evaluation Criteria (Cheson 2014) every 8 weeks (± 7 days) for the first 24 weeks of the first dose, every' 12 weeks (+ 7 days) thereafter until 96weeks, then every 24 weeks (+ 7 days) thereafter until PD / recurrence (Investigator's assessment). Patients who discontinue treatment for reasons other than PD will continue to have the tumor assessments eve ’ 8 weeks ( ± 7 days) or earlier if clinically indicated, and will have subsequent anticancer treatment regimen documented until PD, death, receipt of other anticancer therapy, withdrawal by patient or legal representative, patient lost to follow-up, or study completion, whichever occurs first.

[0128] Patients who discontinue treatment for any reason should have a safety follow-up visit within 30 (± 7) days after the final dose or before initiation of new antineoplastic therapy, whichever occurs first.

[0129] AEs were graded according to NCI CTCAE V5.0. All patients were monitored for safety and all serious adverse events (SAEs) were reported after signing the informed consent form (1CF) and prior to first dose. Patients were closely monitored for safety and all AEs were reported after the first dose until 30 days after the final dose or initiation of new antineoplastic therapy, whichever occurred first. Only SAEs / study protocol defined adverse events of special interest (AESIs) with a reasonable possibility of relationship to study treatment as confirmed by the investigator were reported after 30 days of the final dose or the initiation of a new antineoplastic therapy, whichever occurred first.

[0130] In this study, tumor tissue or peripheral blood samples were collected to detect cytokine changes and EZH2 mutation status, to explore the effect of tumor gene mutations in different samples on drug efficacy, and to explore the effect of tumor gene mutations on drug resistance mechanism.

[0131] Tire study duration is approximately 24 months.Safety Assessments

[0132] AEs (including SAEs) were monitored based on the changes in vital signs, physical examination, 12 electrocardiogram (ECG), laboratory tests and other indicators. AEs were graded according to NCI CTCAE V5.0.

[0133] Efficacy Assessments

[0134] Tumor assessments were performed during the study using the Lugano Evaluation Criteria (Cheson 2014) every 8 weeks (± 7 days) for the first 24 weeks, then every 12 weeks (± 7 days) until 96 weeks, and then every 24 weeks (± 7 days) thereafter until PD / recurrence (investigator assessment) . Patients who discontinued study treatment for reasons other than PD will continue to have tumor assessments every 8 weeks (± 7 days) or earlier (if clinically indicated) and subsequent new anti cancer treatment regimen (PFS Follow-up) will be recorded, until PD, death, receipt of other anticancer therapy, withdrawal by patient or legal representative, loss to follow-up, or end of study, whichever occurs first.

[0135] The following efficacy measures were assessed: CR rate, ORR, TTR, DCR. DOR and PFS.• CR rate: defined as the proportion of patients who achieved CR.• ORR: defined as the proportion of patients who achieved CR or PR.• PFS: defined as the time from tire first dose of study drug to disease rccurrcncc / PD or death,whichever occurs first.• TTR: defined as the time from the first dose of study drug to the first occurrence of an objective response.• DCR: defined as the proportion of patients who achieve CR, PR, or stable disease (SD).• DOR: defined as the time from the first objective response until disease relapse / PD or death. Evaluation of Pharmacokinetics

[0136] Blood samples for PK analysis were collected per protocol.

[0137] Plasma samples were collected by venipuncture for the determination of plasma concentrations of HMPL-689, tazemetostat, and EPZ-6930. Hie detection of drug concentration in plasma was completed in the laboratory designated by the Sponsor. Blood samples were collected, processed and transported according to the requirements in the study-specific laboratory manual.

[0138] The establishment of an analytical method was completed in the laboratory' designated by the Sponsor. Calculation of PK parameters were conducted by the sponsor-designated facility'.

[0139] Concentrations of HMPL-689, tazemetostat, and its metabolite EPZ-6930 in plasma were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0140] The peak concentration (Cmax), trough concentration (Cmm), time to peak concentration (Tmax), elimination half-life (ti / a), area under the plasma concentration-time curve (AUCo-t), apparent clearance (CL / F), apparent volume of distribution (Vz / F) and accumulation ratio (AR) of HMPL-689, tazemetostat and its metabolite EPZ-6930 in plasma were evaluated.Planed Number of Patients

[0141] -66-120 total: 6-20 for dose escalation; -15-20 per cohort in expansion study (4 cohorts of different cancers).Inclusion criteria

[0142] Patients were eligible for this study if all of the following criteria are met:1. Have sufficiently understood this study and voluntarily sign the ICF;2. Age > 18 years;3. Patients with histologically confirmed R / R lymphoma:• Phase Ila dose escalation study: patients with relapsed or refractory lymphoma who have failed standard treatment and have no standard treatment options• Phase lib dose expansion study: o Cohort 1 (DLBCL, FL 3b): Histologically confirmed DLBCL, FL 3b (including primary mediastinal B-cell lymphoma) with relapsed / refractory disease following at least 2 prior lines of standard therapy, including alkylator / anthracycline (unless anthracycline-based chemotherapy is contraindicated) / anti-CD20-based therapy (R-CHOP or equivalent), andmust be considered unable to benefit from intensification treatment with ASCT, defined as meeting at least 1 of the following criteria:- Relapsed / refractory after previous ASCT;- Failure to achieve at least a partial response to standard salvage regimens (e.g., rituximab, ifosfamide, carboplatin, and etoposide [R-ICE] or rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP]);- Intensive therapy is not indicated due to age or significant comorbidities;Ineligibility for intensive therapy due to failure to mobilize an acceptable number of hematopoietic stem cells;- Refusal of intensive treatment and / or ASCT; o Cohort 2 (FL): Histologically confirmed R / R FL (Grade 1, 2, 3a):- Cohort 2A: Patients with at least 2 prior systemic standard therapies, including at least 1 anti-CD20 therapy (rituximab and its biosimilars, Obinutuzumab, etc.) are allowed; patients with prior radiotherapy are allowed, but radiotherapy is not considered as a systematic treatment;Cohort 2B: Patients who have received 1 prior line of systemic standard chemotherapy containing CD20 monoclonal antibody. o Cohort 3 (MCL): Patients with R / R MCL who had prior therapies including: (a) 1 line of systemic standard chemotherapy containing CD20 monoclonal antibody: or (b) progressive disease or intolerance to Bruton's tyrosine kinase (BTK) inhibitors. o Cohort 4 (PTCL): Patients with histologically confirmed R / R PTCL who have failed or cannot tolerate standard therapy with at least one prior systemic standard therapy and / or for whom no effective standard therapy exists. Patients must have at least one measurable lesion by computed tomography (CT) / magnetic resonance imaging (MRI) (the longest diameter of nodal lesion > 1.5 cm or the longest diameter of extranodal lesion > 1 cm); Life expectancy > 12 weeks; Eastern Cooperative Oncology Group (ECOG) perfonnance status of 0-2; Adequate bone marrow function, renal function and hepatic function:• Absolute neutrophil count (ANC) > 1.5 x 109 / L, hemoglobin > 9.0 g / dL, platelets > 75 x 109 / L (without receiving transfusions of granulocyte colony-stimulating factor or other hematopoietic growth factors within 14 days prior to laboratory examination, and without receiving transfusions of platelet within 7 days prior to laboratory examination);Note: If the investigator considers that the above test results lower than the lower limit values as specified in the protocol are caused by the invasion of lymphoma to bone marrow, the patient could be enrolled if acquisition of written approval is obtained from the Sponsor after discussion.• Creatinine clearance > 40 mL / min, which can be calculated using the Cockcroft- Gault formula.• (140 - Age) x (Weight in kg) x (0.85 if female)• 72 x [Serum creatinine (mg / dl)]• Serum total bilirubin < 1.5 x upper limit of normal (ULN), except for unconjugated bilirubinemia of Gilbert's syndrome;• Alkaline phosphatase (ALP, in the absence of bone disease), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN (< 5 x ULN if the subject has liver metastases);8. Currently inactive human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV):• Patients with HBV infection [hepatitis B surface antigen (HbsAg) or hepatitis B core antibody (HbcAb) positive] but negative test results of HBV DNA polymerase chain reaction (PCR) are allowed to be enrolled; these patients require continuous antiviral therapy after enrollment and HBV DNA PCR test will be performed every cycle;• Patients with positive HCV serology but negative HCV RNA test results are allowed to be enrolled;• Patients with positive CMV TgM antibody, but negative CMV DNA test results are allowed to be enrolled;9. Female patients of childbearing potential must agree to use a double contraception method at least 28 days prior to starting study drug, during the treatment period, and for 6 months after final dose; and male patients with partners of childbearing potential must also use an effective double contraception method during the study period and for 3 months after the final dose. A double contraception method includes condoms, sponge plugs, foam, contraceptive jelly, diaphragm or intrauterine device, contraceptives (oral or parenteral), implant (Implanon ®), intravascular injection, or other contraception. Postmenopausal women (> 45 years old and having amenorrhea for > 1 year) and surgically sterilized women are exempt from the criteria.Exclusion Criteria

