WO2021180184A1 - Utilisation de liposomes de chlorhydrate de mitoxantrone - Google Patents

Utilisation de liposomes de chlorhydrate de mitoxantrone Download PDF

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Publication number
WO2021180184A1
WO2021180184A1 PCT/CN2021/080282 CN2021080282W WO2021180184A1 WO 2021180184 A1 WO2021180184 A1 WO 2021180184A1 CN 2021080282 W CN2021080282 W CN 2021080282W WO 2021180184 A1 WO2021180184 A1 WO 2021180184A1
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mitoxantrone
liposome
liver cancer
liposomes
particle size
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PCT/CN2021/080282
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English (en)
Chinese (zh)
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李春雷
张熙
林红梅
李桂霞
李萌萌
王凤霞
王世霞
金鑫
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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 CN202180020059.5A priority Critical patent/CN115279344A/zh
Publication of WO2021180184A1 publication Critical patent/WO2021180184A1/fr

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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
    • 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

Definitions

  • the invention belongs to the technical field of anti-tumor drugs, and specifically relates to the use of mitoxantrone hydrochloride liposomes in the preparation of drugs for treating hepatocellular carcinoma, especially advanced hepatocellular carcinoma.
  • HCC Hepatocellular carcinoma
  • liver cancer is the main pathological type, accounting for about 90%.
  • the progression of hepatitis B or C virus infection to liver cirrhosis and further progression to liver cancer is considered to be a trilogy of liver cancer progression.
  • my country is a major country with hepatitis B and a high incidence of liver cancer. In 2015, the incidence of HCC in my country ranked first in the world.
  • the staging of liver cancer is mainly based on the Barcelona staging system.
  • the five stages of the system are 0 (very early stage), A (early stage), B (middle stage), C (late stage), and D (terminal stage).
  • Stage 0 or A can choose surgical resection, local ablation or liver transplantation.
  • Stage B tumors are confined to the liver, and hepatic artery chemoembolization (TACE) therapy can be selected.
  • TACE hepatic artery chemoembolization
  • more than 80% of patients were found to be at an advanced stage and lost the opportunity for local treatment, and the 5-year survival rate was only 18%.
  • systemic treatment is generally chosen for patients who progress or do not meet the conditions of local treatment.
  • Mitoxantrone hydrochloride is an anthraquinone antitumor drug.
  • the FDA-approved indications are multiple sclerosis, prostate cancer and acute myeloid leukemia. Clinical studies have shown that it is effective for malignant lymphoma, breast cancer and acute myeloid leukemia, lung cancer, melanoma, soft tissue sarcoma, multiple myeloma, and liver cancer.
  • Colorectal cancer, kidney cancer, prostate cancer, endometrial cancer, testicular cancer, ovarian cancer and head and neck cancer have certain curative effects.
  • Liposomes are a new form of drug delivery. Studies have shown that it can change the distribution of encapsulated drugs in the body, so that the drugs are mainly accumulated in tissues and organs such as liver, spleen, lung and bone marrow, thereby increasing the therapeutic index of the drug, reducing the therapeutic dose of the drug and reducing the toxicity of the drug. These characteristics make the application of liposome-loaded drugs in the research of anti-tumor drugs more and more important. Some researchers have conducted research on mitoxantrone liposome preparations.
  • the Chinese patent application 200610102339.8 filed on December 29, 2006 and the PCT application WO2008/080367A1 filed on December 29, 2007, disclose a mitoxantrone liposome, the disclosure of which is hereby incorporated in its entirety as refer to.
  • Mitoxantrone liposomes seem to provide a potential therapeutic method for the treatment of liver cancer, especially advanced liver cancer.
  • Mitoxantrone is mainly metabolized in the liver, and has serious bone marrow suppression toxicity, which causes leukopenia and thrombocytopenia in a dose-dependent manner. Mitoxantrone liposomes further accumulate the drug in the liver, spleen, and bone marrow. Whether this drug aggregation phenomenon will increase the metabolic burden of the liver, spleen, and bone marrow, aggravate the adverse drug reactions, and affect the efficacy of the drugs is a problem that needs to be solved urgently.
  • Doxil doxorubicin hydrochloride liposome
  • ovarian cancer the recommended dose is 50mg/m 2 , intravenously administered once every 4 weeks;
  • Kaposi's sarcoma the recommended dose is 20 mg/m 2 , intravenously administered once every 3 weeks;
  • multiple myeloma the recommended dose is 30 mg/m 2 , intravenously administered on the fourth day after the administration of bortezomib .
