TW201540296A - Use of cabazitaxel in patients with advanced gastric adenocarcinoma who have failed prior chemotherapy regimens - Google Patents
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Abstract
Description
本發明涉及使用卡巴他賽治療晚期胃腺癌,特別是用於先前化療療程失敗的病患。 The present invention relates to the use of cabazitaxel for the treatment of advanced gastric adenocarcinoma, particularly for patients who have failed prior chemotherapy sessions.
胃癌是一個全世界範圍的主要健康問題。據估計,2008年有大約100萬新增胃癌病患(98.8萬例),是全世界範圍內癌症致死的第二大因素(73.8萬例)。超過70%的病例(71.4萬例)出現在發展中國家,全部病例的一半出現在東亞,主要是中國。據估計,最高的致死率也在東亞。 Gastric cancer is a major health problem worldwide. It is estimated that there were approximately 1 million new gastric cancer patients (988,000 cases) in 2008, the second largest cause of cancer death worldwide (738,000 cases). More than 70% of cases (714,000 cases) occur in developing countries, and half of all cases occur in East Asia, mainly China. It is estimated that the highest fatality rate is also in East Asia.
根治性手術(radical surgery)是治癒胃癌的唯一機會。然而,除了在篩查被廣泛執行並且經常有可能被早期檢測的日本以及稍弱程度的韓國之外,大多數病患在初次診斷時其疾病已經不可切除或者已經轉移。然而,即使經過了治療性手術切除,大約60%的病患最終還是會疾病復發。 Radical surgery is the only chance to cure stomach cancer. However, except for Japan, which is widely implemented and often likely to be detected early, and a slightly weaker degree of Korea, most patients have their diseases unremovable or have metastasized at the time of initial diagnosis. However, even after a therapeutic surgical resection, approximately 60% of patients eventually relapse.
儘管在患有不可切除的、復發的、或轉移性胃癌的病患中已經廣泛評估了大量的全身性、緩和性(palliative)化療療程,並且證明與最佳支持性護理(best supportive care)相比可提高生存期,但是對於晚期胃癌,尚沒有全世界接受的標準的一線化療方法。 Although a large number of systemic, palliative chemotherapy regimens have been extensively evaluated in patients with unresectable, recurrent, or metastatic gastric cancer, and demonstrated to be consistent with best supportive care The ratio can improve survival, but for advanced gastric cancer, there is no standard first-line chemotherapy method accepted worldwide.
多西他賽(Docetaxel)無論是作為單一試劑還是與其他試劑組合使用時對胃癌均顯示活性。在一項隨機的跨國III期研究(V325)中,445名患有晚期胃癌並且先前未經治療的病患被隨機接受每3週一次多西他賽、順鉑和5-氟尿嘧啶(DCF)的組合,或者每4週一次順鉑和氟尿嘧啶(CF)的組合。DCF與CF相比,進展時間(Time to progression(TTP))和總體生存期(OS)顯著延長;分別為5.6 vs.3.7月(p<0.001),和9.2 vs.8.6月(p=0.02)。根據該項研究的結果,美國FDA(食品和藥品管理局)批准了DCF方案用於治療先前未接受過晚期疾病化療的病患的晚期胃癌,包括胃食管連接部癌症。目前,多西他賽在大多數亞洲國家已經獲得了相同的適應症(indication),除了在中國大陸地區,一項本地註冊試驗(local registration trial)正在進行中。 Docetaxel exhibits activity against gastric cancer either as a single agent or in combination with other agents. In a randomized, cross-country phase III study (V325), 445 patients with advanced gastric cancer who were previously untreated were randomized to receive docetaxel, cisplatin, and 5-fluorouracil (DCF) every 3 weeks. Combination, or a combination of cisplatin and fluorouracil (CF) once every 4 weeks. The time to progression (TTP) and overall survival (OS) were significantly longer in DCF compared with CF; 5.6 vs. 3.7 months (p < 0.001), and 9.2 vs. 8.6 months (p = 0.02), respectively. . Based on the results of the study, the US FDA (Food and Drug Administration) approved the DCF regimen for the treatment of advanced gastric cancer, including gastroesophageal junction cancer, in patients who have not previously received chemotherapy for advanced disease. Currently, docetaxel has acquired the same indications in most Asian countries, except in mainland China, where a local registration trial is underway.
除了多西他賽以外,其它化療療程,包括5-氟尿嘧啶(5-FU)或其衍生物、多西紫杉醇(paclitaxel)、依立替康(irinotecan)和鉑衍生物也已經在晚期疾病病患的隨機研究中被證明,作為一線用藥(in the first-line setting)可減輕疾病並提高生存期。然而,總體上,總生存期的中值一般小於1年。這些欠佳的長期結果(outcome)強烈提示遠未得以滿足的進一步開發胃癌新型治療劑的需要。 In addition to docetaxel, other chemotherapy regimens, including 5-fluorouracil (5-FU) or its derivatives, paclitaxel, irinotecan, and platinum derivatives have also been used in patients with advanced disease. Randomized studies have shown that in the first-line setting can reduce disease and improve survival. However, overall, the median overall survival is generally less than one year. These poor long-term outcomes strongly suggest the need to further develop new therapeutic agents for gastric cancer that are far from being met.
雷莫司單抗(Ramucirumab),為一種單株抗體VEGFR-2拮抗劑,最近已經進行第III期試驗評估,在經過第一線化療後已進展的 晚期胃癌或胃-食管連接部腺癌病患中可延長總生存期。 Ramucirumab, a monoclonal antibody VEGFR-2 antagonist, has recently been evaluated in Phase III trials and has progressed after first-line chemotherapy. Overall survival can be extended in patients with advanced gastric cancer or gastric-esophageal junction adenocarcinoma.
然而,在第二和第三線配置中仍然迫切需要具有不同作用機制的新型治療法,因為除雷莫司單抗(ramucirumab)之外,迄今還沒有確定的療法在第III期試驗中被證明與最佳支持性護理相比有生存期益處,儘管已經有大量藥劑和組合方案在第II期試驗中被作為第二線療法研究,包括多西他賽、多西紫杉醇、依立替康、多西紫杉醇/順鉑、依立替康/順鉑、和S-1/絲裂黴素。 However, new treatments with different mechanisms of action are still urgently needed in the second and third line configurations, because, with the exception of ramucirumab, no therapies that have been identified so far have been demonstrated in Phase III trials. There is a survival benefit compared to optimal supportive care, although a number of agents and combination regimens have been used as second-line therapy in Phase II trials, including docetaxel, docetaxel, irinotecan, and doxil. Paclitaxel/cisplatin, irinotecan/cisplatin, and S-1/mitomycin.
因此,本發明意圖解決的技術問題是提供一種用於治療晚期胃腺癌,特別是用於先前化療療程失敗的病患的新型第二和/或第三線治療選擇。 Accordingly, the technical problem to be solved by the present invention is to provide a novel second and/or third line treatment option for the treatment of advanced gastric adenocarcinoma, particularly for patients who have failed prior chemotherapy sessions.
本發明涉及一種新型抗腫瘤藥物治療用途,包括具有下式的卡巴他賽:
本發明還涉及治療患有晚期胃腺癌的病患的方法,包括向所述病患給藥有效量的抗腫瘤劑卡巴他賽。 The invention further relates to a method of treating a patient having advanced gastric adenocarcinoma comprising administering to the patient an effective amount of the anti-tumor agent cabazitaxel.
這種抗腫瘤劑可以呈無水鹼(anhydrous base)、水合物或溶劑 化物的形式,意圖用於治療晚期胃腺癌,特別是用於先前化療療程失敗的病患。 The antitumor agent can be anhydrous base, hydrate or solvent The form of the compound is intended to treat advanced gastric adenocarcinoma, especially for patients who have failed previous chemotherapy courses.
在本發明的一些態樣中,卡巴他賽係以15-25mg/m2的劑量給藥(以每次給藥限定)。在本發明的一些態樣中,卡巴他賽從15、20和25mg/m2中選出的劑量給藥(以每次給藥限定),例如15mg/m2之劑量。卡巴他賽可呈丙酮溶劑化物的形式。更特別地,卡巴他賽的丙酮溶劑化物含有按重量計為5%-8%,較佳地5%-7%的丙酮。 In some aspects of the present invention, based cabazitaxel administered at a dose 15-25mg / m 2 (in each administration Limited). In some aspects of the invention, cabazitaxel is administered at a dose selected from 15, 20 and 25 mg/m 2 (defined per administration), for example a dose of 15 mg/m 2 . Cabazitaxel can be in the form of an acetone solvate. More particularly, the acetone solvate of cabazitaxel contains from 5% to 8%, preferably from 5% to 7%, by weight of acetone.
在本發明的一些態樣中,卡巴他賽可以15-25mg/m2的劑量藉由靜脈內輸注給藥,例如從15、20和25mg/m2中選出,例如劑量為15mg/m2,該抗腫瘤藥劑的給藥週期是以每次卡巴他賽給藥之間間隔3週進行重複,根據對先前卡巴他賽給藥的耐受性,該時間間隔可以延長1-2週。 In some aspects of the present invention, can cabazitaxel 15-25mg / m 2 dose is administered by intravenous infusion, for example, selected from 15, 20 and 25mg / m 2, for example, a dose of 15mg / m 2, The dosing cycle of the anti-tumor agent is repeated at intervals of 3 weeks between each administration of cabazitaxel, which may be extended by 1-2 weeks depending on the tolerance to previous administration of cabazitaxel.
