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- るるみ かがんじ
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1 mg
2 mg mg 274mg 1 C 21 H 16 ClF 3 N 4 O 3 C 7 H 8 O 3 S {4-[ ] }-N
3 mg mg 274mg 1 400mg 1 2 2
4 mg mg 274mg 1 400mg epidermal growth factor receptor: EGFR ErbB1 HER-1 platelet-derived growth factor receptor: PDGFR c-kit FLT3 receptor tyrosine kinase: RTK RTK RAS GDP GTP RAF/MEK/ERK ERK Bayer HealthCare Onyx Pharmaceuticals C-RAF RTK C-RAF / RAF/MEK/ERK vascular endothelial growth factor receptor: VEGFR -2 VEGFR-3 PDGFR-β RΤΚ RAF RTK PDGFR KIT RTK VEGF 3
5 1.2 Bayer HealthCare Onyx Pharmaceuticals Motzer 1 19 Overall Survival: OS Progression Free Survival: PFS NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma Nexavar is indicated for the treatment of patients with advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy step 1 step 4 Step 1 4
6 Step 2 Step Step 3 Step 4 Step Step Step Step Step % 2 5
7 ph ph H-NMR 13 C-NMR X %RH PP * %RH PP * lx h * 40 75%RH 12 % 6
8 % % % Step Step Step 1 1 H-NMR mm mm mg
9 mg 200mg 50mg 200mg 4.1 % mg/ mg/ mg/ 3 3 PTP PTP
10 3 PTP 52 PTP %RH 18 PTP 40 75%RH %RH 40 75%RH 30 70%RH %RH lx h 1 % 40 /75%RH % % 13 % 30 /70%RH % % 13 %30 /60%RH % 25 /60%RH % /75%RHPTP 6 40 /75%RH
11 1 Step Step mg M 10
12 M = % % 5 PTP 25 /60 RH /60 RH 30 /60 RH 30 /70 RH 40 /75 RH PTP RH PTP RH 11
13 PTP % % 2 6 PTP MRC-01264/Cancer Res 2004; 64: RAF C-RAF B-RAF V600E B-RAF MEK-1 ERK-1 γ-[ 33 P] ATP C-RAF B-RAF V600E B-RAF IC nmol/L MEK-1 ERK-1 10µmol/L RTK 12
14 FLT-3 c-kit VEGFR-2 VEGFR-2 mouse VEGFR-3 mouse PDGFR-β mouse FGFR-1IC nmol/L EGFR Her-2 insulin-like growth factor receptor-1 IGFR-1 c-met c-yes protein kinase B PKB protein kinase A PKA cdk1/cyclinb protein kinase C α PKCα protein kinase C γ PKCγ pim-1 10µmol/L IC 50 nmol/l C-RAF 6 B-RAF wild-type 22 V600E B-RAF mutant 38 VEGFR-2 90 VEGFR-2 mouse 6 VEGFR-3 mouse 12 VEGFR-β mouse 57 FLT-3 58 c-kit 68 FGFR ERK-1 and MEK-1 >10,000 EGFR HER-2 IGFR-1 c-met c-yes PKB PKA cdk1/cyclinb PKCα PKCγ pim-1 >10,000 MEK1/2 ERK1/2 MEK1/2 ERK1/2 RAF/MEK/ERKRAF MEK ERK RTK RTK RTK RTK IC 50 nmol/l MEK 1/2 phosphorylation MDA-MB ERK 1/2 phosphorylation MDA-MB ERK 1/2 phosphorylation BxPC ERK 1/2 phosphorylation LOX 880 VEGFR-2 phosphorylation NIH 3T3 30 VEGF-ERK 1/2 phosphorylation HUVECs 60 bfgf-erk 1/2 phosphorylation HUVECs 620 VEGFR-3 mouse phosphorylation HEK PDGFR-β phosphorylation HAoSMC 80 FLT-3 phosphorylation ITD HEK MRC MRC MRC RMI RMI MRC MRC RMI-0085 RMI MRC in vivo RENCA 1050mg 13
