ロンサーフ配合錠 t15,ロンサーフ配合錠 t20ƒンサーフ配合錠t15...
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-
T15 T20
2 2CTD
2.7.1
-
2.7.1
2.7.1 ....................................................... 1 2.7.1.1 .................................................................................... 1
2.7.1.1.1 ............................. 1 2.7.1.1.2 ................................................................ 2 2.7.1.1.3 ................................................................ 4 2.7.1.1.4 ............................................................................... 4
2.7.1.2 .................................................................... 7 2.7.1.2.1 B ............................ 7 2.7.1.2.2 T15T20
....................................................................................... 9 2.7.1.2.3 ......................................................................... 10 2.7.1.2.4 ................................... 11
2.7.1.3 ........................................... 12 2.7.1.3.1 ................ 12 2.7.1.3.2 ......................................................................... 12
2.7.1.4 ................................................................................................. 13
-
2.7.1
5-CU 5-carboxyuracil5-
6-HMU 6-hydroxymethyluracil6-
AUC area under the concentration-time curve-
AUC0-t area under the concentration-time curve from time 0 to the time (t) of the last
quantifiable concentrationt AUC
AUC0-12 area under the concentration-time curve from time 0 to 12 hr 12
AUC
AUCinf area under the plasma concentration-time curve from time 0 to infinity
AUC
dThd deoxythymidine
CI confidence interval
CL/F oral clearance
Cmax maximum plasma concentration
FTD trifluridine
FTY 5-(trifluoromethyl)uracil
HPLC high performance liquid chromatography
LC/MS/MS liquid chromatography-tandem mass spectrometry/
PK pharmacokinetics
t1/2 half-life
tmax maximum concentration time
TPI tipiracilthymidine phosphorylase inhibitor
Vd/F apparent volume of distribution
-
2.7.1
FTD 2-deoxy-5-(trifluoromethyl)uridine
trifluridine
TPI 5-chloro-6-[(2-iminopyrrolidin-1-yl)
methyl]pyrimidine-2,4-(1H,3H)-dione
monohydrochloride
tipiracil hydrochloride
FTY 5-(trifluoromethyl)uracil
HN
NH
O
O
CF3
FTD
5-CU 5-carboxyuracil
HN
NH
O
O
COOH
FTD
6-HMU 6-hydroxymethyluracil
NH
HN
O
OHO
TPI
dThd deoxythymidine
O
OH
HO
N
HN
O
O
CH3
HN
NO
O
O
OH
HO
CF3
Cl
HN
NH
O
O
NHCl HN
-
2.7.1
1
2.7.1
2.7.1.1
2.7.1.1.1
FTD TPI
A B TAS-102
A I TAS102-9801
TAS102-9805 II TAS102-9806
I II B III
B 2.7.1.1.1-1
B
B ******** B ***
**** 2.7.1.1.1-2 **** T20 ********
******** T15 T20 ****
T20 ************************************
