Pharmaceutical composition and use thereof

Abstract

Disclosed in the present invention are a pharmaceutical composition and the use thereof. The pharmaceutical composition of the present invention comprises linperlisib or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof, and a chemotherapy regimen drug. The pharmaceutical composition of the present invention is used for the first-line treatment of PTCL. The pharmaceutical composition may provide faster and deeper remission, prolong survival time, have better efficacy and safety in treatment-naive PTCL patients, and can greatly address the unmet clinical needs.

Description

A pharmaceutical composition and application thereof TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition and application thereof BACKGROUND

[0002] Peripheral T-cell lymphoma (PTCL) is a group of highly heterogeneous malignant proliferative diseases derived from post-thymic mature T cells, accounting for about 25-30% of non-Hodgkin lymphomas (NHLs) in China.

[0003] The rarity of PTCL greatly hinders the progress of the disease research. Most of the current chemotherapy regimens are based on the results of clinical trials involving a large number of diffuse large B-cell lymphoma (DLBCL) patients, and lack of high-quality clinical evidence to support their treatment decisions. The first-line treatment of PTCL has relied on anthracycline-containing chemotherapy regimens for decades, of which the most commonly used regimen is CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen. Although CHOP regimen treatment can achieve a higher remission rate, the relapse rate is high and the survival period is short. CHOEP regimen can improve PTCL, with greater toxicity, and no OS benefit for patients of any subtype. The attempt to replace CHOP with PEGS regimen (cisplatin, etoposide, gemcitabine and methylprednisolone) has also failed due to limited efficacy and durability.

[0004] For decades, only rituximab has been approved for the first-line treatment of PTCL, but the breakthrough of rituximab in the treatment of PTCL is only focused on CD30-positive PTCL patients, and the clinical treatment options for CD30-negative patients are still very limited. SUMMARY

[0005] The technical problem to be solved by the present application is to provide a pharmaceutical composition and application thereof to solve the defects of the existing clinical treatment of peripheral T-cell lymphoma, such as the still very limited selection.

[0006] The present application provides a pharmaceutical composition comprising rimpylrizumab or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof and a chemotherapy regimen.

[0007] The chemotherapy regimen can be a conventional chemotherapy regimen for treating tumors in the art, preferably a CHOP regimen.

[0008] The application also provides a use method of the pharmaceutical composition, which comprises the following steps: administering limupilise in combination with CHOP regimen.

[0009] The application also provides an application of the pharmaceutical composition in the preparation of a drug for treating peripheral T-cell lymphoma.

[0010] In the application, the peripheral T-cell lymphoma is preferably untreated peripheral T-cell lymphoma.

[0011] The application also provides a method for treating peripheral T-cell lymphoma, which comprises administering a therapeutically effective amount of the pharmaceutical composition to a patient (for example, a human).

[0012] The patient is preferably all PTCL patients suitable for receiving CHOP regimen first-line chemotherapy.

[0013] The peripheral T-cell lymphoma is preferably untreated peripheral T-cell lymphoma.

[0014] In the method for treating peripheral T-cell lymphoma, limupilise is combined with CHOP treatment.

[0015] In the method for treating peripheral T-cell lymphoma, limupilise 60mg / d is combined with CHOP or limupilise 80mg / d is combined with CHOP.

[0016] In the CHOP regimen, 21 days is one treatment cycle.

[0017] The method for treating peripheral T-cell lymphoma further comprises the following steps: (1) 60mg or 80mg, once a day, orally, until disease progression, intolerance or completion of 6 cycles of combined CHOP treatment;

[0018] (2) after CR and partial remission (PR) of the combined CHOP treatment, patients receive an induction treatment dose of limupilise, one cycle every 28 days, and maintain until disease progression or other reasons cause drug withdrawal, and the maintenance stage of limupilise is not more than 24 months.

[0019] Both before and after meals can be taken, and regular medication at approximately the same time every day is preferred.

[0020] Target population: all PTCL patients suitable for receiving CHOP regimen first-line chemotherapy.

[0021] In the application, the CHOP regimen is: on the first day, intravenous drip: 750mg / m 2 Cyclophosphamide, 40-50mg / m 2 Doxorubicin; 1.4-2.0mg / m 2Vincristine; 100 mg orally on days 1-5.

[0022] In the present application, each cycle of CHOP regimen is 21 days.