15 mg/kg TGI TGI mg/kg84 60mg/kg 90mg/kg TGI 60mg/kg 786-O mg/kg TGITGI 28 15mg/kg mg/kg 30mg/kg TGI % = RENCA mg/kg/day TGI %1 TGI % ND O mg/kg/day TGI % HCT116 DLD-1 Colo-205 HT-29 SKOV-3Mia-PaCa-2 NCI-H23 NCI-H460 A549 LOX IMVI MV7;11 FLT3-ITD FMS-like tyrosine kinase 3-ITDITD k-ras HCT116 DLD-1 NCI-H460 Mia-PaCa-2 b-raf Colo-205 HT-29 MDA-MB-231 ras b-raf ras EGFR Her2 SKOV-3 ras 14
16 in vitro PDGF 2 1MRC in vitro ERKBcl-2Mcl-1 eif4e 786-O µmol/L perk1/2mcl-1 peif4e 15µmol/LERK perk5 15µmol/L Mcl-1 Mcl µmol/L eif4e 1.67µmol/L µmol/L in vivo RENCA 786-O 75mg125mg mg/kg 35 CD31 αsma RENCA 786-O mg/kg 1021 CD31 αsma H3 p-histone H3 RENCA Ki O ERK1/2 ERK1/2 perk1/2 ERK1/2 ERK 2 MRC-01264/Cancer Res 2004; 64: HT-29 Colo-205 MDA-MB mg 30 60mg/kg RAF/MEK/ERK 15
17 ERK CD31 HT-29 MDA-MB-231 ERK Colo-205 V600E BRAF HT-29 Colo MRC Colo-205 RAF/MEK/ERK 3 MRC MRC in vitro M-2N- M-4 N- M-5 N- N- C-RAFB-RAF V600E B-RAF VEGFR-2 PDGFR-β Flt-3 in vitro V600E B-RAF VEGFR-2 PDGFR-β Flt-3 MDA-MB-231 VEGFR-2 NIH 3T3 ERK VEGFR-2 BrdU RAF/MEK/ERK VEGFR-2 PDGFR VEGFR PDGF M2 M5 RAF/MEK/ERK VEGFR-2 PDGFR-β in vivo MDA-MB-231M2 M2 M2 M2 M2 4 1 PH MRC PH GLP R-8318 GLP mg/kg 16
18 PQ QT QRS GLP 1 15% GLP in vitro CHO herg Ikr µmol/L 1 10µmol/L Ikr µmol/L APD 90 90% 10µmol/L methyl-2-pyridyl ethyl -4-piperidinyl carbonyl methane sulfonanilide dihydrochloride dihydrate in vivo QT/QTc 44mg/kg QTc C max 3.1mg/L 6.6µmol/L mg/kg C max mg/L µmol/L 13 C max 7.6mg/L 16.3µmol/L µmol/L in vitro µmol/Lin vitro 400mg 1 2C max 4.9mg/L 10.6µmol/L µmol/Lin vitro 3µmol/L 1/60 2 PH PH mg/kg 73mg/kg2/6 220mg/kg3/ mg/kg PH PH PH PH mg/kg 220mg/kg 56 C max 35mg/L
19 73mg/kg 220mg/kg21% 16% in vitro 5 MRC MRC MRC RMI RMI RMI RMI RMI RMI / RENCA 786-O in vivo H3 Ki-67 VHL 1 MAPK perk perk
20 1 CD30 αsma p-histone H3 Ki-67 2 in vitro in vivo P-P-gp in vitro P P-gp P-gp 3 6Functional Observation Buttery RAF VEGFR VEGF Microvasc Res 2005; 70: VEGFR 19
21 425mg/kg 4136 Grade 3 2/ PK M-2 PK C 14 C3.65mg/kg 4.11mg/kg 3.54mg/kg4.21mg/kg 4.12mg/kg 14 C t 1/ C max t 1/ AUC norm C 1 2C max t 1/2 t 1/2 CL BA BA 20
