Use of EZH2 inhibitors in the preparation of therapeutic agents for T-cell lymphoma

Abstract

The present invention relates to the use of EZH2 inhibitor in the preparation of medicament for treating T cell lymphoma.Specifically, the present invention relates to the use of the compound represented by formula (I) or its pharmaceutically acceptable salt in the preparation of medicament for treating T cell lymphoma. [Formula 1] TIFF2024530310000005.tif46168

Description

[Technical field]

[0001] This application claims priority to Chinese Patent Application No. 2021110016631, filed on August 30, 2021. This application cites the aforementioned Chinese patent application in full.

[0002] The present disclosure relates to the use of an EZH2 inhibitor for the preparation of a medicament for treating T-cell lymphoma, which belongs to the field of pharmacy. [Background technology]

[0003] Enhancer of zeste homolog 2 (EZH2) is a central component of the histone methyltransferase PRC2 (polycomb repressive complex 2). It represses the expression of target genes by catalyzing the trimethylation of lysine 27 at the N-terminus of histone H3 (H3K27Me3) and inducing and maintaining transcriptional repression of chromatin. Most of these target genes play important roles in maintaining embryonic development and resistance to cellular senescence by suppressing cell proliferation and promoting cell differentiation.

[0004] Peripheral T-cell lymphomas (PTCLs), also known as mature T-cell lymphomas, are a group of malignant proliferative disorders with clear heterogeneity that originate from mature T-lymphocytes. NK cell lymphomas and mature T-cell lymphomas are often grouped into one category because the immune symptoms and functions of NK cells are similar to those of T cells.

[0005] At present, there is no standard treatment regimen for PTCL. The usual first-line treatment is CHOP or CHOP-like regimen, with a 5-year survival rate of only about 30%. For relapsed or refractory PTCL (rrPTCL), it is recommended in China and abroad to conduct clinical trials first. Other class I experts recommend treatments including new drugs alone and in combination with chemotherapy, but the efficacy of traditional chemotherapy is not ideal. Currently, chidamide and prasatraxa are approved in China for the treatment of rrPTCL, with ORRs of 27-52% and PFS of 2.1-4.8 months. However, for patients who relapsed or are refractory after treatment with new drugs, there has been no effective treatment so far. In conclusion, the efficacy of traditional chemotherapy in relapsed or refractory PTCL is not ideal. Histone deacetylase (HDAC) inhibitors and folate inhibitors have been approved for use in such patients, but the improvement in efficacy is limited. Summary of the Invention [Problem to be solved by the invention]

[0006] Currently, there is a need to develop and market newer, more effective drugs to improve the prognosis of patients with relapsed or refractory PTCL. [Means for solving the problem]

[0007] The disclosure provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for the treatment of T-cell lymphoma. [ka]

[0008] In some embodiments, the T cell lymphoma of the present disclosure is a peripheral T cell lymphoma (mature T cell lymphoma and NK cell lymphoma).

[0009] In some embodiments, the T cell lymphoma of the present disclosure is angioimmunoblastic T cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), peripheral T lymphoma non-specific (PTCL-NOS), or NK / T cell lymphoma (NKTCL).

[0010] In some embodiments, unless otherwise specified, the T cell lymphoma of the present disclosure is angioimmunoblastic T cell lymphoma or peripheral T lymphoma.

[0011] In some embodiments, the T cell lymphoma of the present disclosure is angioimmunoblastic T cell lymphoma.

[0012] In some embodiments, unless otherwise specified, the T cell lymphoma of the present disclosure is a peripheral T lymphoma.

[0013] In some embodiments, the T cell lymphoma of the present disclosure is relapsed / refractory peripheral T cell lymphoma.

[0014] In some embodiments, the T cell lymphoma of the present disclosure is a peripheral T cell lymphoma that has undergone first line chemotherapy.

[0015] In some embodiments, the T cell lymphoma of the present disclosure is a peripheral T cell lymphoma that has received at least one treatment selected from a histone deacetylase inhibitor, a folate metabolism inhibitor, or an anti-CD30 monoclonal antibody.

[0016] In some embodiments, the T cell lymphoma of the present disclosure is a peripheral T cell lymphoma that has undergone first-line chemotherapy and at least one treatment selected from a histone deacetylase inhibitor, a folate metabolism inhibitor, or an anti-CD30 monoclonal antibody.

[0017] In some embodiments, the dosage of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is selected from 1 mg to 800 mg, administered once or twice daily.