在一些實施方案中,卡巴他賽的有效量可以產生從下組選出的至少一種治療效果,提高病患的生存期: In some embodiments, an effective amount of cabazitaxel can produce at least one therapeutic effect selected from the group consisting of: increasing the survival of the patient:
-提高客觀腫瘤反應率(ORR),定義為根據RECIST 1.1標準(Eur J Cancer 2009;45:228-47)確認的完全反應(CR)或部分反應(PR)、具有最佳腫瘤反應的病患與分析群體病患總數的比例。 - Increasing the objective tumor response rate (ORR), defined as a complete response (CR) or partial response (PR) confirmed by the RECIST 1.1 standard (Eur J Cancer 2009; 45: 228-47), the patient with the best tumor response The ratio to the total number of patients in the analysis group.
-提高無疾病進展生存期(Progression free survival),定義為根據RECIST 1.1標準定義的第一次研究治療日期與放射腫瘤進展日期或由於任何原因導致的死亡之間的時間間隔; - Progression free survival, defined as the time interval between the first study treatment date as defined by the RECIST 1.1 standard and the date of radiation tumor progression or death due to any cause;
-提高總體生存期(OS),定義為第一次研究治療日期與由於任何原因導致的死亡日期之間的時間間隔。 - Increased overall survival (OS), defined as the time interval between the date of the first study treatment and the date of death due to any cause.
本發明還涉及治療晚期胃腺癌病患,特別是先前化療療程失敗的病患的醫藥組成物,其包含臨床上被證明安全且有效量的卡巴 他賽。 The present invention also relates to a pharmaceutical composition for treating a patient with advanced gastric adenocarcinoma, particularly a patient having a previous chemotherapy course of treatment, comprising a clinically proven safe and effective amount of kappa He played.
第1圖為在輸注15、20和25mg/m2卡巴他賽之後的平均卡巴他賽血漿濃度-時間曲線(半對數標度)。 Figure 1 is the average cabazitaxel plasma concentration-time curve (semi-log scale) after infusion of 15, 20 and 25 mg/m 2 cabazitaxel.
第2圖為卡巴他賽輸注之後的單獨和平均(±SD)之卡巴他賽AUC最終。 The second picture shows the Kabbah after docetaxel infusion individual and mean (± SD) of cabazitaxel AUC final.
定義 definition
-有效量,如本文所使用的,係表示可對所治療癌症產生效果的藥物化合物,例如卡巴他賽的量。 An effective amount, as used herein, refers to an amount of a pharmaceutical compound, such as cabazitaxel, that can have an effect on the cancer being treated.
-臨床上被證明的,如本文所使用的,係表示足以滿足FDA批准標準的臨床功效結果。 - Clinically proven, as used herein, refers to clinical efficacy results sufficient to meet FDA approved standards.
-病患,如本文所使用的,同時包括人類和動物。在一個實施方案中,病患是人。 - The patient, as used herein, includes both humans and animals. In one embodiment, the patient is a human.
卡巴他賽屬紫杉烷家族,並具有下式:
卡巴他賽的化學名是4α-乙醯氧基-2α-苯甲醯氧基-5β,20-環氧基-1β-羥基-7β,10β-二甲氧基-9-氧代-11-紫杉烯-13α-基(2R,3S)-3-叔丁氧羰基胺基-2-羥基-3-苯基丙酸酯。卡巴他賽的同義名為(2α,5β,7β,10β,13α)-4-乙醯氧基-13-({(2R,3S)-3-[(叔丁氧羰基)胺基]-2-羥基-3-苯丙醯基}氧)-1-羥基-7,10-二甲氧基-9-氧代-5,20-環氧紫杉-11-烯-2-基苯甲酸酯。 The chemical name of cabazitaxel is 4α-acetoxy-2α-benzylideneoxy-5β,20-epoxy-1β-hydroxy-7β,10β-dimethoxy-9-oxo-11- Taxane-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate. The synonymous name of cabazitaxel is (2α,5β,7β,10β,13α)-4-ethenyloxy-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino)-2 -hydroxy-3-phenylpropenyl}oxy)-1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epipytaxane-11-en-2-ylbenzoic acid ester.
該化合物及其製備方法在WO 96/30355、EP 0817779 B1和US 5847170中被描述,本文引用其內容作為參考。卡巴他賽可以鹼的形式(參考上式)或以水合物的形式給藥。它還可以是溶劑化物,即具有如下特徵的分子複合物,其中結晶溶劑合併到作為活性成分的分子晶體中(相關內容見J.Pharm.Sci.1975,64(8),1269-1288的1276頁)。特別地,它可以是丙酮溶劑化物,更特別地,可以是WO 2005/028462中描述的溶劑化物。其可為卡巴他賽的丙酮溶劑化物,含有按重量計5%-8%,較佳地5%-7%的丙酮(%係表示丙酮含量/(丙酮+卡巴他賽)含量×100)。丙酮含量的平均值為7%,其近似代表了丙酮的化學計量(stoichiometry),對於含有一分子丙酮的溶劑化物而言是6.5%。 The compounds and their preparation are described in WO 96/30355, EP 0 917 779 B1 and US Pat. Cabazitaxel can be administered in the form of a base (refer to the above formula) or in the form of a hydrate. It may also be a solvate, that is, a molecular complex having a characteristic in which a crystallization solvent is incorporated into a molecular crystal as an active ingredient (see J. Pharm. Sci. 1975, 64(8), 1276-1288, 1276 for related content). page). In particular, it may be an acetone solvate and, more particularly, may be a solvate as described in WO 2005/028462 . It may be an acetone solvate of cabazitaxel containing 5% to 8% by weight, preferably 5% to 7% by volume of acetone (% means acetone content / (acetone + cabazitaxel) content x 100). The average acetone content is 7%, which approximately represents the stoichiometry of acetone, which is 6.5% for solvates containing one molecule of acetone.
下面描述的操作規程可製備卡巴他賽的丙酮溶劑化物:在20±5℃(室溫)下,將207g 4α-乙醯氧基-2α-苯甲醯氧基-5β,20-環氧基-1β-羥基-7β,10β-二甲氧基-9-氧代-11-紫杉烯-13α-基(2R,3S)-3-叔丁氧羰基胺基-2-羥基-3-苯丙酸酯溶解於大約2升的丙酮中,製備按重量計為大約92%的溶液,向該溶液中添加940ml純水,隨後將2g從丙酮/水中分離的懸浮於20ml水和20ml丙酮的混合物中之4α-乙醯氧基-2α-苯甲醯氧基-5β,20-環氧基-1β-羥基- 7β,10β-二甲氧基-9-氧代-11-紫杉烯-13α-基(2R,3S)-3-叔丁氧羰基胺基-2-羥基-3-苯丙酸酯懸浮液進行接種(seeding)。對所得混合物攪拌大約10-22個小時,並在4-5個小時內添加1.5升純水。對該混合物攪拌60-90分鐘,然後在減壓下對懸浮液進行過濾。用450ml丙酮和550ml純水製備的溶液在過濾器上對濾餅進行清洗,然後在減壓(0.7kPa)下在55℃烘箱中乾燥4個小時。得到197g含有0.1%水和7.2%丙酮的4α-乙醯氧基-2α-苯甲醯氧基-5β,20-環氧基-1β-羥基-7β,10β-二甲氧基-9-氧代-11-紫杉烯-13α-基(2R,3S)-3-叔丁氧羰基胺基-2-羥基-3-苯丙酸酯丙酮(理論量:化學計量溶劑化物為6.5%)。 The protocol described below can be used to prepare an acetone solvate of cabazitaxel: at 20 ± 5 ° C (room temperature), 207 g of 4α-ethoxycarbonyl-2α-benzylideneoxy-5β, 20-epoxy -1β-hydroxy-7β,10β-dimethoxy-9-oxo-11-taxane-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-benzene The propionate was dissolved in about 2 liters of acetone to prepare a solution of about 92% by weight, and 940 ml of pure water was added to the solution, followed by 2 g of a mixture suspended from acetone/water suspended in 20 ml of water and 20 ml of acetone. 4α-acetoxy-2α-benzylideneoxy-5β, 20-epoxy-1β-hydroxy- 7β,10β-dimethoxy-9-oxo-11-taxane-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate suspension Inoculation. The resulting mixture was stirred for about 10-22 hours and 1.5 liters of pure water was added over a 4-5 hour period. The mixture was stirred for 60-90 minutes and then the suspension was filtered under reduced pressure. The filter cake was washed on a filter with a solution prepared of 450 ml of acetone and 550 ml of pure water, and then dried in an oven at 55 ° C for 4 hours under reduced pressure (0.7 kPa). 197 g of 4α-acetoxy-2α-benzylideneoxy-5β, 20-epoxy-1β-hydroxy-7β, 10β-dimethoxy-9-oxyl containing 0.1% water and 7.2% acetone were obtained. Generation-11-taxane-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate acetone (theoretical amount: 6.5% of stoichiometric solvate).
