Use of Mitoxantrone Hydrochloride Liposomal and Cyclophosphamide, Vincristine, and Prednisone

Abstract

Use of mitoxantrone hydrochloride liposomes and cyclophosphamide, vincristine, and prednisone in the preparation of a drug for treating peripheral T-cell lymphoma (PTCL). The PTCL is preferably treatment-naive PTCL. In addition to the above, other first-line and second-line drugs for treating PTCL may also be used. A method for treating PTCL comprises administering to a patient a therapeutically effective amount of mitoxantrone hydrochloride liposomes, cyclophosphamide, vincristine, and prednisone. This drug combination is safe and tolerable, with minimal toxicity and side effects, and can achieve a higher overall objective response rate (ORR) in treatment-naive PTCL patients.

Description

[Technical field]

[0001] The present invention falls in the field of anti-tumor, specifically relates to the use of Mitoxantrone Hydrochloride Liposome and Cyclophosphamide, Vincristine, Prednisone in the preparation of a medicament for treatment-naive peripheral T-cell lymphoma (PTCL). [Background technology]

[0002] PTCL is a group of lymphoproliferative tumors originating from mature T cells in the thymus, which are clearly heterogeneous and mostly highly aggressive. According to the WHO classification criteria revised in 2016 (Non-Patent Document 1), PTCL includes four categories with a total of more than 30 subtypes, including non-specific peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, extranodal nasal NK / T-cell lymphoma, ALK-positive systemic anaplastic large T-cell lymphoma, ALK-negative systemic anaplastic large T-cell lymphoma, mycosis fungoides / Sezary syndrome, etc. The complex pathological classification reflects the heterogeneity of this group of diseases. There are regional differences in the occurrence of PTCL and the distribution of pathological subtypes. The incidence in Asia is somewhat higher than in Europe and America. In China, PTCL accounts for approximately 25% to 35% of non-Hodgkin's lymphoma (NHL), which is significantly higher than in Western countries (10% to 15%). It is noteworthy that the treatment of PTCL is not optimistic. The application of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like therapy as initial treatment has a low overall response rate, a high recurrence rate, and a poor prognosis. The 5-year survival rate of PTCL subtypes other than ALK-positive systemic anaplastic large T-cell lymphoma (ALCL) is only 14-32% (Non-Patent Document 2).

[0003] Research and investigations into the efficacy of anthracycline-free therapies as first-line treatment for PTCL are being conducted domestically and internationally. However, they have not been proven to be superior to CHOP-like therapies that mainly use anthracyclines. Therefore, anthracycline-containing therapies remain the first-line treatment. Thus, further investigation into safe and effective first-line therapies for PTCL is needed. Mitoxantrone Hydrochloride is an anthracycline drug that has been used in over 30 countries around the world. It is effective in treating various solid cancers, including acute leukemia, blood tumors, lymphoma, and breast cancer. Its side effects are mainly bone marrow suppression, gastrointestinal reactions, and cardiotoxicity. Clinically, it is mainly used to treat acute myeloid leukemia.

[0004] Liposomes are a new form of drug carrier. Research has shown that they can change the distribution of encapsulated drugs in the body, so that the drugs are mainly accumulated in tumor tissues, thereby improving the therapeutic index of the drugs and reducing the therapeutic dose and toxicity of the drugs. These characteristics have made the application of liposomes as drug carriers in the research of antitumor drugs important. Researchers have been conducting research on mitoxantrone liposomal formulations. For example, Patent Document 1 discloses mitoxantrone liposomes, the disclosure of which is incorporated herein by reference in its entirety. Research has shown that liposomal formulations have lower toxicity (especially cardiotoxicity) and the characteristics of passively targeting tumor tissues, and have improved antitumor activity, compared with common mitoxantrone formulations.

[0005] A Phase I clinical trial of mitoxantrone hydrochloride liposome injection as a single agent has completed dose escalation and PK / PD studies in subjects with advanced solid tumors and lymphoma. 2The drug was safe and well tolerated within the dose range of 10 mg / m2, and showed consistent therapeutic efficacy. A key Phase II study of mitoxantrone hydrochloride liposome injection alone was conducted in patients with relapsed / refractory PTCL and enrollment was completed (n=108 patients, dose 20 mg / m2). 2 ). Currently, the objective response rate (ORR) assessed by an independent review committee (IRC) and confirmed by treatment is 40.7%. Given the favorable therapeutic effect of monotherapy with this agent in patients with relapsed / refractory PTCL, this study aims to further explore the concomitant administration of mitoxantrone hydrochloride liposome injection in treatment-naive PTCL patients. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2008 / 080367 [Non-patent literature]

