CN117940164A

CN117940164A - Application of mitoxantrone liposome combined with anti-angiogenesis targeting drug in treatment of ovarian cancer

Info

Publication number: CN117940164A
Application number: CN202380008767.6A
Authority: CN
Inventors: 李春雷; 刘延平; 李彦辉; 罗无瑕; 梁敏; 李萌萌; 杜艳玲; 王彩霞; 李永丰; 王世霞
Original assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd; Shijiazhuang Pharma Group Zhongnuo Pharmaceutical Shijiazhuang Co Ltd
Current assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd; Shijiazhuang Pharma Group Zhongnuo Pharmaceutical Shijiazhuang Co Ltd
Priority date: 2022-04-26
Filing date: 2023-04-25
Publication date: 2024-04-26
Also published as: WO2023207931A1

Abstract

The invention relates to a mitoxantrone liposome combined anti-angiogenesis targeting drug, in particular to application of bevacizumab and sorafenib in treating ovarian cancer, in particular to platinum-resistant recurrent ovarian cancer. The combination of mitoxantrone liposome and anti-angiogenesis targeting drug further improves the efficacy of ovarian cancer, improves the disease remission rate, and can control the progression of the disease, thereby providing a new choice for the treatment of ovarian cancer.

Description

Application of mitoxantrone liposome combined with anti-angiogenesis targeting drug in treatment of ovarian cancer

Technical Field

The invention belongs to the field of anti-tumor, and particularly relates to an application of mitoxantrone liposome combined with an anti-angiogenesis targeting drug, in particular to bevacizumab or sorafenib in treating ovarian cancer, in particular to platinum-resistant recurrent ovarian cancer.

Background

Ovarian cancer is one of the common malignant tumors of females, and once found, is mostly in middle and late stages due to lack of typical symptoms and signs, and has a short survival time. In 2020, there are 55342 cases of ovarian cancer and 37519 cases of death, and the incidence rate is the third place of malignant tumor of female reproductive system and the death rate is the second place. Ovarian cancer is of a variety of pathological types, with 95% of the most common epithelial ovarian cancers being followed by malignant germ cell tumors and sex cord interstitial tumors.

Platinum-containing combination chemotherapy regimens are the primary recommendation for post-operative chemotherapy for advanced ovarian cancer. About 10% -15% of ovarian cancer patients have intrinsic resistance to standard first-line platinum drug combination therapy, and the total survival time is less than 9 months. Even if the patients in the late stage are completely relieved by treatment with a platinum-containing regimen, 70-80% of the patients still have recurrence (Xie Xing, martin, shen Keng, etc., china expert consensus on the treatment of ovarian cancer with polyethylene glycol liposomal doxorubicin (2018), modern gynaecological and obstetrical progress, 2018, 27 (09): 641-644).

In platinum-resistant ovarian cancer, the preferred treatment regimen involves single-drug chemotherapy. Single drug chemotherapy includes doxorubicin liposomes, paclitaxel, topotecan, gemcitabine, docetaxel, etoposide, and the like. Multiple phase III randomized controlled studies showed that doxorubicin liposomes, paclitaxel, topotecan, gemcitabine treated platinum-resistant ovarian cancer with comparable efficacy in two phases, objective Remission Rate (ORR) of only 5% -15%, median Progression Free Survival (PFS) of about 2-4 months, median total survival (OS) of about 8-14 months (Ten Bokkel Huinink W,Gore M,Carmichael J,et al.,Topotecan versus Paclitaxel for The Treatment of Recurrent Epithelial Ovarian Cancer,J Clin Oncol,1997,15(6)：2183-93).II single arm study with docetaxel or etoposide ORR higher than 20%, whereas median OS of 12.7 months, 10.8 months, respectively, did not improve survival (Rose P G,Blessing J A,Ball H G,et al.,A Phase II Study of Docetaxel in Paclitaxel-Resistant Ovarian and Peritoneal Carcinoma：A Gynecologic Oncology Group Study,Gynecol Oncol,2003,88(2)：130-5). compared to the four chemotherapeutic drugs described above and therefore none of the chemotherapeutic drugs was more prominent in efficacy than the other drugs, the ORR rate of single drug chemotherapy was low, the duration of response was short, and the total survival time was about 1 year.

In recent years, the application of the anti-angiogenesis targeting drug to epithelial ovarian cancer has significantly progressed, and the survival rate of the ovarian cancer is expected to be improved. Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (Vascular endothelial growth factor, VEGF). As a first anti-angiogenesis targeting drug, it has been approved for use in a number of solid tumors such as non-small cell lung cancer, breast cancer, renal cancer, cervical cancer, ovarian cancer, etc. In one stage III AURELIA study, bevacizumab combination chemotherapy increased ORR of platinum-resistant ovarian cancer to 27.3%; in terms of safety, bevacizumab group is integrally and safely tolerant, namely, more than or equal to 2-level hypertension (20%), proteinuria (2%), gastrointestinal perforation (2%) and fistula/abscess (2%), more commonly (Eric Pujade-Lauraine,Felix Hilpert et al.,Bevacizumab Combined with Chemotherapy for Platinum-Resistant Recurrent Ovarian Cancer：The AURELIA Open-Label Randomized Phase III Trial,Journal of Clinical Oncology,2014,32(13),1302-1311). sorafenib is a classical multi-target kinase inhibitor, and in vitro experiments show that the bevacizumab group can inhibit tumor cell proliferation targets such as RAF, c-Kit and FLT-3 besides inhibiting signal paths of tumor angiogenesis such as VEGF receptors, platelet-derived growth factor receptors (Platelet-derived growth factor receptor and PDGFR). Sorafenib has been FDA approved for unresectable hepatocellular carcinoma, advanced renal cell carcinoma, and recurrent metastatic thyroid carcinoma. One phase II single arm study showed that sorafenib alone treated platinum resistant ovarian cancer had an ORR of 3.4% and a median OS of 16.33 months, with significant grade 3 or 4 toxicity among 71 subjects including: rash (n=7), hand and foot syndrome (n=9), metabolic toxicity (n=10), gastrointestinal reaction (n=3), etc (Matei D,Sill M W,Lankes H A,et al.,Activity of Sorafenib in Recurrent Ovarian Cancer and Primary Peritoneal Carcinomatosis：A Gynecologic Oncology Group Trial,J Clin Oncol,2011,29(1)：69-75).

In summary, platinum-resistant recurrent ovarian cancer has poor prognosis and short survival time, and the curative effects of the existing drug therapies (including chemotherapy, targeted therapy and the like) are not satisfactory. Thus, there is a need for new drugs or therapies for treating platinum-resistant recurrent ovarian cancer that can increase the rate of disease remission, extend survival, and be safely tolerated.

