奥名润多西他赛-83页PPT精品文档

多西他赛杂质7（多西他赛EP杂质G）Docetaxel Impurity 7（Docetaxel EP Impurity G）32427D 125354-16-710mg-25mg-50mg-100mg 多西他赛杂质8Docetaxel Impurity 832428D N/A10mg-25mg-50mg-100mg多西他赛杂质9Docetaxel Impurity 932429D N/A10mg-25mg-50mg-100mg多西他赛杂质10Docetaxel Impurity 10324210DN/A10mg-25mg-50mg-100mg多西他赛杂质11Docetaxel Impurity 11324211DN/A10mg-25mg-50mg-100mg多西他赛杂质12Docetaxel Impurity 12324212DN/A10mg-25mg-50mg-100mg多西他赛杂质13（2-苯甲酰-2-戊烯基多西他赛）DocetaxelImpurity 13（2-Debenzoyl-2-pentenoylDocetaxel）324213D 1412898-66-810mg-25mg-50mg-100mg多西他赛杂质14Docetaxel Impurity 14324214DN/A10mg-25mg-50mg-100mgImpurity 15D 250mg-100mg多西他赛杂质16DocetaxelImpurity 16324216DN/A10mg-25mg-50mg-100mg多西他赛杂质17Docetaxel Impurity 17324217D 145533-34-210mg-25mg-50mg-100mg多西他赛杂质18DocetaxelImpurity 18324218D 208406-86-410mg-25mg-50mg-100mg多西他赛杂质19DocetaxelImpurity 19324219DN/A10mg-25mg-50mg-100mg多西他赛杂质20Docetaxel Impurity 20324220D 172018-16-510mg-25mg-50mg-100mg多西他赛杂质21DocetaxelImpurity 21324221D 92950-45-310mg-25mg-50mg-100mg多西他赛杂质22DocetaxelImpurity 22324222D 151636-94-110mg-25mg-50mg-100mgImpurity 23D 150mg-100mg多西他赛杂质24DocetaxelImpurity 24324224DN/A10mg-25mg-50mg-100mg多西他赛杂质25Docetaxel Impurity 25324225D 110258-92-910mg-25mg-50mg-100mg多西他赛杂质26DocetaxelImpurity 26324226D 114915-19-410mg-25mg-50mg-100mg多西他赛杂质27DocetaxelImpurity 27324227DN/A10mg-25mg-50mg-100mg多西他赛杂质28Docetaxel Impurity 28324228DN/A10mg-25mg-50mg-100mg多西他赛杂质29Docetaxel Impurity 29324229DN/A10mg-25mg-50mg-100mg多西他赛杂质30Docetaxel Impurity 30324230DN/A10mg-25mg-50mg-100mgImpurity 31D50mg-100mg多西他赛杂质32Docetaxel Impurity 32324232DN/A10mg-25mg-50mg-100mg多西他赛杂质33Docetaxel Impurity 33324233DN/A10mg-25mg-50mg-100mg多西他赛杂质34Docetaxel Impurity 34324234DN/A10mg-25mg-50mg-100mg多西他赛杂质35Docetaxel Impurity 35324235D 1354900-65-410mg-25mg-50mg-100mg多西他赛杂质36Docetaxel Impurity 36324236D 1095547-98-010mg-25mg-50mg-100mg多西他赛杂质37Docetaxel Impurity 37324237D 1095547-96-810mg-25mg-50mg-100mg多西他赛杂质38Docetaxel Impurity 38324238DN/A10mg-25mg-50mg-100mgImpurity 39D50mg-100mg多西他赛杂质40Docetaxel Impurity 40324240D 133524-69-310mg-25mg-50mg-100mg多西他赛杂质41DocetaxelImpurity 41324241DN/A10mg-25mg-50mg-100mg多西他赛杂质42Docetaxel Impurity 42324242DN/A10mg-25mg-50mg-100mg多西他赛杂质43Docetaxel Impurity 43324243D 154306-81-710mg-25mg-50mg-100mg多西他赛杂质44DocetaxelImpurity 44324244D 147058-27-310mg-25mg-50mg-100mg多西他赛杂质45DocetaxelImpurity 45324245D 154428-10-110mg-25mg-50mg-100mg多西他赛杂质46DocetaxelImpurity 46324246D 157240-36-310mg-25mg-50mg-100mgImpurity 47D 58-250mg-100mg多西他赛杂质48Docetaxel Impurity 48324248D 201856-57-710mg-25mg-50mg-100mg多西他赛杂质49DocetaxelImpurity 49324249D 133577-33-010mg-25mg-50mg-100mg多西他赛杂质50DocetaxelImpurity 50324250DN/A10mg-25mg-50mg-100mg多西他赛杂质51Docetaxel Impurity 51324251D119-52-810mg-25mg-50mg-100mg多西他赛杂质52Docetaxel Impurity 52324252DN/A10mg-25mg-50mg-100mg多西他赛杂质53Docetaxel Impurity 53324253D 165173-47-710mg-25mg-50mg-100mg多西他赛杂质54DocetaxelImpurity 54324254DN/A10mg-25mg-50mg-100mg。

