Method for treating peripheral t cell lymphoma

Abstract

A method for treating peripheral T cell lymphoma. Specifically, the present invention relates to use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in combination with the CHOP combination or CHOEP combination in the preparation of a drug for treating mature lymphocytic tumors.

Description

A method for treating peripheral T-cell lymphoma Technical Field

[0001] This disclosure relates to a method for treating peripheral T-cell lymphoma, and belongs to the field of medicine. Background Technology

[0002] Peripheral T-cell lymphoma (PTCL), also known as mature T-cell lymphoma, is a group of highly heterogeneous malignant proliferative diseases originating from mature T cells. Because NK cells (Nature Killer Cells) have similar immunophenotypes and functions to T cells, NK-cell lymphoma and mature T-cell lymphoma are often grouped together (Mature T-cell and NK-cell neoplasms, T / NKCL). China accounts for approximately 25%–30% of NHL cases, significantly higher than in Europe and the United States.

[0003] For newly diagnosed PTCL, both domestic and international guidelines recommend CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone) and CHOP-like ± brentuximab vedotin regimens as first-line treatments. Except for ALK-positive anaplastic large cell lymphoma (ALK+ALCL), these regimens have poor efficacy against other pathological subtypes. Although autologous stem cell transplantation (ASCT) may improve the long-term prognosis of some patients, 80-90% of patients are unable to receive first-line or salvage hematopoietic stem cell transplantation due to disease status or physical limitations. WO2017084494A discloses an EZH2 inhibitor, which has been preliminarily shown to be effective in treating PTCL. Considering the urgent need for more new and effective drugs to improve the prognosis of PTCL patients, this disclosure provides a novel method for treating mature T-lymphocyte tumors using an EZH2 inhibitor in combination with CHOP or CHOEP. Summary of the Invention

[0004] This disclosure provides the use of an EZH2 inhibitor in combination with the CHOP or CHOEP combination in the preparation of a medicament for treating mature lymphocytic tumors.

[0005] Specifically, this disclosure provides the use of the compound of formula (I) or its pharmaceutically acceptable salt in combination with the CHOP or CHOEP combination in the preparation of a medicament for treating mature lymphocytic tumors.

[0006] The CHOP combination includes cyclophosphamide, doxorubicin, vincristine, and prednisone; the CHOEP combination includes cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone.

[0007] In another aspect, this disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which, in combination with the CHOP combination or the CHOEP combination, is used to treat mature lymphocytic tumors.

[0008] Another aspect of this disclosure provides a CHOP combination or CHOEP combination, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used to treat mature lymphocytic tumors.

[0009] This disclosure also provides a method for treating mature lymphocytic tumors by administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with CHOP or CHOEP.

[0010] In some embodiments, the use or method provided in this disclosure refers to a mature lymphocyte tumor as a peripheral T-cell lymphoma.

[0011] In some embodiments, the uses or methods provided in this disclosure are for the peripheral T-cell lymphoma that is newly diagnosed.

[0012] In this disclosure, cyclophosphamide in the CHOP or CHOEP combination is an alkylating agent, which means an agent that exerts an anticancer effect by inhibiting cell proliferation through alkylation of cancer cell DNA.

[0013] In this disclosure, doxorubicin in the CHOP or CHOEP combination is an anti-tumor antibiotic substance that exerts its anti-cancer effect by inhibiting DNA synthesis in cancer cells, cleaving DNA chains, and inhibiting topoisomerase II. Optionally, it can be replaced by daunorubicin or epirubicin. Doxorubicin can also be replaced by other agents that exert their anti-cancer effect by inhibiting DNA synthesis in cancer cells, cleaving DNA chains, and inhibiting topoisomerase II.

[0014] In this disclosure, vincristine in the CHOP or CHOEP combination is an antitumor alkaloid or its derivative. Optionally, it can be replaced by vinorelbine, vincristine, or vinorelbine. Vincristine can also be replaced by other antitumor alkaloids or their derivatives.