****************************************
2.7.1.1.2
2.7.1.2.1 2.7.1.2.2
2.7.1.1.1-1 B I
TAS102-J001TAS102-J002 ************ ****** ************ ******
II TAS102-J003
************* ******* ************* *******
I TAS102-J002TAS102-J004
************** ******* ************** *******
III TPU-TAS-102-301
************** ******* ************* ******* ************** *******
*******************************************
********************************************************************* 2-1
-
2.7.1
2
2.7.1.1.1-2 BT15T20********
T15 T20 B 1) B 1)
FTD 15 15 20 20 TPI 7.065 7.065 9.42 9.42 ****** ****** ****** ****** ****** ******
* * * *
****** *** *** *** ***
**************** *** *** *** *** ****** 6000 *** *** *** *** ****** *** *** *** *** ****** * * * ***********
********
* *********** * ************
** **** **** **** **** **** ****** ****** ****** ****** ******************** **** **** **** **** mg ********************** 1)TPU-TAS-102-301 ********************************************************** 2-2 2-3
2.7.1.1.2
B
2.7.1.1.2-1
-
2.7.1
4
B
T20 T15 ********************************************************
**
2.7.1.1.2.2.2 T15 T20
T15 T20 GL
T20 T15 ***
GL GL
T20
T15 ******************************************************
**
2.7.1.1.3
B
TAS102-J004 5.3.1.1.1
FTDTPICmax
-AUC0-12 AUCinf
90%
10 4 10
0.5 0.5
4
1
FDAGuidance for Industry Food-Effect Bioavailability and Fed Bioequivalence
Studies2002 12
2.7.1.1.4
2.7.1.1.4.1
TAS-102 /
LC/MS/MSTAS-102 FTD
TPI
2.7.1.1.4.1-1
FTD FTYFTD
FTY tert-
LC/MS/MS FTD
5.005000 ng/mL 200200000 ng/mL FTY
TPI TPI
LC/MS/MS
TPI 0.200200 ng/mL 200100000 ng/mL
-
2.7.1
5
5-5-CU5-CU
LC/MS/MS
5-CU 1200 ng/mL
6-6-HMU6-HMU
LC/MS/MS 6-HMU 6-HMU
/LC/MS/MS 6-HMU
1.00500 ng/mL 5050000 ng/mL
dThddThd
LC/MS/MS dThd 0.4200 ng/mL
2.7.1.1.4.1-1 1
***************** ***************** 5.3.1.4.15.3.1.4.3 5.4.1.4.25.3.1.4.3 FTD FTY FTD FTY TPI TPI LC/MS/MS LC/MS/MS LC/MS/MS LC/MS/MS LC/MS/MS LC/MS/MS ng/mL 5
5000 5 5000
200200000
200 200000
0.2 200
200100000
ng/mL 5 5 200 200 0.2 200 *% 1.46.2 1.512.7 1.310.0 1.67.7 2.113.4 1.04.6
**% -4.0 3.0 -7.27.0 -5.02.8 -2.53.8 -3.03.8 2.05.6 *% 1.86.7 1.710.7 1.49.5 1.96.8 2.19.6 1.95.2
**% -4.02.4 -7.76.0 -0.45.5 -2.52.8 1.04.0 2.05.9 6 cycles 6 cycles 6 cycles 6 cycles 6 cycles 6 cycles
24 hrs 24 hrs 24 hrs 24 hrs 24 hrs 24 hrs
48 hrs10C
48 hrs10C
48 hrs10C
48 hrs10C
48 hrs10C
48 hrs10C
370 days -15C
370 days -15C
370 days -15C
370 days -15C
366 days -15C
366 days -15C
*********************** TAS102-J001TAS102-J002TAS102-J004
*: **:
-
2.7.1
6
2.7.1.1.4.1-1 2 ******** ******** **********
******** 11DA0311DA04
5.3.1.4.4 5.3.1.4.5 5.3.1.4.35.3.1.4.6 5.3.1.4.75.3.1.4.8