[0023] The present study is a single-arm, multi-center, phase Ib / II study to evaluate the safety and efficacy of linperisole in combination with CHOP regimen in the treatment of newly diagnosed PTCL. The study is divided into phase Ib safety lead-in period and phase II expansion stage. The main objective of phase Ib safety lead-in period is to determine the recommended phase II dose (RP2D) according to dose-limiting toxicity (DLT), 6 subjects are planned to be enrolled, and the safety after 1 cycle of linperisole (80 mg, once daily) in combination with CHOP regimen is observed, if < 2 DLTs occur, the RP2D of linperisole is 80 mg, once daily; if ≥ 2 DLTs occur, the RP2D of linperisole is 60 mg, once daily. Phase II is the expansion stage, and 6 cycles of linperisole RP2D in combination with CHOP regimen are used for induction treatment. All patients who achieve CR and partial remission (PR) after induction treatment receive maintenance treatment with linperisole at the induction treatment dose, 1 cycle every 28 days, until disease progression or other reasons cause drug discontinuation, and the maintenance stage of linperisole is not more than 24 months. The main objective is to evaluate the efficacy of the combination regimen, and 42 evaluable subjects are planned to be enrolled, when the RP2D is 80 mg once daily, 6 subjects in the safety lead-in period are also included in the phase II analysis.

[0024] In the present application, linperisole is a compound as shown in formula I:

[0025] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present application derived from pharmaceutically acceptable acids or bases. When the compounds of the present application contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the pharmaceutically acceptable base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine, and lysine salts. When the compounds of the present application contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the pharmaceutically acceptable acid in a pure solution or in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids which include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, phosphoric, phosphonic, sulfuric, and the like. The pharmaceutically acceptable acids include organic acids which include, but are not limited to, acetic, propionic, oxalic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, salicylic, tartaric, methanesulfonic, isonicotinic, acid citrate, oleic, tannic, pantothenic, bitartaric, ascorbic, gentisic, fumaric, gluconic, saccharic, formic, ethanesulfonic, pamoic (i.e., l, l'-methylene-bis-(2-hydroxy-3-naphthoate)) and the like. When the compounds of the present application contain both relatively acidic and relatively basic functionalities, base addition salts or acid addition salts can be formed. See, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977) or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, eds., Wiley-VCH, 2002).

[0026] The term "solvate" refers to a compound of the present application in combination with a stoichiometric or non-stoichiometric amount of solvent. The solvent molecules can be present in ordered or disordered arrangements. The solvents include, but are not limited to, water, methanol, ethanol, and the like.

[0027] The terms "pharmaceutically acceptable salt of a solvate" and "solvate" of a pharmaceutically acceptable salt" as described above refer to a compound of the present application in combination with a stoichiometric or non-stoichiometric amount of solvent, prepared from a pharmaceutically acceptable acid or base.

[0028] The term "therapeutically effective amount" refers to the amount of a compound that, when administered to a patient, is sufficient to effect treatment for a disease. The therapeutically effective amount will vary depending on the compound, the disease state being treated, the severity of the disease, the age of the patient, and the like, but can be readily determined by one of skill in the art.

[0029] The "combination therapy" of the present application can be administered concurrently or separately or sequentially in either order. When administered sequentially, the combination can be administered in two or more administrations. The combination administration includes co-administration of separate formulations and consecutive administration in either order, wherein preferably there is overlap in the time periods for which the two (or all) active agents are active in the body.

[0030] In some embodiments, the combination therapy of the present application provides synergistic and / or statistically improved effects over either monotherapy administered, while having a manageable toxicity profile in patients with PTCL.

[0031] Without deviating from the common knowledge in the art, the above-mentioned preferred conditions can be combined in any way, i.e. to obtain each preferred example of the present application.

[0032] The reagents and materials used in the present application are commercially available.

[0033] The positive progress effect of the present application is that the pharmaceutical composition can be used for first-line treatment of PTCL, which can provide faster and deeper remission, complete remission (CR) rate (67.5%), and prolong survival time, has good efficacy and safety in patients with newly diagnosed PTCL, and can greatly solve the unmet clinical needs. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 is a study design diagram.

[0035] Figure 2 is a design diagram of Study 1.

[0036] Figure 3 is a design diagram of Study 2.

[0037] Figure 4 is the response and response duration of Studies 1 and 2.

[0038] Figure 5 is the response and response duration of Study 1.

[0039] Figure 6 is the response and response duration of Study 2. DETAILED DESCRIPTION

[0040] The present application is further illustrated by the following examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples, if not specified, are selected according to conventional methods and conditions, or according to the instructions of the goods.

