WO2021208842A1 - 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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WO2021208842A1
WO2021208842A1 PCT/CN2021/086529 CN2021086529W WO2021208842A1 WO 2021208842 A1 WO2021208842 A1 WO 2021208842A1 CN 2021086529 W CN2021086529 W CN 2021086529W WO 2021208842 A1 WO2021208842 A1 WO 2021208842A1
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liposome
mitoxantrone
lung cancer
small cell
cell lung
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PCT/CN2021/086529
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English (en)
French (fr)
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李春雷
周艺
徐雯
闫玉茹
李永丰
毕宇鑫
王世霞
李晶晶
Original Assignee
石药集团中奇制药技术（石家庄）有限公司
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Priority to CN202180027421.1A priority Critical patent/CN115427020A/zh
Publication of WO2021208842A1 publication Critical patent/WO2021208842A1/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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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 field of anti-tumor drugs, and specifically relates to the use of mitoxantrone hydrochloride liposomes in the preparation of drugs for treating small cell lung cancer.
  • lung cancer is the number one malignant tumor with morbidity and mortality.
  • WHO World Health Organization
  • lung cancer is divided into different histological types such as adenocarcinoma, squamous cell carcinoma, large cell lung cancer, and small cell lung cancer (SCLC).
  • SCLC small cell lung cancer
  • the disease staging of SCLC follows the two-stage method proposed by the Veterans Lung Study Group (VALG) in 1973, which is divided into limited period and extensive period.
  • the National Comprehensive Cancer Network (NCCN) treatment team recommends that the staging of small cell lung cancer should be combined with the VALG two-stage method and the TNM staging method.
  • the 2019 Chinese Society of Clinical Oncology (CSCO) guidelines for the diagnosis and treatment of primary lung cancer pointed out that in addition to T1-2 without mediastinal lymph node metastasis, N0 limited-stage SCLC can be considered for surgical treatment, more than T1-2, Both N0 limited-stage SCLC and extensive-stage SCLC are treated with chemotherapy based on comprehensive treatment.
  • Etoposide combined with platinum is still the standard first-line chemotherapy, and irinotecan combined with platinum is also an effective first-line treatment for extensive-stage SCLC.
  • the remission rate of the first-line chemotherapy for SCLC is relatively high.
  • the limited-stage SCLC can reach 70%-90%, and the extensive-stage SCLC can reach 50%-60%.
  • most patients relapse or progress within 1 year, and the recurrence rate is high, and the re-treatment effect Poor, poor prognosis.
  • the objective response rate of SCLC second-line treatment is only 10-25%, and the median survival time is no more than 6 months.
  • the SCLC second-line program is limited and the efficacy is not good.
  • Mitoxantrone is an anthraquinone antibiotic anti-tumor drug, an effective inhibitor of topoisomerase II, and a cell cycle non-specific drug. It has a killing effect on both proliferating and non-proliferating cancer cells in the human body.
  • mitoxantrone can also be inserted into deoxyribonucleic acid through hydrogen bonding, causing cross-linking and breakage of DNA structure; it can also bind to RNA and interfere with the synthesis of overexpressed RNA in tumor cells, thereby achieving anti-tumor Effect.
  • FDA approved in 1987 Mitoxantrone for injection
  • mitoxantrone for injection has a certain effect on a variety of hematomas and solid tumors such as malignant lymphoma, breast cancer and lung cancer, but it has serious side effects, such as leukopenia and thrombocytopenia caused by bone marrow suppression.
  • Cardiotoxicities such as palpitations, premature beats and abnormal electrocardiograms have caused its clinical application to be very limited. It is mainly used in combination chemotherapy regimens, and there is no report on its use alone for the treatment of lung cancer.
  • WO2008/080367A1 discloses a mitoxantrone liposome. Studies have shown that compared with the common mitoxantrone preparation, the liposome preparation has lower toxicity and can achieve better anti-tumor efficacy at lower doses , Its disclosure content is hereby incorporated by reference in its entirety. However, the above patent documents did not discuss the effectiveness and safety of mitoxantrone liposomes in humans.
  • 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 .
  • 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): recommended dose 3 ⁇ 5mg/kg/day; (3) Cryptococcal meningitis in HIV-infected persons: recommended dose 6mg/kg/day; (4) visceral leishmaniasis with normal immune function Patients: 3mg/kg/day (days 1-5), 3mg/kg/day (days 14, 21); immunocompromised patients with visceral leishmaniasis: 4mg/kg/day (days 1-5) ), 4 mg/kg/day (days 10, 17, 24, 31, 38).
  • the dosage and dosing 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.
  • the preparation of mitoxantrone into liposomes has changed the distribution of the drug in the body, whether it will aggravate severe adverse reactions such as bone marrow suppression and cardiotoxicity, and whether it can accumulate in the lungs to treat SCLC is still inconclusive.
  • the existing second-line treatment options for SCLC cannot meet clinical needs, and the efficacy, safety, and pharmacokinetic characteristics of mitoxantrone hydrochloride liposome injection in SCLC are still unclear.
  • the present invention preliminarily explores the safe and effective dose of mitoxantrone hydrochloride liposome injection for treating SCLC, in order to provide a basis for clinical application.
  • the invention provides the use of mitoxantrone hydrochloride liposomes in the preparation of medicines for the treatment of small cell lung cancer.
  • the mitoxantrone hydrochloride liposome is used as the sole active ingredient to prepare a medicine for treating small cell lung cancer.
  • 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, 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 small cell lung cancer, which includes the following steps: administering a therapeutically effective amount of mitoxantrone hydrochloride liposomes to patients with small cell lung cancer.
  • the mitoxantrone hydrochloride liposome is used alone for the treatment of small cell lung cancer.
  • the present invention also provides a mitoxantrone hydrochloride liposome, which is used to treat small cell lung cancer in patients.
  • the mitoxantrone hydrochloride liposome is used alone to treat small cell lung cancer in patients.
  • the mitoxantrone hydrochloride liposome may be 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 therapeutically effective amount of the mitoxantrone hydrochloride liposome is 8-30 mg/m 2 , more preferably 12-20 mg/m 2 or 16-30 mg/m 2 , with mitoxantrone Quinone meter. Specifically, for example, 12 mg/m 2 , 14 mg/m 2 , 15 mg/m 2 , 16 mg/m 2 , 18 mg/m 2 , 20 mg/m 2 , calculated as mitoxantrone.
  • the total dose (or cumulative dose) 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 , more preferably Not more than 120mg/m 2 , calculated as mitoxantrone.
  • the mitoxantrone hydrochloride liposome is administered intravenously.
  • the instillation administration time of the liposome pharmaceutical preparation is not less than 60 min, preferably 60 min-120 min, and more preferably 90 ⁇ 15 min.