  • Abraxane paclitaxel for injection [albumin-binding type]
  • Metastatic breast cancer the recommended dose of 260mg/m 2 , intravenous drip 30 minutes, once every 3 weeks
  • non-small cell lung cancer the recommended dose of 100mg/m 2 , intravenous drip for 30 minutes, a course of treatment every 21 days, respectively on the first day, the eighth day and the 15th day Medicine; on the first day, paclitaxel for injection (albumin-binding) is administered immediately after administration, once every 21 days
  • Pancreatic cancer the recommended dose is 125mg/m 2 , intravenous drip for 30-40 minutes , Take 28 days as a cycle, and administer once on the first, eighth, and fifteenth days.
  • Paclitaxel for injection (albumin-bound type) will be given gemcitabine immediately after each administration.
  • Another example is AmBisome (Amphotericin B liposomes for injection).
  • the starting doses for the following indications are: (1) Empirical treatment: recommended dose 3mg/kg/day; (2) systemic fungal infection (Aspergillus, Candida, Cryptococcus): the recommended dose is 3 ⁇ 5mg/kg/day; (3) Cryptococcal meningitis in HIV-infected persons: the recommended dose is 6mg/kg/day (days 1-5), 3mg/kg/day (Day 4, 21); Patients with visceral leishmaniasis with low immune function: 4mg/kg/day (days 1-5), 4mg/kg/day (days 10, 17, 24, 31, 38) .
  • the dosage and dosing data are 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 has previous experience in combination therapy for liver cancer, it is difficult to provide a reliable reference for the safety and efficacy of mitoxantrone alone due to its poor effectiveness due to dosage and other reasons.
  • the inventors have carried out exploratory research on mitoxantrone liposomes in solid tumors and lymphomas in the early stage, hepatocellular carcinoma is different from other solid tumors.
  • Mitoxantrone drugs are mainly metabolized by the liver, and the liposomes carry The drug will further accumulate the drug in the liver, spleen, and bone marrow, which will lead to a significant increase in the metabolic load of the liver, spleen, and bone marrow with impaired functions.
  • mitoxantrone liposomes a special dosage form that is different from ordinary injections, its absorption, distribution, and metabolism after entering the body are very complicated. It is suitable for the treatment of different indications, especially in the treatment of different tumors. It is difficult to simply deduce from one indication to another. Therefore, it is necessary to conduct a systematic study on whether mitoxantrone liposomes are suitable for the treatment of liver cancer, especially advanced liver cancer, to clarify its safe and effective dosage, and to provide a reference for clinical treatment.
  • the invention provides the use of mitoxantrone hydrochloride liposomes in the preparation of drugs for treating liver cancer.
  • the liver cancer is advanced liver cancer, or liver cancer that has failed or is intolerant to first-line and/or second-line drug treatment.
  • the mitoxantrone hydrochloride liposome is used as the sole active ingredient to prepare a medicine for treating liver cancer.
  • the medicine is in the form of injection, including liquid injection, powder for injection, tablet for injection, and the like.
  • the drug is a liquid injection, based on mitoxantrone
  • the drug contains an active ingredient of 0.5-5 mg/ml, preferably 1-2 mg/ml, more preferably 1 mg/ml.
  • the present invention also provides a method for treating liver cancer, which includes the following steps: administering a therapeutically effective amount of mitoxantrone hydrochloride liposomes to patients with liver cancer.
  • the therapeutically effective amount refers to 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 total dose (calculated as mitoxantrone) of the liposome administered to each patient does not exceed 200 mg/m 2 , preferably does not exceed 160 mg/m 2 , further preferably does not exceed 140 mg/m 2 , and more It is preferably not more than 120 mg/m 2 .
  • the administration mode of the present invention is intravenous administration.
  • the administration cycle is once every 4 weeks.
  • the instillation administration time of the liposome pharmaceutical preparation is 30 min-120 min, preferably 60 min-120 min, more preferably 90 ⁇ 15 min.
  • the present invention also provides a mitoxantrone hydrochloride liposome, which is used to treat liver cancer in patients.
  • the liver cancer is advanced liver cancer, or liver cancer that has failed or is intolerant to first-line and/or second-line drug treatment.
  • the liposome is in the form of injection, including liquid injection, powder for injection, tablet for injection, and the like.
