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WO2025166537A1 - Méthodes de traitement utilisant un modulateur d'ezh2 - Google Patents

Méthodes de traitement utilisant un modulateur d'ezh2

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Publication number
WO2025166537A1
WO2025166537A1 PCT/CN2024/076295 CN2024076295W WO2025166537A1 WO 2025166537 A1 WO2025166537 A1 WO 2025166537A1 CN 2024076295 W CN2024076295 W CN 2024076295W WO 2025166537 A1 WO2025166537 A1 WO 2025166537A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
patient
acceptable salt
tazemetostat
surufatinib
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/076295
Other languages
English (en)
Inventor
Yongxin Ren
Songhua Fan
Jia Hu
Dongmei Chen
Shiming FAN
Huijing YU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hutchmed Ltd
Epizyme Inc
Original Assignee
Hutchmed Ltd
Epizyme Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hutchmed Ltd, Epizyme Inc filed Critical Hutchmed Ltd
Priority to PCT/CN2024/076295 priority Critical patent/WO2025166537A1/fr
Priority to PCT/CN2024/095035 priority patent/WO2025166944A1/fr
Priority to PCT/US2025/014602 priority patent/WO2025171012A1/fr
Publication of WO2025166537A1 publication Critical patent/WO2025166537A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to methods of treatment comprising administration of an enhancer-of-zeste-homolog-2 (EZH2) modulator.
  • EZH2 enhancer-of-zeste-homolog-2
  • the present disclosure relates to combination therapies comprising an EZH2 modulator and one or more additional therapeutic agents.
  • EZH2 a histone methyltransferase, has been associated with various cancers and poor clinical outcomes.
  • 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 non-Hodgkin’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) .
  • 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 tazemetostat, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.
  • a disease or disorder characterized by aberrant, misregulated, or increased EZH2 activity and/or expression e.g., a cancer
  • the present disclosure provides methods of treating a hematological malignancy.
  • the present disclosure provides methods of treating a solid tumor.
  • 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.
  • 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 e.g., prostate cancer, and ovarian cancer.
  • 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) .
  • a combination of certain agents e.g., an EZH2 inhibitor and one or more additional therapeutic agents
  • FIG. 1B is a graph showing the results of an in vitro study of tazemetostat in combination with amdizalisib in a Farage cell line.
  • 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.
  • FIG. 3 is a Kaplan Meier survival curve of tazemetostat in combination with surufatinib in a human A2780 xenograft tumor model.
  • administering 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. ) .
  • 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.
  • 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.
  • 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.
  • one or more particular routes of administration may be feasible and/or useful in the practice of the present disclosure.
  • administration may be
  • the term “patient, ” means an animal, preferably a mammal, and most preferably a human.
  • a 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.
  • 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.
  • 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.
  • 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.
  • a therapeutically effective amount is administered in a single dose; in some embodiments, multiple unit doses are required to deliver a therapeutically effective amount.
  • relapsed or refractory disease 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 is an oral small molecule inhibitor of enhancer-of-zeste-homolog-2 (EZH2) .
  • EZH2 is a histone methyltransferase (HMT) that is the catalytic subunit of the polyprotein HMT complex, called Polycomb Inhibitory Complex 2 (PRC2) , responsible for the mono-, di-, and tri-methylation of histone H3 lysine 27 (H3K27) .
  • HMT histone methyltransferase
  • PRC2 Polycomb Inhibitory Complex 2
  • 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.
  • R/R refractory follicular lymphoma
  • Tazemetostat has the following structure:
  • Tazemetostat is also known as N- ( (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -5- (ethyl (tetrahydro-2H-pyran-4-yl) amino) -4-methyl-4'- (morpholinomethyl) - [1, 1'-biphenyl] -3-carboxamide.
  • tazemetostat is provided and/or utilized as a salt form (e.g., as a pharmaceutically acceptable salt form) .
  • 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 et al., J. Pharmaceutical Sciences, 1977, 66, 1-19.
  • Amdizalisib (HMPL-689) is a highly potent and selective inhibitor of the p110 ⁇ isoform of phosphatidylinositol 3-kinase (PI3K ⁇ ) , 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) .
  • Amdizalisib has the following structure:
  • Amdizalisib is also known as HMPL-689 or (S) -4-amino-6- ( (1- (3-chloro-6-phenylimidazo [1, 2-b]pyridazin-7-yl) ethyl) amino) pyrimidine-5-carbonitrile.