[0015] In this disclosure, prednisone in the CHOP or CHOEP combination is a hormonal agent that exerts its anticancer effect by inhibiting the secretion and action of a predetermined hormone. Prednisone may be optionally replaced by prednisolone, methylprednisolone, or dexamethasone. Prednisone may also be replaced by other hormonal agents that exert their anticancer effect by inhibiting the secretion and action of a predetermined hormone. Prodrugs of the above agents (which are converted into the agents in the body) are also included in this disclosure.

[0016] In this disclosure, any new combination formed by replacing any component of the CHOP combination or CHOEP combination with a similar drug is still generally referred to in the art as the CHOP combination or CHOEP combination.

[0017] In some embodiments, the use or method provided in this disclosure, the dosage of the cyclophosphamide is 300-1000 mg / m². 2 Specifically, it can be selected from 300mg / m 2 350mg / m 2 400mg / m 2 450mg / m 2 500mg / m 2 550mg / m 2 600mg / m 2 650mg / m 2 700mg / m 2 750mg / m 2 800mg / m 2 850mg / m 2 900mg / m 2 950mg / m 2 and 1000mg / m 2 , or the value between any two points.

[0018] In some embodiments, the use or method provided in this disclosure, the dosage of the cyclophosphamide is 750 mg / m². 2 Administered via intravenous injection.

[0019] In some embodiments, the doxorubicin dosage provided in this disclosure is 1-100 mg / m². 2 Specifically, 1 mg / m 2 5mg / m 2 10mg / m 2 15mg / m 2 20mg / m 2 25mg / m 2 30mg / m 2 35mg / m 2 40mg / m 2 45mg / m 2 50mg / m 2 55mg / m 2 60mg / m 2 65mg / m 2 70mg / m 2 75mg / m 280mg / m 2 85mg / m 2 90mg / m 2 95mg / m 2 and 100mg / m 2 , or the value between any two points.

[0020] In some embodiments, the doxorubicin dosage provided in this disclosure is 50 mg / m². 2 Administered via intravenous injection.

[0021] In some embodiments, the vincristine dosage provided in this disclosure is selected from 0.1-3.0 mg / m². 2 Specifically, it can be selected from 0.1 mg / m 2 0.2 mg / m 2 0.3 mg / m 2 0.4 mg / m 2 0.5 mg / m 2 0.6 mg / m 2 0.7 mg / m 2 0.8 mg / m 2 0.9 mg / m 2 1.0 mg / m 2 1.1 mg / m 2 1.2 mg / m 2 1.3 mg / m 2 1.4 mg / m 2 1.5mg / m 2 1.6 mg / m 2 1.7 mg / m 2 1.8 mg / m 2 1.9 mg / m 2 2.0 mg / m 2 2.1 mg / m 2 2.2 mg / m 2 2.3 mg / m 2 2.4 mg / m 2 2.5mg / m 2 2.6 mg / m 2 2.7 mg / m 2 2.8 mg / m 2 2.9 mg / m 2 3.0 mg / m 2 , or the value between any two points.

[0022] In some embodiments, the vincristine dosage used in the purposes or methods provided in this disclosure is selected from 0.5-2.0 mg / m². 2 Administered via intravenous injection.

[0023] In some embodiments, the use or method provided in this disclosure, the dosage of vincristine is selected from 1.0-1.4 mg / m². 2 Administered via intravenous injection.

[0024] In some embodiments, the use or method provided in this disclosure, the dosage of vincristine is 1.4 mg / m². 2 The maximum dose per administration shall not exceed 2 mg, and shall be administered intravenously.

[0025] In some embodiments, the prednisone dosage provided in this disclosure is selected from 1 to 200 mg, specifically 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, or any value between any two points.

[0026] In some embodiments, the use or method provided in this disclosure, the dose of prednisone is 100 mg, administered orally.

[0027] In some embodiments, the use or method provided in this disclosure, the dosage of etoposide is selected from 1 to 250 mg / m². 2 Specifically, 1 mg / m 2 10mg / m 2 20mg / m 2 30mg / m 2 40mg / m 2 50mg / m 2 60mg / m 2 70mg / m 2 80mg / m 2 90mg / m 2 100mg / m 2 110mg / m 2 120mg / m 2 130mg / m 2 140mg / m 2 150mg / m 2 160mg / m 2 170mg / m 2 180mg / m 2190mg / m 2 200mg / m 2 210mg / m 2 220mg / m 2 230mg / m 2 240mg / m 2 250mg / m 2 , or the value between any two points.

