Use of liposomal mitoxantrone hydrochloride

Abstract

The present application provides the use of liposome mitoxantrone hydrochloride in the preparation of a medicament for treating ovarian cancer, gastric cancer or head and neck squamous cancer, a method for treating ovarian cancer, gastric cancer or head and neck squamous cancer by using liposome mitoxantrone hydrochloride preparation, and a liposome mitoxantrone hydrochloride preparation for treating ovarian cancer, gastric cancer or head and neck squamous cancer.

Description

[0001] Related Applications

[0002] This application claims priority to Chinese Patent Application No. 202011477966.6, filed on December 15, 2020, the entire contents of which are incorporated herein by reference in its entirety for all purposes. TECHNICAL FIELD

[0003] The present application relates generally to the field of medicine, and specifically to the use of mitoxantrone hydrochloride liposome in the treatment of ovarian cancer, gastric cancer or head and neck squamous cell carcinoma. BACKGROUND

[0004] Ovarian cancer is one of the common malignant tumors in women. Due to the lack of typical symptoms and signs, once found, most are in the middle and advanced stages, and the survival time is very short. There are many pathological types of ovarian cancer, among which the most common is epithelial ovarian cancer, accounting for 70%, followed by malignant germ cell tumors and sex cord stromal tumors.

[0005] Due to the difficulty in early diagnosis and drug-resistant recurrent ovarian epithelial cancer, there is no effective treatment for ovarian epithelial cancer. The overall prognosis of ovarian epithelial cancer is poor. Surgery combined with chemotherapy is the main treatment for ovarian malignant tumors, and chemotherapy plays an important role in adjuvant therapy and recurrent therapy. Platinum-based combined chemotherapy regimen is the main recommended regimen for postoperative chemotherapy of advanced ovarian cancer. Even if the patients with advanced disease achieve complete remission after the above treatment, 70%-80% of them will still relapse. The current standard chemotherapy regimen for initial treatment of advanced epithelial ovarian cancer is platinum-based chemotherapy, and the choice of specific regimen needs to consider the individual characteristics of the patient. Other recommended regimens include the treatment regimen of carboplatin combined with anthracycline drug liposome doxorubicin. At the same time, doxorubicin liposome is also recommended to be used as a single drug or in combination with bevacizumab for the treatment of recurrent drug-resistant ovarian cancer; but among the current single-drug treatment drugs for platinum-resistant recurrence, there is no drug that is more outstanding than other drugs in terms of safety and effectiveness.

[0006] Gastric cancer is the fifth most common cancer worldwide. For patients with non-surgical radical opportunity or metastatic gastric cancer, it is currently recognized that comprehensive treatment should be taken mainly by systemic drug treatment. Common systemic chemotherapy drugs include 5-fluorouracil (5-FU), capecitabine, tegafur, cisplatin, oxaliplatin, paclitaxel, docetaxel, albumin paclitaxel, irinotecan, epirubicin, etc. Targeted therapy drugs include trastuzumab and apatinib. The treatment of advanced recurrent / metastatic gastric cancer is difficult, especially the second-line and third-line drugs have poor efficacy and limited choices.

[0007] Head and neck cancer is the sixth most common cancer worldwide, including tumors originating in the nasal cavity, paranasal sinuses and nasopharynx, oropharynx, hypopharynx, cervical esophagus, thyroid, salivary glands, oral cavity, larynx, and ear. 90% of head and neck tumors are squamous cell carcinoma of the head and neck (SCCHN), with more than 550,000 new cases and more than 300,000 deaths worldwide each year. Most patients cannot be cured due to local recurrence and metastasis, and the five-year survival rate is less than 50%. Surgery and radiotherapy and chemotherapy cannot achieve satisfactory treatment effect.

[0008] For patients with recurrent head and neck cancer, only a small number of them can receive radical local treatment such as surgery or radiotherapy again, and most of them, like metastatic patients, need to receive palliative systemic treatment (PS 0-1) or best supportive care (PS≥2). Cisplatin combined with 5-FU (PF regimen) or combined with paclitaxel is a commonly used first-line chemotherapy regimen selection. If the patient is not suitable for receiving cisplatin, carboplatin can be used instead. The above-mentioned regimen can be combined with cetuximab.

[0009] For recurrent metastatic head and neck squamous cell carcinoma that fails to first-line platinum-based drug treatment, there is currently a lack of standard treatment regimen. Commonly used drugs are methotrexate, paclitaxel or docetaxel, cetuximab, and immune checkpoint inhibitors. For patients who fail to first-line platinum-based drug treatment, in the second-line / rescue treatment, immunotherapy drugs or other regimens can be selected according to the PD-L1 detection results.

[0010] Therefore, for refractory cancers such as ovarian cancer, gastric cancer, or head and neck squamous cell carcinoma, better treatment tools and regimens are urgently needed. SUMMARY

[0012] In a first aspect, the present application provides the use of mitoxantrone hydrochloride liposome in the preparation of a medicament for treating ovarian cancer, gastric cancer, or head and neck squamous cell carcinoma.

[0013] In some embodiments, the mitoxantrone hydrochloride liposome is the only active ingredient in the medicament.

[0014] In some embodiments, the medicament or the mitoxantrone hydrochloride liposome has one or more of the following properties:

[0015] (i) the particle size of the mitoxantrone hydrochloride liposome is about 30-80 nm, for example, about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm;

[0016] (ii) the mitoxantrone hydrochloride forms an insoluble precipitate with a polyvalent counterion (such as sulfate, citrate, or phosphate) in the liposome;

[0017] (iii) the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, such that the phase transition temperature of the liposome is higher than body temperature, for example, the phospholipid is selected from the group consisting of hydrogenated soybean lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dipalmitoyl lecithin, distearoyl lecithin, or any combination thereof;

[0018] (iv) the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains hydrogenated soybean lecithin, cholesterol, and distearoyl phosphatidyl ethanolamine modified with polyethylene glycol 2000 (DSPE-PEG2000).

[0019] In some embodiments, the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains hydrogenated soybean lecithin, cholesterol, and distearoyl phosphatidyl ethanolamine modified with polyethylene glycol 2000 in a mass ratio of about 3:1:1, the mitoxantrone hydrochloride forms an insoluble precipitate with the polyvalent anion inside the liposome, and the particle size of the mitoxantrone hydrochloride liposome in the medicament is about 60 nm.

[0020] In some embodiments, the ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer.

[0021] In some embodiments, the gastric cancer is advanced gastric cancer.

[0022] In some embodiments, the head and neck squamous cancer is squamous cancer occurring in the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, hypopharynx, cervical esophagus, thyroid, salivary gland, mouth, larynx, and / or ear.

[0023] In some embodiments, the head and neck squamous cancer is recurrent or metastatic head and neck squamous cancer that has failed first-line treatment, for example, the first-line treatment is cisplatin / carboplatin in combination with 5-FU or a taxane drug, optionally further in combination with cetuximab.

[0024] In some embodiments, the medicament is in an injection form, for example, a liquid injection, a powder for injection, or a tablet for injection.

[0025] In some embodiments, the medicament is a liquid injection.

[0026] In some embodiments, the active ingredient content of the medicament is 0.5-5 mg / ml, for example, 1-2 mg / ml or 1 mg / ml, in terms of mitoxantrone.

[0027] In some embodiments, the active ingredient content of the medicament is 0.5-5 mg / ml, for example, 1-2 mg / ml or 1 mg / ml, in terms of mitoxantrone.

[0028] In some embodiments, the mitoxantrone hydrochloride liposome is the only active ingredient in the pharmaceutical composition. In some embodiments, the active ingredient content of the medicament is 0.5-5 mg / ml, for example, 1-2 mg / ml or 1 mg / ml, in terms of mitoxantrone.

[0029] In some embodiments, the pharmaceutical composition or the mitoxantrone hydrochloride liposome has one or more of the following properties:

[0030] (i) the particle size of the mitoxantrone hydrochloride liposome is about 30-80 nm, for example, about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm;

[0031] (ii) the mitoxantrone hydrochloride forms an insoluble precipitate with a polyvalent counterion (e.g., sulfate, citrate, or phosphate) within the liposome;

[0032] (iii) the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, for example, the phospholipid is selected from the group consisting of hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg lecithin, distearoyl lecithin, dipalmitoyl lecithin, or any combination thereof;

[0033] (iv) the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains hydrogenated soy lecithin, cholesterol, and distearoyl phosphatidyl ethanolamine modified with polyethylene glycol 2000 (DSPE-PEG2000).