  • amdizalisib is provided and/or utilized as a salt form (e.g., as a pharmaceutically 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.
  • 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.
  • VEGFR vascular endothelial growth factor receptors
  • FGFR fibroblast growth factor receptor
  • CSF-1R colony stimulating factor-1 receptor
  • Surufatinib has been the subject of multiple clinical trials and is approved in China for treatment of pancreatic and extra-pancreatic neuroendocrine tumors (NETs) .
  • NETs pancreatic and extra-pancreatic neuroendocrine tumors
  • Surufatinib has the following structure:
  • Surufatinib is also known as sulfatinib or N- (2- (dimethylamino) ethyl) -1- (3- ( (4- ( (2-methyl-1H-indol-5-yl) oxy) pyrimidin-2-yl) amino) phenyl) methanesulfonamide.
  • surufatinib is provided and/or utilized as a salt form (e.g., as a pharmaceutically 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.
  • 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.
  • a disease or disorder characterized by aberrant, misregulated, or increased EZH2 activity and/or expression e.g., a cancer
  • 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.
  • 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
  • the present disclosure provides methods of treating human B cell lymphoma (e.g., follicular lymphoma or diffuse large B cell lymphoma) .
  • the present disclosure provides methods of treating human T cell lymphoma (e.g., peripheral T-cell lymphoma) .
  • 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) .
  • DLBCL diffuse large B cell lymphoma
  • the present disclosure provides methods of treating follicular lymphoma (FL) , e.g., a Grade 1-3a FL 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) .
  • the present disclosure provides methods of treating mantle cell lymphoma (MCL) .
  • MCL mantle cell lymphoma
  • PTCL peripheral T-cell lymphoma
  • the present disclosure provides methods of treating lung cancer (e.g., small cell lung cancer or non-small cell lung cancer) .
  • the present disclosure provides methods of treating prostate cancer.
  • the present disclosure provides methods of treating ovarian cancer.
  • the present disclosure provides methods of treating refractory or relapsed cancer.
  • the present disclosure provides methods of treating previously untreated cancer.
  • 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) amdizalisib, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.
  • the lymphoma is previously untreated lymphoma.
  • the lymphoma is refractory or relapsed lymphoma.
  • 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.
  • a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.
  • the patient has failed prior standard treatment.
  • the patient has had no standard treatment.
  • the patient had progressed on prior standard treatment.
  • the patient is refractory to prior standard treatment.
  • 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.
  • a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.
  • the DLBCL is previously untreated DLBCL.
  • the DLBCL is refractory or relapsed DLBCL.
  • 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.
  • a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.
  • the patient is suffering from Grade 3b DLBCL.
  • the patient has undergone at least two prior lines of standard therapy (e.g., alkylator/anthracycline/anti-CD20-based therapy) .
  • the patient is considered unable to benefit from intensive treatment with autologous hematopoietic stem cell transplantation (ASCT) .
  • ASCT autologous hematopoietic stem cell transplantation
  • 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.
  • the present disclosure provides a method of treating 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.
  • a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.
  • the FL is previously untreated FL.
  • the FL is refractory or relapsed FL.
  • 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.
  • a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.
  • the patient is suffering from Grade 3b FL.
  • the patient is suffering from Grade 1-3a FL.
  • the patient has undergone at least two prior lines of standard therapy (e.g., alkylator/anthracycline/anti-CD20-based therapy) .
  • the patient is considered unable to benefit from intensive treatment with autologous hematopoietic stem cell transplantation (ASCT) .
  • ASCT autologous hematopoietic stem cell transplantation
  • 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.
  • the patient has undergone at least two systemic prior therapies, including at least one anti-CD20-based regimen.
  • a patient has undergone one anti-CD20-based regimen.
  • 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.
  • a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.
  • the patient has undergone one prior line of systemic standard chemotherapy containing a CD20 monoclonal antibody.
  • the patient has previously received a Bruton’s tyrosine kinase (BTK) inhibitor.
  • BTK Bruton’s tyrosine kinase
  • 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.
  • a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.
  • the PTCL is previously untreated PTCL.
  • the PTCL is refractory or relapsed PTCL.
  • 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 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.