Mitoxantrone is a widely used drug in clinical practice at present, and the FDA approved indications are multiple sclerosis, prostate cancer and acute myelogenous leukemia, and has certain curative effects on malignant lymphoma, breast cancer, lung cancer, melanoma, soft tissue sarcoma, multiple myeloma, liver cancer, colorectal cancer, renal cancer, endometrial cancer, testicular tumor, ovarian cancer and head and neck cancer clinically. Compared with the common mitoxantrone preparation, the liposome preparation has lower toxicity (especially cardiac toxicity), has the characteristic of passively targeting tumor tissues, and improves the anti-tumor activity.

The inventor tries to combine mitoxantrone liposome with anti-angiogenesis targeting drugs, particularly bevacizumab and sorafenib, to treat platinum-resistant recurrent ovarian cancer, and as a result, the improved disease remission rate and safe tolerance are realized, thereby providing a new choice for treating platinum-resistant recurrent ovarian cancer.

Disclosure of Invention

The invention relates to an application of mitoxantrone liposome combined with an anti-angiogenesis targeting drug in treating ovarian cancer.

The first aspect of the present invention relates to the use of mitoxantrone liposomes and an anti-angiogenesis targeting drug in the manufacture of a medicament for the treatment of ovarian cancer, wherein the anti-angiogenesis targeting drug is selected from bevacizumab and sorafenib.

A second aspect of the invention relates to the use of mitoxantrone liposomes in the manufacture of a medicament for improving the efficacy of an anti-angiogenesis targeting agent for the treatment of ovarian cancer, wherein the anti-angiogenesis targeting agent is selected from bevacizumab and sorafenib.

A third aspect of the invention relates to a method of treating ovarian cancer, comprising administering to an ovarian cancer patient a therapeutically effective amount of mitoxantrone liposome and an anti-angiogenesis targeting agent, wherein the anti-angiogenesis targeting agent is selected from bevacizumab and sorafenib.

A fourth aspect of the invention relates to a method of improving the efficacy of an anti-angiogenesis targeting agent in the treatment of ovarian cancer, the method comprising further co-administering a therapeutically effective amount of mitoxantrone liposomes on the basis of administration of an anti-angiogenesis targeting agent to an ovarian cancer patient, wherein the anti-angiogenesis targeting agent is selected from bevacizumab and sorafenib.

A fifth aspect of the invention relates to a medicament for the treatment of ovarian cancer, the medicament comprising mitoxantrone liposomes and an anti-angiogenesis targeting agent, wherein the anti-angiogenesis targeting agent is selected from bevacizumab and sorafenib.

A sixth aspect of the invention relates to a composition for the treatment of ovarian cancer, comprising mitoxantrone liposomes and an anti-angiogenesis targeting agent, wherein the anti-angiogenesis targeting agent is selected from bevacizumab and sorafenib.

A seventh aspect of the invention relates to a medicament for improving the efficacy of an anti-angiogenesis targeting drug for the treatment of ovarian cancer, the medicament comprising mitoxantrone liposomes, wherein the anti-angiogenesis targeting drug is selected from bevacizumab and sorafenib.

An eighth aspect of the invention relates to a kit for treating ovarian cancer, comprising mitoxantrone liposomes and an anti-angiogenesis targeting agent, wherein the anti-angiogenesis targeting agent is selected from bevacizumab and sorafenib.

In some embodiments of the above aspects, the ovarian cancer is recurrent ovarian cancer.

In some embodiments of the above aspects, the ovarian cancer is platinum-resistant recurrent ovarian cancer.

In some embodiments of the above aspects, the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

In some embodiments of the above aspects, the mitoxantrone liposome is an injection.

In some embodiments of the above aspects, bevacizumab is an injection.

In some embodiments of the above aspects, the sorafenib is a tablet.

Detailed Description

Definition of the definition

In the following detailed description, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

The term "comprising" (or its equivalent terms such as "comprising," "containing," etc.) as used herein includes "consisting of," unless otherwise specified.

The term "composition" as used herein refers to a combination of two or more active ingredients, wherein each active ingredient may be present in the same formulation for administration together, or each active ingredient may be present in a different formulation for simultaneous or sequential administration, in the same or different modes of administration. In this sense, "composition" and "combination" are used interchangeably.

The term "therapeutically effective amount" or "effective amount" as used herein refers to a dose that exhibits a desired benefit in a treated subject. The "therapeutically effective amount" or "effective amount" will depend on factors such as the species of the subject being treated, the severity of the disease, the frequency of administration, the metabolic profile of the drug substance, and the like, and can be determined by the prescribing physician according to conventional practice. It should be noted that all numerical ranges mentioned in this application include both endpoints of the range, all numbers within the range, and sub-ranges formed by any two of the numbers.

The term "treating" as used herein refers to controlling, alleviating or alleviating the pathological progression of a disease and extending the survival of a subject suffering from the disease.

The terms "subject," "patient," as used herein, include an animal subject, including but not limited to humans and other mammals, such as mice, rats, cats, monkeys, dogs, horses, pigs, etc., to whom the medicament or composition of the application is intended to be administered. Preferably, the subject is a human. Unless indicated, the terms "subject," "patient" are used interchangeably.

The term "platinum-resistant recurrent ovarian cancer" as used herein refers to ovarian cancer that recurs within 1 to 6 months after treatment with at least 4 cycles of a platinum-containing regimen.

Detailed description of embodiments of the invention

In some embodiments, the anti-angiogenesis targeting agent is bevacizumab. In some embodiments, the anti-angiogenesis targeting agent is sorafenib.

In some embodiments, the ovarian cancer is recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

In some embodiments, the mitoxantrone liposome is an injection, including liquid injection, powder for injection, tablet for injection, and the like. When the mitoxantrone liposome is a liquid injection, it contains 0.5-5mg/ml, preferably 1-2mg/ml, more preferably 1mg/ml of active ingredient, calculated as mitoxantrone.

In some embodiments, bevacizumab is an injection, including liquid injection, powder for injection, tablet for injection, and the like. When bevacizumab is a liquid injection, the bevacizumab contains 25mg/ml of active component bevacizumab.

In some embodiments, sorafenib is a tablet containing 200 mg/tablet of active ingredient.

