TW201944997A - The use of chidamide and exemestane in the preparation of combination medicaments for the treatment of breast cancer and combination medicaments - Google Patents
The use of chidamide and exemestane in the preparation of combination medicaments for the treatment of breast cancer and combination medicaments Download PDFInfo
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本發明屬於化學製藥領域，具體涉及一種西達本胺與依西美坦在製備用於治療乳腺癌的聯合用藥物中的用途及其聯合用藥物。The invention belongs to the field of chemical pharmacy, and particularly relates to a use of cidabenzamide and exemestane in preparing a combined medicine for treating breast cancer and a combined medicine thereof.
依西美坦，化學名稱爲 1,4-二烯-3,17-二酮-6-亞甲基雄甾烷或6-亞甲基雄甾-1,4-二烯-3,17-二酮，爲白色或類白色結晶性粉末；無臭。在三氯甲烷中易溶，在乙酸乙酯、丙酮、甲醇或乙醇中溶解，在水中幾乎不溶。臨床上適用於以他莫昔芬治療後病情進展的絕經後晚期乳腺癌患者。Exemestane with the chemical name 1,4-diene-3,17-dione-6-methyleneandrostane or 6-methyleneandroster-1,4-diene-3,17- Dione, white or off-white crystalline powder; odorless. Soluble in chloroform, soluble in ethyl acetate, acetone, methanol or ethanol, and almost insoluble in water. It is clinically applicable to patients with advanced postmenopausal breast cancer treated with tamoxifen.
乳腺癌是全球及我國發病率最高的女性惡性腫瘤，乳腺癌的分子分型與預後和治療反應相關，並在治療决策選擇中占據主導地位。2011年3月St Gallen國際乳腺癌會議上，專家對乳腺癌的分子分型進行了重新討論，並達成了專家共識，根據***受體（ER）、孕激素受體（PgR）、人表皮生長因子受體-2（Her-2）、Ki-67表達情况將乳腺癌分爲Luminal A 型、Luminal B 型、Her-2(+)型、Basal-like型4個亞型。Breast cancer is the most common female malignant tumor in the world and in China. 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 typing of breast cancer and reached an expert consensus. According to the estrogen receptor (ER), progesterone receptor (PgR), human epidermis The expression of growth factor receptor-2 (Her-2) and Ki-67 divided breast cancer into four subtypes: Luminal A, Luminal B, Her-2 (+), and Basal-like.
其中，***受體（ER）陽性乳腺癌約占全部乳腺癌的70%，屬***依賴性腫瘤，通過***與ER相互作用促進乳腺癌細胞的生長。內分泌治療則是通過降低體內***水平或抑制***與受體結合，抑制腫瘤細胞的生長。對於ER陽性乳腺癌，無論是手術後輔助治療還是針對轉移灶的系統治療，內分泌藥物是最基礎和最有效的治療方式。與化療相比，內分泌治療的不良反應輕，耐受性好，能長期應用。Among them, estrogen receptor (ER) -positive breast cancer accounts for about 70% of all breast cancers and belongs to estrogen-dependent tumors. The interaction between estrogen and ER promotes the growth of breast cancer cells. Endocrine therapy is to reduce tumor cell growth by reducing estrogen levels in the body or inhibiting estrogen from binding to receptors. For ER-positive breast cancer, endocrine drugs are the most basic and effective treatment method, whether it is an adjuvant treatment after surgery or a systemic treatment for metastases. Compared with chemotherapy, the adverse effects of endocrine therapy are light, well tolerated, and can be used for a long time.
NCCN（National Comprehensive Cancer Network）乳腺癌指南、中國內分泌治療專家共識指出，對ER陽性的復發或轉移性乳腺癌患者的治療主要以延長生存期、提高生活質量爲目的，應優先毒性較小的內分泌治療。因此，內分泌治療是乳腺癌全身治療的主要手段之一，在乳腺癌臨床治療中具有重要意義。下表1列出了臨床上常用的代表性內分泌治療藥物。表 1 臨床上常用內分泌治療藥物 NCCN (National Comprehensive Cancer Network) breast cancer guidelines and consensus of Chinese endocrine therapy experts point out that the treatment of patients with ER-positive relapsed or metastatic breast cancer is mainly aimed at extending survival and improving quality of life. Priority should be given to less toxic endocrine treatment. Therefore, endocrine therapy is one of the main methods for systemic treatment of breast cancer, and it is of great significance in the clinical treatment of breast cancer. Table 1 below lists representative endocrine therapy drugs commonly used in the clinic. Table 1 Commonly used endocrine therapy drugs
多項臨床研究已證實，依西美坦在ER陽性絕經後乳腺癌的輔助治療、二線治療中療效良好，占據重要地位。此外，其在一線治療中的療效亦較好。Several clinical studies have confirmed that exemestane is effective in adjuvant and second-line treatment of ER-positive postmenopausal breast cancer, occupying an important position. In addition, its efficacy in first-line treatment is also better.
