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1、卵巢上皮性的靶向治疗Targeted Therapies in Epithelial Ovarian Cancer,简介,卵巢癌是最常见的妇科恶性肿瘤之一,也是最常见的死亡原因。五年生存率为30%至92%（期别不同）。75%诊断时已属于晚期，需要手术和化疗。尽管给予患者积极、有效的治疗，早期患者仍有10%40%的复发率，晚期超过70%会复发。仅有10%30%的患者会长期生存。,简介,目前公认的治疗方案铂与紫杉醇的联合（TC）。复发时，铂仍是主要的治疗药物。铂敏感型复发（TFI超过6 个月），继续使用铂可以获得超过50%的缓解率铂耐药型复发(TFI 6）或难治型卵巢癌），如果仍然使用含铂化疗仅能
2、获得1020%的缓解率。目前国际上流行的做法是使用非铂单药治疗，Liposomal doxorubicinGemcitabineTopotecanEtoposideHormonal therapies,对于肿瘤生物学和与调解癌症进展以及耐药的分子通路的充分研究和了解,不同的分子靶向治疗方法,单克隆抗体小分子受体酪氨酸激酶抑制剂阻断下行下游信号通路的药物.,大量的分子靶向治疗的相关研究结果是极其令人鼓舞的,Demetri,G.D.;von Mehren,M.;Blanke,C.D.;van den Abbeele,A.D.;Eisenberg,B.;Roberts,P.J.;Heinrich,M
3、.C.;Tuveson,D.A.;Singer,S.;Janicek,M.;et al.Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.N.Engl.J.Med.2002,347,472480.,Hurwitz,H.;Fehrenbacher,L.;Novotny,W.;Cartwright,T.;Hainsworth,J.;Heim,W.;Berlin,J.;Baron,A.;Griffing,S.;Holmgren,E.;et al.Bevacizumab plus i
4、rinotecan,fluorouracil,and leucovorin for metastatic colorectal cancer.N.Engl.J.Med.2004,350,23352342.Zondor,S.D.;Medina,P.J.Bevacizumab:an angiogenesis inhibitor with efficacy in colorectal and other malignancies.Ann.Pharmacother.2004,38,12581264.,大量的分子靶向治疗的相关研究结果是极其令人鼓舞的,Miller,K.;Wang,M.;Gralow,J
5、.;Dickler,M.;Cobleigh,M.;Perez,E.A.;Shenkier,T.;Cella,D.;Davidson,N.E.Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer.N.Engl.J.Med.2007,357,26662676.Sandler,A.;Herbst,R.Combining Targeted Agents:Blocking the Epidermal Growth Factor and Vascular Endothelial Growth Fac
6、tor Pathways.Clin.Cancer Res.2006,12,44214425s.,大量的分子靶向治疗的相关研究结果是极其令人鼓舞的,Llovet,J.;Ricci,S.;Mazzaferro,V.;Hilgard,P.;Raoul,J.;Zeuzern,S.;Poulin-Costello,M.;Moscovici,M.;Voliotis,D.;Bruix,J.Sorafenib improves survival in advanced Hepatocellular Carcinoma(HCC):Result of a Phase III randomised placebo-
7、controlled trial(SHARP trial).J.Clin.Oncol.2007,25(18S),Abstr.LBA1solid,大量的分子靶向治疗的相关研究结果是极其令人鼓舞的,Escudier,B.;Eisen,T.;Stadler,W.M.;Szczylik,C.;Oudard,S.;Siebels,M.;Negrier,S.;Chevreau,C.;Solska,E.;Desai,A.A.;et al.Sorafenib in advanced clear-cell renal-cell carcinoma.N.Engl.J.Med.2007,356,125134.Mot
8、zer,R.J.;Hutson,T.E.;Tomczak,P.;Michaelson,M.D.;Bukowski,R.M.;Rixe,O.;Oudard,S.;Negrier,S.;Szczylik,C.;Kim,S.T.;et al.Sunitinib versus interferon alfa in metastatic renalcell carcinoma.N.Engl.J.Med.2007,356,115124.,大量的分子靶向治疗的相关研究结果是极其令人鼓舞的,卵巢癌的抗血管形成治疗,卵巢癌抗血管形成治疗,血管形成是正常排卵过程中卵泡成熟和黄体形成等正常生理过程的基础。病理的新血