卡巴他賽可以腸胃外給藥,例如藉由靜脈內給藥。適合於藉由靜脈內輸注給藥的卡巴他賽的蓋侖製劑(galenical)形式是,其中在從表面活性劑、助溶劑、葡萄糖或氯化鈉等選出的賦形劑的存在下,將卡巴他賽溶解於水中。例如,卡巴他賽的蓋侖製劑形式可以如下製備:用含有6ml水和乙醇溶液(95%乙醇按重量計為13%)的無菌藥瓶(vial)稀釋含於無菌藥瓶中的卡巴他賽預混合溶液(80mg卡巴他賽+2ml(溶劑+聚山梨酯80)),以便獲得8ml可隨時用於在灌注袋中再稀釋的溶液。該隨時可再稀釋溶液中的卡巴他賽的濃度為大約10mg/ml。然後,藉由將合適量的該隨時可再稀釋溶液注射到含有水和葡萄糖(大約5%)或氯化鈉(大約0.9%)的灌注袋中製備灌注液。 Cabazitaxel can be administered parenterally, for example by intravenous administration. A galenical form of cabazitaxel suitable for administration by intravenous infusion, wherein in the presence of an excipient selected from a surfactant, a solubilizer, glucose or sodium chloride, kappa He is dissolved in the water. For example, the galenical form of cabazitaxel can be prepared by diluting a cabazitaxel contained in a sterile vial with a sterile vial containing 6 ml of water and ethanol solution (13% by weight of ethanol). The solution was premixed (80 mg cabazitaxel + 2 ml (solvent + polysorbate 80)) to obtain 8 ml of a solution ready for re-dilution in the pouch. The concentration of cabazitaxel in the readily dilutable solution is about 10 mg/ml. The perfusate is then prepared by injecting a suitable amount of the readily re-dilutable solution into a perfusion bag containing water and glucose (about 5%) or sodium chloride (about 0.9%).
本發明的一個態樣是具有下式的化合物:
其可呈鹼的形式,或水合物或溶劑化物的形式,用作患有晚期胃腺癌的病患、特別是先前化療療程失敗的病患的第二線或第三線治療的藥劑。 It may be in the form of a base, or in the form of a hydrate or solvate, for use as a second or third line treatment agent for patients with advanced gastric adenocarcinoma, particularly those with previous chemotherapy regimens.
晚期胃腺癌是例如不可切除的或轉移的胃腺癌,包括胃食管連接部的腺癌。 Advanced gastric adenocarcinomas are, for example, unresectable or metastatic gastric adenocarcinomas, including adenocarcinomas of the gastroesophageal junction.
根據本發明,卡巴他賽可呈丙酮溶劑化物的形式。丙酮溶劑化物可以含有按重量計為5%-8%且較佳地5%-7%的丙酮。 According to the invention, cabazitaxel may be in the form of an acetone solvate. The acetone solvate may contain from 5% to 8% by weight and preferably from 5% to 7% by weight of acetone.
因此,本發明的一個態樣是治療晚期胃腺癌、特別是先前化療療程失敗的病患的方法,包括向有需要的病患給藥有效量的卡巴他賽。 Accordingly, one aspect of the invention is a method of treating an advanced gastric adenocarcinoma, particularly a patient having a previous chemotherapy regimen, comprising administering to a patient in need thereof an effective amount of cabazitaxel.
卡巴他賽的可以15-25mg/m2的劑量(以每次給藥限定)給藥。 在本發明的一些態樣中,卡巴他賽的給藥劑量(以每次給藥限定)從15、20和25mg/m2中選出,例如劑量為15mg/m2。 Cabazitaxel can be administered at a dose of 15-25 mg/m 2 (defined per administration). In some aspects of the present invention, the dose of Cabazitaxel (to define per dose) is selected from 15, 20 and 25mg / m 2, for example, a dose of 15mg / m 2.
卡巴他賽可以按照取決於被治療病患(年齡、體重、治療史等)的方案重複給藥,其可以由有經驗的醫生決定。在本發明的一個態樣中,卡巴他賽按照間歇性程序以每3週給藥一次的時間間隔灌注給藥給病患,時間間隔可以根據先前給藥的耐受性延長1-2週。卡 巴他賽的劑量實例在“實施例”部分中給予。當前推薦的劑量是在1小時輸注中給藥15mg/m2卡巴他賽。 Cabazitaxel can be administered repeatedly according to the regimen depending on the patient being treated (age, weight, treatment history, etc.), which can be determined by an experienced physician. In one aspect of the invention, the cabazitaxel is administered to the patient at intervals of once every three weeks in an intermittent procedure, and the time interval can be extended by 1-2 weeks based on the tolerance of the previous administration. Dosage examples of cabazitaxel are given in the "Examples" section. The currently recommended dose is 15 mg/m 2 of cabazitaxel administered in a one hour infusion.
本發明的另一個態樣是治療患有晚期胃腺癌、特別是先前化療療程失敗的病患的醫藥組成物,包括臨床上被證明安全且有效量的卡巴他賽,如上文中所揭示者。 Another aspect of the invention is a pharmaceutical composition for treating a patient suffering from advanced gastric adenocarcinoma, particularly a previous chemotherapy regimen failure, including a clinically proven safe and effective amount of cabazitaxel, as disclosed above.
本發明的另一個態樣是提高晚期胃腺癌病患、特別是先前化療療程失敗的病患的生存期的方法,包括向病患給藥臨床上被證明有效量的卡巴他賽,如上文中所揭示者。 Another aspect of the invention is a method of increasing the survival of an advanced gastric adenocarcinoma patient, particularly a patient having a previous chemotherapy regimen failure, comprising administering to the patient a clinically proven effective amount of cabazitaxel, as hereinbefore Revealer.
研究題目 Research topics
卡巴他賽單一試劑的2期多中心研究,向先前化療療程失敗的晚期胃腺癌病患每3週給予一次1小時靜脈輸注,以評估安全性、耐受性和抗腫瘤活性。 A phase 2 multicenter study of a single agent of cabazitaxel administered a one-hour intravenous infusion to patients with advanced gastric adenocarcinoma who had failed prior chemotherapy to assess safety, tolerability, and anti-tumor activity.
研究人/試驗地點 Researcher / test location
韓國 Korea
研究目的 Research purposes
主要目的 the main purpose
●在先前化療療程失敗的晚期胃腺癌病患中作為單一試劑以推薦劑量(RD)每3週給藥一次,藉由評估客觀腫瘤反應率(ORR)評估卡巴他賽的抗腫瘤活性 • Evaluate the antitumor activity of cabazitaxel by evaluating the objective tumor response rate (ORR) as a single agent in a single stage of advanced gastric adenocarcinoma with previous chemotherapy failure.
次要目的 Secondary purpose
●作為單一試劑每3週給藥一次,確定卡巴他賽的RD ●As a single reagent every 3 weeks, determine the RD of cabazitaxel
●作為單一試劑每3週給藥一次,評估卡巴他賽的安全性 ●Assessed as a single agent every 3 weeks to assess the safety of cabazitaxel
●估計總生存期(OS)和無疾病進展生存期(PFS) ● Estimated overall survival (OS) and disease-free survival (PFS)
●評估卡巴他賽的藥物動力學(PK)曲線(profile) ● Evaluate the pharmacokinetic (PK) profile of cabazitaxel
研究設計 Research design
這是一項單臂(single-arm)第2期研究。 This is a single-arm phase 2 study.
本研究包括兩個部分:部分1和部分2。 The study consists of two parts: Part 1 and Part 2.
部分1:採用“3+3”劑量增加設計,當作為單一試劑每3週給藥一次時,藉由評估卡巴他賽的劑量限制性毒性(DLT)確定卡巴他賽的最大耐受劑量(MTD)。將治療3到6位病患的序列群組(Sequential cohorts)。 Part 1: Using the “3+3” dose-increasing design, the maximum tolerated dose (MTD) of cabazitaxel was determined by assessing the dose-limiting toxicity (DLT) of cabazitaxel when administered as a single agent every 3 weeks. . Sequential cohorts will be treated for 3 to 6 patients.
如表A所示,將有3個劑量水平,卡巴他賽的起始劑量為20mg/m2(水平1)。研究中卡巴他賽的最低和最高試驗劑量分別為15mg/m2和25mg/m2。 As shown in Table A, there will be 3 dose levels and the initial dose of cabazitaxel is 20 mg/m 2 (level 1). The lowest and highest test doses for cabazitaxel in the study were 15 mg/m 2 and 25 mg/m 2 , respectively .
出於安全原因,用於卡巴他賽實際劑量計算的最大體表面積(BSA)為2.1m2。 For safety reasons, the maximum body surface area (BSA) for the actual dose calculation of cabazitaxel was 2.1 m 2 .
不允許病患內劑量增加。 Do not allow an increase in the dose within the patient.
劑量增加判定規則如表B中定義。劑量增加是根據週期1期間 觀察到的DLT,判定由籌劃指導委員會(Steering Committee)(SC)作出。 The dose increase determination rule is as defined in Table B. The dose increase is based on period 1 The observed DLT is determined by the Steering Committee (SC).
*:如果在水平-1下在週期1期間6位病患中有2位經歷DLT,則由SC作出對下面步驟的判定。 *: If there are 6 patients in the period 1 during the period-1 When the 2 bits experience the DLT, the SC makes a decision on the following steps.
在使用當前劑量水平進行治療的至少3位病患接受完至少1個週期的研究治療(3週)並且根據定義DLT的標準對安全性進行評估之前,不應招募進行下一劑量水平。 At least 3 patients treated with the current dose level should not be enrolled for the next dose level until at least 1 cycle of study treatment (3 weeks) is received and safety is assessed according to the criteria for defining DLT.