  • the administration cycle is once every 1 week, 2 weeks, 3 weeks or 4 weeks.
  • the small cell lung cancer is preferably small cell lung cancer that has failed first-line or second-line treatment.
  • the "small cell lung cancer with failed first-line treatment” is preferably a small cell lung cancer patient who has received systemic first-line treatment and has disease progression or recurrence after 3 months.
  • the “systemic first-line treatment” here refers to 1the subject has received at least 4 cycles of platinum-containing first-line chemotherapy or radiotherapy; or 2the subject has received less than 4 cycles of platinum-containing first-line chemotherapy or radiotherapy Chemotherapy, and the best overall response to treatment is partial remission (PR) or complete remission (CR).
  • first-line or second-line treatment includes but not limited to etoposide, irinotecan, topotecan, irinotecan, gemcitabine, temozolomide, platinum drugs, paclitaxel, docetaxel, vinorelbine, etc.
  • the medicine is used alone or in combination of several kinds.
  • platinum-containing first-line chemotherapy or radiochemotherapy regimen includes but is not limited to: etoposide combined with platinum drugs, and irinotecan combined with platinum drugs.
  • the “total dose (or cumulative dose) of mitoxantrone” or “total dose (or cumulative dose) of mitoxantrone” refers to All mitoxantrone drugs received by the patient, including the mitoxantrone hydrochloride liposome of the present invention, mitoxantrone hydrochloride injection and other mitoxantrone preparations, the amount of mitoxantrone administered with.
  • the "therapeutically effective amount of mitoxantrone hydrochloride liposome” refers to the amount of mitoxantrone hydrochloride liposome administered to a patient each time, and the amount allows effective treatment and control. Or alleviate the patient's small cell lung cancer.
  • 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 /080367A1 is prepared by the method disclosed, and 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 diluting the obtained sample 200 times with 0.9% NaCl solution, 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 animal test results of the present invention show that the mitoxantrone hydrochloride liposome can effectively inhibit the growth of small cell lung cancer transplantation tumors.
  • Clinical research results show that mitoxantrone hydrochloride liposomes can effectively treat small cell lung cancer with good curative effect and few adverse reactions. It also has a good effect on small cell lung cancer patients who have failed first-line or second-line treatment.
  • Example 1 The anti-tumor effect of mitoxantrone liposome injection on human small cell lung cancer NCI-H82 transplantation tumor
  • Test animals female NU/NU mice, provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., animal certificate number 1100111911068194.
  • Mit-lipo mitoxantrone hydrochloride liposome injection, PLM60
  • cisplatin for injection Cisplatin batch number FA4A9026A.
  • Mit-lipo was diluted with 5% glucose injection (5% INJ GS) to an appropriate concentration
  • Cisplatin was dissolved with 0.9% sodium chloride injection (0.9% INJNS) and diluted to an appropriate concentration.
  • mice NU/NU female mice were inoculated subcutaneously in the armpit of the right forelimb with human small cell lung cancer NCI-H82 cells (1 ⁇ 10 7 /pc/0.1mL). On the 11th day after inoculation, 30 small cells with good tumor growth were selected. Mice, the mice were divided into 5 groups according to the tumor volume (D0), 6 mice in each group, with an average tumor volume of about 140mm 3 , and intravenous administration of Mitoxantrone Hydrochloride Liposome Injection (Mit-lipo) 20 , 10, 5mg/kg, 6mg/kg cisplatin and 5% INJ GS (solvent control group) for injection.
  • Mitoxantrone Hydrochloride Liposome Injection Mitsubishi Liposome Injection
  • Mit-lipo 10, 5mg/kg and Cisplatin 6mg/kg dose groups were administered q7d ⁇ 2 (administered once every 7 days, twice in total) , The other groups are given a single dose.
  • the tumor diameter was measured twice a week, and the weight of the mice was weighed, and the data was recorded. By measuring the tumor diameter at different times after the administration, the growth and changes of the tumor were dynamically observed. After the test (D20), the tumor was stripped and weighed to investigate the inhibitory effect of different doses of mitoxantrone hydrochloride liposome injection on human small cell lung cancer NCI-H82 transplantation tumor.
  • Data processing uses SPSS 19.0 statistical software, and uses the Repeated Measure process to analyze the changes in tumor volume, relative tumor volume and body weight between multiple measurements over time, and uses the Multivariate process to compare the tumor volume and relative tumor between groups at each measurement. The difference in volume and the difference in tumor weight between groups were analyzed by One-way ANOVA.
  • the RTV relative tumor volume
  • T/C relative tumor volume proliferation rate
  • tumor weight of the 10mg/kg q7d ⁇ 2 administration group of Mit-lipo were significantly less than that of Mit-lipo 20mg/kg single dose/iv G.
  • the anti-tumor effect of the Mit-lipo 20mg/kg single/i.v. administration group was equivalent to that of the Mit-lipo 5mg/kg q7d ⁇ 2 administration group. It is suggested that the therapeutic effect of multiple administrations of Mit-lipo in small doses is better than that of high-dose one-time shock therapy. This has important implications for how to improve the safety and efficacy of clinical medications.
  • Example 2 The inhibitory effect of mitoxantrone liposome injection on human small cell lung cancer NCI-H69 transplantation tumor
  • Test animals female NU/NU mice, provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., animal certificate number 11000111911065735.
  • Mit-lipo mitoxantrone hydrochloride liposome injection, PLM60
  • cisplatin for injection Cisplatin batch number FA4A9026A.
  • Mit-lipo was diluted with 5% glucose injection (5% INJ GS) to an appropriate concentration
  • Cisplatin was dissolved with 0.9% sodium chloride injection (0.9% INJNS) and diluted to an appropriate concentration.
  • mice NU/NU female mice were inoculated subcutaneously in the armpit of the right forelimb with human small cell lung cancer NCI-H69 cells (1 ⁇ 10 7 /pc/0.1mL). On the 26th day after inoculation, 32 mice with good tumor growth were selected. Mice, the mice were divided into 5 groups according to the tumor volume (D0), each group was 6/8 mice, the average tumor volume was about 150mm 3 , and they were given a single intravenous mitoxantrone hydrochloride liposome injection (Mit -lipo) 20, 10, 5 mg/kg, cisplatin for injection (Cisplatin) 6 mg/kg and 5% INJ GS (solvent control group).
  • Mit -lipo mitoxantrone hydrochloride liposome injection
  • the tumor diameter was measured twice a week, and the weight of the mice was weighed, and the data was recorded. By measuring the tumor diameter at different times after the administration, the growth and changes of the tumor were dynamically observed. After the test (D21), the tumor was removed and the tumor was weighed to investigate the inhibitory effect of different doses of mitoxantrone hydrochloride liposome injection on human small cell lung cancer NCI-H69 transplantation tumor.
