Nüks Yüksek Gradlı Glial Tümörlerde

Transcription

1 Nüks Yüksek Gradlı Glial Tümörlerde Tedavi Prof Dr Gökhan Demir İstanbul Bilim Üniversitesi Tıbbi Onkoloji Bilim Dalı

2 RE-CHALLENGE MGMT Direncini Kırmak 1-Doz Dens Şemalar 2-Doz İntens Şemalar

3 One week on/one week off: A novel active regimen of temozolomide for recurrent glioblastoma W. Wick, MD; J.P. Steinbach, MD; W.M. Küker, MD; NEUROLOGY 2004;62: Prospektif faz II çalışma 21 hasta çalışmaya alınmış temozolomide 150 mg/m2 D1-7, D günde bir Parsiyel yanıt 2 hasta (10%), Stabil hastalık 17 hasta (81%) Medyan progresyonsuz sağklım 5 ay. Altıncı ayda hastaların % 48 i progresyonsuz

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6 TOKSİSİTE

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8 Yeni Ajanlar Etki Hedef Ajan Çalışma Angiogenez VEGF aflibercept Faz I/II VEGF bevacizumab Faz II VEGFR CT-322 Faz II αv/β3,5 integrin cilengitide Faz II/III VEGFR, PDGFR cediranib Faz II VEGFR,EGFR vandetanib Faz I/II Raf, VEGFR sorafenib Faz I/II VEGFR, PDGFR, c-kit vatalanib Faz I/II VEGFR, PDGFR, c-kit pazopanib Faz I Büyüme Faktörü PKC enzastaurin Faz II/III EGFR erlotinib Faz II Ras (FTI) tipifarnib Faz I/II mtor temsirolimus Faz I/II Aşı EGFRvIII CDX-110 Faz II/III CMV pp65 ALT-CMV Faz I/II Diğer mikrotübüller ANG1005 Faz I PARP BSI-201 Faz I/II

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10 Updated Safety and Survival of Patients with Relapsed Glioblastoma Treated with Bevacizumab in the BRAIN Study Timothy Cloughesy 1, James J. Vredenburgh 2, Bann-Mo Day 3, Michael Prados 4, Patrick Y. Wen 5, Tom Mikkelsen 6, David Schiff 7, Lauren E. Abrey 8, W.K. Alfred Yung 9, Nina Paleologos 10, Martin K. Nicholas 11, Randy Jensen 12, Asha Das 3, Henry S. Friedman 1 1 University of California Los Angeles, Los Angeles, CA; 2 Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC; 3 Genentech Inc., South San Francisco, CA; 4 University of California San Francisco, San Francisco, CA; 5 Dana-Farber Cancer Institute, Boston, MA; 6 Henry Ford Hospital, Detroit, MI; 7 University of Virginia, Charlottesville, VA; 8 Memorial Sloan-Kettering Cancer Center, New York, NY; 9 M.D. Anderson Cancer Center, Houston, TX; 10 NorthShore University HealthSystem, Evanston, IL; 11 University of Chicago, Chicago, IL; 12 Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 10

11 BRAIN (phase II, multicenter, noncomparative trial) 167 patients with glioblastoma in first or second relapse Prior radiotherapy and temozolomide Stratification by Karnofsky score (70-80, ) First, second relapse BEV (n=85) 10 mg/kg q2 wks First progressive disease BEV + CPT-11 (n=82) EIAED: 340 mg/m 2 IV/90 min Non-EIAED: 125 mg/m 2 IV/90 min Optional Post-Progression Phase BEV + CPT-11 (n=50) Primary endpoints (by independent radiology review) - OR rate - 6-month PFS Additional assessments - updated safety and survival BEV=bevacizumab, CPT-11=irinotecan, EIAED=enzyme-inducing antiepileptic drug, OR=objective response, PFS=progression-free survival. 11

12 Updated BRAIN Safety* BEV (n=84) Any Grade >3 Grade BEV+CPT-11 (n=79) Any Grade Grade >3 Post Progression BEV+CPT-11 (n=50) Any Grade All Adverse Events, % Hypertension Cerebral hemorrhage Venous thromboembolism Proteinuria Wound healing complications Arterial thromboembolism Gastrointestinal perforation RPLS *Updated 07/2008. Grade >3 BEV=bevacizumab, CPT-11=irinotecan; RPLS=reversible posterior leukoencephalopathy syndrome. 12

13 BRAIN Kaplan-Meier Survival BEV=bevacizumab, CPT-11=irinotecan, CI=confidence interval. 13

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15 Phase I Trial of Vandetanib and Oral Etoposide for Recurrent Malignant Glioma James J. Vredenburgh, David A. Reardon, Annick Desjardins, Katherine Peters, Sridharan Gururangan, James E. Herndon II, Alise Brickhouse, Julie Norfleet, Jennifer Marcello, and Henry S. Friedman Duke University Medical Center, Durham, NC 27710

16 Phase 2 Study of XL184 (BMS ), an Inhibitor of MET, VEGFR2, and RET in Patients with Progressive Glioblastoma Patrick Wen 1, Michael Prados 2, David Reardon 3, David Schiff 4, Tim Cloughesy 5, Tom Mikkelsen 6, Marc Chamberlain 7, Jan Drappatz 1, Tracy Batchelor 1, and John de Groot 8 1 Dana Farber Cancer Center, Boston MA, 2 UCSF, San Francisco, CA; 3 Duke University, Durham, NC; 4 University of Virginia, Charlottesville, VA; 5 University of California, Los Angeles, Los Angeles, CA; 6 Henry Ford Hospital, Detroit, MI; 7 University of Washington, Seattle, WA; 8 MD Anderson Cancer Center, Houston TX XL184 (BMS ) is being co-developed by Exelixis and Bristol-Myers Squibb