[0041] I. Linperis treatment effect of monotherapy

[0042] In September 2023, an NDA was submitted based on a single-arm Phase II clinical study (CTR202110333) for the treatment of adult patients with relapsed and / or refractory peripheral T / NK cell lymphoma who have received prior adequate treatment in the first line. The study was conducted in 25 centers nationwide from April 2021, and was a single-arm, open-label, multi-center, phase II design. The subjects were adult patients with histologically confirmed relapsed and / or refractory PTCL who had failed or progressed after at least one systemic treatment or could not tolerate the systemic treatment. The study treatment was lirmplisel 80 mg orally once daily for 21 consecutive days as a treatment cycle, and the treatment was continued until disease progression or toxicity could not be tolerated. The primary endpoint was ORR evaluated by the Independent Review Committee (IRC) using the 2014 Lugano as the efficacy evaluation standard. A total of 98 adult patients were included in the study, of which 10 were excluded after enrollment and confirmed by IRC evaluation as not meeting the PTCL diagnostic criteria; 88 were eligible adult patients with relapsed / refractory PTCL. Among the 88 eligible subjects, the median age was 57 (range: 25-82) years old; 56 cases (63.6%) were male; the ECOG score was 0-1; 33% were Lugano stage III; 56% were Lugano stage IV; the median number of prior treatments was 2 (range: 1-10); 73% of the subjects were refractory cases; AITL, TCL-NOS, and NK / T accounted for 59%, 30%, and 85.1%, respectively, and other types included ALK-positive or negative ALCL, MEITL, etc. Based on FAS (n=88), 42 subjects achieved remission, and the ORR was 47.7% (95% CI: 37.0%, 58.7%), of which 26 (29.5%) were CR and 16 (18.2%) were PR; the disease control rate was 68.2% (95% CI: 57.4%, 77.7%) (Table 1); the median time to response (TTR) was 1.9 (range: 1.7, 3.8) months. As of April 2023, the median duration of response (DoR) had not been reached (95% CI: 7.8 months, NR), and the 6-month DoR was 75%. The median follow-up was 14.8 months, the median PFS was 5.5 (95% CI: 3.5, 15.6) months, the 6-month OS was 75% (95% CI: 64.5%, 82.7%), and the median OS was 14.2 (95% CI: 7.9, NR) months.

[0043] Table 1 Efficacy results of lirmplisel monotherapy study *: Includes anaplastic large cell lymphoma (ALCL), ALK positive 1 case; anaplastic large cell lymphoma (ALCL), ALK negative 1 case; PTCL with CD4 phenotype 1 case; mature peripheral T-cell lymphoma 1 case; consistent with PTCL with helper T phenotype 1 case; ALCL (ALK?) 1 case; MEITL 2 cases.

[0044] The above-mentioned single-arm phase II clinical trial has preliminarily shown that luspatercept monotherapy has efficacy in relapsed / refractory PTCL patients and is controllable in safety. Among 88 relapsed / refractory PTCL adult patients, 42 subjects obtained remission, and the ORR was 47.7% (95% CI: 37.0%, 58.7%), of which 26 cases (29.5%) were CR, and 16 cases (18.2%) were PR. The median follow-up was 14.8 months, the median PFS was 5.5 (95% CI: 3.5, 15.6) months, the 6-month OS was 75% (95% CI: 64.5%, 82.7%), and the median OS was 14.2 (95% CI: 7.9, NR) months.

[0045] I. Potential risk / benefit assessment

[0046] The current data show that luspatercept monotherapy has good efficacy in PTCL and is controllable in safety. Luspatercept combined with CHOP regimen for first-line treatment of PTCL can provide faster and deeper remission and prolong survival time. However, luspatercept combined with CHOP can have toxicity superposition. In order to evaluate the safety of combination therapy, the study is divided into Ib phase safety lead-in period and II phase expansion stage. The main purpose of the Ib phase safety lead-in period is to determine the recommended phase II dose (RP2D) according to the dose-limiting toxicity (DLT). A total of 6 subjects are planned to be enrolled, and the safety of luspatercept (80 mg, once daily) combined with CHOP regimen after 1 cycle of treatment is observed. If there are < 2 DLTs, the RP2D of luspatercept is 80 mg, once daily; if there are ≥ 2 DLTs, the RP2D of luspatercept is 60 mg, once daily. After evaluating the safety of luspatercept combined with CHOP and assessing its preliminary efficacy in the Ib phase, the II phase expansion stage is entered.

