恶性黑色素瘤药物发展.ppt

Klik om het opmaakprofiel van de modeltitel te bewerken,Klik om de opmaakprofielen van de modeltekst te bewerken,Tweede niveau,Derde niveau,Vierde niveau,Vijfde niveau,*,恶性黑色素瘤药物发展,Alexander M.M.Eggermont,MD,PhD,ErasmusMC-Daniel den Hoed Cancer Center,Rotterdam,Shanghai,CSCO,2008,黑色素瘤治疗靶点,全身治疗,化疗,细胞因子,抗体型疫苗,新的分子靶向药物,促凋亡剂,抗,BRAF,抗,VEGFR2,EGFR,MEK,ERK,抗整合素,抗血管生成制剂,转移潜能,无限增值,血管生成,自主生长信号,肿瘤抑制缺失,阻断,凋亡,(Hanahan&Weinberg,2000),已知肿瘤细胞特征,IV,期黑色素瘤的,III,期临床试验,(1),IV,期黑色素瘤的,III,期临床试验,(1),化疗,+,IL-2,+,IFN,黑色素瘤,生物化疗的纪念,(,从今开始,),一线治疗的研究药物,CTLA4,阻断,T,细胞受体,:MHC,抗原,CD28:B7,CTLA-4:B7,疫苗,?,CTLA-4:T,细胞激活的“刹车”,Copyright 2003 by the National Academy of Sciences,断层扫描示,治疗前病变,(,左侧,),，治疗后达到完全缓解：病例,13,（,A,与,B,）及病例,11,（,C-F,）,Ipilimumab,联合多肽类疫苗治疗进展期黑色素瘤,(NCI),Phan GQ,et al.,Proc.Natl.Acad.Sci,.2003;100:8372-8377.,1.Attia P,et al.,J Clin Oncol,.2005;23:6043-6053.2.Beck K,et al.,J Clin Oncol,.2006;24:2283-2289.,Overview of,Gastrointestinal,(GI)irAEs,Diarrhea is a frequent irAEs,1,2,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 perforation(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&paclitaxel,No evidence of additive toxicities or PK interactions,Antitumor activity in metastatic melanoma patients,Durable partial responses,all lasting 6+months,63%of patients on study for more than 6 months,Antitumor activity was,independent,of BRAF,mutational status,BAY 43-9006,carboplatin&paclitaxel,Summary,BAY 43-9006+Carbo+Taxol vs Carbo+Taxol,ECOG/SWOG/EORTC PHASE III TRIAL,IN 800 PATIENTS,1ST LINE,BAY 43-9006+Carbo+Taxol vs Carbo+Taxol,PRISM Trial in 250 PTS,DTIC/TMZ FAILURES,2ND LINE,FAILED,BAY 43-9006,carboplatin&paclitaxelPHASE III TRIALS,Metastaticpotential,Immortalization,Angiogenesis,Growth signal,independence,Loss of tumor,suppression,Blocked,apoptosis,(Hanahan&Weinberg,2000),Acquired Characteristics of Cancer Cells,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 III Trials in Advanced Melanoma,5 running/starting,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,Vical DNA-vaccine vs DTIC,Phase III Trials in Advanced Melanoma,5 running/starting,Final common pathway of anticancer therapies,Bcl-2,Bcl-2,Bcl-2,Bcl-2,Bcl-2,Bcl-2 blocks apoptosis,Genasense,TM,pretreatment results in decreased Bcl-2 levels,Oblimersen=Genasense enables apoptosis,Largest randomized trial in advanced melanoma,Multicenter(139 sites,9 countries),open-label,Primary endpoint,:overall survival,Secondary endpoints,:progression-free survival;antitumor response(RECIST);safety,N=771(enrollment target reached January 2003),Cycles repeated every 3 weeks(up to 8 cycles),Genasense in melanoma:Phase III trial,DTIC 1000 mg/m on day 1,Genasense,TM,7 mg/kg CIVI x 5 days,followed by DTIC 1000 mg/m on day 6,RANDOMIZATION,1.0,0.4,0.2,0.0,0,20,24,0.8,0.6,4,8,12,16,GM301:overall survival(ITT)months,Overall Survival,24-Months Minimum Follow-up,DTIC,Genasense/,DTIC,Median 9.07.8,HR 0.87,P 0.077,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,Months,0,20,24,4,8,12,16,1.1 x Upper Limit of Normal,Median,HR,P,Genasense/,DTIC,4.6,DTIC,1.11,0.412,4.7,55%,improvement,N=508,Relationship 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+Oblimersenin stage IV melanomaLDH 0.8 UNLDouble blind placebo controlled randomized trial350 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 DTIC,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 proteins(Hsp70),Hsp70,3-6 hrs,:,cardiolipin oxidized in mitochondria,6+hrs,:Cytochrome C release,caspase 9,apoptosis,ROS,Mitochondria,Cytochrome C release,caspase 9 activation,APOPTOSIS,Hsp70,Chemotherapeutic,agent,Elesclomol synergizes with chemotherapeutic agents which 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,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 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,ABRAXANE 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 III 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).,Background THYMOSIN-alpha 1,Extensive Randomized Phase II trials exploring various doses of Thymosin-alpha 1,+,IFNalpha,Results Response Rate,Response,n(%),DIT 1.6,(N=97),DIT 3.2,(N=97),DIT 6.4,(N=98),DT 3.2,(N=99),DI,(N=97),CR,2 (2.1),3 (3.1),2 (2.0),2 (2.0),0,PR,5 (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;14.5,5.1;18.2,3.1;15.6,6.6;20.4,1.3;10.7,By Stratum,n,DIT 1.6,DIT 3.2,DIT 6.4,DT 3.2,DI,M1a,1,2,1,4,0,M1b,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 1.6,DIT 3.2,DIT 6.4,DT 3.2,Tot T,DI,Median,9.3,8.5,10.2,9.3,9.4,6.6,95%CI,7.9;11.0,6.1;11.4,8.2;12.6,6.7;11.5,8.3;10.5,5.2;9.8,Overall Survival in the ITT Population,time(months),Survival Distribution Function,Overall Survival in the ITT Population,time(months),Results Survival in Normal LDH,OS,(months),DIT 1.6,DIT 3.2,DIT 6.4,DT 3.2,Tot T,DI,Median,12.9,12.6,12.8,14.4,12.9,10.8,95%CI,10.3;14.7,10.1;17.1,10.8;15.5,11.7;16.3,12.1;14.5,7.4;13.6,Overall Survival in*Normal LDH,*Normal=LDH,ULN,time(months),Overall Survival in*Normal LDH,time(months),*Normal=LDH,ULN,Survival Distribution Function,Conclusions Thymosin-alpha 1,Thymosin alpha 1 was well tolerated at all doses and regimens,Both arms with Thymosin 3.2 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+Thymosin 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,ALLOVECTIN,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 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：进展期黑色素瘤,4,项进行,/,开始,/4.,准备,