22 14 C PK i.v. p.o. i.v. p.o. i.v. p.o. AUC norm kg h/l C max, norm kg/l n.c n.c n.c t max h n.c. 1.0 n.c n.c t 1/2 h CL L/kg h 0.15 n.c n.c n.c. V ss L/h 0.68 n.c n.c n.c. BA n.a n.a n.a AUC norm AUC C max, norm C max V ss BAAUC norm /AUC norm 100 n.c. not calculated n.a. not applicable 14 C 5mg/kg BA mg/kg 13 AUC AUC norm kg h/l PK AUC norm 1 25mg/kg/ mg/kg/13 1 5mg/kg/ mg/kg/AUC norm kg h/l 125mg/kg/ mg/kg/ 7AUC norm kg h/l 3mg/kg/ mg/kg/ mg/kg/ AUC norm kg h/l3 60mg/kg kg h/l mg/kg/ AUC Colo-20530mg/kg AUC2 21
23 PK Day 1 Day 4 AUC norm kg h/l C max, norm kg/l t max h AUC norm AUC C max, norm C max C 10mg/kg 4 C max t 1/ t 1/ AUC mg-eq h/l 11 AUC 14 C 10mg/kg t 1/ C 10mg/kg t max C max AUC 0-24 AUC 0-24 AUC mg-eq h/l 52AUC 0-24 AUC AUC mg/L 0.1 5mg/L fu HSA α- β- 14 C 22
24 ph fu ph mmol/Lfu 1/5 fu fu % 3 1 in vitro 14 C N- M-3 N-M-2 N- M-1 M-4 M-2 M-3 14 C M-2M-2 M-7 M-8 CYPCYP1A1 1A2 2A6 2B6 2C8 2C9 2C18 2C19 2D6 2E1 3A4 3A5 4A11M-1 M-2 M-3 M-4 CYP3A4 M-2 M-3 CYP3A4 CYP3A4CYP3A4 UGTUGT1A1 A3 1A4 1A6 1A7 1A8 1A9 1A10 2B4 2B7 2B15 2B17 M-7UGT1A9UGT1A9 K m µmol/LUGT1A9 14 C M-2 M-7N- CL CL int = V max /K m 2 UDP- M-7 N- 2 in vivo AUC M AUC M AUC 23
25 M AUCN-M-2 M-7 N-N- Drug Metab Dispos 1998; 26: M M M C 4.11mg/kg 3.54mg/kg 5mg/kg 14 C * i.v n.a p.o n.a i.v ** p.o * 72 ** 24 n.a. not applicable 14 C 4.21mg/kg4.12 5mg/kg C 5mg/kg 27.3 AUC mg/L5 CYP1A2 3A4 CYP1A2 3A4 MTT 10 50mg/L MTT 5 24
26 3mg/L 0.8mg/LCYP1A2 3A4 400mg mg/L fu mg/Lin vitro0.8mg/l 1/20 CYP1A2 3A4 2 CYPCYP1A2 2A6 2E1 CYP2C19 2D6 3A4Ki 17µmol/L µmol/L µmol/LCYP2B6 2C8 2C9Ki µmol/L µmol/L µmol/L CYP3A4CYP3A4 Ki µmol/LCYP3A4 Ki 4.9µmol/L 48.9µmol/L 400mg1 2 C max 7.8mg/L 16.8µmol/L CYPKi CYP3A4 CYP2C19CYP2D6 CYP2C19 2D6 3A4 UGT UGT1A4 α- UGT1A UGT2B7 IC 50 61µmol/L UGT1A4100µmol/L UGT1A6 UGT2B7 UGT1A9 Ki 2.2µmol/L SN-38 UGT1A1Ki µmol/L400mg 1 2 C max 7.8mg/L 16.8µmol/LUGT1A1 1A9Ki UGT1A1 1A mg1 2SN FUDPD µmol/L 5-FU 5-FU 5-FU 3 P-P-gp Caco µmol/L 25
27 efflux P-gp L-MDR12in vitro P-gp Calcein-AM 50µmol/L Calcein-AM P-gp IC µmol/L IC 50 C max 16.8µmol/L P-gpCalcein-AMJ Pharmacol Exp Ther 2001; 299, Eur J Pharm Sci 2001; 12, J Med Chem 2003; 46, P-gp 1 400mg1 2 IC 50 P-gp P-gp P-gpin vitro P-gp IC µmol/L IC 50 1/23 1/7 Clin Pharmacol Ther 2003; 73: 51-60P-gp 6 M-2 N mg/kg M-2 in vitrom-2 M-2 M-2M-2 AUC mg/kg1/18 M-2 14 CM-2 5mg/kgM-2 M-1/M-5M-2 M-2 M-1 M-5 M-2 M-3 M-4 AUC M M-1/M CM mg/L fu M-2 HSA M-2 M-2/ 26
28 CM-2 CYPM-2 CYP CYP2C9 2C19 2D6 3A4Ki µmol/L CYP2C8Ki 3.0µmol/L M-2 CYPM-2 1/10 1/5CYP M P-gp UGT1A1 1A mg/L C max mg/L 9 20mg/L fu fu C max C max mg/L fu Grade Regul Toxicol Pharmacol 28: ,