  • a combination therapy comprising (i) tazemetostat, or a pharmaceutically acceptable salt thereof; and (ii) amdizalisib, or a pharmaceutically acceptable salt thereof.
  • the patient has undergone at least one prior standard systemic therapy.
  • the patient has not undergone an effective standard therapy.
  • a patient has a life expectancy of greater than or equal to 12 weeks.
  • a patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
  • ECG Eastern Cooperative Oncology Group
  • a patient exhibits adequate bone marrow function (e.g., an absolute neutrophil count ⁇ 1.5 ⁇ 10 9 /L, hemoglobin ⁇ 9.0 g/dL, and platelets ⁇ 75 ⁇ 10 9 /L) .
  • a patient exhibits adequate renal function (e.g., creatinine clearance > 40 mL/min) .
  • a patient exhibits adequate hepatic function (e.g., serum total bilirubin ⁇ 1.5 ⁇ 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 ⁇ ULN ( ⁇ 5 ⁇ ULN if the subject has liver metastases) .
  • adequate hepatic function e.g., serum total bilirubin ⁇ 1.5 ⁇ 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 ⁇ ULN ( ⁇ 5 ⁇
  • 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) .
  • MDS/AML/MPN myelodysplastic syndrome
  • MPN e.g., JAK2 V617F
  • a patient does not have a history of T-cell lymphoblastic lymphoma (T-LBL) or T-cell acute lymphoblastic leukemia (T-ALL) .
  • T-LBL T-cell lymphoblastic lymphoma
  • T-ALL T-cell acute lymphoblastic leukemia
  • a patient is not taking strong or moderate inducers or strong inhibitors of cytochrome P450 3A4 (CYP3A42) .
  • a patient is not suffering from toxicity from prior anticancer therapy which has not recovered to ⁇ Grade 1.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • provided combination therapies are administered according to a regimen demonstrated to achieve a particular effect.
  • 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 (C max ) , trough concentration (C min ) , time to peak concentration (T max ) , elimination half-life (t 1/2 ) , area under the plasma concentration-time curve (AUC 0-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.
  • ORR objective response rate
  • C complete response
  • DCR
  • H3K27me3 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) .
  • a combination therapy provided herein (e.g., tazemetostat in combination with amdizalisib or surufatinib) .
  • 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) .
  • 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.
  • 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.
  • 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.
  • a compound herein e.g., tazemetostat
  • 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.
  • 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) .
  • 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.
  • tazemetostat is administered orally. In some embodiments, tazemetostat is administered with or without food.
  • 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) .
  • provided methods comprise administering to a patient in need thereof 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 about 40 mg amdizalisib, or a pharmaceutically acceptable salt thereof, once daily (QD) .
  • 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 pharmaceutically acceptable salt thereof, twice daily (BID) .
  • 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 pharmaceutically 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 pharmaceutically acceptable salt thereof, of about 15 mg.
  • 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 pharmaceutically 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.
  • amdizalisib is administered orally.
  • provided methods comprise administering to a patient in need thereof (i) about 200 mg to about 800 mg tazemetostat, 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, once daily (QD) or about 2.5 mg to about 10 mg amdizalisib, or a pharmaceutically acceptable salt thereof, twice daily (BID) .
  • 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) .
  • 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) .
  • 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) .
  • 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) .
  • provided methods comprise administering to a patient in need thereof about 50 mg to about 400 mg surufatinib, 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 surufatinib, or a pharmaceutically acceptable salt thereof, once daily (QD) . In some embodiments, provided methods comprise administering to a patient in need thereof about 100 mg surufatinib, 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 surufatinib, or a pharmaceutically acceptable salt thereof, once daily (QD) .
  • provided methods comprise administering to a patient in need thereof about 250 mg surufatinib, 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 surufatinib, 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 surufatinib, 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 surufatinib, or a pharmaceutically acceptable salt thereof, once daily (QD) .
  • provided methods comprise administering to a patient in need thereof a total daily dose of surufatinib, or a pharmaceutically 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 surufatinib, 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 surufatinib, 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 surufatinib, or a pharmaceutically acceptable salt thereof, of about 200 mg.
  • 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.
  • surufatinib is administered orally.
  • provided methods comprise administering to a patient in need thereof (i) about 200 mg to about 800 mg tazemetostat, or a pharmaceutically 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) .
  • 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.
  • 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.
  • a dose holiday e.g., an agent is administered for three weeks, followed by a one-week dose holiday
  • 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) .