在過去幾十年中，乳腺癌的內分泌治療雖然取得了長足進展，已成爲ER陽性乳腺癌患者最基礎和最有效的治療手段，但臨床有效性依然受到耐藥性的嚴重制約：接近30%的晚期乳腺癌患者對內分泌治療發生原發性耐藥，即使起始治療顯效或者更換不同類別藥物後顯效者，也最終出現獲得性耐藥，內分泌藥物治療的疾病進展時間平均在一年以內。因此，內分泌治療的耐藥性已成爲乳腺癌臨床治療亟待解决的重大難題和巨大挑戰。In the past few decades, although the endocrine treatment of breast cancer has made great progress, it has become the most basic and effective treatment for ER-positive breast cancer patients, but its clinical effectiveness is still severely restricted by drug resistance: close to 30% Of patients with advanced breast cancer who developed primary resistance to endocrine therapy, even if the initial treatment was effective or changed after different types of drugs were effective, eventually acquired resistance, the disease progression time of endocrine drug treatment on average within one year. Therefore, resistance to endocrine therapy has become a major problem and a huge challenge to be solved in clinical treatment of breast cancer.
西達本胺（Chidamide，愛譜沙）是一種亞型選擇性組蛋白去乙醯化酶（HDAC）抑制劑，化學名爲N-(2-胺基-4-氟苯基)-4-[N-[(E)-3-(3-吡啶)丙烯醯基]胺甲基]苯甲醯胺，爲1.1類新藥。在西達本胺的I期臨床試驗中共入組了 16例實體瘤患者，包括非小細胞肺癌、乳腺癌、結腸癌、直腸癌、胃癌、***癌等，除1例頜下腺腺樣囊性癌獲得部分緩解外，其餘實體瘤均未獲得明確療效，此I期臨床結果顯示西達本胺單藥對於乳腺癌無效，因此，在西達本胺II期臨床試驗中，也沒有繼續入組乳腺癌患者。Chidamide is a subtype selective histone deacetylation enzyme (HDAC) inhibitor. The chemical name is N- (2-amino-4-fluorophenyl) -4- [N-[(E) -3- (3-pyridine) acrylfluorenyl] aminemethyl] benzamidine is a new class 1.1 drug. A total of 16 patients with solid tumors were included in the Phase I clinical trial of sitabamide, including non-small cell lung cancer, breast cancer, colon cancer, rectal cancer, gastric cancer, and prostate cancer, with the exception of one submandibular adenoid cystic carcinoma Except for partial remission, the remaining solid tumors did not have a clear effect. This phase I clinical result showed that cidabenzamide alone was not effective for breast cancer. Therefore, in the phase II clinical trial of cidabenzamide, it did not continue to be included in the breast Cancer patients.
西達本胺被批准用於復發或難治的外周T細胞淋巴瘤（PTCL）的治療。本發明人在研究中出乎意料地發現：將西達本胺與依西美坦聯合使用，可以有效改善乳腺癌的治療，獲得相對於依西美坦單藥治療顯著提高的效果，特別是可顯著延長患者的無進展生存期，提高臨床獲益率和客觀緩解率。Cedaramide is approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). The inventors have unexpectedly discovered in the research that the combined use of cidabenzamide and exemestane can effectively improve the treatment of breast cancer and obtain a significantly improved effect compared to exemestane monotherapy, especially Can significantly prolong the progression-free survival of patients, improve clinical benefit rate and objective response rate.
因此，在第一個方面，本發明提供了西達本胺與依西美坦在製備用於治療乳腺癌的聯合用藥物中的用途。Therefore, in a first aspect, the present invention provides the use of sitabine and exemestane in the manufacture of a combination medicament for treating breast cancer.
西達本胺（Chidamide，愛譜沙）是一種亞型選擇性組蛋白去乙醯化酶（HDAC）抑制劑，化學名爲N-(2-胺基-4-氟苯基)-4-[N-[(E)-3-(3-吡啶)丙烯醯基]胺甲基]苯甲醯胺，爲1.1類新藥。Chidamide is a subtype selective histone deacetylation enzyme (HDAC) inhibitor. The chemical name is N- (2-amino-4-fluorophenyl) -4- [N-[(E) -3- (3-pyridine) acrylfluorenyl] aminemethyl] benzamidine is a new class 1.1 drug.
需要說明的是，在本文中，西達本胺這一術語不僅包括上述化學名下的化學實體，還包括其可藥用鹽、溶劑化物（包括水合物）、異構體、前藥、代謝物。It should be noted that in this article, the term cidabenzamine includes not only the chemical entities under the above chemical names, but also their pharmaceutically acceptable salts, solvates (including hydrates), isomers, prodrugs, and metabolism Thing.
具體來說，在第一方面，本發明提供了以下活性成分之組合在製備用於治療乳腺癌的聯合用藥物中的用途： (a) 西達本胺，包括其可藥用鹽、溶劑化物或水合物；和 (b) 依西美坦。Specifically, in a first aspect, the present invention provides the use of a combination of the following active ingredients in the preparation of a combination medicament for the treatment of breast cancer: (a) Cedaramide, including its pharmaceutically acceptable salts, solvates Or hydrates; and (b) Exemestane.