  • Data processing uses SPSS 19.0 statistical software, and uses the RepeatedMeasure process to analyze the changes in tumor volume, relative tumor volume and body weight between multiple measurements over time, and uses the Multivariate process to compare the tumor volume and relative tumor volume between groups at each measurement. The difference in tumor weight between groups was analyzed by One-way ANOVA.
  • Example 3 The clinical study of mitoxantrone hydrochloride liposome injection in the second-line treatment of small cell lung cancer
  • Group A was given Mitoxantrone Hydrochloride Liposome Injection 20mg/m 2 , dissolved in 250mL of 5% glucose injection, intravenous drip (iv), drip time not less than 60 minutes, repeated every 4 weeks ( Q4W) once for a period of a week is administered on day 1 (D1); B group mitoxantrone liposome injection 15mg / m 2, was dissolved in 250mL 5% glucose injection, intravenous infusion (iv) The instillation time is not less than 60 minutes, and it is repeated every 3 weeks (q3w) as a cycle, and the drug is administered on the first day of each cycle (d1).
  • the test adopts the Simon two-stage (Optimal method) design. It is expected that in the first phase of the trial, Group A and Group B will need to be enrolled to achieve 19 cases with evaluable efficacy. If it is observed that the total number of cases in both complete remission (CR) and partial remission (PR) does not exceed 3 cases, then Both groups suspend the trial; if the total number of CR+PR cases in only one group exceeds 3, the group will enter the second phase to continue the study, and the other group will not enter the second phase trial; if each of the two groups has CR+ The total number of PR cases exceeds 3, and it is up to the investigator and the sponsor to decide which group to enter the second phase of the study based on the actual efficacy and safety situation.
  • CR complete remission
  • PR partial remission
  • the treatment group that enters the second stage can continue to be included in the group of subjects, and 36 cases can be analyzed for efficacy based on the number of cases that can be evaluated for efficacy in the first stage, and the total number of cases that can be analyzed for efficacy in this group reaches 55. .
  • the trial drug is considered to be ineffective and no follow-up clinical development will be carried out. On the contrary, the trial drug is considered to be effective and follow-up clinical studies can be carried out.
  • the research process for each subject is as follows: -28 ⁇ -1 day screening period, treatment period (4-6 cycles), end-of-treatment visit, PFS (progression-free survival) follow-up, and OS (overall survival) follow-up .
  • subjects who meet the selection criteria but do not meet the exclusion criteria will be randomly assigned to group A or group B and receive mitoxantrone hydrochloride liposome injection Liquid treatment.
  • group A all subjects receive a tumor assessment every 8 weeks (group A) or every 6 weeks (group B) to observe the preliminary efficacy of the test drug; at the same time, they need to complete the relevant inspections stipulated in the protocol, and give them according to the protocol.
  • PK pharmacokinetic blood samples were collected at different time points before and after the drug to observe the safety and pharmacokinetic characteristics. Subjects are required to undergo a treatment end visit 28 ( ⁇ 7) days after the last dose.
  • tumor assessment will be conducted every 8 weeks (group A) or every 6 weeks (group B), with a time window of ⁇ 7 days, and PFS visits will be conducted until the subject develops disease and starts a new anti-tumor Treatment, loss to follow-up, death or suspension of the project study (whichever occurs first).
  • the start time of OS follow-up is the end of PFS visit.
  • the investigator needs to contact the patient at least every 8 weeks after this time point, with a time window of ⁇ 7 days to determine Information on survival status and subsequent new anti-tumor treatments until the patient’s death, loss to follow-up or the suspension of the project study (whichever occurs first).
  • the study will end after the last subject completes the last visit.
  • Age from 18 to 70 years old (including 18 years old and 70 years old), no gender limit;
  • the expected survival time is ⁇ 12 weeks
  • Small cell lung cancer that only receives platinum-based chemotherapy or radiotherapy and chemotherapy regimens and has disease progression or recurrence after 3 months (systemic first-line treatment: the subject must have received at least 4 cycles of platinum-based First-line chemotherapy or radiotherapy and chemotherapy; if less than 4 dosing cycles, the best overall response to treatment must be PR or CR);
  • ANC ⁇ Absolute neutrophil count
  • Platelets ⁇ 90 ⁇ 10 9 /L (without receiving platelet transfusion, thrombopoietin, interleukin-11 or other drugs that increase platelets within 2 weeks before the first administration of the study drug);
  • AST ⁇ Aspartate aminotransferase
  • ALT alanine aminotransferase
  • INR International normalized ratio
  • APTT activated partial thromboplastin time
  • LVEF Left ventricular ejection fraction
  • QTc interval ⁇ 480 milliseconds (ms);
  • Live vaccines have been vaccinated within 4 weeks before the first use of the study drug, or live vaccines are expected to be vaccinated during the study period;
  • Interstitial pneumonia drug-induced pneumonia, radiation pneumonia that requires steroid therapy (except for stable radiation pneumonia), active pneumonia with clinical symptoms; or other moderate to severe lung diseases that seriously affect lung function;
  • Severe cardiovascular diseases such as New York Heart Association (NYHA) Grade 2 or higher heart failure, unstable angina, unstable arrhythmia, myocardial infarction or cerebrovascular accident that occurred within 3 months before the first administration;
  • NYHA New York Heart Association
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • HBsAg hepatitis B surface antigen
  • HBcAb hepatitis B core antibody
  • ⁇ Patients with positive HCV antibody test results can be selected for this study only if the HCV RNA test results are within the normal range;
  • HIV Human immunodeficiency virus
  • Subjects can withdraw from the study or suspend the study intervention at any stage of the study without any reason.
  • the reason for the subject's discontinuation or withdrawal from the study should be recorded in the eCRF. If possible, the investigator should conduct an end visit and evaluation of the subjects who withdrew from the study.
  • the small cell lung cancer study currently enrolls 23 small cell lung cancer subjects who have received systemic first-line treatment and who have progressed or recurred after 3 months. Among them, 3 cases were lost to follow-up, 5 cases withdrew, 1 case died, and 14 cases Under treatment. There were 12 subjects who underwent at least one efficacy evaluation, including 1 PR (partial remission), 3 SD (stable disease), 8 PD (disease progression), ORR (objective response rate) was 8.3% (1 /12), DCR (Disease Control Rate) is 33.3% (4/12).
  • group A was 20mg/m 2 q4w, 12 cases were enrolled, 2 cases were lost to follow-up, 3 cases withdrew, and 7 cases were under treatment. There were 6 subjects who had undergone at least one efficacy evaluation, of which 1 case (during the fifth cycle of administration) was evaluated for SD, and the remaining 5 cases were for PD.
