USE OF MITOXANTRONE HYDROCHLORIDE LIPOSOME FOR TREATING BREAST CANCER

Abstract

Mitoxantrone hydrochloride liposome is a unique active ingredient for preparing drugs for treating breast cancer. The breast cancer is preferably advanced breast cancer. A method for treating the breast cancer includes to administer mitoxantrone hydrochloride liposome in a therapeutic effective amount to breast cancer patients, and the therapeutic effective amount means 8-30 mg/m.sup.2, according to mitoxantrone. Clinical trial results show that the mitoxantrone hydrochloride liposome has better efficacy and fewer adverse reactions, and especially significantly reduced cardiotoxicity, compared with a common mitoxantrone hydrochloride injection.

Claims

1. Use of a mitoxantrone hydrochloride liposome for manufacturing a medicament for the treatment of breast cancer.

2. The use according to claim 1, characterized in that, the breast cancer is advanced breast cancer, further preferably advanced recurrent or metastatic breast cancer, more preferably advanced recurrent or metastatic breast cancer that is HER2 negative or refractory to HER2 targeted therapy, and even more preferably advanced recurrent or metastatic breast cancer that is unsuitable for or tolerant to endocrine therapy, HER2 negative or refractory to HER2 targeted therapy.

3. The use according to claim 1, characterized in that, the mitoxantrone hydrochloride liposome plays a role of a sole active ingredient.

4. The use according to claim 1, characterized in that, the medicament is in a dosage form for injection, including a liquid for injection, a powder for injection, a tablet for injection, and the like; preferably, the medicament is a liquid for injection.

5. The use according to claim 4, wherein the medicament comprises 0.5-5 mg/mL, preferably 1-2 mg/mL, and more preferably 1 mg/mL of the active ingredient, on the basis of mitoxantrone.

6. The use according to claim 1, characterized in that, the mitoxantrone hydrochloride liposome has a particle size of about 30-80 nm and comprises: 1) mitoxantrone as active ingredient, which can form a hardly soluble precipitate with multivalent counterions in the liposome, and 2) a phospholipid bilayer containing a phospholipid with a phase transition temperature (Tm) higher than a body temperature, wherein 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; preferably, the mitoxantrone hydrochloride liposome has a particle size of about 35-75 nm, preferably 40-70 nm, further preferably 40-60 nm, and in particular preferably 60 nm; preferably, the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000-modified distearoyl phosphatidyl ethanolamine in a mass ratio of 3:1:1, the particle size is about 60 nm, and the counterion is sulfate ion; or preferably, the phospholipid bilayer of the liposome contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000-modified distearoyl phosphatidyl ethanolamine in a mass ratio of 3:1:1, the particle size is about 40-60 nm, the counterion is sulfate ion, and the mass ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone is 9.58:3.19:3.19:1.

7. A method for treating breast cancer comprising: administering to a patient with breast cancer a therapeutically effective amount of a mitoxantrone hydrochloride liposome alone; preferably, the route of administration is intravenous administration; preferably, for each intravenous administration, the dripping administration time of the mitoxantrone hydrochloride liposome is 30-120 min, preferably 55-120 min or 60-120 min, further preferably not less than 60 min, and even more preferably 60±5 min; or preferably, the frequency of administration is once every 4 weeks; or preferably, the therapeutically effective amount is 8-30 mg/m.sup.2, more preferably 12-20 mg/m.sup.2, on the basis of mitoxantrone; or preferably, the patient receives a total dose of mitoxantrone of no more than 200 mg/m.sup.2, preferably no more than 160 mg/m.sup.2, more preferably no more than 140 mg/m.sup.2, and even more preferably no more than 120 mg/m.sup.2; or preferably, the breast cancer is advanced breast cancer, further preferably advanced recurrent or metastatic breast cancer, more preferably advanced recurrent or metastatic breast cancer that is HER2 negative or refractory to HER2 targeted therapy, and even more preferably advanced recurrent or metastatic breast cancer that is unsuitable for or tolerant to endocrine therapy, HER2 negative or refractory to HER2 targeted therapy.