多西他赛（docetaxel）1概述多西他赛在美国食品药品监督管理局（FDA）相关审评文件中列为窄治疗指数药物（NTIDs）［1］。

依据国内外公开发表的文献资料及相关专业工具书，原研药多西他赛也符合NTIDs的定义及一般特征，其中位有效剂量为18mg/kg，中位致死剂量为30mg/kg，治疗指数（TI）为1.67，属于NTIDs［2-5］。

多西他赛为细胞毒性抗肿瘤药物，1996年获美国FDA批准上市。

多西他赛是我国医保用药，是治疗肺癌、乳腺癌、胃癌、前列腺癌的重要药物之一。

《中国抗癌协会乳腺癌诊治指南与规范（2019年版）》［6］、《中国临床肿瘤学会（CSCO）乳腺癌诊疗指南2020》［7］、《中国晚期乳腺癌规范诊疗指南（2020版）》［8］均推荐多西他赛用于乳腺癌全身治疗。

在国外，美国国家综合癌症网络（NCCN）2020年肿瘤临床实践指南（乳腺癌）［9］、第5版欧洲肿瘤学会（ESO）-欧洲医学肿瘤学会进展期乳腺癌（ABC5）指南［10］、2019年圣加伦（St.Gallen）国际乳腺癌会议指南［11］同样推荐多西他赛用于乳腺癌的全身治疗。

此外，2020年CSCO的各类肿瘤诊疗指南还推荐多西他赛用于非小细胞肺癌［12］、胃癌［13］和前列腺癌［14］的全身治疗。

2安全用药提示2.1替换使用多西他赛的仿制替代带来皮肤毒性风险增加：Yang 等［15］开展的回顾性研究提示，替换原研多西他赛带来皮肤毒性发生率增加。

此外，由于仿制替换可能带来的疗效降低或不良反应增加，可能导致患者的住院时间延长，使患者需要接受额外的医疗项目以改善症状，最终导致患者的综合医疗支出增加，也导致其医保负担加重。

Poirier等［16］开展的一项研究提示，接受仿制多西他赛治疗的患者，中性粒细胞减少性发热的发生率显著高于原研组，部分患者因此需要使用更多粒细胞-集落刺激因子（G-CSF）治疗，因而治疗费用增加；而部分患者可能因此而停药，患者生存等临床疗效指标受到影响。

