贝伐单抗治疗卵巢癌iii期临床实验课件

贝伐单抗治疗卵巢癌III期 临床实验 R.A. Burger,1 M.F. Brady,2 M.A. Bookman,3 R.A. Burger,1 M.F. Brady,2 M.A. Bookman,3 J.L. Walker,4 H.D. Homesley,5 J. Fowler,6 B.J. Monk,7 B.E. Greer,8 M. Boente,9 S.X. Liang10 1Fox Chase Cancer Center, Philadelphia, PA; 2Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY; 3University of Arizona Cancer Center, Tucson, AZ; 4University of Oklahoma Health Sciences Center, Oklahoma City, OK; 5Brody School of Medicine, Greenville, NC; 6James Cancer Hospital at the Ohio State University, Hilliard, OH; 7University of California, Irvine Medical Center, Orange, CA; 8Seattle Cancer Care Alliance, Seattle, WA; 9Minnesota Oncology and Hematology, Minneapolis, MN; 10State University of New York at Stony Brook, Stony Brook, NY, USA n贝伐单抗为人源化单克隆IgG1抗体 n主要作用靶点为抑制VEGF活性 n2004年FDA批准上市用于结直肠癌 n2007年Burger et al和Cannistra et al. 在J Clin Oncol上分别报道贝伐单抗单抗治 疗复发卵巢癌II期临床实验取得较好效果 n2009年NCCN把贝伐单抗列为卵巢上皮性 癌二线治疗內容 n研究的目的：贝伐单抗联合线化疗方案 做为初始治疗方案治疗卵巢上皮癌,腹膜癌 和输卵管是否能可行？ 4 GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Stratification variables: GOG performance status (PS) Stage/debulking status 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Maintenance (16 cycles) (CP) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II (CP + BEV) BEV 15 mg/kg Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III (CP + BEV BEV) 主要观察点 n研究与对照组： PFS Overall survival (OS) safety quality of life correlative laboratory studies 入组条件 nHistologic diagnosis of epithelial OV, PP, or FT cancer nFollowing maximal debulking surgery: stage III optimal (macroscopic residual disease 1 cm) or suboptimal (1 cm), or stage IV nNo prior chemotherapy n112 weeks after initial surgery nGOG PS 02 nNo history of significant vascular events nNo evidence of intestinal obstruction requiring parenteral support nWritten informed consent 入选病人情况 Characteristic Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV BEV (n=623) Median age, years (range) 60 (2586) 60 (2488) 60 (2289) Race, n (%) Non-Hispanic white526 (84)519 (83)521 (84) Asian41 (7) 37 (6)39 (6) Non-Hispanic black25 (4) 28 (5)27 (4) Hispanic21 (3) 28 (5)25 (4) Other, specified8 (1)5 (1)4 (1) GOG PS, n (%) 0311 (50)315 (50)305 (49) 1272 (44)270 (43)267 (43) 242 (7)40 (6)51 (8) 入选病人情况 Characteristic, n (%) Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV BEV (n=623) Stage/residual size III optimal (macroscopic)218 (35)205 (33)216 (35) III suboptimal 254 (41)256 (41)242 (39) IV 153 (25)164 (26)165 (27) Histology Serous 543 (87)523 (84)525 (84) Endometrioid 20 (3)15 (2)25 (4) Clear cell11 (2)23 (4)18 (3) Mucinous8 (1)5 (1)8 (1) Tumor grade 3a412 (66)435 (70)430 (69) 294 (15)77 (12)92 (15) 133 (5)28 (4)16 (3) Not specified/pending86 (14)85 (14)85 (14) 随访观察模式 Months CP + placebo/BEV (6 cycles) Maintenance placebo/BEV (16 cycles) Imaginga CA-125 Exam 9 aConventional CT or MRI 03691215 Same intervals for all modalities: Every 3 months for 2 years, then every 6 months for 3 years, then annually Post-treatment follow-up GOG-0218结果分析: PFS 10 CP (Arm I) Arm I CP (n=625) Patients with event, n (%) 423 (67.7) Median PFS, months10.3 Stratified analysis HR (95% CI) One-sided p-value (log rank) + BEV (Arm II) ap-value boundary = 0.0116 + BEV BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0122436 Arm III CP + BEV BEV (n=623) 360 (57.8) 14.1 0.717 (0.6250.824) 0.0001a Arm II CP + BEV (n=625) 418 (66.9) 11.2 0.908 (0.7591.040) 0.080a 11 分层分析 CP + BEV BEV (Arm III) vs CP (Arm I) Hazard ratio Experimental arm (CP + BEV BEV; Arm III) better Control arm (CP; Arm I) better Stage 3 optimal (n=434) 0.618 Stage 3 suboptimal (n=496) 0.763 Stage 4 (n=318)0.698 PS 0 (n=616)0.710 PS 1/2 (n=632)0.690 Age 60 years (n=629) 0.680 Age 6069 years (n=409) 0.763 Age 70 years (n=210) 0.678 Treatment hazard ratio 总生存率分析 At time of final PFS analysis Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV BEV (n=623) Patients with events, n (%) 156 (25.0) 150 (24.0) 138 (22.2) Median, months39.338.739.7 HRa (95% CI) 1.036 (0.8271.297) 0.915 (0.7271.152) One-sided p-value0.3610.252 Proportion alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 012243648 12 aStratified analysis 625/625/623442/432/437173/162/17146/39/40 