Application of mitoxantrone liposome combined with capecitabine to treatment of nasopharynx cancer

Abstract

The invention relates to the use of mitoxantrone liposome and capecitabine in the treatment of nasopharynx cancer, in particular recurrent and / or metastatic nasopharynx cancer. The present invention also provides a method of treating nasopharynx cancer, particularly recurrent and / or metastatic nasopharynx cancer, comprising administering to a nasopharynx cancer patient a therapeutically effective amount of mitoxantrone liposome and capecitabine. The mitoxantrone liposome and capecitabine are combined to realize a better curative effect in nasopharyngeal carcinoma patients, so that a new treatment choice is provided for the nasopharyngeal carcinoma patients.

Description

Use of mitoxantrone liposome combined with capecitabine in the treatment of nasopharyngeal carcinoma Technical Field

[0001] The present invention belongs to the field of anti-tumor, and specifically relates to the use of mitoxantrone liposomes and capecitabine in treating nasopharyngeal carcinoma, especially recurrent and / or metastatic nasopharyngeal carcinoma. Background Art

[0002] Nasopharyngeal carcinoma (NPC) is a common malignant tumor of the head and neck, originating from the nasopharyngeal mucosa, with a predilection for the pharyngeal recess. It has a distinct regional prevalence, with high incidence in southern my country, Southeast Asia, and North Africa. The age-standardized incidence rate in these regions is 4-25 cases per 100,000 people, 50-100 times the incidence rate in other parts of the world. According to GLOBOCAN data released by the International Agency for Research on Cancer in 2020, there were approximately 133,354 new cases worldwide, with over 70% concentrated in high-incidence areas. Early-stage NPC has a good prognosis, with a 5-year survival rate of 80%-95%, but in advanced stages, it is only 40%-50%. About 30% of nasopharyngeal carcinoma patients will still relapse and / or metastasize after the first treatment. Platinum drugs combined with gemcitabine chemotherapy as the standard first-line treatment for inoperable recurrent or metastatic nasopharyngeal carcinoma can prolong patients' survival, with a median overall survival (OS) of approximately 20 months (Ma SX, Zhou T, Huang Y, et al. The efficacy of first-line chemotherapy in recurrent or metastatic nasopharyngeal carcinoma: a systematic review and meta-analysis. Ann Transl Med, 2018, 6(11): 201).

[0003] For patients with recurrent nasopharyngeal carcinoma, only a small number of them are likely to receive radical local treatment such as surgery or radiotherapy again. Most recurrent patients, like metastatic patients, need palliative systemic treatment or best supportive care. The current standard first-line treatment for recurrent or metastatic nasopharyngeal carcinoma is a PD-1 inhibitor combined with gemcitabine and cisplatin. For patients who have failed first-line platinum-based treatment, there are few treatment options available for patients with recurrent nasopharyngeal carcinoma whose disease worsens after first-line chemotherapy. There is a lack of standard salvage treatment options. Patients are often encouraged to participate in clinical trials, or usually choose monotherapy with unused first-line drugs, including gemcitabine, docetaxel, capecitabine, toripalimab, etc.

[0004] In summary, the treatment of recurrent and / or metastatic nasopharyngeal carcinoma is challenging, especially for patients who have failed first-line platinum-based regimens. Treatment options, including chemotherapy and immunotherapy, are limited and ineffective. Therefore, there is an urgent need to explore new drugs or therapies for recurrent and / or metastatic nasopharyngeal carcinoma.

[0005] Mitoxantrone is an anthracycline drug that has been used in over 30 countries worldwide. It has therapeutic effects on hematologic malignancies such as acute leukemia and lymphoma, as well as various solid tumors such as breast cancer. Its main adverse reactions are bone marrow suppression, gastrointestinal reactions, and cardiotoxicity. Liposomes are a new drug delivery method. Studies have shown that they can alter the in vivo distribution of encapsulated drugs, causing them to accumulate primarily in tumor tissue, thereby improving the therapeutic index, reducing the therapeutic dose, and lowering drug toxicity. These properties have led to the application of liposome drug delivery in anti-tumor drug research. Researchers have conducted research on mitoxantrone liposome formulations. For example, WO2008 / 080367A1 discloses a mitoxantrone liposome (the disclosure of which is incorporated herein by reference in its entirety), which has better anti-tumor effects and reduced toxicity than free mitoxantrone. Based on these favorable properties of mitoxantrone liposomes, it is expected that they will show beneficial effects in the treatment of more types of tumors.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide new drugs and therapies for treating nasopharyngeal carcinoma, especially recurrent and / or metastatic nasopharyngeal carcinoma, which can improve the disease remission rate, prolong the survival period, and are safe and tolerable.

[0008] The present invention relates to use of mitoxantrone liposome combined with capecitabine in treating nasopharyngeal carcinoma.

[0009] The first aspect of the present invention relates to the use of mitoxantrone liposomes and capecitabine in preparing a medicament for treating nasopharyngeal carcinoma.

[0010] In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens.

[0011] In some embodiments, mitoxantrone liposomes and capecitabine are present in the same formulation. In some embodiments, mitoxantrone liposomes and capecitabine are each present in a separate formulation. The formulation can be any clinically accepted dosage form, such as an injectable formulation, an oral formulation, etc. Injectable formulations include liquid injections, injectable powders, and injectable tablets; oral formulations include tablets, capsules, and oral liquid formulations.

[0012] In some embodiments, the mitoxantrone liposome is in the form of an injection, including a liquid injection, a powder for injection, a tablet for injection, etc. When the mitoxantrone liposome is in the form of a liquid injection, the active ingredient is contained in an amount of 0.5-5 mg / ml, preferably 1-2 mg / ml, and more preferably 1 mg / ml, calculated as mitoxantrone.

[0013] In some embodiments, capecitabine is in the form of tablets with a strength of 0.15 g / tablet or 0.5 g / tablet, wherein tablets with a strength of 0.15 g / tablet or 0.5 g / tablet mean that each tablet contains 0.15 g or 0.5 g of capecitabine.

[0014] In some embodiments, mitoxantrone liposomes and capecitabine are used in the preparation of a medicament for treating recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, mitoxantrone liposomes and capecitabine are used in the preparation of a medicament for treating recurrent and / or metastatic nasopharyngeal carcinoma that has failed first-line or second-line platinum-based therapy. In these embodiments, the mitoxantrone liposomes are in the form of an injectable formulation containing 0.5-5 mg / ml of the active ingredient, calculated as mitoxantrone; and the capecitabine is in the form of tablets, with a strength of 0.15 g or 0.5 g per tablet.

[0015] The second aspect of the present invention relates to the use of mitoxantrone liposomes in the preparation of a medicament for improving the efficacy of capecitabine in treating nasopharyngeal carcinoma.

[0016] In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens.

[0017] In some embodiments, the mitoxantrone liposome is in the form of an injection, including a liquid injection, a powder for injection, a tablet for injection, etc. When the mitoxantrone liposome is in the form of a liquid injection, the active ingredient is contained in an amount of 0.5-5 mg / ml, preferably 1-2 mg / ml, and more preferably 1 mg / ml, calculated as mitoxantrone.

[0018] In some embodiments, capecitabine is in the form of tablets with a strength of 0.15 g / tablet or 0.5 g / tablet, wherein tablets with a strength of 0.15 g / tablet or 0.5 g / tablet mean that each tablet contains 0.15 g or 0.5 g of capecitabine.

[0019] In some embodiments, mitoxantrone liposomes are used in the preparation of a medicament for improving the efficacy of capecitabine in treating recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, mitoxantrone liposomes are used in the preparation of a medicament for improving the efficacy of capecitabine in treating recurrent and / or metastatic nasopharyngeal carcinoma that has failed first-line or second-line platinum-containing regimens. In these embodiments, the mitoxantrone liposomes are in the form of an injectable formulation containing 0.5-5 mg / ml of the active ingredient, calculated as mitoxantrone; and capecitabine is in the form of tablets, with a strength of 0.15 g / tablet or 0.5 g / tablet.

[0020] The third aspect of the present invention relates to the use of capecitabine in the preparation of a medicament for improving the efficacy of mitoxantrone liposomes in treating nasopharyngeal carcinoma.

[0021] In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens.

