WO2022218393A1 - 盐酸米托蒽醌脂质体的用途 - Google Patents

盐酸米托蒽醌脂质体的用途 Download PDF

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WO2022218393A1
WO2022218393A1 PCT/CN2022/086959 CN2022086959W WO2022218393A1 WO 2022218393 A1 WO2022218393 A1 WO 2022218393A1 CN 2022086959 W CN2022086959 W CN 2022086959W WO 2022218393 A1 WO2022218393 A1 WO 2022218393A1
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breast cancer
liposome
mitoxantrone hydrochloride
soft tissue
urothelial carcinoma
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PCT/CN2022/086959
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English (en)
French (fr)
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李春雷
刘延平
梁敏
李萌萌
李彤
杨华
王世霞
杨森森
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石药集团中奇制药技术（石家庄）有限公司
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Priority to US18/286,592 priority Critical patent/US20240122875A1/en
Priority to JP2023562628A priority patent/JP2024513965A/ja
Priority to EP22787615.8A priority patent/EP4324456A1/en
Publication of WO2022218393A1 publication Critical patent/WO2022218393A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention belongs to the field of anti-tumor, and specifically relates to the use of mitoxantrone hydrochloride liposome, such as the use in preparation for the treatment of urothelial carcinoma, breast cancer, bone and soft tissue sarcoma.
  • Urothelial carcinoma is a multi-origin malignant tumor originating from the urothelium, including renal pelvis cancer, ureteral cancer, bladder cancer and urethral cancer, etc. It is the most common urinary system tumor. Globally, the incidence of bladder-derived tumors ranked 12th among all solid tumors in 2018, accounting for 2.1% of total tumor deaths (Freddie, Bray, Jacques, Ferlay, Isabelle, & Soerjomataram, et al. (2016). Global cancer statistics 2018: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians.). In China, bladder-derived tumors ranked out of 10 in all tumors in 2015; ranked in men No.
  • cisplatin-resistant, cisplatin-containing chemotherapy regimens such as GC (gemcitabine + cisplatin), MVAC (methotrexate + vinblastine + doxorubicin) prime + cisplatin) is the first recommended program.
  • GC gemcitabine + cisplatin
  • MVAC metalhotrexate + vinblastine + doxorubicin prime + cisplatin
  • Patients who cannot tolerate cisplatin can consider carboplatin-containing regimens, such as gemcitabine + carboplatin regimens.
  • PD-1 inhibitors such as pembrolizumab or atezolizumab
  • chemotherapy drugs such as gemcitabine + paclitaxel or gemcitabine alone can be used.
  • PD-1 inhibitors are preferentially recommended in patients with PD-L1 expression.
  • the current treatment methods include immunotherapy, targeted therapy, ADC drug therapy and chemotherapy.
  • chemotherapy There is currently no standard treatment for third-line and above, and corresponding chemotherapy, targeted therapy, and biological therapy should be selected according to the use of front-line drugs.
  • the first-line chemotherapy is an anthracycline and/or taxane-based regimen.
  • taxane-based regimens or taxane-single-agent regimens are preferred for first-line chemotherapy.
  • Taxanes Those who have used taxanes in adjuvant therapy and the recurrence time > 1 year can use taxanes again.
  • drugs drugs that have not been used in adjuvant therapy and treatment stages are preferred.
  • Drugs that can be considered include capecitabine, vinorelbine, gemcitabine, platinum, erin Brin, Eutitron, another type of taxane (such as nab-paclitaxel) and doxorubicin liposomes can be considered as single or combined regimens, so it is still necessary to continue the research and development and exploration of new drugs for post-line treatment .
  • Classical osteosarcoma is the most common primary bone malignant tumor, with an annual incidence of about 2-3/1 million, accounting for only 0.2% of human malignant tumors. Osteosarcoma can occur in any age group, but it is more common in adolescents. About 75% of the patients are 15-25 years old. The median age of onset is 20 years. There are more males than females with this disease, and the ratio is about 1.4:1, and this difference is especially obvious before the age of 20. About 20% of patients have definite lung metastases at the time of initial diagnosis, and about 30% of patients have lung metastases within 1 year after the diagnosis of osteosarcoma. Before the 1970s, surgery was the only treatment for osteosarcoma, mainly amputation, and the average 5-year survival rate was only 19.7%.
  • Soft tissue sarcoma refers to a group of malignant tumors derived from non-epithelial extraosseous tissue, accounting for about 0.8% of all malignant tumors in humans, with an annual incidence of about 3.4/100,000 in the United States and 4-5/10 in Europe. The annual incidence in my country is about 2.38/100,000 (Siegel R L, Miller K D, Fuchs H E, et al. Cancer Statistics, 2021 [J]. CA: A Cancer Journal for Clinicians, 2021, 71(1) .).) Patients of any age can develop the disease. The ratio of males to females in my country is close to 1:1. With the increase of age, the incidence rate increases significantly.
  • the incidence rate at the age of 80 is about 8 times that at the age of 30.
  • Soft tissue sarcomas are mainly derived from mesoderm and partly from neuroectoderm, including muscle, fat, fibrous tissue, blood vessels, and peripheral nerves. The most common site of occurrence was the extremities (about 53%), followed by the retroperitoneum (19%), the trunk (12%), and the head and neck (11%).
  • tissue source it can be divided into 12 categories, and then according to different morphology and biological behavior, it can be divided into more than 50 subtypes.
  • Common subtypes are: undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma, and synovial sarcoma. The most common soft tissue sarcoma in adolescents and children is rhabdomyosarcoma.
  • Soft tissue sarcoma is mainly manifested as a gradually growing painless mass with strong insidiousness.
  • the disease course can last from several months to several years.
  • the tumor gradually enlarges and compresses nerves or blood vessels, pain, numbness and even limb edema may occur.
  • the mass may grow rapidly in a short period of time, the skin temperature may increase, and the regional lymph nodes may be enlarged. Need to be alert to the possibility of increased tumor grade.
  • Soft tissue sarcomas have a high degree of malignancy, and are characterized by a short course of disease, early hematogenous metastasis, and easy recurrence after treatment.
  • the most common site of metastases from extremity sarcomas is the lung, whereas retroperitoneal and gastrointestinal sarcomas most frequently metastasize to the liver.
  • the overall five-year survival rate for soft tissue sarcomas is about 60 to 80%.
  • Soft tissue sarcoma adopts a comprehensive treatment strategy based on surgery. Radiation, chemotherapy, or concurrent chemoradiation is considered one of the most effective treatment modalities. With the development of tumor combination therapy mode, preoperative treatment + surgery + chemotherapy has been gradually carried out. Its advantages are that it can reduce tumor volume, increase the chance of limb salvage, improve the local control rate, reduce the risk of distant metastasis and recurrence, and improve the patient's prognosis. survival rate. Chemotherapy sensitivity is an important basis for choosing chemotherapy for soft tissue sarcoma. Anthracycline-based regimens are preferred in neoadjuvant and adjuvant therapy.
  • doxorubicin and ifosfamide are the cornerstone drugs. There is currently no accepted second-line chemotherapy regimen for unspecified soft tissue sarcoma.
  • soft tissue sarcoma has a high degree of malignancy.
  • soft tissue sarcoma who have failed first-line treatment, there are limited types of second-line treatment options and limited efficacy. Participating in clinical trials is one of the recommended options. Improving the treatment of patients with soft tissue sarcoma and exploring new drugs have become urgent clinical needs.
  • Mitoxantrone hydrochloride is an anthraquinone chemotherapy drug.
  • the FDA-approved indications for mitoxantrone hydrochloride ordinary injection are multiple sclerosis, prostate cancer and acute myeloid leukemia; it has been approved in China for lymphoma,
  • the recommended dose is 12-14 mg/m 2 for single-agent adults, once every 3-4 weeks; or 4-8 mg/m 2 , once a day for 3-5 days, with an interval of 2-3 weeks ;
  • the combined dose is 5-10 mg/m 2 once.
  • Mitoxantrone is an anthracycline drug, and the main adverse reactions are mainly cardiotoxicity, bone marrow suppression and gastrointestinal reactions.
  • Doxil liposomal doxorubicin hydrochloride
  • ovarian cancer the recommended dose is 50 mg/m 2 , administered intravenously once every 4 weeks;
  • Kaposi's sarcoma the recommended dose is 20 mg/m 2 , administered intravenously once every 3 weeks;
  • Multiple myeloma the recommended dose is 30 mg/m 2 , intravenously administered on the fourth day after bortezomib administration .
  • Abraxane paclitaxel for injection [albumin-bound]
  • paclitaxel for injection [albumin-bound]
  • metastatic breast cancer the recommended dose is 260 mg/m 2 , intravenous infusion for 30 minutes, every 3 weeks.
  • Non-small cell lung cancer recommended dose of 100 mg/m 2 , intravenous infusion for 30 minutes, a course of treatment every 21 days, administered on the 1st day, the 8th day and the 15th day respectively; the injection on the 1st day Carboplatin is administered immediately after administration of paclitaxel (albumin-bound), once every 21 days; (3) Pancreatic cancer: the recommended dose is 125 mg/m 2 , intravenous infusion over 30-40 minutes, with a cycle of 28 days , once on the 1st, 8th and 15th day, and gemcitabine was administered immediately after each administration of paclitaxel for injection (albumin-bound).
  • the starting dose of AmBisome (Amphotericin B liposome for injection) for the treatment of the following indications is: (1) empirical treatment: the recommended dose is 3 mg/kg/day; (2) systemic fungal infections (Aspergillus, Candida , Cryptococcus): the recommended dose is 3-5mg/kg/day; (3) Cryptococcal meningitis in HIV-infected patients: the recommended dose is 6mg/kg/day (1st-5th day), 3mg/kg/day (1st-5th day) 4, 21 days); (4) Immunocompromised patients with visceral leishmaniasis: 4 mg/kg/day (1-5 days), 4 mg/kg/day (10, 17, 24, 31, 38 days) ); dosage and administration data are individually formulated according to the actual situation of the patient to achieve maximum efficacy and minimum toxicity or adverse reactions.
  • Dosage and administration data should be individually formulated according to the specific disease and the actual situation of the patient, in order to achieve the maximum efficacy and minimum toxicity or adverse reactions, and achieve the effect of safe and effective treatment of the disease.
  • mitoxantrone liposome which is different from ordinary injections, its absorption, distribution and metabolism after entering the body are very complicated.
  • the treatment of different indications especially in the treatment of different tumors, it is also It is difficult to simply derive from one indication to another.
  • mitoxantrone liposome is suitable for the treatment of urothelial carcinoma, breast cancer, bone and soft tissue sarcoma, and to clarify its safe and effective dose, so as to provide reference for clinical treatment.
  • the present invention provides the use of mitoxantrone hydrochloride liposomes in the preparation of medicines for treating urothelial carcinoma, breast cancer, bone and soft tissue sarcoma.
  • the urothelial carcinoma is locally advanced or metastatic urothelial carcinoma, more preferably, the urothelial carcinoma is locally advanced or failed platinum-containing chemotherapy regimen and/or PD-1 inhibitor therapy.
  • the breast cancer is HER-2-negative breast cancer, more preferably, the breast cancer is locally advanced or recurrent/metastatic HER-2-negative breast cancer; or, hormone receptor-negative HER-2-negative breast cancer Breast cancer, or, hormone receptor-positive, HER-2-negative breast cancer that is not suitable for or resistant to endocrine therapy; or, HER-2-negative breast cancer that has failed anthracycline and/or taxane therapy; preferred
  • the HER-2 negative breast cancer includes immunohistochemical HER-2 0 or 1+, and immunohistochemical HER-2 2+ needs to be confirmed to be negative by in situ hybridization.