[0018] In some embodiments, the dosage of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof is 2.5 mg, 5.0 mg, 7.5 mg, 10.0 mg, 12.5 mg, 15.0 mg, 17.5 mg, 20.0 mg, 22.5 mg, 25.0 mg, 27.5 mg, 30.0 mg, 32.5 mg, 35.0 mg, 37.5 mg, 40.0 mg, 42.5 mg, 45.0 mg, 47.5 mg, 50.0 mg, 52.5 mg, 55.0 mg, 57.5 mg, 60.0 mg, 62.5 mg, 65.0 mg, 67.5 mg, 70.0 mg, 72.5 mg, 75.0 mg, 76.0 mg, 78.0 mg, 79.0 mg, 80.0 mg, 81.0 mg, 82.0 mg, 83.0 mg, 84.0 mg, 85.0 mg, 86.0 mg, 87.0 mg, 88.0 mg, 89.0 mg, 90.0 mg, 91.0 mg, 92.5 mg, 93.0 mg, 94.0 mg, 95.0 mg, 96.0 mg, 97.0 mg, 98.0 mg, 99.0 mg, 100.0 mg, 101.0 mg, 102.0 mg, 103.0 mg, 104.0 mg, 105.0 mg, 106.0 mg, 107.0 mg, 108.0 mg, 109.0 mg, 110.0 mg, 111.0 mg, 112.0 mg, 113.0 mg, 11 117 .5mg, 120.0mg, 122.5mg, 125.0mg, 127.5mg, 130.0mg, 132.5mg, 135.0mg, 137.5mg, 140.0mg, 142.5mg, 145.0mg, 147.5mg, 150.0mg, 152.5mg, 155.0mg, 157.5mg, 160.0mg, 162.5mg, 165.0mg, 167.5mg, 170.0mg, 172.5mg, 175.0mg, 177.5mg, 180.0mg, 182.5mg, 185.0mg, 187.5mg, 190.0mg, 192.5mg, 195.0 23 5.0mg, 237.5mg, 240.0mg, 242.5mg, 245.0mg, 247.5mg, 250.0mg, 252.5mg, 255.0mg, 257.5mg, 260.0mg, 262.5mg, 265.0mg, 267.5mg, 270.0mg, 272.5mg , 275.0mg, 277.5mg, 280.0mg, 282.5mg, 285.0mg, 287.5mg, 290.0mg, 292.5mg, 295.0mg, 297.5mg, 300.0mg, 302.5mg, 305.0mg, 307.5mg, 310.0mg, 312.5mg, 315.0mg, 317.5mg, 320.0mg, 322.5mg, 325.0mg, 327.5mg, 330.0mg, 332.5mg, 335.0mg, 337.5mg, 340.0mg, 342.5mg, 345.0mg, 347.5mg, 350.0mg, 352.5mg, 355.0mg, 357.5mg, 360.0mg, 362.5mg, 365.0mg, 367.5mg, 370.0mg, 372.5mg, 375.0mg, 377.5mg, 380.0mg, 382.5mg, 385.0mg, 387.5mg, 390.0m g、392.5mg、395.0mg、397.5mg、400.0mg、402.5mg、405.0mg、407.5mg、410.0mg、412.5mg、415.0mg、417.5mg、420.0mg、422.5mg、425.0mg、427.5mg、430 .0mg、432.5mg、435.0mg、437.5mg、440.0mg、442.5mg、445.0mg、447.5mg、450.0mg、452.5mg、455.0mg、457.5mg、460.0mg、462.5mg、465.0mg、467.5mg、 470.0mg, 472.5mg, 475.0mg, 477.5mg, 480.0mg, 482.5mg, 485.0mg, 487.5mg, 490.0mg, 492.5mg, 495.0mg, 497.5mg, 500.0mg, 502.5mg, 505.0mg, 507.5mg, 510.0mg, 512.5mg, 515.0mg, 517.5mg, 520.0mg, 522.5mg, 525.0mg, 527.5mg, 530.0mg, 532.5mg, 535.0mg, 537.5mg, 540.0mg, 542.5mg, 545.0mg, 54 7.5mg, 550.0mg, 552.5mg, 555.0mg, 557.5mg, 560.0mg, 562.5mg, 565.0mg, 567.5mg, 570.0mg, 572.5mg, 575.0mg, 577.5mg, 580.0mg, 582.5mg, 585.0mg, 587.5mg, 590.0mg, 592.5mg, 595.0mg, 597.5mg, 600.0mg, 602.5mg, 605.0mg, 607.5mg, 610.0mg, 612.5mg, 615.0mg, 617.5mg, 620.0mg, 622.5mg, 625.0mg, 627.5mg, 630.0mg, 632.5mg, 635.0mg, 637.5mg, 640.0mg, 642.5mg, 645.0mg, 647.5 mg, 650.0mg, 652.5mg, 655.0mg, 657.5mg, 660.0mg, 662.5mg, 665.0mg, 667.5mg, 670.0mg , 672.5mg, 675.0mg, 677.5mg, 680.0mg, 682.5mg, 685.0mg, 687.5mg, 690.0mg, 692.5mg, 695.0mg, 697.5mg, 700.0mg, 702.5mg, 705.0mg, 707.5mg, 710.0mg, 712.5mg, 715.0mg, 71 7.5mg, 720.0mg, 722.5mg, 725.0mg, 727.5mg, 730.0mg, 732.5mg, 735.0mg, 737.5mg, 740 .0mg, 742.5mg, 745.0mg, 747.5mg, 750.0mg, 752.5mg, 755.0mg, 757.5mg, 760.0mg, 762.5 mg, 765.0 mg, 767.5 mg, 770.0 mg, 772.5 mg, 775.0 mg, 777.5 mg, 780.0 mg, 782.5 mg, 785.0 mg, 787.5 mg, 790.0 mg, 792.5 mg, 795.0 mg, 797.5 mg or 800.0 mg, administered once or twice daily.

