CN115427020A - Application of mitoxantrone hydrochloride liposome - Google Patents
Application of mitoxantrone hydrochloride liposome Download PDFInfo
- Publication number
- CN115427020A CN115427020A CN202180027421.1A CN202180027421A CN115427020A CN 115427020 A CN115427020 A CN 115427020A CN 202180027421 A CN202180027421 A CN 202180027421A CN 115427020 A CN115427020 A CN 115427020A
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- CN
- China
- Prior art keywords
- mitoxantrone
- liposome
- lung cancer
- small cell
- cell lung
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Use of mitoxantrone hydrochloride liposomes for the preparation of a medicament for the treatment of small cell lung cancer, preferably small cell lung cancer that has failed first-line or second-line therapy, more preferably small cell lung cancer that has undergone first-line systemic therapy and has progressed or recurred 3 months later.
Description
Cross reference to related patent applications
The present application claims priority from a prior application entitled "use of mitoxantrone hydrochloride liposomes" with patent application number 202010283296.8 filed on 13.4.2020 by the national intellectual property office. This prior application is incorporated by reference in its entirety.
This patent application refers to PCT application WO2008/080367A1, filed on 12, 29 of 2007, the disclosure of which is incorporated by reference in its entirety.
The invention belongs to the field of antitumor drugs, and particularly relates to application of mitoxantrone hydrochloride liposome in preparation of a drug for treating small cell lung cancer.
Lung cancer is the first malignancy of morbidity and mortality, both globally and in china. According to data published by World Health Organization (WHO), 209 ten thousand new lung cancer cases, accounting for 11.6% of all new cancer cases, 176 ten thousand death cases accounting for 18.4% of all cancer death cases worldwide in 2018 are shown. Lung Cancer is classified into various histological types, such as adenocarcinoma, squamous carcinoma, large Cell Lung Cancer, small Cell Lung Cancer (SCLC), and the like, according to the pathological type. Small cell lung cancer accounts for about 15% of all lung cancers, the disease progresses rapidly, the prognosis is poor, the 5-year survival rate of patients after diagnosis is less than 7%, and the average survival period is less than one year.
SCLC disease staging continues to be a bi-phasic approach proposed by the U.S. Return military administration Lung cancer research Group (VALG) in 1973, which is divided into a local stage and a wide stage. Meanwhile, the National Comprehensive Cancer Network (NCCN) treatment group recommends that the staging of small cell lung Cancer should be combined with the staging method of VALG and TNM staging method. In the guideline for diagnosing and treating primary lung cancer of the Chinese Society of Clinical Oncology (CSCO) of 2019, except that the T1-2 and N0 limited-stage SCLC without mediastinal lymph node metastasis can be considered as operation treatment, the limited-stage SCLC and the extensive-stage SCLC exceeding T1-2 and N0 are both treated by comprehensive treatment mainly based on chemotherapy. Etoposide in combination with platinum remains the standard first-line chemotherapy regimen, and irinotecan in combination with platinum is also an effective first-line treatment regimen for extensive SCLC. The first-line chemotherapy scheme of SCLC has high remission rate, limited-period SCLC can reach 70-90%, and extensive-period SCLC can reach 50-60%, but most patients relapse or progress within 1 year, the relapse rate is high, the secondary treatment effect is poor, and the prognosis is poor. Objective remission rates with SCLC second-line therapy were only 10-25% with median survival not exceeding 6 months. Furthermore, SCLC second-line regimens are limited and poorly therapeutic, with SCLC second-line treatment patients recommended to participate in clinical trials, both under the NCCN 2020.v3 and under the CSCO guideline 2019, except that the topoisomerase I inhibitor topotecan is the second-line treatment level I recommendation for SCLC. There is little accepted treatment after the SCLC trigeminal regimen. Therefore, treatment of SCLC has been a clinically intractable problem, and there is a great unmet clinical need for new drugs to be explored to improve SCLC treatment.
Mitoxantrone is an anthraquinone antibiotic antitumor drug, is effective inhibitor of topoisomerase II, is cell cycle nonspecific drug, and can be used for treating cancer cells with proliferation and non-proliferationAll have killing effect. In addition, mitoxantrone can also be inserted into deoxyribonucleic acid by hydrogen bonding, causing cross-linking and breakage of the DNA structure; can also be combined with RNA to interfere the synthesis of over-expressed RNA in tumor cells, thereby achieving the anti-tumor effect. FDA approval in 1987
Mitoxantrone for acute myeloid leukemia therapy, followed by multiple sclerosis, prostate cancer, etc. Clinical researches show that mitoxantrone for injection has certain curative effect on malignant lymphoma, breast cancer, lung cancer and other blood tumors and solid tumors, but has quite limited clinical application due to relatively serious side effects, such as leucopenia and thrombopenia caused by bone marrow suppression and serious cardiotoxicity, such as palpitation, premature beat, electrocardiogram abnormality and the like, and is mainly used for a combined chemotherapy scheme, and no report of singly using the mitoxantrone for treating the lung cancer exists.
WO2008/080367A1, the disclosure of which is incorporated herein by reference in its entirety, discloses a mitoxantrone liposome formulation, which has been studied to show lower toxicity and better antitumor efficacy at lower doses relative to the mitoxantrone common formulation. However, the above patent documents do not discuss the efficacy and safety of mitoxantrone liposomes in humans.