  • the bone and soft tissue sarcoma is an advanced bone and soft tissue sarcoma, more preferably a metastatic or locally advanced bone and soft tissue sarcoma that has failed at least first-line therapy.
  • mitoxantrone hydrochloride liposome is used as the only active ingredient for preparing a medicament for the treatment of urothelial carcinoma, breast cancer, bone and soft tissue sarcoma.
  • the drug is in the form of injection, including liquid injection, powder for injection, tablet for injection, and the like.
  • the drug is a liquid injection.
  • the medicine when the medicine is a liquid injection, in terms of mitoxantrone, the medicine contains mitoxantrone 0.5-5 mg/ml, preferably 1-2 mg/ml, more preferably 1 mg/ml.
  • the present invention also provides a method for treating urothelial carcinoma, breast cancer, bone and soft tissue sarcoma, and the method is to administer a therapeutically effective amount of mitoxantrone hydrochloride liposome to a patient in need of treatment.
  • the invention also provides the application of mitoxantrone hydrochloride liposome in the treatment of urothelial carcinoma, breast cancer, bone and soft tissue sarcoma.
  • the urothelial carcinoma is locally advanced or metastatic urothelial carcinoma; more preferably, the urothelial carcinoma is locally advanced or failed platinum-containing chemotherapy regimen and/or PD-1 inhibitor therapy Metastatic urothelial carcinoma, or locally advanced or metastatic urothelial carcinoma that has failed platinum-containing chemotherapy regimens but refused PD-1 inhibitor therapy, or, locally advanced or metastatic urothelial carcinoma intolerant to cisplatin sexual urothelial carcinoma.
  • the breast cancer is HER-2-negative breast cancer, more preferably, the breast cancer is locally advanced or recurrent/metastatic HER-2-negative breast cancer; or, hormone receptor-negative HER-2-negative breast cancer Breast cancer, or, hormone receptor-positive, HER-2-negative breast cancer that is not suitable for or resistant to endocrine therapy; or, HER-2-negative breast cancer that has failed anthracycline and/or taxane therapy; preferred Precisely, the HER-2 negative breast cancer includes immunohistochemical HER-2 0 or 1+, and immunohistochemical HER-2 2+ needs to be confirmed to be negative by in situ hybridization;
  • the bone and soft tissue sarcoma is an advanced bone and soft tissue sarcoma, more preferably a metastatic or locally advanced bone and soft tissue sarcoma that has failed at least first-line therapy.
  • the therapeutically effective amount means that the dose of mitoxantrone is 8-30 mg/m 2 , more preferably 12-20 mg/m 2 or 16-30 mg/m 2 . Specific examples are 12 mg/m 2 , 14 mg/m 2 , 16 mg/m 2 , 18 mg/m 2 , and 20 mg/m 2 .
  • the mode of administration of the present invention is intravenous administration.
  • the dosing cycle is every 3 weeks.
  • the treatment given to the patient is 6-8 cycles.
  • the infusion administration time of the liposome pharmaceutical preparation is 30min-120min, preferably 60min-120min, more preferably 60 ⁇ 15min.
  • the present invention also provides a mitoxantrone hydrochloride liposome for treating urothelial carcinoma, breast cancer, bone and soft tissue sarcoma in patients.
  • the liposomes are in injectable dosage forms, including liquid injections, powders for injection, tablets for injection, and the like.
  • the liposome contains mitoxantrone 0.5-5 mg/ml, preferably 1-2 mg/ml, more preferably 1 mg/ml.
  • the liposomes are used alone to treat urothelial carcinoma, breast cancer, bone and soft tissue sarcoma in a patient.
  • the therapeutically effective amount of the liposome is 8-30 mg/m 2 , more preferably 12-20 mg/m 2 or 16-30 mg/m 2 . Specific examples are 12 mg/m 2 , 14 mg/m 2 , 16 mg/m 2 , 18 mg/m 2 , and 20 mg/m 2 .
  • the liposome is administered intravenously.
  • the dosing cycle is every 3 weeks.
  • the treatment given to the patient is 6-8 cycles.
  • the infusion administration time of the liposome is 30min-120min, preferably 60min-120min, more preferably 60 ⁇ 15min.
  • the doses are based on mitoxantrone unless otherwise specified.
  • the mitoxantrone hydrochloride liposomes can be prepared by methods known in the art, and can be mitoxantrone hydrochloride liposomes prepared by any method disclosed in the prior art, for example, using Prepared by the method disclosed in WO2008/080367A1.
  • the drug or mitoxantrone hydrochloride liposome has one or more of the following properties:
  • mitoxantrone hydrochloride liposomes have a particle size of about 30-80 nm, such as about 35-75 nm, about 40-70 nm, about 40-60 nm, or about 60 nm;
  • mitoxantrone hydrochloride forms insoluble precipitates with polyvalent counter ions (eg sulfate, citrate or phosphate) within the liposome;
  • the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains a phospholipid with a phase transition temperature (Tm) above body temperature, such that the phase transition temperature of the liposome is above body temperature, eg, the phospholipid is selected from hydrogenated soy lecithin, phosphatidylcholine, hydrogenated egg yolk lecithin, dipalmitate lecithin, distearate lecithin, or any combination of the above;
  • the phospholipid bilayer in mitoxantrone hydrochloride liposomes contained hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine (DSPE-PEG2000).
  • the phospholipid bilayer in the mitoxantrone hydrochloride liposome contains hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of about 3:1:1, Mitoxantrone hydrochloride forms insoluble precipitates with polyvalent acid ions in the liposome, and the particle size of the mitoxantrone hydrochloride liposome in the drug is about 60 nm.
  • the mitoxantrone hydrochloride liposome is the mitoxantrone hydrochloride liposome with the national medicine approval number H20220001.
  • the mitoxantrone hydrochloride liposome has a particle size of about 30-80 nm and contains: 1) the active ingredient mitoxantrone, which can interact with multivalent counter ions in the liposome Insoluble precipitates are formed, and 2) the phospholipid bilayer contains phospholipids with a phase transition temperature (Tm) higher than body temperature, so that the phase transition temperature of liposomes is higher than body temperature.
  • Tm phase transition temperature
  • the phospholipid with a Tm above body temperature is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin, bis-palmitate or bis-stearate, or any combination thereof, and the particle size is about 35- 75 nm, preferably 40-70 nm, more preferably 40-60 nm, particularly preferably 60 nm.
  • the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine in a mass ratio of 3:1:1, the particle size is about 60 nm, the The counter ion is the sulfate ion.
  • the phospholipid bilayer of the liposome contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000-modified distearoylphosphatidylethanolamine, the mass ratio is 3:1:1, and the particle size is about 40-60nm, the counter ion is sulfate ion, and the weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone in the liposome is 9.58:3.19:3.19:1.
  • mitoxantrone liposomes are prepared as follows: HSPC (hydrogenated soybean lecithin), Chol (cholesterol) and DSPE-PEG2000 (polyethylene glycol 2000 modified distearoyl phosphatidyl Ethanolamine) was weighed according to the mass ratio of (3:1:1) and dissolved in 95% ethanol to obtain a clear solution.
  • the ethanolic phospholipid solution was mixed with 300 mM ammonium sulfate solution, and shaken at 60-65 °C for 1 h to obtain heterogeneous multilamellar liposomes. The particle size of the liposomes is then reduced using a microfluidic device.
  • the obtained sample was diluted 200 times with 0.9% NaCl solution and detected by NanoZS.
  • the average particle size of the particles was about 60 nm, and the main peak was concentrated between 40 and 60 nm.
  • the ammonium sulfate in the outer phase of the blank liposome was then removed using an ultrafiltration device, and the outer phase was replaced with 290 mM sucrose and 10 mM glycine to form a transmembrane ammonium sulfate gradient.
  • mitoxantrone hydrochloride solution (10 mg/mL) was added to blank liposomes, and the drug was loaded at 60-65 °C.
  • the encapsulation efficiency was demonstrated to be about 100% using gel exclusion chromatography.
  • the weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone was 9.58:3.19:3.19:1, and the osmotic pressure of the sucrose-glycine solution was close to the physiological value.
  • glycine-substituted amino acid species used to form the outer phase of the transmembrane ammonium sulfate gradient include, but are not limited to, histidine, asparagine, glutamic acid, leucine, proline, alanine.
  • the mass ratio of HSPC, Chol and DSPE-PEG2000 can be adjusted appropriately.
  • lipid-drug ratio parameter for preparing the lipid-drug ratio parameter in the specific liposome pharmaceutical preparation, those skilled in the art can design, test and finally obtain a suitable lipid-drug ratio, so as to improve the drug load as much as possible and reduce the amount of drug leakage.
  • lipid-drug ratios for the mitoxantrone hydrochloride liposome formulation of the 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 to drug ratio may be about (15-20):1, such as about 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1. Therefore, several advantageous properties of the liposomal formulations of mitoxantrone hydrochloride described above are more important, and the methodologies to achieve these properties are diverse.
  • the first-line, second-line or more than second-line drugs for the treatment of urothelial carcinoma, breast cancer, bone and soft tissue sarcoma described in the present invention refer to drugs approved by drug administrations in China or abroad (such as the United States, the European Union, Japan, South Korea, etc.) for use in urine
  • First-line, second-line or more than second-line drugs for the treatment of epithelial cancer, breast cancer, bone and soft tissue sarcoma including but not limited to: FDA-approved taxanes, PD-1 inhibitors, ifosfamide, etc.
  • mitoxantrone hydrochloride liposome has better therapeutic effect on urothelial carcinoma, breast cancer, bone and soft tissue sarcoma, and can be used for preparing related medicines.
  • PD disease progression
  • RECIST 1.1 Response Evaluation Criteria in Solid Tumors
  • Objective response rate (ORR) (CR+PR)/total number of evaluable cases*100%.
  • DCR Disease control rate
  • Mitoxantrone hydrochloride liposome can effectively treat urothelial carcinoma, breast cancer, bone and soft tissue sarcoma. Compared with ordinary mitoxantrone hydrochloride injection, it has better curative effect and fewer adverse reactions.
  • the mitoxantrone hydrochloride liposome injection used in the following examples was provided by China National Pharmaceutical Group Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd. (National Medicine Zhunzi H20220001).
  • Example 1 Phase II clinical trial evaluating the efficacy and safety of mitoxantrone hydrochloride liposome injection in the treatment of unresectable locally advanced or metastatic urothelial carcinoma
  • the study population is mainly subjects who have failed platinum-containing chemotherapy regimens and PD-1 inhibitors (including those who do not receive PD-1 inhibitors); those who are intolerant to cisplatin require systemic therapy.
  • the study included a screening period, a treatment period, and a follow-up period.
  • the screening period is 28 days, and qualified subjects are screened to enter the treatment period.
  • mitoxantrone hydrochloride liposome injection 20mg/m 2 monotherapy was given, every 3 weeks as a cycle (q3w), and the first day of each cycle was administered for 6 cycles.
  • the follow-up period was started after treatment.
  • the study included a screening period of 4 weeks (28 days), a treatment period of 6 cycles (18 weeks), a final safety follow-up visit, 4 weeks (28 days) after the end of dosing, followed by a survival follow-up every 6 weeks, with each patient continuing The time is about 12 months.
