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KR-102963745-B1 - Uses of Mitoxanthrone Hydrochloride Liposomes and Cyclophosphamide, Vincristine, and Prednisone

KR102963745B1KR 102963745 B1KR102963745 B1KR 102963745B1KR-102963745-B1

Abstract

The present invention provides a use of mitoxantrone hydrochloride liposomes and cyclophosphamide, vincristine, and prednisone in the manufacture of drugs for the treatment of peripheral T-cell lymphoma (PTCL). The PTCL is preferably a first-line PTCL. Additionally, based on the above, first-line and second-line drugs for treating PTCL may be additionally used. The present invention provides a method for treating PTCL, wherein the method involves administering a therapeutically effective amount of mitoxantrone hydrochloride liposomes, cyclophosphamide, vincristine, and prednisone to a patient. The combined administration of the drugs is safely tolerable, has low toxicity and side effects, and can achieve a higher overall ORR rate in patients with first-line PTCL.

Inventors

  • 리 춘레이
  • 샤 쉐펑
  • 리 옌후이
  • 안 나
  • 두 옌링
  • 리 퉁
  • 왕 스샤
  • 쟈 룬루

Assignees

  • 씨에스피씨 종콰이 팔마씨우티컬 테크놀로지 (스자좡) 컴퍼니 리미티드

Dates

Publication Date
20260511
Application Date
20210826
Priority Date
20200827

Claims (15)

  1. A composition comprising mitoxantrone liposomes for use in a method to improve the therapeutic effect of a cyclophosphamide, vincristine, and prednisone therapy regimen in the treatment of treatment-naive peripheral T-cell lymphoma (PTCL), The above mitoxantrone liposome is a mitoxantrone hydrochloride liposome, and The therapeutic effective dose of the above mitoxantrone hydrochloride liposomes is 18 to 30 mg/ m² based on mitoxantrone, and The dose of the above-mentioned cyclophosphamide is 750 mg/ m² , and The dose of the above vincristine is 1.4 mg/ m² , and The above dose of prednisone is 100 mg/day, Composition.
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  4. In paragraph 1, The above mitoxantrone hydrochloride liposomes, prednisone, cyclophosphamide, and vincristine are present in the same preparation or in separate preparations, and When the above-mentioned mitoxantrone hydrochloride liposomes, prednisone, cyclophosphamide, and vincristine are each present in separate formulations, the formulations are identical or different, and When the above mitoxantrone hydrochloride liposomes are in the form of a liquid injectable, the liquid injectable contains 0.5 - 5 mg/ml of mitoxantrone, and If the above prednisone is in the form of a tablet, the content is 5 mg/tablet, and When the above cyclophosphamide is in the form of an injectable powder, the content is 0.2g/bottle, and If the above vincristine is in the form of an injectable powder, the content is 1 mg/vessel, Composition.
  5. In paragraph 1, A composition having a therapeutic effective dose of the above-mentioned mitoxantrone hydrochloride liposome of 18 to 24 mg/ m² based on mitoxantrone.
  6. As a drug for treating treatment-naive peripheral T-cell lymphoma (PTCL), The above drugs include mitoxantrone liposomes, cyclophosphamide, vincristine, and prednisone, and The above mitoxantrone liposome is a mitoxantrone hydrochloride liposome, and The above mitoxantrone hydrochloride liposomes, prednisone, cyclophosphamide, and vincristine are present in the same preparation or in separate preparations, and When the above-mentioned mitoxantrone hydrochloride liposomes, prednisone, cyclophosphamide, and vincristine are each present in separate formulations, the formulations are identical or different, and When the above mitoxantrone hydrochloride liposomes are in the form of a liquid injectable, the liquid injectable contains 0.5 - 5 mg/ml of mitoxantrone, and If the above prednisone is in the form of a tablet, the content is 5 mg/tablet, and When the above cyclophosphamide is in the form of an injectable powder, the content is 0.2g/bottle, and If the above vincristine is in the form of an injectable powder, the content is 1 mg/bottle, and The therapeutic effective dose of the above mitoxantrone hydrochloride liposomes is 18 to 30 mg/ m² based on mitoxantrone, and The dose of the above-mentioned cyclophosphamide is 750 mg/ m² , and The dose of the above vincristine is 1.4 mg/ m² , and The above dose of prednisone is 100 mg/day, Drugs.
  7. In paragraph 6, A drug having a therapeutic effective dose of the above mitoxantrone hydrochloride liposomes of 18 to 24 mg/ m² based on mitoxantrone.
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  9. A formulation for the treatment of treatment-naive peripheral T-cell lymphoma (PTCL), comprising mitoxantrone hydrochloride liposomes, cyclophosphamide, vincristine, and prednisone, Administer prednisone before administering mitoxantrone hydrochloride liposomes, administer vincristine after administering mitoxantrone hydrochloride liposomes, and then administer cyclophosphamide. The administration cycle is once every 4 or 3 weeks, and The therapeutic effective dose of the above mitoxantrone hydrochloride liposomes is 18 to 30 mg/ m² based on mitoxantrone, and The dose of the above-mentioned cyclophosphamide is 750 mg/ m² , and The dose of the above vincristine is 1.4 mg/ m² , and The above dose of prednisone is 100 mg/day, Formulation.
  10. In Paragraph 9, A formulation having a therapeutically effective dose of the above mitoxantrone hydrochloride liposomes of 18 to 24 mg/ m² based on mitoxantrone.
  11. In any one of paragraphs 1, 4, and 5, The above mitoxantrone hydrochloride liposomes have a particle size of 30-80 nm and contain 1) a phospholipid bilayer containing mitoxantrone or a pharmaceutically acceptable salt thereof as an active ingredient, and 2) a phospholipid having a phase transition temperature (Tm) higher than body temperature. The phospholipid above, in which the above Tm is higher than body temperature, is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dipalmitate lecithin or distearate lecithin, or any combination thereof. Composition.
  12. In paragraph 6 or 7, The above mitoxantrone hydrochloride liposomes have a particle size of 30-80 nm and contain 1) a phospholipid bilayer containing mitoxantrone or a pharmaceutically acceptable salt thereof as an active ingredient, and 2) a phospholipid having a phase transition temperature (Tm) higher than body temperature. The phospholipid above, in which the above Tm is higher than body temperature, is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dipalmitate lecithin or distearate lecithin, or any combination thereof. drugs
  13. In Article 9 or Article 10, The above mitoxantrone hydrochloride liposomes have a particle size of 30-80 nm and contain 1) a phospholipid bilayer containing mitoxantrone or a pharmaceutically acceptable salt thereof as an active ingredient, and 2) a phospholipid having a phase transition temperature (Tm) higher than body temperature. The phospholipid above, in which the above Tm is higher than body temperature, is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, dipalmitate lecithin or distearate lecithin, or any combination thereof. Formulation.
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Description