CLINICAL TRIALPhase II,multicenter,open-label,randomized study of YM155plus docetaxel as first-line treatment in patients with HER2-negative metastatic breast cancerMichael R.Clemens •Oleg A.Gladkov •Elaina Gartner •Vladimir Vladimirov •John Crown •Joyce Steinberg •Fei Jie •Anne KeatingReceived:8December 2014/Accepted:8December 2014/Published online:30December 2014ÓThe Author(s)2014.This article is published with open access at Abstract The objective of this study was to assess the efficacy and tolerability of YM155,a survivin suppressor,in combination with docetaxel,compared with docetaxel alone in patients with HER2-negative metastatic breast cancer.This phase II,multicenter,open-label,2-arm study randomized patients (C 18years)with histologically or cytologically confirmed stage IV HER2-negative meta-static breast cancer and C 1measurable lesion,to receive docetaxel alone or docetaxel plus YM155.The primary endpoint was progression-free survival (PFS).Secondary endpoints included objective response rate (ORR),overall survival (OS),duration of response (DOR),clinical benefit rate (CBR),time to response (TTR),biomarker assessment,and analysis of circulating tumor cells.Patients were women diagnosed with HER2-negative breast cancer;mosthad received prior drug therapies.The median PFS was 8.4months with YM155plus docetaxel (n =50)and 10.5months with docetaxel alone (n =51;HR 1.53;95%CI 0.83,2.83;P =0.176).No statistically significant dif-ferences were observed for secondary endpoints,although slightly greater OS (630vs 601days;P =0.768),CBR (84.3vs 82.0%;P =0.855),DOR,and TTR were observed with docetaxel alone compared with YM155plus docetaxel,whereas ORR was similar (25.5vs 26.0).The most common TEAEs observed with YM155plus doce-taxel compared with docetaxel alone were neutropenia (83.3vs 84.3%),alopecia (62.5vs 52.9%),fatigue (50vs 41.2%),and nausea (37.5vs 41.2%).Although YM155is a novel drug that suppresses survivin,YM155plus doce-taxel exhibited no statistically significant differences in endpoints compared with docetaxel alone.The combina-tion regimen was well tolerated.Keywords YM155ÁSurvivin ÁHER2ÁMetastatic breastcancerIntroductionBreast cancer is the most common potentially fatal form of cancer in women and is the leading cause of death from cancer in women worldwide [1].It is estimated that there will be approximately 235,000new cases of invasive breast cancer and more than 40,000breast cancer deaths in the United States in 2014[2].The majority of patients will be diagnosed with early stage disease [3],which is amenable to curative treatment with surgical care and/or radiation [4];however,6–10%of patients will present with meta-static breast cancer [5],and up to 30%of all patients may ultimately develop metastatic disease [6].M.R.Clemens (&)Innere Medizin I,Klinikum Mutterhaus de Borromaerinnen GmbH,Trier,Germanye-mail:Clemens@mutterhaus.deO.A.GladkovChelyabinsk Regional Clinical Oncology Dispensary,Chelyabinsk,RussiaE.GartnerBarbara Ann Karmanos Cancer Institute,Wayne State University,Detroit,MI,USAV.VladimirovPyatigorsk Oncology Dispensary,Pyatigorsk,RussiaJ.CrownIreland Cooperative Oncology Research Group,Dublin,Ireland J.Steinberg ÁF.Jie ÁA.KeatingAstellas Pharma Global Development,Northbrook,IL,USABreast Cancer Res Treat (2015)149:171–179DOI 10.1007/s10549-014-3238-6While metastatic breast cancer generally is incurable, systemic therapy can provide meaningful prolongation of survival and palliation of the distressing symptoms of cancer[7,8].The choice of systemic therapy is increas-ingly determined by biological markers predictive of response to targeted therapy.Patients with hormone receptor positive disease will frequently benefit from endocrine therapies[9].When the nearly inevitable development of resistance to endocrine therapy occurs [10],these patients can still derive benefit from cytotoxic chemotherapy[11].Patients whose cancer has an alteration (usually an amplification)of the HER2gene derive sub-stantial benefit from anti-HER2therapeutics such as trast-uzumab given in combination with chemotherapy or endocrine therapy[12].Approximately15%of patients have tumors that do not express the estrogen or progesterone receptors,and do not have altered HER-2[9].There are currently no markers predictive of response for patients with these‘‘triple neg-ative’’tumors,and conventional cytotoxic chemotherapy remains the standard of care[11].Unfortunately,prognosis remains poor due to high rates of relapse and chemore-sistance in this subset of breast cancer patients[13].New molecularly targeted systemic therapies for triple negative breast cancers(TNBC)are urgently needed.One such candidate target molecule is survivin,a member of the‘‘inhibitor of apoptosis protein’’family that contributes to increased proliferation and resistance to apoptosis in tumor cells[14].Overexpression of survivin has been demonstrated in metastatic breast cancer com-pared with normal breast tissue[15].A recent meta-ana-lysis found that increased expression of survivin was significantly associated with unfavorable overall survival (OS)in patients with breast cancer[16].YM155is a small molecular suppressor of survivin. Continuous infusion of YM155significantly reduced tumor size and the incidence of spontaneous metastasis,as well as prolonged survival,in a mouse model of metastatic TNBC [17].In vitro studies demonstrated that inhibition of apoptosis by survivin required interaction with microtu-bules[18],providing a powerful rationale for the study of survivin together with anti-microtubule agents such as taxanes.YM155in combination with the microtubule-tar-geted agent docetaxel induced greater apoptosis compared with either agent alone,resulting in complete tumor regression in a mouse TNBC xenograft model[19].The