  • AST Alanine aminotransferase
  • ALT aminotransferase
  • Coagulation function prothrombin time (PT), international normalized ratio (INR) ⁇ 1.5x ULN (for receiving anticoagulant drugs such as warfarin, INR ⁇ 3 is allowed);
  • the subjects and their partners take effective contraceptive measures during the trial period to 6 months after the end of the last medication (for example: combined hormones (including estrogen and progesterone) combined with ovulation inhibition, progesterone contraception combined with ovulation inhibition, uterine IUD, intrauterine hormone release system, bilateral vasectomy, bilateral tubal ligation, sex avoidance, etc.); female subjects have negative urine or blood HCG (except for menopause and hysterectomy);
  • Active hepatitis B HbsAg or HBcAb positive and HBV DNA ⁇ 2000IU/mL
  • active hepatitis C HCV antibody positive and HCV RNA higher than the lower limit of the detection value of the research center
  • HIV antibody positive patients HbsAg or HBcAb positive and HBV DNA ⁇ 2000IU/mL
  • Serious thrombosis or embolic events within the past 6 months such as cerebrovascular accident (including transient ischemic attack), pulmonary embolism, etc.;
  • Abnormal cardiac function including:
  • Uncontrollable hypertension defined as multiple measurements of systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg under medication control);
  • Subjects have the right to withdraw from the study at any time for any reason. Subjects will be withdrawn from the study process if any of the following occurs:
  • the inventor of the present invention uses mitoxantrone liposome, and the drug has the effects of slow release, targeting, detoxification, and synergy after entering the human body through intravenous infusion.
  • liposome preparation Higher doses can be used, which can not only improve the effectiveness, but also reduce the incidence of adverse reactions, and the ideal therapeutic effect can be obtained only with a single drug treatment.
  • the research of the present invention shows that in at least 4 subjects (2 subjects after 2 cycles of treatment, 2 subjects after 1 cycle of treatment), SD 2 cases (1 subject after 1 cycle of treatment, 1 subject after 2 cycles of treatment), DCR 50% (2/4). Mitoxantrone liposomes have good efficacy in patients with urothelial carcinoma, especially those who have failed platinum-containing chemotherapy regimens and PD-1 inhibitors. The 2 subjects who were evaluated as SD continued the medication and obtained better curative effect.
  • This plan will improve the treatment plan for urothelial carcinoma, lay the foundation for the combination of drugs to impact first-line and second-line treatment, change the traditional treatment mode of urothelial carcinoma, and look forward to the application of similar high-efficiency and low-toxic chemotherapy drugs in the field of advanced solid tumors.
  • This study is divided into screening period, treatment period, and follow-up period.
  • the screening period is 28 days, and the qualified subjects will enter the treatment period.
  • the subjects received mitoxantrone hydrochloride liposome injection 20mg/m 2 , 3 weeks as a cycle, 6 cycles.
  • the investigator and the sponsor were based on the benefits of the subjects and the Risk determines whether to continue dosing.
  • follow-up included end-of-treatment visit (28 days after last dose) and survival visit (every 6 weeks after end-of-treatment visit), and all subjects were followed up by telephone or visit until death.
  • Tumor evaluation According to RECIST 1.1 criteria, tumor evaluation was performed every 2 cycles during the treatment period and every 6 weeks during the follow-up period until disease progression or initiation of new antitumor therapy.
  • the study included a screening period of 4 weeks (28 days), a treatment period of 6 cycles (18 weeks), an end-of-treatment visit (28 days after the last dose), followed by a survival follow-up every 6 weeks until the patient was lost to follow-up or died, Each patient lasts about 12 months.
  • HER-2 negative breast cancer confirmed by histopathology (including immunohistochemical HER-2 0 or 1+, immunohistochemical HER-2 2+ needs to be confirmed negative by in situ hybridization);
  • At least one measurable lesion at baseline (RECIST 1.1 criteria);
  • AST Alanine aminotransferase
  • ALT aspartate aminotransferase
  • Active hepatitis B HbsAg positive and HBV DNA ⁇ 2000IU/mL
  • active hepatitis C HCV antibody positive and HCV RNA higher than the lower limit of the detection value of the research center
  • HIV antibody positive subjects HbsAg positive and HBV DNA ⁇ 2000IU/mL
  • Abnormal cardiac function includes:
  • CTCAE grade 3 valvular heart disease
  • Uncontrollable hypertension (under drug control, multiple measurements of systolic blood pressure ⁇ 160 mmHg or diastolic blood pressure ⁇ 100 mmHg);
  • Deep vein thrombosis or arterial embolism within the past 6 months including but not limited to superior/inferior vena cava thrombosis, lower extremity deep vein thrombosis, and pulmonary embolism;
  • Subjects have the right to withdraw from the study at any time for any reason. Subjects will be withdrawn from the study process if any of the following occurs:
  • the study of the present invention shows that, at least among the 20 evaluable cases, PR 6 cases (1 case after 7 cycles of treatment, 3 cases after 6 cycles of treatment, 1 case after 5 cycles of treatment, 1 case after 4 cycles of treatment), SD 8 Cases (2 cases underwent 6 cycles of treatment, 2 cases underwent 5 cycles of treatment, 1 case underwent 4 cycles of treatment, 1 case underwent 3 cycles of treatment, and 2 cases underwent 2 cycles of treatment).
  • PR 6 cases (1 case after 7 cycles of treatment, 3 cases after 6 cycles of treatment, 1 case after 5 cycles of treatment, 1 case after 4 cycles of treatment
  • SD 8 Cases (2 cases underwent 6 cycles of treatment, 2 cases underwent 5 cycles of treatment, 1 case underwent 4 cycles of treatment, 1 case underwent 3 cycles of treatment, and 2 cases underwent 2 cycles of treatment).
  • Mitoxantrone liposomes have good curative effect on breast cancer patients, especially in patients with advanced breast cancer who have previously received anthracycline and taxane therapy for failure or recurrence.
  • the inventor's previous clinical research included mitoxantrone hydrochloride monotherapy in the treatment of recurrent/metastatic breast cancer. There were 30 cases in the experimental group and the control group. The experimental group was given mitoxantrone hydrochloride liposome injection 20 mg/m 2 , each time 4 weeks is a cycle. The control group was given mitoxantrone hydrochloride injection 14 mg/m 2 every 4 weeks as a cycle. Results: The experimental group had 4 cases of PR, 11 cases of SD, ORR 13.3% (4/30), DCR 50% (15/30); the control group had 2 cases of PR, 7 cases of SD, the ORR was 6.7% (2/30) , the DCR was 30% (9/30).
  • the inventors of the present invention use mitoxantrone liposomes. After the drug enters the human body through intravenous infusion, it has the effects of slow release, targeting, detoxification and synergism. Not only is the dosage higher than that of ordinary injections, but it is also a single drug treatment. It can not only improve the effectiveness, but also reduce the incidence of adverse reactions.
  • Example 3 Phase Ib clinical trial of mitoxantrone hydrochloride liposome injection in the treatment of advanced bone and soft tissue sarcoma that failed at least first-line therapy
  • the study included a screening period, a treatment period, and a follow-up period.
  • the screening period is 28 days, and qualified subjects are screened to enter the treatment period.
  • subjects received mitoxantrone hydrochloride liposome injection 20 mg/m 2 on the first day, 3 weeks as a treatment cycle (q3w), a total of 6 cycles.
  • q3w treatment cycle
  • the investigator and the sponsor should discuss whether to continue the drug.
  • follow-up period safety follow-up after the last dose (28 ⁇ 7 days after the last dose) and survival follow-up (every 6 weeks after the last dose).
  • Safety evaluation is carried out from the first administration to 28 days after the last administration. Safety evaluation is required before each cycle of administration to decide whether to administer administration in the next cycle. During the entire study period, tumor evaluation was performed according to the RESIST1.1 standard. The treatment period It was performed every two cycles, and the follow-up period was performed every 6 weeks until disease progression, death, or new antitumor therapy.
  • the study included a screening period of 4 weeks (28 days), a treatment period of 6 cycles (18 weeks), a final safety follow-up visit, 4 weeks (28 days) after the end of dosing, followed by a survival follow-up every 6 weeks, with each patient continuing The time is about 12 months.
  • Hemoglobin (Hb) ⁇ 110g/L (within 1 week before the laboratory test, did not receive red blood cell transfusion therapy);
  • Platelets ⁇ 100x 10 9 /L (within 1 week before the laboratory test, did not receive platelet transfusion therapy);
  • AST Alanine aminotransferase
  • ALT aspartate aminotransferase
  • Coagulation function prothrombin time (PT), international normalized ratio (INR) ⁇ 1.5x ULN (for receiving anticoagulant drugs such as warfarin, INR ⁇ 3 is allowed)
  • Subjects and their partners agree to take effective contraceptive measures during the trial and within 6 months after the end of the last medication (for example: combined hormones (including estrogen and progesterone) combined with ovulation inhibition, progesterone contraception combined with ovulation inhibition, IUD, intrauterine hormone releasing system, bilateral tubal ligation, vasectomy, avoidance of sex, etc.);
  • effective contraceptive measures for example: combined hormones (including estrogen and progesterone) combined with ovulation inhibition, progesterone contraception combined with ovulation inhibition, IUD, intrauterine hormone releasing system, bilateral tubal ligation, vasectomy, avoidance of sex, etc.
  • the expected survival time is less than 12 weeks
  • HbsAg or HBcAb positive and HBV DNA ⁇ 1000IU/mL Chronic hepatitis B (HbsAg or HBcAb positive and HBV DNA ⁇ 1000IU/mL), hepatitis C (HCV antibody positive and HCV RNA quantitative detection is higher than the lower limit of the detection value of the research center), HIV antibody positive;
  • Abnormal cardiac function including:
  • CTCAE grade 3 valvular heart disease
  • Uncontrollable hypertension defined as multiple measurements of systolic blood pressure ⁇ 160 mmHg or diastolic blood pressure ⁇ 100 mmHg under medication control);
  • Subjects have the right to withdraw from the study at any time for any reason. Subjects will be withdrawn from the study process if any of the following occurs:
  • the study of the present invention shows that among the evaluable subjects, among 3 subjects with osteosarcoma (2 received 2 cycles of treatment, 1 received 1 cycle of treatment), 1 subject was evaluated as SD (received 1 cycle of treatment) treatment), DCR 33.3% (1/3).
  • Mitoxantrone liposome has good curative effect in patients with osteosarcoma and soft tissue sarcoma.