[0034] In some embodiments, the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains hydrogenated soy lecithin, cholesterol, and distearoyl phosphatidyl ethanolamine modified with polyethylene glycol 2000 in a mass ratio of about 3:1:1, the mitoxantrone hydrochloride forms an insoluble precipitate with a polyvalent acid ion within the liposome, and the particle size of the mitoxantrone hydrochloride liposome in the medicament is about 60 nm.

[0035] In some embodiments, the ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer.

[0036] In some embodiments, the gastric cancer is advanced gastric cancer.

[0037] In some embodiments, the head and neck squamous carcinoma is a squamous carcinoma occurring in the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, hypopharynx, cervical esophagus, thyroid, salivary gland, mouth, larynx, and / or ear.

[0038] In some embodiments, the head and neck squamous carcinoma is recurrent or metastatic head and neck squamous carcinoma that has failed first-line treatment, for example, the first-line treatment is cisplatin / carboplatin in combination with 5-FU or a taxane drug, optionally further in combination with cetuximab.

[0039] In some embodiments, the pharmaceutical composition is in an injection form, for example, a liquid injection, a powder for injection, or a tablet for injection.

[0040] In some embodiments, the pharmaceutical composition is a liquid injection.

[0041] In some embodiments, the active ingredient content of the pharmaceutical composition is 0.5-5 mg / ml, e.g. 1-2 mg / ml or 1 mg / ml, in terms of mitoxantrone.

[0042] In some embodiments, the pharmaceutical composition is administered by intravenous administration; for example, the infusion administration time of the pharmaceutical composition is 30 min-120 min, e.g. 60 min-120 min or 60±15 min, in each intravenous administration.

[0043] In some embodiments, the administration cycle is once every 4 weeks or 3 weeks, e.g. once every 3 weeks.

[0044] In some embodiments, the therapeutically effective amount is 8-30 mg / m 2 , e.g. 12-20 mg / m 2 or 20 mg / m 2 , in terms of mitoxantrone.

[0045] In a third aspect, the present application provides a pharmaceutical composition comprising mitoxantrone hydrochloride liposomes, for use in the treatment of ovarian cancer, gastric cancer or head and neck squamous cancer.

[0046] In some embodiments, the mitoxantrone hydrochloride liposomes are the only active ingredient in the pharmaceutical composition.

[0047] In some embodiments, the pharmaceutical composition or the mitoxantrone hydrochloride liposomes have one or more of the following properties:

[0048] (i) the particle size of the mitoxantrone hydrochloride liposomes is about 30-80 nm, e.g. about 35-75 nm, about 40-70 nm, about 40-60 nm or about 60 nm;

[0049] (ii) the mitoxantrone hydrochloride forms an insoluble precipitate with a multivalent counterion (e.g. sulfate, citrate or phosphate) within the liposomes;

[0050] (iii) the phospholipid bilayer in the mitoxantrone hydrochloride liposomes contains a phospholipid having a phase transition temperature (Tm) higher than body temperature, e.g. selected from hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg lecithin, distearoyl lecithin, dipalmitoyl lecithin or any combination thereof;

[0051] (iv) the phospholipid bilayer in the mitoxantrone hydrochloride liposomes contains hydrogenated soy lecithin, cholesterol and distearoyl phosphatidyl ethanolamine modified with polyethylene glycol 2000 (DSPE-PEG2000).

[0052] In some embodiments, the phospholipid bilayer in the liposomal mitoxantrone hydrochloride contains hydrogenated soybean phosphatidylcholine, cholesterol and distearoylphosphatidyl ethanolamine modified with polyethylene glycol 2000 at a mass ratio of about 3:1:1, the mitoxantrone hydrochloride forms insoluble precipitates with polyvalent anion in the liposome, and the particle size of the liposomal mitoxantrone hydrochloride in the drug is about 60 nm.

[0053] In some embodiments, the ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer.

[0054] In some embodiments, the gastric cancer is advanced gastric cancer.

[0055] In some embodiments, the head and neck squamous carcinoma is squamous carcinoma occurring in the nasal cavity, nasal sinus, nasopharynx, oropharynx, laryngopharynx, cervical esophagus, thyroid, salivary gland, oral cavity, larynx and / or ear.

[0056] In some embodiments, the head and neck squamous carcinoma is recurrent or metastatic head and neck squamous carcinoma that has failed first-line therapy, for example, the first-line therapy is cisplatin / carboplatin combined with 5-FU or paclitaxel drugs, optionally further combined with cetuximab.

[0057] In some embodiments, the pharmaceutical composition is in an injection form, for example, a liquid injection, a powder for injection or a tablet for injection.

[0058] In some embodiments, the pharmaceutical composition is a liquid injection.

[0059] In some embodiments, the active ingredient content of the pharmaceutical composition is 0.5-5 mg / ml, for example, 1-2 mg / ml or 1 mg / ml, based on mitoxantrone.

[0060] DETAILED DESCRIPTION

[0061] Mitoxantrone hydrochloride is an anthraquinone antitumor drug. The FDA-approved indications are multiple sclerosis, prostate cancer and acute myeloid leukemia, and clinical studies show that it has certain efficacy on malignant lymphoma, breast cancer and acute myeloid leukemia, lung cancer, melanoma, soft tissue sarcoma, multiple myeloma, liver cancer, colorectal cancer, renal cancer, prostate cancer, endometrial cancer, testicular tumor, ovarian cancer and head and neck cancer, etc. Due to the presence of relatively serious side effects, such as myelosuppression, causing leukopenia and thrombocytopenia (dose-limiting toxicity), palpitation, premature beat and ECG abnormalities, etc., the clinical dosing of mitoxantrone hydrochloride is limited, and often requires combination therapy. However, previous studies have shown that the effectiveness of these combination therapy regimens is not high. How to further improve the antitumor efficacy without causing serious toxic side effects is a difficult problem faced by the clinical application of mitoxantrone hydrochloride.

[0062] Liposomes are a new form of drug delivery. In the pharmaceutical art, liposome drugs generally refer to microvesicular bodies formed by encapsulating drugs in lipid bilayers. Studies have shown that liposome drugs can change the in vivo distribution of encapsulated drugs, causing the drugs to accumulate mainly in tissues and organs such as the liver, spleen, lungs, and bone marrow, thereby increasing the therapeutic index of the drugs, reducing the therapeutic dose of the drugs, and reducing the toxicity of the drugs. These characteristics make liposome drug delivery an important application in the study of antitumor drugs. The researchers of the applicant of the present application have conducted research on mitoxantrone liposome preparations. For example, Chinese Patent Application No. 200610102339.8 filed on December 29, 2006 and PCT Application WO2008 / 080367A1 filed on December 29, 2007 disclose a mitoxantrone liposome, the entire contents of the above patent applications are incorporated herein for all purposes.

[0063] Mitoxantrone liposome preparations are a special preparation different from ordinary mitoxantrone injections, and their absorption, distribution, and metabolism in the body are significantly different. Therefore, it is difficult to deduce the treatment of different indications, especially the treatment of different tumors, based on the indications of the compound itself or between different tumor types. Therefore, the efficacy and indications of mitoxantrone liposome preparations should be studied independently. The inventors of the present application have conducted in-depth research on the efficacy of mitoxantrone liposome preparations in refractory ovarian cancer, gastric cancer, or head and neck squamous cell carcinoma, and have established the inventions of the present application.

[0064] In the following detailed description, unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art.

[0065] Although the numerical ranges and parameters setting forth the broadest scope of the application are approximations, the numerical values set forth in the specific embodiments are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein. For example, a range of "1 to 10" is to be understood to include any and all subranges between (and including) the minimum value of 1 and the maximum value of 10, that is, any and all subranges beginning with a minimum of 1 or more, e.g. 1 to 6.1, and ending with a maximum of 10 or less, e.g. 5.5 to 10. When the application recites "about" a value or range of values, it is understood that the value or range of values is an approximation, and is acceptable within the context of the application. Typically, the "about" recited in the application indicates a value or range of values within ±10% of the stated value or range of values, e.g. ±9%, or ±8%, or ±7%, or ±6%, or ±5%, or ±4%, or ±3%, or ±2%, or ±1%.

[0066] The term "pharmaceutical composition" as used herein refers to a combination of at least one pharmaceutical agent and optionally a pharmaceutically acceptable carrier or excipient combined together for the purpose of achieving some pharmaceutical goal. In the technical context of the liposome formulation of the present application, the pharmaceutically acceptable carrier is typically an aqueous carrier, such as water, a buffered aqueous solution, an isotonic saline solution (e.g., normal saline, phosphate buffered saline (PBS)), a sugar solution, and the like. While in the technical context of the present application, an injectable formulation is the suitable dosage form (and thus there is a matching type of pharmaceutically acceptable carrier), one skilled in the art would understand that other types of pharmaceutically acceptable carriers can be used if other dosage forms are chosen (e.g., oral).