[0028] In some embodiments, the dosage of etoposide described in this disclosure is 100 mg / m². 2 Administered via intravenous injection.

[0029] In some embodiments, the use or method provided in this disclosure, the administration period is 21 days.

[0030] In some embodiments, the CHOP combination administration method provided in this disclosure is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.0-1.4 mg / m². 2 The medication is administered on day 1 of each dosing cycle; the dose of prednisone is 100 mg, administered on days 1-5 of each dosing cycle; each dosing cycle is 21 days. In the event of a dose interruption, the dosing cycle shall be adjusted as needed.

[0031] In some embodiments, the CHOP combination administration method provided in this disclosure is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.4 mg / m². 2 The maximum dose per administration should not exceed 2 mg, and should be administered on day 1 of each dosing cycle; the dose of prednisone is 100 mg, administered on days 1-5 of each dosing cycle; each dosing cycle is 21 days. If a dose is interrupted, the dosing cycle should be adjusted as needed.

[0032] In some embodiments, the use or method provided in this disclosure, the CHOEP combination administration route is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.0-1.4 mg / m². 2The drug is administered on day 1 of each dosing cycle; the dosage of etoposide is 100 mg / m². 2 The first day of each dosing cycle is for administration on days 1 to 3 of the dosing cycle; the dose of prednisone is 100 mg, administered on days 1 to 5 of each dosing cycle; each dosing cycle is 21 days. If a dose is interrupted, the dosing cycle should be adjusted as needed.

[0033] In some embodiments, the use or method provided in this disclosure, the CHOEP combination administration method is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.4 mg / m². 2 The maximum dose per administration should not exceed 2 mg, and should be administered on day 1 of each dosing cycle; the dosage of etoposide is 100 mg / m². 2 The first day of each dosing cycle is for administration on days 1 to 3 of the dosing cycle; the dose of prednisone is 100 mg, administered on days 1 to 5 of each dosing cycle; each dosing cycle is 21 days. If a dose is interrupted, the dosing cycle should be adjusted as needed.

[0034] In some embodiments, the use or method provided in this disclosure, wherein the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from 1-1000 mg, specifically 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or any value between any two points, and the dosing frequency is once or twice a day.

[0035] In some embodiments, the use or method provided in this disclosure, the dosage of the compound represented by formula (I) is selected from 200 mg, 250 mg, 300 mg, 350 mg, and the frequency of administration is twice a day.

[0036] In some embodiments, the use or method provided in this disclosure, the dosage of the compound represented by formula (I) is 200 mg, administered twice daily.

[0037] In some embodiments, the use or method provided in this disclosure, the dosage of the compound represented by formula (I) is 250 mg, administered twice daily.

[0038] In some embodiments, the use or method provided in this disclosure, the dosage of the compound represented by formula (I) is 300 mg, administered twice daily.

[0039] In some embodiments, the use or method provided in this disclosure, the dosage of the compound represented by formula (I) is 350 mg, administered twice daily.

[0040] In some embodiments, the CHOP combination administration method provided in this disclosure is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.0-1.4 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the dose of prednisone is 100 mg, administered on days 1-5 of each dosing cycle; each dosing cycle is 21 days; the dosage of the compound represented by formula (I) is selected from 200 mg, 250 mg, 300 mg, and 350 mg, and the dosing frequency is twice a day.

[0041] In some embodiments, the CHOP combination administration method provided in this disclosure is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.4 mg / m². 2 The maximum dose per administration shall not exceed 2 mg, and shall be administered on the first day of each administration cycle; the dose of prednisone shall be 100 mg, and shall be administered on the first to fifth days of each administration cycle; each administration cycle shall be 21 days; the dosage of the compound represented by formula (I) shall be selected from 200 mg, 250 mg, 300 mg, and 350 mg, and shall be administered twice daily.