It is well known in the art that liposomes are a novel drug loaded form that can significantly alter the in vivo distribution of the encapsulated drug, and thus, significant differences often occur in the safe and effective dose of liposomal formulations for the treatment of different diseases. For example, doxil (Doxil hydrochloride liposome) has been approved by the FDA for three indications: (1) Ovarian cancer, recommended dose is 50mg/m 2 Once every 4 weeks intravenous administration; (2) Kaposi's sarcoma at a recommended dose of 20mg/m 2 Once every 3 weeks intravenous administration; (3) Multiple myeloma with a recommended dose of 30mg/m 2 Bortezomib was administered intravenously the fourth day after administration. AmBisome (amphotericin B liposome for injection), as well as for the initiation of treatment of the following indicationsThe dosages are respectively as follows: (1) empirical treatment: the recommended dose is 3 mg/kg/day; (2) Systemic fungal infections (aspergillus, candida, cryptococcus): the recommended dosage is 3-5 mg/kg/day; (3) cryptococcal meningitis in HIV-infected persons: the recommended dosage is 6 mg/kg/day; (4) visceral leishmaniasis patients with normal immune function: 3 mg/kg/day (days 1-5), 3 mg/kg/day (days 14, 21); visceral leishmaniasis patients with immunocompromised function: 4 mg/kg/day (days 1-5), 4 mg/kg/day (days 10, 17, 24, 31, 38). Therefore, the safe and effective dose of the same medicinal liposome for treating different indications is different. The dosage and administration data should be customized according to the specific disease species and the actual condition of the patient, so as to achieve the maximum drug effect and the minimum toxicity or adverse reaction, and obtain the effect of safely and effectively treating the disease. Mitoxantrone is prepared into a liposome form, so that the distribution in vivo of the drug is changed, whether serious adverse reactions such as myelosuppression, cardiotoxicity and the like are aggravated or not and whether the mitoxantrone can be accumulated in the lung to treat SCLC or not is not determined at present.
In conclusion, the existing SCLC second-line treatment scheme cannot meet the clinical requirements, and the curative effect, safety, pharmacokinetic characteristics and the like of the mitoxantrone hydrochloride liposome injection in SCLC are not clear. The invention preliminarily explores the safe and effective dose of the mitoxantrone hydrochloride liposome injection for treating SCLC, so as to provide a basis for clinical application.
Disclosure of Invention
The invention provides application of mitoxantrone hydrochloride liposome in preparing a medicament for treating small cell lung cancer. Preferably, mitoxantrone hydrochloride liposomes are used as the sole active ingredient for the preparation of a medicament for the treatment of small cell lung cancer.
In some embodiments, the medicament is in an injectable dosage form, including liquid injections, injectable powders, injectable tablets, and the like. When the medicine is a liquid injection, the medicine contains 0.5-5mg/ml of active ingredients, preferably 1-2mg/ml, and more preferably 1mg/ml of mitoxantrone.
The invention also provides a method for treating small cell lung cancer, which comprises the following steps: administering a therapeutically effective amount of mitoxantrone hydrochloride liposome to a small cell lung cancer patient. Preferably, the mitoxantrone hydrochloride liposome is used alone for treating small cell lung cancer.
The invention also provides mitoxantrone hydrochloride liposome which is used for treating the small cell lung cancer of a patient. Preferably, the mitoxantrone hydrochloride liposome is used alone to treat small cell lung cancer in a patient.
In the context of the present invention, the mitoxantrone hydrochloride liposome may be in the form of an injection, including a liquid injection, an injectable powder, an injectable tablet, and the like. When the medicine is a liquid injection, the medicine contains 0.5-5mg/ml of active ingredients, preferably 1-2mg/ml, and more preferably 1mg/ml of mitoxantrone.
In the context of the present invention, the therapeutically effective amount of mitoxantrone hydrochloride liposomes is 8-30mg/m 2 More preferably 12 to 20mg/m 2 Or 16-30mg/m 2 Calculated as mitoxantrone. Specifically, for example, 12mg/m 2 ，14mg/m 2 ，15mg/m 2 ，16mg/m 2 ，18mg/m 2 ，20mg/m 2 Calculated as mitoxantrone. Preferably, the liposomes are administered to each patient in a total (or cumulative) dose of no more than 200mg/m 2 Preferably not more than 160mg/m 2 Further preferably not more than 140mg/m 2 More preferably not more than 120mg/m 2 Calculated as mitoxantrone.
In the context of the present invention, the mitoxantrone hydrochloride liposome is administered intravenously. Preferably, the administration time of the liposome pharmaceutical preparation by instillation is not less than 60min, preferably 60min to 120min, and further preferably 90 ± 15min, per intravenous administration. Preferably, the dosing cycle is once every 1 week, 2 weeks, 3 weeks or 4 weeks.
In the context of the present invention, the small cell lung cancer is preferably a small cell lung cancer that has failed one-line or two-line therapy. The small cell lung cancer that fails the first-line treatment is preferably a small cell lung cancer patient who has undergone the first-line systemic treatment and has developed disease progression or recurrence after 3 months. As used herein, "systemic first-line therapy" refers to (1) subjects who have undergone at least 4 cycles of platinum-containing first-line chemotherapy or radiotherapy regimens; or (2) the subject has received less than 4 cycles of platinum-containing first-line chemotherapy or radiotherapy, and the optimal overall response to treatment is Partial Remission (PR) or Complete Remission (CR). The "first or second line therapy" regimen described herein includes, but is not limited to, etoposide, irinotecan, topotecan, irinotecan, gemcitabine, temozolomide, platinum-based drugs, paclitaxel, docetaxel, vinorelbine, and the like, used alone or in combination. The "platinum-containing first-line chemotherapy or radiotherapy regimen" herein includes, but is not limited to: etoposide is combined with platinum drugs, and irinotecan is combined with platinum drugs.