[0067] The term "therapeutically effective amount" or "effective amount" as used herein refers to an amount that is sufficient to show benefit to the subject to which it is administered. The actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g., decisions on dosage, etc., is ultimately at the discretion of the physician and will depend on factors such as disease to be treated, individual patient parameters including past medical history, response to previous treatments, delivery site, and method of administration, and other factors known to medical practitioners.

[0068] The "individual," "subject," "patient" of the present application includes all members of the animal kingdom, including, but not limited to, mammals (e.g., mice, rats, cats, monkeys, dogs, horses, pigs, etc.) and humans. Preferably, the individual is a human individual. Unless otherwise indicated, the terms "patient," "subject," or "individual" can be used interchangeably.

[0069] 1. Mitoxantrone HCl liposome and formulation

[0070] Mitoxantrone HCl is an anthracene anti-tumor drug, the structure of which is as follows:

[0071]

[0072] Broadly speaking, a liposome is an artificial membrane. In water, the hydrophilic head of a phospholipid molecule inserts into water, and the hydrophobic tail of the phospholipid molecule extends to the air. After stirring, a spherical liposome of double-layered lipid molecules is formed. In the field of biological medicine, liposomes are often used in gene transfer technology or the preparation of drugs. By taking advantage of the characteristic of liposomes that can fuse with cell membranes, drugs can be delivered into the interior of cells. In the definition of pharmacy, a liposome drug generally refers to a microvesicle formed by encapsulating a drug in a lipid bilayer. The chemical composition of a liposome generally includes phospholipid substances (including natural and synthetic phospholipids) and cholesterol.

[0073] The preparation technology of liposome drug formulations has been reported in the art, and one skilled in the art can refer to the relevant technology to guide the preparation of the mitoxantrone HCl liposome formulation.

[0074] In some embodiments, the liposomal mitoxantrone hydrochloride is the only active ingredient in the medicament.

[0075] In the context of the present application, the inventors have found that the liposomal mitoxantrone hydrochloride formulation prepared using the method disclosed in Chinese Patent Application No. 200610102339.8 or PCT Application WO 2008 / 080367 Al has good efficacy.

[0076] Without being bound by any particular theory, the inventors have found that one or more or all of the following properties are advantageous for the liposomal mitoxantrone hydrochloride formulation:

[0077] I. In the liposomal formulation / drug, the liposomal mitoxantrone hydrochloride has a particle size of about 30-80 nm, such as about 30, 25, 40, 45, 50, 55, 60, 65, 70, 75, or 80 nm. More suitable ranges include about 35-75 nm, about 40-70 nm, about 40-60 nm. In one example (see Example below), the liposomal mitoxantrone hydrochloride has a particle size of about 60 nm. There are various ways to measure particle size, including but not limited to NanoZS.

[0078] II. The liposomal mitoxantrone hydrochloride forms a precipitate with the multivalent counterion (e.g., sulfate, citrate, or phosphate) in the liposome that is difficult to dissolve.

[0079] III. The phospholipid bilayer in the liposomal mitoxantrone hydrochloride contains phospholipids with a phase transition temperature (Tm) higher than body temperature (e.g., 36-38°C), so that the phase transition temperature of the liposome is higher than body temperature. Phospholipid molecules are essential components of the liposome, and different types of phospholipid molecules form liposomes with phase transition properties of solid-gel-liquid at different temperatures, and the composition of phospholipids largely determines the phase transition temperature of the liposome. Suitable types of phospholipids to achieve the desired phase transition temperature of the present application include, but are not limited to, hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dipalmitoyl lecithin, distearoyl lecithin, or any combination of the above. In addition, those skilled in the art can also select other suitable types of phospholipids and ratios based on phase transition temperature tests. In some embodiments, in addition to cholesterol, the phospholipid bilayer in the liposomal mitoxantrone hydrochloride of the present application contains phospholipid molecules including hydrogenated soy lecithin and distearoyl phosphatidyl ethanolamine modified with polyethylene glycol 2000 (DSPE-PEG2000).

[0080] In some embodiments, the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains hydrogenated soy phosphatidylcholine, cholesterol and distearoylphosphatidyl ethanolamine modified with polyethylene glycol 2000 at a mass ratio of about 3:1:1, the mitoxantrone hydrochloride forms a hardly soluble precipitate with the polyvalent anion in the liposome, and the particle size of the mitoxantrone hydrochloride liposome in the drug is about 60 nm.

[0081] In the liposome drug preparation, the "lipid-drug ratio" refers to the mass ratio of the constituent components of the phospholipid bilayer in the liposome (including phospholipids and cholesterol) to the drug (mitoxantrone in this application). For example, in one exemplary liposome drug preparation formula of this application, the lipid-drug ratio refers to the mass ratio of the constituent components of the phospholipid bilayer in the liposome (including HSPC, DSPE-PEG2000 and Chol) to mitoxantrone.

[0082] As a non-limiting example, the mitoxantrone hydrochloride liposome preparation of this application can be prepared according to the following method:

[0083] Hydrogenated soy phosphatidylcholine (HSPC), cholesterol (Chol) and distearoylphosphatidyl ethanolamine modified with polyethylene glycol 2000 (DSPE-PEG2000) are weighed according to a mass ratio of 3:1:1, dissolved in 95% ethanol to obtain a clear solution (i.e. phospholipid ethanol solution). The phospholipid ethanol solution is mixed with a 300 mM ammonium sulfate solution, and hydrated at 60-65°C for lh with shaking to obtain a heterogeneous multi-compartment liposome. The particle size of the liposome is then reduced using a microfluidic device. The obtained sample is diluted 200-fold with a 0.9% NaCl solution, and then detected using a NanoZS. The average particle size is about 60 nm, and the main peak is concentrated between 40-60 nm. The ammonium sulfate in the external phase of the blank liposome is then removed using an ultrafiltration device, and the external phase is replaced with a 290 mM sucrose and 10 mM glycine solution to form a transmembrane ammonium sulfate gradient. Mitoxantrone hydrochloride solution (10 mg / mL, based on mitoxantrone) is added to the blank liposome at a lipid-drug ratio of 16:1, and drug loading is performed at 60-65°C. After about lh of incubation, gel exclusion chromatography shows that the encapsulation efficiency is about 100%. The product thus obtained is designated as PLM60, and is used in the examples described below. The weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone in PLM60 is 9.58:3.19:3.19:1, and the osmotic pressure of the sucrose glycine solution is close to the physiological value.

[0084] It should be understood that many of the 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 alternative amino acid species of glycine in the outer phase for forming the transmembrane ammonium sulfate gradient includes but is not limited to histidine, asparagine, glutamic acid, leucine, proline, alanine. For another example, the mass ratio of HSPC, Chol and DSPE-PEG2000 can be adjusted appropriately. For still another example, for the preparation of the lipid-drug ratio parameter in the specific liposome drug preparation, those skilled in the art can design, test and finally arrive at a suitable lipid-drug ratio to maximize drug loading while minimizing drug leakage. For the mitoxantrone hydrochloride liposome preparation of the present application, the lipid-drug ratio that can be used is a wide range, for example, as low as 2:1 or as high as 30:1, 40:1 or 50:1 can be used, and 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 above-described mitoxantrone hydrochloride liposome preparation are more important, and the methodology for achieving these properties is diverse.

[0085] 2. Indications

[0086] In the present application, the indications of the mitoxantrone hydrochloride liposome preparation include ovarian cancer, gastric cancer, head and neck squamous cell carcinoma. The first-line, second-line or more than second-line drugs for treating ovarian cancer, gastric cancer, head and neck squamous cell carcinoma referred to in the present application refer to the first-line, second-line or more than second-line drugs approved by the drug regulatory departments of China and other countries and regions (such as the United States, the European Union, Japan, South Korea, etc.) for the treatment of ovarian cancer, gastric cancer, head and neck squamous cell carcinoma, including but not limited to: bevacizumab, PD-1 inhibitors, trastuzumab, apatinib, etc. approved by FDA.

[0087] 2.1 Ovarian Cancer

[0088] In some embodiments, the indication of the mitoxantrone hydrochloride liposome preparation is ovarian cancer. In some embodiments, the mitoxantrone hydrochloride liposome is used as the only active ingredient in the drug / drug composition of the present application for the treatment of ovarian cancer.

[0089] In some embodiments, the ovarian cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer. Platinum-refractory or platinum-resistant recurrent ovarian cancer refers to platinum-refractory or platinum-resistant recurrent ovarian cancer that has failed at least standard platinum-containing regimen treatment.

[0090] Suitable drug dosage forms are injection dosage forms, including liquid injections, injection powders, injection tablets. When the drug is a liquid injection, the active ingredient content of the drug is 0.5-5 mg / ml, calculated as mitoxantrone, and a more suitable range includes 1-2 mg / ml or 1 mg / ml.