[0022] In some embodiments, the mitoxantrone liposome is in the form of an injection, including a liquid injection, a powder for injection, a tablet for injection, etc. When the mitoxantrone liposome is in the form of a liquid injection, the active ingredient is contained in an amount of 0.5-5 mg / ml, preferably 1-2 mg / ml, and more preferably 1 mg / ml, calculated as mitoxantrone.

[0023] In some embodiments, capecitabine is in the form of tablets with a strength of 0.15 g / tablet or 0.5 g / tablet, wherein tablets with a strength of 0.15 g / tablet or 0.5 g / tablet mean that each tablet contains 0.15 g or 0.5 g of capecitabine.

[0024] In some embodiments, capecitabine is used in the preparation of a medicament for improving the efficacy of mitoxantrone liposomes in the treatment of recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, capecitabine is used in the preparation of a medicament for improving the efficacy of mitoxantrone liposomes in the treatment of recurrent and / or metastatic nasopharyngeal carcinoma that has failed first-line or second-line platinum-containing regimens. In these embodiments, the mitoxantrone liposomes are in the form of an injectable formulation containing 0.5-5 mg / ml of the active ingredient, calculated as mitoxantrone; and capecitabine is in the form of tablets, with a strength of 0.15 g / tablet or 0.5 g / tablet.

[0025] The fourth aspect of the present invention relates to a method for treating nasopharyngeal carcinoma, comprising administering a therapeutically effective amount of mitoxantrone liposomes and capecitabine to a patient with nasopharyngeal carcinoma.

[0026] The fifth aspect of the present invention relates to a method for improving the efficacy of capecitabine in treating nasopharyngeal carcinoma, comprising administering capecitabine to nasopharyngeal carcinoma patients and further administering a therapeutically effective amount of mitoxantrone liposomes.

[0027] The sixth aspect of the present invention relates to a method for improving the efficacy of mitoxantrone liposomes in treating nasopharyngeal carcinoma, which comprises administering mitoxantrone liposomes to nasopharyngeal carcinoma patients and further administering a therapeutically effective amount of capecitabine.

[0028] In the fourth to sixth aspects described above, the following embodiments are included.

[0029] In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens.

[0030] In some embodiments, mitoxantrone liposomes are administered by injection. In some embodiments, mitoxantrone liposomes are administered at a dose of 8-30 mg / m 2 , preferably 12-24 mg / m 2 , more preferably 12-20 mg / m 2 In some embodiments, mitoxantrone liposomes are administered on day 1 of each dosing cycle. In some embodiments, mitoxantrone liposomes are administered at a dose of 8-30 mg / m2 on day 1 of each dosing cycle. 2 In some embodiments, mitoxantrone liposomes are administered at a dose of, for example, 12 mg / m on day 1 of each dosing cycle. 2 , 14mg / m 2 , 15mg / m 2 , 16mg / m 2 , 18mg / m 2 , 20mg / m 2 or 24 mg / m 2 Preferably, the mitoxantrone liposomes are administered by intravenous drip over a period of 30-120 minutes, preferably 60-120 minutes.

[0031] In some embodiments, capecitabine is administered orally. In some embodiments, capecitabine is administered orally at a dose of 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, capecitabine is administered orally at a dose of 500 mg / m2 on days 1 to 14 of each dosing cycle. In some embodiments, capecitabine is administered orally at a dose of 500 mg / m2 on days 1 to 14 of each dosing cycle. 2 , 750mg / m 2 or 1000 mg / m 2In some embodiments, capecitabine is administered orally twice daily at a dose of 1000 mg / m2 on days 1-14 of each dosing cycle. 2 The dosage is orally administered in tablet form twice a day. Preferably, the administration cycle is 3 weeks.

[0032] In some embodiments, mitoxantrone liposomes are administered once and capecitabine is administered for 14 consecutive days in each dosing cycle. Preferably, a therapeutically effective amount of mitoxantrone liposomes and capecitabine are administered to NPC patients in any order on day 1 of each dosing cycle, and then capecitabine is continued to be administered twice a day on days 2-14. In some embodiments, 8-30 mg / m2 of mitoxantrone liposomes are administered on day 1 of each dosing cycle. 2 The therapeutically effective amount of mitoxantrone liposomes was injected and 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine was administered orally at a dose of 500 mg / m2 on days 2-14 of the cycle. 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, capecitabine is administered orally at a dose of 12-24 mg / m on day 1 of each dosing cycle. 2 The therapeutically effective dose of mitoxantrone liposomes was injected once and 1000 mg / m 2 Capecitabine was administered orally twice at a dose of 1000 mg / m2 on days 2-14 of the cycle. 2 Capecitabine is administered orally twice daily.

[0033] The seventh aspect of the present invention relates to a drug for treating nasopharyngeal carcinoma, comprising mitoxantrone liposomes and capecitabine.

[0034] In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens.

[0035] In some embodiments, mitoxantrone liposomes and capecitabine are present in the same formulation. In some embodiments, mitoxantrone liposomes and capecitabine are each present in a separate formulation. The formulation can be any clinically accepted dosage form, such as an injectable formulation, an oral formulation, etc. Injectable formulations include liquid injections, injectable powders, and injectable tablets; oral formulations include tablets, capsules, and oral liquid formulations.

[0036] In some embodiments, the mitoxantrone liposome is in the form of an injection, including a liquid injection, a powder for injection, a tablet for injection, etc. When the mitoxantrone liposome is in the form of a liquid injection, the active ingredient is contained in an amount of 0.5-5 mg / ml, preferably 1-2 mg / ml, and more preferably 1 mg / ml, calculated as mitoxantrone.

[0037] In some embodiments, capecitabine is in the form of tablets with a strength of 0.15 g / tablet or 0.5 g / tablet, wherein tablets with a strength of 0.15 g / tablet or 0.5 g / tablet mean that each tablet contains 0.15 g or 0.5 g of capecitabine.

[0038] In some embodiments, the drug may further comprise other drugs for treating nasopharyngeal carcinoma, including drugs approved for the treatment of nasopharyngeal carcinoma by drug administration authorities in China or other countries and regions (e.g., the United States, the European Union, Japan, South Korea, etc.).

[0039] In some embodiments, mitoxantrone liposomes are administered by injection. In some embodiments, mitoxantrone liposomes are administered at a dose of 8-30 mg / m 2 , preferably 12-24 mg / m 2 , more preferably 12-20 mg / m 2 In some embodiments, mitoxantrone liposomes are administered on day 1 of each dosing cycle. In some embodiments, mitoxantrone liposomes are administered at a dose of 8-30 mg / m2 on day 1 of each dosing cycle. 2 In some embodiments, mitoxantrone liposomes are administered at a dose of, for example, 12 mg / m on day 1 of each dosing cycle. 2 , 14mg / m 2 , 15mg / m 2 , 16mg / m 2 , 18mg / m 2 , 20mg / m 2 or 24 mg / m 2 Preferably, the mitoxantrone liposomes are administered by intravenous drip over a period of 30-120 minutes, preferably 60-120 minutes.

[0040] In some embodiments, capecitabine is administered orally. In some embodiments, capecitabine is administered orally at a dose of 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2In some embodiments, capecitabine is administered orally at a dose of 500 mg / m2 on days 1 to 14 of each dosing cycle. In some embodiments, capecitabine is administered orally at a dose of 500 mg / m2 on days 1 to 14 of each dosing cycle. 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, capecitabine is administered orally twice daily at a dose of 1000 mg / m2 on days 1-14 of each dosing cycle. 2 The dosage is orally administered in tablet form twice a day. Preferably, the administration cycle is 3 weeks.

[0041] In some embodiments, mitoxantrone liposomes are administered once and capecitabine is administered for 14 consecutive days in each dosing cycle. Preferably, a therapeutically effective amount of mitoxantrone liposomes and capecitabine are administered to NPC patients in any order on day 1 of each dosing cycle, and then capecitabine is continued to be administered twice a day on days 2-14. In some embodiments, 8-30 mg / m2 of mitoxantrone liposomes are administered on day 1 of each dosing cycle. 2 The therapeutically effective amount of mitoxantrone liposomes was injected and 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine was administered orally at a dose of 500 mg / m2 on days 2-14 of the cycle. 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, capecitabine is administered orally at a dose of 12-24 mg / m on day 1 of each dosing cycle. 2 The therapeutically effective dose of mitoxantrone liposomes was injected once and 1000 mg / m 2 Capecitabine was administered orally twice at a dose of 1000 mg / m2 on days 2-14 of the cycle. 2 Capecitabine is administered orally twice daily.