在週期1期間不能進行DLT評估的病患和/或在週期1期間由於除DLT之外的任何原因退出的病患將被代替。 Patients who are unable to perform DLT assessment during cycle 1 and/or patients who withdraw during cycle 1 due to any reason other than DLT will be replaced.
劑量限制性毒性(DLT)的定義: 為了量化DLT,應當研究藥物相關的不良事件(AE)或實驗室檢查異常(laboratory abnormality),由研究人員進行評估。 Definition of dose limiting toxicity (DLT): To quantify DLT, drug-related adverse events (AEs) or laboratory abnormalities should be studied and evaluated by the investigator.
DLT根據國家癌症研究所不良事件通用術語標準,4.03版 (National Cancer Institute Common Terminology Criteria for Adverse Events,Version 4.03)(NCI CTCAE v.4.03)進行定義,作為週期1期間的任何下列事件:●血液學毒性定義為:4級嗜中性白血球減少症>7天持續時間 DLT according to the National Cancer Institute General Terminology Standard for Adverse Events, Version 4.03 (National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03) (NCI CTCAE v.4.03) is defined as any of the following events during Period 1: ● Hematological toxicity is defined as: Grade 4 neutropenia > 7 Day duration
3或4級嗜中性白血球減少症,併發有記載的感染 Grade 3 or 4 neutropenia with concurrent infections
3或4級嗜中性白血球減少症,伴有單次體溫>38.3℃或者持續體溫38℃超過1小時,並具有危及生命的後果(4級發熱性嗜中性白血球減少症) Grade 3 or 4 neutropenia with a single body temperature >38.3 ° C or sustained body temperature 38 ° C for more than 1 hour with life-threatening consequences (grade 4 febrile neutropenia)
3或4級嗜中性白血球減少症,伴有單次體溫>38.3℃或者持續體溫38℃超過1小時,但沒有危及生命的後果(3級發熱性嗜中性白血球減少症),如果嗜中性白血球減少症在7天內沒有改善到<3級並且儘管有恰當的治療,包括適當地使用粒細胞集落刺激因子(G-CSF)仍導致治療延遲或者劑量降低,則可以被看作DLT Grade 3 or 4 neutropenia with a single body temperature >38.3 ° C or sustained body temperature 38 ° C for more than 1 hour, but no life-threatening consequences (grade 3 febrile neutropenia), if neutropenia did not improve to <3 within 7 days and despite proper treatment, including Proper use of granulocyte colony-stimulating factor (G-CSF) still results in treatment delay or dose reduction, which can be considered as DLT
4級血小板減少症或3級血小板減少症且併發嚴重出血 Grade 4 thrombocytopenia or grade 3 thrombocytopenia with severe bleeding
●非血液學毒性定義為:4級非血液學毒性 ● Non-hematologic toxicity is defined as: Grade 4 non-hematologic toxicity
3級非血液學毒性,但不包括可以用恰當的治療進行管理的毒性,除非研究人和發起人(sponsor)同意這種包括是必需的(例如,如果這些事件過於頻繁或者持續時間過長,或者需要使用過多的支持性護理) Grade 3 non-hematologic toxicity, but does not include toxicity that can be managed with appropriate treatment, unless the investigator and sponsor agree that such inclusion is necessary (for example, if these events are too frequent or too long, Or need to use too much supportive care)
3級發熱但無有記載的感染並且無伴隨發生3級或4級嗜中性白血球減少症 Grade 3 fever but no documented infection and no accompanying grade 3 or 4 neutropenia
3級厭食症、噁心或嘔吐 Grade 3 anorexia, nausea or vomiting
3級腹瀉且無最大有效治療(maximal effective therapy) Grade 3 diarrhea without maximum effective therapy
3級疲勞 Level 3 fatigue
3級周圍神經病變,其在下一治療週期之前恢復到1級或基線 Grade 3 peripheral neuropathy, which returns to level 1 or baseline before the next treatment cycle
●由於毒性的延遲恢復導致週期2延遲超過2週 ● Delayed cycle 2 for more than 2 weeks due to delayed recovery of toxicity
在部分1中,可以在週期1之後預防性給予G-CSF,或者如果病患證明有嗜中性白血球減少症和/或其臨床後果的證據,則可以在研究的任何時間治療性給予G-CSF。G-CSF的使用由研究人員判定,並需要記錄在e-CRF中。 In Part 1, G-CSF can be administered prophylactically after Cycle 1, or if the patient demonstrates evidence of neutropenia and/or its clinical consequences, G- can be administered therapeutically at any time during the study. CSF. The use of G-CSF is determined by the investigator and needs to be recorded in the e-CRF.
在部分2中,在研究的任何時間均可預防性或治療性給予G-CSF。 In Part 2, G-CSF can be administered prophylactically or therapeutically at any time during the study.
對於任何經歷了DLT的病患,研究治療必須被延遲,但是在相同或更低劑量下在毒性被解決到1級或基線之後,可以重新開始。研究治療可以被推遲最多2週,以使毒性得以解決。 For any patient who has experienced DLT, the study treatment must be delayed, but the toxicity is resolved at the same or lower doses. After level 1 or baseline, you can start over. Study treatment can be delayed for up to 2 weeks to allow toxicity to be resolved.
最大耐受劑量(MTD)的定義:MTD定義為在最高達25mg/m2的劑量中在週期1期間所有可評估病患中有少於33%經歷DLT的最高劑量水平。它將根據至少6位病患進行定義。 Definition of Maximum Tolerated Dose (MTD): MTD is defined as the highest dose level of less than 33% of all evaluable patients experiencing DLT during the cycle 1 in doses up to 25 mg/m 2 . It will be defined based on at least 6 patients.
推薦劑量(RD)的定義:卡巴他賽對於部分2的RD可以是與MTD相同或更低的劑量水平,但不超過25mg/m2。它將由SC藉由考慮MTD、總體安全性(週期1期間或之後)和PK曲線加以確定。它也將根據至少6位病患進行定義。 Definition of Recommended Dosage (RD): Cabazitaxel for Part 2 can be at the same or lower dose level as MTD, but does not exceed 25 mg/m 2 . It will be determined by the SC by considering the MTD, overall security (during or after Cycle 1), and the PK curve. It will also be defined based on at least 6 patients.
部分2: 在定義RD之後,則向部分2增加後續病患。部分1中處於RD的病患將包含在部分2中,倘若這些病患具有可測量的病變時。 Part 2: After defining the RD, a follow-up patient is added to Part 2. Patients with RD in Part 1 will be included in Part 2 if these patients have measurable lesions.
所有合格的病患將用卡巴他賽單一試劑每3週治療一次,直至發生疾病進展、不可接受的毒性或滿足其它停止標準為止,無論上述哪一種先出現。 All eligible patients will be treated with a single agent of cabazitaxel every 3 weeks until disease progression, unacceptable toxicity, or other stopping criteria are met, regardless of which of the above occurs first.
每位病患的研究期間包括篩選期、註冊、治療期、治療結束和治療後追蹤期。 The study period for each patient included screening period, registration, treatment period, end of treatment, and post-treatment follow-up period.
研究人群 Research population
主要篩選標準:入選標準: Main screening criteria: inclusion criteria:
●在組織學或細胞學上確認患有不可切除的或轉移的胃腺癌,包括胃食管連接部腺癌,並且已在先前存在2種失敗的化療療程。(對於晚期胃癌第二線治療尚未建立護理標準的國家,可以納入先前1種或2種化療療程失敗的病患) • Histological or cytological confirmation of unresectable or metastatic gastric adenocarcinoma, including gastroesophageal junction adenocarcinoma, and two previously failed chemotherapy regimens. (For countries where the second-line treatment of advanced gastric cancer has not established a standard of care, patients with previous one or two chemotherapy failures may be included)
先前化療應包括如下的至少一種:5-FU或衍生物、紫杉烷、鉑或依立替康。 Previous chemotherapy should include at least one of the following: 5-FU or a derivative, taxane, platinum or irinotecan.
先前(新)輔助性化療在治療結束後6個月內復發將被回顧性視為第一次先前緩和性化療。 Recurrence of prior (new) adjuvant chemotherapy within 6 months of the end of treatment will be retrospectively considered as the first prior palliative chemotherapy.
●簽署知情同意書 ● Signing informed consent
病患需要分別為部分1和部分2簽署不同的知情同意書。 Patients need to sign different informed consents for Part 1 and Part 2, respectively.
排除標準 Exclusion criteria
相關方法: Related methods:
●已經接受過>2次用於晚期胃癌的先前全身性化療療程 的病患 ● Has received >2 previous systemic chemotherapy for advanced gastric cancer Patient
●對於進入部分2的病患,沒有根據RECIST 1.1標準的處於基線水平的至少一種可測量病變 • For patients entering Part 2, there is no at least one measurable lesion at baseline level according to RECIST 1.1 criteria
●ECOG體能狀態(performance status)>1 ●ECOG performance status>1
●年齡<18歲或>85歲 ● Age <18 years old or >85 years old
●預期壽命<2個月 ●Life expectancy <2 months
●器官和骨髓功能不足,證據如下:血紅蛋白<9.0g/dL ● Insufficient organ and bone marrow function, the evidence is as follows: hemoglobin <9.0g/dL
絕對嗜中性細胞計數(ANC)<1500/mm3 Absolute neutrophil count (ANC) <1500/mm 3
血小板計數<100000/mm3 Platelet count <100000/mm 3
總膽紅素1.5 x正常值上限(ULN) Total bilirubin 1.5 x upper normal limit (ULN)
如果沒有肝臟轉移證據,則AST和/或ALT2.5 x ULN,或者有肝臟轉移,則AST和/或ALT5.0 x ULN AST and/or ALT if there is no evidence of liver metastasis 2.5 x ULN, or with liver metastasis, AST and / or ALT 5.0 x ULN
血清肌酸酐>1.5 x ULN。如果肌酸酐為1.0-1.5 x ULN,則估計的腎小球濾過率(eGFR)應當根據CKD-EPI公式計算。eGFR<60mL/min/1.73m2的病患將被排除。 Serum creatinine >1.5 x ULN. If creatinine is 1.0-1.5 x ULN, the estimated glomerular filtration rate (eGFR) should be calculated according to the CKD-EPI formula. Patients with eGFR <60 mL/min/1.73 m 2 will be excluded.