[0007] [Non-Patent Document 1] Swerdlow SH,et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19;127(20):2375-2390. [Non-Patent Document 2] Vose J, et al. International peripheral T-cell and natural killer / T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008 Sep 1;26(25):4124-4130. Summary of the Invention

[0008] Unless otherwise specified, "treatment naive" in the present invention uses the following definition. "Treatment naive" is defined as newly diagnosed without prior anti-lymphoma treatment. "Mitoxantrone" includes mitoxantrone and its pharma- ceutically acceptable salts, and the pharma-ceutically acceptable salt of mitoxantrone is preferably mitoxantrone hydrochloride. The mitoxantrone liposome is preferably mitoxantrone hydrochloride liposome.

[0009] The present invention provides the use of mitoxantrone liposomes and cyclophosphamide, vincristine, prednisone in the preparation of a medicament for treating PTCL.

[0010] The PTCL is preferably at least one subtype selected from peripheral T-cell lymphoma, non-specific (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK-positive anaplastic large T-cell lymphoma (ALCL), and ALK-negative anaplastic large T-cell lymphoma (ALCL).

[0011] The present invention also provides the use of mitoxantrone liposomes in the preparation of a medicament for improving the therapeutic effect of cyclophosphamide, vincristine and prednisone on PTCL.

[0012] The present invention provides the use of a combination of cyclophosphamide, vincristine and prednisone in the preparation of a medicament for improving the therapeutic effect of PTCL with mitoxantrone liposome.

[0013] Furthermore, the present invention provides a drug for treating PTCL, which comprises mitoxantrone, cyclophosphamide, vincristine, and prednisone.

[0014] Preferably, said PTCL is treatment naive PTCL.Preferably, said mitoxantrone liposomes are mitoxantrone hydrochloride liposomes.

[0015] Preferably, mitoxantrone hydrochloride liposome, prednisone, cyclophosphamide and vincristine may be present in the same formulation or may be formulated independently. When the above four drugs are formulated, the dosage form may be the same or different. The dosage form may be any clinically acceptable dosage form, such as an injection dosage form or an oral dosage form. The injection dosage form includes liquid injections, powders for injection, tablets for injection, etc., and the oral dosage form includes tablets, capsules, oral liquids, etc. When the mitoxantrone hydrochloride liposome is a liquid injection, the active ingredient is contained in an amount of 0.5 to 5 mg / ml, preferably 1 to 2 mg / ml, more preferably 1 mg / ml based on mitoxantrone. When prednisone is in tablet form, the specification is 5 mg / tablet; when clophosphamide is in powder injection form, the specification is 0.2 g / vial and should be prepared as a 200 mg / 10 ml solution at the time of use; when vincristine is in powder injection form, the specification is 1 mg / vial and should be prepared as a 1 mg / 20 ml solution at the time of use.

[0016] For prednisone, a tablet with a standard of 5 mg / tablet means that each tablet contains 5 mg of prednisone, for cyclophosphamide, a powder injection with a standard of 0.2 g / vial means that each vial of powder injection contains 0.2 g of cyclophosphamide, and for vincristine, a powder injection with a standard of 1 mg / vial means that each vial of powder injection contains 1 mg of vincristine.

[0017] The drugs may further include other drugs for treating PTCL, which refers to drugs approved by the drug administration departments of China or other countries or regions (e.g., the United States, the European Union, Japan, South Korea, etc.) for treating PTCL.

[0018] The present invention provides a method for treating PTCL, characterized in that mitoxantrone hydrochloride liposome and cyclophosphamide, vincristine, and prednisone are administered in effective therapeutic doses to a PTCL patient.

[0019] The present invention further provides a method for improving the therapeutic effect of PTCL by cyclophosphamide, vincristine and prednisone therapy, which comprises administering to a PTCL patient cyclophosphamide, vincristine and prednisone in combination with an effective therapeutic dose of mitoxantrone hydrochloride liposome.

[0020] The present invention further provides a method for improving the therapeutic effect of mitoxantrone hydrochloride liposome on PTCL, which comprises administering mitoxantrone hydrochloride liposome to a PTCL patient and further administering in combination effective therapeutic doses of cyclophosphamide, vincristine, and prednisone.