8. The method according to claim 7, wherein the mitoxantrone hydrochloride liposome has a particle size of about 30-80 nm and comprises: 1) mitoxantrone as active ingredient, which can form a hardly soluble precipitate with multivalent counterions in the liposome, and 2) a phospholipid bilayer containing a phospholipid with a phase transition temperature (Tm) higher than a body temperature, wherein 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 35-75 nm, preferably 40-70 nm, more preferably 40-60 nm, and even more preferably 60 nm; or preferably, the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000-modified distearoyl phosphatidyl ethanolamine in a mass ratio of 3:1:1, the particle size is about 60 nm, and the counterion is sulfate ion; or preferably, the phospholipid bilayer of the liposome contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000-modified distearoyl phosphatidyl ethanolamine in a mass ratio of 3:1:1, the particle size is about 40-60 nm, the counterion is sulfate ion, and the mass ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone is 9.58:3.19:3.19:1.

9. A mitoxantrone hydrochloride liposome for use in treating breast cancer in a patient; preferably, the liposome is in a dosage form for injection, including a liquid for injection, a powder for injection, a tablet for injection, and the like; when the medicament is a liquid injection, the liposome comprises 0.5-5 mg/mL, preferably 1-2 mg/mL, and more preferably 1 mg/mL of active ingredient, on the basis of mitoxantrone; or preferably, the liposomes is used alone for treating breast cancer in the patient; or preferably, a therapeutically effective amount of the liposomes is 8-30 mg/m.sup.2, more preferably 12-20 mg/m.sup.2 or 16-30 mg/m.sup.2, on the basis of mitoxantrone; for a specific example, 12 mg/m.sup.2, 14 mg/m.sup.2, 16 mg/m.sup.2, 18 mg/m.sup.2 and 20 mg/m.sup.2, on the basis of mitoxantrone; or preferably, the route of administration of the liposome is intravenous administration; preferably, the frequency of administration is once every 4 weeks; preferably, for each intravenous administration, the dripping administration time of the liposome is 30-120 min, preferably 55-120 min or 60-120 min, more preferably not less than 60 min, and even more preferably 60±5 min; or preferably, the patient receives a total dose of mitoxantrone of no more than 200 mg/m.sup.2, preferably no more than 160 mg/m.sup.2, more preferably no more than 140 mg/m.sup.2, and even more preferably no more than 120 mg/m.sup.2.

10. The mitoxantrone hydrochloride liposome according to claim 9, wherein the mitoxantrone hydrochloride liposome has a particle size of about 30-80 nm and comprises: 1) mitoxantrone as active ingredient, which can form a hardly soluble precipitate with multivalent counterions in the liposome, and 2) a phospholipid bilayer containing a phospholipid with a phase transition temperature (Tm) higher than a body temperature, wherein 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; preferably, the mitoxantrone hydrochloride liposome has a particle size of about 35-75 nm, preferably 40-70 nm, more preferably 40-60 nm, and even more preferably 60 nm; or preferably, the phospholipid bilayer contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000-modified distearoyl phosphatidyl ethanolamine in a mass ratio of 3:1:1, the particle size is about 60 nm, and the counterion is sulfate ion; or preferably, the phospholipid bilayer of the liposome contains hydrogenated soybean lecithin, cholesterol and polyethylene glycol 2000-modified distearoyl phosphatidyl ethanolamine in a mass ratio of 3:1:1, the particle size is about 40-60 nm, the counterion is sulfate ion, and the mass ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone is 9.58:3.19:3.19:1.

Description

DETAILED DESCRIPTION

Example 1. Mitoxantrone Hydrochloride Liposome Monotherapy for Treatment of Breast Cancer

I. Trial

[0030] The study is a randomized, open-labeled, active controlled, single center study to evaluate the safety and efficacy of the mitoxantrone hydrochloride liposome injection in patients with advanced recurrent or metastatic breast cancer.

[0031] 1. Administration

TABLE-US-00001 TABLE 1 Specific Administration Drug Dosage and route Time and treatment cycle Mitoxantrone 20 mg/m.sup.2, i.v. d1 Continuously i.v. drip for hydrochloride 1 h, once every 4 weeks liposome injection Mitoxantrone 14 mg/m.sup.2, i.v. d1 Continuously i.v. drip for hydrochloride 30 min, once every 4 weeks injection

[0032] Investigational product: mitoxantrone hydrochloride liposome injection (PLM60 (10 mg/10 mL/vial)) was added to 250 mL of 5% glucose at a dose of 20 mg/m.sup.2 and was administered intravenously over 1 h.