[0143] Patients who met any of the following exclusion criteria were excluded from the study:Patients who have previously used EZH2 inhibitors and PI3K inhibitors, or previously could not tolerate EZH2 inhibitors or PI3K inhibitors; Patients with brain metastases or leptomeningeal invasion; Idas thrombocytopenia, neutropenia, or anemia of Grade >3 (per CTCAE 5.0 criteria) and any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS / AML / MPN). Has abnormalities known to be associated with MDS (e.g. del 5q. chr 7 abn) and multiple primary neoplasms (MPN) (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing. History of T-cell lymphoblastic lymphoma (T-LBL) / T-cell acute lymphoblastic leukemia (T-ALL); Take strong or moderate inducers or strong inhibitors of cytochrome P450 3A4 enzyme (CYP3A42 weeks before the first dose of study drug) (except Forsythia suspensa for 3 weeks); Toxicity from prior anticancer therapy has not recovered to < Grade 1 prior to tire first dose of studydrug (except alopecia); Interval between first dose of study drug and other prior anticancer therapies:• Cytotoxic chemotherapy: less than 21 days• Non-cytotoxic chemotherapeutic agents (e.g., small molecule inhibitors): less than 14 days• Nitrosuria: less than 6 weeks• Monoclonal antibody: less than 28 days• Radiotherapy: o Local radiotherapy: less than 14 days o Radioisotope therapy: less than 6 weeks o 50% pelvic or total body radiotherapy: less than 12 weeks• High-dose autologous stem cell transplantation: less than 60 days• High-dose allogeneic stem cell transplantation: less than 90 days (< grade 2 if graft-versus- host disease)Note: Prednisone at a dose not to exceed 10 mg / day (or equivalent corticosteroid) for control of lymphoma-related symptoms is permitted in CID 1, with the intent to taper by the end of cycle 1. Inability to take oral drugs, previous surgery' or severe gastrointestinal diseases such as dysphagia, active gastric ulcer, etc., which in tire opinion of the investigator may affect the absorption of the study drug; Maj or surgery 4 weeks prior to the first dose of study drug (refer to Grade 3 and 4 surgery specified in Management Measures for Clinical Application of Medical Technology implemented on May 1 , 2009);11. Clinically significant cardiovascular disease, including acute myocardial infarction, unstable angina pectoris, coronary artery bypass surgery' within 6 months prior to enrollment, congestive heart failure of New York Heart Association (NYHA) class >3 (including class 3), LVEF < 40%, or hypertension uncontrolled by drugs (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mgHg);12. Hereditary long QT syndrome or QTcF > 480 msec or taking drugs that may cause QT prolongation or torsades de pointes;13. Venous thrombosis or pulmonary embolism within 3 months prior to the first dose of study drug;14. History' of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug;15. Active infection requiring systemic treatment;16. Known hypersensitivity to any component of tazemetostat or HMPL-689;17. For any other diseases, metabolic abnonnalities, physical examination abnormalities or laboratory examination abnormalities of significant clinical significance, according to the judgment of the investigator, there is reason to suspect that the patient has a certain disease or condition that is not suitable for the use of tazemetostat combined with HMPL-689, or it may affect the interpretation of research results or put patients at a high risk.18. Pregnant (positive pregnancy test) or lactating women;19. Patients with previous organ transplantation;20. Patients with other non-cutaneous malignancies (other malignancies with 5-year disease-free survival, or completely resected non-melanotic skin cancer, or cured carcinoma in situ).Statistical Analysis and Sample Size Calculation

[0144] Determination of Sample Size:

[0145] This study was an exploratory Phase II study and there are no formal statistical hypotheses for the dose escalation phase. The sample size was mainly determined based on feasibility and regulatory requirements.

[0146] In the expansion phase, for the DLBCL cohort, a two-stage design will be used. In tire Stage 1 , 10 patients will be enrolled first; if < 1 patient is observed to have an objective response, this cohort study will be tenninated for futility. When the true ORR is only 20%, the probability of stopping the study in Stage 1 will reach 10.74%. Otherwise, stage 2 in DLBCL cohort will be continued with a maximum of 20 patients.

[0147] Statistical Analysis:

[0148] Analytical Procedure: In general, all variables obtained at each observation time point were statistically described, unless the protocol states that statistical description was not required at a specific time point. Continuous variables (such as age) were statistically described using the number ofobservations, mean, quartiles, standard deviation, minimum and maximum; categorical variables were statistically described using the frequency and percentage of each category. For time-to-event variables, data were summarized using the Kaplan-Meier method. If data allowed, medians and quartiles were calculated. The number of people with events and deletions were also presented and Kaplan-Meier curves were plotted.

[0149] Analysis Sets: The analysis sets involved in statistical analysis mainly included:• Full Analysis Set (FAS): includes all patients who receive at least one dose of tazemetostat and HMPL-689. This data set is mainly used for the analysis of efficacy data and safety data.• Efficacy Evaluable Set (EEAS): includes patients in the FAS who have measurable disease at baseline and at least one post-baseline evaluable tumor assessment. This analysis set serves as the supportive analysis set for efficacy.• DLT Analysis Set: includes all DLT evaluable patients. This analysis set is used for analysis and summary of DLT events.• PK analysis set (PKAS): includes all patients who have at least one dose of study drug and have at least one PK sampling and analysis.