  • a provided combination therapy is administered to a patient in need thereof according to a dosing regimen until symptoms of disease are
  • provided combination therapies are administered as one or more unit dosage forms.
  • a “unit dosage form” refers to a physically discrete unit of an active agent (e.g., a therapeutic agent) for administration to a patient.
  • an active agent e.g., a therapeutic agent
  • 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 forms.
  • tazemetostat is administered to a patient in a unit dosage form.
  • a unit dosage form is a capsule or tablet.
  • a unit dosage form comprises about 200 mg tazemetostat, or a pharmaceutically acceptable salt thereof.
  • amdizalisib is administered to a patient in a unit dosage form.
  • a unit dosage form is a capsule or tablet.
  • a unit dosage form comprises about 5 mg to about 40 mg amdizalisib, or a pharmaceutically acceptable salt thereof.
  • a unit dosage form comprises about 5 mg amdizalisib, or a pharmaceutically acceptable salt thereof.
  • a unit dosage form comprises about 10 mg amdizalisib, or a pharmaceutically acceptable salt thereof.
  • a unit dosage form comprises about 20 mg amdizalisib, or a pharmaceutically acceptable salt thereof.
  • a unit dosage form comprises about 30 mg amdizalisib, or a pharmaceutically acceptable salt thereof.
  • a unit dosage form comprises about 40 mg amdizalisib, or a pharmaceutically acceptable salt thereof.
  • surufatinib is administered to a patient in a unit dosage form.
  • a unit dosage form is a capsule or tablet.
  • a unit dosage form comprises about 50 mg to about 400 mg surufatinib, or a pharmaceutically acceptable salt thereof.
  • a unit dosage form comprises about 50 mg surufatinib, or a pharmaceutically acceptable salt thereof.
  • a unit dosage form comprises about 100 mg surufatinib, or a pharmaceutically acceptable salt thereof.
  • a unit dosage form comprises about 200 mg surufatinib, or a pharmaceutically acceptable salt thereof.
  • a unit dosage form comprises about 300 mg surufatinib, or a pharmaceutically acceptable salt thereof.
  • a unit dosage form comprises about 400 mg surufatinib, or a pharmaceutically acceptable salt thereof.
  • provided methods comprise administering one or more compositions comprising one or more therapeutic agents (e.g., tazemetostat, amdizalisib, or surufatinib) .
  • 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.
  • provided compositions are formulated for oral administration.
  • 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 pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, 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.
  • compositions of this disclosure refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • 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
  • compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the 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.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1, 3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • compositions for use in provided methods may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • 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.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • 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, corn, germ, olive, castor, and sesame oils) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • 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 mono
  • 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 the 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.
  • 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.
  • 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 is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • 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.
  • buffering agents include polymeric substances and waxes.
  • Example 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
  • Tazemetostat 800 mg twice daily (BID, approximately 12 hours apart) orally (with or without food) continuously.
  • HMPL-689 The starting dose is 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.
  • Phase IIb Dose Expansion Phase (Phase IIb) : Recommended Phase II dose (RP2D) .
  • Dose Escalation Phase (Phase IIa): 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.
  • MTD maximum tolerated dose
  • RP2D maximum tolerated dose
  • Dose Expansion Phase (Phase IIb): To evaluate the efficacy of tazemetostat in combination with HMPL-689 in patients with lymphoma.
  • Dose Escalation Phase (Phase IIa) : To assess the preliminary efficacy of tazemetostat in combination with HMPL-689.
  • Dose Expansion Phase (Phase IIb): To evaluate tazemetostat safety and tolerability in combination with HMPL-689 in patients with R/R lymphoma
  • Phase IIa and IIb To evaluate the pharmacokinetics (PK) profile of tazemetostat combined with HMPL-689 in patients with R/R lymphoma
  • Dose Escalation Phase Phase IIa : Dose limiting toxicity (DLT) ; RP2D and/or MTD.
  • Dose Expansion Phase Phase IIb: Primary efficacy endpoint is objective response rate (ORR) . Secondary efficacy endpoints are complete response (CR) rate, disease control rate (DCR) , duration of response (DOR) , time to response (TTR) , and progression-free survival (PFS) .