[0091] In the course of treatment, the therapeutically effective amount is usually 8-30 mg / m 2 More suitable ranges include 12-20 mg / m 2 For example, 12 mg / m 2 , 14 mg / m 2 , 16 mg / m 2 , 18 mg / m 2 , 20 mg / m 2 .

[0092] The suitable administration mode of the liposome preparation of mitoxantrone hydrochloride of the present application is intravenous administration. In some embodiments, the administration cycle is once every 4 weeks or 3 weeks. In some specific embodiments, the infusion administration time of the liposome drug preparation is 30 min-120 min, more suitable ranges include 60 min-120 min and 90±15 min for each intravenous administration.

[0093] 2.2 Gastric cancer

[0094] In some embodiments, the indication of the liposome preparation of mitoxantrone hydrochloride is gastric cancer. In some embodiments, the liposome preparation of mitoxantrone hydrochloride is used for treating gastric cancer as the only active ingredient in the drug / drug composition of the present application.

[0095] In some embodiments, the gastric cancer is advanced gastric cancer. The advanced gastric cancer refers to metastatic advanced gastric cancer confirmed by histopathology, including gastroesophageal junction cancer.

[0096] The suitable pharmaceutical dosage form is injection dosage form, including liquid injection, injection powder, injection tablet. When the drug is a liquid injection, the active ingredient content of the drug is 0.5-5 mg / ml, more suitable ranges include 1-2 mg / ml or 1 mg / ml, in terms of mitoxantrone.

[0097] In the course of treatment, the therapeutically effective amount is usually 8-30 mg / m 2 More suitable ranges include 12-20 mg / m 2 For example, 12 mg / m 2 , 14 mg / m 2 , 16 mg / m 2 , 18 mg / m 2 , 20 mg / m 2 .

[0098] Suitable administration of the mitoxantrone hydrochloride liposome formulation of the present application is intravenous administration. In some embodiments, the administration cycle is once every 4 weeks or 3 weeks. In some specific embodiments, the infusion administration time of the liposome drug formulation is 30 min - 120 min, more suitable ranges include 60 min - 120 min and 90 ± 15 min per intravenous administration.

[0099] 2.3. Head and neck squamous cell carcinoma

[0100] In some embodiments, the indication of the mitoxantrone hydrochloride liposome formulation is head and neck squamous cell carcinoma. In some embodiments, the mitoxantrone hydrochloride liposome is used as the only active ingredient in the drug / pharmaceutical composition of the present application for the treatment of head and neck squamous cell carcinoma.

[0101] Head and neck squamous cell carcinoma includes squamous cell carcinoma occurring in the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, hypopharynx, cervical esophagus, thyroid, salivary glands, oral cavity, larynx and / or ear, wherein nasopharyngeal carcinoma is the cancer type of interest of the present application.

[0102] In some embodiments, the head and neck squamous cell carcinoma is recurrent / metastatic head and neck squamous cell carcinoma. In some embodiments, the head and neck squamous cell carcinoma is recurrent / metastatic head and neck squamous cell carcinoma that has failed at least one line of therapy. In some embodiments, cisplatin in combination with 5-fluorouracil (5-FU) (PF regimen) or in combination with paclitaxel is the commonly used first line chemotherapy regimen of choice. If the patient is not eligible for cisplatin, carboplatin can be substituted. The above first line treatment regimens can be combined with cetuximab.

[0103] Suitable pharmaceutical dosage forms are injection dosage forms, including liquid injections, injection powders, injection tablets. When the drug is a liquid injection, the active ingredient content of the drug is 0.5 - 5 mg / ml, more suitable ranges include 1 - 2 mg / ml or 1 mg / ml, based on mitoxantrone.

[0104] During treatment, the therapeutically effective amount is usually 8 - 30 mg / m 2 , more suitable ranges include 12 - 20 mg / m 2 , for example, 12 mg / m 2 , 14 mg / m 2 , 16 mg / m 2 , 18 mg / m 2 , 20 mg / m 2 , based on mitoxantrone, with individual surface area as the reference.

[0105] The suitable administration mode of the mitoxantrone hydrochloride liposome formulation of the present application is intravenous administration. In some embodiments, the administration cycle is once every 4 weeks or 3 weeks. In some specific embodiments, the infusion administration time of the liposome drug formulation is 30 min-120 min, more suitable ranges include 60 min-120 min and 90±15 min for each intravenous administration.

[0106] 3. Dosing regimen

[0107] As described above, the liposome drug formulation is a special type of drug, and the absorption, distribution, metabolism of the liposome drug after entering the body will change compared with the free drug. Therefore, the dosing regimen designed and tested based on the free drug may not be suitable for the liposome formulation of the same drug. Similarly, the dosing regimen designed and tested for a liposome drug formulation in a certain cancer may not be suitable for the application of the liposome drug formulation in other cancer types.

[0108] Previous studies have shown that the safe and effective dose of the same drug may differ greatly when treating different indications, for example:

[0109] Doxil (liposomal doxorubicin hydrochloride) has three indications approved by FDA, which are: (1) ovarian cancer, the recommended dose is 50 mg / m 2 , intravenous administration once every 4 weeks; (2) Kaposi's sarcoma, the recommended dose is 20 mg / m 2 , intravenous administration once every 3 weeks; (3) multiple myeloma, the recommended dose is 30 mg / m 2 , intravenous administration on the fourth day after bortezomib administration.

[0110] Abraxane (paclitaxel albumin for injection) also has different dosing regimens for the three indications approved by FDA: (1) metastatic breast cancer: the recommended dose is 260 mg / m 2 , intravenous infusion for 30 minutes, once every 3 weeks; (2) non-small cell lung cancer: the recommended dose is 100 mg / m 2 , intravenous infusion for 30 minutes, once every 21 days, respectively on the 1st, 8th and 15th day; paclitaxel albumin for injection is administered immediately after the administration of carboplatin, once every 21 days; (3) pancreatic cancer: the recommended dose is 125 mg / m 2 , intravenous infusion for 30-40 minutes, with a 28-day cycle, once on the 1st, 8th and 15th day, paclitaxel albumin for injection is administered immediately after each administration.

[0111] AmBisome (Amphotericin B Liposome for Injection), the initial dose for the following indications is respectively: (1) Empirical treatment: the recommended dose is 3 mg / kg / day; (2) Systemic fungal infection (aspergillus, candida, cryptococcus) : the recommended dose is 3-5 mg / kg / day; (3) Cryptococcal meningitis in HIV-infected patients: the recommended dose is 6 mg / kg / day (1-5 days), 3 mg / kg / day (4, 21 days) ; visceral leishmaniasis in patients with low immune function: 4 mg / kg / day (1-5 days), 4 mg / kg / day (10, 17, 24, 31, 38 days). It can be seen that the safe and effective dose of the same drug for different indications is different. The dose and administration data are individualized according to the specific disease and the actual situation of the patient to achieve maximum efficacy and minimum toxicity or adverse reactions, and to achieve safe and effective treatment of the disease.

[0112] Therefore, for the liposomal mitoxantrone hydrochloride preparation of the present application, there may be different optimal administration regimens for different types of cancer. Examples

[0113] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples are not specified, which are generally carried out according to the conventional conditions, or according to the conditions recommended by the manufacturer.

[0114] Example 1

[0115] The inventors of the present application tested the efficacy of the liposomal mitoxantrone hydrochloride preparation (PLM60) in animal model experiments of ovarian cancer, gastric cancer and head and neck squamous cell carcinoma, and the results showed (not shown in the present application) that PLM60 could effectively treat ovarian cancer, gastric cancer and head and neck squamous cell carcinoma.

[0116] Example 2 Clinical study of liposomal mitoxantrone hydrochloride injection in the treatment of platinum-refractory or platinum-resistant recurrent ovarian cancer

[0117] This example is a single-arm, open-label, multi-center phase Ib study, in which the enrolled subjects will receive liposomal mitoxantrone hydrochloride injection (PLM60) treatment, aiming to evaluate the safety and effectiveness of liposomal mitoxantrone hydrochloride injection in platinum-refractory or platinum-resistant recurrent ovarian cancer subjects.

[0118] In this example and subsequent examples, the following abbreviations are used: complete remission (CR), partial remission (PR), stable disease (SD), objective response rate (ORR), disease control rate (DCR).