[0150] Safety Evaluation: The safety profile was evaluated by drug exposure, the incidence, severity, and causility of AEs to the study drug, changes in laboratory test results, and changes in vital signs. All AEs were graded according to NCI CTCAE V5.0, and coded using the Medical Dictionary' for Regulatory' Activities (MedDRA). The number and frequency of AEs was summarized by system organ class (SOC) and preferred term (PT). Changes in laboratory test results were summarized according to NCI CTCAE V5.0 grading. Changes in vital signs and ECOG performance status scores were compared with baseline levels for descriptive statistics. For laboratory parameters, the maximum toxicity occurring during the study was summarized in the form of counts and percentages.

[0151] Efficacy Evaluation: For the binary outcome measures of ORR, CR rate and CBR, the ClopperPearson method was used to calculate the estimate and its 95% exact CI. If data permit, Kaplan-Meier method were used to estimate 12-month PFS rate, its 95% CI, and median and 95% CI of PFS, TTR and DoR.

[0152] PK Evaluation: PK parameters were analyzed based on the PKAS. Non-compartmental analysis of the plasma drug concentration obtained at the central laboratory was performed using PhoenixWinNonlin. Descriptive statistics were presented for all relevant PK parameters for HMPL-689, tazemetostat, and if applicable, its metabolite EPZ-6930. Tire main PK parameters include but are not limited to: peak concentration (Cmax), trough concentration (Cmm), time to peak concentration (Tmax), elimination half-life (t 12), area under the plasma concentration-time curve (AUC o-t), apparent clearance (CL / F), apparent volume of distribution (Vz / F) and accumulation ratio (AR).

[0153] Descriptive statistical analysis was performed on the plasma concentrations of study drug according to the scheduled sampling time points, and a list of plasma concentrations by individual patient is provided.Results from Phase Ila

[0154] Twenty-one patients were enrolled as of a first cutoff date. Among all patients, the median age was 60 (range 37-74) years old. 52.4% of patients were male, and 85.7% had ECOG performance status score of O or 1. The median line of prior systemic therapy was 3 (range 1-7). No obvious baseline differences were observed between the 20 mg and 30 mg cohorts. Table 1.1 summarizes the baseline characteristics and disease characteristics of the enrolled patients.Table 1.1.IQR, interquartile range: DLBCL, diffuse large B cell lymphoma; FL, follicular lymphoma; PTCL, peripheral T cell lymphoma; PTCL-NOS, peripheral T cell lymphoma, not otherwise specified; AITL, angioimmunoblastic T cell lymphoma; ALK- ALCL, Anaplastic Lymphoma Kinase negative Anaplastic Large Cell Lymphoma; pcALCL, primary cutaneous ALCL; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma.

[0155] Eighteen patients had baseline and at least one evaluable post-baseline tumor evaluations, including 5 FL, 3 DLBCL, 8 PTCL, 1 MZL and 1 MCL. In the 20 mg cohort, 7 (7 / 9, 77.8%) patients achieved partial response (PR) (2 PTCL, 2 DLBCL and 3 FL), and 2 patients were stable disease (SD) (1 MZL and 1 FL). In the 30 mg cohort, 5 (5 / 9, 55.6%) patients achieved PR (1 DLBCL, 1 FL and 3 PTCL), 3 patients were SD (1 MCL and 2 PTCL), and 1 PTCL patient had progression disease (PD). Tire median duration of response, progression-free and overall survival was not reached.

[0156] FIG. 4 is a swimming plot of enrolled patients. Among 21 patients with at least one dose of study drug, 9 patients in the 20 mg cohort (A) and 9 patients in the 30 mg cohort (B) had target lesions at baseline and at least one post-treatment tumor assessment and were included in the swimming plot.

[0157] FIG. 5 is a waterfall plot showing the best change in tumor size of target lesions, assessed by investigator. Among 21 patients with at least one dose of study drug, 8 pts in the 20 mg cohort (A) and 9 pts in the 30 mg cohort (B) had measurable target lesions at baseline and at least one post-treatment tumor assessment with evaluable tumor size change from baseline and were included in the waterfall plot. One patient from the 20 mg cohort was primary cutaneous lymphoma with only skin lesions, which is not measurable, so they were not included in the waterfall plot, and the response was PR at C3D1. SPD=sum of products of perpendicular diameters.

[0158] All patients experienced at least one treatment-related adverse event (TRAE). Among 21 patients, the most common (>20%) TRAEs of all grades included anemia (57.1%). white blood cell, neutrophil, lymphocyte, platelet count decrease (47.6% for each), fatigue (28.6%), AST increase and hypercholesterolemia (23.8% for each). 11 (52.4%) patients experienced a grade >3 TRAE, and the most common (>5%) events in all patients included anemia, white blood cell, lymphocyte, platelet count decrease (19.0% for each) and neutrophil count decrease (14.3%). Dose reduction due to TRAEs were reported in 5 (23.8%) of the 21 patients. Tire most common (5% of patients) TRAEs leading to dose reduction were white blood cell count decrease (2, 9.5%), lymphocyte count decreased (2. 9.5%). platelet count decreased (1, 4.8%), ALT increased (1, 4.8%), pneumonia (1, 4.8%) and hepatic function abnormal (1, 4.8%). 4 (36.4%) patients experienced treatment-related severe adverse events (TRSAEs) in the 30 mg cohort, while 1 (10%) patient in the 20 mg cohort experienced a TRSAE. Table 1.2 summarizes treatment-related adverse events observed during the study. Table 1.3 summarizes grade >3 treatment-related adverse events observedduring the study.Table 1.2.Table 1.3.ALT, Alanine aminotransferase; y-GT, gamma-glutamyl transpeptidase

[0159] FIG. 6 is a graph showing mean concentrations of amdizalisib and tazemetostat in the 20 mg and 30 mg cohorts. Compared with C1D1. an obvious decrease (around 45%) occurred on C1D15 in tenns of AUCo-nh for tazemetostat, which was consistent with the pharmacokinetic behavior of monotherapy. AUCo-24h for amdizalisib on C1D15 was decreased by 20% with combined administration, which was caused by the induction potential of CYP3A4 by tazemetostat.

[0160] Based on these results, the combination of tazemetostat and amdizalisib showed promising efficacy with a manageable safety profile in R / R lymphoma, especially in PTCL and DLBCL. The R2PD was determined to be 20 mg QD of amdizalisib combined with 800 mg BID of tazemetostat, based on the safety, efficacy, and PK results.Example 2: In vitro studies of tazemetostat in combination with amdizalisib in human B-cell and T- cell lymphoma cell lines

[0161] The in vitro combinatorial potential of EZH2 inhibitor tazemetostat with PI3K5 inhibitor amdizalisib in inhibiting the survival of human B-cell and T-cell lymphoma cell lines was evaluated. The following cell lines were used:Abbreviations: DLBCL=diffuse large B-cell lymphoma. CTCL=cutaneous T-cell lymphoma, WT=wild type.