results of a phase I study indicated that YM155was well tolerated with manageable toxicities in patients with advanced solid tumors,including breast cancer,that were refractory to standard therapy[20].Additionally,findings from an open-label,single-arm,single-center study of YM155plus docetaxel in patients with advanced hormone refractory prostate cancer and other tumors showed responses in a few patients with breast cancer,supporting the design and execution of the present study[21].The objective of the current phase II study was to assess the effects of YM155in combination with docetaxel compared with docetaxel alone on progression-free sur-vival(PFS)in patients with HER2-negative metastatic breast cancer.MethodsStudy designThis was a phase II,multicenter,open-label,randomized, 2-arm study(NCT01038804)conducted in the United States,Europe,and Russia.Local institutional review boards and independent ethics committees,or both, approved the study protocol and informed consent forms before use.The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice,the European Clinical Trial Directive,and applicable laws and regulations.Each patient provided written informed consent before study enrollment.Study populationInclusion criteriaPatients aged C18years with histologically or cytologi-cally confirmed stage IV HER2-negative metastatic breast cancer and C1measurable lesion(RECIST criteria,version 1.1)were eligible for enrollment.HER2-negative breast cancer was defined as negativefluorescence in situ hybridization(FISH),0or1?immunohistochemistry (IHC),or IHC2?with negative FISH.Patients had an Eastern Cooperative Oncology Group performance status B1at baseline.In general,priorfirst-line chemotherapy for metastatic breast cancer was not permitted.However,prior cytotoxic therapy was permitted if it was administered in the neoadjuvant or adjuvant setting C3weeks before baseline.Patients with prior docetaxel treatment were eli-gible if they had no evidence of recurrent disease within 12months of completing treatment.Prior treatment with a kinase inhibitor or hormonal therapy also was permitted if administered C4and C2weeks,respectively,before baseline,and prior palliative radiation therapy was allowed if completed C2weeks before baseline.For a brief period, the protocol was amended to enroll patients who had pre-viously receivedfirst-line chemotherapy,but this was revised back to the original criteria of no prior therapy for metastatic disease based upon preclinical data that sug-gested that YM155was a p-glycoprotein substrate.Exclusion criteriaPatients were excluded if they had hypersensitivity to docetaxel or polysorbate80;major surgery,open biopsy,or significant traumatic injury within28days before baseline or anticipated need for major surgery during the study; neuropathy grade C2at baseline;inadequate marrow at baseline;inadequate hepatic function and renal function,or both,at baseline;known brain or leptomeningeal metastasis; known immunodeficiency virus,hepatitis B surface antigen, or hepatitis C antibody;or significant and/or uncon-trolled cardiac,renal,hepatic,or other systemic disorders or significant psychological conditions at baseline.Treatment regimenOne cycle was considered21days and was divided into a 7-day treatment period followed by a14-day(Arm A; YM155plus docetaxel)or a20-day(Arm B;docetaxel alone)observation period.YM155was administered by continuous infusion at a dose of5mg/m2/day for168h.The YM155infusion was initiated on day1within1h of com-pletion of docetaxel dosing using a portable infusion pump to administer study drug through a dedicated central line, port,or peripherally inserted central catheter.Dose reduction of YM155to3.6mg/m2/day was permitted at the investi-gator’s discretion in patients with a grade3or4adverse event(AE),with the exception of weight loss or gain, anorexia,alopecia,and fatigue.Infusion of YM155and docetaxel was interrupted until the AE resolved to grade B1 or returned to baseline,and infusion of YM155could then be restarted at the original dose of5mg/m2/day or reduced to3.6mg/m2/day at the discretion of the investigator.Docetaxel[22]was administered by intravenous infusion for1h on day1every21-day cycle at a dose of75mg/m2in patients treated with YM155plus docetaxel and75or 100mg/m2in patients treated with docetaxel alone at the discretion of the investigator.Dose reduction of docetaxel to 75mg/m2was permitted at the discretion of the investigator in patients with febrile neutropenia or an absolute neutrophil count\500cells/mm3lasting[1week and in patients with severe or cumulative cutaneous reactions.In the event that these AEs were ongoing,further dose reduction of docetaxel to55mg/m2or discontinuation of docetaxel was permitted at the discretion of the investigator.In patients with a grade 3or4AE,with the exception of peripheral neuropathy, weight loss or gain,anorexia,alopecia,and fatigue,doce-taxel treatment was interrupted until the AE resolved to grade B1or returned to baseline and then could be restarted at75for patients receiving100mg or55mg/m2for patients receiving75mg/m2at the time of the AE.Discontinuation of docetaxel treatment was required in patients with grade3 or4neuropathy.Retreatment criteriaThe following criteria must have been met before a patient began the next cycle of treatment:no evidence of disease progression based on radiological and/or clinical assess-ments,and any YM155-and/or docetaxel-related toxicity must have either resolved to a grade of B1or returned to baseline level.AssessmentsThe primary efficacy endpoint was PFS.Subgroup analyses of PFS were performed according to TNBC or hormone receptor positive status.The secondary efficacy endpoints assessed included objective response rate(ORR),OS,dura-tion of response(DOR),clinical