[0119] I. Trial design

[0120] 1. Trial flow

[0121] All subjects enrolled in the study will receive Mitoxantrone Hydrochloride Injection as monotherapy, with a dose of 20mg / m 2 , once every 3 weeks (q3w). The study plans to enroll no less than 30 subjects. Screening-related examinations will be completed within 28 days before dosing, and baseline assessments will be performed to determine the inclusion / exclusion criteria before dosing. All enrolled subjects will receive 8 cycles of treatment, and treatment can be discontinued when the following conditions occur: disease progression (PD), intolerable toxicity, death, or the investigator determines that the subject can no longer benefit from the treatment. For subjects who have completed 8 cycles of treatment, if they are still benefiting from the treatment and can tolerate it, the investigator and the sponsor can discuss whether to continue the treatment to observe and evaluate the preliminary efficacy and safety.

[0122] The trial schedule for each subject is as follows: screening period, treatment period, and follow-up period.

[0123] After the subjects sign the informed consent form and complete all baseline examinations during the screening period, the subjects who meet the inclusion criteria will be treated with Mitoxantrone Hydrochloride Injection according to the enrollment order. All subjects will complete the relevant examinations as specified in the protocol during the entire trial process in the treatment period to observe the safety.

[0124] 2. Study Duration

[0125] This study includes a screening period of 4 weeks (28 days), a treatment period of 8 cycles (24 weeks), a final safety follow-up, a 4-week (28-day) follow-up after dosing, a PFS follow-up every 6 weeks thereafter, and a survival follow-up every 6 weeks after progression. The duration of each patient is expected to be approximately 12 months.

[0126] This study plans to enroll no less than 30 subjects, and the entire cycle of this study is expected to last 24-36 months.

[0127] II. Trial Population:

[0128] Subjects who meet all of the following inclusion criteria and do not meet any of the exclusion criteria can be enrolled in this clinical study.

[0129] (I) Inclusion Criteria:

[0130] The subjects must meet all of the following criteria:

[0131] 1) The subject voluntarily participates in the study and signs the informed consent form;

[0132] 2) Female subjects aged ≥ 18 years;

[0133] 3) Pathologically histologically confirmed epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (except low-grade serous and mucinous carcinoma);

[0134] 4) Subjects who have failed at least standard platinum-based treatment regimens or have relapsed into platinum resistance;

[0135] 5) The baseline contains at least one measurable lesion that meets the definition of RECIST 1.1;

[0136] 6) ECOG score 0-2;

[0137] 7) Expected survival time ≥ 3 months;

[0138] 8) The toxicity of previous antitumor treatment has recovered to ≤ Grade 1 (excluding hair loss, pigmentation, or other toxicities that were considered to pose no safety risk to the subjects in the study);

[0139] 9) The subjects' laboratory test values ​​meet the following requirements:

[0140] • Absolute neutrophil count (ANC) ≥ 1.5 x 10⁻⁶ 9 / L (No G-CSF white blood cell boosting treatment received within 1 week prior to laboratory testing);

[0141] • Hemoglobin (Hb) ≥ 9.0 g / dL (no red blood cell transfusion within 1 week prior to laboratory test);

[0142] ·Platelets ≥75x10 9 / L (without receiving platelet transfusions, thrombopoietin, interleukin-11, or other medications that increase platelet count within one week prior to the laboratory test);

[0143] Creatinine ≤ 1.5x ULN;

[0144] • Total bilirubin ≤1.5x ULN (≤3x ULN for patients with liver metastases);

[0145] • Alanine aminotransferase (AST) / aspartate aminotransferase (ALT) ≤ 2.5 x ULN (for patients with liver metastases,

[0146] ≤5x ULN);

[0147] • Albumin ≥ 3.0 g / dL;

[0148] • Coagulation function: Prothrombin time (PT) and international normalized ratio (INR) ≤ 1.5 x ULN;

[0149] 10) Female subjects with negative urine or serum HCG (except for postmenopausal and hysterectomy) and female subjects of childbearing potential and their partners must agree to use effective contraception (e.g., combined hormonal contraceptives (containing estrogen and progestogen), progestogen contraceptives combined with ovulation inhibition, intrauterine devices, intrauterine hormone release systems, bilateral tubal ligation, vasectomy, avoidance of sexual intercourse, etc.) during the trial and for 6 months after the last dose of study drug;

[0150] 11) Subjects who are able to communicate well with the investigator and who understand and are willing to comply with the requirements of the study.

[0151] (B) Exclusion Criteria:

[0152] Subjects who meet any of the following criteria will be excluded from the trial:

[0153] 1) Severe hypersensitivity to mitoxantrone or liposomal;

[0154] 2) Brain or meningeal metastases;

[0155] 3) Clinical symptoms of pericardial effusion;

[0156] 4) Previous allogeneic organ transplantation or allogeneic bone marrow transplantation;

[0157] 5) Patients with 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 detection of the study center), HIV antibody positive;

[0158] 6) Active bacterial, fungal, viral, or interstitial lung infection requiring systemic treatment within 1 week prior to first dose;

[0159] 7) Any antitumor therapy within 4 weeks prior to first dose;

[0160] 8) Other investigational medicinal products within 4 weeks prior to first dose;

[0161] 9) Major surgery (surgical classification: surgery of grade 3-4, except for the implantation of a venous access port) within 3 months prior to first dose or planned during the study;

[0162] 10) Thrombotic or embolic events such as cerebrovascular accidents (including transient ischemic attacks), pulmonary embolism within the past 6 months;

[0163] 11) Other malignantly active tumors within the past 3 years, except for locally curable cancers that have been cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast;

[0164] 12) Abnormal cardiac function, including:

[0165] • Long QTc syndrome or QTc interval > 480 ms;

[0166] • Complete left bundle branch block, second- or third-degree atrioventricular block;

[0167] • Severe, uncontrolled cardiac arrhythmias requiring medication;

[0168] • NYHA Level 3 or higher;

[0169] • Ejection fraction of the heart is less than 50% or below the lower limit of the laboratory test range of the research center;

[0170] • Heart valve disease with CTCAE > grade 2;

[0171] • Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg on multiple measurements, even when controlled with medication)

[0172] mmHg);

[0173] • A history of myocardial infarction, unstable angina, severe pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction abnormalities within 6 months prior to screening.

[0174] 13) Has previously received doxorubicin or other anthracycline treatment, and the cumulative dose of doxorubicin exceeds 350 mg / m². 2 (Anthracycline equivalent dose calculation: 1mg doxorubicin = 2mg epirubicin = 2mg daunorubicin = 0.5mg demethoxydaunorubicin = 0.45mg mitoxantrone);

[0175] 14) Pregnant or breastfeeding women;

[0176] 15) Suffering from any serious and / or uncontrollable disease, or other diseases that, in the investigator's opinion, may affect a patient's participation in this study (including, but not limited to, uncontrolled diabetes, kidney disease requiring dialysis, severe liver disease, life-threatening autoimmune diseases and bleeding disorders, drug abuse, neurological diseases, etc.).

[0177] 16) Other situations where researchers deem it unsuitable for participation.

[0178] (III) Exit / Termination Criteria

[0179] Subjects must discontinue treatment with the study drug if any of the following conditions occur during the study:

[0180] 1) The subject experiences intolerable toxicity, in the opinion of the investigator, that the risks of continuing treatment with study drug outweigh the benefits

[0181] 2) Progressive disease by imaging assessment

[0182] 3) Progressive disease by clinical assessment or major protocol violation occurs, or subject has poor compliance, in the opinion of the investigator, that the benefits of continuing treatment with study drug outweigh the risks

[0183] 4) The subject becomes pregnant

[0184] 5) Death

[0185] 6) Meets any of the criteria for withdrawal from the study

[0186] All subjects who discontinue treatment will continue to be followed according to the study schedule, except for subjects who discontinue treatment due to death or who meet any of the following criteria for withdrawal from the study.

[0187] The subject has the right to withdraw from the study at any time for any reason. The subject will be withdrawn from the study procedures if any of the following occurs:

[0188] 1) Loss to follow-up;

[0189] 2) The subject withdraws consent or the subject or family member requests withdrawal from the trial

[0190] 3) The study is terminated

[0191] 4) Other

[0192] III. Study Results

[0193] The efficacy of the subjects is evaluated according to the RECIST 1.1 standard, and all adverse events of the subjects are evaluated according to the CTCAE 5.0 standard.

[0194] The inventors of the present application use mitoxantrone liposomes, which have the effects of sustained release, targeting, attenuation, and enhancement after the drug is introduced into the human body through intravenous infusion. Not only is the dose higher than that of ordinary injections, but also it is a single-drug treatment, which can not only improve effectiveness but also reduce the probability of adverse reactions.