  • group B 15 mg/m 2 q3w, 11 cases were enrolled, 1 case was lost to follow-up, 1 case died, 2 cases withdrew, and 7 cases were under treatment.
  • One subject was evaluated as PR in the first evaluation, SD in the second evaluation, PD in the third evaluation, 2 evaluations in SD, and 3 An example is PD.
  • the experimental results of the present invention show that using mitoxantrone liposomes, the drug has the effects of slow release, targeting, attenuation, and synergy after intravenous infusion into the human body.
  • Small cell lung cancer with disease progression or recurrence after one month has a good clinical application prospect.

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Abstract

一种盐酸米托蒽醌脂质体在制备治疗小细胞肺癌的药物中的用途，小细胞肺癌优选为一线或二线治疗失败的小细胞肺癌，更优选接受过系统性一线治疗，3个月后出现疾病进展或复发的小细胞肺癌。

Description

盐酸米托蒽醌脂质体的用途
相关专利申请的交叉引用
本申请要求于2020年4月13日向中国国家知识产权局提交的专利申请号为202010283296.8，发明名称为“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纳入本申请中。
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
本发明属于抗肿瘤药物领域，具体涉及盐酸米托蒽醌脂质体在制备用于治疗小细胞肺癌的药物中的用途。
背景技术
无论是在全球范围内还是在中国，肺癌均是发病率和死亡率居第一位的恶性肿瘤。根据世界卫生组织(WorldHealth Organization，WHO)公布的数据显示，2018年全球新发肺癌病例209万，占所有新发癌症病例的11.6％，死亡病例176万，占所有癌症死亡病例的18.4％。肺癌按病理学类型不同，分为腺癌、鳞癌、大细胞肺癌、小细胞肺癌(Small Cell Lung Cancer,SCLC)等不同组织学类型。小细胞肺癌约占全部肺癌的15％，疾病进展迅速，预后较差，病人确诊后的5年生存率不足7％，平均生存期不足一年。
SCLC的疾病分期沿袭1973年美国退伍军人管理局肺癌研究组(Veterans Lung Study Group,VALG)提出的二分期法，分为局限期和广泛期。同时美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)治疗小组建议小细胞肺癌分期应结合VALG的二分期法和TNM分期法。2019年中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)原发性肺癌诊疗指南中指出，除无纵膈淋巴结转移的T1-2，N0局限期SCLC可考虑手术治疗外，超过T1-2，N0的局限期SCLC及广泛期的SCLC均采取以化疗为主的综合治疗。依托泊苷联合铂类仍为标准一线化疗方案，伊立替康联合铂类也是广泛期SCLC的有效一线治疗方案。SCLC的一线化疗方案缓解率较高，局限期SCLC可达70％-90％，广泛期SCLC可 达50％-60％，但绝大部分患者1年内复发或进展，复发率高，再次治疗效果差，预后不良。SCLC二线治疗的客观缓解率仅10-25％，中位生存期不超过6个月。此外，SCLC二线方案有限且疗效欠佳，除拓扑异构酶I抑制剂拓扑替康为SCLC的二线治疗I级推荐外，2020.V3版NCCN和2019版CSCO指南均推荐SCLC二线治疗患者参加临床试验。SCLC三四线方案之后几乎无公认的治疗方案。因此，SCLC的治疗一直是临床上棘手的问题，存在极大的未满足的临床需求，亟待探索新的药物以改善SCLC的治疗。
米托蒽醌为蒽醌类抗生素类抗肿瘤药物，是拓扑异构酶II的有效抑制剂，是细胞周期非特异性药物，其对人体中增生扩散和未增生扩散的癌细胞都有杀伤作用。除此之外，米托蒽醌还可通过氢键结合插入脱氧核糖核酸中，引起DNA结构的交联和断裂；还能够与RNA结合，干扰肿瘤细胞中过表达RNA的合成，进而达到抗肿瘤的效果。FDA于1987年批准
Figure PCTCN2021086529-appb-000001
(注射用米托蒽醌)用于急性髓性白血病治疗，并在之后陆续获批多发性硬化症、前列腺癌等适应症。临床研究显示注射用米托蒽醌对恶性淋巴瘤、乳腺癌和肺癌等多种血液瘤和实体瘤均有一定疗效，但因存在比较严重的副作用，例如骨髓抑制引起的白细胞和血小板减少，严重的心脏毒性如心悸、早搏及心电图异常等，导致其在临床应用十分受限，主要用于联合化疗方案，并无单独使用治疗肺癌的报道。
WO2008/080367A1公开了一种米托蒽醌脂质体，研究显示，相对于米托蒽醌普通制剂，脂质体制剂的毒性更低，并能在较低剂量下获得更好的抗肿瘤疗效，其公开的内容在这里被全文引入作为参考。然而，上述专利文献未探讨米托蒽醌脂质体在人体中有效性和安全性。
本领域公知，脂质体是一种新型载药形式，可显著改变所包封的药物的体内分布，因此，脂质体制剂治疗不同疾病的安全有效剂量常常出现显著差异。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。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分别为：(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；(4)免疫功能正常的内脏利什曼病患者：3mg/kg/天(第1-5天)，3mg/kg/天(第14、21天)；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)。可见，同一种药物脂质体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。将 米托蒽醌制备成脂质体形式，改变了药物的体内分布，是否会加重骨髓抑制和心脏毒性等严重不良反应，能否在肺部聚集以治疗SCLC，目前都尚无定论。
综上，已有的SCLC二线治疗方案无法满足临床需求，盐酸米托蒽醌脂质体注射液在SCLC中的疗效、安全性及药代动力学特征等尚不明确。本发明初步探索盐酸米托蒽醌脂质体注射液治疗SCLC的安全有效剂量，以期为临床应用提供依据。