優選地，所述乳腺癌爲激素受體陽性晚期乳腺癌；進一步優選地，所述乳腺癌爲經內分泌治療失敗的激素受體陽性晚期乳腺癌。進一步優選地，所述乳腺癌爲經內分泌治療失敗並發生了內臟轉移的激素受體陽性晚期乳腺癌。Preferably, the breast cancer is hormone receptor-positive advanced breast cancer; further preferably, the breast cancer is 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.
在另一方面，本發明提供了一種藥物組合物或聯合用藥物，特別是用於治療激素受體陽性晚期乳腺癌的藥物組合物，包含作爲活性成分的組分(a)和(b)： (a) 西達本胺，包括其可藥用鹽、溶劑化物或水合物；和 (b) 依西美坦。In another aspect, the present invention provides a pharmaceutical composition or a combination drug, particularly a pharmaceutical composition for treating hormone receptor-positive advanced breast cancer, comprising, as active ingredients, components (a) and (b): (a) Cedarabine, including its pharmaceutically acceptable salts, solvates or hydrates; and (b) Exemestane.
優選地，所述藥物組合物還包含可藥用載體。Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
優選地，在所述藥物組合物中，所述組分(a)（按西達本胺計）與組分(b)依西美坦的重量配比爲（2-6）：5。Preferably, in the pharmaceutical composition, the weight ratio of the component (a) (based on cidabenzamide) and the component (b) exemestane is (2-6): 5.
優選地，所述組分(a)（按西達本胺計）與依西美坦的重量配比爲6：5。Preferably, the weight ratio of the component (a) (based on cidabenzamide) to exemestane is 6: 5.
優選地，所述藥物組合物爲片劑的形式。Preferably, the pharmaceutical composition is in the form of a tablet.
在又一方面，本發明提供了一種藥盒，其包含以單一制劑形式存在的或以分開的製劑形式存在的以下活性成分(a)和(b)： (a) 西達本胺，包括其可藥用鹽、溶劑化物或水合物；和 (b) 依西美坦。In yet another aspect, the present invention provides a kit comprising the following active ingredients (a) and (b), either in a single formulation or in a separate formulation: (a) Cedaramide, including its A pharmaceutically acceptable salt, solvate or hydrate; and (b) Exemestane.
在另一方面，本發明還提供了一種治療乳腺癌的方法，包括向有此需要的對象同時、分別或依次給予作爲活性成分的組分(a)和(b)： (a) 西達本胺，包括其可藥用鹽、溶劑化物或水合物；和 (b) 依西美坦。In another aspect, the present invention also provides a method for treating breast cancer, comprising simultaneously, separately or sequentially administering components (a) and (b) as active ingredients to a subject in need thereof: (a) Cedarben Amines, including their pharmaceutically acceptable salts, solvates or hydrates; and (b) exemestane.
在所述治療方法中，所述乳腺癌優選爲激素受體陽性晚期乳腺癌；進一步優選地，所述乳腺癌爲經內分泌治療失敗的激素受體陽性晚期乳腺癌。特別優選地，所述乳腺癌爲發生了內臟轉移的乳腺癌，特別是經內分泌治療失敗並發生了內臟轉移的激素受體陽性晚期乳腺癌。在所述方法中，所述組分(a)（按西達本胺計）與組分(b)依西美坦的重量配比優選爲（2-6）：5；更優選地，所述組分(a)（按西達本胺計）與依西美坦的重量配比爲6：5。In the treatment method, the breast cancer is preferably 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. Particularly preferably, the breast cancer is breast cancer that has undergone visceral metastasis, especially hormone receptor-positive advanced breast cancer that has undergone endocrine therapy and has undergone visceral metastasis. In the method, the weight ratio of the component (a) (based on cidabenzamide) and the component (b) exemestane is preferably (2-6): 5; more preferably, all The weight ratio of the component (a) (based on cidabenzamide) to exemestane is 6: 5.