[0195] As of October 31, 2021 (the study is still ongoing), a total of 47 subjects were enrolled, including 13 cases of platinum-refractory cases and 34 cases of platinum-resistant cases. 39 subjects received at least one efficacy evaluation, with an overall ORR of 17.9% (7 / 39) and a DCR of 59.0% (23 / 39). Among the subjects who were platinum-resistant and had received ≥3 lines of previous treatment, a total of 24 subjects received at least one efficacy evaluation, with an ORR of 29.2% (7 / 24) and a DCR of 62.5 (15 / 24). No intolerable adverse reactions were observed in all subjects.

[0196] From the current experimental results, the mitoxantrone hydrochloride liposome preparation provided by the application can perfect the treatment plan of ovarian cancer, and lay a foundation for subsequent combination drug shock first-line and second-line treatment.

[0197] Example 3 Clinical study of mitoxantrone hydrochloride liposome injection in the treatment of advanced gastric cancer

[0198] This example is a single-arm, open-label, multi-center phase Ib study, and the enrolled subjects will receive mitoxantrone hydrochloride liposome injection (PLM60) treatment, aiming to evaluate the safety and effectiveness of mitoxantrone hydrochloride liposome injection in subjects with advanced gastric cancer.

[0199] I. Test design

[0200] 1. Test procedure

[0201] All enrolled subjects received mitoxantrone hydrochloride liposome injection monotherapy, with a dose of 20 mg / m 2 , once every 3 weeks (q3w). This study plans to enroll 30-60 subjects (male and female) with advanced gastric cancer. Screening-related examinations are completed 28 days before administration, and baseline evaluation is performed to determine the inclusion / exclusion criteria before administration. All enrolled subjects receive a maximum of 8 cycles of treatment, and treatment can be discontinued when the following conditions occur: disease progression (PD), intolerable toxicity, death, and the investigator determines that there is no benefit. Delayed administration can be accepted after the second cycle, but the delay cannot exceed 3 weeks; dose adjustment can be accepted after the second cycle, with a minimum of 12 mg / m 2 . Safety evaluation and efficacy evaluation are performed according to the plan after administration. Follow-up is performed 28 days after the last administration. Subjects who prematurely exit the test procedure should complete the follow-up after the end of the last administration as much as possible. Subjects at the end of treatment enter the follow-up period. In addition to subjects who experience disease progression by imaging evaluation or receive new antitumor treatment, subjects who discontinue treatment for other reasons continue to receive tumor evaluation every 6 weeks until disease progression. When a subject experiences disease progression by imaging evaluation or begins new antitumor treatment, survival follow-up is performed every 6 weeks.

[0202] The test procedure for each subject is as follows: screening period, treatment period, and follow-up period.

[0203] After signing the informed consent form and completing all baseline examinations during the screening period, subjects who meet the inclusion criteria will receive mitoxantrone hydrochloride injection treatment according to the enrollment order. All subjects complete the relevant examinations as specified in the protocol during the entire test period in the treatment period to observe safety.

[0204] 2. Duration of the study

[0205] This study includes a screening period of 4 weeks (28 days), a treatment period of up to 8 cycles (24 weeks), a final safety visit, a 4-week (28-day) follow-up visit after the end of dosing, and then PFS follow-up visits every 6 weeks, and survival follow-up visits every 6 weeks after progression, with an estimated duration of approximately 12 months per patient.

[0206] This study plans to enroll 30-60 subjects, and the entire cycle of the study is expected to be 24-36 months.

[0207] II. Test Population:

[0208] Subjects who meet all of the following inclusion criteria and none of the exclusion criteria can be enrolled in this clinical study.

[0209] (I) Inclusion Criteria:

[0210] Subjects must meet all of the following criteria:

[0211] 1) Subjects voluntarily participate in the study and sign the informed consent form;

[0212] 2) Age ≥ 18 years old, both male and female;

[0213] 3) Subjects with histologically confirmed metastatic advanced gastric cancer (including gastroesophageal junction cancer);

[0214] 4) Subjects assessed by the investigator as suitable for treatment with mitoxantrone hydrochloride liposome injection;

[0215] 5) At least one measurable lesion at baseline that meets the definition of RECIST 1.1;

[0216] 6) ECOG score 0-2;

[0217] 7) Expected survival time ≥ 3 months;

[0218] 8) Toxicity of previous antitumor therapy has recovered to ≤ grade 1 (except for alopecia, pigmentation, or other toxicities deemed by the study to pose no safety risk to the subject);

[0219] 9) The subject's laboratory test values meet the following requirements:

[0220] · Absolute neutrophil count (ANC) ≥ 1.5 x 10 9 / L (within 1 week before laboratory tests, without G-CSF white blood cell increasing treatment);

[0221] · Hemoglobin (Hb) ≥ 9.0 g / dL (within 1 week before laboratory tests, without red blood cell infusion; within 2 weeks without erythropoietin treatment);

[0222] · Platelets ≥ 75 x 10 9 / L (within 1 week prior to laboratory tests, no platelet transfusion; no treatment with thrombopoietin, interleukin-11 or other platelet-raising drugs within 2 weeks);

[0223] • creatinine ≤ 1.5 x ULN;

[0224] • total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN for patients with liver metastases);

[0225] • alanine aminotransferase (AST) / aspartate aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver metastases);

[0226] • albumin ≥ 3.0 g / dL;

[0227] • coagulation function: prothrombin time (PT), international normalized ratio (INR) ≤ 1.5 x ULN;

[0228] 10) Female subjects with negative urine or serum HCG (except for postmenopausal and hysterectomy) and female subjects of childbearing potential must agree to practice effective contraception (e.g., combined hormonal contraceptives containing estrogen and progestogen, progestogen contraceptives combined with ovulation inhibition, intrauterine devices, intrauterine hormone release systems, bilateral tubal ligation, vasectomy, avoidance of sexual intercourse, etc.) during the trial and for 6 months after the end of the last dose;

[0229] 11) Male subjects and their partners must agree to use one of the contraceptive methods described in item 10;

[0230] 12) Subjects must be able to communicate well with the investigator and understand and voluntarily comply with the requirements of the study.

[0231] (B) Exclusion Criteria:

[0232] Subjects meeting any of the following criteria will be excluded from the trial:

[0233] 1) Severe hypersensitivity to mitoxantrone or liposomal;

[0234] 2) Subjects with brain or meningeal metastases;

[0235] 3) Patients with gastric cancer who can be eligible for curative resection;

[0236] 4) Subjects with clinically evident pleural, pericardial or peritoneal effusion who require intervention (subjects with only small amounts of effusion on imaging and no clinical symptoms, who have been treated with drainage within 1 month prior to screening, are excluded);

[0237] 5) Subjects with clinically evident ileus who require intervention;

[0238] 6) CTCAE grade 3-4 gastrointestinal bleeding within 3 months prior to first dose;

[0239] 7) Prior allogeneic organ transplant or allogeneic bone marrow transplant;

[0240] 8) Patients with active hepatitis B (HbsAg or HBcAb positive and HBV DNA > 2000 IU / mL), active hepatitis C (HCV antibody positive and HCV RNA above the lower limit of detection of the study center), HIV antibody positive;

[0241] 9) Active bacterial, fungal, viral infection or interstitial pneumonitis requiring systemic treatment within 1 week prior to first dose;

[0242] 10) Any antitumor therapy within 4 weeks prior to first dose;

[0243] 11) Other investigational medicinal product within 4 weeks prior to first dose;

[0244] 12) Major surgery (surgical classification: surgery grade 3-4, except for the implantation of a venous access port) within 3 months prior to first dose or planned during the study;

[0245] 13) Thrombotic or embolic events such as cerebrovascular accidents (including transient ischemic attacks), pulmonary embolism within the last 6 months;

[0246] 14) Other malignancy active within the last 3 years, except for locally curable cancers that have been cured, such as basal or squamous cell skin cancer, superficial bladder cancer or in situ prostate, cervical or breast cancer;

[0247] 15) Cardiac dysfunction, including:

[0248] • Long QTc syndrome or QTc interval > 480 ms;

[0249] • Complete left bundle branch block, II degree or III degree atrioventricular block;

[0250] • Severe, uncontrolled arrhythmia requiring medical treatment;

[0251] • NYHA > grade 3;

[0252] • Cardiac ejection fraction below 50% or below the lower limit of the range of the study center laboratory examination;

[0253] • CTCAE > grade 2 heart valve disease;

[0254] • Uncontrolled hypertension (defined as systolic blood pressure > 150 mm Hg or diastolic blood pressure > 90 mm Hg on multiple occasions while on medication);

[0255] • History of myocardial infarction, unstable angina, severe pericardial disease within 6 months prior to screening, or evidence of acute ischemic or active conduction system abnormalities on electrocardiogram.