发明内容
本发明提供盐酸米托蒽醌脂质体在制备用于治疗小细胞肺癌的药物中的用途。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小细胞肺癌的药物。
在一些实施方案中，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。当所述药物为液体注射剂时，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。
本发明还提供一种治疗小细胞肺癌的方法，包括以下步骤：给予小细胞肺癌患者治疗有效量的盐酸米托蒽醌脂质体。优选地，所述盐酸米托蒽醌脂质体单独用于治疗小细胞肺癌。
本发明还提供一种盐酸米托蒽醌脂质体，其用于治疗患者的小细胞肺癌。优选地，所述盐酸米托蒽醌脂质体单独用于治疗患者的小细胞肺癌。
在本发明的上下文中，所述盐酸米托蒽醌脂质体可以为注射剂型，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，所述药物含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml。
在本发明的上下文中，所述盐酸米托蒽醌脂质体的治疗有效量为8-30mg/m 2，更优选为12-20mg/m 2或者16-30mg/m 2，以米托蒽醌计。具体例如，12mg/m 2，14mg/m 2，15mg/m 2，16mg/m 2，18mg/m 2，20mg/m 2，以米托蒽醌计。优选地，所述脂质体给予每个患者的总给药剂量(或累计给药剂量)不超过200mg/m 2，优选不超过160mg/m 2，进一步优选不超过140mg/m 2，更优选不超过120mg/m 2，以米托蒽醌计。
在本发明的上下文中，所述盐酸米托蒽醌脂质体的给予方式为静脉给药。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不少于60min，优选60min-120min，进一步优选90±15min。优选地，给药周期为每1周、2周、3周或4周给药一次。
本发明的上下文中，所述的小细胞肺癌优选为一线或二线治疗失败的小细胞肺癌。所述的“一线治疗失败的小细胞肺癌”，优选接受过系统性一线治疗，3个月后出现疾病进展或复发的小细胞肺癌患者。这里的“系统性一线治疗”指①受试者接受过至少4个周期的含铂类一线 化疗或放化疗方案；或者②受试者接受过少于4个周期的含铂类一线化疗或放化疗方案，且治疗最佳总体反应为部分缓解(PR)或完全缓解(CR)。这里所述的“一线或二线治疗”方案包括但不限于依托泊苷、伊立替康、拓扑替康、伊立替康、吉西他滨、替莫唑胺、铂类药物、紫杉醇、多西他赛、长春瑞滨等药物单独使用或几种联合使用。这里的“含铂类一线化疗或放化疗方案”包括但不仅限于：依托泊苷联合铂类药物，伊立替康联合铂类药物。
在本发明的上下文中，所述“米托蒽醌的总给药剂量(或累计给药剂量)”或者“以米托蒽醌计的总给药剂量(或累计给药剂量)”是指患者所接受的所有米托蒽醌药物，包括本发明的盐酸米托蒽醌脂质体、盐酸米托蒽醌注射液以及其他米托蒽醌制剂，以米托蒽醌计的给药量之和。
在本发明的上下文中，所述“盐酸米托蒽醌脂质体的治疗有效量”是指每次给予患者的盐酸米托蒽醌脂质体的量，所述量使得可有效治疗、控制或缓解患者的小细胞肺癌。
在本发明的上下文中，所述剂量如无特别说明，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常规方法制备，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，该专利公开的内容在这里被全文引入作为参考。
在本发明的上下文中，所述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，优选约40-70nm，进一步优选约40-60nm，特别优选约60nm。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。
在本发明的上下文中，所述盐酸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(即磷脂的乙醇溶液)。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％。此处方得到的产品被命名为PLM 60。PLM60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。
本发明动物试验结果表明，盐酸米托蒽醌脂质体能有效抑制小细胞肺癌移植瘤的生长。临床研究结果表明，盐酸米托蒽醌脂质体能有效治疗小细胞肺癌，疗效好，不良反应少，对于一线或二线治疗失败的小细胞肺癌患者也具备良好疗效。
具体实施方案
实施例1 米托蒽醌脂质体注射液对人小细胞肺癌NCI-H82移植瘤的抗肿瘤作用
试验动物：雌性NU/NU小鼠，北京维通利华实验动物技术有限公司提供，动物合格证号1100111911068194。
样品批号：Mit-lipo(盐酸米托蒽醌脂质体注射液，PLM60)批号069190701；注射用顺铂(Cisplatin)批号FA4A9026A。试验时，Mit-lipo用5％葡萄糖注射液(5％INJ GS)稀释至合适浓度，Cisplatin用0.9％氯化钠注射液(0.9％INJNS)溶解后稀释至合适浓度。
试验方法：NU/NU雌性小鼠，右前肢腋部皮下接种人小细胞肺癌NCI-H82细胞(1×10 7/只/0.1mL)，接种后第11天，挑选肿瘤生长良好的30只小鼠，将小鼠按肿瘤体积均衡分为5组(D0)，每组6只小鼠，平均肿瘤体积约140mm 3，分别静脉给予盐酸米托蒽醌脂质体注射液(Mit-lipo)20、10、5mg/kg，注射用顺铂(Cisplatin)6mg/kg及5％INJ GS(溶剂对照组)。由于药物的肿瘤抑制作用较弱，同时结合动物的耐受性，Mit-lipo 10、5mg/kg及Cisplatin 6mg/kg剂量组q7d×2给药(每7天给一次，共给药两次)，其它各组均为单次给药。每周测2次瘤径，并称量小鼠体重，记录数据，通过测量给药后不同时间的肿瘤瘤径，动态观察肿瘤的生长变化情况。试验结束后(D20)，剥瘤称量瘤重，考察不同剂量的盐酸米托蒽醌脂质体注射液对人小细胞肺癌NCI-H82移植瘤的抑制作用。
数据处理采用SPSS 19.0统计软件，采用Repeated Measure过程分析随时间变化的多次测量之间的肿瘤体积、相对肿瘤体积和体重的变化，采用Multivariate过程比较各次测量时组间的肿瘤体积和相对肿瘤体积的差异，组间肿瘤重量差异采用One-way ANOVA分析。