本發明提供的治療乳腺癌的藥物組合或聯合用藥，不限定具體採用的形式。例如，可以是採用包含相同或不同規格的分開的西達本胺與依西美坦的單位制劑的組合形式，也可以在單一制劑中同時包含西達本胺與依西美坦的藥物組合物形式；可以採取西達本胺與依西美坦各自製劑的組合形式（例如藥盒）施用；可以同時施用，也可以分別或依次施用；等等。相比於依西美坦單藥治療而言，對於治療乳腺癌特別是經內分泌治療失敗的激素受體陽性晚期乳腺癌來說，本發明的聯合用藥具有顯著更好的療效和臨床獲益。實施例 1 ：西達本胺片和依西美坦片聯合用藥臨床試驗 The combination or combination of drugs for treating breast cancer provided by the present invention is not limited to a specific adopted form. For example, it may be in the form of a combination of unit preparations containing the same or different specifications of separate cidabenzamide and exemestane, or a pharmaceutical composition containing both cidabenzamide and exemestane in a single formulation. Form; can be administered in the form of a combination of the respective preparations of sitabamide and exemestane (eg, a kit); 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 benefit for the treatment of breast cancer, especially hormone receptor-positive advanced breast cancer that has failed endocrine therapy. Example 1 : Clinical trial of the combined use of Cestabenamide and Exemestane
本次臨床試驗共入選20例患者，入選的患者須滿足下列全部標準： 1) 18~75歲，絕經後女性* 患者； 2) 組織學或細胞學證實的激素受體陽性〈***受體（ER）陽性、孕激素受體（PgR）陰性或陽性〉乳腺癌患者； 3) 至少經一次內分泌藥物治療（無論解救治療或輔助治療）後疾病進展或復發； 4) 入組前無論解救治療或輔助治療的總方案數≤4個，其中解救化療方案數≤1個； 5) 入組前疾病狀態爲不可手術的III期或IV期乳腺癌，至少有一個可測量病灶或者無可測量病灶且爲單純骨轉移的患者； 6) 距末次治療的時間間隔：（a）若末次治療爲內分泌治療，則需≥2周；（b）若末次治療爲化療，則需≥4周； 7) ECOG評分：0或1分； 8) 中性粒細胞絕對值≥1.5×109 /L，血小板≥100×109 /L，血紅蛋白≥ 90g/L； 9) 預期生存時間≥3個月； 10) 自願簽署書面知情同意書。A total of 20 patients were selected for this clinical trial. The selected patients must meet all of 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 relapse after at least one endocrine drug treatment (regardless of rescue treatment or adjuvant treatment); 4) regardless of rescue treatment before enrollment The total number of regimens or adjuvant treatments is ≤4, of which the number of rescue chemotherapy regimens is ≤1; 5) The disease status of patients before the enrollment is inoperable stage III or IV breast cancer with at least one measurable lesion or no measurable lesion Patients with simple bone metastases; 6) Time interval from the last treatment: (a) If the last treatment is endocrine therapy, it needs ≥ 2 weeks; (b) If the last treatment is chemotherapy, it needs ≥ 4 weeks; 7) ECOG score: 0 or 1 points; 8) Absolute neutrophil value ≥ 1.5 × 10 9 / L, platelets ≥ 100 × 10 9 / L, hemoglobin ≥ 90g / L; 9) Expected survival time ≥ 3 months; 10 ) Voluntarily sign written informed consent.
經篩選符合條件的患者，均接受西達本胺片和依西美坦片兩種藥物治療。本實施例臨床試驗採用的藥物名和規格如下： 西達本胺片：爲類白色片，5mg/片。由深圳微芯生物科技有限責任公司研製並提供。遮光，密封，25℃以下保存。 依西美坦片：爲白色糖衣片，除去糖衣片後顯白色，25mg/片。製造商是Pfizer Italia S.r.l.，由深圳微芯生物科技有限責任公司提供。30℃以下保存。After screening the eligible patients, they were treated with two drugs, Cedaramide and Exemestane. The names and specifications of the drugs used in the clinical trials of this example are as follows: Cedaramide tablets: white-like tablets, 5 mg / tablet. Developed and provided by Shenzhen Weixin Biotechnology Co., Ltd. Shaded, sealed and stored below 25 ° C. Exemestane tablets: white sugar-coated tablets, after removing the sugar-coated tablets, it was white, 25 mg / tablet. The manufacturer is Pfizer Italia S.r.l., provided by Shenzhen Microchip Biotechnology Co., Ltd. Store below 30 ° C.
本實施例臨床試驗的治療過程分爲導入期和聯合治療期，具體治療方案如下： ü導入期 導入期共4天，分別單獨口服依西美坦片和西達本胺片各一次。 第1天：早餐後30分鐘口服1片（25mg）依西美坦片。 第2天：早餐後30分鐘口服6片（30mg）西達本胺片。 在導入期第4天進行血常規檢查，在中性粒細胞≥1.5×109 /L、血小板≥ 90×109 /L和血紅蛋白≥ 90g/L的前提下，方可進入聯合治療期。如果導入期第4天的中性粒細胞和/或血小板和/或血紅蛋白未達到規定標準，則延遲進入聯合治療期，並每 1~2天檢查一次血常規。若延遲7天後仍未達到規定標準，則退出試驗。 ü聯合治療期 導入期完成後，隨即進入聯合治療期。在此治療期內，患者同時接受西達本胺片和依西美坦片藥物治療。每4周爲一個治療周期，所有周期的窗口期爲±2天。 西達本胺片：每周口服兩次，6片/次（30mg/次），兩次服藥間隔不應少於3天（如周一和周四、周二和周五、周三和周六等），早餐後30分鐘服用。 依西美坦片：每天口服一次，1片/次（25mg/次），早餐後30分鐘服用。如當天服用西達本胺片，則依西美坦片與西達本胺片同時服用。 所有患者持續治療直至出現以下情况：疾病進展、不能耐受的毒性反應、死亡、退出治療、撤回知情同意或失訪。