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Abstract

提供了盐酸米托蒽醌脂质体在制备用于治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤的药物中的用途。还提供治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤的方法，所述方法为给予所需患者治疗有效量的盐酸米托蒽醌脂质体。盐酸米托蒽醌脂质体能有效治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤，与普通盐酸米托蒽醌注射剂比较，疗效更好，不良反应更少。

Description

盐酸米托蒽醌脂质体的用途
本发明要求享有于2021年4月16日向中国国家知识产权局提交的，专利申请号为202110410490.2，名称为“盐酸米托蒽醌脂质体的用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本发明中。
本专利申请引用2007年12月29日提出的PCT申请WO2008/080367A1，其公开内容的全文通过引用的方式纳入本申请中。
技术领域
本发明属于抗肿瘤领域，具体涉及盐酸米托蒽醌脂质体的用途，如在制备用于治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤中的用途。
背景技术
尿路上皮癌是起源于尿路上皮的一种多源性的恶性肿瘤，包括肾盂癌、输尿管癌、膀胱癌以及尿道癌等，是最常见的泌尿系统肿瘤。在全球，2018年膀胱来源肿瘤发病率在全部实体瘤中排第12位，占肿瘤总死亡例数的2.1％((Freddie,Bray,Jacques,Ferlay,Isabelle,&Soerjomataram,et al.(2018).Global cancer statistics 2018:globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA:a cancer journal for clinicians.)。在中国，2015年膀胱来源肿瘤在所有肿瘤发病率在10位外；在男性排名第7，为6.2/10万人；女性10名外；标化死亡率在全部肿瘤中排名14位，为1.96/10万人(郑荣寿，孙可欣，张思维等.2015年中国恶性肿瘤流行情况分析。中华肿瘤杂志2019年1月第41卷第1期)。膀胱癌中男女发病人数的比约为3:1(Freddie,Bray,Jacques,Ferlay,Isabelle,&Soerjomataram,et al.(2018).Global cancer statistics 2018:globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA:a cancer  journal for clinicians.)。
对于不可切除的局部晚期或转移性尿路上皮癌的一线治疗，如耐受顺铂，含顺铂的化疗方案如GC(吉西他滨+顺铂)、MVAC(甲氨蝶呤+长春碱+阿霉素+顺铂)为首推方案。不能耐受顺铂的患者可以考虑含卡铂的方案，如吉西他滨+卡铂方案。其他的患者，可使用PD-1抑制剂，如帕博利珠单抗或阿替利珠，以及化疗药如吉西他滨+紫杉醇或吉西他滨单药等。PD-L1表达的患者中优先推荐使用PD-1抑制剂。对于患者的二线治疗，目前的治疗手段有免疫治疗、靶向治疗、ADC药物治疗及化疗。三线及以上目前无标准治疗，需根据前线的药物使用情况选择相应的化疗、靶向治疗、生物治疗。
综上，经含铂化疗方案和PD-1抑制剂治疗失败的患者，后续缺乏有效的治疗手段，亟待探索新的药物。
我国女性恶性肿瘤中乳腺癌发病率居第一位，死亡率居第五位，严重威胁中国女性健康(郑荣寿，孙可欣，张思维等.2015年中国恶性肿瘤流行情况分析[J].中华肿瘤杂志，2019，41(1)：19-28.)。2015年我国新发女性乳腺癌病例约30.4万，发病率为45.29/10万，死亡7万余例。约3％～10％的新发乳腺癌病例在确诊时存在远处转移，而在早期病例中30％发展为晚期乳腺癌。晚期乳腺癌的5年生存率仅为20％(国家肿瘤质控中心乳腺癌专家委员会.中国晚期乳腺癌规范诊疗指南(2020版)。
在不可手术的局部晚期、复发或转移的乳腺癌中，对于激素受体阴性、HER-2阳性、术后无病生存时间较短(<2年)、肿瘤发展较快，症状明显、广泛内脏转移、激素受体阳性、内分泌治疗失败者，化疗是不可或缺的治疗方法。既往未使用过化疗者(包括辅助化疗)，一线化疗首选蒽环类和(或)紫杉类药物为基础的方案。蒽环类治疗失败或接近累积剂量，并且既往未使用过紫杉类药物的转移性乳腺癌，一线化疗优先选择紫杉类为基础的方案或紫杉单药方案。辅助治疗用过紫杉类，距离复发时间>1年者，可以再次使用紫杉类，在其他药物的选择中， 优选辅助治疗和治疗阶段未用过的药物。对于蒽环类和紫杉类术前/辅助治疗均失败的复发转移性乳腺癌，目前无标准的化疗方案，可以考虑的药物有卡培他滨、长春瑞滨、吉西他滨、铂类、艾立布林、优替德隆、另一类紫杉(如白蛋白紫杉醇)和多柔比星脂质体，可以考虑单药或联合方案，因此仍需要继续进行后线治疗新型药物的研发和探索。
经典型骨肉瘤是最常见的骨原发性恶性肿瘤，年发病率约为2-3/100万，仅占人类恶性肿瘤的0.2％。骨肉瘤可发生于任何年龄段，好发于青少年，大约75％的患者发病年龄为15-25岁，中位发病年龄为20岁，小于6岁或者大于60岁发病相对罕见。本病男性多于女性，比例约为1.4：1，这种差异在20岁前尤其明显。大约20％初诊时即有明确的肺转移，另外的30％左右患者肺转移在骨肉瘤确诊后的1年内发生。20世纪70年代以前，手术是骨肉瘤的唯一治疗方式，以截肢为主，5年生存率平均仅为19.7％。70年代未期形成了新辅助化疗+手术+辅助化疗的治疗方案，5年生存率显著提高到60-80％(牛晓辉.中国骨肉瘤综合治疗现状与展望[J].中华解剖与临床杂志,2019(01):1-5.)，并沿用至今。而转移性或复发性骨肉瘤患者的生存率在过去30年中几乎没有变化，总体5年存活率约为20％(Meyers P A,Healey J H,Chou A J,et al.Addition of pamidronate to chemotherapy for the treatment of osteosarcoma[J].Cancer,2011,117(8):1736-1744.)。
国际上关于骨肉瘤的化疗方案众多，但并没有具体统一的方案，但由于使用的药物种类和剂量强度相似，其疗效相似。多柔比星、顺铂、异环磷酰胺和大剂量甲氨蝶呤被列为骨肉瘤的一线化疗药物，新辅助化疗亦使用同样的药物。每个患者要选用两种以上药物，并保证足够的剂量强度。其中三药联合方案与两药联合方案相比，5年EFS(无时间生存)率分别为58％及48％，5年OS率分别为70％及62％。骨肉瘤患者一线化疗失败后，由于暂无总体生存率获益的二线治疗方案，参加临床试验是一个获得更好疗效或者最新治疗的机会。
综上所述，目前除手术治疗外，化疗是临床治疗的重要手段。一线化疗失败的晚期或不可切除患者预后差，骨肉瘤的靶向、免疫治疗医学证据尚不充分，寻 求或采用新的细胞毒性药或靶向药物治疗为二线治疗带来契机。
软组织肉瘤是指来源于非上皮性骨外组织的一组恶性肿瘤，大约占到人类所有恶性肿瘤的0.8％，美国年发病率约3.4/10万，欧洲年发病率为4-5/10万，我国年发病率约为2.38/10万(Siegel R L,Miller K D,Fuchs H E,et al.Cancer Statistics,2021[J].CA:A Cancer Journal for Clinicians,2021,71(1).)。任何年龄患者均可发病，我国男女发病人数比例接近1:1，随着年龄的增长，发病率明显增高，根据年龄校准后的发病率，80岁时的发病率约为30岁时的8倍(Burningham Z,Hashibe M,Spector L,et al.The epidemiology of sarcoma[J].Clin Sarcoma Res,2012,2(1):14)。软组织肉瘤主要来源于中胚层，部分来源于神经外胚层，主要包括：肌肉、脂肪、纤维组织、血管及外周神经等组织。最常见的发生部位是四肢(约占53％)，其次是腹膜后(19％)、躯干(12％)、头颈部(11％)。根据组织来源可分12大类，再根据不同形态和生物学行为，可以分50种以上的亚型。常见的亚型有：未分化多形性肉瘤、脂肪肉瘤、平滑肌肉瘤、滑膜肉瘤。青少年及儿童最常见的软组织肉瘤为横纹肌肉瘤。
软组织肉瘤主要表现为逐渐生长的无痛性包块，隐匿性强，病程可数月至数年，当肿瘤逐渐增大压迫神经或血管时，可出现疼痛，麻木甚至肢体水肿。有些病例可出现肿块短期内迅速增大，皮肤温度升高，区域淋巴结肿大等。需要警惕肿瘤级别升高的可能。软组织肉瘤恶性程度高，表现为病程很短，较早出现血行转移及治疗后易复发等特点。肢体肉瘤最常见的转移部位是肺，而腹膜后和胃肠道肉瘤最常转移到肝脏。软组织肉瘤总的五年生存率约60～80％。
软组织肉瘤采用以外科为主的综合治疗策略。放疗、化疗或同步放化疗被认为是最有效的治疗方式之一。随着肿瘤联合治疗模式的发展，已逐渐开展术前治疗+手术+化疗，其优势在于可以缩小肿瘤体积、增加保肢机会，提高局控率、减少远处转移和复发的风险，提高患者的生存率。化疗敏感性是软组织肉瘤是否选择化疗的重要依据。基于蒽环类的方案在新辅助治疗和辅助治疗中是首选。而病 理级别高的软组织肉瘤患者，术后仍有40％-50％的患者会出现局部复发，>50％的患者会发生远处转移。对于转移或复发不能完整切除肿瘤患者采取的化疗为姑息性化疗，其目的是为了使肿瘤缩小、稳定，以减轻症状，延长生存期，提高生活质量。
对转移或复发的不可切除肿瘤来说，姑息性化疗的制定需要因人而异。转移的非多形性横纹肌肉瘤患者，化疗方案应按照高危组选择VAC/VI/VCD/IE交替。而对非特指型软组织肉瘤，多柔比星和异环磷酰胺是基石用药。非特指型软组织肉瘤目前尚无公认的二线化疗方案。
综上所述，软组织肉瘤恶性程度高，对一线治疗失败的软组织肉瘤患者而言，可选择的二线治疗药物种类有限，疗效有限，参加临床试验是推荐方案之一。改善软组织肉瘤患者的治疗，探索新的药物，成为了临床迫切的需求。
盐酸米托蒽醌是一种蒽醌类化疗药物，FDA批准盐酸米托蒽醌普通注射液的适应症为多发性硬化症、前列腺癌和急性髓性白血病；在我国获批适用于淋巴瘤、白血病和乳腺癌等患者，推荐剂量为单药成人12-14mg/m 2，每3-4周一次；或4-8mg/m 2，一日一次，连用3-5日，间隔2-3周；联合使用剂量为5-10mg/m 2一次。米托蒽醌作为蒽环类药物，主要的不良反应主要表现为心脏毒性、骨髓抑制和胃肠道反应等。其中，骨髓抑制和胃肠道反应可通过给予适宜的药物来解决，但是心脏毒性往往会带来严重后果，是蒽环类药物最为严重的不良反应，临床研究和实践观察均显示蒽环类药物导致的心脏毒性多数呈进展性和不可逆性，特别是初次使用蒽环类药物就易造成心脏损伤。慢性剂量累积限制性毒性-心脏毒性是临床医生普遍关注的问题。因此，虽然乳腺癌这一适应症被批准，但是米托蒽醌并未被权威的临床用药指南推荐为乳腺癌的治疗手段。而对于尿路上皮癌、骨与软组织肉瘤，米托蒽醌从未批准这两个适应症。
