TWI709402B - The use of chidamide and exemestane in the preparation of combination medicaments for the treatment of breast cancer and combination medicaments - Google Patents

Abstract

The present invention relates to the use of chidamide and exemestane in the preparation of a combination medicament for the treatment of breast cancer, a pharmaceutical composition or a combination drug comprising chidamide and exemestane, and a method of treating breast cancer by combination use of chidamide and exemestane.

Description

Use of chidamide and exemestane in preparing a combined drug for treating breast cancer and the combined drug

The invention belongs to the field of chemical pharmacy, and specifically relates to a use of chidamide and exemestane in preparing a combined drug for treating breast cancer and the combined drug.

Exemestane, the chemical name is 1,4-diene-3,17-dione-6-methylene androstane or 6-methylene androstan-1,4-diene-3,17- Dione, white or almost white crystalline powder; odorless. It is easily soluble in chloroform, soluble in ethyl acetate, acetone, methanol or ethanol, and almost insoluble in water. Clinically, it is suitable for postmenopausal advanced breast cancer patients whose condition has progressed after tamoxifen treatment.

Breast cancer is the highest incidence of female malignant tumors in the world and in my country. The molecular classification of breast cancer is related to prognosis and treatment response, and it occupies a dominant position in treatment decision-making. At the St Gallen International Breast Cancer Conference in March 2011, experts re-discussed the molecular classification of breast cancer and reached an expert consensus. According to the estrogen receptor (ER), progesterone receptor (PgR), human epidermal The expression of growth factor receptor-2 (Her-2) and Ki-67 divide breast cancer into four subtypes: Luminal A, Luminal B, Her-2(+), and Basal-like.

Among them, estrogen receptor (ER)-positive breast cancer accounts for about 70% of all breast cancers. It is an estrogen-dependent tumor and promotes the growth of breast cancer cells through the interaction of estrogen and ER. Endocrine therapy suppresses the growth of tumor cells by reducing the level of estrogen in the body or inhibiting the binding of estrogen to the receptor. For ER-positive breast cancer, endocrine drugs are the most basic and effective treatment, whether it is adjuvant therapy after surgery or systemic therapy for metastases. Compared with chemotherapy, endocrine therapy has mild side effects, good tolerance, and long-term application.

NCCN (National Comprehensive Cancer Network) breast cancer guidelines and the consensus of Chinese endocrine therapy experts point out that the treatment of ER-positive recurrent or metastatic breast cancer patients is mainly for the purpose of prolonging survival and improving quality of life, and priority should be given to the less toxic endocrine treatment. Therefore, endocrine therapy is one of the main methods of systemic breast cancer treatment, and it is of great significance in the clinical treatment of breast cancer. Table 1 below lists representative endocrine therapy drugs commonly used in clinical practice. Table 1 Commonly used clinical endocrine therapy drugs

A number of clinical studies have confirmed that exemestane has a good effect in the adjuvant treatment and second-line treatment of ER-positive postmenopausal breast cancer and occupies an important position. In addition, its efficacy in first-line treatment is also good.

In the past few decades, although the endocrine therapy of breast cancer has made great progress and has become the most basic and effective treatment for patients with ER-positive breast cancer, its clinical effectiveness is still severely restricted by drug resistance: close to 30% Of advanced breast cancer patients develop primary resistance to endocrine therapy. Even if the initial treatment is effective or those who are effective after changing different types of drugs, acquired resistance will eventually appear. The disease progression time of endocrine drug therapy is less than one year on average. Therefore, the resistance of endocrine therapy has become a major problem and a huge challenge in the clinical treatment of breast cancer.