In some embodiments, there is provided the use of mitoxantrone liposomes and bevacizumab in the manufacture of a medicament for the treatment of ovarian cancer. In some embodiments, there is provided the use of mitoxantrone liposomes and bevacizumab in the manufacture of a medicament for treating platinum resistant recurrent ovarian cancer. In some embodiments, there is provided the use of mitoxantrone liposomes and bevacizumab in the manufacture of a medicament for treating platinum resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In these embodiments, the mitoxantrone liposome is an injection containing 0.5-5mg/ml of active ingredient, calculated as mitoxantrone; bevacizumab is an injection and contains 25mg/ml of active ingredient.

In some embodiments, there is provided the use of mitoxantrone liposomes and sorafenib in the manufacture of a medicament for treating ovarian cancer. In some embodiments, there is provided the use of mitoxantrone liposomes and sorafenib in the manufacture of a medicament for treating platinum resistant recurrent ovarian cancer. In some embodiments, there is provided the use of mitoxantrone liposomes and sorafenib in the manufacture of a medicament for treating platinum resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In these embodiments, the mitoxantrone liposome is an injection containing 0.5-5mg/ml of active ingredient, calculated as mitoxantrone; sorafenib is a tablet containing 200 mg/tablet of active ingredient.

In some embodiments, there is provided the use of mitoxantrone liposomes in the manufacture of a medicament for improving the efficacy of bevacizumab in treating ovarian cancer. In some embodiments, there is provided the use of mitoxantrone liposomes in the manufacture of a medicament for improving the efficacy of bevacizumab in treating platinum-resistant recurrent ovarian cancer. In some embodiments, there is provided the use of mitoxantrone liposomes in the manufacture of a medicament for improving the efficacy of bevacizumab in treating platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In these embodiments, the mitoxantrone liposome is an injection containing 0.5-5mg/ml of active ingredient, calculated as mitoxantrone; bevacizumab is an injection and contains 25mg/ml of active ingredient.

In some embodiments, there is provided the use of mitoxantrone liposomes in the manufacture of a medicament for improving the efficacy of sorafenib in treating ovarian cancer. In some embodiments, there is provided the use of mitoxantrone liposomes in the manufacture of a medicament for improving the efficacy of sorafenib in treating platinum-resistant recurrent ovarian cancer. In some embodiments, there is provided the use of mitoxantrone liposomes in the manufacture of a medicament for improving the efficacy of sorafenib in treating platinum resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. In these embodiments, the mitoxantrone liposome is an injection containing 0.5-5mg/ml of active ingredient, calculated as mitoxantrone; sorafenib is a tablet containing 200 mg/tablet of active ingredient.

In some embodiments, mitoxantrone liposomes are administered by injection. In some embodiments, mitoxantrone liposomes are administered intravenously in a therapeutically effective amount of 8-30mg/m ², preferably 20mg/m ². In some embodiments, mitoxantrone liposomes are administered once every 3 weeks. In some embodiments, mitoxantrone liposomes are administered intravenously every 3 weeks in a therapeutically effective amount of 20mg/m ².

In some embodiments, bevacizumab is administered by injection. In some embodiments, bevacizumab is administered by injection at a dose of 15 mg/kg.

In some embodiments, sorafenib is administered orally. In some embodiments, sorafenib is orally administered at a dose of 400 mg/dose. In some embodiments, sorafenib is administered twice daily. In some embodiments, sorafenib is orally administered twice daily at a dose of 400 mg/dose.

In some embodiments, methods of treating ovarian cancer are provided, comprising administering to an ovarian cancer patient a therapeutically effective amount of mitoxantrone liposome and bevacizumab. In some embodiments, methods of treating ovarian cancer are provided, comprising administering to an ovarian cancer patient a therapeutically effective amount of mitoxantrone liposome, and administering bevacizumab at any time after administration of the mitoxantrone liposome. In some embodiments, methods of treating ovarian cancer are provided, the methods comprising administering to an ovarian cancer patient 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab once every 3 weeks, and administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 1-8 cycles of administration. In some embodiments, methods of treating ovarian cancer are provided, the methods comprising administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab once every 3 weeks to a patient with ovarian cancer, and administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 5-7 cycles of administration. In some embodiments, methods of treating ovarian cancer are provided, the methods comprising administering to an ovarian cancer patient 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab once every 3 weeks, and administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 8 cycles of administration. In the above embodiments, the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

In some embodiments, methods of treating ovarian cancer are provided, comprising administering to an ovarian cancer patient a therapeutically effective amount of mitoxantrone liposomes and sorafenib. In some embodiments, methods of treating ovarian cancer are provided, comprising administering to a patient with ovarian cancer a therapeutically effective amount of mitoxantrone liposomes and administering sorafenib at any time before, during, or after administration of the mitoxantrone liposomes. In some embodiments, methods of treating ovarian cancer are provided, the methods comprising administering to an ovarian cancer patient 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose of sorafenib twice daily, with a 400 mg/dose twice daily maintenance therapy after 1-8 cycles of administration. In some embodiments, methods of treating ovarian cancer are provided, the methods comprising administering to an ovarian cancer patient 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose of sorafenib twice daily, with a 400 mg/dose twice daily maintenance therapy after 5-7 cycles of administration. In some embodiments, a method of treating ovarian cancer is provided, the method comprising administering to a patient with ovarian cancer 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose of sorafenib twice daily, with sorafenib maintenance therapy administered twice daily at 400 mg/dose after 8 cycles of administration. In the above embodiments, the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

In some embodiments, methods of improving the efficacy of bevacizumab in treating ovarian cancer are provided, the methods comprising further co-administering a therapeutically effective amount of mitoxantrone liposomes based on administration of bevacizumab to an ovarian cancer patient. In some embodiments, methods of improving the efficacy of bevacizumab in treating ovarian cancer are provided, the methods comprising administering mitoxantrone liposomes once every 3 weeks at a dose of 20mg/m ² at any time prior to bevacizumab administration. In some embodiments, methods of improving the efficacy of bevacizumab in treating ovarian cancer are provided, the methods comprising administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab to a patient with ovarian cancer once every 3 weeks, administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 1-8 cycles of administration. In some embodiments, methods of improving the efficacy of bevacizumab in treating ovarian cancer are provided, the methods comprising administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab once every 3 weeks to an ovarian cancer patient, and administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 5-7 cycles of administration. In some embodiments, a method of improving the efficacy of bevacizumab in treating ovarian cancer is provided, the method comprising administering to an ovarian cancer patient 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab once every 3 weeks, and administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 8 cycles of administration. In the above embodiments, the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