29 mg/kg 1 g-eq/g * * ** * ** Pharm Pharmacol 55, , C t 1/ , , 1995 t 1/2 3 CYP CYP3A4Ki µmol/L2 Ki CYP3A4 CYP3A4 Biochemistry 33, , , , 1998 Arch Biochem Biophys 433, , 2005Ki KiKi2 CYP3A4 28
30 4 P-gp P-gp BCRP Breast Cancer Resistance ProteinP-gp BCRP BCRP P-gp BCRP P-gp P-gp 5 3 P-gp mg/kg mg/kg mg/kg1000mg/kg 1460mg/kg 1000mg/kg mg/kg/ mg/kg/ mg/kg/ 25mg/kg/ mg/kg/ mg/kg/ mg/kg/ mg/kg/ mg/kg/ mg/kg/ 4 25mg/kg/ 13 5mg/kg/ 12 30mg/kg/ 29
31 2.5mg/kg/ 3mg/kg/ 30mg/kg/ 12 10mg/kg/ mg/kg/13 5mg/kg/ 6 1mg/kg/13 30mg/kg/12 10mg/kg/ mg/kg/ 12 10mg/kg/ 13 30mg/kg/ 25mg/kg/ 4 25mg/kg/ mg/kg/ 5mg/kg/α- MTD 4 30mg/kg/ mg/kg/ 30
32 400mg 1 2 AUC AUC S9 mix in vivo mg/kg/ 2.5mg/kg/ 2.5mg/kg/ 1mg/kg/ 1mg/kg/ 0.2mg/kg/ mg/kg/ 3mg/kg/ 0.3 1mg/kg/ 3mg/kg/ 0.3mg/kg/ 1mg/kg/ 31
33 AUC400mg 1 2 AUC 2 6 N- M-2 BAY M-2 M-2 4 M-2 M mg/kg/5mg/kg/ 25mg/kg/ 5mg/kg/ AST ALT 5mg/kg/ 1mg/kg/ M-2 AUC 5mg/kg/ 25mg/kg/ 400mg 1 2 AUC M-2 M-2 265nm 3T3 in vitro Grade 3 32
34 mg %
35 a 6 100mg 1 4 n=3 50mg mg 1 3 n=3 2 a 3 200mg a 3 400mg b 3 100mg a 3 100mg a 3 100mg a 3 100mg a 6 100mg a 6 200mg a 6 400mg a 6 800mg c 3 100mg mg 50mg mg 50mg c 3 200mg mg 50mg mg 50mg c 4 100mg mg 50mg a mg c 6 400mg 50mg mg 200mg a50mg b 4 c PK mg 50mg mg BA AUC 38 49%50mg200mg 400mg mg AUC C max 30.6mg h/l 4.19mg/L 50mg 40.0mg h/l 5.00mg/L % mg A 50mg 8 B 200mg 2600mg C 200mg 3 PK 23 A AUC C max B % 50mg 34
36 1543.4% 80% BA 50mg mg B 50mg A 200mg mg 5 50mg A B 30% 200mg 30% 50mg AUC C max 50mg200mg AUCBA 250mg BA PK 50mg 200mg A B A B AUC mg h/l C max mg/l t max h * AUC A/B ** , , 1.56 C max A/B ** , , 1.44 AUC 50mg /200mg * C max 50mg /200mg * CV% A B *** 90%CI Kcal Kcal 30400mg 200mg 2 AUC C max
37 t max t max BSA LBM t max BSA LBM PK ph BA ph 1% SLSpH 100mL 200mg 0.1 ph mg/mL BA ph PK ph ph PK AUC 29% BA 36
38 PK EU EU EU AUC 29% BA AUC 4.2 PK CYP3A4 CYP C 100mg AUC 63.5%M % AUC t max %
39 96.3%19.2%77.1% M-7 M % M %M I I mg mg 3 200mg 15 PK 200mg Dose Limitting Toxicity: DLT 3/15 7 MTD DLT 200mg mg mg 6 600mg 7 PK PK PKt max
40 400mg N=6 14 AUC 0-12 AUC 14t 1/ mg AUC 0-12 C max mg 400mg 1 2 N=6 AUC C max AUC C max mg600mg 400mg 39
41 1 2PK Day AUC 0-12 AUC 0- C max t max * t 1/2 R ac- R ac- mg h/l mg h/l mg/l h h C max AUC R ac 100mg Mean N=3 CV mg Mean N=15 CV mg Mean N=6 CV mg Mean N=7 CV mg Mean N=3 CV mg Mean N=10 CV mg Mean N=6 CV mg Mean N=6 CV mg Mean N=3 CV mg Mean ** N=8 CV * ** n=9 R ac -C max C max R ac -AUC AUC R ac AUC 0-12 AUC 0- M-2 M-4 M-5 AUC 0-12 C max 600mg400mg M-2 AUC % M % M % 48 M % M % M Child-Pugh A B mg 1400mg PK PK 400mg 14 AUC 0-12 Child-Pugh A 6B mg h/l 36.69mg h/l 40