Chidamide (Chidamide) is a subtype selective histone deacetylase (HDAC) inhibitor with the chemical name N-(2-amino-4-fluorophenyl)-4- [N-[(E)-3-(3-pyridine)propenyl]aminomethyl]benzamide is a new class 1.1 drug. In the Phase I clinical trial of Chidamide, a total of 16 patients with solid tumors were enrolled, including non-small cell lung cancer, breast cancer, colon cancer, rectal cancer, gastric cancer, prostate cancer, etc., except for 1 case of submandibular adenoid cystic carcinoma Except for partial remission, none of the other solid tumors has a clear curative effect. This phase I clinical result shows that chidamide alone is not effective for breast cancer. Therefore, in the phase II clinical trial of chidamide, no further breast cancer was included Cancer patients.

Chidamide is approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). The inventors unexpectedly discovered in the research that the combined use of chidamide and exemestane can effectively improve the treatment of breast cancer, and obtain a significantly improved effect compared to exemestane monotherapy, especially It can significantly prolong the progression-free survival of patients and improve the clinical benefit rate and objective remission rate.

Therefore, in the first aspect, the present invention provides the use of chidamide and exemestane in the preparation of a combination medicine for the treatment of breast cancer.

Chidamide (Chidamide) is a subtype selective histone deacetylase (HDAC) inhibitor with the chemical name N-(2-amino-4-fluorophenyl)-4- [N-[(E)-3-(3-pyridine)propenyl]aminomethyl]benzamide is a new class 1.1 drug.

It should be noted that in this article, the term chidamide not only includes the chemical entity under the above chemical name, but also includes its pharmaceutically acceptable salts, solvates (including hydrates), isomers, prodrugs, and metabolic Things.

Specifically, in the first aspect, the present invention provides the use of a combination of the following active ingredients in the preparation of a combination medicine for the treatment of breast cancer: (a) Chidamide, including its pharmaceutically acceptable salts and solvates Or hydrate; and (b) Exemestane.

Preferably, the breast cancer is a hormone receptor positive advanced breast cancer; further preferably, the breast cancer is a hormone receptor positive advanced breast cancer that has failed endocrine therapy. Further preferably, the breast cancer is a hormone receptor positive advanced breast cancer that has failed endocrine therapy and has undergone visceral metastasis.

In another aspect, the present invention provides a pharmaceutical composition or combination drug, particularly a pharmaceutical composition for the treatment of hormone receptor-positive advanced breast cancer, comprising components (a) and (b) as active ingredients: (a) Chidamide, including its pharmaceutically acceptable salts, solvates or hydrates; and (b) Exemestane.

Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

Preferably, in the pharmaceutical composition, the weight ratio of the component (a) (based on chidamide) to the component (b) exemestane is (2-6):5.

Preferably, the weight ratio of the component (a) (calculated as Chidamide) to exemestane is 6:5.

Preferably, the pharmaceutical composition is in the form of a tablet.

In yet another aspect, the present invention provides a kit comprising the following active ingredients (a) and (b) in the form of a single preparation or in the form of separate preparations: (a) Chidamide, including it A pharmaceutically acceptable salt, solvate or hydrate; and (b) Exemestane.

In another aspect, the present invention also provides a method for the treatment of breast cancer, comprising simultaneously, separately or sequentially administering components (a) and (b) as active ingredients to a subject in need: (a) Sidaben Amines, including their pharmaceutically acceptable salts, solvates or hydrates; and (b) Exemestane.

In the treatment method, the breast cancer is preferably hormone receptor-positive advanced breast cancer; further preferably, the breast cancer is hormone receptor-positive advanced breast cancer that has failed endocrine therapy. Particularly preferably, the breast cancer is breast cancer with visceral metastasis, especially hormone receptor-positive advanced breast cancer with visceral metastasis that has failed endocrine therapy. In the method, the weight ratio of the component (a) (calculated by chidamide) to the component (b) exemestane is preferably (2-6): 5; more preferably, The weight ratio of said component (a) (calculated as Chidamide) and exemestane is 6:5.