實施例 2 ：西達本胺片和依西美坦片聯合用藥臨床試驗療效結果 The treatment process of the clinical trial of this embodiment is divided into a lead-in period and a combined treatment period, and the specific treatment plan is as follows: ü Lead-in period The lead-in period is 4 days in total, and the exemestane tablet and the cedaramide tablet are taken orally once each. Day 1: Take 1 tablet (25mg) of exemestane orally 30 minutes after breakfast. Day 2: Oral 6 (30mg) Cedaramide tablets 30 minutes after breakfast. A routine blood test is performed on the fourth day of the introduction period, and the combined treatment period can be entered on the premise of neutrophils ≥ 1.5 × 10 9 / L, platelets ≥ 90 × 10 9 / L, and hemoglobin ≥ 90 g / L. If the neutrophils and / or platelets and / or hemoglobin do not meet the required standards on the 4th day of the introduction period, the combination therapy period is delayed and the blood routine is checked every 1 to 2 days. If the required standard is not reached after a delay of 7 days, the test is withdrawn. üCombination therapy period After the introduction period is completed, it immediately enters the combination therapy period. During this treatment period, the patient received both cedaramide and exemestane tablets. Every 4 weeks is a treatment cycle with a window period of ± 2 days for all cycles. Ÿ Sidabenamide tablets: Orally taken 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), taken 30 minutes after breakfast. If you take cidabenem on the same day, you should take cimetanyl and cidabentan at the same time. All patients continued treatment until disease progression, intolerable toxicity, death, withdrawal from treatment, withdrawal of informed consent, or loss of follow-up. Example 2 : Efficacy Results of a Clinical Trial of Combination of Cedaramide and Exemestane
主要療效指標如下： ü客觀緩解率：完全緩解（CR）和部分緩解（PR）患者占分析集總人數的百分比及其95% CI； ü無進展生存期（PFS）：採用kaplan-Meier法估計PFS分布，繪製生存曲線圖。The main efficacy indicators are as follows: ü Objective response rate: the percentage of patients with complete response (CR) and partial response (PR) in the total analysis set and its 95% CI; ü Progression-free survival (PFS): estimated using kaplan-Meier method PFS distribution, draw survival curve.
療效結果：本臨床試驗西達本胺聯合依西美坦治療HR陽性晚期乳腺癌的臨床結果如下，本試驗入組了20例HR陽性HER陰性乳腺癌患者，3例患者實現部分應答，12例患者實現疾病穩定。3例患者因不良反應停藥，3級以上不良反應包括中性粒細胞减少(35%)、血小板减少(30%)、白細胞减少(20%)。
由上述結果可見，相比於依西美坦單藥治療乳腺癌的中位客觀緩解率4.6%和中位無進展生存期4.1個月而言，西達本胺與依西美坦聯合用藥的中位客觀緩解率達到15%，中位無進展生存期達到7.6個月。可見，西達本胺與依西美坦在製備用於治療乳腺癌的聯合用藥物中具有很好的協同作用。實施例 3 ：聯合用藥物組合物 From the above results, it can be seen that compared with the median objective response rate of 4.5% and the median progression-free survival of 4.1 months for exemestane alone in breast cancer, The median objective response rate was 15%, and the median progression-free survival was 7.6 months. It can be seen that cidabenzamide and exemestane have a good synergistic effect in the preparation of a combination drug for treating breast cancer. Example 3 : Combination pharmaceutical composition
本實施例的聯合用藥物組合物包含依西美坦片1片（25mg）和西達本胺片6片（30mg）。實施例 4 ：聯合用藥物組合物 The combined pharmaceutical composition of this embodiment comprises 1 exemestane tablet (25 mg) and 6 cidabenzide tablets (30 mg). Example 4 : Combined pharmaceutical composition
本實施例的聯合用藥物組合物包含依西美坦片1片（25mg）和西達本胺片2片（10mg）。實施例 5 ：聯合用藥物組合物製劑 The combined pharmaceutical composition of this embodiment comprises 1 exemestane tablet (25 mg) and 2 cidabenzide tablets (10 mg). Example 5 : Formulation of combined pharmaceutical composition
本實施例的聯合用藥物組合物製劑包含依西美坦25mg、西達本胺10mg以及可藥用載體。可藥用載體包括：包括《藥用賦形劑手册》（美國藥學協會，1986年10月）或化學工業出版社出版的 《藥用輔料手册》（Handbook of Pharmaceutical Excipients，原著第四版）所列的載體輔料，優選用於片劑製劑的藥用輔料，但並不侷限於這些藥用輔料。實施例 6 ：西達本胺片和依西美坦片聯合用藥的多中心、雙盲、隨機 III 期臨床試驗研究 The combined pharmaceutical composition formulation of this embodiment comprises 25 mg of exemestane, 10 mg of cidabenzamide, and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include: the "Handbook of Pharmaceutical Excipients" (American Pharmaceutical Association, October 1986) or "Handbook of Pharmaceutical Excipients" (Fourth Edition) published by Chemical Industry Press The listed excipients are preferably, but not limited to, those used in tablet formulations. Example 6 : A multi-center, double-blind, randomized phase III clinical trial study on the combined use of Cedaramide and Exemestane