[0019] In some embodiments, the dosage of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof is selected from 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg, administered once or twice daily.

[0020] In some embodiments, the dosage of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is selected from 50 mg, 100 mg, 200 mg, 300 mg, 350 mg, or 400 mg, administered once a day or twice a day.

[0021] In some embodiments, the dosage of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is selected from 200 mg, 300 mg, or 350 mg, administered once a day or twice a day.

[0022] In some embodiments, the dosage of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is 200 mg administered once or twice daily.

[0023] In some embodiments, the dosage of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is 300 mg, administered once or twice daily.

[0024] In some embodiments, the dosage of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is 350 mg, administered once or twice daily.

[0025] In some embodiments, the dosage of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is selected from 200 mg, 300 mg, or 350 mg administered twice daily.

[0026] In some embodiments, the dosage of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is 200 mg administered twice daily.

[0027] In some embodiments, the dosage of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is 300 mg administered twice daily.

[0028] In some embodiments, the dosage of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof is 350 mg administered twice daily.

[0029] Another aspect of the present disclosure provides a method for treating T-cell lymphoma by administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0030] Another aspect of the present disclosure provides a method of treating T-cell lymphoma, comprising administering to a patient 1 to 800 mg of a compound of formula (I) or a pharma- ceutically acceptable salt thereof once or twice daily.

[0031] In some embodiments, the present disclosure provides a method of treating T cell lymphoma with a 28 day dosing cycle.

[0032] Another aspect of the disclosure provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of T-cell lymphoma.

[0033] As used in this disclosure, the term "patient" means a human.

[0034] Acetylase inhibitors described in this disclosure include, but are not limited to, chidamide, belistat, or romidesin. Folate metabolism inhibitors include, but are not limited to, prasa. Anti-CD30 antibodies include, but are not limited to, brentuximab vedotin.

[0035] Another aspect of the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable carriers. The pharmaceutical composition may be specially formulated in a solid or liquid dosage form, particularly for oral or topical administration.

[0036] The disclosure further provides the use of a composition comprising a compound of Formula (I) or a pharma- ceutically acceptable salt thereof and one or more pharma- ceutically acceptable carriers in the preparation of a medicament for the treatment of T-cell lymphoma.

[0037] "Pharmaceutically acceptable carrier" as described in this disclosure means any type of non-toxic inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation excipient.Some examples of substances that can be pharmaceutically acceptable carriers are sugars, such as lactose, or cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate.

[0038] In an optional embodiment, the patient of the present disclosure has been treated with first line chemotherapy and at least one new drug (chidamide, prasa, brentuximab vedotin): -CD30 systemic ALCL: Treat with brentuximab vedotin -NKTCL: Treat with asparaginase / peraspartase regimen -Other subtypes: Treatment with CHOP or CHOP-like regimens (including but not limited to CHOEP, BV+CHP).

[0039] In this disclosure, when relapsed / refractory is described, relapsed refers to the occurrence of progressive disease after response to the last line of treatment, and refractory refers to failure to respond to the last line of treatment.

[0040] ORR: defines the proportion of subjects who achieved best response of CR or PR from the start of first dose to the occurrence of PD or initiation of subsequent new antitumor treatment, whichever occurs first.

[0041] PFS: defined as the date from first dose to first documented PD or death from any cause, whichever occurs first. If the subject has still not experienced PD or death as of the data cutoff date, the cutoff date will be the date of the subject's last efficacy assessment. If the subject does not undergo tumor evaluation, the cutoff date will be the date of first drug administration and PFS will last 1 day.