The drug combination or combination drug for treating breast cancer provided by the present invention does not limit the specific form used. For example, it can be a combination form of a unit preparation containing separate chidamide and exemestane of the same or different specifications, or a pharmaceutical composition containing chidamide and exemestane in a single preparation Form; can take the combined form (such as a kit) of the respective preparations of chidamide and exemestane; can be administered simultaneously, or separately or sequentially; and so on. Compared with exemestane monotherapy, the combination of the present invention has significantly better curative effect and clinical benefits for the treatment of breast cancer, especially hormone receptor-positive advanced breast cancer that has failed endocrine therapy. Example 1 : Clinical trial of combination of Chidamide tablets and exemestane tablets

A total of 20 patients were selected for this clinical trial. The selected patients must meet all the following criteria: 1) 18~75 years old, postmenopausal women ^* patients; 2) Histologically or cytologically confirmed hormone receptor positive (estrogen receptor) (ER) positive, progesterone receptor (PgR) negative or positive> breast cancer patients; 3) Disease progression or recurrence after at least one endocrine drug treatment (regardless of rescue treatment or adjuvant treatment); 4) Regardless of rescue treatment before admission Or the total number of adjuvant treatment regimens is ≤4, among which the number of rescue chemotherapy regimens is ≤1; 5) Stage III or IV breast cancer with inoperable disease status before enrollment, with at least one measurable lesion or no measurable lesion Patients with simple bone metastases; 6) Time interval from last treatment: (a) If the last treatment is endocrine therapy, it takes ≥2 weeks; (b) If the last treatment is chemotherapy, it takes ≥4 weeks; 7) ECOG score: 0 or 1 point; 8) The absolute value of neutrophils ≥ 1.5×10 ⁹ /L, platelets ≥ 100×10 ⁹ /L, hemoglobin ≥ 90g/L; 9) Expected survival time ≥ 3 months; 10 ) Sign written informed consent voluntarily.

After screening, eligible patients were treated with Chidamide tablets and exemestane tablets. The names and specifications of the drugs used in the clinical trials of this example are as follows: Chidamide tablets: white-like tablets, 5 mg/tablet. Developed and provided by Shenzhen Chips Biotechnology Co., Ltd. Shading, sealed, and stored below 25°C. Exemestane tablets: white sugar-coated tablets, white after removing the sugar-coated tablets, 25mg/tablet. The manufacturer is Pfizer Italia S.r.l., provided by Shenzhen Chips Biotechnology Co., Ltd. Store below 30°C.

The treatment process of the clinical trial of this embodiment is divided into a lead-in period and a combined treatment period. The specific treatment plan is as follows: ü Lead-in period The lead-in period is 4 days, and exemestane tablets and chidamide tablets are administered separately once. Day 1: Take 1 tablet (25mg) exemestane orally 30 minutes after breakfast. Day 2: Take 6 tablets (30 mg) of Chidamide orally 30 minutes after breakfast. Routine blood examinations are performed on the 4th day of the lead-in period. Only when neutrophils ≥ 1.5×10 ⁹ /L, platelets ≥ 90×10 ⁹ /L and hemoglobin ≥ 90g/L can enter the combined treatment period. If the neutrophils and/or platelets and/or hemoglobin on the 4th day of the introductory period do not meet the prescribed standards, delay entering the combined treatment period, and check the blood routine every 1 to 2 days. If the specified standard is not reached after a delay of 7 days, the test will be withdrawn. ü Combined treatment period After the lead-in period is completed, the combined treatment period will be entered immediately. During this treatment period, the patient received both chidamide tablets and exemestane tablets. Every 4 weeks is a treatment cycle, and the window period of all cycles is ±2 days. Ÿ Chidamine tablets: Orally twice a week, 6 tablets/time (30mg/time), the interval between two doses should not be less than 3 days (such as Monday and Thursday, Tuesday and Friday, Wednesday and Saturday, etc. ), take 30 minutes after breakfast. Ÿ Exemestane tablets: Orally once a day, 1 tablet/time (25mg/time), take 30 minutes after breakfast. If you take chidamide tablets on the same day, take exemestane tablets and chidamide tablets at the same time. All patients continued treatment until the following conditions: disease progression, intolerable toxicity, death, withdrawal from treatment, withdrawal of informed consent, or loss to follow-up. Example 2 : Curative effect results of clinical trials of combined use of Chidamide tablets and exemestane tablets