研究方法： 本研究爲多中心、雙盲、隨機的III期臨床試驗研究（試驗註冊號：NCT02482753）。入選人群爲年齡18~75歲的絕經後、***受體陽性、HER-2陰性、經既往內分泌（輔助或解救）治療復發/轉移的晚期乳腺癌患者。體力狀况評分（ECOG評分）0分或1分，具有可測量病灶或單純骨轉移病灶。以2：1隨機至試驗組（西達本胺聯合依西美坦）和對照組（安慰劑聯合依西美坦），分層因素爲是否存在內臟轉移。依西美坦25mg每日一次聯合安慰劑/西達本胺30mg每周兩次，至疾病進展或出現不可耐受的毒性反應。主要終點指標爲無進展生存期（PFS），次要終點指標包括總生存期（OS）、客觀緩解率（ORR）、緩解持續時間（DOR）和臨床獲益率（CBR）。 具體的研究方法如下： 1、分層隨機及盲法 本試驗的雙盲對照期爲分層隨機的雙盲試驗。 雙盲對照期試驗中，證實患者符合所有入選/排除標準後，研究者或他/她的指定人員交互式網絡應答系統（IWRS）或者交互式語音應答系統（IVRS）給患者指定一個隨機化編號。指定治療組時，應按照下列因素進行分層： 篩選期時是否有內臟轉移？（是或否） 然後將患者按照2：1隨機分配至試驗組（西達本胺片+依西美坦片）和對照組（安慰劑+依西美坦片）。 從隨機化時起，患者指定的治療組都應對患者、研究者、研究團隊以及試驗執行過程中涉及的任何人保持盲態，直至數據庫鎖定。揭盲前，隨機化數據應嚴格保密，試驗執行過程中涉及的任何人都不能接近。所用的試驗藥物〈西達本胺和西達本胺模擬片（安慰劑）〉在包裝、標籤、給藥方案和外觀方面完全一致，使治療情况可以保密。 2、雙盲對照方法 符合篩選條件的患者根據是否有內臟轉移進行分層，按2：1隨機分配至試驗組和對照組。試驗組：30mg西達本胺片+依西美坦片，對照組：西達本胺模擬片（安慰劑）+依西美坦片。每4周爲一個治療周期，所有周期的窗口期爲±2天。 西達本胺片/安慰劑：每周口服兩次，6片/次，兩次服藥間隔不應少於3天（如周一和周四、周二和周五、周三和周六等），早餐後30分鐘服用。 依西美坦片：每天口服一次，1片/次（25mg/次），早餐後30分鐘服用。如當天服用西達本胺片/安慰劑，則依西美坦片與西達本胺/安慰劑同時服用。 所有患者持續治療直至出現以下情况：疾病進展、不能耐受的毒性反應、死亡、退出治療、撤回知情同意或失訪。 3、劑量調整 試驗過程中，對於患者出現的與試驗藥物相關的≥3級不良事件（AE），在對症治療的基礎上，將主要通過降低西達本胺片/安慰劑劑量、暫停西達本胺片/安慰劑用藥、退出試驗等方式進行處理，不建議調整依西美坦片的用藥。 4、療效評價標準 依據實體瘤RECIST 1.1版（2009年）標準（見附錄1）進行療效評價。可將療效分爲完全緩解、部分緩解、疾病進展和穩定共 4 個級別。 ü 完全緩解（CR）：所有靶病灶消失。所有病理陽性淋巴結（無論是靶病灶還是非靶病灶）的短徑必須縮小至＜10 mm。 ü 部分緩解（PR）：與基線病灶最長直徑（LD）總和比較，靶病灶LD總和至少下降30%。 ü 疾病進展（PD）：靶病灶的LD總和與開始治療以來記錄的病灶最小LD總和比較增加至少20%，並且LD總和的絕對值增加至少5 mm。當一個或多個新病灶出現時，也認爲是PD。 ü 穩定（SD）：與治療開始以來記錄的LD總和最小值比較，病灶LD總和既未達到部分緩解的减少量，也未達到腫瘤進展的增加量。 對於基線期無可測量病灶（按RECIST標準）且爲單純骨轉移患者，出現以下情形之一，則認爲疾病進展（PD）： ü 骨骼中出現一個或多個溶骨性新病灶； ü 骨骼以外的器官或組織中出現一個或多個新病灶； ü 骨骼原有病灶的明確進展。 註：病理性骨折、新的壓縮性骨折或骨轉移導致的併發症不視爲疾病進展，除非滿足以上疾病進展判定條件之一。 5、療效評價手段 通過影像學（包括CT、核磁共振、骨掃描等）對患者的病灶大小進行評估。患者在所有隨訪點採用的影像學手段必須相同。 6、療效評價間隔 ü腫瘤緩解評價：治療期間每2周期一次；若患者因非疾病進展原因（如不良事件、管理原因等）中途退出試驗，應繼續每8周進行一次腫瘤評估，直至患者疾病進展或者開始使用新的抗腫瘤治療（以先發生者爲准）。 ü總生存期評價：患者最後一次服藥後，每12周一次，可通過電話或訪視進行隨訪。直至記錄到約70%（即約230例）患者死亡。 7、獨立影像學評價 雙盲對照期試驗中，由獨立的影像學評價機構在盲態下對所有患者的影像學資料進行獨立分析和判定，其評價結果作爲雙盲對照期試驗療效結果的支持依據。 8、統計方法和數據分析 8.1統計方法：採用全分析集（FAS，Full analysis set），根據意向性治療（ITT）原則，包括所有隨機化後至少服用過一次試驗藥物的患者。 符合方案分析集（PPS, Per Protocol Set）：在FAS的基礎上，符合入選標準、不符合排除標準、具有有效的基線值、依從性好並且沒有違背臨床試驗方案的患者。 安全數據集(SS，Safety Set)：入組後至少服用過一次試驗藥物，且有安全性指標記錄的患者。 療效分析同時採用FAS和PPS，以FAS結果爲主。 安全性分析採用安全數據集。 8.2數據分析方法： 患者人口學/其他基線特徵：採用FAS，按照不同組別列出並總結基線人口學和疾病特徵數據。用描述性匯總統計（如頻率、平均值、中位數、範圍和標準偏差等）列出數值數據。 治療（試驗藥物暴露、合併用藥、依從性）：採用SS，按照不同組別總結試驗藥物治療的暴露時間和劑量。列出劑量調整/暫停用藥的患者數，同時列出劑量調整/暫停用藥的原因。採用SS，列出並總結試驗過程中的合用藥物信息。 患者服藥的依從標準爲實際服用藥量占應用藥量的80%-120%。研究結果： Research methods: This study is a multi-center, double-blind, randomized phase III clinical trial study (trial registration number: NCT02482753). The selected population was patients with advanced breast cancer who were postmenopausal, aged 18 to 75 years, positive for estrogen receptors, negative for HER-2, and had previous endocrine (adjuvant or rescue) treatment for relapse / metastasis. The physical condition score (ECOG score) is 0 or 1 with measurable lesions or simple bone metastases. Randomized 2: 1 to the experimental group (cedarabine combined with exemestane) and the control group (placebo combined with exemestane). The stratification factor was the presence of visceral metastasis. Exemestane 25mg once daily combined with placebo / cedarbenzamide 30mg twice a week until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included 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 blind method The double-blind controlled period of this trial is a stratified randomized double-blind trial. In a double-blind controlled trial, after the patient meets all the inclusion / exclusion criteria, the researcher or his / her designee's Interactive Network Response System (IWRS) or Interactive Voice Response System (IVRS) assigns a randomized number to the patient . When designating treatment groups, stratification should be based on the following factors: Are there visceral metastases during the screening period? (Yes or No) Patients were then randomly assigned to the test group (cedarbenzamide tablet + exemestane tablet) and the control group (placebo + exemestane tablet) at a 2: 1 ratio. From the time of randomization, the patient's designated treatment group should remain blind to the patient, the investigator, the research team, and anyone involved in the trial execution 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 should be accessible. The test drugs used (Sidabenzide and Sidabenzide Simulation Tablets (Placebo)) are completely consistent in packaging, labeling, dosing schedule and appearance, so that the treatment can be kept confidential. 