[0042] The eighth aspect of the present invention relates to a drug for improving the efficacy of capecitabine in treating nasopharyngeal carcinoma, wherein the drug comprises mitoxantrone liposomes.

[0043] The ninth aspect of the present invention relates to a drug for improving the efficacy of mitoxantrone liposomes in treating nasopharyngeal carcinoma, wherein the drug comprises capecitabine.

[0044] In the eighth and ninth aspects described above, the following embodiments are included.

[0045] In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens.

[0046] In some embodiments, the mitoxantrone liposome is in the form of an injection, including a liquid injection, a powder for injection, a tablet for injection, etc. When the mitoxantrone liposome is in the form of a liquid injection, the active ingredient is contained in an amount of 0.5-5 mg / ml, preferably 1-2 mg / ml, and more preferably 1 mg / ml, calculated as mitoxantrone.

[0047] In some embodiments, capecitabine is in the form of tablets with a strength of 0.15 g / tablet or 0.5 g / tablet, wherein tablets with a strength of 0.15 g / tablet or 0.5 g / tablet mean that each tablet contains 0.15 g or 0.5 g of capecitabine.

[0048] In some embodiments, mitoxantrone liposomes are administered by injection. In some embodiments, mitoxantrone liposomes are administered at a dose of 8-30 mg / m 2 , preferably 12-24 mg / m 2 , more preferably 12-20 mg / m 2 In some embodiments, mitoxantrone liposomes are administered on day 1 of each dosing cycle. In some embodiments, mitoxantrone liposomes are administered at a dose of 8-30 mg / m2 on day 1 of each dosing cycle. 2 In some embodiments, mitoxantrone liposomes are administered at a dose of, for example, 12 mg / m on day 1 of each dosing cycle. 2 , 14mg / m 2 , 15mg / m 2 , 16mg / m 2 , 18mg / m 2 , 20mg / m 2 or 24 mg / m 2 Preferably, the mitoxantrone liposomes are administered by intravenous drip over a period of 30-120 minutes, preferably 60-120 minutes.

[0049] In some embodiments, capecitabine is administered orally. In some embodiments, capecitabine is administered orally at a dose of 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2In some embodiments, capecitabine is administered orally at a dose of 500 mg / m2 on days 1 to 14 of each dosing cycle. In some embodiments, capecitabine is administered orally at a dose of 500 mg / m2 on days 1 to 14 of each dosing cycle. 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, capecitabine is administered orally twice daily at a dose of 1000 mg / m2 on days 1-14 of each dosing cycle. 2 The dosage is orally administered in tablet form twice a day. Preferably, the administration cycle is 3 weeks.

[0050] In some embodiments, mitoxantrone liposomes are administered once and capecitabine is administered for 14 consecutive days in each dosing cycle. Preferably, a therapeutically effective amount of mitoxantrone liposomes and capecitabine are administered to NPC patients in any order on day 1 of each dosing cycle, and then capecitabine is continued to be administered twice a day on days 2-14. In some embodiments, 8-30 mg / m2 of mitoxantrone liposomes are administered on day 1 of each dosing cycle. 2 The therapeutically effective amount of mitoxantrone liposomes was injected and 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine was administered orally at a dose of 500 mg / m2 on days 2-14 of the cycle. 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, capecitabine is administered orally at a dose of 12-24 mg / m on day 1 of each dosing cycle. 2 The therapeutically effective dose of mitoxantrone liposomes was injected once and 1000 mg / m 2 Capecitabine was administered orally twice at a dose of 1000 mg / m2 on days 2-14 of the cycle. 2 Capecitabine is administered orally twice daily.

[0051] The tenth aspect of the present invention relates to a composition for treating nasopharyngeal carcinoma, comprising mitoxantrone liposomes and capecitabine.

[0052] The eleventh aspect of the present invention relates to a pharmaceutical combination for treating nasopharyngeal carcinoma, comprising mitoxantrone liposomes and capecitabine.

[0053] In the tenth and eleventh aspects described above, the following embodiments are included.

[0054] In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens.

[0055] In some embodiments, the mitoxantrone liposome is in the form of an injection, including a liquid injection, a powder for injection, a tablet for injection, etc. When the mitoxantrone liposome is in the form of a liquid injection, the active ingredient is contained in an amount of 0.5-5 mg / ml, preferably 1-2 mg / ml, and more preferably 1 mg / ml, calculated as mitoxantrone.

[0056] In some embodiments, capecitabine is in the form of tablets with a strength of 0.15 g / tablet or 0.5 g / tablet, wherein tablets with a strength of 0.15 g / tablet or 0.5 g / tablet mean that each tablet contains 0.15 g or 0.5 g of capecitabine.

[0057] In some embodiments, mitoxantrone liposomes are administered by injection. In some embodiments, mitoxantrone liposomes are administered at a dose of 8-30 mg / m 2 , preferably 12-24 mg / m 2 , more preferably 12-20 mg / m 2 In some embodiments, mitoxantrone liposomes are administered on day 1 of each dosing cycle. In some embodiments, mitoxantrone liposomes are administered at a dose of 8-30 mg / m2 on day 1 of each dosing cycle. 2 In some embodiments, mitoxantrone liposomes are administered at a dose of, for example, 12 mg / m on day 1 of each dosing cycle. 2 , 14mg / m 2 , 15mg / m 2 , 16mg / m 2 , 18mg / m 2 , 20mg / m 2 or 24 mg / m 2 Preferably, the mitoxantrone liposomes are administered by intravenous drip over a period of 30-120 minutes, preferably 60-120 minutes.

[0058] In some embodiments, capecitabine is administered orally. In some embodiments, capecitabine is administered orally at a dose of 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2In some embodiments, capecitabine is administered orally at a dose of 500 mg / m2 on days 1 to 14 of each dosing cycle. In some embodiments, capecitabine is administered orally at a dose of 500 mg / m2 on days 1 to 14 of each dosing cycle. 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, capecitabine is administered orally twice daily at a dose of 1000 mg / m2 on days 1-14 of each dosing cycle. 2 The dosage is orally administered in tablet form twice a day. Preferably, the administration cycle is 3 weeks.

[0059] In some embodiments, mitoxantrone liposomes are administered once and capecitabine is administered for 14 consecutive days in each dosing cycle. Preferably, a therapeutically effective amount of mitoxantrone liposomes and capecitabine are administered to NPC patients in any order on day 1 of each dosing cycle, and then capecitabine is continued to be administered twice a day on days 2-14. In some embodiments, 8-30 mg / m2 of mitoxantrone liposomes are administered on day 1 of each dosing cycle. 2 The therapeutically effective amount of mitoxantrone liposomes was injected and 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine was administered orally at a dose of 500 mg / m2 on days 2-14 of the cycle. 2 , 750mg / m 2 or 1000 mg / m 2 In some embodiments, capecitabine is administered orally at a dose of 12-24 mg / m on day 1 of each dosing cycle. 2 The therapeutically effective dose of mitoxantrone liposomes was injected once and 1000 mg / m 2 Capecitabine was administered orally twice at a dose of 1000 mg / m2 on days 2-14 of the cycle. 2 Capecitabine is administered orally twice daily.

[0060] The twelfth aspect of the present invention relates to a kit for treating nasopharyngeal carcinoma, comprising mitoxantrone liposomes and capecitabine.

[0061] In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma. In some embodiments, the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has failed previous first-line or second-line platinum-containing regimens.

[0062] In some embodiments, liposomal mitoxantrone and capecitabine are each separate formulations.

[0063] In some embodiments, the mitoxantrone liposome is in the form of an injection, including a liquid injection, a powder for injection, a tablet for injection, etc. When the mitoxantrone liposome is in the form of a liquid injection, the active ingredient is contained in an amount of 0.5-5 mg / ml, preferably 1-2 mg / ml, and more preferably 1 mg / ml, calculated as mitoxantrone.

[0064] In some embodiments, capecitabine is in the form of tablets with a strength of 0.15 g / tablet or 0.5 g / tablet, wherein tablets with a strength of 0.15 g / tablet or 0.5 g / tablet mean that each tablet contains 0.15 g or 0.5 g of capecitabine.