[0021] In the above method, the administration of mitoxantrone hydrochloride liposome, cyclophosphamide and vincristine is preferably by injection, and the administration of prednisone is preferably by oral administration. Preferably, the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 8-30 mg / m based on mitoxantrone. 2 , more preferably 12 to 24 mg / m 2 Specifically, for example, 12 mg / m 2 , 14mg / m2, 15mg / m 2 , 16 mg / m 2 , 18 mg / m 2 , 20 mg / m 2 , 24 mg / m 2 The dose of cyclophosphamide is 750 mg / m 2 , and the vincristine dose was 1.4 mg / m 2(Calculated based on body surface area, the maximum dose in each case should not exceed 2 mg), and the dose of prednisone is 100 mg / day. Preferably, the administration cycle is once every 4 weeks or 3 weeks. In each administration cycle, mitoxantrone hydrochloride liposome, cyclophosphamide and vincristine are administered once, and prednisone is administered five consecutive times. Preferably, on the first day of each administration cycle, PTCL patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposome, prednisone, vincristine and cyclophosphamide in any order, and prednisone is administered continuously on days 2 to 5. Preferably, on the first day of each administration cycle, prednisone is administered before administration of mitoxantrone hydrochloride liposome, vincristine is administered after administration of mitoxantrone hydrochloride liposome, and then cyclophosphamide is administered.

[0022] The present invention further provides a composition for treating PTCL, comprising mitoxantrone hydrochloride liposome, cyclophosphamide, vincristine and prednisone, characterized in that on the first day of each administration cycle, an effective therapeutic dose of mitoxantrone hydrochloride liposome, prednisone, vincristine and cyclophosphamide is administered to a PTCL patient in any order, followed by administration of prednisone on days 2 to 5. Preferably, on the first day of each administration cycle, prednisone is administered before administration of mitoxantrone hydrochloride liposome, vincristine is administered after administration of mitoxantrone hydrochloride liposome, and cyclophosphamide is then administered. Preferably, the administration cycle is once every 4 weeks or 3 weeks. Preferably, the dose of the mitoxantrone hydrochloride liposome is 8 to 30 mg / m based on mitoxantrone. 2 , more preferably 12 to 24 mg / m 2 Preferably, the dose of cyclophosphamide is 750 mg / m 2 , and the vincristine dose was 1.4 mg / m 2 (Calculated on the basis of body surface area, the maximum dose in each case should not exceed 2 mg), and the dose of prednisone is 100 mg / day.

[0023] Here, "administration in any order" means that mitoxantrone hydrochloride liposome, cyclophosphamide, vincristine, and prednisone are each formulated and administered in a clinically acceptable manner, there is no mandatory order of administration, and the drugs are not mixed ex vivo.

[0024] The present invention further provides a drug for improving the therapeutic effect of PTCL by a therapy of cyclophosphamide, vincristine and prednisone, comprising mitoxantrone hydrochloride liposome, the mitoxantrone hydrochloride liposome being administered at any time after administration of prednisone and before administration of vincristine and cyclophosphamide. Preferably, on the first day of each administration cycle, PTCL patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposome, prednisone, vincristine and cyclophosphamide in any order, and prednisone is administered continuously on days 2 to 5. Preferably, on the first day of each administration cycle, prednisone is administered before administration of mitoxantrone hydrochloride liposome, vincristine is administered after administration of mitoxantrone hydrochloride liposome, and then cyclophosphamide is administered. Preferably, the dose of the mitoxantrone hydrochloride liposome is 8 to 30 mg / m based on mitoxantrone. 2 , more preferably 12 to 24 mg / m 2 and is administered once every 4 or 3 weeks. Preferably, the dose of cyclophosphamide is 750 mg / m 2 , and the vincristine dose was 1.4 mg / m 2 (Calculated on the basis of body surface area, the maximum dose in each case should not exceed 2 mg), and the dose of prednisone is 100 mg / day.

[0025] The present invention further provides a drug for improving the therapeutic effect of mitoxantrone hydrochloride liposome on PTCL, comprising cyclophosphamide, vincristine and prednisone, wherein the mitoxantrone hydrochloride liposome is administered at any time after administration of prednisone and before administration of vincristine and cyclophosphamide. Preferably, on the first day of each administration cycle, PTCL patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposome, prednisone, vincristine and cyclophosphamide in any order, and prednisone is administered continuously on days 2 to 5. Preferably, on the first day of each administration cycle, prednisone is administered before administration of mitoxantrone hydrochloride liposome, vincristine is administered after administration of mitoxantrone hydrochloride liposome, and then cyclophosphamide is administered. Preferably, the dose of the mitoxantrone hydrochloride liposome is 8 to 30 mg / m based on mitoxantrone. 2 , more preferably 12 to 24 mg / m 2 and is administered once every 4 or 3 weeks. Preferably, the dose of cyclophosphamide is 750 mg / m 2 , and the vincristine dose was 1.4 mg / m 2 (Calculated on the basis of body surface area, the maximum dose in each case should not exceed 2 mg), and the dose of prednisone is 100 mg / day.