试验结果：本试验条件下，与溶剂对照组相比，Mit-lipo 20mg/kg单次静脉给药、Mit-lipo  10、5mg/kg及Cisplatin 6mg/kg q7d×2静脉给药对人小细胞肺癌NCI H82移植瘤的生长均有显著抑制作用(P＜0.05)，并且Mit-lipo各剂量组RTV(相对肿瘤体积)、T/C(相对肿瘤体积增殖率)和瘤重均明显小于Cisplatin 6mg/kg的q7d×2给药组，具体结果见表1-2。而顺铂Cisplatin是小细胞肺癌2019V1.NCCN指南推荐的临床一线用药，提示Mit-lipo治疗小细胞肺癌具有较好的临床应用前景。
值得注意的是，Mit-lipo 10mg/kg的q7d×2给药组RTV(相对肿瘤体积)、T/C(相对肿瘤体积增殖率)和瘤重明显小于Mit-lipo 20mg/kg单次/i.v.给药组。Mit-lipo 20mg/kg单次/i.v.给药组的抑瘤效果与Mit-lipo 5mg/kg的q7d×2给药组相当。提示，Mit-lipo小剂量多次给药的治疗效果优于大剂量一次性冲击疗法。这对于如何提高临床用药的安全性和疗效有重要的启示作用。
表1：对人小细胞肺癌NCI-H82移植瘤肿瘤体积的影响(
Figure PCTCN2021086529-appb-000002
n＝6)
Figure PCTCN2021086529-appb-000003
*P＜0.05， ***P＜0.01， ***P＜0.001，与溶剂对照组比较；D0:首次给药时间；D20：首次给药后20天；RTV：相对肿瘤体积；T/C：相对肿瘤体积增殖率。
表2：对人小细胞肺癌NCI-H82移植瘤瘤重的影响(n＝6)
Figure PCTCN2021086529-appb-000004
*P<0.05， **P<0.01， ***P<0.001，与溶剂对照组比较。
实施例2 米托蒽醌脂质体注射液对人小细胞肺癌NCI-H69移植瘤的抑制作用
试验动物：雌性NU/NU小鼠，北京维通利华实验动物技术有限公司提供，动物合格证号1100111911065735。
样品批号：Mit-lipo(盐酸米托蒽醌脂质体注射液，PLM60)批号069190701；注射用顺铂(Cisplatin)批号FA4A9026A。试验时，Mit-lipo用5％葡萄糖注射液(5％INJ GS)稀释至合适浓度，Cisplatin用0.9％氯化钠注射液(0.9％INJNS)溶解后稀释至合适浓度。
试验方法：NU/NU雌性小鼠，右前肢腋部皮下接种人小细胞肺癌NCI-H69细胞(1×10 7/只/0.1mL)，接种后第26天，挑选肿瘤生长良好的32只小鼠，将小鼠按肿瘤体积均衡分为5组(D0)，每组6/8只小鼠，平均肿瘤体积约150mm 3，分别单次静脉给予盐酸米托蒽醌脂质体注射液(Mit-lipo)20、10、5mg/kg，注射用顺铂(Cisplatin)6mg/kg及5％INJ GS(溶剂对照组)。每周测2次瘤径，并称量小鼠体重，记录数据，通过测量给药后不同时间的肿瘤瘤径，动态观察肿瘤的生长变化情况。试验结束后(D21)，剥瘤称量瘤重，考察不同剂量的盐酸米托蒽醌脂质体注射液对人小细胞肺癌NCI-H69移植瘤的抑制作用。
数据处理采用SPSS 19.0统计软件，采用RepeatedMeasure过程分析随时间变化的多次测量之间的肿瘤体积、相对肿瘤体积和体重的变化，采用Multivariate过程比较各次测量时组间的肿瘤体积和相对肿瘤体积的差异，组间肿瘤重量差异采用One-way ANOVA分析。
试验结果：与溶剂对照组相比，Mit-lipo 20、10、5mg/kg及Cisplatin 6mg/kg单次静脉给药对人小细胞肺癌NCI H69移植瘤的生长均有显著抑制作用(P＜0.001)，瘤重抑制率分别为86.9％、83.8％、73.2％、72.6％。具体结果见表3-4。可见，在Mit-lipo 20、10和5mg/kg的单次/i.v.给药组TV(肿瘤体积)、RTV(相对肿瘤体积)和T/C(相对肿瘤体积增殖率)明显小于Cisplatin 6mg/kg的单次/i.v.给药组。
表3：对人小细胞肺癌NCI-H69移植瘤肿瘤体积的影响(n＝6/8)
Figure PCTCN2021086529-appb-000005
***P<0.001，与溶剂对照组比较。D0：给药当天；D21：给药后21天；RTV：相对肿瘤体积；T/C％：相对肿瘤体积增殖率。
表4：对人小细胞肺癌NCI-H69移植瘤瘤重的影响(n＝6/8)
Figure PCTCN2021086529-appb-000006
***P<0.001，与溶剂对照组比较。
实施例3 盐酸米托蒽醌脂质体注射液二线治疗小细胞肺癌的临床研究
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(PLM60)治疗，旨在评价盐酸米托蒽醌脂质体注射液在小细胞肺癌受试者中不同给药剂量和给药间隔二线治疗SCLC的初步疗效和安全性；为后续研究推荐给药剂量和给药间隔提供依据。
一、试验设计
1.试验分组
本研究仅接受含铂类化疗或放化疗方案系统性一线治疗，3个月后出现疾病进展或复发的小细胞肺癌患者，接受盐酸米托蒽醌脂质体注射液不同给药间隔治疗。依据给药剂量和给药间隔不同，试验分为A组和B组。
A组：盐酸米托蒽醌脂质体注射液20mg/m 2d1 q4w
B组：盐酸米托蒽醌脂质体注射液15mg/m 2d1 q3w
A组予盐酸米托蒽醌脂质体注射液20mg/m 2，溶于250mL的5％葡萄糖注射液中，静脉滴注(iv)，滴注时间不少于60分钟，每4周重复(q4w)一次为一周期，每周期第1天给药(d1)；B组予盐酸米托蒽醌脂质体注射液15mg/m 2，溶于250mL的5％葡萄糖注射液中，静脉滴注(iv)，滴注时间不少于60分钟，每3周重复(q3w)一次为一周期，每周期第1天给药(d1)。两组均接受4～6周期治疗，或至疾病进展(PD)、不能耐受的毒性反应、开始新的抗肿瘤治疗、失访、死亡、研究者决定受试者退出研究治疗或受试者/其法定代理人要求退出研究(以先发生为准)。对于已完成4～6个治疗周期给药的受试者，如仍治疗获益且可耐受，可由研究者与申办方共同商讨后确定是否可继续治疗，观察和评价两组的初步疗效和安全性。
2.试验设计
试验采用Simon二阶段(Optimal法)的设计。预计试验第一阶段A组和B组分别需要入组达到19例可评价疗效的病例，若观察到两组中各自完全缓解(CR)和部分缓解(PR)的病例总数不超过3例，则两组均中止试验；若仅一组中CR+PR的病例总数超过3例，则该组进入第二阶段继续进行研究，另一组不再进入第二阶段试验；若两组中各自CR+PR的病例总数均超过3例，则由研究者和申办方根据实际疗效和安全性情况讨论决定哪组进入第二阶段研究。进入第二阶段的治疗组可继续入组受试者，在第一阶段可评价疗效的病例数基础上再增加可进行疗效分析的病例36例，至该组可进行疗效分析病例总数达到55例。第二阶段结束时，若该组总CR+PR的病例数(包括第一阶段和第二阶段的CR+PR病例数)不超过12例，则认为试验药物无效，不再进行后续临床开发，反之则认为该试验药物有效，可进行后续临床研究。
3.试验流程
每例受试者接受的研究流程如下：﹣28～﹣1天筛选期、治疗期(4～6周期)、治疗结束访视、PFS(无进展生存期)随访及OS(总生存期)随访。