不同肿瘤的药物敏感性不同。已有的研究显示，同一药物在治疗不同适应症时，其给药方案有可能是不同的。例如Doxil(盐酸多柔比星脂质体)在FDA批准 了三个适应症，分别为：(1)卵巢癌，推荐剂量为50mg/m 2，每4周一次静脉内给药；(2)卡波氏肉瘤，推荐剂量为20mg/m 2，每3周一次静脉内给药；(3)多发性骨髓瘤，推荐剂量为30mg/m 2，硼替佐米给药后第四天静脉给药。又如Abraxane(注射用紫杉醇[白蛋白结合型])在FDA获批的也是三个适应症，(1)转移性乳腺癌：推荐剂量260mg/m 2，静脉滴注30分钟，每3周给药一次；(2)非小细胞肺癌：推荐剂量100mg/m 2，静脉滴注30分钟，每21天一个疗程，分别在第1天、第8天和15天给药；第1天注射用紫杉醇(白蛋白结合型)给药后立即给予卡铂，每21天给药一次；(3)胰腺癌：建议使用剂量125mg/m 2，静脉滴注30-40分钟，以28天为一个周期，第1、8、15天各给药一次，注射用紫杉醇(白蛋白结合型)每次给药后立即给予吉西他滨。再如AmBisome(注射用两性霉素B脂质体)治疗以下适应症的起始剂量为：(1)经验治疗：推荐剂量3mg/kg/天；(2)系统真菌感染(曲霉菌，念珠菌，隐球菌)：推荐剂量3～5mg/kg/天；(3)HIV感染者的隐球菌性脑膜炎：推荐剂量6mg/kg/天(第1-5天)，3mg/kg/天(第4、21天)；(4)免疫功能低下的内脏利什曼病患者：4mg/kg/天(第1-5天)，4mg/kg/天(第10、17、24、31、38天)；剂量和给药数据根据患者实际情况个性化制定，以达到最大药效和最小毒性或不良反应。可见，同一种药物治疗不同适应症的安全有效剂量存在差异。剂量和给药数据应根据具体病种和患者实际情况个性化制定，以达到最大药效和最小毒性或不良反应，取得安全有效治疗疾病的效果。对于米托蒽醌脂质体这一不同于普通注射剂的特殊剂型，其在进入体内后的吸收、分布、代谢情况十分复杂，对于不同适应症的治疗，特别是在不同肿瘤的治疗上，也很难由一种适应症简单推导到另一种适应症。
因此，有必要对米托蒽醌脂质体是否适用于尿路上皮癌、乳腺癌、骨与软组织肉瘤的治疗进行系统研究，明确其安全有效剂量，为临床治疗提供参考。
发明内容
本发明提供盐酸米托蒽醌脂质体在制备治疗尿路上皮癌、乳腺癌、骨与软组 织肉瘤的药物中的用途。
优选地，所述尿路上皮癌为局部晚期或转移性尿路上皮癌，更优选地，所述尿路上皮癌为经含铂化疗方案和/或PD-1抑制剂治疗失败的局部晚期或转移性尿路上皮癌；或者，经含铂化疗方案治疗失败，但拒绝接受PD-1抑制剂治疗的局部晚期或转移性尿路上皮癌；或者，对顺铂不耐受的局部晚期或转移性尿路上皮癌。
优选地，所述乳腺癌为HER-2阴性乳腺癌，更优选地，所述乳腺癌为局部晚期或复发/转移性的HER-2阴性乳腺癌；或者，激素受体阴性的HER-2阴性乳腺癌，或者，激素受体阳性但不适合内分泌治疗或内分泌治疗耐药的HER-2阴性乳腺癌；或者，蒽环类和/或紫杉类药物治疗失败的HER-2阴性乳腺癌；优选地，所述HER-2阴性乳腺癌包括免疫组化HER-2 0或1+，免疫组化HER-2 2+需经原位杂交法证实为阴性的乳腺癌。
优选地，所述骨与软组织肉瘤为晚期骨与软组织肉瘤，进一步优选至少经一线治疗失败的转移性或局部晚期的骨与软组织肉瘤。
优选地，盐酸米托蒽醌脂质体作为唯一活性成分用于制备治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤的药物。
优选地，所述药物为注射剂型，包括液体注射剂、注射用粉剂、注射用片剂等等。
优选地，所述药物为液体注射剂。
根据本发明的实施方案，当所述药物为液体注射剂时，以米托蒽醌计，所述药物含米托蒽醌0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
本发明还提供一种治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤的方法，所述方法为给予需要治疗的患者治疗有效量的盐酸米托蒽醌脂质体。
本发明还提供盐酸米托蒽醌脂质体在治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤中的应用。
优选地，所述尿路上皮癌为局部晚期或转移性尿路上皮癌；更优选地，所述 尿路上皮癌为经含铂化疗方案和/或PD-1抑制剂治疗失败的局部晚期或转移性尿路上皮癌，或者，经含铂化疗方案治疗失败，但拒绝接受PD-1抑制剂治疗的局部晚期或转移性尿路上皮癌，或者，对顺铂不耐受的局部晚期或转移性尿路上皮癌。
优选地，所述乳腺癌为HER-2阴性乳腺癌，更优选地，所述乳腺癌为局部晚期或复发/转移性的HER-2阴性乳腺癌；或者，激素受体阴性的HER-2阴性乳腺癌，或者，激素受体阳性但不适合内分泌治疗或内分泌治疗耐药的HER-2阴性乳腺癌；或者，蒽环类和/或紫杉类药物治疗失败的HER-2阴性乳腺癌；优选地，所述HER-2阴性乳腺癌包括免疫组化HER-2 0或1+，免疫组化HER-2 2+需经原位杂交法证实为阴性的乳腺癌；
优选地，所述骨与软组织肉瘤为晚期骨与软组织肉瘤，进一步优选至少经一线治疗失败的转移性或局部晚期的骨与软组织肉瘤。
优选地，以米托蒽醌计，所述治疗有效量是指米托蒽醌剂量为8-30mg/m 2，更优选为12-20mg/m 2或者16-30mg/m 2。具体例如，12mg/m 2，14mg/m 2，16mg/m 2，18mg/m 2，20mg/m 2。
优选地，本发明所述的给予方式为静脉给药。优选地，给药周期为每3周给药一次。优选地，给予患者的治疗为6-8个周期。优选地，每次静脉给药，所述脂质体药物制剂的滴注给药时间为30min-120min，优选60min-120min，进一步优选60±15min。
本发明还提供一种盐酸米托蒽醌脂质体，其用于治疗患者的尿路上皮癌、乳腺癌、骨与软组织肉瘤。
在一些实施方案中，所述脂质体为注射剂型，包括液体注射剂、注射用粉剂、注射用片剂等等。当所述药物为液体注射剂时，以米托蒽醌计，所述脂质体含米托蒽醌0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
在一些实施方案中，所述脂质体单独用于治疗患者的尿路上皮癌、乳腺癌、骨与软组织肉瘤。
在一些实施方案中，所述脂质体的治疗有效量(以米托蒽醌计)是8-30mg/m 2，更优选为12-20mg/m 2或者16-30mg/m 2。具体例如，12mg/m 2，14mg/m 2，16mg/m 2，18mg/m 2，20mg/m 2。
在一些实施方案中，所述脂质体的给药方式为静脉给药。优选地，给药周期为每3周给药一次。优选地，给予患者的治疗为6-8个周期。优选地，每次静脉给药，所述脂质体的滴注给药时间为30min-120min，优选60min-120min，进一步优选60±15min。
在本发明的上下文中，所述的剂量如无特别说明，则以米托蒽醌计。
在本发明的上下文中，所述的盐酸米托蒽醌脂质体可以采用本领域已知方法制备，可以是现有技术公开任意一种方法制备的盐酸米托蒽醌脂质体，例如采用WO2008/080367A1公开的方法制备。
在一些实施方案中，药物或盐酸米托蒽醌脂质体具有以下一项或多项性质：
(i)盐酸米托蒽醌脂质体的粒径为约30-80nm，例如约35-75nm、约40-70nm、约40-60nm或约60nm；
(ii)盐酸米托蒽醌与脂质体内的多价反离子(例如硫酸根、柠檬酸根或磷酸根)形成难以溶解的沉淀；
(iii)盐酸米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，从而脂质体的相转变温度高于体温，例如，所述磷脂选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合；
(iv)盐酸米托蒽醌脂质体中的磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG2000)。
(iiv)盐酸米托蒽醌脂质体中的磷脂双分子层含有质量比为约3:1:1的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，盐酸米托蒽醌与脂质体内的多价酸根离子形成难以溶解的沉淀，并且所述盐酸米托蒽醌脂质体在 所述药物中的粒径为约60nm。
(iiiv)盐酸米托蒽醌脂质体为国药准字H20220001的盐酸米托蒽醌脂质体。
在本发明的上下文中，所述的盐酸米托蒽醌脂质体，其粒径为约30-80nm，含有：1)活性成分米托蒽醌，它可以和脂质体内的多价反离子形成难以溶解的沉淀，2)磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，从而脂质体的相转变温度高于体温。所述Tm高于体温的磷脂为磷脂酰胆碱、氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂或双硬脂酸卵磷脂或者其任何组合，所述粒径为约35-75nm，优选40-70nm，进一步优选40-60nm，特别优选60nm。优选，所述磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，质量比为3:1:1，所述粒径为约60nm，所述反离子为硫酸根离子。优选，所述脂质体的磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，质量比为3:1:1，所述粒径为约40-60nm，所述反离子为硫酸根离子，脂质体中HSPC：Chol：DSPE-PEG2000：米托蒽醌的重量比为9.58:3.19:3.19:1。
在本发明的上下文中，米托蒽醌脂质体的制备方法如下：将HSPC(氢化大豆卵磷脂)、Chol(胆固醇)和DSPE-PEG2000(聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺)按照(3:1:1)的质量比称重，溶解于95％乙醇中，得到澄明溶液。将磷脂的乙醇溶液与300mM的硫酸铵溶液混合，在60-65℃震荡水化1h，得到不均匀的多室脂质体。之后使用微射流设备降低脂质体的粒度。将所获得的样品用浓度0.9％的NaCl溶液稀释200倍后，用NanoZS进行检测，粒子的平均粒度约为60nm，主峰集中在40-60nm之间。之后使用超滤装置移去空白脂质体外相的硫酸铵，将外相置换成290mM蔗糖及10mM甘氨酸，以便形成跨膜硫酸铵梯度。按照脂药比16:1的比例，在空白脂质体中加入米托蒽醌盐酸盐溶液(10mg/mL)，在60-65℃进行载药。孵育约1h后，使用凝胶排阻色谱可证明包封效率约为100％。其中HSPC：Chol：DSPE-PEG2000：米托蒽醌的重量比为9.58:3.19:3.19:1，蔗糖 甘氨酸溶液的渗透压与生理值接近。