[0042] In some embodiments, the CHOP combination administration method provided in this disclosure is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.4 mg / m². 2The maximum dose per administration shall not exceed 2 mg, and shall be administered on day 1 of each administration cycle; the dose of prednisone shall be 100 mg, and shall be administered on days 1-5 of each administration cycle; each administration cycle shall be 21 days; the dosage of the compound represented by formula (I) shall be selected from 250 mg and 300 mg, and shall be administered twice daily.

[0043] In some embodiments, the CHOP combination administration method provided in this disclosure is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.4 mg / m². 2 The maximum dose per administration shall not exceed 2 mg, and shall be administered on day 1 of each administration cycle; the dose of prednisone shall be 100 mg, and shall be administered on days 1-5 of each administration cycle; each administration cycle shall be 21 days; the dose of the compound represented by formula (I) shall be 250 mg, and shall be administered twice daily.

[0044] In some embodiments, the CHOP combination administration method provided in this disclosure is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.4 mg / m². 2 The maximum dose per administration shall not exceed 2 mg, and shall be administered on day 1 of each administration cycle; the dose of prednisone shall be 100 mg, and shall be administered on days 1-5 of each administration cycle; each administration cycle shall be 21 days; the dose of the compound represented by formula (I) shall be 300 mg, and shall be administered twice daily.

[0045] In some embodiments, the use or method provided in this disclosure, the CHOEP combination administration route is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.0-1.4 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the dosage of etoposide is 100 mg / m². 2The drug is administered on day 1 of each dosing cycle, from day 1 to day 3 of each dosing cycle; the dose of prednisone is 100 mg, administered on day 1 to day 5 of each dosing cycle; each dosing cycle is 21 days; the dosage of the compound represented by formula (I) is selected from 200 mg, 250 mg, 300 mg, and 350 mg, and the dosing frequency is twice a day.

[0046] In some embodiments, the use or method provided in this disclosure, the CHOEP combination administration method is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.4 mg / m². 2 The maximum dose per administration should not exceed 2 mg, and should be administered on day 1 of each dosing cycle; the dosage of etoposide is 100 mg / m². 2 The drug is administered on day 1 of each dosing cycle, from day 1 to day 3 of each dosing cycle; the dose of prednisone is 100 mg, administered on day 1 to day 5 of each dosing cycle; each dosing cycle is 21 days; the dosage of the compound represented by formula (I) is selected from 200 mg, 250 mg, 300 mg, and 350 mg, and the dosing frequency is twice a day.

[0047] In some embodiments, the use or method provided in this disclosure involves administration for 6-8 cycles.

[0048] In some embodiments, the use or method provided in this disclosure involves administration for 6 cycles.

[0049] In some implementations, the uses or methods provided in this disclosure achieve an objective response rate (ORR) ≥ 75%.

[0050] In some implementations, the uses or methods provided in this disclosure achieve an objective response rate (ORR) of ≥80%.

[0051] In some implementations, the uses or methods provided in this disclosure achieve an objective response rate (ORR) of ≥85%.

[0052] In some implementations, the uses or methods provided in this disclosure achieve an objective response rate (ORR) ≥ 90%.

[0053] In some implementations, the uses or methods provided in this disclosure result in an objective response rate (ORR) ≥ 75% after the completion of combination therapy.

[0054] In some implementations, the uses or methods provided in this disclosure result in an objective response rate (ORR) ≥ 80% after the completion of combination therapy.

[0055] In some embodiments, the uses or methods provided in this disclosure include the step of maintaining treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof as a monotherapy after combination therapy has ended.

[0056] In an optional implementation, during the maintenance treatment phase, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is selected from 1-1000 mg, specifically 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, or any value between any two points, and the dosing frequency is once or twice a day.

[0057] In an optional implementation, during the maintenance treatment phase, the dosage of the compound represented by formula (I) is selected from 200 mg, 250 mg, 300 mg, and 350 mg, and the administration frequency is twice a day.

[0058] In an optional implementation, during the maintenance treatment phase, the compound represented by formula (I) is administered at a dose of 350 mg twice daily.