[0065] In the above aspects, capecitabine can be provided in the form of a pharmaceutical preparation, such as a tablet. Such pharmaceutical preparations are commercially available.

[0066] In the above aspects, "mitoxantrone" includes mitoxantrone and pharmaceutically acceptable salts thereof, preferably mitoxantrone hydrochloride. Mitoxantrone liposomes are preferably mitoxantrone hydrochloride liposomes.

[0067] In all the above aspects, there is no particular limitation on mitoxantrone liposomes. Without being bound by any particular theory, the inventors of the present application have found that one or more of the following properties are advantageous for mitoxantrone liposome formulations:

[0068] (i) Mitoxantrone liposomes are mitoxantrone hydrochloride liposomes;

[0069] (ii) the particle size of the mitoxantrone liposomes is about 30-80 nm, e.g., about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm; e.g., about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 nm. Particle size can be determined by various methods, including, but not limited to, NanoZS.

[0070] (iii) Mitoxantrone forms insoluble precipitates with multivalent counterions (e.g., sulfate, citrate, or phosphate) within the liposome;

[0071] (iv) the phospholipid bilayer in the mitoxantrone liposome contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, thereby the phase transition temperature of the liposome is higher than body temperature. The phospholipid includes but is not limited to hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, disalmitate lecithin, distearate lecithin, or any combination thereof;

[0072] (v) The phospholipid bilayer in mitoxantrone liposomes contains hydrogenated soybean lecithin, cholesterol, and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000 (DSPE-PEG2000);

[0073] (vi) the phospholipid bilayer in the mitoxantrone liposomes contains hydrogenated soy lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of approximately 3:1:1, mitoxantrone hydrochloride forms an insoluble precipitate with the multivalent counterions within the liposomes, and the particle size of the mitoxantrone hydrochloride liposomes is approximately 60 nm;

[0074] (vii) a mitoxantrone liposome preparation prepared by the method disclosed in Chinese Patent Application No. 200610102339.8 or PCT Application No. WO2008 / 080367A1; and

[0075] (viii) Mitoxantrone liposomes are mitoxantrone liposomes with national drug approval number H20220001.

[0076] Preferably, the mitoxantrone liposomes meet one or more of the following requirements:

[0077] (i) the mitoxantrone liposome is a mitoxantrone hydrochloride liposome;

[0078] (ii) the particle size of mitoxantrone liposomes is 30-80 nm;

[0079] (iii) mitoxantrone forms an insoluble precipitate with multivalent counterions within the liposome; and

[0080] (iv) The phospholipid bilayer in the mitoxantrone liposome contains a phospholipid with a phase transition temperature (Tm) higher than body temperature, which is selected from hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, disalmitate lecithin, distearate lecithin or any combination thereof.

[0081] Preferably, the mitoxantrone liposomes are mitoxantrone hydrochloride liposomes. The therapeutically effective amount or dosage of the mitoxantrone liposomes or mitoxantrone hydrochloride liposomes is calculated based on mitoxantrone.

[0082] The mitoxantrone liposomes can be prepared by conventional methods in the art, or by any method disclosed in the prior art, such as the method disclosed in WO2008 / 080367 A1, the disclosure of which is incorporated herein by reference in its entirety. As a non-limiting example, the mitoxantrone hydrochloride liposome formulation of the present application can be prepared according to the following method, wherein the "lipid-to-drug ratio" refers to the mass ratio of the components of the phospholipid bilayer (including HSPC, DSPE-PEG2000, and Chol) to mitoxantrone in the liposome:

[0083] Hydrogenated soy phosphatidylcholine (HSPC), cholesterol (Chol), and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine (DSPE-PEG2000) were weighed in a 3:1:1 mass ratio and dissolved in 95% ethanol to obtain a clear solution (i.e., the ethanolic phospholipid solution). The ethanolic phospholipid solution was mixed with a 300 mM ammonium sulfate solution and hydrated at 60-65°C for 1 hour to produce heterogeneous multilamellar liposomes. The liposomes were then size-reduced using a microfluidizer. The resulting sample was diluted 200-fold with a 0.9% NaCl solution and analyzed using a NanoZS. The average particle size was approximately 60 nm, with a major peak concentrated between 40 and 60 nm. The ammonium sulfate in the blank liposome external phase was then removed using an ultrafiltration device and replaced with 290 mM sucrose and 10 mM glycine to form a transmembrane ammonium sulfate gradient. A mitoxantrone hydrochloride solution (10 mg / mL, calculated as mitoxantrone) was added to blank liposomes at a lipid-drug ratio of 16:1 and drug loading was performed at 60-65°C. After approximately one hour of incubation, gel exclusion chromatography demonstrated an encapsulation efficiency of approximately 100%. The resulting product was designated PLM60. The weight ratio of HSPC: Chol: DSPE-PEG2000: mitoxantrone in PLM60 was 9.58:3.19:3.19:1. The osmotic pressure of the sucrose-glycine solution was close to physiological values.

[0084] It should be understood that the various technical details and parameters in the above exemplary preparation methods can be adjusted and determined by those skilled in the art within a reasonable range. For example, the amino acid types that can replace glycine in the external phase used to form the transmembrane ammonium sulfate gradient include, but are not limited to, histidine, asparagine, glutamic acid, leucine, proline, and alanine. For another example, the mass ratio of HSPC, Chol, and DSPE-PEG2000 can be appropriately adjusted. For another example, for the lipid-drug ratio parameters in the preparation of a specific liposome drug formulation, those skilled in the art can design, test, and ultimately determine a suitable lipid-drug ratio to maximize drug loading while minimizing drug leakage. For the mitoxantrone hydrochloride liposome formulation of the present application, a wide range of lipid-drug ratios can be used, for example, as low as 2:1 or as high as 30:1, 40:1, or 50:1. A more suitable lipid-drug ratio can be about (15-20):1, for example, about 15:1, 16:1, 17:1, 18:1, 19:1, or 20:1. Therefore, the several advantageous properties of the liposomal formulation of mitoxantrone hydrochloride described above are more important, and the methodologies for achieving these properties are diverse.

[0085] In the context of the present invention, unless defined otherwise, all technical and scientific terms used have the same meanings as understood by one of ordinary skill in the art.

[0086] As used herein, the term "comprising" (or equivalents thereof such as "including," "containing," etc.) includes the case of "consisting of" unless otherwise stated.

[0087] As used herein, the term "composition" refers to a combination of two or more active ingredients, wherein the active ingredients can be present in the same formulation and administered together, or the active ingredients can be present in different formulations and administered simultaneously or sequentially using the same or different administration routes. In this sense, "composition" and "combination" are used interchangeably.

[0088] As used herein, the term "therapeutically effective amount" or "effective amount" refers to a dose that demonstrates the desired benefit in the subject being treated. The amount of "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 characteristics of the drug, and can be determined by the prescribing physician based on routine practice. It should be noted that all numerical ranges mentioned in this application include both endpoints of the range, all values ​​within the range, and subranges formed by any two values ​​within the range.

[0089] As used herein, the term "treat" refers to controlling, alleviating or relieving the pathological progression of a disease and prolonging the survival of a subject suffering from the disease.

[0090] As used herein, the terms "subject," "subject," and "patient" include animal individuals to whom the medicament or composition of the present application is intended to be administered, including but not limited to humans and other mammals, such as mice, rats, cats, monkeys, dogs, horses, pigs, and the like. Preferably, the subject is a human. Unless otherwise indicated, the terms "subject," "subject," and "patient" are used interchangeably.

[0091] The term "recurrent nasopharyngeal carcinoma" used in this article refers to pathologically confirmed nasopharyngeal carcinoma that has completely disappeared clinically after radical radiotherapy, and then 6 months after the end of treatment, a tumor with the same pathological type as the original tumor reappears locally or regionally.

[0092] The term "metastatic nasopharyngeal carcinoma" as used herein refers to nasopharyngeal carcinoma with distant metastasis.

[0093] As used herein, the term "administered in any order" means that separate formulations of mitoxantrone liposomes and capecitabine are administered separately in a clinically acceptable manner, with no mandatory requirement for the order of administration, and the drugs do not mix in vitro.