●在本研究招募前4週內接受過先前手術、化療、靶向試劑、研究試劑、或其它抗癌療法(對於含絲裂黴素的療程為6週) ● Previous surgery, chemotherapy, targeting agents, research reagents, or other anticancer therapies within 4 weeks prior to the study enrollment (6 weeks for mitomycin-containing)
●在招募前6週內接受過先前放射療法(用於局部疼痛控制的緩和性放療除外) ●Pre-existing radiation therapy within 6 weeks prior to enrollment (except for palliative radiotherapy for local pain management)
●先前用卡巴他賽治療過 ● Previously treated with cabazitaxel
●在本研究招募前2週內投予過造血生長因子包括G-CSF或輸血 ● Hematopoietic growth factors including G-CSF or blood transfusion within 2 weeks prior to the study enrollment
●已知有癌症的腦或柔腦膜參入(involvement) ●Involvement of brain or flexible meninges known to have cancer
●患有已知的後天免疫缺乏症候群(AIDS)相關疾病或已知HIV感染並需要抗逆轉錄病毒治療的病患。 Patients with known acquired immunodeficiency syndrome (AIDS)-related diseases or known HIV infections and requiring antiretroviral therapy.
●患有活動性水痘-帶狀皰疹感染或已知B型或C型肝炎感染的病患 ● Patients with active varicella-zoster infection or known hepatitis B or C infection
●活躍的繼發性癌症,包括先前的惡性疾病,其中病患已經無疾病5年。然而,除黑色素瘤或原位子宮頸癌之外,在招募前超過4週內得到恰當治療的淺表層皮膚癌不被看作排除原因 ● Active secondary cancer, including previous malignant diseases, in which the patient has no disease 5 years. However, in addition to melanoma or cervical cancer in situ, superficial skin cancer that is properly treated for more than 4 weeks prior to enrollment is not considered a cause of exclusion.
●其它同時發生的嚴重疾病或醫學狀況(medical condition),包括需要全身性抗生素/抗真菌藥物用藥的活躍感染 ● other concurrent serious illnesses or medical conditions, including active infections requiring systemic antibiotic/antimycotic medications
●先前抗癌療法除脫髮和2級周圍神經病變之外的所有臨床上顯著的毒性影響不能恢復到NCI CTCAE v.4.031級 ●All clinically significant toxic effects of previous anticancer therapies other than alopecia and grade 2 peripheral neuropathy cannot be restored to NCI CTCAE v.4.03 Level 1
●同時在另一項臨床試驗中治療或者與任何其它抗癌療法同時治療,包括化療、靶向療法、放射療法,或者在研究期間計劃接受這些治療 ● Simultaneous treatment in another clinical trial or concurrent treatment with any other anti-cancer therapy, including chemotherapy, targeted therapy, radiation therapy, or planning to receive these treatments during the study
●不願意或者不能夠服從排定的訪問、治療方案、實驗室檢測和其它研究程序 ● Unwilling or unable to comply with scheduled visits, treatment plans, laboratory tests, and other research procedures
●任何嚴重的或慢性醫學或精神病學狀況,或者需要進一步研究的顯著實驗室異常,其可能給病患安全造成不合理的危險,抑制方案參與,或者干擾研究結果的解釋,並且研究人員可判定該病患不適合進入本研究 ● Any serious or chronic medical or psychiatric condition, or significant laboratory abnormalities that require further investigation, which may pose an unreasonable risk to the patient's safety, inhibit program participation, or interfere with the interpretation of the study results, and the researcher may determine The patient is not suitable for entering this study
●對於有生育潛能的婦女:懷孕、哺乳、在註冊前7天內 缺少陰性懷孕測試,或者從病患簽署知情同意書開始到末次研究給藥之後3個月內期間缺少高度有效的生育控制避孕方法同意書 ●For women with fertility potential: pregnancy, breastfeeding, within 7 days before registration Lack of a negative pregnancy test, or a lack of consent for a highly effective birth control contraceptive method from the time the patient signs the informed consent form to the 3 months after the last study dose
●作為直接參與方案實施的研究人員、助理研究人員、研究助理、藥劑師、臨床研究協調員、或其它職工及其親屬的病患 ● Patients who are directly involved in the implementation of the program, assistant researchers, research assistants, pharmacists, clinical research coordinators, or other employees and their relatives
與對卡巴他賽的當前認知相關的內容: Content related to the current perception of cabazitaxel:
●對用聚山梨醇酯80配製的藥物,例如多西紫杉醇,具有嚴重超敏感反應3級的歷史 ●Severe hypersensitivity to drugs formulated with polysorbate 80, such as docetaxel Level 3 history
●同時或計劃用CYP3A強抑制劑或誘導劑治療。對於已經使用這些藥物的病患,在第一個研究治療劑量之前需要有1週的清除期 ● Simultaneously or planned to be treated with a strong inhibitor or inducer of CYP3A. For patients who have already used these drugs, a one-week washout period is required before the first study treatment dose
病患的總預期數目:在本研究中將治療最多達45位病患:部分1中有9-18位病患用於評估DLT,而部分2中有大約33位合格病患,包括最多6位在部分1中用RD治療的病患,只要這些病患具有可測量的病變即可。 Total expected number of patients: Up to 45 patients will be treated in this study: 9-18 patients in Part 1 were used to assess DLT, while in Part 2 there were approximately 33 eligible patients, including up to 6 Patients treated with RD in Part 1 as long as these patients have measurable lesions.
對於部分2,將包含至少10位用1種先前化療療程治療但失敗的病患,和至少10位用紫杉烷治療但失敗的病患。 For Part 2, at least 10 patients treated with one prior chemotherapy regimen but failed, and at least 10 patients treated with taxane but failed will be included.
研究處理 Research processing
卡巴他賽(XRP6258) Cabazitaxel (XRP6258)
研究產品 Research product
製劑 preparation
卡巴他賽作為無菌、非致熱、非水性、黃色至褐黃色濃縮物提供,用於60mg/1.5ml輸注溶液,並包裝在一個用橡皮塞塞好的15mL清潔(clear)I型玻璃小瓶中。塞子用鋁蓋壓褶固定(crimped)到小瓶上,並用一個淺綠色塑料鉗口帽(flip-off cap)封蓋。溶液含有作為賦形劑的聚山梨醇酯80。 Cabazitaxel is supplied as a sterile, non-pyrogenic, non-aqueous, yellow to brownish yellow concentrate for 60 mg/1.5 ml infusion solution and packaged in a 15 mL clear Type I glass vial stoppered with a rubber stopper . The stopper was crimped to the vial with an aluminum cap and capped with a light green plastic flip-off cap. The solution contains polysorbate 80 as an excipient.
用於輸注溶液的卡巴他賽濃縮物將在如臨床研究方案中所述進行使用之前被稀釋。 The cabazitaxel concentrate for the infusion solution will be diluted prior to use as described in the clinical study protocol.
卡巴他賽的溶劑作為用於注射的13% w/w乙醇水溶液提供。該溶劑在一個用橡皮塞塞住的15mL單劑量清潔I型玻璃小瓶內提供。 橡皮塞用金色鋁蓋壓褶固定到小瓶上,並用一個清潔塑料鉗口帽封蓋。 The solvent for cabazitaxel was supplied as a 13% w/w aqueous solution of ethanol for injection. The solvent was supplied in a 15 mL single dose cleaned Type I glass vial stoppered with a rubber stopper. The rubber stopper is crimped to the vial with a gold-colored aluminum cover and capped with a clean plastic jaw cap.
用於給藥的卡巴他賽輸注溶液的製備需要製備一個60mg/6mL(名義濃度)的預混合溶液。這必須用用於注射的13% w/w乙醇水溶液執行,添加用於輸注溶液的卡巴他賽濃縮物。 Preparation of a cabazitaxel infusion solution for administration requires preparation of a 60 mg/6 mL (nominal concentration) premix solution. This must be performed with a 13% w/w aqueous solution of ethanol for injection, adding a cabazitaxel concentrate for the infusion solution.
每個卡巴他賽小瓶和每個溶劑小瓶要過量填充(overfilled),以確保在製備預混合物之後能夠提取出60mg劑量。每個卡巴他賽小瓶必須用溶劑小瓶的全部內容物稀釋。 Each cabazitaxel vial and each solvent vial are overfilled to ensure that a 60 mg dose can be extracted after preparation of the premix. Each cabazitaxel vial must be diluted with the entire contents of the solvent vial.
給藥途徑: 卡巴他賽將靜脈內給藥。 Route of administration: Cabazitaxel will be administered intravenously.