[0026] Preferably, for each intravenous administration, the infusion administration time of the liposome drug formulation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90±15 minutes.

[0027] All doses of mitoxantrone hydrochloride liposomes according to the present invention are based on mitoxantrone.

[0028] The mitoxantrone hydrochloride liposome of the present invention can be prepared by any method known in the art, and may be prepared by any method disclosed in the prior art, such as the method disclosed in WO2008 / 080367A1, the disclosure of which is incorporated herein by reference in its entirety.

[0029] In some embodiments, the mitoxantrone liposome according to the present invention has a particle size of about 30-80 nm and contains 1) mitoxantrone or a pharma- ceutically acceptable salt thereof as an active ingredient capable of forming an insoluble precipitate with a multivalent counterion in the liposome, and 2) a phospholipid bilayer containing a phospholipid having a phase transition temperature (Tm) higher than body temperature such that the phase transition temperature of the liposome is higher than body temperature. The phospholipid having a Tm higher than body temperature is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dipalmitoyl lecithin, or distearoyl lecithin, or any combination thereof, and preferably, the particle size of the mitoxantrone liposome is about 35-75 nm, preferably about 40-70 nm, more preferably 40-60 nm, and particularly preferably 60 nm. In some embodiments, the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of 3:1:1, the liposome has a particle size of about 60 nm, and the counter ion is sulfate.

[0030] In some embodiments, the method for preparing mitoxantrone hydrochloride liposomes according to the present invention is as follows: HSPC (hydrogenated soybean lecithin), Chol (cholesterol) and DSPE-PEG2000 (polyethylene glycol 2000 modified distearoylphosphatidylethanolamine) are weighed according to a mass ratio of (3:1:1) and dissolved in 95% ethanol to obtain a transparent solution (i.e., an ethanol solution of phospholipids). The ethanol solution of phospholipids is mixed with a 300 mM ammonium sulfate solution and hydrated by shaking at 60-65°C for 1 hour to obtain heterogeneous multi-layer liposomes. Then, a microfluidic device is used to reduce the particle size of the liposomes. The obtained sample was diluted 200 times with a 0.9% NaCl solution and detected by NanoZS, and the average particle size of the particles was about 60 nm, with the main peak concentrated between 40 and 60 nm. Then, the ammonium sulfate in the external phase of the blank liposomes is removed using an ultrafiltration device to form a transmembrane ammonium sulfate gradient, and the external phase is replaced with 290 mM sucrose and 10 mM glycine. According to a lipid-drug ratio of 16:1, mitoxantrone hydrochloride solution (10 mg / mL) is added to the blank liposomes to load the drug at 60-65 C. After about 1 h of incubation, the encapsulation efficiency was demonstrated to be about 100% using gel exclusion chromatography. The product obtained with this formulation was named PLM60. The weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone in PLM60 is 9.58:3.19:3.19:1, and the osmotic pressure of the sucrose-glycine solution is close to the physiological value.

[0031] Beneficial Effects The use of mitoxantrone hydrochloride liposomes of the present invention in combination with cyclophosphamide, vincristine and prednisone is safe and tolerable to patients, with low toxicity and side effects, and can obtain a higher overall ORR rate in treatment-naive PTCL patients. With an increase in the number of administration cycles, the therapeutic effect is expected to be further improved, thereby improving the progression-free survival (PFS) and 5-year overall survival (OS) of patients. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] The following examples are illustrative of the present invention and are not intended to limit the scope of the present invention.

[0033] Example 1 Clinical Study of Mitoxantrone Hydrochloride Liposome Injection in Combination with Cyclophosphamide, Vincristine, and Prednisone in the Treatment of Treatment-Naive PTCL This study is a single-arm, open-label, multicenter, phase Ib clinical trial of various doses of mitoxantrone hydrochloride liposome injection combined with fixed doses of cyclophosphamide, vincristine, and prednisone in treatment-naive PTCL subjects to investigate the safety and tolerability of the above regimens, identify the optimal dose of mitoxantrone hydrochloride liposome injection in the above drug combination therapy, evaluate the therapeutic efficacy, and observe the pharmacokinetic characteristics. The study is divided into a dose-escalation phase and a dose-expansion phase.