[0094] Additional embodiments of the present invention

[0095] Embodiment 1. Use of mitoxantrone liposomes and capecitabine in the preparation of a medicament for the treatment of nasopharyngeal carcinoma. Preferably, the nasopharyngeal carcinoma is recurrent metastatic nasopharyngeal carcinoma. Preferably, the recurrent metastatic nasopharyngeal carcinoma is recurrent metastatic nasopharyngeal carcinoma that has failed first-line or second-line platinum-containing regimens. Even more preferably, the recurrent metastatic nasopharyngeal carcinoma has at least one evaluable lesion at baseline according to the RECIST 1.1 standard. The area must not have received radiotherapy in the past, or there is evidence that the lesion has significantly progressed after the end of radiotherapy.

[0096] Embodiment 2. Use of mitoxantrone liposomes in the preparation of a medicament for improving the efficacy of capecitabine treatment for nasopharyngeal carcinoma. Preferably, the nasopharyngeal carcinoma is recurrent metastatic nasopharyngeal carcinoma. Preferably, the recurrent metastatic nasopharyngeal carcinoma is recurrent metastatic nasopharyngeal carcinoma that has previously failed first-line or second-line platinum-containing regimens. Even more preferably, the recurrent metastatic nasopharyngeal carcinoma has at least one evaluable lesion at baseline according to the RECIST 1.1 standard. The area must not have received radiotherapy in the past, or there is evidence that the lesion has significantly progressed after the completion of radiotherapy.

[0097] Embodiment 3. The use according to embodiment 1 or 2, characterized in that the mitoxantrone liposomes are mitoxantrone hydrochloride liposomes.

[0098] Embodiment 4. The use according to Embodiment 3, characterized in that the mitoxantrone hydrochloride liposomes and capecitabine may be present in the same preparation or may be separately prepared; when the two drugs are prepared separately, the dosage forms may be the same or different; when the mitoxantrone hydrochloride liposomes are in the form of a liquid injection, the active ingredient is contained in an amount of 0.5-5 mg / ml, preferably 1-2 mg / ml, more preferably 1 mg / ml, calculated as mitoxantrone; when capecitabine is in the form of tablets, the specification is 0.15 g / tablet or 0.5 g / tablet.

[0099] Embodiment 5. The use according to any one of Embodiments 1-4, characterized in that the drug further comprises other drugs for treating nasopharyngeal carcinoma.

[0100] Embodiment 6. A drug for treating nasopharyngeal carcinoma, characterized in that it comprises mitoxantrone liposomes and capecitabine; the mitoxantrone liposomes are preferably mitoxantrone hydrochloride liposomes; the mitoxantrone hydrochloride liposomes and capecitabine may be present in the same preparation or may be separately formulated; when the two drugs are formulated separately, the dosage forms may be the same or different; when the mitoxantrone hydrochloride liposomes are a liquid injection, the active ingredient is contained in an amount of 0.5-5 mg / ml, preferably 1-2 mg / ml, and more preferably 1 mg / ml, calculated as mitoxantrone; when capecitabine is in the form of tablets, the strength is 0.15 g / tablet or 0.5 g / tablet.

[0101] Embodiment 7. The drug according to Embodiment 6, characterized in that the drug further comprises other drugs for treating nasopharyngeal carcinoma.

[0102] Embodiment 8. A method for treating nasopharyngeal carcinoma, characterized in that: an effective therapeutic dose of mitoxantrone hydrochloride liposomes and capecitabine is administered to a patient with nasopharyngeal carcinoma; the mitoxantrone hydrochloride liposomes are preferably administered by injection; and the capecitabine is preferably administered orally; preferably, the effective therapeutic dose of the mitoxantrone hydrochloride liposomes is 8-30 mg / m 2 , more preferably 12-20 mg / m 2 Capecitabine 1000 mg / m 2 , administered twice a day.

[0103] Embodiment 9. A method for improving the efficacy of capecitabine treatment for nasopharyngeal carcinoma, characterized by: on the basis of using capecitabine for nasopharyngeal carcinoma patients, further using an effective therapeutic dose of mitoxantrone hydrochloride liposomes.

[0104] Embodiment 10. A composition for treating nasopharyngeal carcinoma, comprising mitoxantrone liposomes and capecitabine, wherein an effective therapeutic dose of mitoxantrone liposomes and capecitabine is administered to a nasopharyngeal carcinoma patient in any order on the first day of each administration cycle, and capecitabine is continuously administered on days 2 to 14. Preferably, the administration cycle is once every 3 weeks.

[0105] Embodiment 11. A drug for improving the efficacy of capecitabine treatment for nasopharyngeal carcinoma, characterized in that it contains mitoxantrone hydrochloride liposomes, and the mitoxantrone hydrochloride liposomes are administered at any time before or after the administration of capecitabine on the first day of each administration cycle, at a dose of 8-30 mg / m 2 , more preferably 12-20 mg / m 2 , administered once every 3 weeks.

[0106] Embodiment 12. The use according to any one of embodiments 1 to 5, wherein the mitoxantrone liposome has one or more of the following properties:

[0107] (i) the particle size of the mitoxantrone hydrochloride liposomes is about 30-80 nm, for example, about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm;

[0108] (ii) Mitoxantrone hydrochloride forms insoluble precipitates with multivalent counterions (e.g., sulfate, citrate, or phosphate) within the liposome;

[0109] (iii) the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, so that the phase transition temperature of the liposome is higher than body temperature, for example, the phospholipid is selected from hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, disalmitate lecithin, distearate lecithin or any combination thereof;

[0110] (iv) The phospholipid bilayer in mitoxantrone hydrochloride liposomes contains hydrogenated soybean lecithin, cholesterol, and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000 (DSPE-PEG2000);

[0111] (v) The phospholipid bilayer in the mitoxantrone hydrochloride liposomes contains hydrogenated soy lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of about 3:1:1. Mitoxantrone hydrochloride forms an insoluble precipitate with the multivalent acid ions in the liposomes, and the particle size of the mitoxantrone hydrochloride liposomes containing the drug is about 60 nm.

[0112] Embodiment 13. The medicament of embodiment 6, 7, or 11, the method of 8 or 9, or the composition of claim 10, wherein the mitoxantrone liposomes have one or more of the following properties:

[0113] (i) the particle size of the mitoxantrone hydrochloride liposomes is about 30-80 nm, for example, about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm;

[0114] (ii) Mitoxantrone hydrochloride forms insoluble precipitates with multivalent counterions (e.g., sulfate, citrate, or phosphate) within the liposome;

[0115] (iii) the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, so that the phase transition temperature of the liposome is higher than body temperature, for example, the phospholipid is selected from hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, disalmitate lecithin, distearate lecithin or any combination thereof;

[0116] (iv) The phospholipid bilayer in mitoxantrone hydrochloride liposomes contains hydrogenated soybean lecithin, cholesterol, and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000 (DSPE-PEG2000);

[0117] (v) The phospholipid bilayer in the mitoxantrone hydrochloride liposomes contains hydrogenated soy lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of about 3:1:1. Mitoxantrone hydrochloride forms an insoluble precipitate with the multivalent acid ions in the liposomes, and the particle size of the mitoxantrone hydrochloride liposomes in the drug is about 60 nm. Beneficial effects

[0118] Compared with the capecitabine monotherapy, the combination of mitoxantrone liposomes and capecitabine of the present invention achieves better optimal therapeutic effects in the treatment of recurrent and / or metastatic nasopharyngeal carcinoma and is safe and tolerable, thereby providing a new treatment option for patients with recurrent and / or metastatic nasopharyngeal carcinoma. DETAILED DESCRIPTION

[0119] The following examples are intended to illustrate the present invention in detail and should not be construed as limiting the scope of the present invention.

[0120] Example 1 A randomized, open, positive-controlled, multicenter phase III clinical study comparing mitoxantrone hydrochloride liposome injection combined with capecitabine and capecitabine alone in subjects with recurrent and / or metastatic nasopharyngeal carcinoma who have failed platinum-containing regimens

[0121] The test drug, mitoxantrone hydrochloride liposome injection, was provided by CSPC Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd. (National Medicine Standard No. H20220001), 1.0 mg / ml.

[0122] Capecitabine tablets are a commercially available preparation.