应当理解的是，上述示例性制备方法中的多个技术细节和参数可以由本领域技术人员在合理的范围内进行调试和确定。例如，用于形成跨膜硫酸铵梯度的外相中的甘氨酸可替换的氨基酸种类包括但不限于组氨酸、天冬酰胺、谷氨酸、亮氨酸、脯氨酸、丙氨酸。再例如，HSPC、Chol和DSPE-PEG2000的质量比可以进行适当的调整。还例如，对于制备具体脂质体药物制剂中的脂药比参数，本领域技术人员可以设计、测试并最终得出合适的脂药比，以尽量提高载药量同时减少药物漏出量，对于本申请的盐酸米托蒽醌脂质体制剂而言，可以使用的脂药比是宽范围的，例如低至2:1或高至30:1、40:1或50：1都是可以的，更为适合的脂药比可以为约(15-20):1,例如约15：1、16：1、17：1、18：1、19：1或20：1。因此，上文描述的盐酸米托蒽醌脂质体制剂的数点有利性质是更为重要的，实现这些性质的方法学是多样的。
本发明所述的治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤的一线、二线或二线以上药物是指中国或国外(例如美国、欧盟、日本、韩国等等)药物管理部门批准用于尿路上皮癌、乳腺癌、骨与软组织肉瘤治疗的一线、二线或二线以上药物，包括但不仅限于：FDA批准的紫杉类药物、PD-1抑制剂、异环磷酰胺等。
有益效果
本发明申请人研究中意外发现盐酸米托蒽醌脂质体对尿路上皮癌、乳腺癌、骨与软组织肉瘤具有更好的治疗效果，可用于制备相关药物。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
在本发明中使用以下简写：
CR：完全缓解，具体定义依据国际研究通用的“实体瘤疗效评价标准(RECIST1.1)”。
PR：部分缓解，具体定义依据国际研究通用的“实体瘤疗效评价标准(RECIST1.1)”。
SD：疾病稳定，具体定义依据国际研究通用的“实体瘤疗效评价标准(RECIST1.1)”。
PD：疾病进展，具体定义依据国际研究通用的“实体瘤疗效评价标准(RECIST1.1)”。
客观缓解率(ORR)＝(CR+PR)/总的可评价病例数*100％。
疾病控制率(DCR)＝(CR+PR+SD)/总的可评价病例数*100％。
为考察盐酸米托蒽醌脂质体治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤的效果，发明人开展了临床研究。盐酸米托蒽醌脂质体能有效治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤，与普通盐酸米托蒽醌注射剂比较，疗效更好，不良反应更少。以下实施例中使用的盐酸米托蒽醌脂质体注射液由石药集团中诺药业(石家庄)有限公司提供(国药准字H20220001)。
实施例1 评价盐酸米托蒽醌脂质体注射液治疗不可切除的局部晚期或转移性尿路上皮癌的有效性和安全性的II期临床试验
这是一项开放、多中心的II期研究，纳入的受试者将接受盐酸米托蒽醌脂质体注射液治疗，旨在评价盐酸米托蒽醌脂质体注射液在不可切除的局部晚期或转移性尿路上皮癌的有效性和安全性。
一、试验设计
1.试验流程
入组40例不可切除的局部晚期或转移性尿路上皮癌受试者。研究人群主要为经含铂化疗方案和PD-1抑制剂治疗失败的受试者(包括不接受PD-1抑制剂治疗)；对顺铂不耐受的，需经过全身治疗。研究包括筛选期、治疗期和随访期。筛选期为28天，筛选合格受试者进入治疗期。治疗期给予盐酸米托蒽醌脂质体注射液20mg/m 2单药治疗，每3周为一个周期(q3w)，每周期首日给药，给药6个周期。治疗结束后进入随访期。随访期需进行末次给药后的安全性随访(末次给药后28天)和生存随访(末次给药后每6周进行一次)。从首次给药至末次给药后28天进行安全性评价，每周期给药前需进行安全性评价以决定下一周期是否给药。整个研究期间肿瘤评价根据RECIST1.1标准，每两个周期进行一次，直至疾病进展、死亡或接受新的抗肿瘤治疗。
2.研究持续时间
本研究包括筛选期4周(28天)，治疗期6个周期(18周)，末次安全随访，给药结束后4周(28天)，随后每6周进行一次生存随访，每位患者持续时间约12个月。
本研究入组40例受试者，本研究整个周期18～24个月。
二、试验人群：
符合下列全部入选标准并且没有任一排除标准的受试者才可入选本项临床研究。
(一)入选标准
1)受试者自愿参加研究，并签署知情同意书；
2)年龄≥18周岁，男女不限；
3)经组织学确诊的尿路上皮癌；
4)经含铂化疗方案和PD-1抑制剂治疗失败的受试者(包括不接受PD-1抑制剂治疗)；对顺铂不耐受的，需经过全身治疗；
5)基线至少存在一处符合RECIST 1.1定义的可评估病灶；
6)ECOG评分0～1；
7)受试者实验室检查数值符合以下要求：
·中性粒细胞绝对值(ANC)≥1.5x10 9/L(实验室检查前1周内，未接受G-CSF升白治疗)；
·血红蛋白(Hb)＞9.0g/dL(实验室检查前1周内，未接受输注红细胞)；
·血小板≥75x10 9/L(实验室检查前1周内，未接受输注血小板)；
·肌酐≤1.5x ULN；
·总胆红素≤1.5x ULN(对肝转移受试者，≤3x ULN)；
·丙氨酸氨基转移酶(AST)/天冬氨酸氨基转移酶(ALT)≤3x ULN(对肝转移受试者，≤5x ULN)；
·凝血功能：凝血酶原时间(PT)、国际标准化比值(INR)≤1.5x ULN(对于接受华法林等抗凝治疗药物允许INR≤3)；
8)受试者及其伴侣在试验期间至末次用药结束后6个月内采取有效的避孕措施(例如：联合激素(含雌激素和孕激素)结合抑制排卵、孕激素避孕结合抑制排卵、宫内节育器、宫内激素释放系统、双侧输精管结扎术、双侧输卵管结扎术、避免性行为等)；女性受试者尿或血HCG阴性(绝经和子宫切除除外)；
(二)排除标准
1)对米托蒽醌或脂质体类药物严重过敏；
2)脑或脑膜转移受试者；
3)既往异体器官移植或异体骨髓移植；
4)生存期<12周；
5)活动性乙型肝炎(HbsAg或HBcAb阳性且HBV DNA≥2000IU/mL)、活动性丙型肝炎(HCV抗体阳性且HCVRNA高于研究中心检测值下限)、HIV抗体阳性的患者；
6)在首次药物给药前1周内患有需要静脉输注的活动性细菌感染或真菌感染 或病毒感染；
7)在首次给药前4周内接受过任何抗肿瘤治疗者(中药或中成药为给药前2周)；
8)在首次给药前4周内接受过其他临床试验用药品治疗；
9)在首次给药前3个月内接受过重大手术，或者计划在研究期间进行重大手术者；
10)存在既往抗肿瘤治疗毒性＞1级(脱发、色素沉着或研究中认为对受试者无安全性风险的其他毒性除外)；
11)在过去6个月内出现严重的血栓形成或栓塞事件，例如脑血管意外(包括短暂性脑缺血发作)、肺栓塞等；
12)既往3年内患有其他恶性活动性肿瘤；已治愈的局部可治性癌症除外，例如基底或鳞状细胞皮肤癌或原位前列腺、宫颈或乳腺癌；
13)心脏功能异常，包括：
·长QTc综合征或QTc间期>480ms；
·完全性左束支传导阻滞，II度或III度房室传导阻滞(经起搏器植入术治疗后除外)；
·需要药物治疗的严重、未控制的心律失常；
·慢性充血性心力衰竭病史，NYHA≥3级；
·6个月内心脏射血分数低于50％；
·CTCAE＞2级的心脏瓣膜病；
·不可控的高血压(定义为在药物控制情况下，多次测量收缩压>150mmHg或舒张压>100mmHg)；
·在筛选前6个月内出现心肌梗死、不稳定型心绞痛、严重的心包疾病病史、有急性缺血性或严重的传导系异常的心电图证据。
14)曾接受过阿霉素或其他蒽环类治疗，且阿霉素累积剂量超过350mg/m 2 (蒽环类等效剂量计算：1mg阿霉素＝2mg表柔比星＝2mg吡柔比星＝0.5mg去甲氧柔红霉素＝0.45mg米托蒽醌；阿霉素脂质体除外)；
15)怀孕或哺乳期妇女；
16)患有任何严重的和/或不可控制的疾病，经研究者判定，可能影响患者参加本研究的其他疾病(包括但不限于，未得到有效控制的糖尿病、需要透析的肾脏疾病、严重的肝脏疾病、危及生命的自身免疫系统疾病和出血性疾病、药物滥用、神经系统疾病等)；
17)其他研究者判定不适宜参加的情况。
(三)退出治疗及退出研究标准
受试者在研究过程中出现以下任一情况是必须停止继续接受试验用药品治疗的：
1)受试者出现无法耐受的毒性，研究者认为继续接受试验用药品治疗风险大于获益；
2)治疗期间出现的合并疾病不允许后续继续给药；
3)影像学评估的疾病进展；
4)临床评估的疾病进展或出现重大方案违背，或受试者依从性差，经研究者判定认为继续接受试验用药品治疗无法获益；
5)受试者妊娠；
6)死亡；
7)满足退出研究标准中的任一项。
所有退出治疗的受试者需继续按照研究计划进行后续的随访，除外停止治疗的原因为死亡，或满足下述任一项退出研究标准的受试者。
受试者有权在任何时间以任何原因退出研究。出现下列任一情况，受试者将退出研究流程：
1)失访；
2)受试者或家属(在受试者本人无法做出决定时)要求退出试验；
3)研究终止；
4)其他。
三、研究结果
经含铂化疗方案和PD-1抑制剂治疗失败的受试者(包括不接受PD-1抑制剂治疗)，以及对顺铂不耐受的，经过全身治疗的受试者，后续缺乏比较有效的治疗手段，亟待探索新的药物。本发明的发明人使用米托蒽醌脂质体，药物通过静脉输注进入人体后有缓释、靶向、减毒、增效的作用，相对于米托蒽醌普通注射剂，脂质体制剂可以采用更高的剂量，既可以提高有效性，同时降低不良反应发生几率，仅使用单药治疗就能获得理想的治疗效果。
本发明的研究表明，至少在4例受试者(2例受试者经过2周期治疗，2例受试者经过1周期治疗)中，SD 2例(1例受试者经过1周期治疗，1例受试者经过2周期治疗)，DCR 50％(2/4)。米托蒽醌脂质体对尿路上皮癌患者，特别是含铂化疗方案和PD-1抑制剂治疗失败的患者有良好疗效。对评价为SD的2例受试者继续用药，获得了更好的疗效。
本方案将完善尿路上皮癌的治疗方案，为联合用药冲击一线、二线治疗打下基础，改变尿路上皮癌传统的治疗模式，期待类似高效低毒的化疗药在晚期实体瘤领域的应用。
实施例2 盐酸米托蒽醌脂质体注射液治疗HER-2阴性晚期乳腺癌的II期临床试验
这是一项开放、多中心的II期研究，纳入的受试者将接受盐酸米托蒽醌脂质体注射液治疗，旨在评价盐酸米托蒽醌脂质体注射液治疗HER-2阴性晚期乳腺癌的安全性和有效性。
一、试验设计
1.试验流程