[0034] I. Study Design 1. Dose Escalation Phase (1) Overall design This study consisted of a screening period, a treatment period, and a follow-up period. Subjects will sign an informed consent form and complete all baseline assessments during the screening period. Subjects who qualify at screening will enter the treatment period, during which the dose of mitoxantrone hydrochloride liposome injection will be gradually increased from the low dose group to the high dose group. Each cycle will last 4 weeks (28 days), and DLT will be confirmed during the first treatment cycle. All subjects will collect PK blood samples at different time points before and after treatment according to the plan, and complete relevant tests as specified in the plan during treatment to observe safety, tolerability, and treatment efficacy. The same subject will only receive one dose of treatment and dosing schedule during the study period. After the treatment period, they will enter the follow-up period.

[0035] (2) Dose Escalation and Administration Plans In the dose escalation phase of mitoxantrone hydrochloride liposome (PLM60), the initial dose was 12 mg / m 2 (based on mitoxantrone), 12 mg / m 2 , 15 mg / m 2 , 18 mg / m 2 Three dose groups will be pre-defined. The drug will be administered intravenously on the first day (D1) of each cycle. For vincristine, the dose is 1.4 mg / m 2 (calculated based on body surface area, the maximum dose in each case should not exceed 2 mg) is administered intravenously on D1, after administration of mitoxantrone hydrochloride liposomes. For cyclophosphamide, the dose is 750 mg / m 2 and is administered intravenously on D1, after administration of mitoxantrone hydrochloride liposome and vincristine. Regarding prednisone, the dose is 100 mg / day and is orally administered on D1 to D5. On D1, it is administered before administration of mitoxantrone hydrochloride liposome, and on D2 to D5, only prednisone is administered, which is sufficient to meet the clinical administration requirements when using prednisone alone.

[0036] If a subject experiences DLT, the original treatment plan will be discontinued and the investigator will manage the case according to clinical diagnosis and treatment criteria and monitor until toxicity is Grade 1 or less or returns to baseline levels. If the investigator determines that the benefits of continuing treatment on the original plan outweigh the risks, the subject may continue into the treatment period (dosage the same as the original dose) with the sponsor's consent. Subjects will be removed from the study if the investigator determines that continuation on the original plan is not appropriate.

[0037] (3) Requirements for continuous administration 1) Neutrophil count ≥ 1.5 × 10 9 / L, hemoglobin ≥ 80g / L, platelet count ≥ 75 × 10 9 / L must be satisfied. 2) Non-hematologic toxicities (excluding alopecia) must be ≤ Grade 1 or return to baseline levels, regardless of whether medical treatment for drug toxicity is administered. 3) If the above conditions are not met, in principle, the dosage will not be reduced and administration can be delayed, but not for more than 14 days. 4) If toxicity has not resolved by the time treatment conditions 1 and 2 are met, and / or if the treatment delay exceeds 14 days, continued treatment may be permitted after contacting the sponsor if the investigator determines that the patient would still benefit.

[0038] 2. Dose expansion phase The results of the dose escalation phase study will determine the phase II recommended dose (RP2D) of mitoxantrone hydrochloride liposome in combination with mitoxantrone hydrochloride liposome, cyclophosphamide, vincristine and prednisone, after which the dose expansion phase can be entered.

[0039] This study consists of a screening period, a treatment period, and a follow-up period. Mitoxantrone hydrochloride liposome injection will be expanded to the RP2D dose, and the doses of cyclophosphamide, vincristine, and prednisone will be the same as those in the titration phase. The treatment will be divided into two groups, a Q4W (28 days) group and a Q3W (21 days) group, and each group will be expanded to 10 to 20 cases.

[0040] Eligible subjects who have been screened according to the study procedure will be assigned to the Q4W or Q3W group in a crossover manner. During the treatment period, the Q4W group will have one cycle of 28 days, and the Q3W group will have one cycle of 21 days, and six cycles of administration will be planned. The treatment will continue until the completion of six cycles of treatment, disease progression, death, intolerable toxicity, the investigator determines that other treatment measures (including changes in chemotherapy plan, ASCT, radiation therapy, etc.) are necessary, or the subject voluntarily discontinues treatment (whichever occurs first). During the treatment period, PK blood sampling and related tests will be performed according to the plan's requirements, and safety and therapeutic effects will be observed. At the end of the treatment period, a follow-up period will begin.

[0041] 3. Study completion time The end of the study is defined as the last subject completing the last visit.