[0123] (1) Research objectives

[0124] This study is a randomized, open-label, positive-controlled, multicenter phase III clinical study aimed to evaluate the efficacy and safety of mitoxantrone hydrochloride liposome injection combined with capecitabine compared with capecitabine monotherapy in subjects with recurrent and / or metastatic nasopharyngeal carcinoma.

[0125] (2) Research methods

[0126] 1. Study Design

[0127] This study was divided into a screening period (-28 days to 0 days), a treatment period, an end-of-treatment (EOT) visit period, and a follow-up period.

[0128] The enrolled population included subjects with recurrent and / or metastatic nasopharyngeal carcinoma who had failed first-line or second-line platinum-based therapy. Eligible subjects were randomly assigned to the experimental and control groups in a 1:1 ratio (stratification factors: ① Eastern Cooperative Oncology Group score: 0 vs. 1; ② presence of liver metastases: any vs. none; ③ gender: male vs. female).

[0129] The experimental group received mitoxantrone hydrochloride liposome injection (20 mg / m 2 ) combined with capecitabine (1000 mg / m 2 The patients were treated with liposome mitoxantrone hydrochloride (mitoxantrone liposome) twice daily on day 1 of each cycle, and capecitabine on days 1 through 14. Each 3-week cycle consisted of a combined treatment. After eight cycles of liposome mitoxantrone hydrochloride, the investigators assessed the patient's risk-benefit ratio to determine whether to continue treatment until disease progression or intolerance, with capecitabine continued. The control group received capecitabine monotherapy on days 1 through 14 of each 3-week cycle. All subjects in the experimental group underwent sparse blood sampling.

[0130] The minimum allowable dose reduction guidelines are detailed in Table 1. If further dose reductions are necessary, the study drug must be discontinued. Once the dose is reduced, all subsequent cycles should maintain the reduced dose level or, if necessary, further reduce the dose. Dose escalation is not permitted in this study.

[0131] If the subject experiences the following adverse events related to the investigational drug after administration, the dose of mitoxantrone may be reduced in the next treatment cycle after evaluation by the investigator. The dose level of mitoxantrone liposome is only allowed to be reduced once per cycle. If necessary, the dose of capecitabine may be reduced within the current treatment cycle.

[0132] Table 1 Dosage adjustment scheme

[0133] During the study, the Independent Data Monitoring Committee (IDMC) will conduct safety assessments after two cycles of treatment for the first 40 patients enrolled (approximately 20 patients in each group) and throughout the study. Enrollment will continue during the safety assessment period. All subjects will receive medication until disease progression, intolerable toxicity, withdrawal of informed consent, initiation of new anti-tumor treatment, loss of follow-up, death, or end of the study, whichever occurs first, as determined by the RECIST1.1 criteria. If the patient has no more treatment options after the investigator first determines that the patient's disease has progressed, and the investigator determines that the patient can continue to benefit from the trial treatment, the patient can continue to receive trial treatment in this trial until disease progression assessed by the IRC or the investigator determines that the patient no longer benefits.

[0134] 2. Trial population:

[0135] 2.1 Inclusion criteria:

[0136] Patients who meet all of the following criteria can be included in this study:

[0137] 1) The subjects voluntarily participated in the study and signed the informed consent form;

[0138] 2) Age ≥ 18 years old

[0139] 3) nasopharyngeal carcinoma confirmed by histopathology;

[0140] 4) Recurrent and / or metastatic nasopharyngeal carcinoma that has failed first-line or second-line platinum-based therapy;

[0141] 5) According to RECIST 1.1 criteria, there is at least one evaluable lesion at baseline;

[0142] 6) ECOG score 0-1;

[0143] 7) The toxicity of previous anti-tumor treatment has recovered to ≤ Grade 1 (excluding hair loss, pigmentation, or other toxicities that are considered to pose no safety risk to the subjects in the study);

[0144] 8) The subject's laboratory test values ​​meet the following requirements (the following indicators can be achieved without blood transfusion or growth factor treatment within 14 days before the screening sample collection):

[0145] Absolute neutrophil count (ANC) ≥1.5 x 10 9 / L;

[0146] Hemoglobin (Hb) ≥9.0 g / dL;

[0147] ●Platelets≥90×10 9 / L;

[0148] Creatinine ≤1.5 times the ULN;

[0149] Total bilirubin ≤1.5 × ULN (≤3 × ULN for patients with liver metastases);

[0150] Alanine aminotransferase (ALT) / aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases);

[0151] ● Coagulation function: Prothrombin time (PT) international normalized ratio (INR) ≤ 1.5 × ULN;

[0152] 9) Female subjects with negative blood HCG (except those undergoing menopause and hysterectomy). Female subjects of childbearing age and their partners should take effective contraceptive measures during the trial and within 6 months after the last medication (for example: combined hormones (containing estrogen and progestin) combined with ovulation suppression, progestin contraception combined with ovulation suppression, intrauterine device, intrauterine hormone-releasing system, bilateral tubal ligation, vasectomy, abstaining from sexual intercourse, etc.);

[0153] 10) The male subject and his partner agree to take one of the contraceptive measures described in Article 9.

[0154] 2.2 Exclusion criteria:

[0155] Patients who meet any of the following exclusion criteria are not eligible for inclusion in this study:

[0156] 1) Severe allergy to mitoxantrone or liposomes; severe, unexpected reaction to fluorouracils in the past or known allergy to fluorouracils;

[0157] 2) Active leptomeningeal disease or poorly controlled brain metastases. Patients with suspected or confirmed brain metastases are allowed to enroll if they have no obvious symptoms and imaging results ≥28 days before the first dose of the study drug show stable disease and no treatment (such as radiotherapy, surgery or corticosteroids) is required to control the symptoms of brain metastases;

[0158] 3) expected survival time < 3 months;

[0159] 4) Active hepatitis B (HbsAg or HBcAb positive and HBV DNA ≥ 2000 IU / mL), active hepatitis C (HCV antibody positive and HCV RNA higher than the lower limit of the research center's detection value), HIV antibody positive;

[0160] 5) Active bacterial infection, fungal infection, viral infection or interstitial pneumonia requiring systemic treatment within 1 week before study drug administration;

[0161] 6) Patients who have received chemotherapy, small molecule inhibitors, immunotherapy (such as interleukin, interferon or thymosin) or other anti-tumor treatments within 4 weeks or 5 half-lives (whichever is shorter but at least 2 weeks) before administration; patients who have received treatment with Chinese patent medicine with anti-tumor activity within 14 days before administration;

[0162] 7) Received other clinical research drugs within 4 weeks before the first dose;

[0163] 8) Patients who have undergone major surgery within 3 months before the first dose, or plan to undergo major surgery during the study;

[0164] 9) Severe embolic events such as cerebrovascular accident (including transient ischemic attack) and pulmonary embolism in the past 6 months;

[0165] 10. Patients with active malignant tumors within 2 years before the first dose, excluding nasopharyngeal carcinoma studied in this trial and any locally curable tumors that have received radical treatment (such as resected basal cell or squamous cell skin cancer, superficial bladder cancer, cervical or breast carcinoma in situ);

[0166] 11) Abnormal heart function, including:

[0167] Long QTc syndrome or QTc interval >480 milliseconds;

[0168] Complete left bundle branch block, second- or third-degree atrioventricular block;

[0169] Severe, uncontrolled arrhythmias requiring medication;

[0170] ●History of chronic congestive heart failure with NYHA class 3 or higher;

[0171] An ejection fraction less than 50% or less than the lower limit of the study center's laboratory test range within the past 6 months;

[0172] Valvular heart disease according to CTCAE version 5.0 grade 3 or higher;

[0173] Uncontrolled hypertension (defined as systolic blood pressure >160 mmHg or diastolic blood pressure >90 mmHg, measured while controlled with medication);

[0174] ● History of myocardial infarction, unstable angina, severe pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities within 6 months prior to screening;

[0175] 12) Patients who have received doxorubicin or other anthracycline therapy, and the cumulative dose of doxorubicin exceeds 350 mg / m 2 (Anthracycline equivalent dose calculation: 1 mg doxorubicin = 2 mg epirubicin = 2 mg daunorubicin = 0.5 mg idarubicin = 0.45 mg mitoxantrone);

[0176] 13) Pregnant or breastfeeding women;

[0177] 14) Suffering from any serious and / or uncontrollable disease, or other diseases that, as determined by the investigator, may affect the patient's participation in this study (including but not limited to uncontrolled diabetes, kidney disease requiring dialysis, severe liver disease, life-threatening autoimmune disease and bleeding disorders, drug abuse, neurological disease, etc.);

[0178] 15) Other situations where the researcher determines that the participant is not suitable for participation.