劑量方案: 部分1: 在每個週期的第一天,病患藉由IV輸注超過1小時以每個劑量水平所限定的劑量投予卡巴他賽。所需的IV前驅用藥(premedication)包括:抗組胺藥(右氯苯那敏(dexchlorpheniramine)5mg、苯海拉明25mg、或等效抗組胺藥);皮質類固醇(地塞米松8mg或等效皮質類固醇);H2拮抗劑(雷尼替丁50mg或等效H2拮抗劑)。這些前驅用藥將在每個卡巴他賽劑量之前至少30分鐘藉由IV輸注給藥。抗嘔吐預防(口服或靜脈內)可以在任何需要的時刻給藥。 Dosage schedule: Part 1: On the first day of each cycle, patients were given cabazitaxel at a dose defined by each dose level by IV infusion for more than 1 hour. The required IV premedication includes: antihistamines (dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or equivalent antihistamines); corticosteroids (dexamethasone 8 mg or equivalent) Corticosteroids; H2 antagonists (ranitidine 50 mg or equivalent H2 antagonists). These prodrugs will be administered by IV infusion at least 30 minutes prior to each cabazitaxel dose. Anti-vomiting prevention (oral or intravenous) can be administered at any desired time.
對於曾具有DLT的病患,可以在相同或更低劑量下繼續進一步的治療。繼續從這些病患收集安全性數據。 For patients who have had DLT, further treatment can be continued at the same or lower dose. Continue to collect safety data from these patients.
部分2: 病患將在每個週期的第一天按照部分1中相同的方式接受卡巴他賽。 Part 2: Patients will receive cabazitaxel in the same manner as in Part 1 on the first day of each cycle.
部分1和部分2的週期長度均為3週。在ANC1500/mm3,血小板計數75000/mm3,血清肌酸酐1.5 x UIN,肝功能測試在指示排除標準範圍內,和非血液學毒性(排除脫髮、局部反應和其它雖然不舒服但不會導致病患嚴重發病的毒性)恢復到1級或基線之前,不應開始新的週期。對於任何顯著的毒性應當進行劑量修改(見表C:卡巴他賽劑量減少時程)。在治療週期之間可允許最多2週的治療延遲。如果治療延遲超過2週,則病患應當中斷研究治療。 Both section 1 and section 2 have a period length of 3 weeks. At ANC 1500/mm 3 , platelet count 75000/mm 3 , serum creatinine 1.5 x UIN, liver function test within the indicated exclusion criteria, and non-hematologic toxicity (excluding hair loss, local reactions and other toxicities that are uncomfortable but do not cause serious disease) A new cycle should not be started before level 1 or baseline. Dose modifications should be made for any significant toxicity (see Table C: Cabazitaxel dose reduction time course). A maximum of 2 weeks of treatment delay can be allowed between treatment cycles. If the treatment is delayed for more than 2 weeks, the patient should discontinue the study treatment.
主要和次要終點 Primary and secondary endpoints
主要終點:-ORR,定義為部分2中具有根據RECIST 1.1標準確認的完全反應(CR)或部分反應(PR)的最佳腫瘤反應的病患相對于分析人群中病患總數的比例。 Primary endpoint: -ORR, defined as the proportion of patients with the best tumor response in Part 2 with complete response (CR) or partial response (PR) confirmed according to RECIST 1.1 criteria relative to the total number of patients in the analyzed population.
次要終點: Secondary end point:
-當在週期1期間作為單一試劑給藥時,藉由評估卡巴他賽的DLT確定部分1的MTD和RD - MTD and RD of Part 1 were determined by evaluating the DLT of cabazitaxel when administered as a single agent during Cycle 1.
-卡巴他賽的安全性分佈,包括AE/SAE和臨床實驗室參數 - Safety distribution of cabazitaxel, including AE/SAE and clinical laboratory parameters
-OS,定義為從第一次研究治療日期至由於任何原因造成的死亡日期之間的時間間隔 -OS, defined as the time interval from the date of the first study treatment to the date of death due to any cause
-PFS,定義為從第一次研究治療日期至由於任何原因造成的放射腫瘤進展日期之間的時間間隔 -PFS, defined as the time interval from the date of the first study treatment to the date of radiation tumor progression due to any cause
-卡巴他賽的PK曲線和最大血漿濃度(C最大)、濃度-時間曲線下面積(AUC)、AUC最終、終末半衰期(t1/2)、血漿清除率(CL)和穩態分佈體積(Vss)等參數 - cabazitaxel the PK profile and the maximum plasma concentration (C max), concentration - area under time curve (AUC), AUC final, terminal half-life (t1 / 2), the plasma clearance (CL) and volume of distribution at steady state (Vss And other parameters
評定時程 Time course
安全性數據: 生命指徵(Vital sign)、用藥和手術史、身體檢查、ECOG PS、和實驗室測試(包括完全血液計數、生物化學和尿液分析)將在給藥之前和在整個研究的指定時間間隔內獲得。治療中出現的不良事件(TEAE)將在研究期間和在末次研究給藥劑量後長達30天內收集。 AE將根據NCI CTCAE v.4.03進行分級。 Security data: Vital sign, medication and surgery history, physical examination, ECOG PS, and laboratory tests (including complete blood count, biochemistry, and urine analysis) will be administered prior to dosing and throughout the study's designated time interval obtain. Adverse events (TEAE) that occurred during treatment will be collected during the study and up to 30 days after the last study dose. The AE will be graded according to NCI CTCAE v.4.03.
眼科檢查將在篩選期間執行(這不應當延遲研究治療的開始),並且如果需要追蹤檢查,則僅在治療結束時進行。 The ophthalmic examination will be performed during screening (this should not delay the start of the study treatment) and, if a follow-up examination is required, only at the end of treatment.
功效數據: 抗腫瘤活性藉由胸部、腹部、骨盆和任何其它區域的(如果臨床上有指示的話)電腦斷層掃描(CT)或磁共振成像(MRI)進行評估。 這些檢查將在基線(篩選時),每6週,任何懷疑有疾病進展的時刻,或者直至疾病發生進展時執行,每次評估使用相同的方法。在疾病發生進展之前中斷研究治療的病患將每6週進行一次腫瘤評估,直至疾病發生進展或者新的抗癌療法開始。 Efficacy data: Antitumor activity is assessed by computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, pelvis, and any other area (if clinically indicated). These tests will be performed at baseline (at screening), every 6 weeks, at any time when disease progression is suspected, or until disease progression, using the same method for each assessment. Patients who discontinued the study treatment before the disease progressed will undergo a tumor assessment every 6 weeks until the disease progresses or a new anticancer therapy begins.
藥物動力學數據: 卡巴他賽PK:藉由標準PK採樣方法從部分1中招募的全部病患和部分2中的12位中國病患中收集血液樣品(在週期1期間和在C2D1開始時研究藥物輸注之前)。 Pharmacokinetic data: Cabazitaxel PK: Blood samples were collected from all patients enrolled in Part 1 and 12 Chinese patients in Part 2 by standard PK sampling method (during period 1 and prior to study drug infusion at the beginning of C2D1).
統計學考慮 Statistical considerations
樣品大小的確定: 研究的部分1用於藉由評估週期1期間觀察到的DLT確定卡巴他賽的MTD,並為部分2確定RD。部分1中可評估病患的數目範圍 是9-18位。 Determination of sample size: Part 1 of the study was used to determine the MTD of cabazitaxel by evaluating the DLT observed during cycle 1, and to determine RD for section 2. The number of patients that can be assessed in Part 1 It is 9-18.
研究的部分2是用於估計研究人群中在RD下的ORR。樣品大小計算使用具有Yates連續性校正的單樣本卡方方法。零假設是反應率等於5%,替換性假設(alternative hypothesis)是反應率等於20%。 總共33位治療病患將保證當真實反應率等於20%、單側alpha水平為0.025時,檢驗效能(power)不小於80%。如果在33位病患中觀察到5個反應,則拒絕零假設而支持替換性假設。 Part 2 of the study was used to estimate the ORR at RD in the study population. The sample size calculation uses a one-sample chi-square method with Yates continuity correction. The null hypothesis is that the response rate is equal to 5%, and the alternative hypothesis is that the reaction rate is equal to 20%. A total of 33 patients will be guaranteed a power of not less than 80% when the true response rate is equal to 20% and the unilateral alpha level is 0.025. If observed in 33 patients Five responses reject the null hypothesis and support the alternative hypothesis.
部分2中的33位病患中,將可包含最多6位在部分1中以RD治療的病患,只要他們具有可測量的病變即可。因此,在本研究中將總共治療最多達45位病患。 Of the 33 patients in Part 2, up to 6 patients treated with RD in Part 1 may be included as long as they have measurable lesions. Therefore, a total of up to 45 patients will be treated in this study.
分析人群: DLT可評估人群:該人群包括部分1中的全部註冊病患,他們在週期1中接受了完全劑量的研究藥物並完成了DLT評估,或者在週期1中接受了部分劑量的研究藥物並且發生了DLT。與DLT評估相關的分析將根據DLT可評估人群執行。 Analysis of the crowd: DLT evaluable population: This population includes all registered patients in Part 1 who received a full dose of study drug and completed a DLT assessment in Cycle 1, or received a partial dose of study drug in Cycle 1 and occurred DLT. The analysis associated with the DLT assessment will be performed according to the DLT evaluable population.