[0042] II. Subject of the test (1) Selection criteria Patients who meet all of the following criteria can be selected for this study. 1. Patients fully understand this study, voluntarily participate, and sign the Informed Consent Form (ICF). 2. Age: 18-70 years (inclusive). 3. Treatment-naive, histopathologically confirmed PTCL of any of the following subtypes: (1) Non-specific peripheral T-cell lymphoma (PTCL-NOS) (2) Angioimmunoblastic T-cell lymphoma (AITL) (3) Anaplastic large T-cell lymphoma (ALCL), ALK positive (4) Anaplastic large T cell lymphoma (ALCL), ALK negative (5) Other subtypes of PTCL that are deemed by the investigator to be eligible for enrollment and approved by the sponsor 4. PTCL with affinity for fluorodeoxyglucose (FDG) that can be evaluated by PET / CT. 5.ECOG score is 0-1. 6. Laboratory tests meet the following criteria: (1) Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L (2) Platelet (PLT) ≧75×10 9 / L (3) Hemoglobin (HB) ≥ 80g / L (4) Serum total bilirubin (TBIL) ≦ 1.5 times the upper limit of normal (ULN) (5) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the ULN (6) Serum creatinine (Scr) ≦ 1.5 times ULN 7. Female patients must meet one of the following criteria: (1) Menopausal; menstruation has stopped for at least one year. (2) Those of childbearing age must meet the following conditions: a) A blood pregnancy test prior to enrollment in this study was negative. b) Agree to use an accepted highly effective form of contraception (defined as consistently used correctly with an annual failure rate of less than 1% such as combined hormonal (containing estrogen and progesterone) combined with ovulation suppression, progesterone contraception combined with ovulation suppression, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, or vasectomy) throughout the study period and for at least 12 months after the end of the final dose. 8. Male patients or their partners agree to practice one of the highly effective contraceptive methods described in article 7 for the duration of the study and will provide effective contraception throughout the entire treatment period and for at least 12 months after the end of the last dose.

[0043] (2) Exclusion criteria Those who met any of the following exclusion criteria were not eligible for this study. 1. Histopathology is one of the following subtypes: (1) Extranodal nasal type NK / T cell lymphoma (NKTCL) (2) Primary cutaneous T-cell lymphomas, such as mycosis fungoides (MF) / Sézary syndrome (SS) and primary cutaneous anaplastic large cell lymphoma (3) Leukemia-type PTCL, such as adult T-cell leukemia / lymphoma 2. Patients with leukemic stage of lymphoma (≥20% lymphoma cells in bone marrow examination) or with central nervous system (CNS) involvement or concurrent hemophagocytic syndrome. 3.Expected survival is less than 6 months. 4. Have a history of allergy to anthracyclines or liposomal drugs. 5. There are contraindications to the use of cyclophosphamide, vincristine, and prednisone. 6. Received anti-lymphoma therapy except for short-term or low-dose glucocorticoids (short-term glucocorticoids defined as prednisone or equivalent prednisone ≤ 100 mg / day and for < 7 days; low-dose glucocorticoids defined as preprednisone or equivalent prednisone ≤ 30 mg / day). 7. Have cardiac dysfunction or significant cardiac disease, including but not limited to: (1) Within 6 months prior to screening, the patient had developed cardiac disease accompanied by symptoms requiring therapeutic intervention, such as myocardial infarction, congestive heart failure, viral myocarditis, unstable angina, or arrhythmia. (2) Cardiac function class is II to IV (New York Heart Association classification, NYHA). (3) Ejection fraction (EF) detected by echocardiography was less than 50% or the lower limit of the study center. (4) have a history of persistent cardiomyopathy; (5) QTc > 450 milliseconds or congenital long QT syndrome. 8. Positive for type B surface antigen and HBV-DNA titer higher than the upper limit of the research center, or positive for hepatitis C (HCV) antibody, or positive for human immunodeficiency virus (HIV) antibody on initial screening. 9.Has undergone major surgery within 4-6 weeks prior to screening or is scheduled to undergo major surgery during the study period. 10.Has had a severe infection within 4 weeks prior to screening and is deemed by the investigator to be unsuitable for chemotherapy. 11.Has poorly controlled hypertension at screening. 12.Having poorly controlled diabetes at screening. 13. History of active visceral bleeding within 3 months prior to screening. 14. History of malignancy within the past 5 years that may affect the conduct of the study plan or the analysis of the results (excluding cured basal cell carcinoma of the skin, non-invasive cervical cancer, non-invasive breast cancer, non-invasive gastrointestinal mucosal cancer, and localized prostate cancer). 15. After solid organ transplantation. 16. Have a history of psychiatric illness or cognitive impairment. 17. Have a history of drug abuse (narcotics used for non-medical purposes, psychotropic drugs) or drug dependence (sedatives, analgesics, narcotics, stimulants, antipsychotics, etc.). 18. Pregnant or lactating women. 19. The researcher determines that participation in this study is not appropriate.