[0059] In some embodiments, the peripheral T-cell lymphomas described in this disclosure are selected from the group consisting of:

[0060] The combined administration methods described in this disclosure are selected from simultaneous administration, independently prepared and co-administered, or independently prepared and sequentially administered.

[0061] The combined routes of administration described in this disclosure are selected from oral administration, parenteral administration, and transdermal administration, wherein parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

[0062] In the scheme described in this disclosure, the combination may optionally include other components, including but not limited to other anti-tumor drugs.

[0063] The uses or methods provided in this disclosure can significantly prolong progression-free survival (PFS) compared to existing treatment options.

[0064] The uses or methods provided in this disclosure can significantly prolong overall survival (OS) compared to existing treatment options.

[0065] The uses or methods provided in this disclosure can significantly prolong progression-free survival (PFS) and overall survival (OS) compared to existing treatment options.

[0066] Terminology Explanation

[0067] The term "newly diagnosed peripheral T-cell lymphoma" as used in this disclosure refers to patients or subjects who have not received systemic anti-PTCL treatment.

[0068] The term "combination" as used in this disclosure refers to a route of administration that involves administering at least one dose of an EZH2 inhibitor in combination with CHOP or CHOPE over a specified time period, wherein all administered drugs exhibit pharmacological effects. The time period can be within a single dosing cycle, specifically within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours.

[0069] The EZH2 inhibitor and the CHOP or CHOPE combination can be administered simultaneously or sequentially. This duration includes treatment in which the EZH2 inhibitor and the CHOP or CHOPE combination are administered via the same or different routes of administration. The combined administration methods described in this disclosure are selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.

[0070] An "effective amount" includes the amount sufficient to improve or prevent the symptoms or condition of a medically diagnosed disease. An effective amount also means the amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0071] Progression-free survival (PFS) is defined as the date from the first dose of medication to the first recorded date of progression of disease (PD) or death from any cause, whichever comes first.

[0072] Objective response rate (ORR): Defined as the proportion of subjects who achieve CR or partial response (PR) from the first dose to the onset of PD or the start of subsequent new anti-tumor therapy, whichever comes first.

[0073] Duration of Response (DOR): Defined as the time from the first assessment of CR or PR to the first assessment of PD or death from any cause, whichever comes first.

[0074] Treatment response time (TTR): defined as the time from the date of first administration to the first assessment of CR or PR.

[0075] Overall Survival (OS): Defined as the time from the date of first administration to the subject's death from any cause. Detailed Implementation

[0076] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0077] Example 1. An open-label, multicenter phase Ib / II clinical trial of the compound shown in formula (I) in combination with CHOP / CHOEP for treatment-naïve peripheral T-cell lymphoma.

[0078] 1.1. Research Objectives

[0079] 1.1 Main Research Objectives

[0080] The safety and tolerability of the compound shown in Formula (I) in combination with CHOP / CHOEP in patients with treatment-naïve peripheral T-cell lymphoma were evaluated to determine the maximum tolerated dose (MTD) and the recommended dose for use in a phase II clinical trial (RP2D).

[0081] 1.2 Secondary Research Objectives

[0082] Preliminary evaluation of the efficacy of the compound CHOP / CHOEP (Formula (I)) in treatment-naïve patients with peripheral T-cell lymphoma.

[0083] 1.2. Study Endpoint

[0084] 1.2.1 Primary study endpoint

[0085] Safety endpoints: incidence, severity, and abnormal laboratory indicators of adverse events (AEs).

[0086] MTD, RP2D

[0087] 1.2.2 Secondary study endpoints

[0088] Preliminary efficacy endpoints: Objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR).

[0089] 1.3 Research Design

[0090] Cohort 1:

[0091] Treatment-naïve PTCL patients were enrolled and received chemotherapy with the compound shown in formula (I) in combination with the CHOP regimen.

[0092] Selected subjects received a pre-defined dose of the compound shown in formula (I) in combination with CHOP chemotherapy, with one cycle lasting 21 days and a DLT observation period of 21 days.

[0093] CHOP: 6-8 cycles of continuous chemotherapy until treatment is terminated due to disease progression, intolerance to toxicity, or the investigator's determination that the medication must be discontinued.