受试者签署知情同意书并在筛选期内完善所有基线检查后，符合入选标准且不符合排除标准的受试者将随机分配至A组或B组，接受盐酸米托蒽醌脂质体注射液的治疗。所有受试者在治疗期，每8周(A组)或每6周(B组)接受一次肿瘤评估，以观察试验药物的初步疗效；同时需完成方案规定的相关检查，并依据方案在给药前后的不同时间点采集PK(药代动力学)血样，以观察安全性和药代动力学特征。受试者需在末次给药后28(±7)天进行治疗结束访视。从首次用药起，每8周(A组)或每6周(B组)进行一次肿瘤评估，时间窗为±7天，进行PFS访视，直至受试者出现疾病进展、开始新的抗肿瘤治疗、失访、死亡或该项目研究中止(以先发生者为准)。OS随访开始时间为PFS结束访视时间，针对入组并接受研究药物治疗的受试者，研究者需在此时间点之后的至少每8周联系一次患者，时间窗为±7天，以确定生存状态和后续新的抗肿瘤治疗的信息，直至患者死亡、失访或该项目研究中止(以先发生为准)。
4.研究结束时间
本研究将在最后一例受试者完成最后一次访视后结束。
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.自愿参加本研究，并签署知情同意书；
2.年龄18～70周岁(含18周岁及70周岁)，性别不限；
3.ECOG体力状况(PS)评分0～2；
4.预计生存期≥12周；
5.经组织学确诊的小细胞肺癌(除外混合其它病理类型的小细胞肺癌)；
6.仅接受含铂类化疗或放化疗方案系统性一线治疗，3个月后出现疾病进展或复发的小细胞肺癌(系统性一线治疗：受试者必须接受过至少4个周期的含铂类一线化疗或放化疗方案；若少于4个给药周期，治疗最佳总体反应必须是PR或CR)；
7.至少存在一处符合RECIST v1.1定义的可测量病灶；
·对于既往进行过放射性治疗的病灶，仅当该病灶在放疗后出现明确疾病进展，才可将该病灶纳入可测量病灶；
8.具有适当的器官功能，实验室检查值需要满足如下要求：
·白细胞计数≥3.0×10 9/L(研究药物首次给药前2周内，未接受G-CSF升白治疗)；
·中性粒细胞绝对计数(ANC)≥1.5×10 9/L(研究药物首次给药前2周内，未接受G-CSF升白治疗)；
·血红蛋白≥90g/L(研究药物首次给药前2周内，未接受输注红细胞或促红细胞生成素治疗)；
·血小板≥90×10 9/L(研究药物首次给药前2周内，未接受输注血小板、促血小板生成素、白介素-11或其他升高血小板的药物治疗)；
·天冬氨酸转氨酶(AST)和丙氨酸转氨酶(ALT)≤2.5倍正常值上限(ULN)(如合并肝转移，则AST和ALT≤5倍ULN可接受)；
·血清总胆红素(TBIL)≤1.5倍ULN；
·白蛋白≥30g/L；
·血清肌酐≤1.5倍ULN或计算的肌酐清除率≥50ml/min；
·国际标准化比值(INR)或活化部分凝血活酶时间(APTT)≤1.5ULN(适用于未接受抗凝治疗者；接受抗凝治疗者，要求抗凝药物剂量稳定，且INR、APTT在可接受范围内)；
·左室射血分数(LVEF)≥50％，且QTc间期≤480毫秒(ms)；
9.育龄期女性，包括处于绝经期但尚未达到绝经后状态(自然闭经连续12个月)且未接受过绝育手术(卵巢和/或子宫切除)者，在首次给药前7天内血妊娠试验必须阴性，并愿 意从研究开始至停用试验药物后6个月内采取足够的避孕措施。
10.男性患者，必须同意从研究开始至停用试验药物后6个月内采取足够的避孕措施(含杀精剂的男用避孕套，或提供成功进行输精管结扎的证据；无生育能力的性伴侣，或女性伴侣使用含杀精剂的宫内节育器，含杀精剂的女用安全套，含杀精剂的避孕海绵，阴道内避孕，含杀精剂的隔膜，含杀精剂的宫颈帽，或口服/植入/经皮或注射用避孕药)。
(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.针对小细胞肺癌原发灶曾行根治性手术治疗；
2.首次使用研究药物前4周内曾接受任何抗肿瘤治疗(包括但不限于化疗、放疗和靶向治疗等)；具有抗肿瘤适应症的中药或中成药洗脱期为2周；缓解骨转移疼痛的局部姑息性放疗洗脱期为2周。
3.首次使用研究药物前4周内曾参加其他临床试验并接受研究药物治疗；
4.首次使用研究药物前4周之内接种过活疫苗，或预计研究期间需要接种活疫苗；
5.首次使用研究药物前1周之内接受过全身类固醇治疗；
6.首次使用研究药物前4周之内接受过大型手术或预期在研究期间接受大型手术；
7.中枢神经转移(除外治疗后且症状稳定的大脑和小脑转移)：
·脑干(中脑、脑桥、延髓)及脊髓转移；
·脑膜转移；
·需用于脑部疾病的持续的皮质类固醇治疗；
·在脑部放疗结束后至首次给药前影像学检查，脑部病灶发现进展；
8.未控制的心包积液、胸腔积液或腹腔积液；
9.间质性肺炎、药物性肺炎、需要类固醇治疗的放射性肺炎(已稳定的放射性肺炎除外)，有临床症状的活动性肺炎；或其他严重影响肺功能的中重度肺部疾病；
10.存在重度感染，包括但不仅限于需住院治疗的感染并发症、菌血症、重症肺炎等；
11.严重的心血管疾病，如纽约心脏病协会(NYHA)2级以上心力衰竭、不稳定型心绞痛、不稳定性心律失常、首次给药前3个月内发生的心肌梗死或脑血管意外；
12.活动性自身免疫性疾病，允许白癜风、血糖控制良好的I型糖尿病、仅需要激素替代疗法治疗的自身免疫性甲状腺炎入选本研究；
13.活动性病毒性肝炎患者，包括乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)感染者：
·乙型肝炎表面抗原(HBsAg)或乙型肝炎核心抗体(HBcAb)检测结果阳性的患者，仅当HBV DNA的检测结果在正常范围内才能入选本研究；
·HCV抗体检测结果阳性的患者，仅当HCV RNA的检测结果在正常范围内才能入选本研究；
14.人免疫缺陷病毒(HIV)抗体阳性者；
15.活动性结核；
16.有脂质体类药物过敏史或米托蒽醌过敏史；
17.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柔红霉素＝0.5mg去甲氧柔红霉素＝0.45mg米托蒽醌)；
18.5年内患有任何其他恶性肿瘤(除外已根治性切除且未复发的皮肤基底细胞癌、皮肤鳞状细胞癌、浅表性膀胱癌、局部前列腺癌、原位宫颈癌或其他原位癌)；
19.存在既往抗肿瘤治疗的毒性未恢复至≤1级的(脱发，色素沉着除外，或研究者认为对受试者无安全风险的其他毒性除外)；
20.既往接受过同种异体骨髓移植或实体器官移植者；
21.已知有精神疾病、酗酒、吸毒或药物滥用等情况；
22.哺乳期女性；
23.根据研究者判断，其他任何可妨碍患者安全参与和完成该临床试验的严重医学疾病和/或临床实验室检查异常，或依从性不佳，不适合参加本临床试验。
(三)退出/终止标准
受试者可以在研究的任何阶段不需要任何理由退出研究或中止研究干预。受试者中止或退出研究的原因应记录在eCRF中，如果可能，研究者应对退出研究的受试者进行结束访视和评价。
如果发生以下情况受试者必须退出研究：
·撤回知情同意书
·在研究过程中参加了其他临床研究(OS随访除外)
三、研究结果
