惡性黑色素瘤藥物發(fā)展

1、惡性黑色素瘤惡性黑色素瘤 藥物發(fā)展藥物發(fā)展 黑色素瘤治療靶點黑色素瘤治療靶點 全身治療全身治療 化療化療 細胞因子細胞因子 抗體型疫苗抗體型疫苗 新的分子靶向藥物新的分子靶向藥物 促凋亡劑促凋亡劑 抗抗BRAF 抗抗VEGFR2 EGFR, MEK, ERK 抗整合素抗整合素 抗血管生成制劑抗血管生成制劑 轉(zhuǎn)移潛能轉(zhuǎn)移潛能 無限增值無限增值 血管生成血管生成 自主生長信號自主生長信號 腫瘤抑制缺失腫瘤抑制缺失阻斷阻斷 凋亡凋亡 (Hanahan 100:8372-8377. 一例進展期黑色素瘤患者一例進展期黑色素瘤患者Ipilimumab相關(guān)性皮相關(guān)性皮 疹疹 Ipilimumab 刺激黑色刺

2、激黑色 素素細細胞免疫胞免疫識別識別 (A) 網(wǎng)狀網(wǎng)狀紅紅斑斑樣樣皮疹皮疹 (B) 血管周血管周圍圍淋巴淋巴細細胞胞 浸浸潤潤突破表皮突破表皮 (C) CD4+ T細細胞胞臨臨近近 死亡的黑色素死亡的黑色素細細胞胞 (D) CD8+ T細細胞胞臨臨近近 死亡的黑色素死亡的黑色素細細胞胞 1. Hodi SF, et al. Proc Natl Acad Sci. 2003;100:4712-4717. 1. Attia P, et al. J Clin Oncol. 2005;23:6043-6053. 2. Beck K, et al. J Clin Oncol. 2006;24:2283-

3、2289. Overview of Gastrointestinal (GI) irAEs Diarrhea is a frequent irAEs1,2 Most cases are mild or moderate Watery to frank blood Biopsy usually demonstrates inflammatory colitis Management algorithm established Most cases respond to either symptomatic treatment or steroids Can rarely lead to GI p

4、erforation ( 6 months = 63% N=54 9 months = 40% N=50 12 months = 22% N=41 Flaherty et al, 2007 BAY 43-9006 is well tolerated with full doses of carboplatin antitumor response (RECIST); safety N = 771 (enrollment target reached January 2003) Cycles repeated every 3 weeks (up to 8 cycles) Genasense in

5、 melanoma: Phase III trial DTIC 1000 mg/m on day 1 GenasenseTM 7 mg/kg CIVI x 5 days followed by DTIC 1000 mg/m on day 6 RANDOMIZATION 1.0 0.4 0.2 0.0 02024 0.8 0.6 481216 GM301:overall survival (ITT) months Overall Survival 24-Months Minimum Follow-up DTIC Genasense/ DTIC Median 9.07.8 HR 0.87 P 0.

6、077 Months Proportion surviving 21% improvement 38% improvement N = 771 Overall Survival Baseline LDH Proportion surviving Proportion surviving 1.0 0.4 0.2 0.0 0.8 0.6 Month s 02024481216 1.1 x Upper Limit of Normal Median HR P Genasense/ DTIC 4.6 DTIC 1.11 0.412 4.7 55% improvement N = 508 Relation

7、ship Between LDH and Survival 0.8 1.1 2.0 5.0 N 274 234 157 76 19 LDH Kaplan-Meier survival curves at 24-month minimum follow-up by LDH category: Study GM301 (overall p 0.0001) Survival curves at 24-month minimum follow-up among patients with baseline LDH value 0.8 x ULN AGENDA TRIAL DTIC vs DTIC +

8、Oblimersen in stage IV melanoma LDH 0.8 UNL Double blind placebo controlled randomized trial 350 pts ongoing OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH ELESCLOMOL (STA-4783) ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DT

9、IC Up to 1.2 UNL LDH VACCINES Allovectin, Vical DNA-vaccine vs DTIC Phase III Trials in Advanced Melanoma 5 running/starting Elesclomol treatment induces ROS - apoptosis elesclomol ROS Mitochondria Cytochrome C release, caspase 9 activation APOPTOSIS 0-1 hr: ROS increase 1-3 hrs: increase in stress

10、proteins (Hsp70) Hsp70 3-6 hrs: cardiolipin oxidized in mitochondria 6+ hrs: Cytochrome C release, caspase 9, apoptosis N H3CNN N CH3 HH S OO S ROS Mitochondria Cytochrome C release, caspase 9 activation APOPTOSIS Hsp70 Chemotherapeutic agent Elesclomol synergizes with chemotherapeutic agents which