[0047] II. Implementation of study treatment

[0048] (A) Selection of study population

[0049] Patients must meet all the following inclusion criteria to be eligible for data collection for this study.

[0050] 1) Pathologically confirmed PTCL, including ALK-positive anaplastic large cell lymphoma (ALCL) with IPI score > 2, ALK-negative ALCL, PTCL NOS, angioimmunoblastic T-cell lymphoma (AITL), enteropathy-associated T-cell lymphoma, and hepatosplenic T-cell lymphoma;

[0051] 2) PTCL with CD30 expression < 10%, or PTCL with CD30 expression > 10% and unable to receive treatment with brentuximab vedotin;

[0052] 3) No prior anti-tumor treatment;

[0053] 4) Presence of at least one measurable lesion: lymph node lesion longest diameter (LDi) 1.5 cm or one extranodal lesion LDi > 1 cm (according to Lugano classification 2014);

[0054] 5) Age 18-70 years, both male and female;

[0055] 6) Eastern Cooperative Oncology Group (ECOG) performance status 0-2;

[0056] 7) Life expectancy > 3 months;

[0057] 8) Adequate bone marrow and organ function;

[0058] 9) Without hemophagocytic syndrome; if the patient has clinically diagnosed hemophagocytic syndrome, after treatment with targeted anti-hemophagocytic syndrome drugs, the patient's general physical condition is assessed by the investigator to determine whether they can be enrolled.

[0059] 10) Voluntary participation in clinical research, signing informed consent, willing to follow and have the ability to complete all test procedures.

[0060] Exclusion criteria: Patients meeting any of the following exclusion criteria will not be eligible for the study:

[0061] Patients will not be included in this study if they meet any of the following conditions:

[0062] 1) Received PI3K inhibitor treatment before enrollment;

[0063] 2) History of other primary aggressive malignancy that was not in remission or remission for no more than 3 years;

[0064] 3) With central nervous system (meninges or brain parenchyma) involvement;

[0065] 4) Known allergy to any drug in the study

[0066] 5) Participated in other drug clinical trials within 4 weeks before the start of the study;

[0067] 6) Pregnant or lactating women;

[0068] 7) Active infection, except for tumor-related B symptoms fever;

[0069] 8) Comorbidities and medical history:

[0070] a) Having multiple factors affecting oral medication (such as inability to swallow, chronic diarrhea and intestinal obstruction, etc.);

[0071] b) Having a history of substance abuse and being unable to quit or having a mental disorder;

[0072] c) Subjects with any severe and / or uncontrolled illness, including:

[0073] 1. Uncontrolled blood pressure (systolic BP ≥ 150 mmHg or diastolic BP ≥ 100 mmHg);

[0074] 2. Having ≥ grade 2 myocardial ischemia or myocardial infarction, arrhythmia (including QTc ≥ 450 ms (male), QTc ≥ 470 ms (female)) and ≥ grade 2 congestive heart failure (New York Heart Association (NYHA) classification);

[0075] 3. Active interstitial pneumonia or other chronic lung disease resulting in severely impaired lung function, defined as FEV1 and DLCOc < 60% of normal predicted value; history of interstitial pneumonia due to COVID-19.

[0076] 4. Liver abnormalities:

[0077] I. Decompensated cirrhosis (Child-Pugh liver function classification of B or C grade)

[0078] II. Known history of clinically significant liver disease. Including viral hepatitis, known as hepatitis B virus (HBV) carriers must exclude active HBV infection, i.e. HBV DNA positive (> 2500 copies / mL or > 500 IU / mL, and greater than the upper limit of normal); known hepatitis C virus infection (HCV) and HCV RNA positive (> 1 x 103copies / mL). Note: HBsAg-positive subjects who meet the inclusion criteria for hepatitis B, regardless of whether their HBV DNA is measurable, must continue antiviral treatment (nucleoside analogs are recommended) and regular monitoring of HBV DNA; for subjects with hepatitis B HBcAb positive but HBsAg negative, regular monitoring of HBV DNA is required, and preventive antiviral treatment is recommended; hepatitis C subjects require regular monitoring of HCV RNA.

[0079] 5. Renal failure requiring hemodialysis or peritoneal dialysis;

[0080] 6. Subjects with uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage;

[0081] 7. Poorly controlled diabetes mellitus (fasting blood glucose (FBG) >10 mmol / L);

[0082] 8. Urine routine suggesting urine protein ≥++, and confirmed 24-hour urine protein quantification >1.0 g;

[0083] 9. History of immunodeficiency, including positive HIV test, or suffering from other acquired, congenital immunodeficiency diseases, or history of organ transplantation;

[0084] 10. According to the researchers, there are serious accompanying diseases that endanger patient safety or affect patient completion of the study.