[0162] Methods: Lymphoma cells in exponential growth phase were seeded into T25 flasks and pretreated with six concentrations of tazemetostat or DMSO for 4 to 7 days. Cells were washed and then split into 96-well plates manually and co-treated with tazemetostat and amdizalisib using HP D300 digital dispenser (Tccan group) based on matrix design in 7 x 9 arrays (6 concentrations of tazemetostat and 8 concentrations of amdizalisib. plus DMSO), and incubated for additional 3 days. SU-DHL-10 cells were plated in 96-well plate and co-treated with tazemetostat and amdizalisib directly for 4 days without pretreatment with tazemetostat. The top concentrations of compounds used in these assays were near the IC50of each agent. After 3-day’s co-treatment (4 days for SU-DHL-10), cell viability was determined via detecting ATP concentration using CellTiter-Glo® (Promega) luminescent assay.

[0163] Data analysis: The inhibition rate of compounds at each test point was calculated according to following equation:Inhibition rate (%) = (1 -(Luminescencecompound - LuminescenceBackground) / (LuminescenceDMso - LuminescenceBackground))x100%Where:Luminescencecompound represents the luminescence intensity of cells with tested compound LuminescenceBackground represents the luminescence intensity of cell medium (without cells) LuminescenceDMso represents the luminescence intensity of cells with DMSO only

[0164] The combination behavior was characterized using Excess over Bliss (EOB) Scores (see Bansal M, Yang J, Karan C, et al. A community computational challenge to predict the activity of pairs of compounds. Nat Biotechnol. 2014:32(12): 1213-1222) according to following equation:EOB Score = 100 x (Ya b,o- (Ya+Yb-Ya* Yb))Where:Yarepresents the observed inhibition rate with tazemetostat treated alone at dose a Ybrepresents the observed inhibition rate with amdizalisib treated alone at dose bYab, o represents the observed combined inhibition rate with tazemetostat at dose a and amdizalisib at dose b.

[0165] Average of the EOB Scores was determined by calculating EOB Scores across the entire doseresponse matrix (total EOB Scores / 48) and was used to define the combination effect: combinations with average EOB Score > 0 indicating synergy, average EOB Score = 0, additivity, and those with average EOB Score < 0, antagonism (see Makela P, Zhang SM, Rudd SG. Drug synergy scoring using minimal dose response matrices. BMC Res Notes. 2021 Jan 19; 14(1):27).

[0166] Results: From these in vitro combination studies, a synergistic effect of tazemetostat plus amdizalisib was observed in all of the tested cell lines (all average EOB score > 0), including six B-cell lymphoma cell lines (SU-DHL-6, Karpas-422, SU-DHL-10, SU-DHL-5, Farage, and TMD8) and two T- cell lymphoma cell lines (H9 and HH) tested, regardless of EZH2 mutation status. Tire results are summarized in Table 1, and graphs of the results for the Karpas-422 and Farage cell lines are shown in FIG. 1A and FIG. IB, respectively.Table 1.Example 3: In vivo efficacy study of tazemetostat in combination with amdizalisib in SU-DHL-6 subcutaneous xenograft model

[0167] The benefit of co-treatment with tazemetostat and amdizalisib versus either monotherapy in SU-DHL-6 subcutaneous xenograft model in CB17-SCID mice was evaluated.

[0168] Methods: Human diffuse large B-ccll lymphoma (DLBCL) SU-DHL-6 (ATCC®) cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum. Tumor cells in exponential growth phase were harvested and inoculated subcutaneously into the right flanks of female CB17-SCID mice (Shanghai Lingchang BioTech Co., Ltd.) with 1 x 107cells per mouse. Mice were randomly assigned into following four groups with 8 mice per group according to the tumor volume: vehicle control, tazemetostat(250 mg / kg), amdizalisib (50 mg / kg), and the combination of tazemetostat (250 mg / kg) with amdisalisib (50 mg / kg). Tazemetostat was formulated in 0.5% CMC-Na with 0.1% Tween-80, and amdizalisib was prepared in 0.5% CMC-Na (pH 2.1). All compounds were administered twice daily by oral gavage. Tumor volumes and body weights of the mice were measured twice a week. Mice were taken out from the study and euthanized once tumor volume exceeded 3500 mm3. The anti -tumor activity was evaluated by tumor growth inhibition.

[0169] Data analysis: The following equations were used for data analysis:Relative body weight (RBW) = (BWt / BW0) * 100%Where:BWtrepresents the body weight on the day post treatment;BWo represents initial body weight before treatment.Tumor volume (TV) = 0.5 x long diameter x short diameter2. Data was expressed as Mean ± standard deviation (SD).Tumor growth inhibition rate (TGI) = [l-(TVt-TVo) drug treatment / (TVt-TVo) vehicle control]x100%.Where:TVt represents the tumor volume on the day post treatment;TVo represents initial tumor volume before treatment.

[0170] Statistical comparisons between different groups on tumor volume changes (TVt-TVo) were calculated using Student’s t-test by Excel software, wherein p < 0.05 indicates a statistically significant difference, p < 0.01 as extremely statistically significant.

[0171] Combination index was expressed by CR (combination ratio) value (see Yamada H, Uchida N, Maekawa R and Yoshioka T. Sequence-dependent antitumor efficacy of combination chemotherapy with nedaplatin, a newly developed platinum, and paclitaxel. Cancer Letters. 2001; 172: 17-25) according to following equation:CR=M(A+B) / (MA*MB)Where:MA and MB represent the mean T / Cs of drug A and drug B, respectively; M(A+B) is the mean T / C of drug A with drug B;T: TVtof treatment group, C: TVt of vehicle control group;

[0172] Combinations with CR value < 1 demonstrated synergy, those with CR value = 1. additivity, and those with CR value >1, antagonism.

[0173] Results: As shown in Table 2, after 20 days treatment, compared with vehicle control group, amdizalisb at 50 mg / kg inhibited tumor growth with TGI of 60.9%; tazemetostat at 250 mg / kg did not inhibit tumor growth (TGI of -7.6%); tazemetostat in combination with amdizalisib significantly improvedthe anti-tumor efficacy with TGI of 87.3%, and the CR value was 0.11, indicating a synergistic effect. The combination treatment was well tolerated with no significant loss of body weight in mice. Mice in vehicle and tazemetostat-treatment groups were sacrificed due to oversized tumor volume, and the dosing in amdizalisb and combination treatment groups was continued for three more days (23 days). The even greater difference of tumor volume was seen between these two groups, further confirming the combination benefit of tazemetostat with amdizalisb in delaying tumor growth. These results are also shown in FIG. 2.Table 2.Note: **: p < 0.01, compared with vehicle group;##: p<0.01, compared with amdizalisib group:p<0.01, compared with tazemetostat group.Example 4: Efficacy of Tazemetostat in combination with Surufatinib in DMS-114 subcutaneous xenograft models

[0174] The combination benefit of tazemetostat and surufatinib cotreatment versus either monotherapy in DMS-114 (SMARCA2 / 4Loss) subcutaneous xenograft model in nude mice was evaluated.