42 Motzer mg PK 131 6C trough,ss 72 C trough,ss mg/L400mg mg/L400mg mg/L Part 1 Br J Cancer 2005; 92, MTD 1 50mg mg PK mg 1 2 t 1/ mg t 1/ C max AUC 0-12 t 1/2 C max AUC 0-12 t 1/ AUC 0-12 C max mg mg h/l mg/L AUC % PK 1 2 AUC 0-12,ss 100mg 23.8mg h/l 200mg 16.1mg h/l 600mg 6 I Ann Oncol 2005; 16,
43 2 50mg 2 50mg 1 50mg mg mg mg mg mg mg mg mg mg mg mg mg mg C max AUC mg600mg 2.00mg/L 10.1mg h/l 400mg2.87mg/L 21.8mg h/l 28C max AUC mg mg/L mg h/l t 1/ AUC t 1/2 7 I mg PK 7 400mg C max AUC 0-12 t 1/2 t max 6.17mg/L 56.61mg h/l I mg PK AUC 0-12 C max 800mgAUC 0-12 C max 600mg 42
44 Dose mg N AUC 0-12 mg h/l C max mg/l t max * h a b c d e CV% * a 21 b 13 c 19 d 18 e mg 1 2 Child-Pugh A B Child-Pugh A 15 B 6 PK 28 Child-Pugh B C max,ss AUC 0-8,ss 5.97mg/L 30.3mg h/l Child-Pugh A 4.92mg/L 25.4mg h/l Child-Pugh B M-5 AUC 0-8ss C max,ss 1.13mg h/l 0.26mg/L Child-Pugh A 1.98mg h/l 0.33mg/L M-5 Child-Pugh B Child-Pugh A M-2 M-4 AUC 0-8,ss C max,ss Child-Pugh mg/m mg/m mg 200mg 400mg PK mg PK mg 200mg C max dfdu AUC 0-tn C max 400mg 50mg C max C max
45 1.15mg/L mg/L 1 15 dfdu CL dfdu Clin Pharmacokinet 2005; 44: C max 3 C max mg1 2 AUC 0-12,ss C max,ss mg/m mg PK 27 AUC % AUC 0-48 C max 400mg 50mg % C max 4 AUC 0-8,ss C max,ss 200mg18 17%400mg 50mg % 400mg 200mg CYP3A4 CYP3A4 Ki=29µmol/L mg/m mg 200mg 50mg 400mg 50mg 200mg
46 54 PK 36 AUC400mg 50mg C max 58% 400mg AUC 21% C max 34% 100mg AUC 0-8,ss 22% C max,ss 200mgAUC 0-8,ss C max,ss 36 26%400mgAUC 0-8,ss C max,ss SN-38 CYP3A4 SN-38SN-38 UGT1A1 Clin Pharmacol Ther 2004; 75, CYP3A4 UGT1A mg/m mg mg 200mg 400mg PK mg/m 2 400mg AUC C max 26 36%SN-38 AUC C max % 140mg400mgAUC 0-48 C max 42 73%SN-38 67%400mg 125mg/m 2 AUC 0-10,ss C max,ss 68 78% 140mg Cancer Chemother Pharmacol 2006; 57, CYP3A4KCZ 150mg 2KCZ 400mg mg KCZ AUC t 1/2 M-2 KCZM-2 in vitrom-2 CYP3A KCZM-2 45
47 KCZ CYP3A PK 18CYP2C19 2D6 3A4 CYP Pharmacogenetics 1995; 5, Clin Pharmacol Ther 2000; 68, mg mg 30mg 2mg AUC15% C max 1-AUC 0-tn C max 20% % 6 3% 400mg 1 2 PKAUC M-7 M CYP2C19 2D6 3A Motzer 442 / mg PT-INR PT-INR 46
48 in vivocyp2c9 CYP3A4 CYP3A th annual meeting 2006-AACR ERK VHL svegfr-2 Progression Free Survival: PFS VEGF PFS VEGF PFS RNA 6 1 C max AUC C trough PK C max AUC 0-12 C trough AUC 0-12 C max C trough 100mg 100mg 400mg AUC AUC 0-12 M-2 M-4 M-5 M % % 1 2 PK PK N N C max mg/l mg AUC 0-12 mg h/l C trough mg/l C max mg/l mg AUC 0-12 mg h/l C trough mg/l