[0033] Reference product: mitoxantrone hydrochloride injection (5 mg/5 mL/vial, manufactured by Sichuan Sunnyhope Pharmaceutical, Inc., supplied by CSPC ZHONGQI Pharmaceutical Technology (Shijiazhuang) Co., Ltd., Lot No. 1501201) was added to 100 mL of 5% glucose injection at a dose of 14 mg/m.sup.2 and was administered intravenously over 30 min.

[0034] 2. Inclusion Criteria:

[0035] The inclusion criteria for the patient in this study are as follows:

[0036] 1) Voluntary participation and written informed consent;

[0037] 2) Aged 18 to 75 years (inclusive), female;

[0038] 3) Pathologically and/or cytologically confirmed recurrent, metastatic breast cancer; and failed for at least two lines of chemotherapies to the recurrent or metastatic lesions;

[0039] 4) Suitable for chemotherapy;

[0040] 5) HER2 negative patients (definition: IHC 0 or 1+; IHC 2+and FISH negative); HER2 positive patients unable to undergo anti-HER2 targeted therapy (definition: IHC 3+; or FISH positive);

[0041] 6) Unsuitable for endocrine therapy or confirmed endocrine resistance;

[0042] 7) Having at least one measurable lesion (according to RECIST 1.1 criteria, diameter≥10 mm by spiral CT scan);

[0043] 8) If there is an anthracycline-containing adjuvant chemotherapy, an interval of more than 12-month was required from the last dose of the prior adjuvant chemotherapy to the recurrence;

[0044] 9) ECOG score of 0-2 (for ECOG scale, see Appendix 1), and an expected life expectancy of at least 3 months;

[0045] 10) Normal cardiac function (NYHA class I, LVEF ≥50%);

[0046] 11) All subjects of child-bearing age (fertile) must take medically well-known effective contraceptive measures;

[0047] 12) The blood, liver and kidney function test results are in the following ranges: [0048] White Blood Cell (WBC)≥3.0×10.sup.9/L, [0049] Absolute Neutrophil Count (ANC)≥1.5×10.sup.9/L, [0050] PLT≥75×10.sup.9/L, [0051] Blood Hb≥90 g/L, [0052] Tbil≤1.5×Upper Limit of Normal (ULN), [0053] ALT and AST≤2.5×ULN (for subject with liver metastasis, ≤5×ULN), [0054] Cr≤1.5×ULN.

[0055] Note: Anti-HER 2 targeted therapy may not be available for HER2-positive patients due to unaffordability, toxicity, or tolerance reasons. HER2-positive patients who were unable to undergo anti-HER 2 targeted therapy could be enrolled.

[0056] 3. Safety Assessment:

[0057] The safety assessment indicators included: vital signs, adverse events, laboratory tests (complete blood test, routine urinalysis, blood biochemistry, electrocardiogram, echocardiogram), and early withdrawal. Safety assessment criteria: NCI-CTC 4.0.

[0058] 4. Efficacy Evaluation:

[0059] A tumor assessment was performed at baseline.

[0060] During the treatment period, the efficacy evaluation was performed once every two cycles; in addition, when the efficacy evaluation result was PR or CR, the efficacy should be radiologically confirmed after 4 weeks. After the completion of the treatment, the evaluation was performed every 3 months until disease progression. Tumor evaluation was performed according to RECIST 1.1 criteria.

[0061] Primary efficacy endpoint: objective response rate (ORR), referring to the ratio of subjects reaching PR and CR.

[0062] Secondary efficacy endpoint: progression-free survival (PFS), referring to the time from the start of randomization to disease progression or death.

II. Trial Results

[0063] 1. Efficacy Analysis:

[0064] In this study, 60 eligible breast cancer patients were randomized to the treatment and control groups with 30 subjects in each. Of the 60 subjects, 42 subjects were treated for <4 cycles, of whom 19 were in the treatment group and 23 were in the control group; 18 subjects received more than 4 cycles of treatment, of whom 11 were in the treatment group and 7 were in the control group.