本研究分为筛选期、治疗期、随访期。筛选期为28天，筛选合格的受试者进入治疗期。治疗期间受试者接受盐酸米托蒽醌脂质体注射液20mg/m 2，3周为一个周期，6个周期，完成6个周期治疗后，研究者和申办方根据受试者获益和风险决定是否继续给药。随访包括治疗结束访视(末次给药后28天)和生存随访(治疗结束访视后每6周一次)，所有受试者需通过电话或访视进行生存随访，直到受试者死亡。
肿瘤评估：根据RECIST 1.1标准，治疗期每2个周期进行一次肿瘤评估，随访期每6周进行一次肿瘤评估，直至疾病进展或开始新的抗肿瘤治疗。
安全性评价：每周期治疗前和治疗结束访视完成生命体征、体格检查、体重、ECOG体力评分、12导联心电图、超声心动图检查、实验室检查。每周期D8和D15行血常规检查。
2.研究持续时间
本研究包括筛选期4周(28天)，治疗期6个周期(18周)，治疗结束访视(末次给药后28天)，随后每6周进行一次生存随访直至患者失访或死亡，每位患者持续时间约12个月。
本研究入组73例受试者，本研究整个周期约36个月。
二、试验人群：
符合下列全部入选标准并且没有任一排除标准的受试者才可入选本项临床研究。
(一)入选标准：
受试者必须符合以下所有标准：
1)受试者自愿参加研究，并签署知情同意书；
2)年龄18～75岁(包括18岁和75岁)；
3)经组织病理学确诊的HER-2阴性乳腺癌(包括免疫组化HER-2 0或1+，免疫组化HER-2 2+需经原位杂交法证实为阴性)；
4)经一线及以上化疗后疾病进展的不可手术的局部晚期或复发/转移性乳腺癌；
5)激素受体阴性或激素受体阳性但不适合内分泌治疗或内分泌治疗耐药的乳腺癌；
6)既往至少接受过一种蒽环类和一种紫杉类药物的治疗(可以接受既往因心脏毒性高危因素未使用蒽环类药物的受试者)，最多接受四种化疗方案治疗；
7)基线至少有一个可测量病灶(RECIST 1.1标准)；
8)ECOG评分0～2分；
9)良好的器官功能(首次应用研究药物前2周内没有接受过输血或生长因子支持治疗)，包括：
·中性粒细胞绝对值(ANC)≥1.5×10 9/L；
·血红蛋白(Hb)≥90g/L；
·血小板≥90×10 9/L；
·肌酐≤1.5倍正常值上限；
·总胆红素≤1.5倍正常值上限；
·丙氨酸氨基转移酶(AST)和天冬氨酸氨基转移酶(ALT)≤3倍正常值上限(肝转移患者≤5倍正常值上限)；
10)妊娠检查结果为阴性，育龄期受试者承诺从研究开始到研究末次用药后6个月内采取有效的避孕措施或禁欲；
11)有良好的依从性并愿意配合随访。
(二)排除标准：
符合以下任一标准的受试者均将从本试验中排除：
1)对米托蒽醌或脂质体严重过敏；
2)既往3年内患有其他恶性肿瘤，不包括已经根治的宫颈原位癌、皮肤基底细胞癌或鳞状；
3)脑转移和膜受试者；
4)活动性乙型肝炎(HbsAg阳性且HBV DNA≥2000IU/mL)、活动性丙型肝炎(HCV抗体阳性且HCV RNA高于研究中心检测值下限)、HIV抗体阳性的受试者；
5)预期生存时间＜3个月；
6)既往接受过的蒽环类药物累积剂量换算为多柔比星>350mg/m 2(蒽环类药物等效剂量计算：1mg多柔比星＝2mg表柔比星＝2mg吡柔比星＝2mg柔红霉素＝0.5mg去甲氧柔红霉素＝0.45mg米托蒽醌，阿霉素脂质体除外)；
7)既往抗肿瘤治疗毒性未恢复至≤1级(脱发、色素沉着或研究中认为对受试者无安全性风险的其他毒性除外)；
8)心脏功能异常包括：
·长QTc综合征或QTc间期>480ms；
·完全性左束支传导阻滞，II度/III度房室传导阻滞；
·需要药物治疗的严重、未控制的心律失常；
·慢性充血性心力衰竭病史且NYHA≥3级；
·在筛选前6个月内心脏射血分数低于50％；
·CTCAE≥3级的心脏瓣膜病；
·在筛选前6个月内出现心肌梗死、不稳定心绞痛、严重室性心律失常、严重的心包疾病病史、有急性缺血性或活动性传导系异常的心电图证据。
9)不可控的高血压(在药物控制情况下，多次测量收缩压≥160mmHg或舒张压≥100mmHg)；
10)在首次给药前1周内患有需要静脉输注治疗的活动性细菌感染、真菌感染、病毒感染；
11)在首次给药前4周内接受过任何抗肿瘤治疗(包括化疗、放疗、分子靶向治疗、免疫治疗、内分泌治疗)，在首次给药前2周内接受过免疫调节剂作为 恶性肿瘤辅助治疗，在首次给药前2周内接受过任何抗肿瘤中成药(扶正类中成药和缓解症状类中成药除外)。
12)在首次给药前4周内接受过其他临床研究药物治疗者；
13)在首次给药前12周内接受过重大手术，或者计划在研究期间进行重大手术者；
14)既往6个月内深静脉血栓形成或动脉栓塞，包括但不限于上腔/下腔静脉血栓形成、下肢深静脉血栓形成、肺栓塞；
15)哺乳期妇女；
16)患有任何严重的和/或不可控制的疾病，经研究者判定，可能影响患者参加本研究的其他疾病(包括但不限于未有效控制的糖尿病、需要透析的肾脏疾病、严重的肝脏疾病、危及生命的自身免疫系统疾病和出血性疾病、药物滥用、神经系统疾病等)；
17)其他研究者判定不适宜参加的情况。
(三)退出治疗及退出研究标准
受试者在研究过程中出现以下任一情况是必须停止继续接受研究药物治疗的：
1)受试者出现无法耐受的毒性，研究者认为继续接受研究药物治疗风险大于获益；
2)影像学评估的疾病进展；
3)临床评估的疾病进展或出现重大方案违背，或受试者依从性差，经研究者判定认为继续接受研究药物治疗无法获益；
4)受试者妊娠；
5)死亡；
6)满足退出研究标准中的任意一项。
所有退出治疗的受试者需继续按照研究计划进行后续的随访，除外停止治疗 的原因为死亡，或满足下述任一项退出研究标准的受试者。
受试者有权在任何时间以任何原因退出研究。出现下列任一情况，受试者将退出研究流程：
1)失访；
2)受试者撤回知情同意或受试者或家属要求退出试验；
3)研究终止；
4)其他。
三、研究结果
对于既往接受过蒽环类和紫杉类治疗失败或复发的晚期乳腺癌亟待探索新的治疗。
本发明的研究表明，至少在可评估病例20例中，PR 6例(1例经过7周期治疗，3例经过6周期治疗，1例经过5周期治疗，1例经过4周期治疗)，SD 8例(2例经过6周期治疗，2例经过5周期治疗，1例经过4周期治疗，1例经过3周期治疗，2例经过2周期治疗)。ORR 30％(6/20),DCR 70％(14/20)。
米托蒽醌脂质体对乳腺癌患者，特别是既往接受过蒽环类和紫杉类治疗失败或复发的晚期乳腺癌患者有良好疗效。对评价为PR和SD的14例受试者继续用药，获得了更好的疗效。
发明人既往的临床研究中纳入盐酸米托蒽醌单药治疗复发/转移乳腺癌，试验组和对照组各30例，试验组给予盐酸米托蒽醌脂质体注射液20mg/m 2，每4周为一个周期。对照组给予盐酸米托蒽醌注射液14mg/m 2，每4周为一个周期。结果：试验组PR 4例，SD 11例，ORR13.3％(4/30),DCR 50％(15/30)；对照组PR 2例，SD 7例，ORR为6.7％(2/30)，DCR为30％(9/30)。
本发明的发明人使用米托蒽醌脂质体，药物通过静脉输注进入人体后有缓释、靶向、减毒、增效的作用，不仅剂量高于普通注射剂，且为单药治疗，既可以提高有效性，同时降低不良反应发生几率。
实施例3 盐酸米托蒽醌脂质体注射液治疗至少一线治疗失败的晚期骨与软组织肉瘤的Ib期临床试验
这是一项开放、多中心的Ib期研究，纳入的受试者将接受盐酸米托蒽醌脂质体注射液治疗，旨在评价盐酸米托蒽醌脂质体注射液对既往至少一线治疗失败的转移或不可切除的骨与软组织肉瘤的安全性和有效性。
一、试验设计
1.试验流程
研究包括筛选期、治疗期和随访期。
筛选期为28天，筛选合格受试者进入治疗期。治疗期受试者接受盐酸米托蒽醌脂质体注射液20mg/m 2第1天治疗，3周为一个治疗周期(q3w)，共6周期。对于已完成6周期治疗的受试者，根据受试者的风险和获益，由研究者与申办者共同讨论后确定是否继续用药。随访期需进行末次给药后的安全性随访(末次给药后28±7天)和生存随访(末次给药后每6周进行一次)。
从首次给药至末次给药后28天进行安全性评价，每周期给药前需进行安全性评价，以决定下一周期是否给药，整个研究期间根据RESIST1.1标准进行肿瘤评价，治疗期每两个周期进行一次，随访期每6周进行一次,直至疾病进展、死亡或者接受新的抗肿瘤治疗。
2.研究持续时间
本研究包括筛选期4周(28天)，治疗期6个周期(18周)，末次安全随访，给药结束后4周(28天)，随后每6周进行一次生存随访，每位患者持续时间约12个月。
本研究入组不少于50例受试者，本研究整个周期24～36个月。
二、试验人群：
符合下列全部入选标准并且没有任一排除标准的受试者才可入选本项临床研究。
(一)入选标准：
受试者必须符合以下所有标准：
1)受试者自愿参加研究，并签署知情同意书；
2)年龄≥18周岁，男女不限；
3)经病理组织学确诊的，骨肉瘤或非特指型软组织肉瘤(软组织肉瘤类型中不包括：化疗高度敏感肉瘤如胚胎性/腺泡性横纹肌肉瘤、尤文肉瘤，化疗极不敏感的肉瘤如腺泡状软组织肉瘤、骨外粘液性软骨肉瘤，需要特殊处理的肉瘤如胃肠道间质瘤、侵袭性纤维瘤病等)；
4)既往至少经一线治疗失败的转移或不可切除的骨肉瘤或软组织肉瘤；
5)基线至少存在一处符合RECIST 1.1定义的可测量病灶；
6)ECOG评分0～1；
7)实验室检查数值必须符合以下标准：
·中性粒细胞绝对值(ANC)≥2.0x10 9/L(实验室检查前1周内，未接受G-CSF升白治疗)；
·血红蛋白(Hb)≥110g/L(实验室检查前1周内，未接受输注红细胞治疗)；
·血小板≥100x 10 9/L(实验室检查前1周内，未接受输注血小板治疗)；
·肌酐≤1.5x ULN；
·总胆红素≤1.5x正常值上限(ULN)(合并肝转移受试者，≤3.0x ULN)；
·丙氨酸氨基转移酶(AST)/天冬氨酸氨基转移酶(ALT)≤3.0x ULN(合并肝转移受试者，≤5.0x ULN)；
·凝血功能：凝血酶原时间(PT)、国际标准化比值(INR)≤1.5x ULN(对于接受华法林等抗凝治疗药物允许INR≤3)
8)女性受试者尿或血HCG阴性(绝经和子宫切除除外)；
9)受试者及其伴侣同意在试验期间和末次用药结束后6个月内采取有效的避孕措施(例如：联合激素(含雌激素和孕激素)结合抑制排卵、孕激素避孕结合 抑制排卵、宫内节育器、宫内激素释放系统、双侧输卵管结扎术、输精管结扎术、避免性行为等)；
(二)排除标准：
符合以下任一标准的受试者均将从本试验中排除：
1)对米托蒽醌或脂质体类药物严重过敏；
2)脑或脑膜转移；
3)既往异体器官移植或异体骨髓移植；
4)预计生存时间＜12周；
5)慢性乙型肝炎(HbsAg或HBcAb阳性且HBV DNA≥1000IU/mL)、丙型肝炎(HCV抗体阳性且HCV RNA定量检测高于研究中心检测值下限)、HIV抗体阳性；
6)存在既往抗肿瘤治疗毒性＞1级(脱发、色素沉着或研究中认为对受试者无安全性风险的其他毒性除外)；
7)首次给药前1周内患有需要全身治疗的活动性细菌感染、真菌感染、病毒感染；