benefit rate(CBR),and time to response(TTR).Patients were evaluated by computed tomography,magnetic resonance imaging,or both,every 6weeks(cycle1and2)within5days of the initial docetaxel infusion and every12weeks thereafter.Objective tumor assessments were determined using RECIST,version1.1.Blood samples were collected from all patients during screening and cycles1–3to assess biomarkers,including caspase-cleaved cytokeratin18(M30ApoptosenseÒELISA,PEVIVA AB,Broma,Sweden),a tumor apoptosis marker.Blood samples were collected during cycles1and 2for analysis of circulating tumor cells.Safety and tolerability assessments included AEs and clinical laboratory evaluations.Statistical analysesThe efficacy analyses were conducted on the full analysis set(FAS)and per protocol(PP)set.The FAS included all patients randomized into the study and was considered the primary analysis set.The PP set included all randomized patients who were administered C1dose of their assigned study regimen,had histologically or cytologically proven adenocarcinoma of the breast that was HER2-negative,had no known brain or leptomeningeal metastasis,had no his-tory of other malignancy within5years before thefirst dose of YM155,except for treated basal or squamous cell carcinoma of the skin or in situ cervical cancer,and did not have major protocol deviations.Demographic data and baseline disease and treatment characteristics were summarized using descriptive statis-tics.The median PFS,including subgroup analyses of PFS, OS,and DOR were estimated using the Kaplan–Meier method reported with corresponding95%CI.PFS and OS were analyzed between treatment arms using a two-sided log-rank test stratified by prior taxane therapy and triple negative status(a=0.05).PFS also was comparedbetween treatment arms using the hazard ratio,corre-sponding95%CI,and P value from the stratified Cox proportional hazards regression model.ORR and CBR were compared between treatment arms using the stratified Cochran-Mantel-Haenszel test,and the difference in response rates and corresponding95%CIs were estimated using large sample methods and unpooled variance esti-mates.The TTR was summarized using descriptive statistics.Approximately100patients(randomized in a1:1ratio) stratified by prior taxane therapy and triple negative status (yes or no for both)were required to observe67PFS events (progressive disease or death).The sample size had55% power to detect a true hazard ratio of0.60(median PFS of 10vs6months).Safety was assessed in all patients who received C1 dose of study regimen and summarized using descriptive statistics or frequency distributions,as appropriate. ResultsBaseline demographics and characteristicsOf119patients screened,101were enrolled and random-ized to treatment and99received the drug.At baseline,all patients were women diagnosed with HER2-negative metastatic breast cancer,and the majority had received prior drug therapies,principally in the adjuvant or neoad-juvant setting(Table1).Table1Baseline characteristics(full analysis set)NOS not otherwise specifieda HER2,estrogen,and progesterone receptors Characteristic YM155?docetaxel(n=50)Docetaxel(n=51)Total(N=101) Sex,n(%)Female50(100)51(100)101(100) Median age,years(range)57.0(34–79)55.0(25–77)55.0(25–79) Race,n(%)White47(94.0)48(94.1)95(94.1) Black or African American1(2.0)1(2.0)2(2.0) Asian1(2.0)01(1.0) Other1(2.0)2(3.9)3(3.0) Subtype at diagnosis,n(%)Ductal37(74.0)33(64.7)70(69.3) Lobular4(8.0)8(15.7)12(11.9) Paget’s disease and infiltrating2(4.0)02(2.0) Medullary,NOS01(2.0)1(1.0) Papillary01(2.0)1(1.0) Other7(14.0)8(15.7)15(14.9) Tumor grade,n(%)Grade11(2.0)2(3.9)3(3.0) Grade224(48.0)19(37.3)43(42.6) Grade315(30.0)16(31.4)31(30.7) Unknown10(20.0)14(27.5)24(23.8) Tumor receptor status,n(%)Triple receptor negative a13(26.0)12(23.5)25(24.8) Estrogen receptor statusPositive34(68.0)35(68.6)69(68.3) Negative13(26.0)14(27.5)27(26.7) Unknown3(6.0)2(3.9)5(5.0) Progesterone receptor statusPositive22(44.0)33(64.7)55(54.5) Negative23(46.0)14(27.5)37(36.6) Unknown5(10.0)4(7.8)9(8.9) Prior drug therapy,n(%)43(86.0)44(86.3)87(86.1) Prior taxane therapy,n(%)11(22.0)9(17.6)20(19.8)Treatment exposurePatients in the YM155plus docetaxel group completed a median of6.0cycles of YM155infusion;4(8.3%)patients experienced YM155dose reduction,and8(16.7%)patients experienced an interruption.In addition,patients in this arm received a median of6.0cycles and a cumulative total dose of679.0mg of docetaxel infusion;9(18.8%)patients experienced a dose reduction and no patients an interruption.Patients in the docetaxel arm completed a median of 7.43cycles and received a median cumulative total dose of 827.5mg of docetaxel infusion;12(23.5%)patients experienced a dose reduction and no patients experienced an interruption.Primary and secondary endpointsThe median PFS was8.4months in patients treated with YM155plus docetaxel compared with10.5months in patients administered docetaxel alone.This difference was not statistically significant(P=0.172;Table2).Kaplan–Meier plots of PFS are presented in Fig.1a.The docetaxelTable2Analysis of primary and secondary efficacy endpoints for the full analysis populationCBR clinical benefit rate,DOR duration of response,FAS full analysis set,NA not available, ORR objective response rate,OS overall survival,PFS progression-free survival*At the time of data cutoff, median DOR had not been reached Clinical outcome YM155?Docetaxel(FAS,n=50)Docetaxel(FAS,n=51)P valueFASPrimary efficacy endpointMedian(95%CI)PFS,days251.0(172,333)315.0(202,433)0.172 HR(95%CI) 1.53(0.83,2.83)0.176 Secondary efficacy endpointsORR,n(%)13(26.0)13(25.5)0.987 CBR,n(%)41(82.0)43(84.3)0.855 Median OS,days601.0630.00.768 Median DOR,days231.5NA*NAarm demonstrated slightly better secondary endpoints com-pared with the YM155plus