49 PK N N C max mg/l mg AUC 0-12 mg h/l C trough mg/l C max mg/l mg AUC 0-12 mg h/l C trough mg/l CV% PK PK J Clin Pharmacol Ther 2000; 38, Clin Pharmacol Ther 1990; 48, CYP3A4 UGT1A9 CYP3A4 Neurotoxicology 2000; 21, UGT1A9 2UGT1A9*3 *5 J Clin Pharmacol 2004; 44: CYP3A4KCZ CYP PK mg 1 2 AUC 0-12 C max C trough Grade 400mgGrade Grade Grade 48
50 Grade 1 PK mg PK 6 1 AUC C max 600mg 400mg 600mg 400mg 800mg 600mg mg AUC C max AUC 0-12 C max C trough PK PK 6 1 PK 400mg AUC C max PK PK AUC C max PK PK mg 76.4kg 63.4kg67.0kg 24 C max C max 16 AUC C max AUC 49
51 400mg PK C max mg/l % % % t max h * AUC 0-tn mg h/l % % % AUC mg h/l % % % t 1/2 h % 22.6% 31% % CV% * PK 24pH PK AUC AUC PK 2 Grade 6 2 PK C max AUC 0-12 C trough PR 4 2 SD PD PK 50
52 3 1 AUC 0-12ss mg h/l AUC FDA FDA FDA FDA PK AUC FDA20 The results of pharmacokinetic studies conducted in Japan demonstrated a 55% decrease in exposure (mean steady-state AUC) in Asian patients compared to Caucasian patients. FDA caucasian 400mg PKblacks 20 AUC C max n= n= n= n=2 * 28.9, , 1.11 n=1 * * PK 6 Limited pharmacokinetic data on sorafenib 400 mg twice daily in Japanese patients (n=6) showed a 45% lower systemic exposure (mean steady-state AUC) as compared to pooled phase I pharmacokinetic data in Caucasian patients (n=25). The clinical significance of this finding is not known. 20 FDA PK PK PK
53 AUC mg mg mg 400mg mg mg mg mg/L Grade mg mg/ 200mg mg1 1 52
54 400mg mg mg mg mg mg GEM L-OHP PK mg 200mg
55 400mg 600mg mg 400mg mg mg 200mg 600mg 200mg 400mg 50mg mg 200mg mg 50mg 200mg mg 14 C mg 400mg mg 1 800mg mg mg mg 200mg 300mg 400mg 600mg 800mg 1 Part / mg 2 50mg 1 50mg mg mg 200mg 400mg 600mg /7 100mg 200mg 400mg 600mg 800mg /7 50mg 1 50mg1 1 1 /3 200mg 400mg 50mg 400mg 200mg mg/m mg 200mg 400mg 50mg 400mg 200mg mg/m mg/m mg 200mg 400mg 50mg 400mg 200mg mg/m mg 200mg 400mg 50mg 400mg 200mg mg/m mg 200mg mg mg1 2 2mg 20mg 30mg 54
56 501 Part B mg mg 400mg mg I mg mg 17 CR 0 PR 1 200mgSD 6 100mg 2 200mg 4PD mg 1 200mg mg 3 200mg mg DLT P-1 DLT 1400mg 30200mg 1 Grade 1 Grade 4 2 I mg mg 6 600mg mg 12 CR 0 PR 1 600mg SD 8 400mg 600mg 4 PD 3 400mg 600mg 1 600mg 1 55
57 PR DLT 600mg 1 Grade 3 DLT 1 400mg mg 600mg 1 600mg 400mg mg 1 400mg mg mg mg 400mg 2 200mg mg Motzer Simon optimal design mg RECIST 129 intent-to-treat ITT CR+PR / %CI7.3, 19.4Progression Free Survival: PFS %CI 178.0,