6-HMU 6-HMU dThd 5-CU LC/MS/MS LC/MS/MS LC/MS/MS LC/MS/MS ng/mL 1.00 500 50.0 50000 0.4 200 1 200 ng/mL 1.00 50.0 0.4 1 *% 1.6 5.5 0.5 6.4 1.9 13.3 1.1 6.2
**% -4.0 2.0 -2.0 10.8 -4.0 0.0 -5.5 -2.5 *% 2.6 7.2 1.6 5.7 2.3 10.2 2.6 10.4
**% -1.2 4.8 -3.0 6.0 -0.8 0.3 -9.0 -4.4 6 cycles 6 cycles 6 cycles 3 cycles
24 hr 24 hr 8 hrice-bath 4 hrs
48 hrs10C 48 hrs10C 48 hrs10C 48 hrs10C
42 days -15C
39 days -15C
368 days -15C
185 days -80C
***********************
TAS102-J001 TAS102-J004 *: **:
2.7.1.1.4.2
2.7.1.1.4.2-1
7 7 20 755 9 10 28
338 9
10 28 338
2.7.1.1.4.2-1 ***** HPLC ************************
************************ ******** 1 2
pH 1.2 1
***** HPLC
pH *** McIlvaine
***** HPLC
pH 6.8 2
***** HPLC
-
2.7.1
7
2.7.1.2
2.7.1.2-1
2.7.1.2-1
TAS102-J004 11DA23
5.3.1.1.1
A B 1 2 1 1 1 5 A 1 2 B 1 2 35 mg/m2/
A 8 B 8
2.7.1.2.1 B
B
2.7.1.2.1-1 2.7.1.2.1-2 T15 T20
B
B
2.7.1.2.1-1 B *** T15
% *% B
FTD TPI FTD TPI FTD TPI pH 1.250 rpm *** *** *** *** *****
**** ***** ****
pH ***50 rpm *** *** *** *** ***** ****
***** ****
pH 6.850 rpm *** *** *** *** ***** ****
***** ****
50 rpm *** *** *** *** ***** ****
***** ****
pH ****** rpm *** *** *** *** ***** ****
***** ****
* pH 1.2 1 pH *** McIlvaine pH 6.8 2 ********************************************************** 6.2.1.1-1
-
2.7.1
8
2.7.1.2.1-2 B *** T20
% *% B
FTD TPI FTD TPI FTD TPI pH 1.250 rpm *** *** *** *** *****
**** ***** ****
pH ***50 rpm *** *** *** *** ***** ****
***** ****
pH 6.850 rpm *** *** *** *** ***** ****
***** ****
50 rpm *** *** *** *** ***** ****
***** ****
pH ****** rpm *** *** *** *** ***** ****
***** ****
* pH 1.2 1 pH *** McIlvaine pH 6.8 2 ********************************************************** 6.2.1.1-2
-
2.7.1
9
2.7.1.2.2 T15 T20
2.7.1.2.2.1 BT15 T20
B T15 T20
2.7.1.2.2.1-1
T15 T20
B T15 T20
2.7.1.2.2.1-1 B T15 T20 ***
% *%
T20
T15
FTD TPI FTD TPI FTD TPI pH 1.250 rpm *** *** *** *** *****
**** ***** ****
pH ***50 rpm *** *** *** *** ***** ****
***** ****
pH 6.850 rpm *** *** *** *** ***** ****
***** ****
50 rpm *** *** *** *** ***** ****
***** ****
pH ****** rpm *** *** *** *** ***** ****
***** ****
* pH 1.2 1 pH *** McIlvaine pH 6.8 2 **************************************************************** 6.2-1
2.7.1.2.2.2 T15 T20
T15T20
2.7.1.2.2.2-1
T15 T20
T15 T20
-
2.7.1
10
2.7.1.2.2.2-1 T15 T20 ***
% *%
T20
T15
FTD TPI FTD TPI FTD TPI pH 1.250 rpm *** *** *** *** *****
**** ***** ****
pH ***50 rpm *** *** *** *** ***** ****
***** ****
pH 6.850 rpm *** *** *** *** ***** ****
***** ****
50 rpm *** *** *** *** ***** ****
***** ****
pH ****** rpm *** *** *** *** ***** ****