[0175] Methods: Human small cell lung cancer (SCLC) DMS-114 (ATCC®) cells were cultured and expanded in Waymouth's MB 752 / 1 medium containing 10% fetal bovine serum. Tumor cells in logarithmic growth stage were harvested, mixed with equal volume of matrigel and implanted subcutaneously into the right flanks of BALB / c nude mice (Shanghai Lingchang BioTech Co.. Ltd.) with 8 x 106cells per mouse.

[0176] Mice were randomly divided into six groups with 10 mice per group according to tumor volume shown in Table 3 : vehicle control, surufatinib (80 mg / kg), tazemetostat-low dose ( 100 mg / kg), tazemetostat- high dose (400 mg / kg), the combination-low dose (surufatinib 80 mg / kg in combination with tazemetostat 100 mg / kg) and tire combination-high dose (surufatinib 80 mg / kg in combination with tazemetostat 400 mg / kg). Tazemetostat were grinded and suspended with 0.5% CMC-Na supplement with 0.1% Tween 80, surufatinib were suspended with 0.5% CMC-Na. All compounds were administered by oral gavage according to the schedule shown in Table 3. The tumor volumes and body weights of the mice were measured twice a week. The anti-tumor activity was evaluated by tumor grow th inhibition.Table 3.Note: qd, once per day; bid, twice per day.

[0177] Data analysis: The following equations were used for data analysis:Relative body weight (RBW) = (BWt / BWo) x 100%Where:BWt represents the body weight on the day post treatment;BWo represents initial body weight before treatment.Tumor volume (TV) = 0.5 x long diameter x short diameter2. Data was expressed as Mean ± standard deviation (SD).Tumor grow th inhibition rate (TGI) = [l-(TVt-TVo) drug treatment / (TVt-TVo) vehicle]x100%.Where:TVtrepresents the tumor volume on the day post treatment;TVo represents initial tumor volume before treatment.

[0178] The statistical comparison of changes in tumor volume (TVt-TVo) between two groups were analyzed using Student t-test by Excel, wherein p < 0.05 indicates a statistically significant difference, p < 0.01 as extremely statistically significant.

[0179] Combination index was expressed by CR (combination ratio) value according to following equations:CR=MA+B) (MAXMB)Where:MA and MB are the mean T / Cs of drug A and B alone, respectively;M(A+B) is the mean T / C of drug A plus drug B;T: TVtof treatment group, C: TVt of vehicle control group;

[0180] If CR value < 1, it should indicate synergistic effect, those with CR = 1, additivity, and CR >1, antagonism.

[0181] Results: As shown in Table 4, in the human SCLC DMS-114 xenograft tumor model, on day 30 of treatment, surufatinib at 80 mg / kg led to 40.7% reduction of tumor growth, and tazemetostat at 100 and 400 mg / kg induced TGI with 22.9% and 56.0%, respectively. But the combination-low dose and combination-high dose did show much stronger inhibiting effect w ith TGI of 68.0% and 91.2%, respectively, statistically improving efficacy in comparison with their corresponding mono treatment group. CR values of the combination-low and high dose group were 0.76 and 0.57, respectively, indicating synergistic effect. The combination treatment was well tolerated with no significant loss of body weight in mice.Table 4.Note: **, p<0.01 vs vehicle; ##, p<0.01 vs Tazemetostat-100 mg / kg alone; $$, p<0.01 vs Tazemetostat-400 mg / kg alone; &, p<0.05 vs Surufatinib alone, &&, p<0.01 vs Surufatinib alone.Example 5: Efficacy of Tazemetostat in combination with Surufatinib in NCI-H82 subcutaneous xenograft models

[0182] Tire combination benefit of tazemetostat and surufatinib cotreatment versus either monotherapy in NCI-H82 subcutaneous xenograft model in nude mice was evaluated.

[0183] Methods: Human small cell lung cancer (SCLC) NCI-H82 (ATCC®) cells were cultured and expanded in RPMI-1640 medium containing 10% fetal bovine serum. Tumor cells in logarithmic growth stage were harvested, mixed with equal volume of matrigel and implanted subcutaneously into the right flanks of BALB / c nude mice (Shanghai Lingchang BioTech Co., Ltd.) with 1 x 106cells per mouse.

[0184] Mice were randomly divided into four groups with 8 mice per group according to tumor volume shown in Table 5: vehicle control, surufatinib (80 mg / kg), tazemetostat (400 mg / kg) and the combination (surufatinib 80 mg / kg in combination with tazemetostat 400 mg / kg), tazemetostat were grinded and suspended with 0.5% CMC-Na supplement with 0.1% Tween 80, surufatinib were suspended with 0.5% CMC -Na. All compounds were administered by oral gavage according to the schedule shown in Table 5. Tire tumor volumes and body weights of the mice were measured twice a week. The anti-tumor activity was evaluated by tumor growth inhibition.Table 5.Note: qd, once per day; bid, twice per day.

[0185] Data analysis: The following equations were used for data analysis:Relative body weight (RBW) = (BWt / BWo) x 100%Where:BWtrepresents the body weight on the day post treatment;BWo represents initial body weight before treatment.Tumor volume (TV) = 0.5 x long diameter x short diameter2. Data was expressed as Mean ± standard deviation (SD).Tumor growth inhibition rate (TGI) = [l-(TVt-TVo) drug treatment / (TVt-TVo) vehicle]x100%.Where:TVt represents the tumor volume on the day post treatment;TVo represents initial tumor volume before treatment.

[0186] Tire statistical comparison of changes in tumor volume (TVt-TVo) between two groups wereanalyzed using Student t-test by Excel, wherein p < 0.05 indicates a statistically significant difference, p < 0.01 as extremely statistically significant.

[0187] Combination index was expressed by CR (combination ratio) Value according to following equations:CR=M(A+B> / '(MAXMB)Where:MA and MB are the mean T / Cs of drug A and B alone, respectively;M(A+B) is the mean T / C of drug A plus drug B;T: TVt of treatment group, C: TVt of vehicle control group;

[0188] If CR value < 1, it should indicate synergistic effect, those with CR = 1, additivity, and CR >1, antagonism.

[0189] Results: As shown in Table 6, in the SCLC human NCI-H82 xenograft tumor model, on day 28 of treatment, surufatinib at 80 mg / kg inhibited tumor growth with 57.0% TGI; tazemetostat at 400 mg / kg only showed minor anti-tumor efficacy with 21 .3% TGI; but their combination significantly increased the antitumor effect with a TGI of 83.8% and showed a significant synergistic combinational effect (CR value was 0.58). Tire combination treatment was well tolerated with no significant loss of body weight in mice.Table 6.qote: **, p<0.01 vs vehicle; ##, p<0.01 vs Tazemetostat alone ; &, p<0.05 vs Surufatinib alone.Example 6: Efficacy of Tazemetostat in combination with Surufatinib in NCI-H69 subcutaneous xenograft models

[0190] Tire combination benefit of tazemetostat and surufatinib cotreatment versus either monotherapy in NCI-H69 subcutaneous xenograft model in nude mice was evaluated.