[0179] 3. Evaluation Criteria

[0180] Primary study endpoint:

[0181] Independent Review Committee (IRC)-assessed progression-free survival (PFS)

[0182] Overall survival (OS)

[0183] Secondary study endpoints:

[0184] Investigator- and IRC-assessed objective response rate (ORR), disease control rate (DCR), and duration of response (DOR)

[0185] Investigator-assessed progression-free survival (PFS)

[0186] Frequency and severity of AEs (NCI CTCAE 5.0); changes in vital signs, physical examination, electrocardiogram, and safety laboratory parameters

[0187] ●Total and free mitoxantrone plasma concentrations.

[0188] Note: The above abbreviations have the following meanings:

[0189] PFS: progression-free survival, defined as the time between the start of study drug and the date of disease progression (PD) or death, whichever occurs first;

[0190] OS: Overall survival, defined as the time from the start of study drug use to death from any cause;

[0191] ORR: objective response rate, defined as the proportion of subjects with complete response (CR) and partial response (PR);

[0192] DCR: disease control rate, defined as the proportion of subjects with complete remission (CR), partial remission (PR), and stable disease (SD);

[0193] DOR: duration of response, defined as the time from the first assessment of CR or PR to the first assessment of PD or death from any cause.

[0194] (3) Research results

[0195] As of July 31, 2023, a total of 62 cases were enrolled in this study, including 32 cases in the experimental group and 30 cases in the control group; 4 cases were withdrawn from the group (1 case in the control group withdrew the informed consent and 2 cases died; 1 case in the experimental group died), and 58 cases were still in the group.

[0196] 1. Baseline characteristics of the subjects

[0197] Among the 32 subjects in the experimental group, 56.9% had metastatic nasopharyngeal carcinoma, 18.8% had recurrent nasopharyngeal carcinoma, and 34.4% had both recurrent and metastatic nasopharyngeal carcinoma. Among the 30 subjects in the control group, 30% had metastatic nasopharyngeal carcinoma, 13.3% had recurrent nasopharyngeal carcinoma, and 56.7% had both recurrent and metastatic nasopharyngeal carcinoma (see Table 2 for details).

[0198] Table 2 Baseline characteristics of the subjects

[0199] 2. Efficacy evaluation

[0200] As of July 31, 2023, a total of 9 subjects in the trial group underwent best efficacy (BOR) evaluation, of which 1 was PD (11.1%), 3 were SD (33.3%), and 5 were PR (55.6%).

[0201] Table 3 Best efficacy evaluation of the experimental group

[0202] In the control group, 5 subjects underwent best response rate (BOR) evaluation, of which 3 subjects had PD (60%), 1 had SD (20%), and 1 had PR (20%).

[0203] Table 4 Best efficacy evaluation of the control group

[0204] The above results show that the efficacy of mitoxantrone liposome combined with capecitabine in the treatment of recurrent and / or metastatic nasopharyngeal carcinoma is better than that of capecitabine monotherapy.

[0205] 3. Safety evaluation

[0206] A total of 9 patients in the experimental group experienced serious adverse events (SAEs), including hematological adverse events such as decreased white blood cell count, decreased neutrophil count, decreased platelet count, and anemia, as well as hyponatremia, hypokalemia, and lung infection. No serious cardiac adverse reactions were observed. A total of 3 patients in the control group experienced SAEs, including bacterial pneumonia, severe pneumonia, and post-resuscitation cardiac arrest syndrome.

[0207] Table 5 SAE overview of the control group and experimental group

Claims

1. Use of mitoxantrone liposomes and capecitabine in the preparation of a medicament for treating nasopharyngeal carcinoma.

2. Use of mitoxantrone liposomes in the preparation of a medicament for improving the efficacy of capecitabine in treating nasopharyngeal carcinoma.

3. The use according to claim 1 or 2, wherein the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, preferably, the recurrent and / or metastatic nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has previously received first-line or second-line platinum-containing regimen treatment.

4. The method according to any one of claims 1 to 3, wherein the mitoxantrone liposome satisfies one or more of the following conditions: (i) Mitoxantrone liposomes are mitoxantrone hydrochloride liposomes; (ii) the particle size of the mitoxantrone liposomes is about 30-80 nm, such as about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm; (iii) mitoxantrone forms insoluble precipitates with multivalent counterions such as sulfate, citrate, or phosphate within the liposome; and (iv) The phospholipid bilayer in the mitoxantrone liposome contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, which is selected from hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, disalmitate lecithin, distearate lecithin or any combination thereof, preferably selected from hydrogenated soy lecithin, cholesterol and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000, more preferably hydrogenated soy lecithin, cholesterol and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000 in a mass ratio of about 3:1:

1.

5. The use according to any one of claims 1 to 4, wherein the mitoxantrone liposome is mitoxantrone hydrochloride liposome.

6. The use according to any one of claims 1 to 5, wherein the mitoxantrone liposome is a liquid injection containing 0.5-5 mg / ml, preferably 1-2 mg / ml, more preferably 1 mg / ml of the active ingredient calculated as mitoxantrone.

7. The use according to any one of claims 1 to 6, wherein capecitabine is in the form of a tablet.

8. The use according to any one of claims 1 to 7, wherein the medicine further comprises other drugs for treating nasopharyngeal carcinoma.

9. A drug for treating nasopharyngeal carcinoma, comprising mitoxantrone liposome and capecitabine.

10. A drug for improving the efficacy of capecitabine in treating nasopharyngeal carcinoma, comprising mitoxantrone liposomes.

11. The drug according to claim 9 or 10, wherein the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, preferably, the recurrent and / or metastatic nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has previously received first-line or second-line platinum-containing regimen treatment.

12. The drug according to any one of claims 9 to 11, wherein the mitoxantrone liposome satisfies one or more of the following: (i) Mitoxantrone liposomes are mitoxantrone hydrochloride liposomes; (ii) the particle size of the mitoxantrone liposomes is about 30-80 nm, such as about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm; (iii) mitoxantrone forms insoluble precipitates with multivalent counterions such as sulfate, citrate, or phosphate within the liposome; and (iv) The phospholipid bilayer in the mitoxantrone liposome contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, which is selected from hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, disalmitate lecithin, distearate lecithin or any combination thereof, preferably selected from hydrogenated soy lecithin, cholesterol and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000, more preferably hydrogenated soy lecithin, cholesterol and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000 in a mass ratio of about 3:1:

1.

13. The drug according to any one of claims 9 to 12, wherein the mitoxantrone liposome is mitoxantrone hydrochloride liposome.

14. The drug according to any one of claims 9 to 13, wherein the mitoxantrone liposome is a liquid injection containing 0.5-5 mg / ml, preferably 1-2 mg / ml, more preferably 1 mg / ml of the active ingredient calculated as mitoxantrone.

15. The medicament according to any one of claims 9 to 14, wherein capecitabine is in the form of a tablet.

16. The drug according to any one of claims 9 to 15, wherein the mitoxantrone liposome is administered by injection, preferably, the mitoxantrone liposome is administered at a dose of 8-30 mg / m on the first day of each administration cycle. 2 , preferably 12-24 mg / m 2 , more preferably 12-20 mg / m 2 The therapeutically effective amount is administered by injection.

17. The drug according to any one of claims 9 to 16, wherein capecitabine is administered orally, preferably, capecitabine is administered at a dose of 500 mg / m2 on days 1 to 14 of each administration cycle. 2 , 750mg / m 2 or 1000 mg / m 2 The dose is administered orally twice daily.

18. The drug according to any one of claims 9 to 17, wherein the treatment comprises 8 to 30 mg / m2 on day 1 of each dosing cycle. 2 The therapeutically effective amount of mitoxantrone liposomes was injected and 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine was administered orally at a dose of 500 mg / m2 on days 2-14 of the cycle. 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine was administered orally at a dose of 1 mg / kg.

19. The drug of any one of claims 9 to 18, wherein the treatment comprises 20 mg / m2 on day 1 of each dosing cycle. 2 The therapeutically effective dose of mitoxantrone liposomes was injected once and 1000 mg / m 2 Capecitabine was administered orally twice at a dose of 1000 mg / m2 on days 2-14 of the cycle. 2 Capecitabine is administered orally twice daily.