2. The double-blind control method Patients who met the screening conditions were stratified according to whether there were visceral metastases, and were randomly assigned to the experimental group and the control group according to 2: 1. The test group: 30 mg of Cedarbenzamide Tablets + Exemestane Tablets, and the control group: Cedarbenzamine Simulated Tablets (Placebo) + Exemestane Tablets. Every 4 weeks is a treatment cycle with a window period of ± 2 days for all cycles. Cedarabine tablets / placebo: twice a week orally, 6 tablets / times, 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 after 30 minutes. Exemestane tablets: Orally once a day, 1 tablet / time (25mg / time), taken 30 minutes after breakfast. If taking Cedarabine / Placebo on the same day, Exemestane Tablets should be taken at the same time as Cedarabine / Placebo. All patients continued treatment until disease progression, intolerable toxicity, death, withdrawal from treatment, withdrawal of informed consent, or loss of follow-up. 3. In the course of the dose adjustment test, for patients with grade ≥3 adverse events (AE) related to the test drug, based on symptomatic treatment, it will mainly be through reducing the dose of sitabine amine tablets / placebo and suspending Treatment with this amine tablet / placebo, withdrawal from the trial, etc. It is not recommended to adjust the administration of exemestane tablets. 4. Efficacy evaluation criteria Efficacy evaluation was performed according to the RECIST version 1.1 (2009) standard (see Appendix 1) for solid tumors. Efficacy can be divided into four levels: complete response, partial response, disease progression and stability. ü Complete remission (CR): all target lesions disappear. The short diameter of all pathologically positive lymph nodes (whether target or non-target) must be reduced to <10 mm. ü Partial remission (PR): Compared with the sum of the longest diameter (LD) of the baseline lesion, the sum of the LD of the target lesion decreased by at least 30%. ü Disease progression (PD): The total sum of LD of the target lesion is increased by at least 20% compared with the minimum sum of LD of the lesion recorded since the start of treatment, and the absolute value of the sum of LD is increased by at least 5 mm. PD is also considered when one or more new lesions appear. ü Stability (SD): Compared with the minimum LD total recorded since the start of treatment, the total LD of the lesion has neither reached a reduction in partial remission nor an increase in tumor progression. For patients with no measurable lesions at baseline (according to the RECIST standard) and patients with simple bone metastases, disease progression (PD) is considered to occur in one of the following cases: ü One or more new osteolytic lesions appear in the bone; ü Bone One or more new lesions appear in organs or tissues other than that; ü Clear progression of existing bone lesions. Note: Complications caused by pathological fractures, new compression fractures, or bone metastases are not considered disease progression, unless one of the above conditions for determining disease progression is met. 5. Efficacy evaluation means to evaluate the lesion size of the patient through imaging (including CT, MRI, bone scan, etc.). Patients must use the same imaging technique at all follow-up points. 