[0065] Treatment group: among the 30 breast cancer subjects, 4 had partial response (PR), and 11 had stable disease (SD), showing an ORR of 13.3% (4/30), and a disease control rate (PR+SD) of 50% (15/30); Control group: among the 30 breast cancer subjects, 2 had partial response (PR), and 7 had stable disease (SD), showing an ORR of 6.7% (2/30), and a disease control rate (PR+SD) of 30% (9/30). In FAS, the median PFS was 2.3 months for the treatment group and 1.86 months for the control group, and the PFS in the treatment group was numerically higher than the control group. In FAS, the 3-, 6-and 12-month progression-free survival rates of the two groups (treatment group vs. control group) were 43.3% vs. 26.7%, 21.9% vs. 20%, and 16.4% vs. 0%, respectively.

[0066] The objective response rates (13.3% vs. 6.7%) and disease control rates (50% vs. 30%) of the treatment group were numerically superior to those of the control group. The efficacy of the mitoxantrone hydrochloride liposome monotherapy for treating breast cancer is detailed in the following tables.

TABLE-US-00002 TABLE 2 Inter-group comparative analysis of best overall response of the two groups FAS (N = 60) PPS (N = 58) Treatment Control Treatment Control Efficacy group group group group evaluation (n = 30) (n = 30) Statistics P value (n = 30) (n = 28) Statistics P value Best overall 3.626 0.2818 1.932 0.4276* response evaluation PR 4 (13.3%) 2 (6.7%) 4 (13.3%) 2 (7.1%) SD 11 (36.7%) 7 (23.3%) 11 (36.7%) 7 (28.6%) PD 15 (50.0%) 19 (63.3%) 15 (50.0%) 19 (67.9%) NA 0 (0.0) 2 (6.7%) 0 (0.0) 0 (0.0) Note: Fisher's exact probability was used.

TABLE-US-00003 TABLE 3 Median PFS and inter-group comparative analysis of the two groups FAS (N = 60) PPS (N = 58) Median Median Number of PFS Log-rank Number of PFS Log-rank Group N events (%) (month) 95% CI P value N events (%) (month) 95% CI P value Treatment 30 24(80.0) 2.30 1.741, 0.565 30 24(80.0) 2.30 1.741, 0.689 group 3.910 3.910 Control 30 25(83.3) 1.86 1.741, 28 23(82.14) 1.86 1.741, group 2.398 2.004

TABLE-US-00004 TABLE 4 Progression-free survival rate and 95% confidence intervals of the two groups FAS(N= 60) PPS(N=58) Treatment group Control group Treatment group Control group Progression- Progression- Progression- Progression- PFS free survival free survival free survival free survival (Months) rate 95% CI rate 95% CI rate 95% CI rate 95% CI 3 43.3 25.6~59.9 26.7 12.6~43.0 43.3 25.6~59.9 28.6 13.5~45.6 6 21.9 8.9~38.4 20.0 6.9~38.0 21.9 8.9~38.4 21.4 7.0~40.3 12 16.4 5.1~33.4 0 0 16.4 5.1~33.4 0 0 Note: The abbreviations above have the following meanings: CR: complete response, defined explicitly according to the “Response Evaluation Criteria in Solid Tumors” (RECIST 1.1). PR: partial response, defined explicitly according to the “Response Evaluation Criteria in Solid Tumors” (RECIST 1.1). PD: progressive disease, defined explicitly according to the “Response Evaluation Criteria in Solid Tumors” (RECIST 1.1). SD: stable disease, defined explicitly according to the “Response Evaluation Criteria in Solid Tumors” (RECIST 1.1). FAS: full analysis set, statistical term. PPS: per protocol set, statistical term. Overall response rate (ORR) = (CR + PR)/total number of evaluable patients × 100%.