  • the drug is a liquid injection, based on mitoxantrone
  • the liposome contains the active ingredient (calculated as mitoxantrone) 0.5-5 mg/ml, preferably 1-2 mg/ml, more preferably 1 mg/ml .
  • the liposomes are used alone to treat liver cancer in patients.
  • the therapeutically effective amount of the liposome (calculated as 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 liposome is administered intravenously.
  • the administration cycle is once every 4 weeks.
  • the infusion time of the liposome is 30 min-120 min, preferably 60 min-120 min, and more preferably 90 ⁇ 15 min.
  • the total dose of mitoxantrone received by the patient does not exceed 200 mg/m 2 , preferably does not exceed 160 mg/m 2 , further preferably does not exceed 140 mg/m 2 , and more preferably does not exceed 120 mg/m 2 .
  • the “total administered dose of mitoxantrone” or “total administered dose (in terms of mitoxantrone)” refers to all mitoxantrone drugs received by the patient, including the The invented mitoxantrone hydrochloride liposomes, mitoxantrone hydrochloride injection and other mitoxantrone preparations are the sum of the doses of mitoxantrone.
  • the dosage is calculated as mitoxantrone.
  • the mitoxantrone hydrochloride liposomes can be prepared by conventional methods in the art, and can be mitoxantrone hydrochloride liposomes prepared by any method disclosed in the prior art, for example, WO2008 /080367 Prepared by the method disclosed in A1, the content of the patent disclosure is incorporated herein by reference in its entirety.
  • the mitoxantrone hydrochloride liposome has a particle size of about 30-80nm and contains: 1) the active ingredient mitoxantrone, which can form with multivalent counter ions in the liposome The precipitate that is difficult to dissolve, 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 higher than body temperature is phosphatidylcholine, hydrogenated soy lecithin, hydrogenated egg yolk lecithin, distearic acid lecithin, distearic acid lecithin, or any combination thereof, and the particle size is about 35- 75nm, preferably about 40-70nm, more preferably about 40-60nm, particularly preferably about 60nm.
  • the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol, and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine, the mass ratio is 3:1:1, the particle size is about 60nm, and the counterion For 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 40-60 nm, 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.
  • the preparation method of the mitoxantrone hydrochloride liposome is as follows: HSPC (hydrogenated soy lecithin), Chol (cholesterol) and DSPE-PEG2000 (polyethylene glycol 2000 modified distearyl Acylphosphatidylethanolamine) is weighed at a mass ratio of 3:1:1 and dissolved in 95% ethanol to obtain a clear solution (ie, an ethanol solution of phospholipids). The ethanol solution of phospholipids was mixed with 300 mM ammonium sulfate solution, and the mixture was shaken and hydrated at 60-65° C. for 1 hour to obtain heterogeneous multilamellar liposomes.
  • HSPC hydrogenated soy lecithin
  • Chol cholesterol
  • DSPE-PEG2000 polyethylene glycol 2000 modified distearyl Acylphosphatidylethanolamine
  • a microfluidic device was used to reduce the particle size of the liposomes. After the obtained sample was diluted 200 times with NaCl solution with a concentration of 0.9%, it was detected with NanoZS. The average particle size of the particles was about 60nm, and the main peak was concentrated between 40-60nm. Afterwards, an ultrafiltration device was used to remove the ammonium sulfate in the outer phase of the blank liposome, 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 the blank liposomes, and the drug was loaded at 60-65°C. After incubating for about 1 hour, gel exclusion chromatography can prove that the encapsulation efficiency is about 100%.
  • the product obtained from this prescription was named PLM 60.
  • 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.
  • the first-line and second-line drugs for the treatment of liver cancer refer to the first-line and second-line drugs approved by the drug administration of China or foreign countries (such as the United States, the European Union, Japan, South Korea, etc.) for the treatment of liver cancer, including but Not limited to: FDA-approved first-line molecular targeted drugs for the treatment of advanced HCC, sorafenib, lenvatinib, etc., second-line drugs PD-1 inhibitors, regofini, etc.
  • the animal test results of the present invention show that the mitoxantrone hydrochloride liposome can effectively treat liver cancer, and has better curative effect and lower toxicity than ordinary mitoxantrone hydrochloride injection.
  • Preliminary clinical research results show that mitoxantrone hydrochloride liposomes can effectively treat advanced liver cancer, and the doses of 12mg/m 2 and 16mg/m 2 are safe and well tolerated.