Uses of Mitoxanthrone Hydrochloride Liposomes and Cyclophosphamide, Vincristine, and Prednisone The present invention relates to the field of antitumor drugs, specifically to the use of mitoxantrone hydrochloride liposomes and cyclophosphamide, vincristine, and prednisone in the manufacture of drugs for the initial treatment of peripheral t-cell lymphoma (PTCL). PTCL is a group of lymphoproliferative tumors originating from postthymic mature T cells, characterized by significant heterogeneity and, in most cases, high aggressiveness. According to the 2016 revised WHO classification criteria (Swerdlow SH, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19; 127(20): 2375-2390.), PTCL encompasses four categories with a total of more than 30 subtypes, including peripheral T-cell lymphoma unspecified, angioimmunoblastic T-cell lymphoma, extranodal nasal NK/T-cell lymphoma, ALK+ systemic anaplastic large T-cell lymphoma, ALK-systemic anaplastic large T-cell lymphoma, and mycosis fungoides/Sizary syndrome; this complex pathological classification reflects the heterogeneity of the disease group. The incidence and distribution of pathological subtypes of PTCL vary regionally. The incidence rate in Asia is slightly higher than in Europe and the United States. In China, PTCL accounts for approximately 25%–35% of non-Hodgkin lymphomas (NHL), which is significantly higher than in Europe and the United States (10%–15%). It is important to note that the treatment of PTCL is not optimistic; the overall response rate to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or first-line CHOP therapy is not high, and the disease is prone to recurrence and has a poor prognosis. Excluding ALK+ systemic anaplastic large T-cell lymphoma (ALCL), the 5-year survival rate for other subtypes of PTCL is only 14-32% (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.). Although there have been domestic and international studies investigating the efficacy of anthracycline-free regimens as a first-line treatment for PTCL, they have not been proven to be superior to CHOP regimens based on anthracycline drugs; therefore, the first-line status of anthracycline-containing regimens remains unshaken. As can be seen from this, safe and efficient first-line treatment regimens for PTCL still require further research. Mitoxantrone hydrochloride is an anthracycline drug that has been used in over 30 countries worldwide and is effective in treating various solid tumors, including breast cancer, hematological malignancies such as acute leukemia and lymphoma. Side effects primarily include bone marrow suppression, gastrointestinal reactions, and cardiotoxicity. Clinically, it is mainly used for the treatment of acute myeloid leukemia. Liposomes represent a novel form of drug loading. Studies have shown that they can alter the distribution of encapsulated drugs within the body, allowing the drugs to accumulate primarily in tumor tissues, thereby enhancing the therapeutic index of the drug, reducing the therapeutic dose, and decreasing drug toxicity. Due to these characteristics, drug loading via liposomes is receiving significant attention in anti-tumor drug research. Some researchers have conducted studies on mitoxantrone liposomal formulations. For example, WO2008/080367A1 discloses mitoxantrone liposomes, the full text of which is incorporated herein by reference. Studies have shown that, compared to conventional mitoxantrone formulations, liposomal formulations exhibit lower toxicity (particularly cardiotoxicity) and possess the characteristic of passively targeting tumor tissues, thereby enhancing anti-tumor activity. Phase 1 clinical trials of Mitosantronic Hydrochloride Liposomal Injection as a monotherapy completed dose escalation exploration and PK/PD studies in subjects with advanced solid tumors and lymphomas. According to the results, the product demonstrated safety, tolerability, and consistent therapeutic effects within a dose range of 6-30 mg/ m² . A pivotal Phase 2 clinical trial of Mitosantronic Hydrochloride Liposomal Injection as a monotherapy was conducted and enrollment was completed in patients with relapsed/refractory PTCL (n=108 cases, administered dose 20 mg/ m² ), and the current objective response rate (ORR), evaluated and confirmed by the Independent Review Committee (IRC), is 40.7%. Considering the excellent monotherapy efficacy of this product in patients with relapsed/refractory PTCL, this study aims to further investigate the combination therapy of Mitosantronic Hydrochloride Liposomal Injection in treatment-naïve PTCL patients. The following examples are specific descriptions of the present invention and should not limit the scope of the present invention. Example 1 Clinical study of mitoxantrone hydrochloride liposomal inject