  • ORR objective response rate
  • DCR disease control rate
  • DOR duration of response
  • TTR time to response
  • PFS progression-free survival
  • Dose Escalation Phase (Phase IIa) : ORR, CR rate, DCR, DOR, TTR, and PFS.
  • Dose Expansion Phase Phase IIb: Incidence, severity, and causality to study drug of treatment-emergent adverse events (TEAEs) as determined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE 5.0) .
  • Phase IIa and IIb To evaluate the PK profile of Tazemetostat (including its metabolite EPZ-6930, N- ( (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4-methyl-4'- (morpholinomethyl) -5- ( (tetrahydro-2H-pyran-4-yl) amino) - [1, 1'-biphenyl] -3-carboxamide) ; to evaluate the PK profile of HMPL-689; and to preliminarily evaluate the relationship between efficacy, safety, tolerability, and PK.
  • Tazemetostat including its metabolite EPZ-6930, N- ( (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl) -4-methyl-4'- (morpholinomethyl) -5- ( (tetrahydro-2H-pyran-4-yl) amino) - [1, 1'-biphen
  • phase II clinical study of tazemetostat combined with HMPL-689 in patients with R/R lymphoma.
  • the study includes 2 phases: a dose escalation phase (phase IIa) and a dose expansion phase (phase IIb) .
  • RP2D will be determined based on the further safety and preliminary efficacy determine the RP2D.
  • DLT is defined as a patient who experiences, 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) :
  • G-CSF granulocyte-colony stimulating factor
  • DLT evaluable patients are defined as those who meet both of the following criteria during the DLT assessment window:
  • the total dose of HMPL-689 and tazemetostat received during DLT assessment is no less than 70%of the planned dose.
  • MTD is defined as the maximum dose at which ⁇ 33%of patients experience DLT during the DLT observation period.
  • patients can receive subsequent study drug treatment or dose reduction or discontinuation, according to the dose modification principle defined in protocol.
  • 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.
  • a Drug Safety Monitoring Committee consisting of the Principal Investigator or other designated investigators, the Sponsor's Clinical Project Leader, Medical Monitor, Safety Reporting Liaison, and PK scientists, is 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.
  • Multiple expansion cohorts are set up according to different tumor types, and about 15-20 patients are 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 include patients who had progressed on or were refractory to standard therapy.
  • Cohort 1 Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) Grade 3b, relapsed/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) :
  • Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) Grade 3b relapsed/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 auto
  • Cohort 2A is initiated firstly, and the decision on whether to start cohort 2B is made after efficacy evaluation.
  • PTCL Peripheral T-cell lymphoma
  • AEs are graded according to NCI CTCAE V5.0. All patients are monitored for safety and all serious adverse events (SAEs) are reported after signing the informed consent form (ICF) and prior to first dose. Patients are closely monitored for safety and all AEs are 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 are reported after 30 days of the final dose or the initiation of a new antineoplastic therapy, whichever occurs first.
  • SAEs/study protocol defined adverse events of special interest (AESIs) with a reasonable possibility of relationship to study treatment as confirmed by the investigator are reported after 30 days of the final dose or the initiation of a new antineoplastic therapy, whichever occurs first.
  • tumor tissue or peripheral blood samples are 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.
  • Tumor assessments are 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 discontinue 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 anticancer 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.
  • ⁇ ORR defined as the proportion of patients who achieved CR or PR.
  • ⁇ PFS defined as the time from the first dose of study drug to disease recurrence/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.
  • Blood samples for PK analysis are collected per protocol.
  • Plasma samples are collected by venipuncture for the determination of plasma concentrations of HMPL-689, tazemetostat, and EPZ-6930. The detection of drug concentration in plasma is completed in the laboratory designated by the Sponsor. Blood samples are collected, processed and transported according to the requirements in the study-specific laboratory manual.
  • Concentrations of HMPL-689, tazemetostat, and its metabolite EPZ-6930 in plasma are determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.
  • Phase IIa dose escalation study patients with relapsed or refractory lymphoma who have failed standard treatment and have no standard treatment options
  • ⁇ 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) , and must be considered unable to benefit from intensification treatment with ASCT, defined as meeting at least 1 of the following criteria:
  • ⁇ Cohort 3 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.