[0094] Compounds shown in Formula (I): During the combination chemotherapy phase, the drug is administered twice daily at a pre-set dose; patients in complete remission after completing combination chemotherapy may continue to receive 350 mg BID until treatment is terminated due to disease progression, intolerance to toxicity, or the investigator's determination that the drug must be discontinued.

[0095] The pre-set dose groups of the compound shown in Formula (I) are 200 mg BID (starting dose), 250 mg BID, 300 mg BID, 350 mg BID and 150 mg BID (e.g., 200 mg is higher than MTD).

[0096] Aside from the initial dose, subsequent dose escalation will be determined by the Safety Monitoring Committee (SMC) based on obtained drug safety data, including discussions, to determine the dose for the next dose group and whether additional dose groups are necessary. Patients who have completed combination therapy and are in complete remission may continue treatment with 350 mg BID of the compound shown in formula (I) until disease progression, intolerable toxicity, informed withdrawal of the subject, or the investigator determines that discontinuation of the medication is necessary. The total treatment duration is recommended not to exceed 24 months.

[0097] We plan to select at least one dose group that has completed dose escalation to continue dose expansion to a total of 12-20 cases. Subjects who received the same dose level during the dose escalation phase can be included in this phase analysis.

[0098] Cohort 2:

[0099] Treatment-naïve PTCL patients aged 18-65 years were enrolled and received chemotherapy with the compound shown in formula (I) in combination with the CHOEP regimen.

[0100] CHOEP: 6-8 cycles of continuous chemotherapy until treatment is terminated due to disease progression, intolerance to toxicity, or the investigator's determination that it is necessary to discontinue the medication.

[0101] Compound (I): During the combination chemotherapy phase, the compound is administered twice daily at a pre-set dose. Patients in complete remission after completing combination chemotherapy may continue to receive compound (I) at a dose of 350 mg BID until treatment is terminated due to disease progression, intolerance to toxicity, or the investigator's decision that treatment must be discontinued.

[0102] Qualified subjects received a pre-specified dose of the compound shown in Formula (I) in combination with CHOEP chemotherapy, with one cycle lasting 21 days and a DLT observation period of 21 days. Based on the data from the treatment with the compound shown in Formula (I) in combination with CHOP, the starting dose was determined by the SMC, and it was expected that 2-3 dose groups would be selected for dose escalation (e.g., starting from the previous dose group of the compound shown in Formula (I) in combination with CHOP RP2D).

[0103] Aside from the initial dose, subsequent dose escalation will be determined by the Safety Monitoring Committee (SMC) based on obtained drug safety data, including discussions, to determine the dose for the next dose group and whether additional dose groups are necessary. Patients in remission after completing combination therapy may continue treatment with 350 mg BID of the compound shown in formula (I) until disease progression, intolerable toxicity, informed withdrawal of the subject, or the investigator's determination that discontinuation of the medication is necessary. The total treatment duration is recommended not to exceed 24 months.

[0104] We plan to select at least one dose group that has completed dose escalation to continue dose expansion to a total of 12-20 cases. Subjects who received the same dose level during the dose escalation phase can be included in this phase analysis.

[0105] 1.4 Inclusion criteria

[0106] 1. Histologically confirmed peripheral T-cell lymphoma, see Table a below for details.

[0107] Table a

[0108] 2. Has not received systemic anti-PTCL treatment.

[0109] 1.5 Drugs and Dosage Forms

[0110] The compound shown in formula (I), Prepared according to the method disclosed in WO2017084494A.

[0111] Table b

[0112] 1.6 Administration method

[0113] The compound shown in formula (I)

[0114] The medication can be administered orally after meals or on an empty stomach. Subjects should take the compound tablets shown in Formula (I) orally once in the morning and once in the evening, with an interval of 12 ± 2 hours between the two doses. One cycle is 21 days, and treatment should be discontinued until the subject discontinues the medication due to confirmed disease progression, intolerance to toxicity, or the investigator's decision that the medication must be discontinued.