11、act via the intrinsic mitochondrial apoptotic pathway Elesclomol sensitizes the mitochondria to other cancer drugs, thus facilitating their ability to induce apoptosis without increasing their toxicity to normal cells elesclomol N H3CNN N CH3 HH S OO S OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LD

12、H STA-4783 ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNL LDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH VACCINES Allovectin, Vical DNA-vaccine vs DTIC Phase III Trials in Advanced Melanoma 5 running/starting ABRAXANE Albumine wrapped Paclitaxel ABRAXA

13、NE IN BREAST CANCER ABRAXANE in BREAST CANCER OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH VACCINES Allovectin, Vical DNA-vaccine vs DTIC Phase II

14、I Trials in Advanced Melanoma 5 running/starting Thymosin alpha 1 is an immunomodulatory compound that promotes T cell maturation and upregulates T cell response. T1 showed clinical potential benefit in a previous pilot study in melanoma patients (Rasi et al. Melanoma Research, 2000). STEM CELL NK C

15、ELL Thymosin alpha 1: mechanism of action CANCEROUS CELL CANCEROUS CELL ImmunomodulatoryDirect effects on cancer cells MHC I expression of tumor antigens Cancer cell growth T-cell apoptosis CD4+ T-CELL CD8+ T-CELL T-cell production IL-2, IFN- IL-4, IL-10 Background THYMOSIN- alpha 1 Day 1 THYMOSIN 1

16、 1.6, 3.2 or 6.4 mg/die s.c. THYMOSIN 1 1.6, 3.2 or 6.4mg/die s.c. Day 8Day 11Day 15Day 18 DTIC 800 mg/m2 i.v. IFN 3 MIU s.c.IFN 3 MIU s.c. Day 18Day 11 Extensive Randomized Phase II trials exploring various doses of Thymosin-alpha 1 + IFNalpha Results Response Rate Response n (%) DIT 1.6 (N=97) DIT

17、 3.2 (N=97) DIT 6.4 (N=98) DT 3.2 (N=99) DI (N=97) CR2 (2.1)3 (3.1)2 (2.0)2 (2.0)0 PR5 (5.1)7 (7.2)4 (4.1)10 (10.1)4 (4.1) RR (PR+CR)7 (7.2)10* (10.3)6 (6.1)12* (12.1)4 (4.1) RR 95% C.I.3.1 ; 14.55.1 ; 18.23.1 ; 15.66.6 ; 20.41.3 ; 10.7 By Stratum, n DIT 1.6 DIT 3.2 DIT 6.4DT 3.2DI M1a 1 2 1 4 0 M1b

18、 4 4 1 2 2 M1c 2 4 4 6 2 Table 2. RESPONSE RATE, OVERALL AND BY STRATUM *The null hypothesis was rejected CR=Complete Response; PR=Partial Response; RR=Response Rate; C.I.=Confidence Interval Results Survival in the ITT Population OS (months)DIT 1.6DIT 3.2DIT 6.4DT 3.2Tot TDI Median9.38.510.29.39.46

19、.6 95% CI7.9 ; 11.06.1; 11.48.2 ; 12.66.7 ; 11.58.3 ; 10.55.2 ; 9.8 Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 Time (months) 0510152025303540 STRATA:Treatment=DICensored Treatment=DI Treatment=DIT1.6Censored Treatment=DIT1.6 Treatment=DIT3.2Censored Treatment=DIT3.2 Treatment=DIT6.4Cens

20、ored Treatment=DIT6.4 Treatment=DT3.2Censored Treatment=DT3.2 Overall Survival in the ITT Population Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 Time (months) 0510152025303540 STRATA:Treatment=DICensored Treatment=DI Treatment=DIT1.6Censored Treatment=DIT1.6 Treatment=DIT3.2Censored Trea

21、tment=DIT3.2 Treatment=DIT6.4Censored Treatment=DIT6.4 Treatment=DT3.2Censored Treatment=DT3.2 time (months) Survival Distribution Function Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 Time (months) 0510152025303540 STRATA:Treatment=DI Censored Treatment=DI Treatment=TOTAL THYM Censored T

22、reatment=TOTAL THYM Overall Survival in the ITT Population Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 Time (months) 0.02.55.07.510.012.515.017.520.022.5 STRATA:Treatment=DI Censored Treatment=DI Treatment=TOTAL THYM Censored Treatment=TOTAL THYM Survival Distribution Function 0.00 0.25

23、0.50 0.75 1.00 Time (months) 0.02.55.07.510.012.515.017.520.022.5 STRATA:Treatment=DI Censored Treatment=DI Treatment=TOTAL THYM Censored Treatment=TOTAL THYM time (months) Results Survival in Normal LDH OS (months)DIT 1.6 DIT 3.2 DIT 6.4DT 3.2Tot TDI Median12.912.612.814.412.910.8 95% CI10.3 ; 14.7

