Microsoft Word - Approved PI-clean (updated )

2007 02 14 2007 03 23 2008 06 30 2008 07 01 2008 07 29 2010 02 12 2010 05 27 2011 09 14 2012 05 15 2012 08 24 2014 01 06 INR / 1 >60 Capecitabine Tablets Kapeitabin Pian 5 --5--N-[()]- O N H N O Me 4 3 O 1 2 N HO OH F O 1

C 15 H 22 FN 3 O 6 359.35 0.15g XELODA 150 0.5g XELODA 500 Dukes C DFS 5 (5-FU/LV) OS 5-FU/LV Dukes C XELOX 400 mg/m 2 6 (1) 0.15g (2)0.5g 1250mg/m 2 2 1 2500mg/m 2 2 1 3 30 1250 mg/m 2 2 2 1 75 mg/m 2 3 1 1 130 mg/m 2 2 1000 mg/m 2 2 2 1 1 2 1250 mg/m 2 1000 mg/m 2 () Dukes C 6 1250mg/m 2 2 2 1 3 8 24 2

1. 1250mg/m 2 m 2 (75%) 950 mg/m 2 (50%) 625 mg/m 2 * mg * (mg) * (mg) 150mg 500mg 1.25 1500-3 1150 800 1.26~1.37 1650 1 3 1300 800 1.38~1.51 1800 2 3 1450 950 1.52~1.65 2000-4 1500 1000 1.66~1.77 2150 1 4 1650 1000 1.78~1.91 2300 2 4 1800 1150 1.92~2.05 2500-5 1950 1300 2.06~2.17 2650 1 5 2000 1300 2.18 2800 2 5 2150 1450 * 1 2. 1000mg/m 2 m 2 * mg (75%) 750 mg/m 2 * (mg) (50%) 500mg/m 2 * (mg) 150mg 500mg 1.26 1150 1 2 800 600 1.27~1.38 1300 2 2 1000 600 1.39~1.52 1450 3 2 1100 750 1.53~1.66 1600 4 2 1200 800 1.67~1.78 1750 5 2 1300 800 1.79~1.92 1800 2 3 1400 900 1.93~2.06 2000-4 1500 1000 2.07~2.18 2150 1 4 1600 1050 2.19 2300 2 4 1750 1100 * 1 3

3 4 3. NCIC * 2 3 4 14 0~1 14 0~1 75% 50% 2 / 0~1 3 / 0~1 3 0~1 75% 55mg/m 2 4

NCIC * 2 3 4 14 0~1 75% 14 0~1 50% 2 / 0~1 3 / 0~1 2 0~1 75% 55mg/m 2 14 0~1 50% 3 0~1 50% 2 / 0~1 3 2 0~1 5

NCIC * 2 3 4 50% * NCIC CTC 4 4. NCIC * % 1 2-0~1 100% - 0~1 75% - 0~1 50% - 3-0~1 75% - 0~1 50% - 4-0~1 * 1 2 3 1 4 1 50% 50% 6

=51-80ml/[Cockroft Gault ] =30-50ml/ 75% 1250mg/m 2 2 950mg/m 2 2 2 4 3 4 Cockroft Gault = 140[][kg] 72[mg/dl] = 0.85 >60 65 3~4 6034 60 75% 1000mg/m 2 1 2 2 1 80mg/m 2 3 1 2 15, ANC 1000 x 10 6 /l 100,000 x 10 6 /l 3 5 5. (X)P ANC (x 10 6 (x 10 6 /l) /l) 1500 100,000 X: 100% P: 100% 1000 < 1500 100,000 X: 75% P: 75% 7