[0042] DoR: Defined as the time from first assessment of CR or PR to first assessment of PD or death from any cause, whichever occurs first. If the subject has still not experienced PD or death as of the data cutoff date, the cutoff date will be the date of the subject's last efficacy assessment. Only subjects who achieved CR or PR.

[0043] Progression (PD) defines a worsening of the subject's condition due to the indication under study. Includes radiographic progression, laboratory progression, and progression of clinical symptoms and signs. The appearance of new lesions or progression of existing lesions is considered to be progressive (PD). Events that are life-threatening, require hospitalization or prolonged hospitalization, lead to permanent or severe disability / inability / impact on ability to work due to symptoms and signs of disease progression, or lead to congenital disability should not be reported as SAEs. Death due to symptoms and signs of disease progression should be reported as an SAE.

[0044] An "effective amount" or "therapeutic effective amount" of the present disclosure includes an amount sufficient to ameliorate or prevent symptoms of a medical condition or disorder. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary based on factors including the condition being treated, the patient's general health, the route and dose of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen to avoid significant side effects or toxic effects. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Specific embodiments The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0046] Embodiment 1. Efficacy Testing of Compounds of Formula (I) in Peripheral T-Cell Lymphoma 1.1 Drug: Compound of formula (1) (WO2017084494A), strength: 50 mg / tablet, 200 mg / tablet. 1.2 Dosage regimen: 350 mg twice daily, 28 days per cycle. 1.3 Inclusion criteria: Relapsed or refractory T-lymphocytic lymphoma.

[0047] A total of 24 patients with relapsed or refractory PTCL were enrolled in the 350 mg group, of which 16 received chidamide, and all patients were analyzed for efficacy data without distinction between prior and prior chidamide therapy. For details, see Table 1.

[0048] [Table 1]

[0049] Twenty-four patients with PTCL were enrolled, with an ORR of 50%, including 9 patients with PTCL-NOS and 15 patients with AITL. The ORRs in the two groups were 44.4% and 53.3%, respectively. In the ES set, 18 patients had an ORR of 66.7%, including 7 patients with PTCL-NOS and 11 patients with AITL. The ORRs in the two groups were 57.1% and 72.7%, respectively.

[0050] Of the 24 enrolled PTCL patients, 16 patients received chidamide, with an ORR of 56.3%, including 6 PTCL-NOS patients and 10 AITL patients. The ORRs in the two groups were 66.7% and 50.0%, respectively. In the ES set, 14 patients had an ORR of 64.3%, including 6 PTCL-NOS patients and 8 AITL patients. The ORRs in the two groups were 66.7% and 62.5%, respectively.

Claims

1. A composition for the treatment of T-cell lymphoma, said composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. 【Chemical 1】

2. The composition of claim 1 , wherein the T-cell lymphoma is peripheral T-cell lymphoma (PTCL).

3. 2. The composition of claim 1, wherein the T-cell lymphoma is relapsed or refractory PTCL (rrPTCL).

4. 2. The composition of claim 1, wherein the T-cell lymphoma is angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), peripheral T-lymphoma-not specific (PTCL-NOS), or NK / T-cell lymphoma (NKTCL).

5. The composition described in claim 4, wherein the T-cell lymphoma is AITL.

6. The composition described in claim 4, wherein the T-cell lymphoma is ALCL.

7. The composition of claim 2, wherein the peripheral T-cell lymphoma is a peripheral T-cell lymphoma that has been treated with first-line chemotherapy.

8. The composition of claim 7, wherein the chemotherapy comprises CHOP, CHOEP, or BV+CHP.

9. The composition described in claim 1, wherein the peripheral T-cell lymphoma is a peripheral T-cell lymphoma being treated with first-line chemotherapy and at least one treatment selected from a histone deacetylase inhibitor, a folate metabolism inhibitor, or an anti-CD30 monoclonal antibody.

10. The composition described in claim 1, wherein the peripheral T-cell lymphoma is a peripheral T-cell lymphoma being treated with a histone deacetylase inhibitor, a folate metabolism inhibitor, or an anti-CD30 monoclonal antibody.

11. The composition of any one of claims 1 to 10, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day or twice a day at a dosage of 1 mg to 800 mg.

12. The composition of claim 11, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily or twice daily at a dosage selected from the group consisting of 200 mg, 300 mg, and 350 mg.

13. The composition of claim 11, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dosage of 300 mg once a day or twice a day.

14. The composition of claim 13, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily.

15. The composition of claim 11, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once a day or twice a day at a dosage of 350 mg.

16. The composition of claim 15, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily.

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