8)首次给药前4周内接受过局部或全身抗肿瘤治疗(中药或中成药为给药前2周)；
9)首次给药前4周内接受过其他临床试验用药品治疗；
10)既往6个月内出现严重血栓形成，包括肺栓塞、内脏栓塞、深静脉血栓等；
11)既往3年内患有其他恶性活动性肿瘤，已治愈的局部可治性癌症除外，例如基底或鳞状细胞皮肤癌、浅表膀胱癌或原位前列腺、宫颈或乳腺癌；
12)心脏功能异常，包括：
·长QTc综合征或QTc间期>480ms；
·完全性左束支传导阻滞，II度或III度房室传导阻滞(经起搏器植入术治疗 后除外)；
·需要药物治疗的严重、未控制的心律失常；
·慢性充血性心力衰竭病史，且NYHA≥3级；
·既往6个月内左室射血分数低于50％；
·CTCAE≥3级的心脏瓣膜病；
·不可控的高血压(定义为在药物控制情况下，多次测量收缩压≥160mmHg或舒张压≥100mmHg)；
·在筛选前6个月内出现心肌梗死、不稳定心绞痛、严重的心包疾病病史、有急性缺血性或严重的活动性传导系异常的心电图证据。
13)曾接受过阿霉素或其他蒽环类治疗，且阿霉素累积剂量超过400mg/m 2(蒽环类等效剂量计算：1mg阿霉素＝2mg表柔比星＝2mg柔红霉素＝0.5mg去甲氧柔红霉素＝0.45mg米托蒽醌)；阿霉素脂质体累积剂量超过900mg/m 2；
14)怀孕或哺乳期妇女；
15)患有任何严重的和/或不可控制的疾病，经研究者判定，可能影响参加本研究的其他疾病(包括但不限于，未得到有效控制的糖尿病、需要透析的肾脏疾病、严重的肝脏疾病、危及生命的自身免疫系统疾病和出血性疾病、药物滥用、神经系统疾病等)；
16)其他研究者判定不适宜参加的情况。
(三)退出治疗及研究标准
受试者在研究过程中出现以下任一情况是必须停止继续接受试验用药品治疗的：
1)受试者出现无法耐受的毒性，研究者认为继续接受试验用药品治疗风险大于获益；
2)治疗期间出现的合并疾病不允许后续继续给药；
3)影像学评估的疾病进展；
4)临床评估的疾病进展或出现重大方案违背，或受试者依从性差，经研究者判定认为继续接受试验用药品治疗无法获益；
5)受试者妊娠；
6)死亡；
7)满足退出研究标准中的任何一项。
所有退出治疗的受试者需继续按照研究计划进行后续的随访，除外停止治疗的原因为死亡，或满足下列任一项退出研究标准的受试者。
受试者有权在任何时间以任何原因退出研究。出现下列任一情况，受试者将退出研究流程：
1)失访；
2)受试者或家属要求退出试验；
3)研究终止；
4)其他。
三、研究结果
对于无手术根治机会或转移性骨与软组织肉瘤受试者，经一线标准治疗后，二线治疗药物疗效欠佳，因此改善治疗一直是临床棘手的问题，亟待探索新的治疗。米托蒽醌脂质体在爬坡研究(HE071-01)中，12mg/m 2和14mg/m 2组晚期软组织肉瘤受试者已经显示出一定疗效。本发明的发明人使用米托蒽醌脂质体，药物通过静脉输注进入人体后有缓释、靶向、减毒、增效的作用，不仅剂量高于普通注射剂，且为单药治疗，既可以提高有效性，同时降低不良反应发生几率。
本发明的研究表明，在可评价受试者中，骨肉瘤3例受试者(2例接受2周期治疗，1例接受1周期治疗)中，1例受试者评价为SD(接受1周期治疗)，DCR 33.3％(1/3)。
在软组织肉瘤中，12例受试者(1例治疗6周期，2例治疗5周期，2例治疗4周期，1例治疗3周期，6例治疗2周期)中，8例受试者评价为SD(1例治疗6周期，2 例治疗5周期，2例治疗4周期，1例治疗3周期，2例治疗2周期；其中3例受试者肿瘤体积有所减小)，DCR 66.7％(8/12)。
米托蒽醌脂质体对骨肉瘤和软组织肉瘤患者，有良好疗效。评价为SD的9例受试者继续用药，获得了更好的疗效。
以上对本发明技术方案的实施方式进行了示例性的说明。应当理解，本发明的保护范围不拘囿于上述实施方式。凡在本发明的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。

Claims (10)

  1. 盐酸米托蒽醌脂质体在制备用于治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤的药物中的用途。
  2. 盐酸米托蒽醌脂质体作为唯一活性成分在制备用于治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤的药物中的用途。
  3. 如权利要求1或2所述的用途，其特征在于，所述尿路上皮癌为局部晚期或转移性尿路上皮癌；更优选地，所述尿路上皮癌为经含铂化疗方案和/或PD-1抑制剂治疗失败的局部晚期或转移性尿路上皮癌，或者，经含铂化疗方案治疗失败，但拒绝接受PD-1抑制剂治疗的局部晚期或转移性尿路上皮癌，或者，对顺铂不耐受的局部晚期或转移性尿路上皮癌；
    优选地，所述乳腺癌为HER-2阴性乳腺癌；更优选地，所述乳腺癌为局部晚期或复发/转移性的HER-2阴性乳腺癌，或者，激素受体阴性的HER-2阴性乳腺癌，或者激素受体阳性但不适合内分泌治疗或内分泌治疗耐药的HER-2阴性乳腺癌，或者，蒽环类和/或紫杉类药物治疗失败的HER-2阴性乳腺癌；优选地，所述HER-2阴性乳腺癌包括免疫组化HER-2 0或1+，免疫组化HER-2 2+需经原位杂交法证实为阴性的乳腺癌；
    优选地，所述骨与软组织肉瘤为晚期骨与软组织肉瘤，进一步优选至少经一线治疗失败的转移性或局部晚期的骨与软组织肉瘤。
  4. 如权利要求1或2所述的用途，其特征在于，所述药物为注射剂型，包括液体注射剂、注射用粉剂、注射用片剂等等；
    优选地，所述药物为液体注射剂；
    优选地，以米托蒽醌计，所述药物含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
  5. 一种治疗尿路上皮癌的方法，所述方法为给予尿路上皮癌患者治疗有效量的盐酸米托蒽醌脂质体；优选的，所述尿路上皮癌为局部晚期或转移性尿路 上皮癌，更优选地所述尿路上皮癌为经含铂化疗方案和/或PD-1抑制剂治疗失败的局部晚期或转移性尿路上皮癌，或者，经含铂化疗方案治疗失败，但拒绝接受PD-1抑制剂治疗的局部晚期或转移性尿路上皮癌，或者，对顺铂不耐受的局部晚期或转移性尿路上皮癌。
  6. 一种治疗乳腺癌的方法，所述方法为给予乳腺癌患者治疗有效量的盐酸米托蒽醌脂质体；优选地，所述乳腺癌为HER-2阴性乳腺癌；更优选的，所述乳腺癌为局部晚期或复发/转移性的HER-2阴性乳腺癌，或者，激素受体阴性的HER-2阴性乳腺癌，或者激素受体阳性但不适合内分泌治疗或内分泌治疗耐药的HER-2阴性乳腺癌；或者，蒽环类和/或紫杉类药物治疗失败的HER-2阴性乳腺癌；优选地，所述HER-2阴性乳腺癌包括免疫组化HER-2 0或1+，免疫组化HER-2 2+需经原位杂交法证实为阴性的乳腺癌。
  7. 一种治疗骨与软组织肉瘤的方法，所述方法为给予骨与软组织肉瘤患者治疗有效量的盐酸米托蒽醌脂质体；优选的，所述骨与软组织肉瘤为晚期骨与软组织肉瘤，进一步优选至少经一线治疗失败的转移性或局部晚期的骨与软组织肉瘤。
  8. 如权利要求5-7中任一项所述的方法，其特征在于所述的给予方式为静脉给药；优选的，每次静脉给药，所述脂质体药物制剂的滴注给药时间为30min-120min，优选60min-120min，进一步优选60±15min；
    优选地，所述给药周期为每4周或3周给药一次，优选每3周给药一次；
    优选地，以米托蒽醌计，所述治疗有效量为8-30mg/m 2，优选为12-20mg/m 2，更优选20mg/m 2。
  9. 一种盐酸米托蒽醌脂质体，其用于治疗尿路上皮癌、乳腺癌、骨与软组织肉瘤，其特征在于：给予尿路上皮癌、乳腺癌、骨与软组织肉瘤患者治疗有效量的盐酸米托蒽醌脂质体；以米托蒽醌计，所述治疗有效量为8-30mg/m 2，优选为12-20mg/m 2，更优选20mg/m 2；
    优选地，所述的给予方式为静脉给药；优选的，每次静脉给药，所述脂质 体药物制剂的滴注给药时间为30min-120min，优选60min-120min，进一步优选60±15min；
    优选地，所述给药周期为每4周或3周给药一次，优选每3周给药一次。
  10. 权利要求1-9中任一项所述的用途、方法或脂质体，其特征在于，所述盐酸米托蒽醌脂质体具有以下一项或多项性质：(i)盐酸米托蒽醌脂质体的粒径为约30-80nm，例如约35-75nm、约40-70nm、约40-60nm或约60nm；
    (ii)盐酸米托蒽醌与脂质体内的多价反离子(例如硫酸根、柠檬酸根或磷酸根)形成难以溶解的沉淀；
    (iii)盐酸米托蒽醌脂质体中的磷脂双分子层含有相转变温度(Tm)高于体温的磷脂，从而脂质体的相转变温度高于体温，例如，所述磷脂选自氢化大豆卵磷脂、磷脂酰胆碱、氢化蛋黄卵磷脂、双软脂酸卵磷脂、双硬脂酸卵磷脂或者以上的任何组合；
    (iv)盐酸米托蒽醌脂质体中的磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺(DSPE-PEG2000)；
    (iiv)盐酸米托蒽醌脂质体中的磷脂双分子层含有质量比为约3:1:1的氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，盐酸米托蒽醌与脂质体内的多价酸根离子形成难以溶解的沉淀，并且所述盐酸米托蒽醌脂质体在所述药物中的粒径为约60nm；
    优选地，所述盐酸米托蒽醌脂质体的粒径为约30-80nm，其含有：1)活性成分米托蒽醌，它可以和脂质体内的多价反离子形成难以溶解的沉淀，2)磷脂双分子层含有相转变温度(Tm)高于体温的磷脂；所述Tm高于体温的磷脂为磷脂酰胆碱、氢化大豆卵磷脂、氢化蛋黄卵磷脂、双软脂酸卵磷脂或双硬脂酸卵磷脂或者其任何组合；
    优选地，所述盐酸米托蒽醌脂质体的粒径为约35-75nm，优选40-70nm，进一步优选40-60nm，特别优选60nm；
    或优选地，所述磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000 修饰的二硬脂酰磷脂酰乙醇胺，质量比为3:1:1，所述粒径为约60nm，所述反离子为硫酸根离子；
    或优选地，所述脂质体的磷脂双分子层含有氢化大豆卵磷脂、胆固醇和聚乙二醇2000修饰的二硬脂酰磷脂酰乙醇胺，质量比为3:1:1，所述粒径为约40-60nm，所述反离子为硫酸根离子，脂质体中HSPC：Chol：DSPE-PEG2000：米托蒽醌的重量比为9.58:3.19:3.19:1。
PCT/CN2022/086959 2021-04-16 2022-04-15 盐酸米托蒽醌脂质体的用途 WO2022218393A1 (zh)

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