In the context of the present invention, the "total dose (or cumulative dose) of mitoxantrone" or "total dose (or cumulative dose) of mitoxantrone" refers to the sum of the doses of mitoxantrone drug, including mitoxantrone hydrochloride liposome of the present invention, mitoxantrone hydrochloride injection, and other mitoxantrone preparations, as mitoxantrone, that a patient receives.
In the context of the present invention, the "therapeutically effective amount of mitoxantrone hydrochloride liposomes" refers to the amount of mitoxantrone hydrochloride liposomes per administration to a patient that is effective to treat, control or ameliorate small cell lung cancer in the patient.
In the context of the present invention, the dosage is calculated as mitoxantrone unless otherwise specified.
In the context of the present invention, the mitoxantrone hydrochloride liposomes may be prepared by methods conventional in the art, and may be mitoxantrone hydrochloride liposomes prepared by any method known in the art, for example, by the method disclosed in WO2008/080367A1, the disclosure of which is incorporated herein by reference in its entirety.
In the context of the present invention, the mitoxantrone hydrochloride liposomes, having a particle size of about 30 to 80nm, comprise: 1) Mitoxantrone, an active ingredient, which forms a poorly soluble precipitate with multivalent counter ions in liposomes, 2) phospholipid bilayers contain phospholipids with a phase transition temperature (Tm) above body temperature, whereby the phase transition temperature of the liposomes is above body temperature. The phospholipid having a Tm higher than body temperature is phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated yolk lecithin, dipalmitoyl lecithin or distearoyl lecithin or any combination thereof, and the particle size is about 35 to 75nm, preferably about 40 to 70nm, more preferably about 40 to 60nm, particularly preferably about 60nm. The phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoyl phosphatidyl ethanolamine, the mass ratio is 3. Preferably, the phospholipid bilayer of the liposome comprises hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoyl phosphatidyl ethanolamine, the mass ratio is 3: chol: DSPE-PEG2000: mitoxantrone weight ratio 9.58.
In the context of the present invention, the mitoxantrone hydrochloride liposomes are prepared as follows: HSPC (hydrogenated soy lecithin), chol (cholesterol), and DSPE-PEG2000 (polyethylene glycol 2000 modified distearoylphosphatidylethanolamine) were weighed at a mass ratio of 3. Mixing the ethanol solution of phospholipid with 300mM ammonium sulfate solution, and shaking and hydrating at 60-65 ℃ for 1h to obtain the heterogeneous multi-chamber liposome. The particle size of the liposomes is then reduced using a microfluidizer. The obtained sample was diluted 200 times with 0.9% NaCl solution and the average particle size of the particles was about 60nm and the main peak was concentrated between 40-60nm as measured by NanoZS. The blank liposome external phase was then removed of ammonium sulfate using an ultrafiltration device and the external phase was replaced with 290mM sucrose and 10mM glycine to form a transmembrane ammonium sulfate gradient. According to the ratio of lipid to drug of 16. After about 1h of incubation, the encapsulation efficiency was about 100% as demonstrated using gel exclusion chromatography. The product obtained from this prescription was named PLM 60. HSPC in PLM 60: chol: DSPE-PEG2000: mitoxantrone weight ratio 9.58.
The animal test result shows that the mitoxantrone hydrochloride liposome can effectively inhibit the growth of small cell lung cancer transplanted tumors. Clinical research results show that the mitoxantrone hydrochloride liposome can effectively treat the small cell lung cancer, has good curative effect and few adverse reactions, and also has good curative effect on small cell lung cancer patients who fail in one-line or two-line treatment.
Example 1 antitumor Effect of mitoxantrone liposome injection solution on human Small cell Lung cancer NCI-H82 transplantation tumor
Test animals: female NU/NU mice, available from Beijing Wittingle laboratory animal technology, inc., with an animal certification number of 1100111911068194.
Sample batch number: mit-lipo (mitoxantrone hydrochloride liposome injection, PLM 60) batch No. 069190701; cisplatin (cissplatin) batch number FA4a9026A for injection. For the assay, mit-lipo was diluted to appropriate concentration with 5% glucose injection (5% INJ GS), cisplatin was dissolved with 0.9% sodium chloride injection (0.9% INJNS) and diluted to appropriate concentration.
The test method comprises the following steps: NU/NU female mice, right forelimb axillary subcutaneous inoculation of human Small cell Lung cancer NCI-H82 cells (1X 10) 7 0.1 mL), on day 11 post-inoculation, 30 mice with good tumor growth were selected and divided into 5 groups (D0) by tumor volume balance, 6 mice per group, with an average tumor volume of about 140mm 3 Mitoxantrone hydrochloride liposome injection (Mit-lipo) was administered intravenously at 20, 10 and 5mg/kg, and Cisplatin for injection (Cisplatin) was administered at 6mg/kg and 5% INJ GS (solvent control). Because of the weak tumor-inhibiting effect of the drug combined with the tolerance of the animals, the dose groups q7d 2 of Mit-lipo 10, 5mg/kg and Cisplatin 6mg/kg were administered (once every 7 days, twice in total), and the other groups were administered in a single dose. Tumor size was measured 2 times per week and mice were weighed, data were recorded, and tumor growth was dynamically observed by measuring tumor size at different times after dosing. After the test (D20), tumor weight was measured by tumor removal, and the inhibitory effect of mitoxantrone hydrochloride liposome injection at different doses on human small cell lung cancer NCI-H82 transplanted tumors was examined.