24、 10.1 ; 17.1 10.8 ; 15.5 11.7 ; 16.3 12.1 ; 14.5 7.4 ; 13.6 Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 Time (months) 0510152025303540 STRATA:Treatment=DI Censored Treatment=DI Treatment=TOTAL THYM Censored Treatment=TOTAL THYM Overall Survival in *Normal LDH Survival Distribution Functi

25、on 0.00 0.25 0.50 0.75 1.00 Time (months) 0.02.55.07.510.012.515.017.520.022.5 STRATA:Treatment=DI Censored Treatment=DI Treatment=TOTAL THYM Censored Treatment=TOTAL THYM Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 Time (months) 0.02.55.07.510.012.515.017.520.022.5 STRATA:Treatment=DI C

26、ensored Treatment=DI Treatment=TOTAL THYM Censored Treatment=TOTAL THYM *Normal=LDHULN time (months) Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 Time (months) 0510152025303540 STRATA:Treatment=DICensored Treatment=DI Treatment=DIT1.6Censored Treatment=DIT1.6 Treatment=DIT3.2Censored Trea

27、tment=DIT3.2 Treatment=DIT6.4Censored Treatment=DIT6.4 Treatment=DT3.2Censored Treatment=DT3.2 Overall Survival in *Normal LDH Survival Distribution Function 0.00 0.25 0.50 0.75 1.00 Time (months) 0510152025303540 STRATA:Treatment=DICensored Treatment=DI Treatment=DIT1.6Censored Treatment=DIT1.6 Tre

28、atment=DIT3.2Censored Treatment=DIT3.2 Treatment=DIT6.4Censored Treatment=DIT6.4 Treatment=DT3.2Censored Treatment=DT3.2 time (months) *Normal=LDHULN Survival Distribution Function Conclusions Thymosin-alpha 1 Thymosin alpha 1 was well tolerated at all doses and regimens Both arms with Thymosin 3.2

29、mg reached the response rate required to reject the null hypothesis Data on Overall Survival and Progression Free Survival, particularly in the population with normal LDH level, support the conduction of a phase III program The best candidate regimen for a future phase III trial seems to be DTIC + T

30、hymosin 3.2 mg The role of Interferon alpha in the therapeutic combination is debatable OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 + Taxol vs Taxol Up to 2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH VACCINES ALLO

31、VECTIN DNA-vaccine vs DTIC Phase III Trials in Advanced Melanoma 5 running/starting OBLIMERSEN Oblimersen + DTIC vs DTIC 1mm 2 yrs PEG-IFN vs OBSERVATION 1000 pts ULCERATION BIOLOGY THANK YOU FOR YOUR ATTENTION OBLIMERSEN Oblimersen + DTIC vs DTIC 0.8 UNL LDH STA-4783 ST-4783 + Taxol vs Taxol Up to

32、2x UNL LDH ABRAXANE Abraxane vs DTIC Up to 2x UNLLDH THYMOSIN-alpha THYMOSIN + DTIC vs DTIC Up to 1.2 UNL LDH AVASTIN Stage IV ? Phase III in stage IIB-III VACCINES Vical DNA-vaccine vs DTIC GSK MAGE-3 vs DTIC or Placebo Biovex vs DTIC MoAb IL2-Mab contructs vs DTIC III期 ：進展期黑色素瘤 4項進行/開始 / 4 . 準(zhǔn)備 CT

33、LA4 阻斷阻斷 抗抗CTLA-4 單克隆抗體單克隆抗體 IL-2 B7 MHC TCR CD28 . . . . . . . . . . . . . . . Antigen APC T-cell CTLA-4 B7 MHC TCR CD28 Antigen B7 MHC TCR CD28 CTLA-4 . . . . . . . . . . . . . . . Antigen 抗抗CTLA-4 單克隆抗體單克隆抗體 MHC IL-2 非清髓性淋巴細胞刪除化療后輸注過繼細胞 治療難治性轉(zhuǎn)移性黑色素瘤 Mark E. Dudley, John R. Wunderlich, James C. Ya

34、ng, Richard M. Sherry, Suzanne L. Topalian, Nicholas P. Restifo, Richard E. Royal, Udai Kammula, Don E. White, Sharon A. Mavroukakis, Linda J. Rogers, Gerald J. Gracia, Stephanie A. Jones, David P. Mangiameli, Michelle M. Pelletier, Juan Gea- Banacloche, Michael R. Robinson, David M. Berman, Armando C. Filie, Andrea Abati, Steven A. Rosenberg Journal of Clinical Oncology, Vol 23, No 10 (