9、管形成是卵巢肿瘤生长和发育的关键因素。研究证明：微血管密度的增加VEGF及其受体的过度表达和恶劣的临床行为、腹水的形成密切相关。,卵巢癌抗血管形成治疗,动物模型证明：阻断VEGF可抑制腹水形成减慢肿瘤的生长,Martin,L.;Schilder,R.Novel approaches in advancing the treatment of epithelial ovarian cancer:the role of angiogenesis inhibition.J.Clin.Oncol.2007,25,2894901.Stone,P.J.;Goodheart,M.J.;Rose,S.L.;D
10、eYoung,B.R.;Buller,R.E.The influence of microvessel density on ovarian carcinogenesis.Gynecol.Oncol.2003,90,566571.Goodheart,M.J.;Ritchie,J.M.;Rose,S.L.;Fruehauf,J.P.;DeYoung,B.R.;Buller,R.E.The relationship of molecular markers of p53 function and angiogenesis to prognosis of stage I epithelial ova
11、rian cancer.Clin.Cancer Res.2005,11,37333742.Hefler,L.A.;Mustea,A.;Konsgen,D.;Concin,N.;Tanner,B.;Strick,R.;Heinze,G.;Grimm,C.;Schuster,E.;Tempfer,C.;et al.Vascular endothelial growth factor gene polymorphisms are associated with prognosis in ovarian cancer.Clin.Cancer Res.2007,13,898901.Byrne,A.T.;
12、Ross,L.;Holash,J.;Nakanishi,M.;Hu,L.;Hofmann,J.I.;Yancopoulos,G.D.;Jaffe,R.B.Vascular endothelial growth factor-trap decreases tumor burden,inhibits ascites,and causes dramatic vascular remodeling in an ovarian cancer model.Clin.Cancer Res.2003,9,57215728.,卵巢癌抗血管形成治疗,抗血管形成治疗：可抑制新血管生长导致内皮细胞凋亡阻断造血和内皮祖
13、细胞共同形成新血管使得血管正常化,Schumacher,J.J.;Dings,R.P.;Cosin,J.;Subramanian,I.V.;Auersperg,N.;Ramikrishnan,S.Modulation of angiogenic phenotype alters tumorigenicity in rat ovarian epithelial cells.Cancer Res.2007,67,36833690.,血管形成开关和抗血管形成疗法,体细胞突变,无血管小肿瘤,肿瘤分泌血管形成因子刺激血管形成,肿瘤快速生长和转移,血管形成抑制剂可能会逆转这个过程,卵巢癌抗血管形成治疗,抗
14、血管形成作用主要是通过VEGF与VEGFR的结合，抑制受体酪氨酸激酶的活化和下游分子通过血管破坏剂阻断脆弱的肿瘤血管,Spannuth,W.A.;Sood,A.K.;Coleman,R.L.Angiogenesis as a strategic target for ovarian cancer therapy.Nat.Clin.Pract.Oncol.2008,5,194204.Rosa,D.D.;Clamp,A.R.;Collinson,F.;Jayson,G.C.Antiangiogenic therapy for ovarian cancer.Curr.Opin.Oncol.2007,
15、19,497505.,VEGFR,VEGF/VEGFR 为新抗癌药物开发的首要目标,VEGFR,针对VEGF通路的靶向治疗,Bevacizumab(Avastin),Bevacizumab(Avastin,Genentech)是一种149-kDa的针对人VEGF 的重组人源化单克隆IgG1抗体 临床前卵巢癌模型研究发现单独应用对于肿瘤负荷影响甚微，但是对于腹水的控制效果显著与紫杉醇合用，无论是肿瘤负荷的减小还是腹水的控制菌效果明显和顺铂合用，有较好的效果，且化疗后继续使用可明显延缓复发和延长生存，也提示本应用比较适合维持治疗,单药应用有效，无论是铂敏感型复发还是铂耐药型复发效果相当,联合化疗药
16、物治疗效果可能会相应提高,和一线化疗联合应用，效果可观！有必要进行进一步研究,Bevacizumab联合化疗治疗复发性卵巢癌,耐药细胞系卵巢癌原位小鼠模型：Docetaxel节律化疗联合AEE788(一种联合的EGFR和VEGFR抑制剂)取得了较好的疗效,Kamat,A.A.;Kim,T.J.;Landen,C.N.,Jr.;Lu,C.;Han,L.Y.;Lin,Y.G.;Merritt,W.M.;Thaker,P.H.;Gershenson,D.M.;Bischoff,F.Z.;et al.Metronomic chemotherapy enhances the efficacy of an
17、tivascular therapy in ovarian cancer.Cancer Res.2007,67,281288.,Bevacizumab联合TC(卵巢癌初治）,Bevacizumab-TC作为卵巢癌的初治方案获得75%80%的有效率伴有可接受的毒性,Micha,J.P.;Goldstein,B.H.;Rettenmaier,M.A.;Genesen,M.;Graham,C.;Bader,K.;Lopez,K.L.;Nickle,M.;Brown,J.V.,III.A phase II study of outpatient first-line paclitaxel,carbop