58 / PD Cancer Chemother Pharmacol 2006; 57, I mg 400mg mg PR 1 PR mg DLT 1 800mg DLT DLT 1 400mg1 2 57
59 Part 1 Br J Cancer 2005; 92, MTD mg mg PR 1 PR 1 600mg 1 400mg1 2 MTD 1 400mg I Ann Oncol 2005; 16, mg mg mg PR 1 400mg1 2 MTD 1 400mg I mg PR 1 800mg1 2 3 DLT Grade 3 2 Grade 2 Grade 3 1 MTD 1 600mg1 2 58
60 I mg PR 50mg Clin Colorectal Cancer 2005; 5, Ann Oncol 2006; 17,
61 mg WHO PD MR 25 SD 400mg SD Part B 202 PD 43 MR 79 SD 65 SD MR 79 4 MR 52 PR22 MR ITT ITT Motzer CI 31.9, / CI 7.0, 35.56/33 p= ECOG Cochran-Mantel-Haenszel Progression Free Survival: PFS n= CI 37, 75 n= CI 84, 191 PFS p= ECOG PS
62 : Motzer 442 / mg 1 2 Overall Survival: OSOS PFS PD ITT ITT / % 170/ % 260/ % 264/ % Motzer 200/ % 194/ % 184/ % 191/ % PFS PD 147/ /385 PFS PFS CI 0.35, 0.55 p< Motzer 61
63 Progression Free Survival Probability (%) Patients at Risk Days from Randomization PFS Kaplan-Meier ITT PFS 20 Food and Drug Administration: FDA / /452 ITT OS 20 OS 0.04 O Brien-Fleming α OS CI 0.54, 0.94 p=0.015 Motzer CI 0.63, 0.95 p=0.015 Motzer CI 0.74, 1.04 p = Motzer Kaplan-Meier OS ITT N=452 N=451 N=452 N=451 N=452 N=451 n, % % % % % % % MST p Log-rank
64 %CI 0.54, , , Survival Probability (%) Survival Probability (%) Patients at Risk Days from Randomization OS Kaplan-Meier Patients at Risk Days from Randomization OS Kaplan-Meier / / IFN -2 63
65 IL-2 IFN OS PFS OS PFS PFS 90% 363 PD PFS PFS OS 220 OS % 9% MST 446 MST OS OS PFS CI 0.35, 0.55 PFS RECIST / CI 7.3, RECIST 2.1 7/ / RECIST 64
66 % / IFN IL /769 New Engl J Med 2005; 353: Motzer J Clin Oncol 1999; 17: ECOG PS LDH Am J Surg Patho 2002; 26: Motzer PFS ITT IFN-α IL-2 N=72 N=65N=313 N=319 PD % % % % % PFS %CI 0.19, ,
67 PFS ITT 1 N=46 2N=83 PFS PR SD PD PFS PFS ITT n, % IFN IL-2 N=312 N=324 N=73 N=60 N=313 N=319 N=72 N=65 PD % 50.6% 37.7% 50.7% 41.7% 52.1% 39.8% 44.4% 30.8% PFS %CI 0.34, , , , PFS PFS ITT N PFS
68 Motzer Motzer PFS PFS Motzer PFS ITT N=194 N=200 N=191 N=184 N=52 N=77 PD % % % % % % % PFS NA NA 95%CI 0.39, , 0.53 NA NA N.A * N=14 N=13 N=15 N=17 N=2 N=0 PD % % % % % 2 100% NA PFS NA NA 95%CI 0.02, , 1.64 NA *12 NA Motzer Motzer J Clin Oncol 1999; 17: Motzer PFS
69 / RECIST SD 14 PD / SD n, Grade Grade 3 Grade N N= N=
70 # at risk a N=131 # of events b % week week week week week week week week week a : b : # at risk a N=384 N=384 # of events b % # at risk a # of events b % cycle cycle cycle cycle cycle cycle cycle cycle cycle a : b : Grade 3 Grade 3 2 Grade