[0067] 2. Safety Analysis:

[0068] For the drug mitoxantrone, the most serious adverse event is cardiotoxicity. Clinical studies and practical observations have shown that the cardiotoxicity caused by anthracyclines are mainly progressive and irreversible. Especially anthracyclines can easily cause cardiac damage at first use. Cardiotoxicity is a common concern for clinicians since it is a long-term cumulative dose-limiting toxicity. The incidence of increased troponin T and the incidence of increased brain natriuretic peptide were used as indices for examining cardiotoxicity in this trial. The change of the cardiac troponin T level can reflect myocardium damage with high sensitivity; brain natriuretic peptide is a polypeptide hormone secreted by cardiomyocytes in the heart ventricles in response to stretching caused by increased ventricular blood volume and increased ventricular pressure.

[0069] From Table 5 it can be seen that: 1) The incidence of increased troponin T was 3.3% for the treatment group and 36.7% for the control group, with an extremely significant difference. Therefore, the liposome dosage form can significantly reduce the cardiotoxicity of mitoxantrone hydrochloride; 2) The incidence of increased brain natriuretic peptides was the same for the two groups (33.3% vs 33.3%). However, as can be seen from Tables 6 and 7, the levels of increase were different, and the number of cases and severity of the treatment group were significantly lower than those of the control group.

[0070] The overall incidence rate of adverse events was 100% for the treatment group and the control group, and the most common adverse events were hematological toxicity. Among the adverse events that occurred at least 30% in the groups, the incidences of decreased white blood cell count (86.7% vs 96.7%), decreased neutrophil count (80.0% vs 96.7%), increased conjugated bilirubin (53.3% vs 56.7%), increased aspartate aminotransferase (40.0% vs 53.3%) and increased troponin T (3.3% vs 36.7%) of the treatment group were lower than those in the control group, and the incidences of anemia (76.7% vs 46.7%), skin hyperpigmentation (66.7% vs 3.3%) and decreased platelet count (56.7% vs 53.3%) of the treatment group were higher than those in the control group.

[0071] The trail results demonstrated that the mitoxantrone hydrochloride liposome has a trend superior to mitoxantrone hydrochloride in numerical values of objective response rate, disease control rate, progression-free survival and other indicators in treating advanced recurrent or metastatic breast cancer, and the cardiotoxicity of the mitoxantrone hydrochloride liposome is significantly lower than that of mitoxantrone hydrochloride.

TABLE-US-00005 TABLE 5 Incidence of adverse events Treatment Control Item group (%) group (%) Increased troponin T 1 (3.3%) 11 (36.7%) Increased brain natriuretic peptide 10 (33.3%) 10 (33.30%) Decreased white blood cell count 26 (86.7%) 29 (96.70%) Decreased neutrophil count 24 (80.0%) 29 (96.70%) Anemia 23 (76.7%) 14 (46.70%) Increased conjugated bilirubin 16 (53.3%) 17 (56.70%) Decreased platelet count 17 (56.7%) 16 (53.30%) Increased aspartate aminotransferase 12 (40.0%) 16 (53.30%) Increased blood bilirubin 9 (30.0%) 6 (20.00%) Fever 7 (23.3%) 3 (10.0%) Increased alanine aminotransferase 6 (20.0%) 8 (26.70%)

TABLE-US-00006 TABLE 6 Analysis of number of subjects with increased brain natriuretic peptide and severity Treatment group (n = 30) Control group (n = 30) Grade Grade Grade Grade Grade Grade Grade Grade 1 2 3 4 1 2 3 4 Increased brain 10(33.3%) — — — 9(30.0%) 1(3.3%) — — natriuretic peptide

TABLE-US-00007 TABLE 7 Analysis of number of cases with increased brain natriuretic peptide and severity Treatment group (n = 30) Control group (n = 30) Grade Grade Grade Grade Grade Grade Grade Grade 1 2 3 4 1 2 3 4 Increased brain 13 — — — 15 1 — — natriuretic peptide

TABLE-US-00008 APPENDIX 1 ECOG scale Zubrod-ECOG-WHO (ZPS, 5 grades) Physical condition Grade Fully active 0 Symptomatic but completely ambulatory; able to carry 1 out work of a light or sedentary nature Able to tolerate tumor symptoms, capable of all 2 self-care, <50% in bed during the day Seriously symptomatic; >50% in bed during the day, 3 but not bedbound, capable of only limited self-care Bedbound 4 Death 5