The main efficacy indicators are as follows: ü Objective remission rate: the percentage of patients with complete remission (CR) and partial remission (PR) in the total number of analysis sets and their 95% CI; ü Progression-free survival (PFS): estimated by kaplan-Meier method PFS distribution, plot survival curve.

Efficacy results: The clinical results of this clinical trial of Chidamide combined with exemestane in the treatment of HR-positive advanced breast cancer are as follows. This trial enrolled 20 patients with HR-positive and HER-negative breast cancer, 3 patients achieved partial response, and 12 patients The patient achieves stable disease. Three patients discontinued the drug due to adverse reactions. Adverse reactions above grade 3 included neutropenia (35%), thrombocytopenia (30%), and leukopenia (20%).

It can be seen from the above results that compared with the median objective response rate of 4.6% and the median progression-free survival of 4.1 months of exemestane monotherapy for breast cancer, the combination of chidamide and exemestane is effective The median objective response rate reached 15%, and the median progression-free survival period reached 7.6 months. It can be seen that chidamide and exemestane have a good synergistic effect in the preparation of a combination drug for the treatment of breast cancer. Example 3 : Combined pharmaceutical composition

The combined pharmaceutical composition of this embodiment includes 1 exemestane tablet (25 mg) and 6 chidamide tablets (30 mg). Example 4 : Combined pharmaceutical composition

The combined pharmaceutical composition of this embodiment includes 1 exemestane tablet (25 mg) and 2 chidamide tablets (10 mg). Example 5 : Preparation of combined pharmaceutical composition

The combination pharmaceutical composition preparation of this embodiment contains 25 mg of exemestane, 10 mg of chidamide and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include: including the "Handbook of Pharmaceutical Excipients" (American Pharmaceutical Association, October 1986) or the "Handbook of Pharmaceutical Excipients" (Handbook of Pharmaceutical Excipients, Fourth Edition) published by the Chemical Industry Press The carrier excipients listed are preferably pharmaceutical excipients used in tablet formulations, but are not limited to these pharmaceutical excipients. Example 6 : Multi-center, double-blind, randomized phase III clinical trial study of the combination of chidamide tablets and exemestane tablets