18、latin,and bevacizumab for advanced-stage epithelial ovarian,peritoneal,and fallopian tube cancer.Int.J.Gynecol.Cancer 2007,17,771776.Campos,S.M.;Dizon,D.S.;Cannistra,S.A.;Roche,M.;Krasner,C.N.;Berlin,S.T.;Horowitz,N.S.;DiSilvestro,P.;Matulonis,U.A.;Penson,R.T.Safety of maintenance bevacizumab after
19、first-line chemotherapy for advanced ovarian and mllerian cancers.J.Clin.Oncol.2007,25(18S),Abstr.5517.,Epithelial Ovarian or Primary Peritoneal Cancer,Suboptimal Cytoreduction,Collaborative design(GOG,NCI,Genentech,),GOG218:Ovarian(stage III,-,IV),x 6,Paclitaxel 175 mg/mq,(3 h),Carboplatin AUC=6.0,
20、Bevacizumab 15 mg/kg q21d*,II,x 6,I,Paclitaxel 175 mg/m,2,(3 h),Carboplatin AUC=6.0,Placebo q21d*,Placebo,(14 m total),Placebo,(14 m total),Bevacizumab,(14 m total),x 6,Paclitaxel 175 mg/m,2,(3 h),Carboplatin AUC=6.0,Bevacizumab 15 mg/kg q21d*,III,Open:,Sep,-,05,-,-,Target Accrual:,2000 pts(3 Y),Acc
21、rual 11/2006:190,BEVACIZUMAB,RANDOMISATION,GOG218告诉我们,作为一线化疗联合贝伐单抗并没有优势,而化疗后的维持治疗对于预后更加有益,但是获得益处也是有代价的,Bevacizumab(AvastinTM)trial ICON 7,RANDOMISATION,Carboplatin AUC 6Paclitaxel 175 mg/m,q 21 x 6 cycles,q 21 x 6 cycles,Carboplatin AUC 6Paclitaxel 175 mg/mBevacizumab 7.5 mg/m,Observation,Bevacizuma
22、b 7.5 mg/m,q 21 x 12 cycles,ICON7虽然设计和GOG218不同,但是似乎也可以看到应用贝伐单抗的好处,而这点益处也是十分有限的,RANDOMISATION,Gemcitabine 1000 mg/mqdays 1 and 8Carboplatin AUC 4 day 1Bevacizumab 15 mg/kg day 1q 21 days x 6*,BV(to 51 wks),Platinum Sensitive Ovarian CancerOCEAN STUDY-RANDOMIZED PHASE IIMemorial Sloan Kettering US,Gem
23、citabine 1000 mg/mqdays 1 and 8Carboplatin AUC 4 day 1Placebo IV day 1q 21 days x 6,Placebo(to 51 wks),BVto PD,*Up to 10 cycles allowed,其它抗VEGF药物-Aflibercept,阻断VEGF信号传输通路最有效的方法之一就是通过应用诱饵VEGF受体预防VEGF和其正常的受体相结合Aflibercept(VEGF Trap),就是这样一种可溶性的诱饵受体。是一个包含VEGFR-1 and-2的VEGF结合域的融合蛋白,Phase II Trial VEGF Tr
24、ap Ovarian Cancer,Study design,Recurrent Ovarian Cancer3-4 lines treatmentPlatinum-resistantResistant:Topotecan and/or LiposomalDoxorubicin,VEGF Trap2 mg/kg IVq 2 weeks,VEGF Trap4 mg/kg IVq 2 weeks,Randomized(1:1)Double-BlindedN=200,Radiological Response:PR=10%(Stage 1,n=84)PR=8%(Stage 2,n=162)Prolo
25、nged disease controlSD=41%at 14 wksCA-125 responses(13%)and ascites resolution(29%)VEGF Trap demostrates an acceptable safety profileLow incidence of GI perforation(1%),First pt May 2006Patients randomized 162Ongoing treatment 35 ptsEstimate accrual 200 pts,TEW WP.ASCO 2007.Abs 5508,RANDOMISATION,Pl