No. at risk Outcome Arm I CP (n=625) Arm II CP + BEV (n=625) Arm III CP + BEV BEV (n=623) Deaths, n (%) 156 (25.0) 150 (24.0) 138 (22.2) 1-year survival, %90.690.491.3 GOG-0218: Mean Patient-Reported TOI Score During Chemotherapy TOI = Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary (FACT-O TOI): FACT-G Physical Well-Being (7 items), Functional Well-Being (7 items) and the Ovarian Cancer Subscale (12 item) 112 100 90 80 70 60 50 40 30 20 10 0 Mean TOI score RandomizationPre-cycle 4Pre-cycle 7 CP (Arm I)CP + BEV BEV (Arm III) 14 112 100 90 80 70 60 50 40 30 20 10 0 GOG-0218:结论 nCP + BEV BEV维护方案在PFS优于CP 和CP + BEV nBEV联合线化疗方案做为初始治疗方案 治疗卵巢上皮癌,腹膜癌和输卵管癌患者时 病人可以耐受，副反应与BEV单药使用相 似 nCP + BEV BEV维护方案可考虑用于卵 巢上皮癌,腹膜癌和输卵管癌一线治疗 血管生成素抑制剂AMG 386联合紫杉醇周疗方 案治疗复发卵巢上皮癌的II期临床研究 Beth Y. Karlan,1 Amit M. Oza,2 Vincent L. Hansen,3 Gary E. Richardson,4 Diane Provencher,5 Prafull Ghatage,6 Marjan Tassoudji,7 Daniel E. Stepan,7 David M. Weinreich,7 Ignace B. Vergote8 1Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Princess Margaret Hospital, Toronto, ON, Canada; 3Northern Utah Associates, Ogden, UT, USA; 4Cabrini Hospital, Melbourne, VIC, Australia; 5CHUM-Hpital Notre-Dame, Montreal, QC, Canada; 6Tom Baker Cancer Centre, Calgary, AB, Canada; 7Amgen Inc., Thousand Oaks, CA, USA; 8University Hospital Leuven, European Union. n80%就诊时为晚期卵巢癌的患者将会复发 并最终死亡 n复发后经治疗，铂类敏感患者平均PFS 9.4- 11.3 months，铂类耐药为3.7-4.0 months2 nAMG 386为重组的多肽溶合蛋白 n临床前动物实验证实AMG 386能抑制移稙 的生长 nI期临床实验显示有较的耐受性，无明显的 毒副反应 n其中1例病人用药后一直维持PR伏态达156 周以上 研究的目的： n血管生成素抑制剂AMG 386联合紫杉醇周疗 方案治疗复发卵巢上皮癌是否影响患者的 PFS n其次评价 n疗效 n安全 n药代动力学 n机体抗AMG 386抗体的产生 20060342研究设计： PD Arm A AMG 386 10 mg/kg IV weekly Paclitaxel* Arm B AMG 386 3 mg/kg IV weekly Paclitaxel Arm C Placebo IV weekly Paclitaxel Open-label AMG 386 10 mg/kg IV weekly Treatment until: Progressive Disease (PD) Unacceptable toxicity Consent withdrawn R A N D O M I Z A T I O N *Paclitaxel 80 mg/m2 IV weekly, 3 weeks on/1 week off Tumor assessments: CT or MRI scans of the chest, abdomen, and pelvis every 8 weeks CA-125 lab values, centrally every 8 weeks and locally as needed This study was conducted at 38 sites in 5 countries 161 patients were randomized 入选标准： nHistologically or cytologically documented epithelial ovarian (FIGO stage II-IV), fallopian tube, or primary peritoneal cancer nRadiographically documented progression per RECIST or CA -125 (GCIG Criteria) Measurable or non-measurable disease n 3 previous anticancer therapies, but at least one platinum-containing regimen nAdequate renal and hepatic function nGOG performance status of 0 or 1 PFS结果： *PFS is defined as time from randomization to disease progression per RECIST, CA-125 (GCIG criteria), clinical progression, or death. AMG 386 10 mg/kg3 mg/kgPlacebo Median PFS, months 7.2 5.74.6 Cox model HR (Arm A+B vs pbo) (80% CI) P-value 0.76 (0.59, 0.98) 0.17 Trend test, P-value0.037 分层PFS风险分析： *HRs with 80% confidence intervals. Arm A (AMG 386 10 mg/kg) vs Arm C (placebo) Arm B (AMG 386 3 mg/kg) vs Arm C (placebo) 影像学反应： AMG 386 Arm A 10 mg/kg (N=53) Arm B 3 mg/kg (N=53) Arm C Placebo (N=55) Patients with measurable disease at baseline, n (%) 46 (87)47 (89)52 (95) Best response assessment, n (%) Complete response (CR)2 (4)1 (2)0 Partial response (PR)15 (33)8 (17)14 (27) Stable disease (SD)20 (43)22 (47)18 (35) Progressive disease (PD)6 (13)8 (17)13 (25) Unevaluable001 (2) Not done3 (7)8 (17)6 (12) Confirmed objective response (CR+PR), n (%) 17 (37)9 (19)14 (27) CA-125测定 AMG 386 10 mg/kg (N=53) AMG 386 3 mg/kg (N=53) Placebo (N=55) Patients evaluated for CA-125 response, n (%)39 (74)37 (70)32 (58) Confirmed CA-125 response*, n (%) 29 (71)22 (58)11 (28) One value was truncated at 300 (ie 468) One value was truncated at 300 (ie 488) 副反应 25% of Patients AMG 386 Arm A 10 mg/kg (N=53) Arm B 3 mg/kg (N=52) Arm C Placebo (N=55) Adverse Event Any grade (%) Grade 3 (%) Any grade (%) Grade 3 (%) Any grade (%) Grade 3 (%) Peripheral edema714516294 Fatigue652726515 Nausea522582402 Alopecia500382360 Diarrhea422364290 Peripheral neuropathy3810262314 Constipation382230310 Cough350300222 Abdominal pain332324365 Pain in extremity290280180 Headache290250130 Vomiting27426