In some embodiments, methods of improving the efficacy of sorafenib in treating ovarian cancer are provided, the methods comprising further co-administering a therapeutically effective amount of mitoxantrone liposomes based on the administration of sorafenib to ovarian cancer patients. In some embodiments, methods of improving the efficacy of sorafenib in treating ovarian cancer are provided, the methods comprising administering mitoxantrone liposomes at a dose of 20mg/m ² once every 3 weeks at any time before, during, or after sorafenib administration. In some embodiments, there is provided a method of improving the efficacy of sorafenib in treating ovarian cancer, the method comprising administering to a patient with ovarian cancer 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose of sorafenib twice daily, twice daily maintenance therapy at 400 mg/dose after 1-8 cycles of administration. In some embodiments, there is provided a method of improving the efficacy of sorafenib in treating ovarian cancer, the method comprising administering to a patient with ovarian cancer 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose twice daily of sorafenib, the sorafenib maintenance treatment being administered at 400 mg/dose twice daily after 5-7 cycles. In some embodiments, a method of improving the efficacy of sorafenib in treating ovarian cancer is provided, the method comprising administering to an ovarian cancer patient 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose of sorafenib twice daily, twice daily at 400 mg/dose of sorafenib maintenance therapy after 8 cycles of administration. In the above embodiments, the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

In some embodiments, the medicament comprises mitoxantrone liposomes and bevacizumab. In some embodiments, the medicament comprises mitoxantrone liposomes and sorafenib. In some embodiments, the medicament optionally comprises other first-line, second-line medicaments known in the art for treating ovarian cancer.

In some embodiments, the composition comprises mitoxantrone liposomes and bevacizumab. In some embodiments, the composition comprises mitoxantrone liposomes and sorafenib.

In some embodiments, the treatment comprises administering to the ovarian cancer patient a therapeutically effective amount of mitoxantrone liposome and bevacizumab. In some embodiments, the treatment comprises administering a therapeutically effective amount of mitoxantrone liposomes to an ovarian cancer patient and bevacizumab at any time after administration of the mitoxantrone liposomes. In some embodiments, the treatment comprises administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab to an ovarian cancer patient once every 3 weeks, and administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 1-8 cycles of administration. In some embodiments, the treatment comprises administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab to an ovarian cancer patient once every 3 weeks, and administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 5-7 cycles of administration. In some embodiments, the treatment comprises administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab to the ovarian cancer patient once every 3 weeks, and administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 8 cycles of administration. In the above embodiments, the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

In some embodiments, the treatment comprises administering to the ovarian cancer patient a therapeutically effective amount of mitoxantrone liposomes and sorafenib. In some embodiments, the treatment comprises administering a therapeutically effective amount of mitoxantrone liposomes to ovarian cancer patients and sorafenib at any time before, during, or after administration of the mitoxantrone liposomes. In some embodiments, the treatment comprises administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose of sorafenib twice daily for 1-8 cycles followed by 400 mg/dose of sorafenib maintenance therapy twice daily. In some embodiments, the treatment comprises administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose of sorafenib twice daily for 5-7 cycles followed by 400 mg/dose of sorafenib maintenance therapy twice daily. In some embodiments, the treatment comprises administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose of sorafenib twice daily for 8 cycles followed by 400 mg/dose of sorafenib maintenance therapy twice daily. In the above embodiments, the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

In some embodiments, a medicament is provided for improving the efficacy of bevacizumab in treating ovarian cancer, the improvement comprising further co-administering a therapeutically effective amount of mitoxantrone liposomes on the basis of bevacizumab administration to an ovarian cancer patient. In some embodiments, a medicament is provided for improving the efficacy of bevacizumab in treating ovarian cancer, the improvement comprising administering mitoxantrone liposomes once every 3 weeks at a dose of 20mg/m ² at any time prior to bevacizumab administration. In some embodiments, a medicament is provided for improving the efficacy of bevacizumab in treating ovarian cancer, the improvement comprising administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab to a patient with ovarian cancer once every 3 weeks, administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 1-8 cycles of administration. In some embodiments, a medicament is provided for improving the efficacy of bevacizumab in treating ovarian cancer, the improvement comprising administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab to a patient with ovarian cancer once every 3 weeks, administering bevacizumab maintenance therapy once every 3 weeks at 15mg/kg after 5-7 cycles of administration. In some embodiments, a medicament is provided for improving the efficacy of bevacizumab in treating ovarian cancer, the improvement comprising administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab once every 3 weeks to an ovarian cancer patient, the bevacizumab maintenance therapy being administered at 15mg/kg once every 3 weeks after 8 cycles of administration. In the above embodiments, the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

In some embodiments, a medicament is provided for improving the efficacy of sorafenib in treating ovarian cancer, the improvement comprising further co-administering a therapeutically effective amount of mitoxantrone liposomes on the basis of sorafenib administration to ovarian cancer patients. In some embodiments, a medicament is provided for improving the efficacy of sorafenib in treating ovarian cancer, the improvement comprising administering mitoxantrone liposomes once every 3 weeks at a dose of 20mg/m ² at any time before, during, or after sorafenib administration. In some embodiments, a medicament is provided for improving the efficacy of sorafenib in treating ovarian cancer, the improvement comprising administering to a patient with ovarian cancer 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose of sorafenib twice daily for 1-8 cycles followed by 400 mg/dose of sorafenib maintenance therapy twice daily. In some embodiments, a medicament is provided for improving the efficacy of sorafenib in treating ovarian cancer, the improvement comprising administering to a patient with ovarian cancer 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose twice daily of sorafenib, the sorafenib maintenance treatment being administered at 400 mg/dose twice daily after 5-7 cycles. In some embodiments, a medicament is provided for improving the efficacy of sorafenib in treating ovarian cancer, the improvement comprising administering to a patient with ovarian cancer 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome once every 3 weeks and 400 mg/dose of sorafenib twice daily, with 400 mg/dose of sorafenib maintenance therapy twice daily after 8 cycles of administration. In the above embodiments, the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

In some embodiments, the mitoxantrone liposome and the anti-angiogenesis targeting agent are each separate formulations.

In some embodiments, the kit comprises mitoxantrone liposomes and bevacizumab. In some embodiments, the mitoxantrone liposome is an injection containing 0.5-5mg/ml of active ingredient, calculated as mitoxantrone; bevacizumab is an injection and contains 25mg/ml of active ingredient.

In some embodiments, the kit comprises mitoxantrone liposomes and sorafenib. In some embodiments, the mitoxantrone liposome is an injection containing 0.5-5mg/ml of active ingredient, calculated as mitoxantrone; sorafenib is a tablet containing 200 mg/tablet of active ingredient.

In the above aspects, bevacizumab may be provided in the form of a pharmaceutical formulation, for example an injection. Such pharmaceutical formulations are commercially available.