[0191] Methods: Human small cell lung cancer (SCLC) NCI-H69 (ATCC®) cells were cultured and expanded in RPMI-1640 medium containing 10% fetal bovine serum. Tumor cells in logarithmic growthstage were harvested, mixed with equal volume of matrigel and implanted subcutaneously into the right flanks of BALB / c nude mice (Shanghai Lingchang BioTech Co., Ltd.) with 5 x 106cells per mouse.

[0192] Mice were randomly divided into six groups with 8 mice per group according to tumor volume shown in Table 7: vehicle control, surufatinib (80 rng / kg), tazemetostat-low dose (200 mg / kg), tazemetostat- high dose (400 mg / kg), the combination-low dose (surufatinib 80 mg / kg in combination with tazemetostat 200 mg / kg) and the combination-high dose (surufatinib 80 mg / kg in combination with tazemetostat 400 mg / kg). Tazemetostat were grinded and suspended with 0.5% CMC-Na supplement with 0.1% Tween 80, surufatinib were suspended with 0.5% CMC-Na. All compounds were administered by oral gavage according to the schedule shown in Table 7. Tire tumor volumes and body weights of the mice were measured twice a week. The anti-tumor activity was evaluated by tumor grow th inhibition.Table 7.Note: qd, once per day; bid, twice per day.

[0193] Data analysis: The following equations were used for data analysis:Relative body weight (RBW) = (BWt / BWo)x100%Where:BWt represents the body weight on the day post treatment;BWo represents initial body weight before treatment.Tumor volume (TV) = 0.5 x long diameter x short diameter2. Data was expressed as Mean ± standard deviation (SD).Tumor grow th inhibition rate (TGI) = [l-(TVt-TVo) drug treatment / (TVt-TVo) vehicle]x100%.Where:TVtrepresents the tumor volume on the day post treatment;TVo represents initial tumor volume before treatment.

[0194] If tire average tumor volume after compound treatment were lower than that before treatment, tumor regression rate (TRR) could be calculated.TRR = (TVo-TVt) / TVo x 100%

[0195] The statistical comparison of changes in tumor volume (TVt-TVo) between two groups were analyzed using Student t-test by Excel, wherein p < 0.05 indicates a statistically significant difference, p < 0.01 as extremely statistically significant.

[0196] Combination index was expressed by CR (combination ratio) Value according to following equations:CR=M(A+B) / (MAXMB)Where:MAand MBare the mean T / Cs of drug A and B alone, respectively;M(A+B) is the mean T / C of drug A plus drug B;T: TVtof treatment group, C: TVt of vehicle control group;

[0197] If CR value < I, it should indicate synergistic effect, those with CR = 1, additivity, and CR >1, antagonism.

[0198] Results: As shown in Table 8, in the human SCLC NCI-H69 xenograft tumor model, on day 42 of treatment, tazemetostat alone at 200 or 400 mg / kg did not biologically and statistically inhibit tumor growth. Similarly, surufatinib at 80 mg / kg only led TGI 37.0%, while surufatinib in combination with tazemetostat at 200 and 400 mg / kg produced TGI of 76.2% and 106.8%, with CR value of 0.35 and 0.40, respectively, indicating a strong synergistic effect. Furthermore, the combination-high dose treatment induced tumor shrinking with a TRR of 18.3%. All the combination treatment was well tolerated with no significant loss of body weight in mice.Table 8.Note: *, p<0.01 vs vehicle**, p<0.01 vs vehicle; ##, p<0.01 vs Tazcmctostat-200 mg / kg alone ; $$, p<0.01 vs Tazemetostat 400 mg / kg alone; &, p<0.05 vs Surufatinib alone, &&, p<0.01 vs Surufatinib alone.Example 7: Efficacy of Tazemetostat in combination with Surufatinib in NCI-H441 subcutaneous xenograft models

[0199] The combination benefit of tazemetostat and surufatinib cotreatment versus either monotherapy in NCI-H441 subcutaneous xenograft model in nude mice was evaluated.

[0200] Methods: Human non-small cell lung cancer (NSCLC) NCI-H441 (ATCC®) cells were cultured and expanded in RPMI-1640 medium containing 10% fetal bovine serum. Tumor cells in logarithmic growth stage were harvested, mixed with equal volume of matrigel and implanted subcutaneously into the right flanks of BALB / c nude mice (Shanghai Lingchang BioTech Co., Ltd.) with 5 x 106cells per mouse.

[0201] Mice were randomly divided into four groups according to tumor volume with 8 mice per group shown in Table 9: vehicle control, surufatinib (80 mg / kg), tazemetostat (350 mg / kg) and the combination (surufatinib 80 mg / kg in combination with tazemetostat 350 mg / kg). Tazemetostat were grinded and suspended with 0.5% CMC-Na supplement with 0.1% Tween 80, surufatinib were suspended with 0.5% CMC-Na. All compounds were administered by oral gavage according to the schedule shown in Table 9. The tumor volumes and body weights of the mice were measured twice a w eek. The anti-tumor activity was evaluated by tumor growth inhibition.Table 9.Note: qd, once per day; bid, twice per day.

[0202] Data analysis: The following equations were used for data analysis:Relative body weight (RBW) = (BWt / BWo) x 100%Where:BWtrepresents the body weight on the day post treatment;BWo represents initial body weight before treatment.Tumor volume (TV) = 0.5 x long diameter x short diameter2. Data was expressed as Mean ± standard deviation (SD).Tumor growth inhibition rate (TGI) = [l-(TVt-TVo) drug treatment / (TVt-TVo) vehicle]x100%.Where:TVt represents the tumor volume on the day post treatment;TVo represents initial tumor volume before treatment.

[0203] The statistical comparison of changes in tumor volume (TVt-TVo) between two groups were analyzed using Student t-test by Excel, wherein p < 0.05 indicates a statistically significant difference, p < 0.01 as extremely statistically significant.

[0204] Combination index was expressed by CR (combination ratio) value according to following equations:CR=M(A+B) / (MAXMB)Where:MAand MBare the mean T / Cs of drug A and B alone, respectively;M(A+B) is the mean T / C of drug A plus drug B;T: TVtof treatment group, C: TVt of vehicle control group;

[0205] If CR value < 1. it should indicate synergistic effect, those with CR = 1, additivity, and CR >1,antagonism.

[0206] Results: As shown in Table 10, in the human NSCLC NCI-H441 xenograft tumor model, on day 28 of treatment, surufatinib at 80 mg / kg remarkably inhibited tumor growth with 60.5% TGI; tazemetostat at 350 mg / kg showed no efficacy on tumor grow th inhibition with 13.9% TGI; tazemetostat in combination with surufatinib significantly increased the antitumor effect with TGI of 93.3% and showed a significant synergistic combinational effect (CR value was 0.42). The combination treatment was well tolerated with no significant loss of body weight in mice.Table 10.Note: ,**, p<0.01 vs vehicle; ##, p<0.01 vs Surufatinib-80 mg / kg alone; &&, p<0.01 vs Tazemetostat - 350 mg / kg alone.Example 8: Efficacy of Tazemetostat in combination with Surufatinib in NCI-H1581 subcutaneous xenograft models

[0207] The combination benefit of tazemetostat and surufatinib cotreatment versus either monotherapy in NCI-H1581 (SMARCA2 / 4Loss) subcutaneous xenograft model in nude mice was evaluated.