  • BTK Bruton's tyrosine kinase
  • PTCL Cohort 4
  • Absolute neutrophil count (ANC) ⁇ 1.5 ⁇ 10 9 /L, hemoglobin ⁇ 9.0 g/dL, platelets ⁇ 75 ⁇ 10 9 /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) ;
  • Alkaline phosphatase (ALP, in the absence of bone disease) , alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ⁇ 3 ⁇ ULN ( ⁇ 5 ⁇ ULN if the subject has liver metastases) ;
  • HIV human immunodeficiency virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • CMV cytomegalovirus
  • a double contraception method includes condoms, sponge plugs, foam, contraceptive jelly, diaphragm or intrauterine device, contraceptives (oral or parenteral) , implant 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.
  • MDS 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.
  • MPN multiple primary neoplasms
  • T-LBL T-cell lymphoblastic lymphoma
  • T-ALL T-cell acute lymphoblastic leukemia
  • Toxicity from prior anticancer therapy has not recovered to ⁇ Grade 1 prior to the first dose of study drug (except alopecia) ;
  • Non-cytotoxic chemotherapeutic agents e.g., small molecule inhibitors
  • Radioisotope therapy less than 6 weeks
  • Prednisone at a dose not to exceed 10 mg/day (or equivalent corticosteroid) for control of lymphoma-related symptoms is permitted in C1D1, with the intent to taper by the end of cycle 1.
  • This study is an exploratory Phase II study and there are no formal statistical hypotheses for the dose escalation phase.
  • the sample size is mainly determined based on feasibility and regulatory requirements.
  • stage 1 10 patients will be enrolled first; if ⁇ 1 patient is observed to have an objective response, this cohort study will be terminated 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.
  • Analytical Procedure In general, all variables obtained at each observation time point are statistically described, unless the protocol states that statistical description is not required at a specific time point. Continuous variables (such as age) are statistically described using the number of observations, mean, quartiles, standard deviation, minimum and maximum; categorical variables are statistically described using the frequency and percentage of each category. For time-to-event variables, data are summarized using the Kaplan-Meier method. If data allowed, medians and quartiles are calculated. The number of people with events and deletions are also presented and Kaplan-Meier curves are plotted.
  • Analysis Sets The analysis sets involved in statistical analysis mainly include:
  • FAS Full Analysis Set
  • DLT Analysis Set includes all DLT evaluable patients. This analysis set is used for analysis and summary of DLT events.
  • PK analysis set includes all patients who have at least one dose of study drug and have at least one PK sampling and analysis.
  • the safety profile is 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 are graded according to NCI CTCAE V5.0, and coded using the Medical Dictionary for Regulatory Activities (MedDRA) . The number and frequency of AEs is summarized by system organ class (SOC) and preferred term (PT) . Changes in laboratory test results are summarized according to NCI CTCAE V5.0 grading. Changes in vital signs and ECOG performance status scores are compared with baseline levels for descriptive statistics. For laboratory parameters, the maximum toxicity occurring during the study is summarized in the form of counts and percentages.
  • SOC system organ class
  • PT preferred term
  • PK parameters are analyzed based on the PKAS. Non-compartmental analysis of the plasma drug concentration obtained at the central laboratory is performed using PhoenixWinNonlin. Descriptive statistics are presented for all relevant PK parameters for HMPL-689, tazemetostat, and if applicable, its metabolite EPZ-6930.
  • the main PK parameters include but are not limited to: peak concentration (C max ) , trough concentration (C min ) , time to peak concentration (T max ) , elimination half-life (t 1/2 ) , area under the plasma concentration-time curve (AUC 0-t ) , apparent clearance (CL/F) , apparent volume of distribution (Vz/F) and accumulation ratio (AR) .
  • DLBCL diffuse large B-cell lymphoma
  • CTCL cutaneous T-cell lymphoma
  • WT wild type.
  • 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 (Tecan 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 IC 50 of each agent.
  • cell viability was determined via detecting ATP concentration using (Promega) luminescent assay.
  • Inhibition rate (%) (1- (Luminescence Compound -Luminescence Background ) / (Luminescence DMSO -Luminescence Background ) ) ⁇ 100%
  • Luminescence Compound represents the luminescence intensity of cells with tested compound
  • Luminescence Background represents the luminescence intensity of cell medium (without cells)
  • Luminescence DMSO represents the luminescence intensity of cells with DMSO only
  • EOB Score 100 ⁇ (Y a b, O - (Y a +Y b -Y a ⁇ Y b ) )
  • Y a represents the observed inhibition rate with tazemetostat treated alone at dose a
  • Y b represents the observed inhibition rate with amdizalisib treated alone at dose b
  • O represents the observed combined inhibition rate with tazemetostat at dose a and amdizalisib at dose b.