[0115] CHOP administration method

[0116] Cyclophosphamide 750 mg / m 2Day 1 of each cycle; Doxorubicin 50 mg / m² 2 Day 1 of each cycle; vincristine 1.4 mg / m² 2 <Maximum dose 2mg>, Day 1 of each cycle; Prednisone 100mg, Days 1-5 of each cycle, the first day of administration marks the start of a new cycle, if no dose is taken, pause, each cycle is 21 days.

[0117] CHOEP administration method

[0118] Cyclophosphamide 750 mg / m 2 Day 1 of each cycle; Doxorubicin 50 mg / m² 2 Day 1 of each cycle; vincristine 1.4 mg / m² 2 <Maximum dose 2mg>, Day 1 of each cycle; Etoposide 100mg / m² 2 Days 1-3 of each cycle; Prednisone 100mg, days 1-5 of each cycle; the first day of administration marks the start of a new cycle, and if there is no dose, the cycle is paused, with each cycle lasting 21 days.

[0119] 1.7 Test Results

[0120] To date, 50 subjects have received treatment with the compound shown in formula (I) in combination with the CHOP regimen. The specific enrollment is as follows: 3 subjects in the 200mg dose group, 15 subjects in the 250mg dose group, and 32 subjects in the 300mg dose group (the 250mg and 300mg dose groups were expanded). All subjects have received at least one efficacy evaluation. The specific results are shown in Table 1.

[0121] Table 1.

[0122] In addition, all subjects treated with the 200mg dose group achieved remission.

[0123] Subjects in both the 250mg and 300mg dose groups have completed the combined chemotherapy phase. The disease remission status at the end of chemotherapy is shown in Table 2.

[0124] Table 2.

[0125] The clinical trial data presented in Tables 1 and 2 show that combination therapy for treatment-naïve peripheral T-cell lymphoma patients achieved a high disease remission rate.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with the CHOP or CHOEP combination in the preparation of a medicament for treating mature lymphocytic tumors. The CHOP combination includes cyclophosphamide, doxorubicin, vincristine, and prednisone; the CHOEP combination includes cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone.

2. According to claim 1, the mature lymphocyte tumor is a peripheral T-cell lymphoma.

3. The use according to claim 2, wherein the peripheral T-cell lymphoma is a newly diagnosed peripheral T-cell lymphoma.

4. The use according to any one of claims 1 to 3, wherein the doxorubicin may optionally be replaced by daunorubicin or epirubicin.

5. The use according to any one of claims 1 to 4, wherein the vincristine may optionally be replaced by vinorelbine, vinblastine, or vinorelbine.

6. The use according to any one of claims 1 to 5, wherein the prednisolone is optionally replaced by prednisolone, methylprednisolone, or dexamethasone.

7. The use according to any one of claims 1 to 6, wherein the dosage of the cyclophosphamide is selected from 300-1000 mg / m². 2 300mg / m 2 350mg / m 2 400mg / m 2 450mg / m 2 500mg / m 2 550mg / m 2 600mg / m 2 650mg / m 2 700mg / m 2 750mg / m 2 800mg / m 2 850mg / m 2 900mg / m 2 950mg / m 2 and 1000mg / m 2 The optimal concentration is 750 mg / m². 2 .

8. The use according to any one of claims 1 to 7, wherein the dosage of doxorubicin is selected from 1-100 mg / m². 2 1 mg / m 2 5mg / m 2 10mg / m 2 15mg / m 2 20mg / m 2 25mg / m 2 30mg / m 2 35mg / m 2 40mg / m 2 45mg / m 2 50mg / m 2 55mg / m 2 60mg / m 2 65mg / m 2 70mg / m 2 75mg / m 2 80mg / m 2 85mg / m 2 90mg / m 2 95mg / m 2 and 100mg / m 2 The optimal concentration is 50 mg / m². 2 .

9. The use according to any one of claims 1 to 8, wherein the dosage of vincristine is selected from 0.1-3.0 mg / m². 2 The preferred dosage is 0.5-2.0 mg / m³. 2 The optimal dosage is 1.0-1.4 mg / m². 2 .

10. The use according to any one of claims 1 to 9, wherein the dosage of prednisone is selected from 1 to 200 mg, preferably 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, and most preferably 100 mg.