6. Efficacy evaluation interval ü tumor remission evaluation: once every 2 cycles during the treatment period; if the patient withdraws from the trial partway due to non-disease reasons (such as adverse events, management reasons, etc.), tumor evaluation should be continued every 8 weeks until the patient's disease Progression or initiation of new antitumor treatments (whichever comes first). ü Overall survival assessment: Patients can be followed up by phone or visit every 12 weeks after the last medication. Until about 70% (ie, about 230) of patients died. 7. In the double-blind controlled phase trial of independent radiological evaluation, independent imaging evaluation agencies independently analyze and judge the imaging data of all patients under blindness. The evaluation results are used to support the efficacy results of the double-blind controlled phase trial. in accordance with. 8. Statistical methods and data analysis 8.1 Statistical methods: A full analysis set (FAS) is used, according to the intention-to-treat (ITT) principle, including all patients who have taken at least one test drug after randomization. PPS (Per Protocol Set): Based on FAS, patients who meet the inclusion criteria, do not meet the exclusion criteria, have valid baseline values, have good compliance, and have not violated the clinical trial protocol. Safety Data Set (SS): Patients who have taken at least one test drug after enrollment and have a record of safety indicators. Efficacy analysis used both FAS and PPS, with FAS results as the main factor. Security analysis uses secure data sets. 8.2 Data analysis methods: Patient demographics / other baseline characteristics: Use FAS to list and summarize baseline demographic and disease characteristics data according to different groups. List descriptive statistics with descriptive summary statistics such as frequency, average, median, range, and standard deviation. Treatment (experimental drug exposure, combined use, compliance): SS was used to summarize the exposure time and dose of experimental drug treatment according to different groups. List the number of patients with dose adjustment / pause and the reasons for dose adjustment / pause. SS was used to list and summarize the drug information during the trial. The compliance standard for patients is that the actual dosage is 80% -120% of the applied dosage. Research result:
本臨床試驗在中國22家大型醫院共入組365例患者，其中244例隨機進入試驗組，121 例隨機進入對照組。全分析集（FAS）人群分析結果顯示，試驗組和對照組的中位PFS分別爲7.4個月（95% CI, 5.5 - 9.2）和3.8個月（95% CI, 3.7 - 5.5）（HR=0.755; 95% CI, 0.582 - 0.978; P=0.0336）。無論有無內臟轉移，西達本胺聯合依西美坦均較依西美坦單藥治療延長了患者的PFS，其中在有內臟轉移的患者中差異更明顯（PFS分別爲5.5個月和2.0個月）。試驗組與對照組的客觀緩解率分別爲18.4%和9.1%（P=0.026），臨床獲益率分別爲46.7%和35.5%（P=0.034）。A total of 365 patients were enrolled in this clinical trial at 22 large hospitals in China, of which 244 were randomly entered into the test group and 121 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) (HR = 0.755; 95% CI, 0.582-0.978; P = 0.0336). Regardless of the presence or absence of visceral metastasis, the combination of Cestabenamide and Exemestane prolonged PFS in patients compared with exemestane monotherapy, and the differences were more pronounced in patients with visceral metastases (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).
對於經內分泌治療失敗並發生了內臟轉移的激素受體陽性晚期乳腺癌，西達本胺聯合依西美坦較依西美坦單藥治療能更顯著地延長患者的PFS，本臨床試驗中西達本胺聯合依西美坦組相比於依西美坦聯合安慰劑組的中位PFS從2.0個月延長至5.5個月。For hormone-receptor-positive advanced breast cancer that failed endocrine therapy and had visceral metastasis, the combination of cimetanide and exemestane can significantly prolong the patient's PFS compared to exemestane monotherapy. The median PFS of the exemestane plus exemestane group compared with the exemestane plus placebo group was extended from 2.0 months to 5.5 months.
上述擴大的臨床研究結果進一步證實：與依西美坦單藥治療相比，西達本胺與依西美坦聯合用藥可顯著提高中位客觀緩解率，延長中位無進展生存期，提高臨床獲益率。因此，西達本胺與依西美坦在製備用於治療乳腺癌的聯合用藥物中具有明確的協同作用。The above-mentioned expanded clinical research results further confirm that compared with exemestane monotherapy, the combination of cidabenzamide and exemestane can significantly improve the median objective response rate, extend the median progression-free survival, and improve clinical Profitability. Therefore, cidabenzamide and exemestane have a clear synergistic effect in the preparation of a combination drug for the treatment of breast cancer.
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