In the above aspects, the sorafenib is preferably sorafenib tosylate. Sorafenib may be provided in the form of a pharmaceutical formulation, for example, a tablet. Such pharmaceutical formulations are commercially available.

In the above aspects, mitoxantrone liposome is not particularly limited. Without being bound by any particular theory, the inventors of the present application found that one or more of the following properties are advantageous for mitoxantrone liposome formulations:

(i) The mitoxantrone liposome is mitoxantrone hydrochloride liposome;

(ii) Mitoxantrone liposomes have a particle size of about 30-80nm, for example about 35-75nm, about 40-70nm, about 40-60nm, or about 60nm; such as about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or 80nm. There are a variety of ways of particle size determination including, but not limited to NanoZS;

(iii) Mitoxantrone forms a poorly soluble precipitate with multivalent counterions (e.g., sulfate, citrate, or phosphate) within the liposome;

(iv) The phospholipid bilayer in mitoxantrone liposomes contains phospholipids with a phase transition temperature (Tm) above body temperature, so that the liposome has a phase transition temperature above body temperature. The phospholipids include, but are not limited to, hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dipalmitate lecithin, distearate lecithin, or any combination thereof;

(v) The phospholipid bilayer in mitoxantrone liposome contains hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000 modified distearoyl phosphatidylethanolamine (DSPE-PEG 2000);

(vi) The phospholipid bilayer in the mitoxantrone liposome contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoyl phosphatidylethanolamine in a mass ratio of about 3:1:1, mitoxantrone hydrochloride forms a precipitate with multivalent acid radical ions in the liposome that is difficult to dissolve, and the mitoxantrone hydrochloride liposome has a particle size of about 60nm;

(vii) Mitoxantrone liposome formulations prepared using methods disclosed in chinese patent application 200610102339.8 or PCT application WO2008/080367 A1; and

(Viii) The mitoxantrone liposome is the mitoxantrone liposome of national drug standard H20220001.

Preferably, the mitoxantrone liposome meets one or more of the following:

(i) The mitoxantrone liposome is mitoxantrone hydrochloride liposome;

(ii) The particle size of mitoxantrone liposome is 30-80nm;

(iii) Mitoxantrone forms a poorly soluble precipitate with multivalent counterions within the liposome; and

(Iv) The phospholipid bilayer in mitoxantrone liposomes contains a phospholipid having a phase transition temperature (Tm) above body temperature selected from hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dipalmitate lecithin, distearate lecithin, or any combination thereof.

Preferably, the mitoxantrone liposome is a mitoxantrone hydrochloride liposome. The mitoxantrone liposome or mitoxantrone hydrochloride liposome is in a therapeutically effective amount or dose.

The mitoxantrone liposomes can be prepared using methods conventional in the art, or can be prepared using any of the methods disclosed in the prior art, for example, using the methods disclosed in WO2008/080367 A1, the disclosure of which is incorporated herein by reference in its entirety. By way of non-limiting example, the mitoxantrone hydrochloride liposome formulation of the present application can be prepared according to the following method, wherein "lipid drug ratio" refers to the mass ratio of the composition of the phospholipid bilayer in the liposome (including HSPC, DSPE-PEG2000 and Chol) to mitoxantrone:

Hydrogenated soybean lecithin (HSPC), cholesterol (Chol) and polyethylene glycol 2000 modified distearoyl phosphatidylethanolamine (DSPE-PEG 2000) were weighed in a mass ratio of 3:1:1 and dissolved in 95% ethanol to give a clear solution (i.e. an ethanol solution of phospholipids). Mixing ethanol solution of phospholipid with 300mM ammonium sulfate solution, and oscillating at 60-65deg.C for hydration lh to obtain heterogeneous multi-chamber liposome. The particle size of the liposomes was then reduced using a microfluidic device. The obtained sample was diluted 200 times with 0.9% NaCl solution, and then detected by nanoZS, wherein the average particle size of the particles was about 60nm, and the main peak was concentrated between 40 and 60 nm. The empty liposome external phase was then removed using an ultrafiltration device and the external phase was replaced with 290mM sucrose and 10mM glycine to form a transmembrane ammonium sulfate gradient. Mitoxantrone hydrochloride solution (10 mg/mL based on mitoxantrone) was added to the blank liposomes at a ratio of 16:1 between the lipid and drug loading at 60-65 ℃. After incubation for about lh, encapsulation efficiency was demonstrated to be about 100% using gel exclusion chromatography. The product thus obtained was designated PLM60. The weight ratio of HSPC to Chol to DSPE-PEG2000 to mitoxantrone in PLM60 was 9.58:3.19:3.19:1, and the osmotic pressure of the sucrose glycine solution was similar to physiological values.

It should be understood that numerous technical details and parameters in the above-described exemplary preparation methods may be adapted and determined by one skilled in the art within a reasonable scope. For example, glycine-replaceable amino acid species in the outer phase used to form the transmembrane ammonium sulfate gradient include, but are not limited to, histidine, asparagine, glutamic acid, leucine, proline, alanine. As another example, the mass ratios of HSPC, chol and DSPE-PEG2000 may be suitably adjusted. Also for example, for lipid-drug ratio parameters in preparing a particular liposomal pharmaceutical formulation, one skilled in the art can design, test, and ultimately arrive at a suitable lipid-drug ratio to maximize drug loading while reducing drug leakage. For the mitoxantrone hydrochloride liposomal formulations of the application, lipid drug ratios that may be used are wide ranging, e.g., as low as 2:1 or as high as 30:1, 40:1, or 50:1, more suitable lipid drug ratios may be about (15-20) to 1, e.g., about 15:1, 16:1, 17:1, 18:1, 19:1, or 20:1. Thus, several of the advantageous properties of the mitoxantrone hydrochloride liposomal formulations described above are more important and the methodologies for achieving these properties are varied.

Advantageous effects

By administering mitoxantrone liposomes in combination with an anti-angiogenesis targeting agent such as bevacizumab or sorafenib to ovarian cancer patients, the efficacy of the platinum-resistant recurrent ovarian cancer can be improved, the rate of disease remission can be increased, and the progression of the disease can be controlled, prolonging survival.

Examples

The following examples are intended to illustrate the invention in detail and should not be construed as limiting the scope of the invention.

Mitoxantrone hydrochloride liposome injection used in the following examples was supplied by the North pharmaceutical industry (Shijia) Inc. of the Shi-yaku group (national drug standard H20220001).