  • Example 3 In vivo efficacy study of tazemetostat in combination with amdizalisib in SU-DHL-6 subcutaneous xenograft model
  • DLBCL Human diffuse large B-cell lymphoma
  • SU-DHL-6 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 ⁇ 10 7 cells 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) .
  • vehicle control tazemetostat (250 mg/kg)
  • amdizalisib 50 mg/kg
  • 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 mm 3 . The anti-tumor activity was evaluated by tumor growth inhibition.
  • Relative body weight (RBW) (BW t /BW 0 ) ⁇ 100%
  • BW t represents the body weight on the day post treatment
  • BW 0 represents initial body weight before treatment.
  • Tumor volume (TV) 0.5 ⁇ long diameter ⁇ short diameter 2 .
  • Data was expressed as Mean ⁇ standard deviation (SD) .
  • Tumor growth inhibition rate [1- (TV t -TV 0 ) drug treatment / (TV t -TV 0 ) vehicle control ] ⁇ 100%.
  • TV t represents the tumor volume on the day post treatment
  • TV 0 represents initial tumor volume before treatment.
  • 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:
  • M (A+B) is the mean T/C of drug A with drug B;
  • T TV t of treatment group
  • C TV t of vehicle control group
  • 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.
  • Example 4 Efficacy of Tazemetostat in combination with Surufatinib in DMS-114 subcutaneous xenograft models
  • 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 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 3. The tumor volumes and body weights of the mice were measured twice a week. The anti-tumor activity was evaluated by tumor growth inhibition.
  • Relative body weight (RBW) (BW t /BW 0 ) ⁇ 100%
  • BW t represents the body weight on the day post treatment
  • BW 0 represents initial body weight before treatment.
  • Tumor volume (TV) 0.5 ⁇ long diameter ⁇ short diameter 2 .
  • Data was expressed as Mean ⁇ standard deviation (SD) .
  • Tumor growth inhibition rate [1- (TV t -TV 0 ) drug treatment / (TV t -TV 0 ) vehicle ] ⁇ 100%.
  • TV t represents the tumor volume on the day post treatment
  • TV 0 represents initial tumor volume before treatment.
  • Combination index was expressed by CR (combination ratio) value according to following equations:
  • M A and M B 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 TV t of treatment group
  • C TV t of vehicle control group
  • Example 5 Efficacy of Tazemetostat in combination with Surufatinib in NCI-H82 subcutaneous xenograft models
  • Tumor volume (TV) 0.5 ⁇ long diameter ⁇ short diameter 2 .
  • Data was expressed as Mean ⁇ standard deviation (SD) .
  • TV t represents the tumor volume on the day post treatment
  • TV 0 represents initial tumor volume before treatment.
  • Combination index was expressed by CR (combination ratio) Value according to following equations:
  • M A and M B 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 TV t of treatment group
  • C TV t of vehicle control group
  • SCLC Human small cell lung cancer
  • mice were randomly divided into six groups with 8 mice per group according to tumor volume shown in Table 7: vehicle control, surufatinib (80 mg/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. The tumor volumes and body weights of the mice were measured twice a week. The anti-tumor activity was evaluated by tumor growth inhibition.
  • BW t represents the body weight on the day post treatment
  • BW 0 represents initial body weight before treatment.
  • Tumor growth inhibition rate [1- (TV t -TV 0 ) drug treatment / (TV t -TV 0 ) vehicle ] ⁇ 100%.
  • TV t represents the tumor volume on the day post treatment
  • TV 0 represents initial tumor volume before treatment.
  • TRR tumor regression rate
  • TRR (TV 0 -TV t ) /TV 0 ⁇ 100%
  • Combination index was expressed by CR (combination ratio) Value according to following equations:
  • M A and M B 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 TV t of treatment group
  • C TV t of vehicle control group
  • Example 7 Efficacy of Tazemetostat in combination with Surufatinib in NCI-H441 subcutaneous xenograft models
  • NCI-H441 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 ⁇ 10 6 cells per mouse.
  • 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 week. The anti-tumor activity was evaluated by tumor growth inhibition.