經過修改的意向治療(mITT)人群:該人群包括部分2中的全部受治病患。該人群是用於部分2中所有功效分析的主要人群。 Modified intention to treat (mITT) population: This population includes all of the treated patients in Part 2. This population is the primary population used for all efficacy analyses in Part 2.
ORR可評估人群:該人群是mITT人群的亞組。它包括部分2中接受了至少2個週期的研究治療,具有基線腫瘤評估,並且在第一次研究治療之後不早于5週(35天)內進行了至少一次基線後腫瘤評估的所有病患。此外,在第一次計劃好的基線後腫瘤評估之前已根據RECIST 1.1發生了疾病進展的病患將被定義為早期進展,並且也被看作可用於評估ORR。 ORR evaluable population: This population is a subgroup of the mITT population. It includes all patients who underwent at least 2 cycles of study treatment in Part 2, had a baseline tumor assessment, and had at least one post-baseline tumor assessment no earlier than 5 weeks (35 days) after the first study treatment. . In addition, patients who have progressed according to RECIST 1.1 prior to the first planned baseline post-tumor assessment will be defined as early progression and are also considered useful for assessing ORR.
安全性人群:該人群包括所有接受了至少一個劑量(包括部分 劑量)研究藥物的病患。該人群將在所有安全性綜述(safety summaries)中使用。將分別對部分1和部分2進行安全性分析。 Safety population: This population includes all received at least one dose (including parts) Dosage) The patient who studied the drug. This population will be used in all safety summaries. Part 1 and Part 2 will be analyzed for safety separately.
主要終點分析: ORR將被計算為部分2中具有確認的CR或PR的最佳反應的病患相對于mITT人群中病患總數的比值。反應率使用具有Yates校正的卡方檢驗進行檢查。反應率的95%信賴區間將使用正態近似值提供。 Primary endpoint analysis: The ORR will be calculated as the ratio of patients with the best response to confirmed CR or PR in Part 2 to the total number of patients in the mITT population. The reaction rate was checked using a chi-square test with Yates correction. The 95% confidence interval for the response rate will be provided using a normal approximation.
ORR的數據截止日期是部分2的每位病患均被第一次確認基線後腫瘤評估(post-baseline tumor assessment)或者中斷研究治療的日期,無論哪一項最先發生。 The data cut-off date for the ORR is the date on which each patient in Part 2 was first confirmed for a post-baseline tumor assessment or discontinued study treatment, whichever occurred first.
次要終點分析 Secondary endpoint analysis
在部分1中,MTD和RD將在週期1期間藉由DLT評估加以確定。由於樣品尺寸小,該分析僅是描述性的。 In Part 1, MTD and RD will be determined by DLT evaluation during Cycle 1. This analysis is only descriptive due to the small sample size.
部分1的截止日期是RD被確定的日期。 The expiration date of Part 1 is the date on which the RD is determined.
卡巴他賽的安全性分佈,包括AE/SAE和實驗室參數,將藉由病患中的頻率和最差等級進行綜述。每位病患和每個週期的最差等級將使用NCI CTCAE v.4.03為所選不良事件和實驗室測量結果進行列表。 The safety profile of cabazitaxel, including AE/SAE and laboratory parameters, will be reviewed by frequency and worst grades in patients. The worst grade for each patient and each cycle will be listed using NCI CTCAE v.4.03 for selected adverse events and laboratory measurements.
總生存期將使用Kaplan-Meier生存統計進行綜述。Kaplan-Meier曲線的圖形展示將分別提供。如果在研究期間沒有觀察到死亡,則OS數據將在病患已知仍存活的最後日期或者研究結束(EOS)時進行審查,無論哪一項最先發生。 The overall survival will be reviewed using Kaplan-Meier survival statistics. A graphical display of the Kaplan-Meier curves will be provided separately. If no death is observed during the study, the OS data will be reviewed on the last date the patient is known to be alive or at the end of the study (EOS), whichever occurs first.
PFD將使用Kaplan-Meier生存統計進行綜述。Kaplan-Meier曲線的圖形展示將分別提供。如果沒有觀察到死亡或疾病進展,則PFS數據將在最後一次無疾病進展證據的可得腫瘤評估的日期或在EOS時進行審查,無論哪一項最先發生。 PFD will be reviewed using Kaplan-Meier survival statistics. A graphical display of the Kaplan-Meier curves will be provided separately. If no death or disease progression is observed, the PFS data will be reviewed on the date of the last available tumor assessment without evidence of disease progression or at EOS, whichever occurs first.
藥物動力學參數將使用描述性統計進行綜述。 Pharmacokinetic parameters will be reviewed using descriptive statistics.
研究週期的持續時間(每位病患) Duration of the study period (per patient)
研究包括: The research includes:
-篩選期:從簽署知情同意書之日到註冊。不應當超過14天。 - Screening period: from the date of signing the informed consent form to the registration. Should not exceed 14 days.
-註冊:在篩選期間所有基線檢查完成後,根據入選/排除標準確認病患的合格性之時。 - Registration: When all baseline examinations are completed during screening, the patient's eligibility is confirmed according to the inclusion/exclusion criteria.
-治療期:研究藥物在註冊3天內開始。治療週期為3週,當存在未解決的毒性時可以延遲達2週。研究藥物的給藥之日是給定週期的第一天。所有病患將連續接受治療,直至發生疾病進展、不可接受的毒性、或滿足其它中斷標準為止 - Treatment period: The study drug begins within 3 days of registration. The treatment period is 3 weeks and can be delayed for up to 2 weeks when there is unresolved toxicity. The date of administration of the study drug is the first day of a given cycle. All patients will continue to receive treatment until disease progression, unacceptable toxicity, or other disruption criteria are met
-治療結束(EOT):當病患出於任何原因(排除死亡或失去追蹤)中斷研究治療時,應當在研究治療末次劑量之後30天內進行EOT評估。如果由於治療延遲導致中斷判定在末次治療劑量後超過30天才得出,則EOT評估應當在作出這種判定之後的7天內執行。 - End of Treatment (EOT): When a patient discontinues a study treatment for any reason (excluding death or loss of follow-up), an EOT assessment should be performed within 30 days of the study of the last dose of treatment. If the interruption decision is made more than 30 days after the last treatment dose due to treatment delay, the EOT assessment should be performed within 7 days of making such a determination.
-治療後追蹤期:在EOT之後,病患將每2個月當面或藉由電話聯繫一次,以檢查生存狀態和新抗癌療法的使用,直至死亡或EOS,無論哪一項最先發生。 - Post-treatment follow-up period: After EOT, patients will be contacted every 2 months or by phone to check the status of life and the use of new anti-cancer therapies until death or EOS, whichever occurs first.
在疾病進展之前中斷研究治療的病患將每6週進行腫瘤評估,直至疾病進展或者開始新的抗癌療法。在數據截止日期之後扔接受治療的病患可以繼續治療,直至發生疾病進展、不可接受的毒性或滿足其它中斷標準。在本週期內將收集研究藥物給藥,無論與研究藥物有何關係的所有SAE,和被認為與研究藥物有關的AE,和中斷原因。 Patients who discontinue study treatment prior to disease progression will undergo tumor assessment every 6 weeks until disease progression or initiation of new anticancer therapies. Patients who are thrown away after the data cut-off date can continue treatment until disease progression, unacceptable toxicity, or other disruption criteria are met. The study drug will be administered during this cycle, regardless of all SAEs associated with the study drug, and the AEs considered to be associated with the study drug, and the cause of the discontinuation.
所有病患的研究將在部分1和部分2中招募的全部病患均達到EOT之後的3個月結束。 All patients' studies will end in 3 months after all patients recruited in Sections 1 and 2 have reached EOT.
結果result
病患人群 Patient population
-本研究包含16位病患(8位男性,8位女性)(表1) - This study included 16 patients (8 males, 8 females) (Table 1)
-中值年齡為50.0歲,並且14/16病患(87.5%)<65歲 - The median age is 50.0 years old, and 14/16 patients (87.5%) <65 years old
-所有病患的原發腫瘤位置在胃部;所有病患具有轉移性疾病(表2) - The primary tumor location of all patients is in the stomach; all patients have metastatic disease (Table 2)
-13位病患(81.3%)具有先前治療性或緩和性胃切除術,1位病患(6.3%)接受過先前放射療法。7位病患(43.8%)先前曾被給予輔助性化療,先前緩和性化療療程的中值是2(範圍1-2)。11位病患(68.8%)先前曾經有紫杉烷暴露。 - 13 patients (81.3%) had prior therapeutic or palliative gastrectomy and 1 patient (6.3%) had prior radiation therapy. Seven patients (43.8%) had previously been given adjuvant chemotherapy, and the median duration of prior palliative chemotherapy was 2 (range 1-2). Eleven patients (68.8%) had previously had taxane exposure.
劑量增加 Dose increase
●在DL1下,在前3位病患中均沒有出現DLT。 ● Under DL1, no DLT occurred in the first 3 patients.
●在DL2下,招募了4位病患(因為1位病患永久中斷)。僅觀察到1例DLT(4級發熱性嗜中性白血球減少症)。然而,全部4位病患 均經歷過發熱性嗜中性白血球減少症。 ● Under DL2, 4 patients were recruited (because 1 patient was permanently interrupted). Only one case of DLT (grade 4 febrile neutropenia) was observed. However, all 4 patients Both experienced febrile neutropenia.