Data processing was performed using SPSS 19.0 statistical software, using the reproduced Measure procedure to analyze changes in tumor volume, relative tumor volume, and body weight between measurements over time, using the Multivariate procedure to compare differences in tumor volume and relative tumor volume between groups at each measurement, and using One-way ANOVA to analyze differences in tumor weight between groups.
And (3) test results: under the test conditions, compared with a solvent control group, the intravenous administration of 20mg/kg of Mit-lipo, 10mg/kg of Mit-lipo and 5mg/kg of Cisplatin 6mg/kg of q7d x 2 all have obvious inhibition effect (P is less than 0.05) on the growth of the human small cell lung cancer NCI H82 transplanted tumor, and the RTV (relative tumor volume), T/C (relative tumor volume proliferation rate) and tumor weight average of each dose group of Mit-lipo are obviously less than that of the q7d x 2 administration group of Cisplatin 6mg/kg, and the specific results are shown in tables 1-2. Cisplatin Cisplatin is a first-line clinical medicine recommended by the small cell lung cancer 2019V1.NCCN guidelines, and the fact that Mit-lipo has a good clinical application prospect in treating small cell lung cancer is suggested.
It is noted that the q7d × 2 dosing group RTV (relative tumor volume), T/C (relative tumor volume proliferation rate) and tumor weight of Mit-lipo 10mg/kg are significantly less than those of the single dose/i.v. dosing group of Mit-lipo 20 mg/kg. The anti-tumor effect of the Mit-lipo 20mg/kg single dose/i.v. administration group was comparable to that of the Mit-lipo 5mg/kg q7d × 2 administration group. It is suggested that the therapeutic effect of the Mit-lipo multiple small dose administration is better than that of the large dose one-time shock therapy. The method has important revelation on how to improve the safety and curative effect of clinical medication.
Table 1: effect on tumor volume in human Small cell Lung carcinoma NCI-H82 transplants (
n＝6)
* P＜0.05， *** P＜0.01， *** P is less than 0.001, compared with a solvent control group; d0 is the first administration time; d20: 20 days after the first administration; RTV: relative tumor volume; T/C: relative tumor volume proliferation rate.
Table 2: effect on human Small cell Lung carcinoma NCI-H82 transplantation tumor weight (n = 6)
* P<0.05， ** P<0.01， *** P<0.001, compared to the solvent control group.
Example 2 mitoxantrone liposome injection for inhibiting human Small cell Lung cancer NCI-H69 transplantable tumors
Test animals: female NU/NU mice, available from Beijing Wittingle laboratory animal technology, inc., with an animal certification number of 1100111911065735.
Sample batch number: mit-lipo (mitoxantrone hydrochloride liposome injection, PLM 60) batch No. 069190701; cisplatin for injection (cissplatin) lot number FA4a9026A. For the experiments, mit-lipo was diluted to the appropriate concentration with 5% glucose injection (5% INJ GS) and Cisplatin was dissolved with 0.9% sodium chloride injection (0.9% INJNS).
The test method comprises the following steps: NU/NU female mice, right anterior axillary subcutaneous inoculation of human Small cell Lung cancer NCI-H69 cells (1X 10) 7 /0.1 mL), on day 26 post-inoculation, 32 mice with good tumor growth were picked and divided into 5 groups (D0) with 6/8 mice in each group with a balanced tumor volume, with an average tumor volume of about 150mm 3 Separately, mitoxantrone hydrochloride liposome injection (Mit-lipo) 20, 10, 5mg/kg, cisplatin for injection (Cisplatin) 6mg/kg and INJ GS (solvent control group) 5% were intravenously administered once. Tumor diameters were measured 2 times a week, and the mice were weighed, and data were recorded to dynamically observe changes in tumor growth by measuring tumor diameters at different times after administration. After the test (D21), tumor weight was weighed by tumor removal and different doses of mitoxantrone hydrochloride liposome injection were examinedThe injection has effect in inhibiting small cell lung cancer NCI-H69 transplantation tumor.
Data processing was performed using SPSS 19.0 statistical software, using the repeat measure process to analyze changes in tumor volume, relative tumor volume, and body weight between measurements over time, using the Multivariate process to compare differences in tumor volume and relative tumor volume between groups at each measurement, and using One-way ANOVA to analyze differences in tumor weight between groups.
And (3) test results: compared with a solvent control group, mit-lipo 20, 10, 5mg/kg and Cisplatin 6mg/kg have obvious inhibition effect (P is less than 0.001) on the growth of human small cell lung cancer NCI H69 transplantation tumor by single intravenous administration, and the tumor weight inhibition rates are 86.9%, 83.8%, 73.2% and 72.6% respectively. The specific results are shown in tables 3-4. As can be seen, the single dose/i.v. administration of TV (tumor volume), RTV (relative tumor volume) and T/C (relative tumor volume proliferation rate) at Mit-lipo 20, 10 and 5mg/kg is significantly less than that of Cisplatin 6 mg/kg.
Table 3: effect on tumor volume of human Small cell Lung carcinoma NCI-H69 transplanted tumors (n = 6/8)
*** P<0.001, compared to the solvent control group. D0: the day of dosing; d21: 21 days after administration; RTV: relative tumor volume; T/C%: relative tumor volume proliferation rate.