< 1000 / < 100,000 X: ANC 1000 100,000, ANC 1000 < 1500 75% ANC 1500 100% P: ANC 1000 100,000, ANC 1000 < 1500 75% ANC 1500 100% 6 6. XP 4 5 * X: 75% P: 75% 4 * X: 50% P: 50%,, * NCIC X: 0~1 50% P: 0~1 50% 23 4 3 30ml/min 7 60ml/min Cockroft-Gault 1 <60ml/min 24 7 7. 60 ml/min 41-59 ml/min mg/m 2 ml/min 45 8

ml/min 45 mg/m 2 40 ml/min * 30 ml/min * 40ml/min> 30 ml/min 34 60 mg/m 2 2 NCI-CTC 7 1/10 5/100 - < 1/10 1/1000 - < 1/100 1 III 995 974 5-FU/LV 4 II N=319 3 1 II 2 III N=630 NCIC CTC 8. 5% ( 10%) ( 5% - < 10%) (G3/4:1%) (G3/4: 3%) (G3/4:<1%) (G3/4:<1%) (G3/4:<1%) (G3/4:<1%) (G3/4:<1%) (G3/4: 13%) (G3/4: 4%) (G3/4: 4%) * (G3/4: 4%) (G3/4: 3%) - (G3/4: 17%) (G3/4:<1%) (G3/4: 3%) (G3/4:<1%) * (G3/4:<1%) (G3/4: 1%) (G3/4:<1%) (G3/4:1%) (G3/4:1%) (G3/4:<1%) (G3/4:<1%) (G3/4:<1%) (G3/4:<1%) 9

7 2% N=949 7 N=949 5% / / / 9 5% 9. 10% 5% - <10% + + + + + + 10

+ + 3/4, (2%)/(3%) 5% 995 949 10. a 1250 mg/m 2 3/4 (%) 1.6 1.1 3.5 1.1 2.3 0.3 3.1 44.4 11

3.6 / 2.4 2.0 0.3 0.5 0.4 20 4.4 a NCIC CTC 302 11. 1000 mg/m 2 2 5-FU 800 mg/m 2 /d, 1 5, 2 80 mg/m 2 1 3 80 mg/m 2, 1 3 (N=156) 3/4 (%) 4 (%) (N=155) 3/4 (%) 4 (%) 23.1 3.2 19.4 8.4 23.1 2.6 21.9 8.4 / 26.9 3.2 25.2 8.4 5.1 0.6 3.9 1.9 9.6 0.6 6.5 1.3 7.1 1.3 5.8 1.3 3.8 1.3 2.6 1.3 1.9 0.6 4.5 0.6 ALT (SGPT) 0.0 0.0 3.2 0.6 AST (SGOT) 0.0 0.0 3.2 1.3 5.2 00 3.9 0.0 0.6 0.0 1.3 0.0 4.5 0.6 1.9 0.0 4.5 0.6 3.2 0.0 (WBC) 8.3 1.3 11 2.6 - Stevens-Johnson TEN NOS 12

DPD 30 ml/ 2 () DPD 5- DPD 5- Stevens-Johnson TEN - 79 11 360 1 3 1 // /2 // 3 / / 2 3 1 3 B6 B6 >3.0 ULN ALT AST>2.5 ULN 3.0 ULN 2.5 ULN S- AUC +57% P450-2C9 INR PT 13

5-30~50 ml/min[cockroft Gault] 3 4 30~50 ml/min[cockroft Gault] 75% 2~4, 18 60~79 3 4 80 65 3 4 60 3 4 60 / 1 20mg S- AUC 57%INR 91% INR PT P-450 2C9 P-450 2C9 14

CYP2C9-30 Maalox 5 -DFCR 5 -DFUR5-FU FBAL 5-4 / 1331mg/m 2 / 2 n=392510mg/m 2 n=34lv 1657 mg/m 2 2 n=35 60mg/ 1250 mg/m 2 2 2 1 Dukes C (X-ACT ) 5- /5FU/LVDFS1987 5-1250 mg/m 2 2 2 1 3 8 24 5-425 mg/m 2 20 mg/m 2 1 5 4 6 24 18 75 Dukes C 8 ECOG 0 1(KPS 70%)ANC 1.5x10 9 /L 100 10 9 /L 1.5 15