26、aceboEvery 2 wks,AVE0005(VEGF Trap)Every 2 wks,A Multicenter,Randomized,Double-Blind,Placebo-Controlled,Parallel-Arm Study of the Effect of Intravenous AVE0005(VEGF Trap)Administered Every 2 Weeks in Advanced Ovarian Cancer Patients With Recurrent Symptomatic Malignant Ascites,Primary Outcome Measur
27、es:Time to repeat paracentesis Secondary Outcome Measures:Ascites Impact Measure(patient questionnaire)60-Day frequency of paracentesis Safety Tolerability Tumor assessments Quality of life Total Enrollment:54 Study start:June 2006,from The National Cancer Institutes PDQ database,其它抗VEGF药物-受体酪氨酸激酶抑制
28、剂,活化的受体酪氨酸激酶(TKIs)磷酸化激活下游的信号转导通路的信号分子，导致肿瘤细胞的增殖和生存。这些磷酸化依赖的机制对促进生长因子（如VEGF 和PDGF）的活性至关重要，针对细胞内的酪氨酸激酶的组成部分阻止其磷酸化而抑制了VEGF的生物活性，从而达到有效抵抗肿瘤作用。,口服VEGFR酪氨酸激酶抑制剂治疗复发性卵巢癌的II期临床试验,舒尼替尼,西地尼布,索拉非尼,帕唑帕尼,伊马替尼,抗血管内皮生长因子和多靶治疗的联合,为了增强疗效，目前一直酝酿通过抑制血管内皮生长因子信号传输通路中的不同点而达到垂直阻断的策略。,抗血管内皮生长因子和多靶治疗的联合,抗血管内皮生长因子和多靶治疗的联合,So
29、rafenib和bevacizumab联合的I期临床试验13例患者中，较持久的PR有6例。毒性反应比单药治疗明显增加2/3高血压79%发生1-3级的手足综合征2例发生肠瘘,Azad,N.S.;Posadas,E.M.;Kwitkowski,V.E.;Steinberg,S.M.;Jain,L.;Annunziata,C.M.;Minasian,L.;Sarosy,G.;Kotz,H.L.;Premkumar,A.;et al.Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxic
30、ity and antitumor activity.J.Clin.Oncol.2008,26,37093714.,抗血管内皮生长因子和多靶治疗的联合,将bevacizumab 和erlotinib联合治疗复发性卵巢癌的II期临床试验中13例病人中2例发生致命的肠穿孔伴有更高比例的3级腹泻导致实验提前终止。,Nimeiri,H.S.;Oza,A.M.;Morgan,R.J.;Friberg,G.;Kasza,K.;Faoro,L.;Salgia,R.;Stadler,W.M.;Vokes,E.E.;Fleming,G.F.Efficacy and safety of bevacizumab p
31、lus erlotinib for patients with recurrent ovarian,primary peritoneal,and fallopian tube cancer:a trial of the Chicago,PMH,and California Phase II Consortia.Gynecol.Oncol.2008,110,4955.,抗血管内皮生长因子和多靶治疗的联合,bevacizumab 和panitumumab联合治疗转移性结直肠癌预后差副反应重 试验提前终止,Hecht,J.R.;Mitchell,E.;Chidiac,T.;Scroggin,C.;H
32、agenstad,C.;Spigel,D.;Marshall,J.;Cohn,A.;McCollum,D.;Stella,P;et al.A randomized phase IIIB trial of chemotherapy,bevacizumab,and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer.J.Clin.Oncol.2009,27,672680.,Pazopanib 多靶向抑制剂,每日一次,口服给药，抑制血管形成和阻断肿瘤生长,肿瘤需要新
33、血管(血管形成)刺激其生长VEGF是通过其受体VEGFR促进血管形成的生长因子，VEGFR是蛋白激酶Pazopanib阻断了VEGFR和PDGFR的激酶而抑制血管形成和肿瘤生长,Pazopanib(GW786034)in women with advanced epithelial ovarian,fallopian tube and peritoneal cancers:Initial results of a phase II study.,Pts with epithelial ovarian,fallopian tube or primary peritoneal carcinoma;