Table 4: effect on human Small cell Lung carcinoma NCI-H69 graft tumor weight (n = 6/8)
*** P<0.001, compared to a solvent control.
Example 3 clinical study of mitoxantrone hydrochloride liposome injection for second line treatment of Small cell Lung cancer
This is an open, multicenter phase II study, where the included subjects will receive mitoxantrone hydrochloride liposome injection (PLM 60) therapy, aimed at evaluating the primary efficacy and safety of mitoxantrone hydrochloride liposome injection in the second line of treatment SCLC at different dosing doses and dosing intervals in small cell lung cancer subjects; provides basis for recommending the administration dosage and the administration interval for subsequent study.
1. Design of experiments
1. Test grouping
The study only receives the systemic first-line treatment of the platinum-containing chemotherapy or radiotherapy and chemotherapy scheme, and small cell lung cancer patients with disease progression or relapse after 3 months receive different administration interval treatments of mitoxantrone hydrochloride liposome injection. The test was divided into groups a and B depending on the dose and interval of administration.
Group A: mitoxantrone hydrochloride liposome injection 20mg/m 2 d1 q4w
Group B: mitoxantrone hydrochloride liposome injection 15mg/m 2 d1 q3w
Group A mitoxantrone hydrochloride liposome injection 20mg/m 2 (iii) dissolved in 250mL of a 5% glucose injection solution and administered by intravenous drip (iv) for a period of not less than 60 minutes repeated every 4 weeks (q 4 w) for one cycle, on day 1 of each cycle (d 1); group B mitoxantrone hydrochloride liposome injection 15mg/m 2 (iii) dissolved in 250mL of a 5% glucose injection solution and intravenously instilled (iv) for not less than 60 minutes in a cycle of repeated (q 3 w) every 3 weeks for administration on day 1 of the cycle (d 1). Both groups received 4-6 cycles of treatment, or until disease Progression (PD), intolerant toxicity, initiation of new anti-tumor therapy, loss of access, death, investigator's decision to withdraw from study treatment or subject/his legal representative required withdrawal from study (whichever occurred first). For subjects who have completed 4-6 treatment cycles, if treatment is still beneficial and tolerable, the investigator can determine whether treatment can be continued after a co-consultation with the sponsor, and observe and evaluate the primary efficacy and safety of both groups.
2. Design of experiments
The experiment was designed using the Simon two-stage (Optimal) method. It is expected that group A and group B in the first phase of the trial will require 19 cases to be included in each group to achieve an evaluable efficacy, and both groups will abort the trial if no more than 3 total cases of Complete Remission (CR) and Partial Remission (PR) are observed in each of the two groups; if the total number of CR + PR cases in only one group exceeds 3, the group enters a second stage for continuing the research, and the other group does not enter the second stage test; if the total number of CR + PR cases in each group exceeded 3, the investigator and the sponsor decided which group to enter the second phase of the study based on the actual efficacy and safety profile discussion. The treatment group entering the second stage can continue to enter the group of subjects, and 36 cases capable of being subjected to curative effect analysis are increased on the basis of the number of cases capable of evaluating curative effect in the first stage until the total number of cases capable of being subjected to curative effect analysis in the group reaches 55 cases. At the end of the second phase, if the number of total CR + PR cases (including the number of CR + PR cases in the first and second phases) does not exceed 12, the test drug is considered to be ineffective and no further clinical development is performed, otherwise the test drug is considered to be effective and a further clinical study may be performed.
3. Test procedure
The study protocol for each subject was as follows: screening period of-28 to-1 days, treatment period (4-6 periods), treatment end visit, PFS (progression-free survival) visit and OS (overall survival) visit.
Subjects signed informed consent and completed all baseline checks during the screening period, subjects who met the inclusion criteria and who did not meet the exclusion criteria were randomly assigned to group a or group B and received treatment with mitoxantrone hydrochloride liposomal injection. All subjects received tumor assessments every 8 weeks (group a) or every 6 weeks (group B) during the treatment period to observe the primary efficacy of the test drug; at the same time, the relevant examinations specified by the protocol were performed, and PK (pharmacokinetic) blood samples were collected at different time points before and after the administration according to the protocol to observe safety and pharmacokinetic characteristics. Subjects were given an end-of-treatment visit 28 (± 7) days after the last dose. From the first dose, tumor assessments were performed every 8 weeks (group a) or every 6 weeks (group B) with a time window of ± 7 days for PFS visits until subject disease progression, initiation of new anti-tumor therapy, missed visits, death or discontinuation of the study (whichever occurred first). OS follow-up start time is PFS end visit time, and for subjects who entered the group and received study drug treatment, 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 survival status and information on subsequent new anti-tumor treatments, until the patient dies, loses visit, or the study is discontinued (whichever occurs first).
4. End time of study
The study will end after the last subject completed the last visit.
2. Test population
Subjects who met all of the following inclusion criteria and did not have any exclusion criteria were eligible for inclusion in the clinical study.