  • Example 1 The inhibitory effect of mitoxantrone hydrochloride liposomes on H22 solid tumors
  • sorafenib the first-line treatment drug for advanced HCC approved by the FDA is sorafenib, so in Examples 2 and 3 of the present invention, sorafenib tosylate is used as a positive control drug.
  • Test animals female NU/NU mice, provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., animal certificate number 1100111911079092.
  • NU/NU mice were subcutaneously inoculated with human liver cancer BEL-7402 cells to construct a xenograft tumor model. After the animals are inoculated with tumor cells, they are administered in groups after the tumor grows to about 100-200 mm 3. During the experiment, the animal body weight and tumor volume were monitored twice a week, and the tumor volume (TV), relative tumor volume (RTV), and relative tumor volume growth rate (T/C) values were calculated. After the experiment, the tumor weight was weighed and the tumor weight was calculated. Inhibition rate.
  • TV tumor volume
  • RV relative tumor volume
  • T/C relative tumor volume growth rate
  • Tumor volume (TV) 1/2 ⁇ a ⁇ b 2 , where a and b represent the length and short diameter of the tumor respectively.
  • RTV TV t /TV 0 .
  • TV 0 is the tumor volume measured when the drug is divided into cages (that is, D 0 ), and TV t is the tumor volume at each measurement.
  • T/C(%) (TRTV/CRTV) ⁇ 100% (TRTV: RTV of the administration group; CRTV: RTV of the solvent control group).
  • Tumor weight inhibition rate (%) (1-tumor weight in the administration group/tumor weight in the solvent control group) ⁇ 100%.
  • Mit-lipo mitoxantrone hydrochloride liposome (PLM60)
  • Sorafenib Sorafenib tosylate
  • Mit-lipo is diluted with 5% dextrose injection (5% INJ GS) to a suitable concentration
  • Sorafenib is dissolved in a mixture of castor oil and absolute ethanol (volume ratio is 1:1)
  • vortexed and ultrasonicated to a uniform solution
  • ultrapure water castor oil: absolute ethanol: ultrapure water volume ratio 1:1:6
  • D0 day of administration
  • D16 16 days after administration
  • RTV relative tumor volume
  • T/C% relative tumor volume growth rate.
  • Example 3 The inhibitory effect of mitoxantrone hydrochloride liposomes on human liver cancer SMMC-7721 transplanted tumor
  • Test animals female NU/NU mice, provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., animal certificate number 1100112011003025.
  • Test drugs Mit-lipo (mitoxantrone hydrochloride liposome (PLM60)), Sorafenib (sorafenib tosylate). Mit-lipo is diluted with 5% dextrose injection (5% INJ GS) to a suitable concentration, Sorafenib is dissolved in a mixture of castor oil and absolute ethanol (volume ratio is 1:1), vortexed and ultrasonicated to a uniform solution, and then Add ultrapure water (castor oil: absolute ethanol: ultrapure water volume ratio 1:1:6), and dilute to a suitable concentration.
  • PLM60 mitoxantrone hydrochloride liposome
  • Sorafenib sorafenib tosylate.
  • Mit-lipo is diluted with 5% dextrose injection (5% INJ GS) to a suitable concentration
  • Sorafenib is dissolved in a mixture of castor oil and absolute ethanol (volume ratio is 1:1)
  • NU/NU mice were subcutaneously inoculated with human liver cancer SMMC-7721 cells to construct a xenograft tumor model. After the animals are inoculated with tumor cells, they are administered in groups after the tumor grows to about 100-200 mm 3. During the experiment, the animal body weight and tumor volume were monitored twice a week, and the tumor volume (TV), relative tumor volume (RTV), and relative tumor volume growth rate (T/C) values were calculated. After the experiment, the tumor weight was weighed and the tumor weight was calculated. Inhibition rate.
  • TV tumor volume
  • RV relative tumor volume
  • T/C relative tumor volume growth rate
  • Tumor volume (TV) 1/2 ⁇ a ⁇ b 2 , where a and b represent the length and short diameter of the tumor respectively.
  • RTV TV t /TV 0 .
  • TV 0 is the tumor volume measured when the drug is divided into cages (that is, D 0 ), and TV t is the tumor volume at each measurement.
  • T/C(%) (TRTV/CRTV) ⁇ 100% (TRTV: RTV of the administration group; CRTV: RTV of the solvent control group).
  • Tumor weight inhibition rate (%) (1-tumor weight in the administration group/tumor weight in the solvent control group) ⁇ 100%.