Example 1 clinical study of mitoxantrone hydrochloride liposomes in combination with anti-angiogenesis targeting drugs for the treatment of ovarian cancer

The study is a single-arm, multi-center and open phase Ib clinical study, is incorporated into platinum-resistant recurrent ovarian cancer patients, and aims to explore the safety and curative effect of single-drug and combined treatment of mitoxantrone hydrochloride liposome injection single drug or combined anti-angiogenesis targeting drug. The study was divided into a single drug exploration phase and a combined exploration phase.

1. Study design

Single drug discovery phase

At this stage, not less than 30 subjects were grouped. The screening period is 28 days, and the qualified subjects are screened to enter the treatment period. Mitoxantrone hydrochloride liposome injection is administered 20mg/m ² during the treatment period, once every 3 weeks (q 3 w), for a total of 8 cycles. For subjects who have completed 8 treatment cycles, if treatment is still beneficial and tolerable, a determination is made by the investigator after co-discussion with the sponsor as to whether treatment can continue. Safety evaluation is carried out according to the plan in the treatment period, and curative effect evaluation is carried out every two periods. The treatment is finished, the follow-up period is entered, and safety evaluation and curative effect evaluation are carried out 28 days after the last administration; efficacy evaluation is then performed every 6 weeks until disease progression or a new anti-tumor therapy is initiated; survival follow-up was then performed every 6 weeks.

Joint exploration phase

After the safety and the curative effect of the mitoxantrone hydrochloride liposome single drug are preliminarily obtained in the single drug exploration stage, the research enters the combined exploration stage. Screening period is 28 days, and qualified subjects are screened to enter treatment period, and are distributed to a combination A queue or a combination B queue according to the group entering sequence. After cohorts a 30 subjects are scheduled to be in the group, cohorts 26 subjects are continued to be in the group B.

Joint a queue: mitoxantrone hydrochloride liposomes (20 mg/m ²) are administered in combination with bevacizumab injection (15 mg/kg), once every 3 weeks (q 3 w), and up to 8 cycles later in maintenance phase, bevacizumab (15 mg/kg, q3 w) is administered for maintenance treatment until disease progression, death, intolerable toxicity or the investigator decides that no benefit can be obtained.

Joint B queue: mitoxantrone hydrochloride liposomes (20 mg/m ²) are administered once every 3 weeks (q 3 w) in combination with sorafenib tosylate [400 mg/dose, calculated as sorafenib, twice daily (bid) ] and orally administered every 3 weeks, and the combination is administered to the mitoxantrone hydrochloride liposomes for up to 8 cycles before a maintenance period, with sorafenib tosylate (400 mg/dose, bid) maintenance therapy until disease progression, death, intolerable toxicity or the investigator decides that no benefit can be obtained.

Safety evaluation is carried out according to the plan in the treatment period, and curative effect evaluation is carried out every two periods. The treatment is finished, the follow-up period is entered, and safety evaluation and curative effect evaluation are carried out 28 days after the last administration; efficacy evaluation is then performed every 6 weeks until disease progression or a new anti-tumor therapy is initiated; survival follow-up was then performed every 6 weeks.

2. Test crowd

First, selection criteria

Subject formulas meeting all of the following criteria may be entered into the selection study:

1) The subjects voluntarily participated in the study and signed informed consent;

2) Female subjects with ages greater than or equal to 18 years old;

3) Pathologically diagnosed epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer (except mucinous cancer and low grade serous);

4) Single drug exploration phase: a platinum resistant relapsing subject who failed at least treatment with a standard platinum-containing regimen; joint exploration: a platinum resistant relapsed subject who failed at least treatment with a standard platinum-containing regimen, and who is only allowed to receive no more than 1-line system treatment regimen after platinum resistance;

5) The baseline has at least one measurable lesion that meets the RECIST 1.1 definition;

6) Single drug exploration phase: ECOG scores 0-2; joint exploration: ECOG scores 0-1;

7) The toxicity of the prior anti-tumor treatment is recovered to be less than or equal to CTCAE grade 1 (except alopecia, pigmentation or other toxicity which is considered to have no safety risk for the subjects in the study);

8) The laboratory test values of the subjects meet the following requirements:

● Absolute value (ANC) of neutrophil (1.5x10 ⁹/L) (1 week before laboratory examination, no G-CSF liter autonomous treatment);

● Hemoglobin (Hb). Gtoreq.90 g/L (within 1 week prior to laboratory examination, no infused erythrocyte therapy was received);

● Platelets not less than 100x10 ⁹/L (1 week prior to laboratory examination, without infusion of platelets, thrombopoietin, interleukin-11 or other platelet-increasing medications);

● Creatinine is less than or equal to 1.5 XULN, urine protein is less than 2+ (when the baseline urine protein is more than or equal to 2+, the urine protein is quantitatively detected within 7 days for 24 hours, and the urine protein can be selected when the urine protein is less than 1 g);

● Total bilirubin is less than or equal to 1.5 xULN;

● Alanine Aminotransferase (AST)/aspartate Aminotransferase (ALT) is less than or equal to 2.5 XULN;

● Albumin is more than or equal to 3.0g/dL;

● Coagulation function: prothrombin Time (PT), international Normalized Ratio (INR) 1.5 XULN (or INR typically between 2-3 when patients are treated with warfarin stable therapeutic doses), and Partial Thromboplastin Time (PTT) 1.2 XULN; if the patient receives a stable dose of an anticoagulant for at least 2 weeks before the initiation of the first study treatment and the INR or Activated Partial Thromboplastin Time (APTT) is within therapeutic range (based on study center criteria), then the whole dose of oral or injectable anticoagulant is allowed;

9) Female subjects were urine or blood HCG negative (except for menopause and hysterectomy), women of childbearing age and their partners took effective contraceptive measures during the trial period and within 6 months after the end of the last dose (e.g.: combination of hormones (estrogen and progestogen-containing) to inhibit ovulation, progestogen-contraceptive combination to inhibit ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomy, avoidance of sexual activity, etc.);

10 Subjects were able to communicate well with the investigator and understand and voluntarily follow the individual requirements of the study.