34、ECOG PS 0-1 complete CA-125 response to initial platinum-based CT1-2 prior regimens Two stage designPrimary endpoint CA-125 response,Pazopanib 800 mg QD until PD,CA125 response rate 7/15(47%),SD 4/15(27%),PD 4/15(27%)Median time to response 29 daysMost common G AEs diarrhea and ALT elevations,Ongoin
35、g the stage II of enrollement,M Friedlander.ASCO 2007.Abs 5561,血管破坏剂Vascular Disrupting Agents,血管破坏剂（VDA）作用于已经建立的肿瘤血管的内皮细胞和周细胞，导致肿瘤缺血坏死。VDAs主要分为两种类型配体导向VDAs：配体导向VDAs包括联系在一起的靶点和效应基，但是由于其临床疗效十分有限，以及费用、特异性、毒性等问题。小分子：包括两类合成黄酮类：通过诱导局部因子产生微管结合剂,Gridelli,C.;Rossi,A.;Maione,P.;Rossi,E.;Castaldo,V.;Sacco,P.C
36、.;Colantuoni,G.Vascular disrupting agents:a novel mechanism of action in the battle against non-small cell lung cancer.Oncologist 2009,14,612620.,血管破坏剂Vascular Disrupting Agents,Combretastatin是一种微管结合剂，研究证明当其与化疗药物联合应用时会产生协同作用，一项II期临床试验，将combretastatin与TC联合应用治疗卵巢癌，副反应不重，但有效率仅为14%这种联合不会有很好的前景。,Zweifel,
37、M.;Jayson,G.;Reed,N.;Osborne,R.;Hassan,B.;Shrreves,G.;Poupard,L.;Walicke,A.;Balkissoon,J.;Chaplin,D.;et al.Combretastatin A-4 phosphate(CA4P)carboplatin and paclitaxel in patients with platinum-resistant ovarian cancer:Final phase II trial results.J.Clin.Oncol.2009,27(15S),Abstr.5502.,抗血管形成药物的安全记录,B
38、evacizumab常见的毒副反应高血压蛋白尿轻微出血血栓栓塞伤口愈合不良大出血胃肠穿孔(GIP)可逆性后部白质脑病气管食管瘘,胃肠穿孔(GIP),所有相关研究的荟萃分析:发生胃肠穿孔的危险为0.9%，且伴有21.7%的死亡率 几项非随机的卵巢癌研究发现发生胃肠穿孔的危险明显增高，为 5.4%(几乎是结直肠癌的两倍 3.1%)发生胃肠穿孔的的危险为015%，似乎和用药的剂量以及加用化疗药物无关。晚期病例易发生GIP多，伴肠梗阻以及营养不良易患GIP 对于那些伴有广泛浆膜病变以及肠梗阻危险的患者不适合应用bevacizumab,高血压,应用bevacizumab和TKIs较常见 随机研究进行荟萃
39、分析后发现和剂量有关，低剂量时(2.57.5 mg/kg)发生高血压的风险是3.0高剂量时(1015 mg/kg)时为7.5蛋白尿低剂量时为1.4，高剂量时为1.661。用bevacizumab平均131天开始出现血压高，而口服应用TKIs数天至数周发生多数情况下，停药后血压会很快恢复正常.口服TKI也可引起胃肠反应，主要表现腹泻。很少的情况下可发生甲低。,表皮生长因子受体Epidermal Growth Factor Receptor,ERB family,EGFR/HER1(ErbB1)*HER2(ErbB2)o HER3(ErbB3)HER4(ErbB4),MoAb,TKI,表皮生长因子
40、受体,表皮生长因子受体(EGFR,也叫ErbB1)是ErbB家族(ErbB1-4)的酪氨酸激酶受体，在很多上皮性肿瘤中被不正常激活。对于人类肿瘤来讲，受体的过度表达常常和恶劣的临床行为相关的。目前的研究表明：表皮生长因子受体是治疗癌症的有前途的目标,表皮生长因子受体,针对表皮生长因子受体的化合物主要有两个主要类别，包括低分子量酪氨酸激酶抑制剂（TKIs）抗EGFR单克隆抗体(MAbs)这些均处于不同的发展阶段,表皮生长因子受体,EGFR在卵巢癌中过度表达的比例是很高的 移植瘤模型研究发现将anti-EGFR与化疗药物联合应用可以增强细胞毒作用研究主要包括单克隆抗体（cetuximab、matu
41、zumab）EGFR口服受体酪氨酸激酶抑制剂(gefitinib、erlotinib）对于铂耐药型复发卵巢癌来讲，单药应用效果十分温和，通常不超过10%对于铂敏感型复发和初治卵巢癌来讲化疗效果就好多了毒性反应主要包括乏力、皮疹和胃肠道毒性,抗-EGFR单克隆抗体和低分子量TKIs,抗-EGFR单克隆抗体和低分子量TKIs,抗-EGFR单克隆抗体和低分子量TKIs,表皮生长因子受体,由于发现那些有KRAS突变的肿瘤对于抗EGFR治疗无效研究发现某些卵巢癌尤其是低级别的浆液性癌和粘液性癌的肿瘤形成过程中与KRAS通路有关,Shih,I.M.;Kurman,R.J.Ovarian tumorigen
42、esis:a proposed model based on morphological and molecular genetic analysis.Am.J.Pathol 2004,164,15111518.,表皮生长因子受体,ErbB2(也叫HER2)的过度表达仅见于5%的卵巢癌病人.很难能获得ErbB2的过度表达与对于trastuzumab（ErbB2单克隆抗体）疗效的关系。在一项837例利用trastuzumab治疗复发和难治性卵巢癌的研究中，有效率仅为7%（47例伴有ErbB2过度表达75.,Bookman,M.A.;Darcy,K.M.;Clarke-Pearson,D.;Boo