Research method: This study is a multi-center, double-blind, randomized phase III clinical trial study (trial registration number: NCT02482753). The selected population is postmenopausal patients aged 18 to 75 years, estrogen receptor positive, HER-2 negative, and recurrence/metastasis patients with previous endocrine (adjuvant or rescue) treatment. The physical status score (ECOG score) is 0 or 1, with measurable lesions or simple bone metastases. Randomized 2:1 to the test group (sidamamide combined with exemestane) and the control group (placebo combined with exemestane), and the stratification factor was whether there was visceral metastasis. Exemestane 25mg once a day combined with placebo/chidamide 30mg twice a week, until disease progression or intolerable toxicity occurs. The primary endpoint is progression-free survival (PFS), and the secondary endpoints include overall survival (OS), objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR). The specific research methods are as follows: 1. Stratified randomized and blinded method The double-blind control period of this trial is a stratified randomized double-blind trial. In a double-blind controlled phase trial, after confirming that the patient meets all the inclusion/exclusion criteria, the researcher or his/her designated person will assign a randomization number to the patient using the Interactive Network Response System (IWRS) or Interactive Voice Response System (IVRS) . When designating treatment groups, stratification should be based on the following factors: Are there visceral metastases during the screening period? (Yes or No) Then the patients were randomly assigned to the test group (sidamamide tablets + exemestane tablets) and control group (placebo + exemestane tablets) according to 2:1. From the time of randomization, the treatment group designated by the patient should be blinded to the patient, investigator, research team, and anyone involved in the execution of the trial until the database is locked. Before unblinding, the randomized data should be kept strictly confidential, and no one involved in the execution of the trial can be approached. The test drugs used (Cidamide and Chidamide simulation tablets (placebo)) are completely consistent in packaging, labeling, dosing schedule and appearance, so that the treatment can be kept confidential. 2. Double-blind control method Patients who meet the screening criteria are stratified according to whether there is visceral metastasis, and randomly assigned to the experimental group and the control group according to 2:1. Test group: 30mg chidamide tablets + exemestane tablets, control group: chidamide simulated tablets (placebo) + exemestane tablets. Every 4 weeks is a treatment cycle, and the window period of all cycles is ±2 days. Chidamide tablets/placebo: Orally twice a week, 6 tablets/time, the interval between two doses should not be less than 3 days (such as Monday and Thursday, Tuesday and Friday, Wednesday and Saturday, etc.), breakfast Take it after 30 minutes. Exemestane tablets: Orally once a day, 1 tablet/time (25mg/time), take 30 minutes after breakfast. If Chidamide tablets/placebo is taken on the same day, exemestane tablets and Chidamide/placebo will be taken at the same time. All patients continued treatment until the following conditions: disease progression, intolerable toxicity, death, withdrawal from treatment, withdrawal of informed consent, or loss to follow-up. 3. During the dose adjustment trial, for patients with ≥ Grade 3 adverse events (AE) related to the trial drug, on the basis of symptomatic treatment, the main method will be to reduce the dose of Chidamide tablets/placebo and suspend Chidamide. It is not recommended to adjust the medication of Exemestane tablets. 4. The efficacy evaluation standard is based on the solid tumor RECIST 1.1 (2009) standard (see Appendix 1) for efficacy evaluation. The efficacy can be divided into four levels: complete remission, partial remission, disease progression, and stability. ü Complete remission (CR): All target lesions disappeared. The short diameter of all pathologically positive lymph nodes (whether target lesions or non-target lesions) must be reduced to <10 mm. ü Partial remission (PR): Compared with the total longest diameter (LD) of the baseline lesion, the total LD of the target lesion is reduced by at least 30%. ü Disease progression (PD): The total LD of the target lesion is increased by at least 20% compared with the minimum LD of the lesion recorded since the start of treatment, and the absolute value of the total LD is increased by at least 5 mm. When one or more new lesions appear, it is also considered PD. ü Stable (SD): Compared with the minimum sum of LD recorded since the start of treatment, the sum of LD of the lesion has neither achieved a partial remission reduction nor an increase in tumor progression. For patients with no measurable lesions at baseline (according to RECIST criteria) and simple bone metastases, disease progression (PD) is considered if one of the following occurs: ü One or more new osteolytic lesions in the bone; ü Bone One or more new lesions appear in other organs or tissues; ü A clear progression of the original lesions in the bones. Note: Complications caused by pathological fractures, new compression fractures or bone metastases are not considered as disease progression, unless one of the above conditions for determining disease progression is met. 5. Efficacy evaluation methods use imaging (including CT, MRI, bone scan, etc.) to evaluate the size of the patient’s lesions. The imaging methods used by patients at all follow-up points must be the same. 6. Efficacy evaluation interval ü Tumor remission evaluation: once every 2 cycles during treatment; if the patient withdraws from the trial due to non-progressive reasons (such as adverse events, management reasons, etc.), tumor evaluation should continue every 8 weeks until the patient is sick Progress or start a new anti-tumor treatment (whichever occurs first). ü Overall survival evaluation: After the last medication, the patient can be followed up every 12 weeks by phone or visit. Until it was recorded that about 70% (ie about 230) of the patients died. 7. In the double-blind controlled phase trial of independent imaging evaluation, an independent imaging evaluation agency will independently analyze and judge the imaging data of all patients under the blind state, and the evaluation results will be used as the support for the efficacy results of the double-blind controlled phase trial in accordance with. 8. Statistical methods and data analysis 8.1 Statistical methods: Full analysis set (FAS, Full analysis set) is used, according to the principle of intention to treat (ITT), including all patients who have taken the trial drug at least once after randomization. Per Protocol Set (PPS, Per Protocol Set): On the basis of FAS, patients who meet the selection criteria, do not meet the exclusion criteria, have a valid baseline value, have good compliance, and do not violate the clinical trial protocol. Safety Data Set (SS, Safety Set): Patients who have taken the trial drug at least once after enrollment and have safety index records. The curative effect analysis uses both FAS and PPS, with FAS results as the main. Safety analysis uses safety data sets. 8.2 Data analysis method: Patient demography/other baseline characteristics: using FAS, list and summarize the baseline demographic and disease characteristics data according to different groups. Use descriptive summary statistics (such as frequency, average, median, range, and standard deviation) to list numerical data. Treatment (experimental drug exposure, combined medication, compliance): use SS to summarize the exposure time and dose of experimental drug treatment according to different groups. List the number of patients with dose adjustment/suspend medication, and list the reasons for dose adjustment/suspend medication. Using SS, list and summarize the information of co-administered drugs during the trial. The compliance standard for patients' medication is that the actual dosage of medication accounts for 80%-120% of the applied medication. Research result:

In this clinical trial, a total of 365 patients were enrolled in 22 large hospitals in China, of which 244 patients were randomly entered into the experimental group and 121 patients were randomly entered into the control group. The results of the full analysis set (FAS) population analysis showed that the median PFS of the experimental group and the control group were 7.4 months (95% CI, 5.5-9.2) and 3.8 months (95% CI, 3.7-5.5), respectively (HR= 0.755; 95% CI, 0.582-0.978; P=0.0336). No matter with or without visceral metastasis, Chidamide combined with exemestane prolonged the PFS of patients compared with exemestane monotherapy, and the difference was more obvious in patients with visceral metastasis (PFS was 5.5 months and 2.0, respectively month). The objective response rates of the experimental group and the control group were 18.4% and 9.1% (P=0.026), and the clinical benefit rates were 46.7% and 35.5% (P=0.034).

For hormone-receptor-positive advanced breast cancer that has failed endocrine therapy and has visceral metastasis, chidamide combined with exemestane can prolong the PFS of patients more significantly than exemestane monotherapy. In this clinical trial, Xidar The median PFS of the amine combined with exemestane group was extended from 2.0 months to 5.5 months compared with the exemestane combined placebo group.

The results of the above-mentioned expanded clinical research further confirmed that: compared with exemestane monotherapy, the combination of chidamide and exemestane can significantly increase the median objective response rate, prolong the median progression-free survival, and improve the clinical Yield rate. Therefore, chidamide and exemestane have a clear synergistic effect in the preparation of a combination drug for the treatment of breast cancer.

Claims (5)

Use of a combination of the following active ingredients in the preparation of a combination medicine for the treatment of breast cancer: (a) Chidamide, including its pharmaceutically acceptable salts; and (b) exemestane, wherein the breast The cancer is advanced breast cancer that is hormone receptor-positive, has failed endocrine therapy and has visceral metastasis. The use according to claim 1, wherein the combination of active ingredients further comprises a pharmaceutically acceptable carrier. The use according to claim 1, wherein the weight ratio of component (a) and component (b) exemestane based on chidamide is (2-6): 5. The use according to claim 3, wherein the weight ratio of component (a) based on chidamide and exemestane is 6:5. The use according to any one of claims 1 to 4, wherein the combination of active ingredients is in the form of a tablet.