ULN 1.5 ULN/ (AST/ALT) 2.5 ULN 12 5FU/LV 12. (n, %) (n, %) ECOG 0 (n, %) 1 (n, %) PT1 (n, %) PT2 (n, %) PT3 (n, %) PT4 (n, %) (n, %) pn1 (n, %) pn2 (n, %) (n, %) (n=1004) 62 (25~80) 542 (54) 461 (46) 849 (85) 152 (15) 12 (1) 90 (9) 763 (76) 138 (14) 1 (0.1) 695 (69) 305 (30) 4 (0.4) 5-FU/LV (n=983) 63 (22~82) 532 (54) 451 (46) 830 (85) 147 (15) 6 (0.6) 92 (9) 746 (76) 139 (14) 0 (0) 694 (71) 288 (29) 1 (0.1) 1250 mg/m 2 30 50 ml/min 13 16

13. XACT N = 995 5-FU/LV N = 974 % 93 92 % 83 87 % 15 5 % 46 29 % 42 44 % 57 52 53 DFS 5-FU/LV 0.8795% 0.76-1.00) 1.20 5-FU/LV 1.20 75% 5-FU/LV 53 0.8895%C.I. 0.74-1.05p0.169 14. a 5/ (n=1004) 5-FU/LV (n=983) 53 53 3 66.0 62.9 HR (/5-FU/LV) (HR95% C.I. p b ) a 85% 3 0.87 (0.76 1.00) p = 0.055 b 5-FU/LV Log-rank 1207 120 1 2 603 1250 mg/m 2 2 2 1 3 604 5-FU 20 mg/m 2 5 425mg/m 2 1 5 28 WHO IRC IRC 5-FU/LV 15 17

15. 1 2 n=302 5-FU/LV n=303 n=301 5-FU/LV n=301 64 63 64 64 23~86 24~87 29~84 36~86 % 18160 19765 17257 17357 % 12140 10635 12943 12843 Karnofsky PS 90 70-100 90 70-100 90 70-100 90 70-100 % 22274 23277 19966 19665 % 7926 7023 10134 10535 % 5-FU % 5217 6221 4214 4214 8428 11036 5619 4114 III 16 17 16. 5-FU/LV 1 n=302 5-FU/LVn=303 %95% 2116~26 118~15 p 0.0014 95% 128120~136 131105~153 /5-FU/LV 95% 0.99 0.84-1.17 380321~434 407366~446 /5-FU/LV 95% 1.00 0.84~1.18 17. 5-FU/LV 2 n=301 5-FU/LVn=301 %95% 2116~26 1410~18 p 0.027 18

95% 137128~165 131102~156 /5-FU/LV 95% 0.97 0.82~1.14 404367~452 369338~430 /5-FU/LV 95% 0.92 0.78~1.09 1. 1 2 Kaplan-Meier 1 2 5-FU/LV 5-FU 5-FU/LV 5-FU/LV 10 5-FU 5-FU/LV 5-FU/LV 1 2 95% 5-FU/LV 5-FU/LV 50% 2 5-FU/LV 61% 1 10% 5-FU/LV 50% 5-FU/LV 5-FU/LV 16 17 1 III (NO16966) 19

(BV) 2 XELOX FOLFOX-4 2 2 XELOX +, FOLFOX-4 +, XELOX + BV FOLFOX-4+BV 18. NO16966 FOLFOX-4 85 mg/m 2 1 2 2 FOLFOX-4 200 mg/m 2 1 2 + 2 2 5-FU 400 mg/m 2 600 mg/ m 2 5-FU /, 1 2 2 22 5 mg/kg 1, FOLFOX-4, 30-90 2 XELOX 130 mg/m 2 1, 3 2 XELOX+ 1000 mg/m 2 2 ( 2 2 1 ) 7.5 mg/kg 1, XELOX, 3 30-90 5-FU: XELOX FOLFOX-4 () XELOX FOLFOX-4 XELOX FOLFOX-4 XELOX FOLFOX-4 ( 1.01 [97.5% CI 0.84, 1.22]) 1.5 19. 1 (EPP ITT, NO16966 ) : XELOX/XELOX+P/ XELOX+BV (EPP * : N=967; ITT ** : N=1017) () FOLFOX-4/FOLFOX-4+P / FOLFOX-4+BV (EPP * : N = 937; ITT ** : N= 1017) HR (97.5% CI) 20