docetaxel arm,but no statisti-cally significant differences between the treatment arms were observed (Table 2;Fig.1b–d).In addition,median PFS,OS,and DOR values were similar between the FAS and PP populations,with no significant differences between treatment arms for the PP population (data not shown).Biomarker analyses for the presence of caspase-cleaved cytokeratin 18,a specific marker for epithelial cell apop-tosis,suggested a slightly higher percentage of tumor apoptosis with YM155plus docetaxel (31.4%)compared with docetaxel alone (18.3%).Circulating tumor cells were very low and no differences could be shown betweenTable 3Treatment-emergent adverse events occurring in C 10%in either treatment arm (safety analysis population)Parameter,n (%)YM155?docetaxel (n =48)Docetaxel (n =51)Hematologic Neutropenia 40(83.3)43(84.3)Leukopenia 13(27.1)17(33.3)Anemia13(27.1)6(11.8)Febrile neutropenia 11(22.9)5(9.8)Lymphopenia 3(6.3)6(11.8)Nonhematologic Alopecia 30(62.5)27(52.9)Fatigue 24(50.0)21(41.2)Nausea 18(37.5)21(41.2)Dyspnea 16(33.3)7(13.7)Diarrhea 11(22.9)10(19.6)Edema peripheral 9(18.8)12(23.5)Neuropathy peripheral 7(14.6)12(23.5)Stomatitis 11(22.9)8(15.7)Decreased appetite 8(16.7)9(17.6)Asthenia 7(14.6)8(15.7)Constipation 6(12.5)8(15.7)Cough 6(12.5)8(15.7)Dysgeusia 5(10.4)9(17.6)Headache8(16.7)5(9.8)Mucosal inflammation 8(16.7)5(9.8)Pyrexia 8(16.7)5(9.8)Arthralgia 8(16.7)4(7.9)Back pain 9(18.8)2(3.9)Bone pain 4(8.3)7(13.7)Nail disorder 6(12.5)5(9.8)Urinary tract infection 6(12.5)5(9.8)Pain in extremity 4(8.3)6(11.8)Insomnia6(12.5)3(5.9)Peripheral sensory neuropathy 3(6.3)6(11.8)Myalgia2(4.2)6(11.8)Oropharyngeal pain5(10.4)Table 4Treatment-emergent grade C 3adverse events (safety ana-lysis population)Parameter,n (%)YM155?Docetaxel (n =48)Docetaxel (n =51)Grade 3Neutropenia 19(39.6)12(23.5)Leukopenia6(12.5)8(15.7)Febrile neutropenia 8(16.7)4(7.8)Lymphophenia 3(6.3)4(7.8)Dyspnea 3(6.3)1(2.0)Pneumonia2(4.2)2(3.9)Central line infection 2(4.2)1(2.0)Palmar-plantarerythrodysasthesia syndrome 1(2.1)2(3.9)Deep vein thrombosis 2(4.2)0Pleural effusion 2(4.2)0Increased alanine aminotransferase 02(3.9)Peripheal neuropathy 02(3.9)Anemia 1(2.1)1(2.0)Asthenia 1(2.1)1(2.0)Atrial fibrillation 1(2.1)1(2.0)Bone pain1(2.1)1(2.0)Catheter-related infection 1(2.1)1(2.0)Cellulitis 1(2.1)1(2.0)Dehydration1(2.1)1(2.0)Decreased white blood cell count 1(2.1)1(2.0)Syncope 1(2.1)1(2.0)Atrial thrombosis 1(2.1)0Clostridium difficile colitis 1(2.1)0Decreased appetite 1(2.1)0Diarrhea1(2.1)0Electrocardiogram T wave inversion 1(2.1)0Excoriation 1(2.1)0Hypoalbuminemia 1(2.1)0Hypotension 1(2.1)0Increased gamma-glutamyltransferase 1(2.1)0Mucosal inflammation 1(2.1)0Nail disorder 1(2.1)0Pericarditis 1(2.1)0Platelet disorder 1(2.1)0Polyneuropathy 1(2.1)0Pulmonary embolism 1(2.1)0Respiratory failure 1(2.1)0Stomatitis1(2.1)0Superior vena cava occlusion 1(2.1)0Thrombosis1(2.1)0Vascular access complication 1(2.1)0Back pain1(2.0)the two treatment arms.However,for both analyses,the sample sizes were very small and no statistical correlations could be made.Safety and tolerabilityAll patients in the safety analysis population(n=99) experienced C1TEAE(Table3).The most common TE-AEs in both treatment groups were neutropenia,alopecia, fatigue,and nausea.Most TEAEs were grade3or4,and the events reported in the YM155plus docetaxel arm were judged more often to be possibly or probably related to study drug,whereas none of the events in the docetaxel alone arm were judged to be possibly or probably related (Tables3,4).The most common drug-related TEAEs in the YM155 plus docetaxel arm were neutropenia(n=18[37.5%]), fatigue(n=13[27.1%]),and febrile neutropenia(n=9 [18.8%]).A total of14(29.2%)patients administered YM155plus docetaxel and9(17.6%)patients adminis-tered docetaxel alone experienced a TEAE leading to study discontinuation.TEAEs leading to study discontinuation that occurred in C2patients in a treatment arm were febrile neutropenia and leukopenia(each n=2[4.2%])in patients administered YM155plus docetaxel andfluid retention,palmar-plantar erythrodysesthesia syndrome,and peripheral neuropathy(each n=2[3.9%])in patients administered docetaxel alone.Serious AEs(SAEs)were experienced by25(52.1%) patients administered YM155plus docetaxel and17 (33.3%)administered docetaxel alone(Table5).SAEs that occurred in C5%of patients in either treatment group included febrile neutropenia,neutropenia,and pneumonia (Table5).A total of56(56.6%)patients died during the study;28(58.3%)patients were treated with YM155plus docetaxel and28(54.9%)patients received docetaxel alone. Most of the deaths(87.5%)were attributed to breast cancer. In patients administered YM155plus docetaxel,two deaths were attributed to hepatic failure,one to a cerebrovascular accident,one to general state degradation,and the cause of death in one patient was unknown.In patients who received docetaxel alone,one death was attributed to sepsis;in oneTable4continuedParameter,n(%)YM155?Docetaxel(n=48)Docetaxel (n=51)Bronchitis01(2.0) Catheter site infection01(2.0) Cerebral infarction01(2.0) Decreased neutrophil count01(2.0) Fatigue01(2.0) Fluid retention01(2.0) Herpes zoster01(2.0) Hydronephrosis01(2.0) Hyponatremia01(2.0) Hypophosphatemia01(2.0) Increased blood glucose01(2.0) Infective arthritis01(2.0) Neck pain01(2.0) Pain in extremity01(2.0) Paresthesia01(2.0) Pelvic pain01(2.0) Peripheral edema01(2.0) Pleurisy01(2.0) Pyrexia01(2.0) Rash01(2.0) Wound infection01(2.0) Grade4Neutropenia21(43.8)30(58.8) Leukopenia5(10.4)4(7.8) Febrile neutropenia2(4.2)1(2.0) Decreased neutrophil count1(2.1)1(2.0) Decreased white blood cellcount1(2.1)1(2.0) Pulmonary embolism1(2.1)1(2.0) Catheter sepsis1(2.1)0 Fatigue1(2.1)0 Increased blood creatinine1(2.1)0 Infection1(2.1)0 Metastases to central nervoussystem01(2.0) Sepsis1(2.1)0 