  • the tumor weight inhibition rates in the Mit-lipo 15, 10, 5 mg/kg and Sorafenib 30 mg/kg groups were 77.7%, 59.6%, 48.0%, and 51.2%, respectively.
  • a single intravenous administration of Mit-lipo 15, 10, and 5 mg/kg can significantly reduce the tumor weight of the transplanted tumor (P ⁇ 0.01).
  • the specific results are shown in Table 5.
  • This study is a dose-escalation phase study.
  • the main purpose is to determine the MTD (maximum tolerated dose) or RP2D (recommended dose for phase 2 study) of Mitoxantrone Hydrochloride Liposome Injection.
  • Approximately 10-18 subjects will be included in this phase.
  • Subjects will receive drug treatment on the first day of each cycle, one treatment cycle every 4 weeks, and administration on the first day of each cycle until the subject’s disease progresses, Untolerable toxicity, completion of 6 treatment cycles, withdrawal of informed consent, death, or the investigator's decision to withdraw from the study (whichever occurs first), for subjects who have completed 6 treatment cycles If the treatment is still beneficial and tolerable, the investigator and the sponsor can determine whether the treatment can be continued.
  • test procedure for each subject is arranged as follows: a 4-week screening period, a total of 4 weeks of DLT (dose limiting toxicity) observation period after the first administration, extended administration period and follow-up period.
  • DLT dose limiting toxicity
  • the subjects who meet the selection criteria will enter different dose groups from low to high in the order of entry, and receive mitoxantrone hydrochloride liposome injections Liquid treatment. All subjects collected PK (pharmacokinetics) blood samples at different time points before and after the administration according to the protocol, and completed the relevant inspections stipulated in the protocol during the entire trial period of the treatment period to observe safety and tolerability.
  • PK pharmacokinetics
  • the dose climbing is carried out according to the 3+3 principle, while taking into account the exposure of patients to lower ineffective doses as much as possible, the 12mg/m 2 group is included in 1 Three subjects were included in each of the remaining two dose groups.
  • the subject can continue to be given the study drug treatment according to the established cycle, and the dose and the first The dosage is the same for 1 cycle.
  • PD disease progression
  • 6 treatment cycles are completed, death, intolerable toxicity, completion of the scheduled treatment cycle, the investigator's decision or the subject voluntarily withdraws from the treatment (whichever occurs first), for the completion of 6
  • Subjects who are administered for one treatment cycle, if the treatment is still beneficial and tolerable, can be determined by the investigator and the sponsor after discussing whether the treatment can be continued.
  • the dosing period at least once every 2 weeks for safety follow-up (at least weekly blood test), at the end of the second cycle, the end of the fourth cycle and every 8 weeks (every two cycles) after the tumor efficacy evaluation (such as The tumor-related symptoms are aggravated, and the investigator considers it necessary to shorten the time for tumor evaluation).
  • the expected survival period is ⁇ 12 weeks
  • Advanced hepatocellular carcinoma diagnosed by histopathology and/or cytology reaching locally advanced (unresectable) or distant metastasis, and at least one measurable focus without local treatment (defined according to the RECIST 1.1 standard );
  • Child-Pugh liver function classification Grade A or B ( ⁇ 7 points), total bilirubin ⁇ 1.5 times the upper limit of normal, albumin ⁇ 28g/L, Child-Pugh score of albumin and bilirubin Only one of the indicators can be worth 2 points;
  • Previous first-line and second-line systemic treatment failures are defined as: a) disease progression during treatment or after the last administration (according to the RECIST 1.1 version standard); b) intolerance to systemic anti-liver cancer treatment regimens.