(one) inclusion criteria
The subject must meet all of the following criteria:
1. voluntarily participate in the study and sign informed consent;
2. age 18-70 years (including 18 years and 70 years), with no limitation on the nature;
ECOG physical condition (PS) score is 0-2;
4. the expected life is more than or equal to 12 weeks;
5. histologically confirmed small cell lung cancer (except mixed with other pathological types);
6. (ii) small cell lung cancer that has progressed or recurred 3 months after receiving only platinum-containing chemotherapy or radiotherapy regimens for the first line of therapy (first line of therapy: the subject must receive at least 4 cycles of platinum-containing first line chemotherapy or radiotherapy regimens; if less than 4 cycles of administration, the optimal overall response to treatment must be PR or CR);
7. at least one measurable lesion meeting RECIST v1.1 definition;
for a lesion that has been previously treated with radiation, the lesion can be incorporated into a measurable lesion only if it has a clear disease progression after radiation treatment;
8. with proper organ function, laboratory examination values need to meet the following requirements:
white blood cell count ≥ 3.0X 10 9 L (study drug received no G-CSF leukocyte-increasing treatment within 2 weeks prior to first dose);
absolute Neutrophil Count (ANC) ≥ 1.5X 10 9 L (within 2 weeks prior to the first dose of study drug, not receiving G-CSF leukocyte increasing treatment);
hemoglobin > 90g/L (study drug not treated by infusion of red blood cells or erythropoietin within 2 weeks prior to first dose);
platelet ≥ 90X 10 9 L (no platelet infusion, thrombopoietin, interleukin-11, or other platelet raising medication was received within 2 weeks prior to the first dose of study medication);
aspartate Aminotransferase (AST) and alanine Aminotransferase (ALT) at 2.5 times the Upper Limit of Normal (ULN) (if combined with liver metastasis, AST and ALT at 5 times ULN are acceptable);
serum Total Bilirubin (TBIL) is less than or equal to 1.5 times ULN;
albumin is greater than or equal to 30g/L;
serum creatinine is less than or equal to 1.5 times ULN or the calculated creatinine clearance is greater than or equal to 50ml/min;
an International Normalized Ratio (INR) or Activated Partial Thromboplastin Time (APTT) of 1.5ULN (for patients not receiving anticoagulation therapy; for patients receiving anticoagulation therapy, requiring stable anticoagulation drug dose and INR, APTT being within acceptable ranges);
left Ventricular Ejection Fraction (LVEF) is more than or equal to 50%, and QTc interval is less than or equal to 480 milliseconds (ms);
9. women of childbearing age, including those who are menopausal but have not reached a postmenopausal state (natural amenorrhea for 12 months) and who have not undergone a sterilization procedure (ovariectomy and/or hysterectomy), must be negative in blood pregnancy within 7 days prior to the first dose and wish to take adequate contraceptive measures from the start of the study to 6 months after the test drug is discontinued.
10. Male patients must agree to take adequate contraceptive measures from the start of the study to within 6 months after the test drug is discontinued (male condoms containing spermicide or provide evidence of successful vasoligation; infertile sexual partners, or female partners use intrauterine devices containing spermicide, female condoms containing spermicide, contraceptive sponges containing spermicide, intravaginal contraceptives, diaphragms containing spermicide, cervical caps containing spermicide, or oral/implant/transdermal or injectable contraceptives).
(II) exclusion criteria
Subjects who meet any of the following criteria will be excluded from this trial:
1. radical operation treatment is carried out aiming at the primary focus of the small cell lung cancer;
2. any anti-tumor therapy (including but not limited to chemotherapy, radiation therapy, and targeted therapy, etc.) was received within 4 weeks prior to the first use of the study drug; the elution period of the traditional Chinese medicine or Chinese patent medicine with anti-tumor indication is 2 weeks; the washout period of local palliative radiotherapy to relieve pain from bone metastases was 2 weeks.
3. Other clinical trials were enrolled and received study medication within 4 weeks prior to the first use of study medication;
4. live vaccines were administered within 4 weeks prior to the first use of study medication, or live vaccine inoculation was expected to be required during the study;
5. systemic steroid treatment was received within 1 week prior to the first study drug use;
6. large surgery was performed within 4 weeks prior to the first use of study medication or was expected during the study;
7. central nervous metastases (except after treatment and symptomatically stable brain and cerebellar metastases):
brainstem (midbrain, pons, medulla oblongata) and spinal cord metastases;
meningeal metastasis;
required for continuous corticosteroid treatment of brain diseases;
imaging examination is carried out after the cerebral radiotherapy is finished until the first administration, and the development of the cerebral lesion is found;
8. uncontrolled pericardial, pleural, or peritoneal fluid;
9. interstitial pneumonia, drug pneumonia, radiation pneumonia requiring steroid therapy (except stabilized radiation pneumonia), active pneumonia with clinical symptoms; or other moderate to severe lung diseases that severely affect lung function;
10. severe infections exist, including but not limited to, complications of hospitalization, bacteremia, severe pneumonia, etc.;
11. severe cardiovascular diseases, such as heart failure above grade 2 of the New York Heart Association (NYHA), unstable angina, unstable arrhythmia, myocardial infarction or cerebrovascular accident occurring within 3 months prior to the first administration;
12. active autoimmune diseases, i.e. leucoderma, type I diabetes with good blood sugar control, and autoimmune thyroiditis which only needs hormone replacement therapy to treat are selected for research;
13. active viral hepatitis patients, including those infected with Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV):
patients with positive detection of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb), and can be selected from this study only if the result of HBV DNA detection is within the normal range;
patients with positive HCV antibody detection, who can be selected for the study only if the HCV RNA detection is within the normal range;
14. those positive for Human Immunodeficiency Virus (HIV) antibodies;
15. active tuberculosis;
16. (ii) a history of liposomal drug allergy or mitoxantrone allergy;
17. has been treated by adriamycin or other anthracyclines, and the adriamycin accumulated dose exceeds 350mg/m 2 (anthracycline equivalent dose calculation: 1mg doxorubicin =2mg epirubicin =2mg daunorubicin =0.5mg demethoxydaunorubicin =0.45mg mitoxantrone);
any other malignancy (except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, local prostate cancer, carcinoma in situ of the cervix or other carcinoma in situ) that has been radically resected and has not recurred within 18.5 years;
19. there is no return to grade 1 of toxicity of the prior anti-tumor treatments (except for hair loss, pigmentation, or other toxicity that the investigator deems to be not a safety risk to the subject);
20. those who have previously received allogeneic bone marrow transplantation or solid organ transplantation;
21. mental disorders, alcohol abuse, drug abuse, and the like;
22. lactating women;
23. any other serious medical condition and/or clinical laboratory test abnormality that could prevent the patient from safely participating and completing the clinical trial, or the compliance was poor and not suitable for participating in the clinical trial, as judged by the investigator.