17 Best Time Point Response per IRF in All Patients with 1 Post-Baseline Scan: Anti-Angiogenic Naïve vs Pretreated 80 Anti-angiogenic Naïve Anti-angiogenic Pretreated Percent change in SPD from baseline g Anti-angiogenic Naïve 54/97 (56%) 39/97 (40%) * * * Patients experienced disease stabilization (-49% to +24% change in SPD) Patients experienced 50% reduction in SPD *bevacuzimab pretreated * * * * * ** * * * * * * ** ** * * * * ** Antiangiogenic Pretreated 43/51 (84%) 5/51 (10%) 17

18 Kişiye Özel Onkoloji Inhibitor Category (Class) Specifics Conc. 1 Conc. 2 Conc. 3 AG 1478 Tyrosine Kinase Inhibitor (Tyrphostin) EGFR (ErbB1) 1 um 5 um 10 um RG Tyrosine Kinase Inhibitor (Tyrphostin) EGFR kinase 1 um 5 um 50 um AG494 Tyrosine Kinase Inhibitor (Tyrphostin) EGFR kinase 1 um 10 um 50 um PD Tyrosine Kinase Inhibitor (Tyrphostin) EGFR kinase 2.5 um 5 um 25 um U0126 MAPK Inhibitor MEK1, MEK2 (ATP non-competitive) 1 um 5 um 10 um MEK Inhibitor I MEK Inhibitor MEK (ATP non-competitive 5 um 10 um 20 um Sorafenib multikinase inhibitor (ERK pathway) VEGFR, PDGFR, Raf kinases, c-kit 1 um 2.5 um 5 um Gefitinib Tyrosine Kinase Inhibitor (EGFR inhibitor) EGFR 1 um 10 um 20 um Sunitinib (multiple) Tyrosine Kinase inhibitor FLT3, PDGFRs, VEGFRs, Kit kinase inhibitor 0.1 um 1 um 10 um Imatinib (Gleevec) Tyrosine kinase inhibitor abl, PDGFR, c-kit 0.5 um 1 um 2 um Erlotinib tyrosine kinase inhibitor EGFR 1 um 5 um 10 um Cediranib tyrosine kinase inhibitor all 3 VEGFRs 1 nm 10 nm 100 nm Akt Inhibitor IV Akt inhibitor ATP binding site of a kinase upstream of Akt, but downstream of PI3-K 1 um 5 um 10 um Akt Inhibitor VIIII Akt inhibitor Akt1, Akt2, Akt3 100 nm 300 nm 3 um LY PI3K inhibitor acts on ATP binding site of PI3K 1 um 5 um 10 um Ro PKC inhibitor PKCα 1.25 um 2.5 um 5 um PI-103 PI3K inhibitor DNA-PK, p110α, p110β, p110δ, p110γ, PI3-KC2β, mtor1, mtor2 (ATP-competitive) 0.25 um 0.5 um 1 um PI3-Kγ Inhibitor PI3K inhibitor: PI3-Kγ (ATP-competitive) p110γ, p110α, p110β, p110δ 100 nm 250 nm 500 nm PI3-Kγ Inhibitor II PI3K inhibitor: PI3-Kγ (ATP-competitive) PI3-Kγ 125 nm 250 nm 500 nm PI3-Kα Inhibitor IV PI3K inhibitor p110α, p110β, p110γ, PI3-K C2β 0.25 um 0.5 um 1 um PI3-Kα Inhibitor VIII PI3K inhibitor (ATP-competitive) DNA-PK, p110α 0.25 um 0.5 um 1 um Rapamycin mtor inhibitor (Macrolide) FKBP12 (directly binds mtorc1) 0.5 nm 5 nm 50 nm Wortmannin PI3K inhibitor Class I, II, and III PI3K members 0.5 um 1.5 um 3 um PDK1/Akt/Fit Dual Pathway Inhibitor PDK1 and Akt inhibitor PDK1 and Akt 0.5 um 1 um 2 um Perifosine Akt inhibitor (in PI3K pathway) Akt 6 um 9 um 12 um Everolimus mtor inhibitor mtorc1 10 nm 100 nm 200 nm Temsirolimus mtor inhibitor PKBP nm 1 nm 10 nm Mevastatin HMG-CoA reductase inhibitor (Statin) HMG-CoA reductase 1 um 10 um 100 um Simvastatin HMG-CoA reductase inhibitor (Statin) HMG-CoA reductase, blocks Ras function through inhibition of farsenylation 2.5 um 5 um 10 um Fluvastatin HMG-CoA reductase inhibitor (Statin) HMG-CoA reductase 1 um 5 um 10 um

19 100 Percent Inhibition Tumor 24 hours Percent Inhibition Tumor 48 hours

20 PROGNOSTİK FAKTÖRLER

21 Monika E. Hegi, Ph.D., Annie-Claire Diserens, M.Sc., Thierry Gorlia, M.Sc., Marie-France Hamou, et al

22 Yeni tanı konmuş GBM hastalarında genel sağkalım ve progresyonsuz sağkalım için moleküler belirteçler: Alman Glioma çalışma grubu prospektif çalışması IDH-1: Isositrat Dehidrogenaz 1 mutasyonu