[0256] 16) Received anthracycline therapy and cumulative dose of anthracycline 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);

[0257] 17) Pregnant or lactating women;

[0258] 18) Have any serious and / or uncontrolled illness, other illness that in the opinion of the Investigator, can affect the patient's participation in the study (including but not limited to, uncontrolled diabetes mellitus, renal disease requiring dialysis, severe liver disease, life-threatening autoimmune system disease and bleeding disorder, drug abuse, nervous system disease, etc.);

[0259] 19) Other conditions that in the opinion of the Investigator are inappropriate for participation.

[0260] (iii) Withdrawal / termination criteria

[0261] A subject must be discontinued from study drug treatment if any of the following occur during the study:

[0262] 1) The subject experiences intolerable toxicity, in the opinion of the Investigator, the risks of continuing study drug treatment outweigh the benefits

[0263] 2) Progressive disease as assessed by imaging

[0264] 3) Progressive disease as assessed by clinical or the subject has poor compliance and in the opinion of the Investigator, the subject will not benefit from continuing study drug treatment

[0265] 4) The subject becomes pregnant

[0266] 5) Death

[0267] 6) Any of the withdrawal criteria are met

[0268] All subjects who withdraw from treatment must continue to be followed according to the study schedule, except for subjects who discontinue treatment due to death or who meet any of the following withdrawal criteria.

[0269] The subject has the right to withdraw from the study at any time for any reason. The subject will be withdrawn from the study procedure if any of the following occurs:

[0270] 1) loss of follow-up;

[0271] 2) withdrawal of informed consent by the subject or request by the subject or family member to withdraw from the trial

[0272] 3) termination of the study

[0273] 4) other

[0274] III. Study Results

[0275] The efficacy of the subject is evaluated according to the RECIST 1.1 standard, and all adverse events of the subject are evaluated according to the CTCAE 5.0 standard. The inventors of the present application expect that the use of mitoxantrone liposome has the effects of sustained release, targeting, attenuation and enhancement after the drug is introduced into the human body through intravenous infusion, not only the dose is higher than that of ordinary injection, but also it is single-drug treatment, which can not only improve the effectiveness, but also reduce the probability of adverse reactions.

[0276] Example 4 Clinical study of mitoxantrone hydrochloride liposome injection in the treatment of recurrent / metastatic head and neck squamous cell carcinoma

[0277] This example is a single-arm, open-label, multi-center phase Ib study, in which the enrolled subjects will receive mitoxantrone hydrochloride liposome injection (PLM60) treatment, aiming to evaluate the safety and effectiveness of mitoxantrone hydrochloride liposome injection in subjects with recurrent / metastatic head and neck squamous cell carcinoma.

[0278] I. Trial design

[0279] 1. Trial procedure

[0280] All enrolled subjects receive single-drug treatment of mitoxantrone hydrochloride liposome injection, with a dose of 20 mg / m 2 , once every 3 weeks (q3w). This study plans to enroll no less than 30 subjects (male and female) with recurrent / metastatic head and neck squamous cell carcinoma. The screening-related examinations are completed 28 days before administration, and the baseline evaluation is performed to determine the inclusion / exclusion criteria before administration. All enrolled subjects receive 8 cycles of treatment, which can be discontinued when the following conditions occur: disease progression (PD), intolerable toxicity, death, and the researcher determines that the subject cannot continue to benefit. Delayed administration can be accepted after the second cycle, but the delay cannot exceed 3 weeks; dose adjustment can be accepted after the second cycle, with a minimum of 12 mg / m 2 . Safety evaluation and efficacy evaluation are performed according to the plan after administration. Follow-up is performed 28 days after the last administration. Subjects who withdraw from the trial procedure should complete the follow-up after the end of the last administration as much as possible.

[0281] Subjects who complete treatment enter a follow-up period. Subjects who discontinue treatment for reasons other than radiographic disease progression or initiation of new antineoplastic therapy undergo tumor assessments every 6 weeks until disease progression. When a subject experiences radiographic disease progression or initiation of new antineoplastic therapy, survival follow-up occurs every 6 weeks.

[0282] The trial schedule for each subject is as follows: screening period, treatment period, and follow-up period.

[0283] After signing the informed consent form and completing all baseline assessments during the screening period, subjects who meet the inclusion criteria will receive mitoxantrone hydrochloride injection according to the order of enrollment. All subjects will undergo the relevant examinations required by the protocol during the entire trial process in the treatment period to observe safety.

[0284] 2. Study duration

[0285] This study includes a screening period of 4 weeks (28 days), a treatment period of 8 cycles (24 weeks), a final safety follow-up 4 weeks after drug administration (28 days), and then a PFS follow-up every 6 weeks, a survival follow-up every 6 weeks after progression, with an estimated duration of about 12 months for each patient.

[0286] This study plans to enroll at least 30 subjects, and the entire cycle of this study is expected to last 24-36 months.

[0287] II. Trial population:

[0288] Subjects who meet all of the following inclusion criteria and do not meet any of the exclusion criteria can be enrolled in this clinical study.

[0289] (I) Inclusion criteria:

[0290] The subject must meet all of the following criteria:

[0291] 1) The subject voluntarily participates in the study and signs the informed consent form;

[0292] 2) Age ≥ 18 years old, male or female;

[0293] 3) Pathologically histologically diagnosed head and neck squamous cell carcinoma (including nasopharyngeal carcinoma);

[0294] 4) Patients with recurrent / metastatic head and neck squamous cell carcinoma who have failed at least 1 line of treatment;

[0295] 5) At least one measurable lesion at baseline that meets the definition of RECIST 1.1;

[0296] 6) ECOG score 0-1;

[0297] 7) Prior anti-neoplastic therapy toxicity recovered to Grade ≤ 1 (except alopecia, pigmentation, or other toxicities deemed not to be a safety risk to the subject by the Investigator);

[0298] 8) Subject laboratory test values meet the following requirements:

[0299] • Absolute neutrophil count (ANC) ≥ 1.5 x 10 9 / L (within 1 week prior to laboratory tests, without G-CSF treatment to elevate white blood cells);

[0300] • Hemoglobin (Hb) ≥ 8.0 g / dL (within 3 months prior to laboratory tests, without transfusion of red blood cells or erythropoietin treatment);

[0301] • Platelets ≥ 75 x 10 9 / L (within 1 week prior to laboratory tests, without transfusion of platelets, thrombopoietin, interleukin-11 or other drugs to elevate platelets);

[0302] • Creatinine ≤ 1.5 x ULN;

[0303] • Total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN for patients with liver metastasis);

[0304] • Alanine aminotransferase (AST) / aspartate aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver metastasis);

[0305] • Albumin ≥ 3.0 g / dL;

[0306] • Coagulation function: prothrombin time (PT), international normalized ratio (INR) ≤ 1.5 x ULN;

[0307] 9) Female subjects are negative for urine or serum HCG (except for menopause and hysterectomy), and female subjects of childbearing potential agree to take effective contraceptive measures (such as combined hormones containing estrogen and progestin, progestin contraception combined with ovulation inhibition, intrauterine device, intrauterine hormone release system, bilateral tubal ligation, vasectomy, avoidance of sexual behavior, etc.) during the trial and within 6 months after the last dose;

[0308] 10) Male subjects and their partners agree to take one of the contraceptive measures described in item 9;

[0309] (B) Exclusion Criteria:

[0310] Subjects meeting any of the following criteria will be excluded from the trial:

[0311] 1) Severe allergy to mitoxantrone or liposome;

[0312] 2) Brain or meningeal metastases in the subject;

[0313] 3) Previous allogeneic organ transplant or allogeneic bone marrow transplant;

[0314] 4) Life expectancy < 3 months;

[0315] 5) Patients with active hepatitis B (HbsAg or HBcAb positive and HBV DNA > 2000 IU / mL), active hepatitis C (HCV antibody positive and HCV RNA above the lower limit of detection of the study center), HIV antibody positive;

[0316] 6) Active bacterial, fungal, viral, or interstitial lung infection requiring systemic treatment within 1 week prior to first dose;

[0317] 7) Any antitumor therapy within 4 weeks prior to first dose;

[0318] 8) Other investigational medicinal product within 4 weeks prior to first dose;

[0319] 9) Major surgery within 3 months prior to first dose, or planned major surgery during the study;

[0320] 10) Thromboembolic or embolic events, such as cerebrovascular accidents (including transient ischemic attacks), pulmonary embolism, within the past 6 months;

[0321] 11) Other malignancy active within the past 3 years, with the exception of locally curable cancers that have been cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or pre-invasive prostate, cervical, or breast cancer;

[0322] 12) Cardiac dysfunction, including:

[0323] • Long QTc syndrome or QTc interval > 480 ms;

[0324] • Complete left bundle branch block, II degree or III degree atrioventricular block;

[0325] • Severe, uncontrolled arrhythmias requiring medication;

[0326] • History of chronic congestive heart failure and NYHA > grade 3;

[0327] • Previous cardiac ejection fraction below 50% or below the lower limit of the range of the study center laboratory tests;

[0328] • CTCAE > grade 2 heart valve disease;

[0329] • Uncontrolled hypertension (defined as a systolic blood pressure > 150 mm Hg or diastolic blood pressure > 90 mm Hg on medication)

[0330] • History of myocardial infarction, unstable angina, severe pericardial disease, evidence of acute ischemic or active conduction system abnormalities on ECG within 6 months prior to screening.