(III) Exit/terminate criteria
The subject may withdraw from the study or discontinue study intervention at any stage of the study without any reason. The reason for subject discontinuation or withdrawal from the study should be recorded in the eCRF, and the investigator should perform an end visit and evaluation, if possible, of subjects withdrawing from the study.
Subjects must withdraw from the study if:
withdraw informed consent
Other clinical studies were participated in the course of the study (except for OS follow-up)
3. Results of the study
Small cell lung cancer study a total of 23 subjects currently enrolled in the group who received first line of systemic treatment and developed disease progression or recurrence after 3 months, 3 of which were out of visit, 5 were withdrawn, 1 died, and 14 were under treatment. At least 1 treatment effect evaluation was performed on 12 subjects, of which 1 PR (partial remission), 3 SD (stable disease), 8 PD (disease progression), ORR (objective remission rate) was 8.3% (1/12), and DCR (disease control rate) was 33.3% (4/12).
Wherein, the A group is 20mg/m 2 q4w, group 12, 2 missed visits, 3 withdrawals and 7 under treatment. There were 6 subjects who had been evaluated for at least 1 treatment effect, of which 1 (in the 5 th cycle administration) evaluated SD and the remaining 5 were PD. Group B15 mg/m 2 q3w, in 11 cases, 1 case missed visit, 1 case dead,2 cases were withdrawn and 7 cases were under treatment. There were 6 subjects who had been evaluated for at least 1 treatment effect, wherein 1 subject was evaluated for PR for the first time, SD for the second time, PD for the third time, SD for 2, and PD for the remaining 3.
At present, SAE (Severe adverse event) does not occur in all subjects in the small cell lung cancer project, 4 AE (grade 3) or more occur, wherein 2 times are lymphocyte count reduction, the determination is possible to be unrelated to the tested medicament, 1 case is neutrophile count reduction, the determination is positively related to the tested medicament, 1 case is adverse reaction of grade 3 infusion on the day of C1D1 administration, the determination is positively related to the tested medicament, and the administration is stopped.
The results show that the mitoxantrone hydrochloride liposome has certain curative effect on small cell lung cancer which is treated by systemic first-line treatment and has disease progression or relapse after 3 months.
The experimental result of the invention shows that the mitoxantrone liposome has the functions of slow release, targeting, attenuation and synergy after the medicament enters a human body through intravenous infusion, and has good clinical application prospect for the small cell lung cancer which is subjected to the first-line systemic therapy and has disease progression or relapse after 3 months.
Claims (10)
- Use of mitoxantrone hydrochloride liposome in preparation of medicine for treating small cell lung cancer is provided.
- Use of mitoxantrone hydrochloride liposomes as sole active ingredient for the preparation of a medicament for the treatment of small cell lung cancer.
- The use of claim 1 or 2, wherein the small cell lung cancer is a first or second line treatment failed small cell lung cancer; preferably small cell lung cancer that has undergone first line of care systemically and has developed disease progression or recurrence after 3 months.
- The use of any one of claims 1-3, wherein the medicament is in an injectable dosage form, including liquid injection, injectable powder, injectable tablet, and the like; preferably, the medicament is a liquid injection.
- Use according to claim 4, wherein the medicament contains 0.5-5mg/ml, preferably 1-2mg/ml, more preferably 1mg/ml of active ingredient, calculated as mitoxantrone.
- The use of any one of claims 1-5, wherein the mitoxantrone hydrochloride liposome has a particle size of about 30-80nm and comprises: 1) Mitoxantrone, an active ingredient, which forms a poorly soluble precipitate with multivalent counter ions within liposomes, 2) phospholipid bilayers contain phospholipids with a phase transition temperature (Tm) above body temperature, whereby the phase transition temperature of the liposomes is above body temperature. The phospholipid with Tm higher than body temperature is phosphatidyl choline, hydrogenated soybean lecithin, hydrogenated yolk lecithin, dipalmitin lecithin or distearoyl lecithin or any combination thereof;or preferably, the particle size of the liposomes is about 35-75nm, preferably about 40-70nm, further preferably about 40-60nm;or preferably, the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoyl phosphatidyl ethanolamine, the mass ratio is 3;or preferably, the phospholipid bilayer of the liposome comprises hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoyl phosphatidyl ethanolamine, the mass ratio is 3: chol: DSPE-PEG2000: mitoxantrone weight ratio 9.58.