[0208] Methods: Human non-small cell lung cancer (NSCLC) NCI-H1581 (ATCC®) cells were cultured and expanded in RPMI-1640 medium containing 10% fetal bovine serum. Tumor cells in logarithmic growth stage were harvested, mixed with equal volume of matrigel and implanted subcutaneously into the right flanks of BALB / c nude mice (Shanghai Lingchang BioTech Co., Ltd.) with 5 x 10bcells per mouse.

[0209] Mice were randomly divided into six groups with 8 mice per group according to tumor volume shown in Table 11: vehicle control, surufatinib-low dose (40 mg / kg), surufatinib-high dose (120 mg / kg), tazemetostat (350 mg / kg), the combination-low dose (surufatinib 40 mg / kg in combination withtazemetostat 350 mg / kg) and the combination-high dose (surufatinib 120 mg / kg in combination with tazemetostat 350 mg / kg). Tazemetostat were grinded and suspended with 0.5% CMC-Na supplement with 0.1% Tween 80, surufatinib were suspended with 0.5% CMC-Na. All compounds were administered by oral gavage according to tire schedule shown in Table 11. The tumor volumes and body weights of the mice were measured twice a week. Hie anti-tumor activity was evaluated by tumor growth inhibition.

[0210] Data analysis: The following equations were used for data analysis:Relative body weight (RBW) = (BWt / BWo) x 100%Where:BWt represents the body weight on the day post treatment;BWo represents initial body weight before treatment.Tumor volume (TV) = 0.5 x long diameter x short diameter2. Data was expressed as Mean ± standard deviation (SD).Tumor grow th inhibition rate (TGI) = [l-(TVt-TVo) drug treatment / (TVt-TVo) vehicle]x100%.Where:TVtrepresents the tumor volume on the day post treatment;TVo represents initial tumor volume before treatment.

[0211] The statistical comparison of changes in tumor volume (TVt-TVo) between two groups were analyzed using Student t-test by Excel, wherein p < 0.05 indicates a statistically significant difference, p < 0.01 as extremely statistically significant.

[0212] Combination index was expressed by CR (combination ratio) value according to following equations:CR=M(A+B> / (MAXMB)Where:MA and MB are the mean T / Cs of drug A and B alone, respectively;M(A+B) is the mean T / C of drug A plus drug B;T: TVt of treatment group, C: TVt of vehicle control group;

[0213] If CR value < 1, it should indicate synergistic effect, those w ith CR = 1, additivity, and CR >1, antagonism.

[0214] Results: As shown in Table 12. in the human NCI-H1581 xenograft tumor model, on day 21 of treatment, surufatinib at 40 and 120 mg / kg dose-dependently inhibited tumor growth with TGI of 29.2% and 70.0%, respectively. Tazemetostat at the dose of 350 mg / kg showed no tumor growth inhibition. Combination treatment of tazemetostat at 350 mg / kg with surufatinib at 40 and 120 mg / kg inhibited the tumor growth by 57.9% and 86.3%, with CR value of 0.54 and 0.44, respectively, indicating synergistic combinational anti-tumor effect. Moreover, the combination treatment was well tolerated with no obviousloss of body weight.Table 12.Note: *, p<0.05 vs vehicle, **, p<0.01 vs vehicle; ##, p<0.01 vs Surufatinib -40 mg / kg alone ; $$, p<0.01 vs Surufatinib -120 mg / kg alone ; &&, p<0.01 vs Tazemetostat alone.Example 9: Efficacy of Tazemetostat in combination with Surufatinib in LNCaP subcutaneous xenograft models

[0215] The combination benefit of Tazemetostat and Surufatinib versus either monotherapy in LNCaP(SMARCA2 / 4mut. ARIDlA / BMut) subcutaneous xenograft model in NOD-SCID mice was evaluated.

[0216] Methods: Human Prostate cancer cell line LNCaP (ATCC®) cells were cultured and expanded in RPMI-1640 medium containing 10% fetal bovine serum. Tumor cells in logarithmic growth stage were harvested, mixed with equal volume of matrigel and implanted subcutaneously into the right flanks of NOD-SCID mice (Shanghai Lingchang BioTech Co., Ltd.) with 1.3 * 107cells per mouse.

[0217] Mice were randomly divided into four groups with 6 mice per group according to tumor volume shown in Table 13: vehicle control, surufatinib (80 mg / kg), tazemetostat (200 mg / kg) and the combination (surufatinib 80 mg / kg in combination with tazemetostat 200 mg / kg). Tazemetostat were grinded and suspended with 0.5% CMC-Na supplement with 0.1% Tween 80, surufatinib were suspended with 0.5% CMC -Na, and the mice were administered according to the schedule shown in Table 13. The tumor volumes and body weights of the mice were measured twice a week. The anti-tumor activity was evaluated by tumor grow th inhibition.Table 13.Note: qd, once per day; bid, twice per day.

[0218] Data analysis: The following equations were used for data analysis:Relative body weight (RBW) = (BWt / BWo) x 100%Where:BWt represents the body weight on the day post treatment;BWo represents initial body weight before treatment.Tumor volume (TV) = 0.5 x long diameter x short diameter2. Data was expressed as Mean ± standard deviation (SD).Tumor growth inhibition rate (TGI) = [l-(TVt-TVo) drug treatment / (TVt-TVo) vehicle]x100%.Where:TVtrepresents the tumor volume on the day post treatment;TVo represents initial tumor volume before treatment.

[0219] Tire comparison of changes in tumor volume (TVt-TVo) between two groups were analyzed using Student t-test by Excel, wherein p < 0.05 indicates a statistically significant difference, p < 0.01 as extremely statistically significant.

[0220] Combination index was expressed by CR (combination ratio) Value according to following equations:CR=M(A+B) / (MAX MB) ^Where:MA and MB are the mean T / Cs of drug A and B alone, respectively;M(A+B) is the mean T / C of drug A plus drug B;T: TVtof treatment group, C: TVt of vehicle control group;

[0221] If CR value < 1, it should indicate synergy, CR value = 1, additivity, and CR value >1,antagonism.

[0222] Results: As shown in Table 14, in the human LNCaP xenograft tumor model, on day 28 of treatment, single-agent treatment of surufatinib and tazemetostat led to tumor grow th inhibition by 30.8% and 28%, respectively with no statistical significance, while their combination treatment significantly improved the anti-tumor efficacy with a TGI of 75.4% and had a CR value was 0.57, indicating synergistic anti -tumor effect. The combination treatment was well tolerated with no significant loss of body weight in mice.Table 14.Note: **, p<0.01 vs vehicle;##. p<0.01 vs Tazemetostat alone ; p<0.01 vs Surufatinib alone.Example 10. Efficacy of Tazemetostat in combination with Surufatinib in A2780 subcutaneous xenograft models

[0223] The combination benefit of tazemetostat and surufatinib cotreatment versus either monotherapy in A2780 subcutaneous xenograft model in nude mice was evaluated.