[0085] (II) Study treatment

[0086] 1.1 Test drug

[0087] Limpidum

[0088] - Dosage form: tablet

[0089] - Specification: 20 mg / tablet

[0090] - Appearance: yellow or yellowish film-coated tablets

[0091] - Route of administration: oral

[0092] - Batch number: see drug label

[0093] - Validity period: 24 months

[0094] - Storage conditions: sealed, stored in dry place not more than 30℃

[0095] - Manufacturer: Shanghai Yeli Pharmaceutical Co., Ltd. R&D, produced and provided by designated third-party companies.

[0096] CHOP regimen: cyclophosphamide, doxorubicin, vincristine, prednisone

[0097] Dosage form, specification, appearance, route of administration, batch number, validity period, storage conditions, manufacturer, etc. See drug instructions.

[0098] 1.2 Study drug dosage and route of administration

[0099] The primary objective of the Phase lb safety run-in period is to determine the recommended Phase II dose (RP2D) based on dose-limiting toxicities (DLTs) and to evaluate the safety of 6 subjects after 1 cycle of induction treatment with lym- pilase (80 mg once daily) in combination with CHOP. If < 2 DLTs are observed, the RP2D of lym- pilase is 80 mg once daily. If > 2 DLTs are observed, the RP2D of lym- pilase is 60 mg once daily.

[0100] Phase II is an expansion phase with 6 cycles of lym- pilase RP2D in combination with CHOP for induction treatment. All patients who achieve CR and partial remission (PR) after induction treatment receive maintenance treatment with lym- pilase at the induction treatment dose, 1 cycle every 28 days, until disease progression or other reasons for discontinuation. The maintenance phase of lym- pilase is not to exceed 24 months. The primary objective is to evaluate the efficacy of the combination regimen. 42 evaluable subjects are planned to be enrolled. When the RP2D is 80 mg once daily, the 6 subjects in the safety run-in period are also included in the analysis of Phase II.

[0101] Lym-pilase can be taken before or after meals, and the medication should be taken at approximately the same time each day, if possible.

[0102] CHOP regimen:

[0103] CHOP a Dosing and schedule

[0104] IV: intravenous infusion; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone

[0105] a The intravenous infusion of the CHOP regimen can be completed within 2 days. b If, during the study, a drug is lacking, an equivalent replacement can be made. For example, epirubicin: 70 mg / m2, D1, intravenous infusion

[0106] Day 6-21: days 6-21

[0107] Sample size: 6 subjects in Phase lb and 42 subjects in Phase II.

[0108] Phase lb (safety run-in period): 6 subjects are enrolled to evaluate the safety of the combination treatment.

[0109] Phase II: The sample size was calculated by Fleming's two-stage design method. The primary endpoint was to evaluate the CR rate of L-CHOP regimen in the treatment of newly diagnosed PTCL. According to the data of CR rate of CHOP regimen in the treatment of newly diagnosed PTCL reported in the literature (37.1-62%), the P0=0.40, P1=0.60 of the subjects were assumed, the significance level a was set to one-sided 0.05, and β=0.20. A total of 42 evaluable subjects were required to provide a test of no less than 80% confidence to test the difference between the test regimen and the historical control treatment. Specifically, 34 patients were recruited in the first stage. If the number of CR subjects was ≤17, the regimen was terminated due to ineffectiveness. If the number of CR subjects was ≥20, the regimen was terminated due to effectiveness. If the number of CR subjects was >17 and <20, 8 more patients were recruited in the second stage. If the total number of CR subjects in the two stages was ≥23, the L-CHOP regimen was considered effective in the treatment of newly diagnosed PTCL.

[0110] Currently, the Ib phase of the study has been completed, and the II phase of the study is in the expansion phase.

[0111] Study 1 L-CHOP regimen for previously untreated peripheral T-cell lymphoma (PTCL), followed by maintenance treatment with lirilumab.

[0112] Objective: To evaluate the efficacy and safety of L-CHOP regimen as first-line treatment for patients with peripheral T-cell lymphoma (PTCL).

[0113] Design: Single-arm, open-label phase I investigator-initiated clinical trial (IIT). Patients who have undergone safety induction will continue to receive study treatment if no safety issues arise.