- A method of treating small cell lung cancer, comprising the steps of: administering a therapeutically effective amount of mitoxantrone hydrochloride liposome to a small cell lung cancer patient; or preferably, the small cell lung cancer is a first or second line treatment failed small cell lung cancer; or more preferably small cell lung cancer that has undergone first line of care systemically and has developed disease progression or recurrence after 3 months;or preferably, the liposomes are used alone for the treatment of small cell lung cancer;or preferably, the liposome is in injection dosage forms, including liquid injection, powder for injection, tablet for injection and the like; preferably, the liposome is a liquid injection; when the liposome is a liquid injection, the active ingredient in the liposome is 0.5-5mg/ml, preferably 1-2mg/ml, more preferably 1mg/ml;or preferably, the mitoxantrone hydrochloride liposome has a therapeutically effective amount of 8-30mg/m 2 More preferably 12 to 20mg/m 2 Or 16-30mg/m 2 Calculated as mitoxantrone; for example, the therapeutically effective amount is 12mg/m 2 ，14mg/m 2 ，15 mg/m 2 ，16mg/m 2 ，18mg/m 2 ，20mg/m 2 Calculated as mitoxantrone;or preferably, the liposomes are administered to each patient in a total (or cumulative) dose of no more than 200mg/m 2 Preferably not more than 160mg/m 2 Further preferably not more than 140mg/m 2 More preferably not more than 120mg/m 2 Calculated as mitoxantrone;or preferably, the mitoxantrone hydrochloride liposome is administered intravenously; preferably, the administration time of the liposome pharmaceutical preparation by instillation is not less than 60min, preferably 60min-120min, and further preferably 90 +/-15 min, for each intravenous administration;or preferably, the mitoxantrone hydrochloride liposome is administered once every 3 or 4 weeks.
- The method of claim 7, wherein the mitoxantrone hydrochloride liposome has a particle size of about 30-80nm and comprises: 1) Mitoxantrone, an active ingredient, which forms a poorly soluble precipitate with multivalent counter ions in liposomes, 2) phospholipid bilayers contain phospholipids with a phase transition temperature (Tm) above body temperature, whereby the phase transition temperature of the liposomes is above body temperature. The phospholipid with Tm higher than body temperature is phosphatidyl choline, hydrogenated soybean lecithin, hydrogenated yolk lecithin, dipalmitin lecithin or distearoyl lecithin or any combination thereof;or preferably, the particle size of the liposomes is about 35-75nm, preferably about 40-70nm, further preferably about 40-60nm;or preferably, the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoyl phosphatidyl ethanolamine, the mass ratio is 3;or preferably, the phospholipid bilayer of the liposome comprises hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoyl phosphatidyl ethanolamine, the mass ratio is 3: chol: DSPE-PEG2000: the weight ratio of mitoxantrone is 9.58.
- Mitoxantrone hydrochloride liposome for treating small cell lung cancer in a patient;or preferably, the small cell lung cancer is a first or second line treatment failed small cell lung cancer; or more preferably small cell lung cancer that has undergone first line of care systemically and has developed disease progression or recurrence after 3 months;or preferably, the liposomes are used alone for the treatment of small cell lung cancer;or preferably, the liposome is in injection dosage forms, including liquid injection, powder for injection, tablets for injection and the like; preferably, the liposome is a liquid injection; when the injection is a liquid injection, the liposome contains 0.5-5mg/ml of active ingredient, preferably 1-2mg/ml, and more preferably 1mg/ml, calculated by mitoxantrone;or preferably, the mitoxantrone hydrochloride liposome has a therapeutically effective amount of 8-30mg/m 2 More preferably 12 to 20mg/m 2 Or 16-30mg/m 2 Calculated as mitoxantrone; for example, the therapeutically effective amount is 12mg/m 2 ，14mg/m 2 ，15mg/m 2 ，16mg/m 2 ，18mg/m 2 ，20mg/m 2 Calculated as mitoxantrone;or preferably, the liposomes are administered to each patient in a total (or cumulative) dose of no more than 200mg/m 2 Preferably not more than 160mg/m 2 And further preferably not more than 140mg/m 2 More preferably not more than 120mg/m 2 Calculated as mitoxantrone;or preferably, the mitoxantrone hydrochloride liposome is administered intravenously; preferably, the administration time of the liposome pharmaceutical preparation by instillation is not less than 60min, preferably 60min-120min, and further preferably 90 +/-15 min, for each intravenous administration;or preferably, the mitoxantrone hydrochloride liposome is administered once every 3 or 4 weeks.
- The mitoxantrone hydrochloride liposome of claim 9, wherein the mitoxantrone hydrochloride liposome has a particle size of about 30-80nm and comprises: 1) Mitoxantrone, an active ingredient, which forms a poorly soluble precipitate with multivalent counter ions in liposomes, 2) phospholipid bilayers comprising phospholipids with a phase transition temperature (Tm) above body temperature; the phospholipid with Tm higher than body temperature is phosphatidyl choline, hydrogenated soybean lecithin, hydrogenated yolk lecithin, dipalmitoyl lecithin or distearoyl lecithin or any combination thereof;or preferably, the mitoxantrone hydrochloride liposome has a particle size of about 35-75nm, preferably 40-70nm, more preferably 40-60nm, and particularly preferably 60nm;or preferably, the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoyl phosphatidyl ethanolamine, the mass ratio is 3;or preferably, the phospholipid bilayer of the liposome comprises hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000 modified distearoyl phosphatidyl ethanolamine, the mass ratio is 3: chol: DSPE-PEG2000: the weight ratio of mitoxantrone is 9.58.
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| WO2021208842A1 (en) | 2021-10-21 |
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