●因此,在DL1下又招募了3位額外的病患,以便在更低劑量下進一步探究安全性。在3位病患中有2位發生了2例DLT(4級嗜中性白血球減少症>7天持續時間)。 ● Therefore, three additional patients were recruited under DL1 to further explore safety at lower doses. Two patients with DLT (grade 4 neutropenia > 7-day duration) occurred in 2 of 3 patients.
●作為反應,開放DL-1,在6位DLT可評估病患中沒有觀察到DLT;因此,DL-1(15mg/m2)被確認為MTD。 In the reaction, DL-1 was opened, and no DLT was observed in the 6-position DLT evaluable patients; therefore, DL-1 (15 mg/m 2 ) was confirmed as MTD.
研究治療暴露 Study treatment exposure
●給藥週期的中值:DL1下為5(1-6),DL2下為1.5(1-6),在DL-1下為3(2-6)。 The median value of the dosing period: 5 (1-6) at DL1, 1.5 (1-6) at DL2, and 3 (2-6) at DL-1.
●中斷的最常見原因是進展性疾病(93.8%)。1位病患(6.3%)由於與研究藥物無關的AE而中斷治療。 ● The most common cause of interruption is progressive disease (93.8%). One patient (6.3%) discontinued treatment due to AEs unrelated to the study drug.
安全性 safety
●全部16位病患均經歷了至少一次AE(無論出於何種原因),其中13位(81.3%)具有1次3/4級AE(表3)。最頻繁的所有等級AE(全部病患的>35%)是嗜中性白血球減少症(n=11,68.8%),食欲下降(n=8,50.0%),貧血,發熱性嗜中性白血球減少症和噁心(所有均n=6,37.5%)。最頻繁的3/4級AE(>10%的病患)是嗜中性白血球減少症(n=10,62.5%)和發熱性嗜中性白血球減少症(n=6,37.5%),發生發熱性嗜中性白血球減少症的6位病患中的5位先前接受過紫杉烷療法。 ● All 16 patients experienced at least one AE (for whatever reason), 13 of whom (81.3%) had 1 time 3/4 AE (Table 3). The most frequent all grades AE (>35% of all patients) were neutropenia (n=11, 68.8%), decreased appetite (n=8,50.0%), anemia, febrile neutrophils Reduced and nausea (all n=6, 37.5%). The most frequent grade 3/4 AE (>10% of patients) was neutropenia (n=10, 62.5%) and febrile neutropenia (n=6, 37.5%), occurred Five of the six patients with febrile neutropenia had previously received taxane therapy.
●3級的非血液學AE在所有DL下均不頻繁。 ● Grade 3 non-hematologic AEs were infrequent under all DLs.
●所有等級的血液學異常包括貧血(n=16,100%)、嗜中性白 血球減少症(n=14,87.5%)、白血球減少症(n=13,81.2%)和血小板減少症(n=6,37.5%)。3/4級血液異常包括白血球減少症和嗜中性白血球減少症(二者均為n=10,62.5%)。未報告3/4級貧血或血小板減少症。 ●All grades of hematological abnormalities including anemia (n=16,100%), neutrophil Hematocrit (n=14, 87.5%), leukopenia (n=13, 81.2%) and thrombocytopenia (n=6, 37.5%). Grade 3/4 blood abnormalities include leukopenia and neutropenia (both n=10, 62.5%). Grade 3/4 anemia or thrombocytopenia has not been reported.
●10位病患(62.5%)經歷了15次SAE(無論出於何種原因)。唯一在>1位病患中發生的SAE是發熱性嗜中性白血球減少症(n=6,37.5%;全為3/4級並且與研究治療有關)。 ● Ten patients (62.5%) experienced 15 SAEs (for whatever reason). The only SAE that occurred in >1 patients was febrile neutropenia (n=6, 37.5%; all grades 3/4 and related to study treatment).
●在6位病患(37.5%)中發生了由於AE導致的劑量減少:在DL1下有3級發熱性嗜中性白血球減少症(n=2)和4級嗜中性白血球減少症(n=2),在DL2下有3或4級發熱性嗜中性白血球減少症(n=2)。 ● A dose reduction due to AE occurred in 6 patients (37.5%): Grade 3 febrile neutropenia (n=2) and Grade 4 neutropenia (n=4) under DL1 = 2) There were 3 or 4 febrile neutropenia (n=2) under DL2.
功效 efficacy
●DL-1下的一位病患(6.3%)具有部分反應(PR)作為最佳總反應;這位病患先前未接受過紫杉烷療法。 • One patient (6.3%) under DL-1 had a partial response (PR) as the best overall response; the patient had not previously received taxane therapy.
●8位病患(50%)(5位病患處於DL1,1位病患處於DL2,2位病患處於DL-1)具有穩定的疾病作為最佳總反應,包括1位處於DL1並具有未確認的PR的病患,其先前接受過紫杉烷療法。 ● 8 patients (50%) (5 patients in DL1, 1 patient in DL2, 2 patients in DL-1) with stable disease as the best overall response, including 1 in DL1 and Patients with unconfirmed PR who had previously received taxane therapy.
●1位病患(6.3%)由於AE和沒有基線後腫瘤評估而中斷研究治療。 • One patient (6.3%) discontinued study treatment due to AE and no post-baseline tumor assessment.
PK PK
●卡巴他賽在每個DL下的平均血漿濃度-時間曲線如圖1所示。 The mean plasma concentration-time curve for cabazitaxel at each DL is shown in Figure 1.
●與先前I期研究一致,卡巴他賽在15-25mg/m2的劑量範圍內總體PK曲線的特徵是長末端消除半衰期(73.05h)、高清除率(33.6L/h/m2)和大分佈容積(大約2420L/m2) • Consistent with previous Phase I studies, the overall PK profile of cabazitaxel in the dose range of 15-25 mg/m 2 was characterized by long terminal elimination half-life (73.05 h), high clearance (33.6 L/h/m 2 ) and Large volume of distribution (about 2420L/m 2 )
●在所有DL下對劑量成比例性(Dose proportionality)進行評估;對於從15到25mg/m2的1.67倍劑量增加,C最大,AUC最終和AUC的相應估計比值分別為2.06,2.08和2.03(表4,圖2)。儘管所估計比值的信賴區間較寬,這主要是由於最低劑量(15mg/m2)下的變異性較高,但是在20和25mg/m2之間確證了劑量均衡性的偏差很少。 • Dose proportionality was evaluated at all DLs; for a 1.67-fold dose increase from 15 to 25 mg/m 2 , the C- maximum , AUC final and AUC corresponding estimated ratios were 2.06, 2.08 and 2.03, respectively. Table 4, Figure 2). Although the confidence interval of the estimated ratio is wider, this is mainly due to the higher variability at the lowest dose (15 mg/m 2 ), but the deviation of dose balance is confirmed to be small between 20 and 25 mg/m 2 .
●沒有觀察到劑量效應。對於20-25mg/m2劑量,總末端半衰期為92.7h,清除率為31.6L/h/m2。 • No dose effects were observed. For the 20-25 mg/m 2 dose, the total terminal half-life was 92.7 h and the clearance was 31.6 L/h/m 2 .
討論和結論 Discussion and conclusion
●卡巴他賽在患有晚期胃癌的亞洲病患中的MTD為15mg/m2。 ● The MTD of cabazitaxel in Asian patients with advanced gastric cancer is 15 mg/m 2 .
●與先前研究一致,卡巴他賽最顯著的毒性是嗜中性白血球減少症及其相關併發症。在安全性概貌中沒有意外發現。 • Consistent with previous studies, the most significant toxicity of cabazitaxel is neutropenia and its associated complications. No surprises were found in the security profile.
●本研究中卡巴他賽頻繁出現的嗜中性白血球減少症併發症可能部分是由於病患嚴重的前處理特性,以及由於先前紫杉烷療法導致的積累性骨髓毒性。接受過2次先前化療的病患的大部分,以及發生發熱性嗜中性白血球減少症的6位病患中的5位先前接受過紫杉烷療法。 ● The frequent complications of neutropenia in cabazitaxel in this study may be due in part to the patient's severe pretreatment characteristics and cumulative bone marrow toxicity due to previous taxane therapy. The majority of patients who had received 2 prior chemotherapy, and 5 of the 6 patients who developed febrile neutropenia had previously received taxane therapy.
●觀察到兩個PR,一個在15mg/m2並且沒有先前紫杉烷療法的病患中被確認,一個在20mg/m2並且具有先前紫杉烷療法的病患中未被確認。 • Two PRs were observed, one was confirmed in patients with 15 mg/m 2 and no previous taxane therapy, and one was not confirmed in patients with 20 mg/m 2 and with previous taxane therapy.
●卡巴他賽在本亞洲人群中的PK參數與I期研究中在高加索人群中觀察到的相似,因此種族差異性不大可能解釋MTD之差異性。 The PK parameters of cabazitaxel in this Asian population are similar to those observed in the Caucasian phase in the Phase I study, so racial differences are unlikely to explain the differences in MTD.
ECOG PS,Eastern Cooperative Oncology Group體能狀態 ECOG PS, Eastern Cooperative Oncology Group fitness status
AE,副作用 AE, side effects
C最大,3.67x劑量1.41;AUC最大,6.28 x劑量1.44;AUC,9.53 x劑量1.38 C max , 3.67x dose 1.41 ; AUC max , 6.28 x dose 1.44 ; AUC, 9.53 x dose 1.38
AUC,在濃度-時間曲線下的面積;Cmax,最大血漿濃度 AUC, area under the concentration-time curve; C max , maximum plasma concentration
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