(II) exclusion criteria

Subjects meeting any of the following criteria were not enrolled in the study

1) It is known that allergic reaction to the study drug or any of its adjuvants or to other monoclonal antibodies is too severe;

2) Central nervous system metastasis, except for symptom-stable brain metastasis after treatment (symptom-stable brain metastasis is defined as: brain symptom relief after systemic treatment or local radiotherapy, 2-4 weeks after cessation of treatment, asymptomatic subjects);

3) CT or color Doppler ultrasound shows that there is a great deal of pleural effusion, a great deal of pelvic/peritoneal effusion, and a great deal of pericardial effusion;

4) Previous allogeneic organ transplantation or allogeneic bone marrow transplantation;

5) Patients with active hepatitis b (HbsAg or HBcAb positive and HBV DNA above the upper limit of normal), active hepatitis c (HCV antibody positive and HCV RNA above the lower limit of study center detection), HIV antibody positive;

6) Study drug administration was preceded by 1 week of active bacterial infection, fungal infection, viral infection or interstitial pneumonia in need of systemic treatment;

7) The radiotherapy of any part of the abdomen or the pelvis is accepted in the past;

8) Previously accepted Sorafenib-like tyrosine kinase inhibitors;

9) Treatment with aspirin (> 325 mg/day), clopidogrel (> 75 mg/day) or dipyridamole, ticlopidine or cilostazol within 10 days prior to first administration;

10 Any antitumor therapeutic person (except for traditional Chinese medicine or Chinese patent medicine) received within 4 weeks before the first administration, and traditional Chinese medicine or Chinese patent medicine with antitumor indication received within 2 weeks before the first administration;

11 Receiving additional clinical study medication within 4 weeks prior to the first administration;

12 A major surgery was accepted within 3 months prior to the first administration (surgical grading: level 3-4 surgery, excluding intravenous port implantation), or hollow needle biopsies or other minor surgery (excluding placement of vascular access devices) within 7 days prior to first administration, or major operators scheduled to be performed during the study;

13 Any clinically identifiable thrombosis, embolism, venous or arterial event such as deep vein thrombosis, pulmonary embolism, cerebrovascular accident, transient ischemic attacks, subarachnoid hemorrhage, etc. (except asymptomatic catheter-related venous thrombosis) occurs 6 months prior to first administration;

14 Combining peripheral vascular diseases with CTCAE of grade 2 or more;

15 3 months prior to the first administration, a level 2 or more CTCAE pulmonary hemorrhage event or any other level 3 or more CTCAE hemorrhage event;

16 Active bleeding or bleeding tendencies (e.g., known hemorrhagic diseases, coagulation disorders, or tumors involving large blood vessels);

17 Severe unhealed wounds, ulcers or fractures;

18 A person with clinical symptoms of gastrointestinal obstruction and in need of parenteral nutrition supplementation;

19 A history of ileus, abdominal fistulas, gastrointestinal perforations, or intra-abdominal abscesses within 6 months prior to the first administration;

20 A) a subject suffering from epilepsy in need of drug treatment;

21 Patients (e.g., phenytoin, carbamazepine, phenobarbital, dexamethasone (daily dose greater than 16 mg), rifampin, or rifapentine) with a potent CYP3A4 inducer within 4 weeks prior to first administration;

22 In 3 years prior to the first administration, other malignant active tumors, except for the cured locally treatable cancers, such as basal or squamous cell skin cancer, superficial bladder cancer or in situ prostate, cervical or breast cancer;

23 With a history of hypertensive crisis or hypertensive encephalopathy;

24 Cardiac dysfunction, comprising:

● Long QTc syndrome or QTc interval > 480ms;

● Complete left bundle branch block, degree II or III atrioventricular block;

● Serious, uncontrolled arrhythmias requiring medication;

● NYHA is more than or equal to grade 2;

● Cardiac ejection fraction below 50% or below the lower limit of the laboratory examination value range at the research center;

● Heart valve disease with CTCAE > 2 grade;

● Uncontrollable hypertension (defined as multiple measurements of systolic > 150mmHg or diastolic > 90mmHg under drug control);

● Myocardial infarction, unstable angina, history of severe pericardial disease, and electrocardiographic evidence of acute ischemic or active abnormalities in the conduction system occurred within 6 months prior to the first administration.

25 Doxorubicin or other anthracycline therapy, and the cumulative dosage of doxorubicin exceeds 350mg/m ² (anthracycline equivalent dose calculation: 1mg doxorubicin = 2mg epirubicin = 2mg pirarubicin = 2mg daunorubicin = 0.5mg nordaunorubicin = 0.45mg mitoxantrone; except for doxorubicin liposomes);

26 Expected survival time < 3 months;

27 A pregnant or lactating woman;

28 Any serious and/or uncontrollable disease, other diseases that the researcher decides may affect the patient's participation in the study (including, but not limited to, diabetes mellitus which is not effectively controlled, kidney diseases which require dialysis, severe liver diseases, life threatening autoimmune and hemorrhagic diseases, drug abuse, neurological diseases, etc.);

Other researchers determined that participation was unsuitable.

(III) Exit/termination criteria

The subject had any of the following occurred during the study, and the subject was withdrawn from the study.

(1) Losing access;

(2) Subjects withdraw informed consent or subjects or family members require withdrawal from the trial;

(3) Termination of the study;

(4) Others.

3. Results of the study

1. Evaluation of efficacy

Subjects were evaluated for pre-drug baseline levels and efficacy during treatment according to RECIST 1.1 criteria.

Up to month 12 of 2022, a total of 5 platinum-resistant epithelial ovarian cancer subjects were enrolled and received mitoxantrone liposome + bevacizumab treatment.

At least one treatment effect evaluation is carried out on 5 cases, and the best treatment effect is as follows: PR 2 cases, SD 1 cases, PD 2 cases. Calculated, ORR is 40.0% and DCR is 60.0%. The results are shown in the following table:

Note that: the abbreviations mentioned above have the following meanings: CR: complete remission, defined as the disappearance of all evidence of disease. PR: local remission, defined as measurable focal shrinkage, with no new foci. PD: disease progression is defined as the appearance of any new lesion, or an increase of 50% or more in the original lesion than the lowest point. SD: disease stability, defined as not belonging to either case. Total remission rate (ORR) = (cr+pr)/total number of evaluable cases 100% Disease Control Rate (DCR) = (cr+pr+sd)/total number of evaluable cases 100%.

2. Safety evaluation

Among TEAEs occurring in subjects, the most common is still hematologic toxicity common in chemotherapy, such as decreased white blood cell count, decreased neutrophil count, decreased platelet count, and the like. The adverse reaction can be recovered or improved after symptomatic treatment, and no serious adverse reaction which is not acceptable is seen.

3. Typical cases:

No. 1: paclitaxel liposome + nedaplatin chemotherapy is administered 8-pass after bilateral ovarian high-grade serous carcinoma surgery. The patient was treated again for "abdominal pain 6 months" 2 years and 10 months after the end of chemotherapy, and the secondary tumor cell debulking was confirmed after tumor recurrence, and the albumin paclitaxel + carboplatin chemotherapy 1 course and the albumin paclitaxel + lobaplatin chemotherapy 3 course were administered after the operation. Albumin paclitaxel + carboplatin 2-pass was administered after the disease progression was reviewed. After progression the group test was entered. Mitoxantrone hydrochloride liposomes (20 mg/m ²) in combination with bevacizumab injection (15 mg/kg) were administered once every 3 weeks (q 3 w) for 5 cycles following the in-vivo trial.