71 / Grade Grade % Grade CTCAE Ver3 n, % n, % / N=384 N=384 N=384 N=384 / Grade Grade 3 Grade Grade 3 Grade Grade 3 Grade Grade Grade 4 /
72 Grade %Grade %Grade (11.7 ) INR / 2/ / / 3/ / 6 1.6% 2 0.5%
73 20 80 PSUR n, % n, % N=131* N=343* N=340* Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 Grade Grade 3 Grade * I Grade 3/4 7/ Grade 3 4 3/ I 6 Grade / Grade 1 1 Grade
74 Grade 3 Grade n, % n, % N=131* N=343* N=340* Grade Grade 3 Grade 4 Grade Grade 3 Grade 4 Grade Grade 3 Grade ALT AST ALP * Grade Grade 4 ALT AST Grade 3 INR 20mg/dL 73
75 Grade Grade Grade
76 n, % n, % N=131* N=384 N=384 Grade Grade 3 Grade Grade3 Grade Grade Grade Grade DLT : / / Grade 3 4/ Grade / / / / Grade Grade Grade
77 Grade 3 10/15 CCDS N= Grade N=451 I I mg/4mL 400mg/16mL /
78 N=131 n, % Grade Grade 3 Grade 4 Grade N=384 n, % N=384 n, % Grade Grade 3 Grade 4 Grade 5 Grade Grade 3 Grade 4 Grade Bayer HealthCare EU IFN-α IL-2 77
79 UICC Union Internationale Contre le Cancer TNM Gerota T4NanyMany 2cm 2 TanyN2Many TanyNanyM1 TNM National Cancer Institute: NCI mg
80 1 I N=31 I N=164 C max AUC 0-12 C trough Grade Grade Grade Grade PR C max AUC 0-12 C trough PK mg 1 2 PFS mg Kcal Kcal 30400mg 200mg 2 AUC C max mg AUC 79
81 mg mg mg NCI-CTC CTCAE Ver 3.0 Grade 1 Grade Grade 2 Grade 3 Grade /µl 38.5 Grade 4 25,000/µL Grade Grade 312 Grade 412 4Grade 23Grade 3 Grade Grade 2 2 Grade 3Grade 4 CTCAE Version 3.0 Grade 2 80
82 NCI CTCAE Grade 4 7 Grade Grade 312 Grade 41 4Grade 23Grade 3 Grade Grade 2 2 Grade 3Grade 4 CTCAE Ver 3.0 Grade 2 NCI CTCAE Grade 3 Grade 2 /23 17 Grade 312 Grade 41 4Grade 23Grade 3 Grade 2 1.5~2 Grade 2 2 Grade 3Grade 4 CTCAE Ver 3.0 Grade 2 81
83 Grade Grade 3 NCI CTCAE Grade 3 Skin Toxicity grading Grade Skin Toxicity grading Grade Skin Toxicity grading Grade 4 1 Grade 3 Grade Grade 312 Grade 41 4Grade 23Grade 3 Grade / / / / Grade
84 11515 PFS / / / PFS / / / PFS ECCO 13the European Cancer Conference, 2005 J Clin Oncol 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S June 20 Supplement, 2006: 4538 J Clin Oncol 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S June 20 Supplement, 2006: mg 1 2 IFN 1 1,000 IU 3 IFN IFN IFN-α-2b IU mg 1 2 IFN IFN 83
85 IFN ERK RNA VEGF RNA IFN
86 I % % / Grade Grade Grade 1 Grade Grade 1 Grade 3 1 Grade 3 / 1 2 I / /
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