  • Relative body weight (RBW) (BW t /BW 0 ) ⁇ 100%
  • BW t represents the body weight on the day post treatment
  • BW 0 represents initial body weight before treatment.
  • Tumor volume (TV) 0.5 ⁇ long diameter ⁇ short diameter 2 .
  • Data was expressed as Mean ⁇ standard deviation (SD) .
  • Tumor growth inhibition rate [1- (TV t -TV 0 ) drug treatment / (TV t -TV 0 ) vehicle ] ⁇ 100%.
  • TV t represents the tumor volume on the day post treatment
  • Combination index was expressed by CR (combination ratio) value according to following equations:
  • M A and M B 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 TV t of treatment group
  • C TV t of vehicle control group
  • Example 8 Efficacy of Tazemetostat in combination with Surufatinib in NCI-H1581 subcutaneous xenograft models
  • NCI-H1581 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 ⁇ 10 6 cells per mouse.
  • 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 with tazemetostat 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 the schedule shown in Table 11. The tumor volumes and body weights of the mice were measured twice a week. The anti-tumor activity was evaluated by tumor growth inhibition.
  • BW t represents the body weight on the day post treatment
  • BW 0 represents initial body weight before treatment.
  • Tumor volume (TV) 0.5 ⁇ long diameter ⁇ short diameter 2 .
  • Data was expressed as Mean ⁇ standard deviation (SD) .
  • TV t represents the tumor volume on the day post treatment
  • TV 0 represents initial tumor volume before treatment.
  • Combination index was expressed by CR (combination ratio) value according to following equations:
  • M A and M B 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 TV t of treatment group
  • C TV t of vehicle control group
  • Example 9 Efficacy of Tazemetostat in combination with Surufatinib in LNCaP subcutaneous xenograft models
  • Human Prostate cancer cell line LNCaP 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 ⁇ 10 7 cells per mouse.
  • 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 growth inhibition.
  • Relative body weight (RBW) (BW t /BW 0 ) ⁇ 100%
  • BW t represents the body weight on the day post treatment
  • BW 0 represents initial body weight before treatment.
  • Tumor volume (TV) 0.5 ⁇ long diameter ⁇ short diameter 2 .
  • Data was expressed as Mean ⁇ standard deviation (SD) .
  • Tumor growth inhibition rate [1- (TV t -TV 0 ) drug treatment / (TV t -TV 0 ) vehicle ] ⁇ 100%.
  • TV t represents the tumor volume on the day post treatment
  • TV 0 represents initial tumor volume before treatment.
  • Combination index was expressed by CR (combination ratio) Value according to following equations:
  • M A and M B 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 TV t of treatment group
  • C TV t of vehicle control group
  • Human ovarian endometroid adenocarcinoma cell line A2780 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 3 ⁇ 10 6 cells per mouse.
  • 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 Table 15. Tumor volumes and body weights of the mice were measured twice or three times a week, and clinical observation was done regularly and lasted for 21 days.
  • Relative body weight (RBW) (BW t /BW 0 ) ⁇ 100%
  • BW t represents the body weight on the day post treatment
  • BW 0 represents initial body weight before treatment.
  • Tumor volume (TV) 0.5 ⁇ long diameter ⁇ short diameter 2 .
  • ILS (%) [ (MST drug treated -MST vehicle control ) /MST vehicle control ] ⁇ 100%
  • MST represented median survival time
  • 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.

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Abstract

L'invention concerne des méthodes de traitement utilisant un modulateur d'EZH2 (par exemple, le tazémétostat). Dans certains modes de réalisation, les méthodes de traitement consistent en une polythérapie utilisant un modulateur d'EZH2 (par exemple, le tazémétostat) et un agent thérapeutique supplémentaire.
PCT/CN2024/076295 2024-02-06 2024-02-06 Méthodes de traitement utilisant un modulateur d'ezh2 Pending WO2025166537A1 (fr)

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BISSERIER MALIK, WAJAPEYEE NARENDRA: "Mechanisms of resistance to EZH2 inhibitors in diffuse large B-cell lymphomas", BLOOD, ELSEVIER, AMSTERDAM, NL, vol. 131, no. 19, 10 May 2018 (2018-05-10), AMSTERDAM, NL, pages 2125 - 2137, XP093342683, ISSN: 0006-4971, DOI: 10.1182/blood-2017-08-804344 *
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