[0114] Primary endpoint: Complete remission rate after 6 cycles of L-CHOP regimen.

[0115] Key inclusion criteria:

[0116] (1) Adult patients aged 18 years or older, regardless of gender;

[0117] (2) Pathologically diagnosed as previously untreated peripheral T-cell lymphoma (PTCL), including but not limited to: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALK positive or negative);

[0118] (3) At least one measurable target lesion (according to Lugano criteria 2014);

[0119] (4) Good organ function;

[0120] (5) Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.

[0121] Study 2: L-CHOP regimen for previously untreated nodal T-follicular helper lymphoma (nTFHL) followed by transplantation and maintenance with rilzabtagene autoleucel

[0122] Objective: To evaluate the efficacy and safety of L-CHOP as first-line treatment for patients with nTFHL (nodal T-cell / histiocyte-rich large B-cell lymphoma).

[0123] Design: Single-arm, open-label investigator-initiated clinical trial

[0124] Primary endpoint: 2-year PFS rate

[0125] Secondary endpoints: Complete remission rate after 6 cycles of treatment, safety.

[0126] Key inclusion criteria:

[0127] Adult patients, 18 years of age and older, male or female, who are likely to be candidates for autologous hematopoietic stem cell transplantation (ASCT);

[0128] Pathologically confirmed previously untreated nodal T-follicular helper lymphoma (nTFHL), including nTFHL with autoimmune manifestations (nTFHL-AI), follicular nTFHL (nTFHL-F), and nTFHL not otherwise specified (nTFHL-NOS);

[0129] At least one measurable target lesion (according to Lugano 2014 criteria);

[0130] Good organ function;

[0131] Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2.

[0132] Demographics and baseline characteristics of patients with newly diagnosed peripheral T-cell lymphoma (PTCL) in Study 1 and Study 2:

[0133] 54 patients were enrolled, including 34 males and 20 females

[0134] Study 1, 26 patients

[0135] Study 2 28 patients

[0136] Median age: 57 years

[0137] ECOG: 0-2, 100%

[0138] PTCL subtypes: 41 patients with AITL, 9 patients with PTCL NOS, 2 patients with ALCL, 1 patient with nTFHL-F, 1 patient with nTFHL-NOS.

[0139] Figure 4 is the response and duration of response for Studies 1 and 2. As can be seen, the overall response rate was 100%, 67.5% complete response, 32.5% partial response.

[0140] Figure 5 is the response and duration of response for Study 1. As can be seen, the overall response rate was 100%, 52.6% complete response, 47.4% partial response.

[0141] Figure 6 is the response and duration of response for Study 2. As can be seen, the overall response rate was 100%, 80.9% complete response, 19.1% partial response.

[0142] Safety:

[0143] Limpoprisib in combination with CHOP regimen demonstrated a well-tolerated safety profile in previously untreated patients with peripheral T-cell lymphoma (PTCL).

[0144] As in previous studies with linperlisib monotherapy, a lower level of severe gastrointestinal and liver toxicities was observed with other phosphatidylinositol 3-kinase (PI3K) class drugs.

[0145] The overall safety profile was consistent with other linperlisib clinical study results.

[0146] Efficacy

[0147] Limpoprisib in combination with CHOP regimen resulted in a 100% response rate, and all responses occurred during treatment with L-CHOP regimen.

[0148] Limpoprisib in combination with CHOP regimen treatment demonstrated a high complete response (CR) rate (67.5%), while the complete response rate for linperlisib monotherapy was 29.6%.

[0149] L-CHOP regimen was compatible with patients who were to undergo stem cell transplantation later.

[0150] Deep responses were predictive of longer duration of response and led to durable clinical benefit.

[0151] It is to be understood that the embodiments and examples described herein are merely illustrative of the principles of the present application and that various modifications can be made by persons skilled in the art without departing from the scope and nature of the application as defined in the appended claims. All publications, patents and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

1. A pharmaceutical composition comprising rimnplise or a pharmaceutically acceptable salt, metabolite, solvate or prodrug thereof and a chemotherapy regimen.

2. The pharmaceutical composition of claim 1, wherein, The chemotherapy regimen is CHOP regimen.

3. A method of using a pharmaceutical composition as claimed in claim 1 or 2, characterized in that, It comprises the step of combining rimnplise with CHOP regimen.

4. Use of a pharmaceutical composition according to claim 1 or 2 for the manufacture of a medicament for the treatment of peripheral T-cell lymphoma.

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