[0044] 3.Research results The study is currently in the dose escalation phase, with a pre-specified dose of 12 mg / m 2 , 15 mg / m 2 , 18 mg / m 2 The dose-escalation study was completed for all three dose groups, with no events leading to the halting of dose escalation. After contacting and discussing with the sponsor, the investigators decided to continue with the dose escalation at 21 mg / m 2 An additional dose group was added (3 patients enrolled).

[0045] Treatment efficacy was evaluated using PET-CT according to the 2014 version of the Lugano criteria.

[0046] A total of 22 treatment-naive PTCL subjects were enrolled in this study, of which 18 are currently undergoing treatment and 4 have left the study (3 due to disease progression and 1 due to poor efficacy of treatment). Among them, 13 subjects were enrolled and underwent one efficacy evaluation (84 days) and the following were considered.

[0047] The dosage of mitoxantrone hydrochloride liposome (PLM60) is as shown in Table 1 below. The dose of vincristine (powder injection standard is 1 mg / vial) is 1.4 mg / m 2 is administered intravenously on the first day of each cycle following administration of mitoxantrone hydrochloride liposome. The dose of cyclophosphamide (powder injection standard is 0.2 g / vial) is 750 mg / m 2It is administered intravenously on the first day of each cycle, following administration of mitoxantrone hydrochloride liposome and vincristine. The dose of prednisone (5 mg per tablet) was 100 mg / day, orally administered on days 1 to 5 of each cycle. On day 1 of each cycle, prednisone was administered before administration of mitoxantrone hydrochloride liposome, and on days 2 to 5 of each cycle, prednisone alone was administered.

[0048] The evaluation results are shown in Table 1 below. [Table 1]

[0049] As a result, the use of the mitoxantrone hydrochloride liposome of the present invention in combination with cyclophosphamide, vincristine and prednisone at the above doses is safe and tolerable, with low toxicity and side effects, and can achieve a high overall ORR rate in treatment-naive PTCL patients. With the increase in the dose of mitoxantrone liposome, the therapeutic effect showed a tendency to improve. At present, most patients have only undergone one therapeutic effect evaluation, and it is expected that the therapeutic effect will further improve with the increase in the administration cycle. Among them, in the high-dose group of mitoxantrone hydrochloride liposome, the therapeutic effect was superior to the clinical standard treatment (CHOP therapy).

Claims

1. 1. Use of mitoxantrone liposomes and cyclophosphamide, vincristine, and prednisone in the preparation of a medicament for treating treatment-naive PTCL, comprising: The mitoxantrone liposome is a mitoxantrone hydrochloride liposome, and the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 18-30 mg / m2 based on mitoxantrone. ２ and the dose of cyclophosphamide is 750 mg / m ２ , the dose of vincristine is 1.4 mg / m ２ , the dose of prednisone is 100 mg / day, Use.

2. 2. Use of mitoxantrone liposomes in the preparation of a medicament for improving the efficacy of a therapeutic regimen of cyclophosphamide, vincristine and prednisone in the treatment of treatment-naive PTCL, comprising: The mitoxantrone liposome is a mitoxantrone hydrochloride liposome, and the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 18-30 mg / m2 based on mitoxantrone. ２ and the dose of cyclophosphamide is 750 mg / m ２ , the dose of vincristine is 1.4 mg / m ２ , the dose of prednisone is 100 mg / day, Use.

3. The mitoxantrone hydrochloride liposome, the prednisone, the cyclophosphamide and the vincristine may be present in the same formulation or in separate formulations; When the four drugs are present in separate formulations, the dosage forms may be the same or different. When the mitoxantrone hydrochloride liposome is in the form of a liquid injection, the liquid injection contains an active ingredient of 0.5 to 5 mg / ml based on mitoxantrone; when the prednisone is in tablet form, each of the tablets contains 5 mg of the prednisone; When the cyclophosphamide is in the form of a powder injection, each vial of the powder injection contains 0.2 g of the cyclophosphamide; When the vincristine is in the form of a powder injection, each vial of the powder injection contains 1 mg of the vincristine; 2. The use according to claim 1.

4. The use according to any one of claims 1 to 3, wherein the medicament further comprises another drug for treating treatment-naive PTCL.