小细胞肺癌研究目前共入组23例接受过系统性一线治疗且3个月后出现疾病进展或复发的小细胞肺癌受试者，其中3例失访，5例退出，1例死亡，14例正在治疗中。至少进行了1次疗效评价的受试者12例，其中1例PR(部分缓解)，3例SD(疾病稳定)，8例PD(疾 病进展)，ORR(客观缓解率)为8.3％(1/12)，DCR(疾病控制率)为33.3％(4/12)。
其中，A组20mg/m 2q4w，入组12例，2例失访，3例退出，7例正在治疗中。至少进行了1次疗效评估的受试者有6例，其中1例(第5周期给药中)评价SD，其余5例为PD。B组15mg/m 2q3w，入组11例，1例失访，1例死亡，2例退出，7例正在治疗中。至少进行了1次疗效评估的受试者有6例，其中1例受试者第一次评价为PR，第二次评价为SD，第三次评价为PD，2例评价为SD，其余3例为PD。
目前小细胞肺癌项目所有受试者均未发生SAE(严重不良事件)，大于等于3级的AE发生4次，其中2次为淋巴细胞计数降低，判定可能与受试药物无关，1例中性粒细胞计数降低，判定与受试药物肯定有关，1例由于C1D1给药当天发生3级输注不良反应，判定与受试药物肯定有关，并停止用药。
以上结果表明，盐酸米托蒽醌脂质体对于接受过系统性一线治疗且3个月后出现疾病进展或复发的小细胞肺癌有一定的疗效。
本发明的的实验结果表明，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，对于接受过系统性一线治疗且3个月后出现疾病进展或复发的小细胞肺癌有良好的临床应用前景。

Claims (10)

  1. 盐酸米托蒽醌脂质体在制备用于治疗小细胞肺癌的药物中的用途。
  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小细胞肺癌的药物中的用途。
  3. 如权利要求1或2所述的用途，其中，所述小细胞肺癌为一线或二线治疗失败的小细胞肺癌；优选接受过系统性一线治疗，3个月后出现疾病进展或复发的小细胞肺癌。
  4. 如权利要求1-3中任一项所述的用途，其中，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。
  5. 如权利要求4所述的用途，其中，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。
  6. 如权利要求1-5中任一项所述的用途，其中，所述盐酸米托蒽醌脂质体粒径为约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；
    或优选地，所述脂质体的粒径为约35-75nm，优选约40-70nm，进一步优选约40-60nm；
    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。
  7. 一种治疗小细胞肺癌的方法，包括以下步骤：给予小细胞肺癌患者治疗有效量的盐酸米托蒽醌脂质体；或优选地，所述小细胞肺癌为一线或二线治疗失败的小细胞肺癌；或更优选为接受过系统性一线治疗，3个月后出现疾病进展或复发的小细胞肺癌；
    或优选地，所述脂质体单独用于治疗小细胞肺癌；
    或优选地，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；优选地，所述脂质体为液体注射剂；当为液体注射剂时，以米托蒽醌计，所述脂质体含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml；
    或优选地，所述盐酸米托蒽醌脂质体的治疗有效量为8-30mg/m 2，更优选为12-20mg/m 2或者16-30mg/m 2，以米托蒽醌计；具体例如，所述治疗有效量为12mg/m 2，14mg/m 2，15 mg/m 2，16mg/m 2，18mg/m 2，20mg/m 2，以米托蒽醌计；
    或优选地，所述脂质体给予每个患者的总给药剂量(或累计给药剂量)不超过200mg/m 2，优选不超过160mg/m 2，进一步优选不超过140mg/m 2，更优选不超过120mg/m 2，以米托蒽醌计；
    或优选地，所述盐酸米托蒽醌脂质体的给予方式为静脉给药；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不少于60min，优选60min-120min，进一步优选90±15min；
    或优选地，所述盐酸米托蒽醌脂质体的给药周期为每3周或4周给药一次。
  8. 如权利要求7所述的方法，其中，所述盐酸米托蒽醌脂质体粒径为约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；
    或优选地，所述脂质体的粒径为约35-75nm，优选约40-70nm，进一步优选约40-60nm；
    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。
  9. 一种盐酸米托蒽醌脂质体，其用于治疗患者的小细胞肺癌；
    或优选地，所述小细胞肺癌为一线或二线治疗失败的小细胞肺癌；或更优选为接受过系统性一线治疗，3个月后出现疾病进展或复发的小细胞肺癌；
    或优选地，所述脂质体单独用于治疗小细胞肺癌；
    或优选地，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；优选地，所述脂质体为液体注射剂；当为液体注射剂时，以米托蒽醌计，所述脂质体含活性成分0.5-5mg/ml，优选1-2mg/ml，更优选1mg/ml；
    或优选地，所述盐酸米托蒽醌脂质体的治疗有效量为8-30mg/m 2，更优选为12-20mg/m 2或者16-30mg/m 2，以米托蒽醌计；具体例如，所述治疗有效量为12mg/m 2，14mg/m 2，15mg/m 2，16mg/m 2，18mg/m 2，20mg/m 2，以米托蒽醌计；
    或优选地，所述脂质体给予每个患者的总给药剂量(或累计给药剂量)不超过200mg/m 2， 优选不超过160mg/m 2，进一步优选不超过140mg/m 2，更优选不超过120mg/m 2，以米托蒽醌计；
    或优选地，所述盐酸米托蒽醌脂质体的给予方式为静脉给药；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不少于60min，优选60min-120min，进一步优选90±15min；
    或优选地，所述盐酸米托蒽醌脂质体的给药周期为每3周或4周给药一次。
  10. 如权利要求9所述的盐酸米托蒽醌脂质体，其中，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；
    或优选地，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。
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