11. The use according to any one of claims 1 to 10, wherein the dosage of the etoposide is selected from 1 to 250 mg / m². 2 1 mg / m 2 10mg / m 2 20mg / m 2 30mg / m 2 40mg / m 2 50mg / m 2 60mg / m 2 70mg / m 2 80mg / m 2 90mg / m 2 100mg / m 2 110mg / m 2 120mg / m 2 130mg / m 2 140mg / m 2 150mg / m 2 160mg / m 2 170mg / m 2 180mg / m 2 190mg / m 2 200mg / m 2 210mg / m 2 220mg / m 2 230mg / m 2 240mg / m 2 250mg / m 2 The optimal concentration is 100 mg / m². 2 .

12. The use according to any one of claims 1 to 11, wherein the administration period is 21 days.

13. The use according to claim 12, wherein the CHOP combination administration method is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.0-1.4 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the dose of prednisone is 100 mg, administered on days 1-5 of each dosing cycle; each dosing cycle is 21 days.

14. According to claim 12, the CHOEP combination administration method is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.0-1.4 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the dosage of etoposide is 100 mg / m². 2 The first day of each dosing cycle is day 1 to day 3 of the dosing cycle; the dose of prednisone is 100 mg, and it is administered on days 1 to 5 of each dosing cycle; each dosing cycle is 21 days.

15. The use according to any one of claims 1 to 14, wherein the dosage of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 1-1000 mg, and the frequency of administration is once or twice a day; preferably, the dosage is selected from 200 mg, 250 mg, 300 mg, or 350 mg, and the frequency of administration is twice a day; most preferably, the dosage is selected from 250 mg or 300 mg, and the frequency of administration is twice a day, particularly the dosage is 300 mg, and the frequency of administration is twice a day.

16. The use according to any one of claims 1-10, 12-13, and 15, wherein the CHOP combination administration method is as follows: the cyclophosphamide dosage is 750 mg / m². 2 Dosage is administered on day 1 of each dosing cycle; the dosage of doxorubicin is 50 mg / m². 2 The drug is administered on day 1 of each dosing cycle; the vincristine dosage is 1.4 mg / m². 2 The maximum dose per administration shall not exceed 2 mg, and shall be administered on the first day of each administration cycle; the dose of prednisone shall be 100 mg, and shall be administered on the first to fifth days of each administration cycle; each administration cycle shall be 21 days; the dosage of the compound represented by formula (I) shall be selected from 200 mg, 250 mg, 300 mg, and 350 mg, and shall be administered twice daily.

17. The use according to any one of claims 1-10, 12-13, 15-16, wherein the administration time is 6-8 cycles.

18. The use according to any one of claims 1-10, 12-13, 15-17, with an objective response rate (ORR) ≥ 75%.

19. The use according to any one of claims 1-10, 12-13, 15-18, comprising the step of maintenance therapy with the compound of formula (I) or its pharmaceutically acceptable salt as monotherapy after the completion of combination therapy.

20. In the use according to claim 19, during the maintenance treatment phase, the dosage of the compound of formula (I) or its pharmaceutically acceptable salt is selected from 1-1000 mg, and the frequency of administration is once or twice a day; preferably, the dosage of the compound of formula (I) is 350 mg, and the frequency of administration is twice a day.

21. A compound of formula (I) according to any one of claims 1-20, or a pharmaceutically acceptable salt thereof, in combination with the CHOP combination or the CHOEP combination for the treatment of mature lymphocytic tumors, preferably peripheral T-cell lymphomas, most preferably newly diagnosed peripheral T-cell lymphomas, wherein the CHOP combination comprises cyclophosphamide, doxorubicin, vincristine and prednisone; and the CHOEP combination comprises cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone.

22. A CHOP combination or CHOEP combination according to any one of claims 1-20, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is used to treat mature lymphocytic tumors, preferably peripheral T-cell lymphomas, most preferably newly diagnosed peripheral T-cell lymphomas, wherein the CHOP combination comprises cyclophosphamide, doxorubicin, vincristine and prednisone; and the CHOEP combination comprises cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone.

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