43、thby,R.A.;Horowitz,I.R.Evaluation of monoclonal humanized anti-HER2 antibody,trastuzumab,in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2:a phase II trial of theGynecologic Oncology Group.J.Clin.Oncol.2003,21,28390.,表皮生长因子受体,Pertuzumab,一种人源
44、化单克隆抗体，它可抑制ErbB2与其他EGFRs形成二聚体，对于复发性卵巢癌的作用平平，单药应用仅为5%,Gordon,M.S.;Matei,D.;Aghajanian,C.;Matulonis,U.A.;Brewer,M.;Fleming,G.F.;Hainsworth,J.D.;Garcia,A.A.;Pegram,M.D.;Schilder,R.J.;et al.Clinical activity of pertuzumab(rhuMAb 2C4),a HER dimerization inhibitor,in advanced ovarian cancer:potential pred
45、ictive relationship with tumor HER2 activation status.J.Clin.Oncol.2006,24,43244332.,表皮生长因子受体,已经完成的吉西他滨联合pertuzumab与否治疗铂耐药型复发卵巢癌的II期临床试验进行再分析发现低水平的ErB3(也叫HER3)代表这些患者可能会从化疗方案中加用pertuzumab而获益77.,Amler,L.;Makhija,S.;Januario,T.;Matulonis,U.A.;Strauss,A.;Dizon,D.S.;Sliwkowski,M.X.;Dolezal,M.;Tong,B.;Pat
46、on,V.HER pathway gene expression analysis in a phase II study of pertuzumab+gemcitabine vs.gemcitabine+placebo in patients with platinum-resistant epithelial ovarian cancer.J.Clin.Oncol.2008,26(15S),Abstr.5522.,Randomized Pertuzumab(HER2)Phase II in Platin-sensitive ovarian cancer,RANDOMISATION,As A
47、rm A plus concomittant Pertuzumab 3 wkly iv,followed by 11 courses maintenance Pertuzumab,6 courses of Paclitaxel/Carbo orGem/Carbo,Relapse 2nd line Platin-free6 months,Accrual closed 11/2006:n=147,Arm A,Arm B,A Phase II Study of Sunitinib(SU11248;NSC 736511;IND 74019)in Patients With Recurrent Epit
48、helial Ovarian,Fallopian Tube or Primary Peritoneal Carcinoma,Histologically Ovarian epithelial cancer,Fallopian tube cancer,Primary peritoneal cancer Advanced and/or metastatic disease 1 but no more than 2 prior chemotherapy regimensMeasurable diseasePrimary endpoint objective response,oral sunitin
49、ib once daily on days 1-28,every 42 days for up to 6 courses,Total Enrollment:25 Study start:January 2007,from The National Cancer Institutes PDQ database,A randomized Phase II Study of Paclitaxel/Carboplatin With or Without Sorafenib in the First-Line Treatment of Patients With Stage II/IV Epitheli
50、al Ovarian cancer,RANDOMISATION,Carboplatin AUC 6Paclitaxel 175 mg/m,q 21 x 6 cycles,q 21 x 6 cycles,Carboplatin AUC 6Paclitaxel 175 mg/mSorafenib 400mg PO bid,Observation,Sorafenib to PD Or 12 months,SCRI,Study start:Oct 2006Expected completion:Oct 2009Total enrollment:60 pts,from The National Canc