Septic shock1(2.1)0 Thoracic vertebral fracture1(2.1)0 Grade5Breast cancer1(2.1)0 Cerebrovascular accident1(2.1)0Table5Most common serious adverse events regardless of causality occurring in C5%of patients(safety analysis population)SAE,n(%)YM155?docetaxel(n=48)Docetaxel(n=51)Total(N=99) Any SAE25(52.1)17(33.3)42(42.4) HematologicFebrile neutropenia10(20.8)4(7.8)14(14.1) Neutropenia5(10.4)4(7.8)9(9.1) NonhematologicPneumonia3(6.3)2(3.9)5(5.1) SAE serious adverse eventpatient,the cause of death was unknown.None of the deaths were related to the study medications.Three patients discontinued treatment due to abnor-malities in laboratory values(increased gamma-glutamyl-transferase,increased blood urea nitrogen and blood creatinine,and platelet disorder/thrombopathy);all of these abnormalities were considered possibly or probably related to YM155.Other laboratoryfindings were generally not clinically significant.No cardiac safety signals were detected during the study.DiscussionFindings from this study of patients with HER2-negative metastatic breast cancer treated with YM155in combina-tion with docetaxel exhibited no statistically significant differences in the primary endpoint of PFS or secondary endpoints compared with patients administered docetaxel alone.The combination of YM155plus docetaxel was well tolerated.The most common drug-related TEAEs in the YM155plus docetaxel arm were expected and included neutropenia,fatigue,and febrile neutropenia.Renal failure was reported in a previous study with YM155and was considered to be related to YM155[23].In the present study,one patient in the combination arm discontinued with elevated blood urea nitrogen and creatinine levels that were deemed related to study drug;these events resolved 11and25days following onset,respectively.YM155was administered as a continuous intravenous infusion for168h in a21-day cycle.Preclinical data suggest that bolus infusion may increase the risk for renal and/or cardiovascular toxicity.Although continuous infu-sion is more time-consuming and may be less convenient, the need for continuous infusion did not affect recruitment in the present study,and patients experienced no difficulty with drug administration over a long period of time.An urgent unmet need for additional therapeutic options in patients with TNBC exists because of their high risk of relapse and poor long-term prognosis[24,25].A positive outcome was expected from this study because YM155is a novel drug that suppresses survivin at both the mRNA and protein levels[26];survivin is a protein that is associated with decreased apoptosis and has been shown to be more highly expressed in metastatic breast cancer compared with normal breast tissue[27].YM155is also highly distributed to tumor tissues relative to normal plasma[26].Although these preclinical data provide a good rationale for evalu-ating YM155in breast cancer,findings from the present study demonstrated that YM155plus docetaxel exhibited no statistically significant differences in PFS,ORR,OS, DOR,or CBR compared with patients administered doce-taxel alone.However,this study also had some limitations,including the lack of formal pharmacokinetic interaction analysis between YM155and docetaxel.In addition,the limited amount of biomarker data available leaves open the ques-tion of whether there is a patient population more likely to benefit from the combination of YM155with docetaxel. Improved availability and use of biomarkers could help identify patients with TNBC or other types of cancer who might benefit from specific inhibition of survivin.Although development of YM155in patients with TNBC is not proceeding,further research into drugs effective at target-ing the survivin pathway is warranted. Acknowledgments Funding for the study and editorial assistance in preparation of the manuscript was provided by Astellas.Editorial assistance was provided by Craig D.Albright,PhD,Anny S.Wu, PharmD,and Brett Mahon,PhD,of Complete Healthcare Commu-nications,Inc.(Chadds Ford,PA).Conflict of interest Michael R.Clemens has received research funding from Astellas.Oleg A.Gladkov,Elaina Gartner,and Vladi-mir Vladimirov have nothing to disclose.John Crown consulted for Astellas and received honoraria from Sanofi.Anne Keating,Fei Jie, and Joyce Steinberg are Astellas employees.Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which per-mits any noncommercial use,distribution,and reproduction in any medium,provided the original author(s)and the source are credited. References1.Global Cancer Facts&Figures.(2011)American Cancer Society.Available via /acs/groups/content/@epide miologysurveilance/documents/document/acspc-027766.pdf.Accessed22May20142.Siegel R,Ma J,Zou Z,Jemal A(2014)Cancer statistics,2014.CA Cancer J Clin64:9–293.Cianfrocca M,Goldstein LJ(2004)Prognostic and predictivefactors in early-stage breast cancer.Oncologist9:606–6164.About Breast Cancer:Stages0and1(2012)National BreastCancer Foundation,Inc.Available via http://www.national /breast-cancer-stage-0-and-stage-1.Accessed15 May20145.Most common statistics cited for MBC(2014)Metastatic BreastCancer Network.Available via /education/cate gory/most-commonly-used-statistics-for-mbc.Accessed15May 20146.O’Shaughnessy J(2005)Extending survival with chemotherapyin metastatic breast cancer.Oncologist10(Suppl3):20–297.Coiffier B,Lepage E,Briere J,Herbrecht R,Tilly H,BouabdallahR,Morel P,Van Den Neste E,Salles G,Gaulard P,Reyes F, Lederlin P,Gisselbrecht C(2002)CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.N Engl J Med346:235–242 8.Chia SK,Speers CH,D’Yachkova Y,Kang A,Malfair-Taylor S,Barnett J,Coldman A,Gelmon KA,O’Reilly SE,Olivotto IA (2007)The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with meta-static breast cancer.Cancer110:973–979。