EPP ITT : EPP ITT : EPP ITT : EPP ITT 241 244 577 581 242 244 600 602 () *EPP=**ITT= 259 259 549 553 259 259 594 596 1.05 (0.94; 1.18) 1.04 (0.93; 1.16) 0.97 (0.84; 1.14) 0.96 (0.83; 1.12) HR (97.5% CI) 1.02 (0.92; 1.14) 1.01 (0.91; 1.12) 1.00 (0.88; 1.13) 0.99 (0.88; 1.12) III (CAIRO) 1000 mg/m 2 2 3 (ORR)(PFS)(OS) 5-FU (FOLFIRI) II (AIO KRK 0604) 800 mg/m 2 2 3 115 (XELIRI): (800 mg/m 2 2 2 1 ), ( 200 mg/m 2 30 3 ), ( 7.5 mg/kg 30-90 3 ) 118 : (1000 mg/m 2 2 2 1 ), ( 130 mg/m 2 2 3 ), ( 7.5 mg/m 2 30-90 3 ) 6 80% (XELIRI) 74% (XELOX )() 47% (XELIRI) 45% (XELOX) III (NO16967) 627 XELOX FOLFOX-4 XELOX FOLFOX-4 15 XELOX FOLFOX-4() XELOX FOLFOX-4 2.1 6 21

20. 6 (PPP ITT NO16967 ) : PPP ITT : PPP ITT : PPP ITT : PPP ITT XELOX (PPP * : N=251; ITT ** : N=313) 154 144 388 363 154 143 393 363 () FOLFOX-4 (PPP * : N = 252; ITT ** : N= 314) 168 146 401 382 6 () *PPP=**ITT= 166 146 402 382 HR (95% CI) 1.03 (0.87; 1.24) 0.97 (0.83; 1.14) 1.07 (0.88; 1.31) 1.03 (0.87; 1.23) HR (95% CI) 1.04 (0.87; 1.24) 0.97 (0.83; 1.14) 1.05 (0.88; 1.27) 1.02 (0.86; 1.21) NO16966 2 NO16967 XELOX FOLFOX-4 1.00 [95% CI: 0.88; 1.14] 193 (XELOX 508 ) 204 (FOLFOX-4500 ) XELOX FOLFOX-4 ( 1.01[95% CI: 0.87; 1.17]) 468 (XELOX) 478 (FOLFOX-4) I III I 3 14 7 3 75 mg/m 2 1250 mg/m 2 2 2 1 100mg/m 2 3 III 75 511 255 3 1250 mg/m 2 2 2 1 75 mg/m 2 1 256 3 100 mg/m 2 22

1 21 21. + n=255 n=256 52 51 Karnofsky PS 90 90 1 5-FU 4 2 12 0 1 2 3 12147% 11645% 10742% 9537% 7329% 255100% 19677% 2510% 197% 6526% 4116% 7831% 5120% 8935% 12348% 4317% 00% 1 10 18 12549% 12248% 11946% 9939% 7329% 256100% 18974% 229% 197% 7329% 4016% 7429% 5020% 8031% 13553% 3915% 21% 22 2 3 23

22. / p 186 128 0.0001 0.643 95% 165-198 105-136 442 352 0.0126 0.775 95% 375-497 298-387 1 32% 22% 0.009 NA 2 1 IRC 2 NA= 2. Kaplan-Meier vs 3. Kaplan-Meier vs 24

24 162 IV 50% 1 1255 mg/m 2 2 2 1 3 n=162n=135 23 6 23. n=135 n162 55 56 Karnofsky PS 90 90 1-2 3-4 >5 1 4332% 6346% 2922% 10175% 3022% 43% 6037% 6943% 3421% 11068% 3522% 1710% 25

5-FU n=135 135100% 12290% 11081% n162 162100% 14791% 13382% 2 1 2 2 10376% 5541% 4332% 12477% 6741% 5131% 24 24. n=43 0 1 11 1 11 1 95% 1 2 1 2 25.6% 13.541.2 154 63 233 2 43 102 255 135 18.5%1 24 24 90 306 42 /C/S ( ) 26