No. 2: after diagnosis of bilateral ovarian high grade serous carcinoma, ovarian cancer debulking + mesenteric tumor resection was performed. The albumin paclitaxel + carboplatin regimen was administered 8-pass post-surgery and the progress was assessed 5 months after the last dose and entered into the group trial. Mitoxantrone hydrochloride liposomes (20 mg/m ²) were administered in combination with bevacizumab injection (15 mg/kg) once every 3 weeks (q 3 w), 7 cycles after combination into the maintenance phase, bevacizumab (15 mg/kg, q3 w) was administered for 4 cycles of maintenance.

The foregoing is merely a specific embodiment of the present invention, but the scope of the present invention is not limited thereto. Any person skilled in the art will readily recognize that various changes and substitutions are possible within the scope of the invention disclosed herein, and are within the scope of the invention. The protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

Use of mitoxantrone liposomes and an anti-angiogenesis targeting agent in the manufacture of a medicament for treating ovarian cancer, wherein the anti-angiogenesis targeting agent is selected from bevacizumab and sorafenib.
The use of claim 1, wherein the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.
The use of claim 1 or 2, wherein the mitoxantrone liposome meets one or more of the following:

(i) The mitoxantrone liposome is mitoxantrone hydrochloride liposome;

(ii) The particle size of mitoxantrone liposome is 30-80nm;

(iii) Mitoxantrone forms a poorly soluble precipitate with multivalent counterions within the liposome; and

(Iv) The phospholipid bilayer in mitoxantrone liposomes contains a phospholipid having a phase transition temperature (Tm) above body temperature selected from hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dipalmitate lecithin, distearate lecithin, or any combination thereof.
The use of claim 1 or 2, wherein the mitoxantrone liposome is an injection.
The use of claim 1 or 2, wherein bevacizumab is an injection, or sorafenib is a tablet.
A method of treating ovarian cancer comprising administering to an ovarian cancer patient a therapeutically effective amount of mitoxantrone liposome and an anti-angiogenesis targeting agent, wherein the anti-angiogenesis targeting agent is selected from bevacizumab and sorafenib.
The method of claim 6, wherein the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
The method of claim 6 or 7, wherein the mitoxantrone liposome meets one or more of the following:

(i) The mitoxantrone liposome is mitoxantrone hydrochloride liposome;

(ii) The particle size of mitoxantrone liposome is 30-80nm;

(iii) Mitoxantrone forms a poorly soluble precipitate with multivalent counterions within the liposome; and

(Iv) The phospholipid bilayer in mitoxantrone liposomes contains a phospholipid having a phase transition temperature (Tm) above body temperature selected from hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dipalmitate lecithin, distearate lecithin, or any combination thereof.
The method of claim 6 or 7, wherein the mitoxantrone liposome is administered intravenously every 3 weeks in a therapeutically effective amount of 8-30mg/m ².
The method of claim 6 or 7, wherein bevacizumab is administered by injection, or sorafenib is administered orally.
The method of claim 6 or 7, comprising: administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab once every 3 weeks to ovarian cancer patients for 1-8 cycles followed by 15mg/kg of bevacizumab maintenance therapy once every 3 weeks, or

A therapeutically effective amount of mitoxantrone liposome and 400 mg/dose of sorafenib are administered once every 3 weeks for ovarian cancer patients, and twice daily maintenance therapy is administered at 400 mg/dose twice daily for 1-8 cycles.
A composition for treating ovarian cancer comprising mitoxantrone liposomes and an anti-angiogenesis targeting agent, wherein the anti-angiogenesis targeting agent is selected from bevacizumab and sorafenib.
The composition of claim 12, wherein the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
The composition of claim 12 or 13, wherein the mitoxantrone liposome meets one or more of the following:

(i) The mitoxantrone liposome is mitoxantrone hydrochloride liposome;

(ii) The particle size of mitoxantrone liposome is 30-80nm;

(iii) Mitoxantrone forms a poorly soluble precipitate with multivalent counterions within the liposome; and

(Iv) The phospholipid bilayer in mitoxantrone liposomes contains a phospholipid having a phase transition temperature (Tm) above body temperature selected from hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dipalmitate lecithin, distearate lecithin, or any combination thereof.
The composition of claim 12 or 13, wherein the mitoxantrone liposome is administered intravenously every 3 weeks in a therapeutically effective amount of 8-30mg/m ².
The composition of claim 12 or 13, wherein bevacizumab is administered by injection, or sorafenib is administered orally.
The composition of claim 12 or 13, wherein the treatment comprises: administering 20mg/m ² of a therapeutically effective amount of mitoxantrone liposome and 15mg/kg of a therapeutically effective amount of bevacizumab once every 3 weeks to ovarian cancer patients for 1-8 cycles followed by 15mg/kg of bevacizumab maintenance therapy once every 3 weeks, or

A therapeutically effective amount of mitoxantrone liposome and 400 mg/dose of sorafenib are administered once every 3 weeks for ovarian cancer patients, and twice daily maintenance therapy is administered at 400 mg/dose twice daily for 1-8 cycles.
A kit for treating ovarian cancer comprising mitoxantrone liposomes and an anti-angiogenesis targeting agent selected from bevacizumab and sorafenib.
The kit of claim 18, wherein the ovarian cancer is recurrent ovarian cancer, preferably platinum-resistant recurrent ovarian cancer, more preferably platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
The kit of claim 18 or 19, wherein the mitoxantrone liposome meets one or more of the following:

(i) The mitoxantrone liposome is mitoxantrone hydrochloride liposome;

(ii) The particle size of mitoxantrone liposome is 30-80nm;

(iii) Mitoxantrone forms a poorly soluble precipitate with multivalent counterions within the liposome; and

(Iv) The phospholipid bilayer in mitoxantrone liposomes contains a phospholipid having a phase transition temperature (Tm) above body temperature selected from hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dipalmitate lecithin, distearate lecithin, or any combination thereof.
The kit of claim 18 or 19, wherein the mitoxantrone liposome and the anti-angiogenic targeting agent are each present in separate formulations.
The kit of claim 18 or 19, wherein the mitoxantrone liposome is an injection.
The kit of claim 18 or 19, wherein bevacizumab is an injection or sorafenib is a tablet.