20. The medicament according to any one of claims 16 to 19, wherein the administration cycle is three weeks.

21. The drug according to any one of claims 9 to 20, wherein the drug further comprises other drugs for treating nasopharyngeal carcinoma.

22. A method for treating nasopharyngeal carcinoma, comprising administering a therapeutically effective amount of mitoxantrone liposome and capecitabine to a patient with nasopharyngeal carcinoma.

23. A method for improving the efficacy of capecitabine in treating nasopharyngeal carcinoma, comprising administering capecitabine to a nasopharyngeal carcinoma patient and further administering a therapeutically effective amount of mitoxantrone liposomes.

24. The method according to claim 22 or 23, wherein the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, preferably, the recurrent and / or metastatic nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma that has previously received first-line or second-line platinum-containing regimen treatment.

25. The method of any one of claims 22-24, wherein the mitoxantrone liposomes satisfy one or more of the following: (i) Mitoxantrone liposomes are mitoxantrone hydrochloride liposomes; (ii) the particle size of the mitoxantrone liposomes is about 30-80 nm, such as about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm; (iii) mitoxantrone forms insoluble precipitates with multivalent counterions such as sulfate, citrate, or phosphate within the liposome; and (iv) The phospholipid bilayer in the mitoxantrone liposome contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, which is selected from hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, disalmitate lecithin, distearate lecithin or any combination thereof, preferably selected from hydrogenated soy lecithin, cholesterol and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000, more preferably hydrogenated soy lecithin, cholesterol and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000 in a mass ratio of about 3:1:

1.

26. The method of any one of claims 22-25, wherein the mitoxantrone liposomes are mitoxantrone hydrochloride liposomes.

27. The method according to any one of claims 22 to 26, wherein the mitoxantrone liposome is a liquid injection containing 0.5-5 mg / ml, preferably 1-2 mg / ml, more preferably 1 mg / ml of the active ingredient calculated as mitoxantrone.

28. The method of any one of claims 22-27, wherein capecitabine is in the form of a tablet.

29. The method according to any one of claims 22 to 28, wherein mitoxantrone liposomes are administered by injection, preferably, mitoxantrone liposomes are administered at a dose of 8-30 mg / m on day 1 of each administration cycle. 2 , preferably 12-24 mg / m 2 , more preferably 12-20 mg / m 2 The therapeutically effective amount is administered by injection.

30. The method of any one of claims 22 to 29, wherein capecitabine is administered orally, preferably, capecitabine is administered at a dose of 500 mg / m2 on days 1 to 14 of each dosing cycle. 2 , 750mg / m 2 or 1000 mg / m 2 The dose is administered orally twice daily.

31. The method of any one of claims 22-30, wherein the method comprises administering 8-30 mg / m2 of the drug on day 1 of each dosing cycle. 2 The therapeutically effective amount of mitoxantrone liposomes was injected and 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine was administered orally at a dose of 500 mg / m2 on days 2-14 of the cycle. 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine was administered orally at a dose of 1 mg / kg.

32. The method of any one of claims 22-31, wherein the method comprises administering 20 mg / m2 of the drug on day 1 of each dosing cycle. 2 The therapeutically effective dose of mitoxantrone liposomes was injected once and 1000 mg / m 2 Capecitabine was administered orally twice at a dose of 1000 mg / m2 on days 2-14 of the cycle. 2 Capecitabine is administered orally twice daily.

33. The method of any one of claims 29-32, wherein the administration period is three weeks.

34. A pharmaceutical combination for treating nasopharyngeal carcinoma, comprising liposome mitoxantrone and capecitabine.

35. The pharmaceutical combination according to claim 34, wherein the nasopharyngeal carcinoma is recurrent and / or metastatic nasopharyngeal carcinoma, preferably, the recurrent and / or metastatic nasopharyngeal carcinoma is a recurrent and / or metastatic nasopharyngeal carcinoma that has previously received first-line or second-line platinum-containing regimen treatment.

36. The pharmaceutical combination of claim 34 or 35, wherein the mitoxantrone liposomes satisfy one or more of the following: (i) Mitoxantrone liposomes are mitoxantrone hydrochloride liposomes; (ii) the particle size of the mitoxantrone liposomes is about 30-80 nm, such as about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm; (iii) mitoxantrone forms insoluble precipitates with multivalent counterions such as sulfate, citrate, or phosphate within the liposome; and (iv) The phospholipid bilayer in the mitoxantrone liposome contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, which is selected from hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, disalmitate lecithin, distearate lecithin or any combination thereof, preferably selected from hydrogenated soy lecithin, cholesterol and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000, more preferably hydrogenated soy lecithin, cholesterol and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000 in a mass ratio of about 3:1:

1.

37. The pharmaceutical combination according to any one of claims 34 to 36, wherein the mitoxantrone liposomes are mitoxantrone hydrochloride liposomes.

38. The pharmaceutical combination according to any one of claims 34 to 37, wherein the mitoxantrone liposome is a liquid injection containing 0.5-5 mg / ml, preferably 1-2 mg / ml, more preferably 1 mg / ml of the active ingredient calculated as mitoxantrone.

39. The pharmaceutical combination according to any one of claims 34 to 38, wherein capecitabine is in the form of a tablet.

40. The pharmaceutical combination according to any one of claims 34 to 39, wherein mitoxantrone liposomes are administered by injection, preferably, mitoxantrone liposomes are administered at a dose of 8-30 mg / m on day 1 of each administration cycle. 2 , preferably 12-24 mg / m 2 , more preferably 12-20 mg / m 2 The therapeutically effective amount is administered by injection.

41. The pharmaceutical combination according to any one of claims 34 to 40, wherein capecitabine is administered orally, preferably, capecitabine is administered at a dose of 500 mg / m2 on days 1 to 14 of each administration cycle. 2 , 750mg / m 2 or 1000 mg / m 2 The dose is administered orally twice daily.

42. The pharmaceutical combination of any one of claims 34 to 41, wherein the treatment comprises 8 to 30 mg / m2 on day 1 of each dosing cycle. 2 The therapeutically effective amount of mitoxantrone liposomes was injected and 500 mg / m 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine was administered orally at a dose of 500 mg / m2 on days 2-14 of the cycle. 2 , 750mg / m 2 or 1000 mg / m 2 Capecitabine was administered orally at a dose of 1 mg / kg.

43. The pharmaceutical combination of any one of claims 34 to 42, wherein the treatment comprises 20 mg / m2 on day 1 of each dosing cycle. 2 The therapeutically effective dose of mitoxantrone liposomes was injected once and 1000 mg / m 2 Capecitabine was administered orally twice at a dose of 1000 mg / m2 on days 2-14 of the cycle. 2 Capecitabine is administered orally twice daily.

44. The pharmaceutical combination of any one of claims 40-43, wherein the administration cycle is three weeks.

45. A kit comprising liposome mitoxantrone and capecitabine.

46. ​​The kit of claim 45, wherein the mitoxantrone liposomes satisfy one or more of the following: (i) Mitoxantrone liposomes are mitoxantrone hydrochloride liposomes; (ii) the particle size of the mitoxantrone liposomes is about 30-80 nm, such as about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm; (iii) mitoxantrone forms insoluble precipitates with multivalent counterions such as sulfate, citrate, or phosphate within the liposome; and (iv) The phospholipid bilayer in the mitoxantrone liposome contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, which is selected from hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, disalmitate lecithin, distearate lecithin or any combination thereof, preferably selected from hydrogenated soy lecithin, cholesterol and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000, more preferably hydrogenated soy lecithin, cholesterol and distearoylphosphatidylethanolamine modified with polyethylene glycol 2000 in a mass ratio of about 3:1:

1. The kit according to claim 45 or 46, wherein the mitoxantrone liposomes are mitoxantrone hydrochloride liposomes.

48. The kit according to any one of claims 45 to 47, wherein the mitoxantrone liposomes are in the form of liquid injections, containing 0.5-5 mg / ml, preferably 1-2 mg / ml, more preferably 1 mg / ml of the active ingredient, calculated as mitoxantrone.

49. The kit of any one of claims 45-48, wherein capecitabine is in the form of a tablet.