[0331] 13) Received anthracyclines or other anthracycline therapy with cumulative dose of anthracyclines exceeding 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);

[0332] 14) Pregnant or lactating women;

[0333] 15) Have any serious and / or uncontrolled illness, other illness(es) that in the opinion of the Investigator, can affect the patient's participation in the study (including but not limited to, uncontrolled diabetes mellitus, renal disease requiring dialysis, severe liver disease, life-threatening autoimmune system disease and bleeding disorder, drug abuse, nervous system disease, etc.);

[0334] 16) Other conditions that in the opinion of the Investigator are inappropriate for participation.

[0335] (iii) Withdrawal / termination criteria

[0336] A subject must be discontinued from study drug treatment if any of the following occur during the study:

[0337] 1) The subject experiences intolerable toxicity, in the opinion of the Investigator, the risks of continuing study drug treatment outweigh the benefits

[0338] 2) Progressive disease as assessed by imaging

[0339] 3) Progressive disease as assessed by clinical evaluation or major protocol violations occur, or the subject has poor compliance, in the opinion of the Investigator, the benefits of continuing study drug treatment are outweighed by the risks

[0340] 4) The subject becomes pregnant

[0341] 5) Death

[0342] 6) Meets any of the criteria for withdrawal from the study

[0343] All subjects who withdraw from treatment must continue to be followed according to the study schedule, except for those who withdraw due to death or who meet any of the following criteria for withdrawal from the study.

[0344] The subject has the right to withdraw from the study at any time for any reason. The subject will be withdrawn from the study procedure if any of the following occurs:

[0345] 1) loss of follow-up;

[0346] 2) the subject withdraws consent or the subject or family member requests withdrawal from the trial

[0347] 3) the study is terminated

[0348] 4) other

[0349] III. Study Results

[0350] The efficacy of the subject is evaluated according to the RECIST 1.1 standard, and all adverse events of the subject are evaluated according to the CTCAE 5.0 standard.

[0351] The inventors of the present application expect that the use of mitoxantrone liposomes has the effects of sustained release, targeting, attenuation and enhancement after the drug is introduced into the human body through intravenous infusion, not only has a higher dose than ordinary injections, but also is a single drug treatment, which can not only improve effectiveness, but also reduce the probability of adverse reactions.

[0352] As of November 5, 2021 (the study is still ongoing), 34 subjects have been enrolled, including 23 cases of nasopharyngeal carcinoma and 11 cases of non-nasopharyngeal carcinoma (5 cases of tongue cancer, 2 cases of hypopharyngeal cancer, 2 cases of tonsil cancer, 1 case of laryngeal cancer and 1 case of gum cancer), all of which were given mitoxantrone hydrochloride liposome injection 20 mg / m 2 , once every 3 weeks (q3w); the efficacy evaluation was performed once every 2 cycles after drug administration. 19 subjects received at least one efficacy evaluation (including 18 nasopharyngeal carcinoma subjects and 1 non-nasopharyngeal carcinoma (hypopharyngeal carcinoma) subject). The results of the efficacy analysis are as follows: the overall ORR was 42.1% (8 / 19), and the DCR was 78.9% (15 / 19); the nasopharyngeal carcinoma ORR was 38.8% (7 / 18), and the DCR was 77.8% (14 / 18); the efficacy evaluation of 1 case of hypopharyngeal carcinoma was PR. No intolerable adverse reactions were observed in all subjects.

[0353] From the current experimental results, the mitoxantrone hydrochloride liposome preparation provided in the present application is expected to fill the gap in the second-line treatment of head and neck squamous cell carcinoma and lay the foundation for subsequent combination drug impact on first-line treatment.

[0354] The foregoing description is merely exemplary of preferred embodiments of this application and is not intended to limit the scope of the combination of features necessary for practicing this application. The title provided is not intended to limit the various embodiments of this application. The terms "comprising," "including," and "having" are intended to be open-ended and allow for there to be items or components that are not specifically mentioned or shown in the embodiments. Furthermore, the singular forms "a", "an", and "the" are intended to mean "one or more" unless expressly specified otherwise. Also, the terms "or" and "when" are intended to mean "and / or" unless expressly specified otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All publications and patents mentioned in this application are incorporated herein by reference. Various modifications and variations of the described methods and compositions of the application will be apparent to those skilled in the art without departing from the scope and spirit of the application. Although the application has been described by reference to specific preferred embodiments, it should be understood that the application is not intended to be unduly limited by such specific embodiments. Indeed, various modifications of the described modes of carrying out the application that are obvious to those skilled in the art are intended to be within the scope of the application.

Claims

1. Use of liposomal mitoxantrone hydrochloride in the manufacture of a medicament for the treatment of head and neck squamous cell carcinoma, wherein the head and neck squamous cell carcinoma is relapsed or metastatic head and neck squamous cell carcinoma that has failed a first line therapy.

2. The use of claim 1, wherein the liposomal mitoxantrone hydrochloride is the only active ingredient in the medicament.

3. The use of claim 1, wherein the medicament or the liposomal mitoxantrone hydrochloride has one or more of the following properties: (i) the particle size of the liposomal mitoxantrone hydrochloride is 30-80 nm; (ii) the liposomal mitoxantrone hydrochloride forms an insoluble precipitate with a polyvalent counterion in the liposome; (iii) the phospholipid bilayer in the liposomal mitoxantrone hydrochloride contains a phospholipid having a phase transition temperature higher than body temperature, so that the phase transition temperature of the liposome is higher than body temperature; (iv) the phospholipid bilayer in the liposomal mitoxantrone hydrochloride contains hydrogenated soybean phosphatidylcholine, cholesterol, and distearoylphosphatidyl ethanolamine modified with polyethylene glycol 2000.

4. The use of claim 3, wherein the particle size of the liposomal mitoxantrone hydrochloride is 35-75 nm.

5. The use of claim 3, wherein the particle size of the liposomal mitoxantrone hydrochloride is 40-70 nm.

6. The use of claim 3, wherein the particle size of the liposomal mitoxantrone hydrochloride is 40-60 nm.

7. The use of claim 3, wherein the particle size of the liposomal mitoxantrone hydrochloride is about 60 nm.

8. The use of claim 3, wherein the polyvalent counterion is sulfate, citrate, or phosphate.

9. The use of claim 3, wherein the phospholipid is selected from the group consisting of hydrogenated soybean phosphatidylcholine, phosphatidylcholine, hydrogenated egg yolk phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, or any combination thereof.

10. The use of claim 1, wherein the phospholipid bilayer in the liposomal mitoxantrone hydrochloride contains hydrogenated soybean phosphatidylcholine, cholesterol, and distearoylphosphatidyl ethanolamine modified with polyethylene glycol 2000 at a mass ratio of about 3:1:1, the liposomal mitoxantrone hydrochloride forms an insoluble precipitate with a polyvalent acid ion in the liposome, and the particle size of the liposomal mitoxantrone hydrochloride in the medicament is about 60 nm.

11. The use of any one of claims 1-10, wherein the head and neck squamous cell carcinoma is squamous cell carcinoma occurring in the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, hypopharynx, cervical esophagus, thyroid, salivary gland, oral cavity, larynx, and / or ear.

12. The use of any one of claims 1-10, wherein the first line therapy is cisplatin / carboplatin in combination with 5-FU or a taxane drug.

13. The use of any one of claims 1-10, wherein the first line therapy is cisplatin / carboplatin in combination with 5-FU or a taxane drug, and further in combination with cetuximab.

14. The use of any one of claims 1-10, wherein the medicament is in an injectable form.

15. The use of claim 14, wherein the medicament is a liquid injection, a powder for injection, or a tablet for injection.

16. The use of claim 14, wherein the medicament is a liquid injection. ​ ​ ​ ​ 17. The use according to claim 16, wherein the active ingredient content of the medicament is 0.5-5 mg / ml in terms of mitoxantrone.

18. The use according to claim 16, wherein the active ingredient content of the medicament is 1-2 mg / ml in terms of mitoxantrone.

19. The use according to claim 16, wherein the active ingredient content of the medicament is 1 mg / ml in terms of mitoxantrone.

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