  • Routine blood test white blood cell count ⁇ 3.0 ⁇ 10 9 /L, absolute neutrophil value ⁇ 1.5 ⁇ 10 9 /L (without G-CSF and other supportive treatment), platelet ⁇ 75 ⁇ 10 9 /L (without infusion Supportive therapy such as platelets or TPO), hemoglobin ⁇ 80g/L (no need for blood transfusion therapy or supportive therapy such as erythropoietin);
  • Coagulation function prothrombin time (PT) prolonged ⁇ 4s or activated partial thromboplastin time (APTT) ⁇ 1.5 times the upper limit of normal;
  • doxorubicin or other anthracycline therapy including local administration during interventional surgery, the total cumulative dose of doxorubicin>360mg/m 2 (conversion of other anthracycline drugs: 1mg doxorubicin equivalent In 2mg epirubicin);
  • the subject has received any targeted therapy (including sorafenib, lenvatinib, and regorafenib) or anti-liver cancer treatments within 2 weeks before the first administration of the study drug;
  • any targeted therapy including sorafenib, lenvatinib, and regorafenib
  • anti-liver cancer treatments within 2 weeks before the first administration of the study drug
  • Any local treatment including but not limited to percutaneous ethanol injection, radiofrequency or microwave or cryoablation, hepatic artery chemoembolization, hepatic artery perfusion, etc.) within 4 weeks before the first administration
  • the study drug has received blood transfusion, blood products (except plasma/human albumin used to control ascites, etc.) or drugs that stimulate blood cell production (such as granulocyte colony stimulating factor G-CSF) within 2 weeks before the first medication.
  • blood products except plasma/human albumin used to control ascites, etc.
  • drugs that stimulate blood cell production such as granulocyte colony stimulating factor G-CSF
  • the subject has known intrahepatic cholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma, liver cancer and fibrolamellar cell carcinoma caused by autoimmune hepatitis;
  • HCV Human immunodeficiency virus
  • HCV hepatitis C virus
  • Uncontrollable or serious heart and cardiovascular and cerebrovascular diseases including any of the following:
  • ⁇ High blood pressure that is difficult to control defined as multiple measurements of systolic blood pressure ⁇ 140mmHg or diastolic blood pressure ⁇ 90mmHg under drug control);
  • ⁇ Arterial or venous thrombosis or embolism events subjects with transient ischemic attack, lacunar infarction of no clinical significance can be included
  • deep vein thrombosis or pulmonary embolism occurred within 6 months before the start of study treatment .
  • subjects with known tumor thrombosis or deep vein thrombosis those who remain stable after anticoagulant treatment for ⁇ 4 weeks are eligible for inclusion;
  • the subject has a serious or uncontrolled systemic disease, which is not suitable for entry into this study or affects the compliance of the protocol, or significantly interferes with the correct evaluation of the safety, toxicity, and effectiveness of the study drug.
  • Subjects can withdraw from the study treatment and evaluation without any reason at any stage of the study. Subjects must withdraw if:
  • the clinical study enrolled a total of eight cases of hepatocellular carcinoma, wherein the 12mg / m 2 dose group 1 cases, 16mg / m 2 dose group 7 cases. All DLT observations have been completed so far, and no DLT incident has occurred. It shows that the mitoxantrone hydrochloride liposome injection is safe and well tolerated in the treatment of advanced liver cancer.
  • This plan will fill the gap in the third-line treatment of liver cancer, lay the foundation for the subsequent combination of drugs to impact the first-line and second-line treatments, change the traditional treatment model of liver cancer, that is, excessive dependence on TACE, and look forward to similar high-efficiency and low-toxic chemotherapeutics in the field of advanced solid tumors Applications.

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Abstract

Utilisation de liposomes de chlorhydrate de mitoxantrone dans la préparation d'un médicament pour le traitement d'un cancer du foie. Le cancer du foie est, de préférence, un cancer du foie avancé, et un cancer du foie sur lequel un traitement médicamenteux de première intention et/ou de seconde intention échoue ou conduit à une intolérance. L'invention concerne également un procédé de traitement d'un cancer du foie, le procédé consistant : à fournir une quantité thérapeutiquement efficace de liposomes de chlorhydrate de mitoxantrone à des patients atteints d'un cancer du foie. Les résultats d'essais chez l'animal indiquent que les liposomes de chlorhydrate de mitoxantrone présentent une meilleure efficacité et une moindre toxicité. Les résultats de recherches cliniques préliminaires indiquent que les liposomes de chlorhydrate de mitoxantrone peuvent traiter efficacement un cancer du foie avancé et offrent une bonne innocuité et une bonne tolérabilité.
PCT/CN2021/080282 2020-03-12 2021-03-11 Utilisation de liposomes de chlorhydrate de mitoxantrone WO2021180184A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024017293A1 (fr) * 2022-07-20 2024-01-25 石药集团中奇制药技术（石家庄）有限公司 Utilisation de liposome de chlorhydrate de mitoxantrone

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WO2024017293A1 (fr) * 2022-07-20 2024-01-25 石药集团中奇制药技术（石家庄）有限公司 Utilisation de liposome de chlorhydrate de mitoxantrone

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