[0224] Methods: Human ovarian endometroid adenocarcinoma cell line A2780 (ECACC ®) cells were cultured and expanded in RPMI-1640 medium containing 10% fetal bovine serum. Tumor cells in logarithmic growth stage were harvested, mixed with equal volume of matrigel and implanted subcutaneously into the right flanks of BALB / c nude mice (Shanghai Lingchang BioTcch Co., Ltd.) with 3 x 106cells per mouse.

[0225] Mice were randomly divided into the following four groups with 7 mice per group according to tumor volume: vehicle control, surufatinib (80 mg / kg), tazemetostat (350 mg / kg) and the combination (surufatinib 80 mg / kg in combination with tazemetostat 350 mg / kg). Tazemetostat were grinded and suspended with 0.5% CMC-Na supplement with 0.1% Tween 80, surufatinib were suspended with 0.5% CMC -Na, and the mice were administered according to the schedule shown in Tabic 15. Tumor volumesand body weights of the mice were measured twice or three times a week, and clinical observation was done regularly and lasted for 21 days.Table 15.Note: qd. once per day: bid, twice per day.

[0226] Data analysis: The following equations were used for data analysis:Relative body weight (RBW) = (BWt / BWo) x 100%Where:BWt represents the body weight on the day post treatment;BWo represents initial body weight before treatment.Tumor volume (TV) = 0.5 x long diameter x short diameter2.

[0227] To analyze anti-tumor activity for each groups on delaying tumor growth and increased life span (ILS), Kaplan Meier survival analysis was applied: the study endpoint or censor point was set as TV > 1000 mm3, median survival time (MST) was determined and differences between groups of survival were analyzed by the log-rank test, and differences were considered significant at p<0.05 or extremely statistically significant at p<0.01.

[0228] Percentage increase in life span (ILS) was calculated by the formula:ILS (%) = [(MSTdmg treated ” M^STvehicle control) / M^STyehicle control] X 1OO%Where:MST represented median survival time;

[0229] If a treated group prolonged 25% ILS and showed significantly statistic difference (p<0.05), it would be considered as positive drug effect.

[0230] Results: As shown in Table 16 and FIG. 3. in the human ovarian cancer A2780 xenograft tumor model, the median survival time of vehicle group was 10 days; surufatinib alone prolonged the MST to 19 days with a corresponding ILS at 90%, the same ILS was also observed in tazemetostat monotherapy group:the combination treatment significantly improved the MST since no any animal reached the endpoint at day 21, and statistical significance (p<0.01) was achieved when compared with either of single agent treatment groups. The combination treatment was well tolerated with no significant loss of body weight in mice during treatment.Table 16.

[0231] While we have described a number of embodiments of this disclosure, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

CLAIMS1. A method of treating a disease or disorder characterized by aberrant, misregulated, or increased EZH2 activity and / or expression comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising tazemetostat, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from amdizalisib and surufatinib, or a pharmaceutically acceptable salt thereof.

2. A method of treating a cancer selected from lymphoma, lung cancer, prostate cancer, and ovarian cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a combination therapy comprising tazemetostat, or a pharmacally acceptable salt thereof, and one or more additional therapeutic agents selected from amdizalisib and surufatinib, or a pharmaceutically acceptable salt thereof.

3. A method of treating a cancer selected from lymphoma, lung cancer, prostate cancer, and ovarian cancer, comprising administering to a patient in need thereof a therapeutically effective amount of tazemetostat, or a pharmacally acceptable salt thereof, wherein the patient is receiving or has received an additional therapeutic agent selected from amdizalisib and surufatinib, or a pharmaceutically acceptable salt thereof.

4. The method of any one of claims 1-3, wherein the method comprises administering about 200 mg to about 800 mg tazemetostat, or a pharmacally acceptable salt thereof, twice daily.

5. The method of claim 4, wherein tire method comprises administering about 800 mg tazemetostat, or a pharmaceutically acceptable salt thereof, twice daily.

6. The method of any one of claims 1-5, wherein the method comprises administering tazemetostat hydrobromide.

7. The method of any one of claim 1-6, wherein tazemetostat is administered orally.

8. The method of any one of claims 1-7, wherein the additional therapeutic agent is amdizalisib, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the patient is suffering from lymphoma.

10. The method of claim 8, wherein the patient is suffering from relapsed or refractory lymphoma.

11. Tire method of claim 8, wherein the patient is suffering from diffuse large B-cell lymphoma.

12. The method of claim 8, wherein the patient is suffering from follicular lymphoma.

13. The method of claim 8, wherein the patient is suffering from mantle cell lymphoma.

14. Tire method of claim 8, wherein the patient is suffering from peripheral T-cell lymphoma.

15. The method of any one of claims 11-14, wherein the lymphoma is relapsed or refractory lymphoma.

16. The method of any one of claims 9-15, wherein the patient has undergone at least two prior lines of standard therapy.

17. The method of any one of claims 9-1 , wherein the patient has undergone at least one prior line of standard therapy.

18. The method of any one of claims 9-15, wherein the patient has not undergone any prior lines of standard therapy.

19. The method of any one of claims 8-18, wherein the method comprises administering about 5 mg to about 40 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD) or about 2.5 mg to about 10 mg amdizalisib, or a pharmaceutically acceptable salt thereof, twice daily (BID).

20. Tire method of claim 19, wherein the method comprises administering about 5 mg to about 40 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD).

21. The method of claim 20, wherein the method comprises administering about 20 mg amdizalisib. or a pharmaceutically acceptable salt thereof, once daily (QD).

22. Tire method of claim 20, wherein the method comprises administering about 30 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD).

23. The method of any one of claims 8-22, wherein amdizalisib is administered orally.

24. Tire method of any one of claims 1-7, wherein the additional therapeutic agent is surufatinib, or a pharmacally acceptable salt thereof.

25. The method of claim 24, wherein the patient is suffering from small cell lung cancer.

26. Tire method of claim 24, wherein the patient is suffering from non-small cell lung cancer.

27. The method of claim 24, wherein the patient is suffering from prostate cancer.

28. The method of claim 24, wherein the patient is suffering from ovarian cancer.

29. Tire method of any one of claims 24-28, wherein the method comprises administering about 50 mg to about 400 mg surufatinib, or a pharmacally acceptable salt thereof, once daily (QD).

30. The method of claim 29, wherein the method comprises administering about 200 mg surufatinib, or a pharmaceutically acceptable salt thereof, once daily (QD).

31. Tire method of claim 29, wherein tire method comprises administering about 250 mg surufatinib, or a pharmacally acceptable salt thereof, once daily (QD).

32. The method of claim 29, wherein the method comprises administering about 300 mg surufatinib, or a pharmaceutically acceptable salt thereof, once daily (QD).

33. Tire method of any one of claims 24-32, wherein surufatinib is administered orally.

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