/ 5-FU/ (N =160) (N = 156) 65 (40.6%) 64 (41.0%) / 40 (25.0%) 18 (11.3%) 37 (23.1%) 40 (25.6%) 17 (10.9%) 35 (22.4%) 316 160 1000 mg/m 2 2 2 1 80 mg/m 2 2 3 156 5-FU 800 mg/m 2 1 5 3 1 80mg/m 2 1 2 3 1 ( 25) 25. (ITT) / (%), () Karnofsky (%) () / (%) 2 (%) /(XP) n=160 64/36 55 (26~74) 80 (70~100) 11.3 70.6 147 (91.9) 78 (48.8) 103 (64.4) 119 (74.4) 158 (98.8) 31 (19.4) 148 (92.5) 120 (75.0) 146 (91.3) 5-FU/(FP) n=156 69/31 55 (33~73) 80 (70~100) 9.6 57.7 143 (91.7) 83 (53.2) 104 (66.7) 118 (75.6) 152 (97.4) 39 (25.0) 147 (94.2) 116 (74.4) 139 (89.1) 5-FU/ /5-FU/10%20% 2645 26. / 5-FU/(PP ) /n=139 5-FU/n=137 7.3 6.3 95% CI 0.81 (0.63, 1.04) p 0.0008 11.1 10.1 95% CI p 0.85 (0.65, 1.11) 0.2425 27

/n=139 5-FU/n=137 6.5 6.0 95% CI p 0.83 (0.61, 1.12) 0.2150 4 Kaplan-Meier 5 Kaplan-Meier 127 / 63 5-FU/ 64 /(PFS) 5-FU/ / 5-FU/(OS) (TTP) FP 27 6 7 27. / 5-FU/ /n=52 5-FU/n=54 7.3 4.5 28

95% CI 0.50(0.31,0.81) p 0.0267 10.5 9.5 95% CI p 0.60(0.38, 0.94) 0.1074 5.6 4.4 95% CI p 0.56(0.31,1.03) 0.088 6 Kaplan-Meier 7 Kaplan-Meier 5-FU 5--2-FdUMP 5- FUTPFdUMP 29

N 5,10 -TS 2 - [] DNA RNA UTP FUTP RNA Ames V79/HPRT 760mg/kg/ 5 -DFUR AUC 0.7 5-5-FU 60KD 5 - -5-5 -DFCR 5 -DFCR 5 --5-5 -DFURdThdPase 5 -DFUR 5-FU 5-FU H3C NH-CO-O N F O N O NH2 N F O N H3C O Carboxylesterase HO OH HO OH Capecitabine 5 -DFCR O HN O N H3C O HO OH 5 -DFUR F Cyd deaminase dthdpase O HN O N H 5-FU F 7 5-FU 2.9 0.9 8.0 5-FU 30

200 500-3500mg/m 2 / 5 -DFCR 5 -DFUR 5-FU AUC 14 5-FU AUC 34% 5-FU 3/4 5-FU AUC 85% 1.5 T max 2 5-FU C max AUC 0-60% 35% 5-FU C max AUC 0-43% 21% 5-FU T max 1.5 60% 35% 5-FU 5-FU 5--56-FUH 2 5- FUPA β- FUPA α--β-fbal 95.5% 2.6% FBAL 57% 3% 26 I C max AUC 5-FU 5 -DFUR 505 1250mg/m 2 2 202 303 455 /22 28 5 -DFUR5-FU FBAL 27 86 5 -DFUR 5-FU FBAL 20% AUC 15% 13 AST/ALT 1255mg/m 2 n=14 AUC 0- C max 60% 5-FU AUC 0- C max 1250mg/m 2 2 =30-50ml/<30ml/ FBAL >80ml/ 85% 258% 5 -DFUR 42% 71% 25% 25,15~30 31

0.15g30 /60 / 0.5g12 /60 / 36 YBH08582008 0.15g H20073023 0.5g H20073024 1100 021-28922888 021-50801800 800-820-8780 www.xeloda.com.cn Xeloda 32