5. Mitoxantrone liposomes and cyclophosphamide, vincristine, and prednisone, the mitoxantrone liposomes are mitoxantrone hydrochloride liposomes; The mitoxantrone hydrochloride liposome, prednisone, cyclophosphamide and vincristine may be present in the same formulation or each may be present in a separate formulation; When the four drugs are present in separate formulations, the dosage forms may be the same or different. When the mitoxantrone hydrochloride liposome is in the form of a liquid injection, the liquid injection contains an active ingredient of 0.5 to 5 mg / ml based on mitoxantrone; when the prednisone is in tablet form, each of the tablets contains 5 mg of the prednisone; When the cyclophosphamide is in the form of a powder injection, each vial of the powder injection contains 0.2 g of the cyclophosphamide; When the vincristine is in the form of a powder injection, each vial of the powder injection contains 1 mg of the vincristine; A drug for treating treatment-naive PTCL, wherein the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 18-30 mg / m2 based on mitoxantrone. ２ and the dose of cyclophosphamide is 750 mg / m ２ , the dose of vincristine is 1.4 mg / m ２ , the dose of prednisone is 100 mg / day,

6. administering to treatment-naïve PTCL patients effective therapeutic doses of said mitoxantrone hydrochloride liposomes and said cyclophosphamide, said vincristine, and said prednisone; The mitoxantrone hydrochloride liposome, the cyclophosphamide and the vincristine are administered by injection; The prednisone is administered orally; The effective therapeutic dose of the mitoxantrone hydrochloride liposome is 18-24 mg / m2 based on mitoxantrone. ２ The use according to claim 1,

7. Mitoxantrone hydrochloride liposome and cyclophosphamide, vincristine, and prednisone, The mitoxantrone hydrochloride liposome, prednisone, cyclophosphamide and vincristine are each present in a separate formulation. A drug for treating treatment-naive PTCL, comprising: On the first day of each administration cycle, a treatment-naive PTCL patient is administered an effective therapeutic dose of the mitoxantrone hydrochloride liposome, the prednisone, the vincristine, and the cyclophosphamide in any order, and the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 18 to 30 mg / m2 based on mitoxantrone. ２ and the dose of cyclophosphamide is 750 mg / m ２ , the dose of vincristine is 1.4 mg / m ２ , the dose of prednisone is 100 mg / day,

8. 8. The method of claim 7, wherein the prednisone is administered before the administration of the mitoxantrone hydrochloride liposome, the vincristine is administered after the administration of the mitoxantrone hydrochloride liposome, and then the cyclophosphamide is administered, and the administration cycle is once every 4 weeks or 3 weeks.

9. A medicament for improving the efficacy of a therapeutic regimen of cyclophosphamide, vincristine and prednisone in the treatment of treatment-naive PTCL, comprising mitoxantrone hydrochloride liposomes, the mitoxantrone hydrochloride liposomes being administered any time after the administration of prednisone and before the administration of vincristine and the cyclophosphamide on the first day of each administration cycle, at a dose of 18-30 mg / m ２ , a drug administered once every four or three weeks.

10. The mitoxantrone hydrochloride liposome is administered at a concentration of 18 to 24 mg / m ２ The method of claim 9, wherein the medicament is administered at a dose of

11. The use according to claim 1, wherein the mitoxantrone liposome has a particle size of about 30 to 80 nm and contains 1) mitoxantrone or a pharma- ceutically acceptable salt thereof as an active ingredient, and 2) a phospholipid bilayer containing a phospholipid having a phase transition temperature (Tm) higher than body temperature, wherein the phospholipid having a Tm higher than body temperature is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dipalmitoyl lecithin, distearoyl lecithin, or any combination thereof.

12. The use according to claim 3, wherein the mitoxantrone liposome has a particle size of about 30 to 80 nm and contains 1) mitoxantrone or a pharma- ceutically acceptable salt thereof as an active ingredient, and 2) a phospholipid bilayer containing a phospholipid having a phase transition temperature (Tm) higher than body temperature, wherein the phospholipid having a Tm higher than body temperature is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dipalmitoyl lecithin, distearoyl lecithin, or any combination thereof.

13. The drug according to claim 5, 8 or 9, wherein the mitoxantrone hydrochloride liposome has a particle size of about 30-80 nm and contains 1) mitoxantrone or a pharma- ceutically acceptable salt thereof as an active ingredient, and 2) a phospholipid bilayer containing a phospholipid having a phase transition temperature (Tm) higher than body temperature, wherein the phospholipid having a Tm higher than body temperature is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dipalmitoyl lecithin, distearoyl lecithin, or any combination thereof.

14. The use according to claim 6, wherein the mitoxantrone hydrochloride liposome has a particle size of about 30 to 80 nm and contains 1) mitoxantrone or a pharma- ceutically acceptable salt thereof as an active ingredient, and 2) a phospholipid bilayer containing a phospholipid having a phase transition temperature (Tm) higher than body temperature, wherein the phospholipid having a Tm higher than body temperature is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dipalmitoyl lecithin, distearoyl lecithin, or any combination thereof.

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