通用名称：多西他赛注射液商品名称：奥名润汉语拼音：duoxitasaizhusheye批准文号：国药准字H20064301药品分类：化学药品生产企业：江苏奥赛康药业股份有限公司(国产)药品性质：处方药相关疾病：晚期乳腺癌,转移性乳腺癌,晚期非小细胞肺癌,转移性非小细胞肺癌, 性状：本品为淡橙黄色至橙黄色澄明液体。

主要成份：本品主要成份为多西他赛，其化学名为:[2aR-(2aα，4β，4aβ，6β，9α，(aR*，βS*)，11α，12α，12aα，12bα)]-β-[[(1，1-二甲基乙氧基)羰基]氨基]- α-羟基苯丙酸[12b-乙酰氧-12-苯甲酰氧-2a，。

，4，4a，5，6，9，10，11，12，12a，12b-十二氢-4，6，11-三羟基-4a，8，13，13-四甲基-5-氧代-7，11-亚甲基-1H-环癸五烯并-[3，4]苯并[1，2-b]氧杂丁环-9-基]酯。

适应症：1.多西他赛适于先期化疗失败的晚期或转移性乳腺癌的治疗。

除非属于临床禁忌，先期治疗应包括蒽环类抗癌药。

2.多西他赛适于使用以顺铂为主的化疗失败的晚期或转移性非小细胞肺癌的治疗。

规格：0.5ml∶20mg不良反应：1.骨髓抑制:中性粒细胞减少是最常见的副反应而且通常较严重（低于500个/mm3），可逆转且不蓄积。

2.过敏反应:部分病例可发生严重过敏反应，其特征为低血压与支气管痉挛，需要中断治疗。

停止滴注并立即治疗后病人可恢复正常。

部分病例也可发生轻度过敏反应。

如脸红，伴有或不伴有搔痒的红斑，胸闷，背痛，呼吸困难，药物热或寒战。

3.皮肤反应常表现为红斑，主要见于手?足，也可发生在臂部，脸部及胸部的局部皮疹，有时伴有搔痒。

皮疹通常可能在滴注多西他赛后一周内发生，但可在下次滴注前恢复。

严重症状如皮疹后出现脱皮则极少发生。

可能会发生指（趾）甲病变。

以色素沉着或变淡为特点，有时发生疼痛和指甲脱落。

4.体液潴留包括水肿，也有报道极少数病例发生胸腔积液，腹水，心包积液，毛细血管通透性增加以及体重增加。

多西他赛简介1.简介多西他赛（Docetaxol）是由欧洲浆果紫杉的针叶中提取的化合物半合成的紫杉醇衍生物，由法国的Rhone-Poulenc Rorer公司开发并上市。

其作用机理与紫杉醇类似，通过促进微管双聚体装配成微管，同时防止去多聚化过程而使微管稳定，阻滞细胞于G2和M期，抑制细胞进一步分裂，从而抑制癌细胞的有丝分裂和增殖。

多西他赛的药理作用比紫杉醇强，在细胞内浓度比紫杉醇高3倍，并在细胞内滞留时间长。

其对微管亲和力是紫杉醇的2倍；作为微管稳定剂和装配促进剂，活性比紫杉醇大2倍；作为微管解聚抑制剂，活性比紫杉醇大2倍。

在体外抗瘤活性试验中，已证实多西他赛的抗瘤活性是紫杉醇的1.3~12倍。

多烯紫杉醇抗瘤谱广、抗肿瘤作用强，对难治性的乳腺癌、非小细胞肺癌等的疗效均较突出，临床应用潜力深厚。

然而多西他赛难溶于水，且脂溶性也不大，严重影响了其临床应用。

目前上市品种仅为多西他赛注射液，是用吐温-80及乙醇作溶剂配制而成，易引起较多不良反应，如刺激、溶血、过敏反应、神经毒性、心血管毒性等等。

且使用前要使用抗过敏药物，给患者带来了极大的不便和痛苦。

本项目旨在解决多西他赛水溶性及稳定性问题，进而避免因使用吐温-80而引起的溶血、过敏等不良反应问题。

本项目的意义在于为临床提供一种安全有效的多西他赛静脉给药新制剂，同时对脂质体的制备工艺进行创新，在提高载药量的同时解决其稳定性问题，也为其它同性质药物制剂的制备提供借鉴作用。

2.研究现状及创新性中国专利CN1931157A公开一种可以注射或口服的多西他赛脂质体及其固体制剂。

其以磷脂、胆固醇为基本膜材，加入适当的附加剂，采用多种方法制备了各种类型的脂质体，制得的脂质体粒径小，包封率高，稳定性好且毒副作用低，基本达到了临床注射要求。

但制备的脂质体浓度较低，生产时需容积较大的容器，成本高，不适合大剂量给药。

抗肿瘤一、抗瘤谱多西他赛可用于乳腺癌，NSCLC（非小细胞肺癌），胰腺癌，软组织肉瘤，头颈癌，胃癌，卵巢癌，前列腺癌等。