***** ****
* pH 1.2 1 pH *** McIlvaine pH 6.8 2 ************************************************************** 6.2.1
2.7.1.2.3
B
TAS102-J004 5.3.1.1.1 FTD TPI
CmaxAUC0-12 AUCinf
90%Guidance for
Industry Food-Effect Bioavailability and Fed Bioequivalence Studies
TAS-102
2 2 16
A B 2
1 35 mg/m2 TAS-102 12
4
FTD TPI B 2
FTD AUC0-12AUCinf AUC0-t/ 90%
0.81.25FTD CmaxTPI Cmax TPI AUC
90%
FTD
TPI tmax
2.7.2.2.2.2
-
2.7.1
11
2.7.1.2.3-1 FTD / 90%
PK Parameters Geometric Mean Ratio 90% Confidence Intervals (Fed/Fasting) Lower to Upper
Cmax 0.6074 0.5037 0.7323 AUC0-t* 0.9561 0.8566 1.0671 AUC0-12 0.9560 0.8566 1.0670 AUCinf 0.9559 0.8556 1.0680
* Secondary objective parameter 5.3.1.1.1 TAS102-J004 CSR 11.4.2.3-1
2.7.1.2.3-2 TPI / 90%
PK Parameters Geometric Mean Ratio 90% Confidence Intervals (Fed/Fasting) Lower to Upper
Cmax 0.5578 0.4732 0.6576 AUC0-t* 0.5526 0.4802 0.6358 AUC0-12 0.5526 0.4802 0.6358 AUCinf 0.5581 0.4872 0.6392
* Secondary objective parameter 5.3.1.1.1 TAS102-J004 CSR 11.4.2.3-2
2.7.1.2.3-3 FTD TPI tmax
Compound PK Parameters Fasting State Fed State
p value (N=14) (N=14)
FTD tmax (hr) 1.00 (0.252.00) 1.00 (0.504.00) 0.0938 TPI tmax (hr) 2.00 (1.004.00) 2.00 (1.006.00) 0.1875
Median (MinMax), p valueWilcoxon signed-rank test 5.3.1.1.1 TAS102-J004 CSR 11.4.2.3-6
2.7.1.2.4
13 6 1 796 5.1.
B
B
5.3.1.2.1
B ************************
T15 ** T20 **
2.7.1.1.2.1
FTDTPI********************
B *********************************
B
2.7.1.2.1
FTD TPI ****** 5.3.1.2.1
-
2.7.1
12
B
5.3.1.2.1
2.7.1.3
2.7.1.3.1
I II B III
****************************
I II
III II
2.7.1.3.2
FTD AUC FTD CmaxTPI Cmax AUC
40% FTD TPI
TAS-102 FTD AUC
FTD CmaxTPI Cmax AUC TAS-102
TAS102-J001 FTD
Cmax 2.7.2.2.2.1.3
Cmax TAS-102
-
2.7.1
13
2.7.1.4
2.7.1.4-1 in vitro B ***%
FTD TPI TAS102-J004
B
********
T15 12 pH 1.250 rpm *** *** *********
pH ***50 rpm *** *** pH 6.850 rpm *** *** 50 rpm *** *** pH ****** rpm *** ***
** pH ***50 rpm *** *** pH ***50 rpm *** ***
******** T20
12 pH 1.250 rpm *** *** pH ***50 rpm *** *** pH 6.850 rpm *** *** 50 rpm *** *** pH ****** rpm *** ***
** pH ***50 rpm *** *** pH ***50 rpm *** ***
pH 1.2 1 pH ***pH*** pH *** McIlvaine pH 6.8 2
-
2.7.1
14
2.7.1.4-2 in vitro ***%
FTD TPI TPU-TAS-102-301
********
T15 12 pH 1.250 rpm *** *** *********
pH ***50 rpm *** *** pH 6.850 rpm *** *** 50 rpm *** *** pH ****** rpm *** ***
******** T20
12 pH 1.250 rpm *** *** pH ***50 rpm *** *** pH 6.850 rpm *** *** 50 rpm *** *** pH ****** rpm *** ***
pH 1.2 1 pH *** McIlvaine pH 6.8 2
2.7.1.4-3 FTD
*Secondary objective parameter
M/F
mg/m2
FTD PK
N Cmax
ng/mL tmax hr
AUC0-t nghr/mL
AUC0-12 nghr/mL
AUCinf nghr/mL
t1/2 hr
CL/F L/hr/kg
Vd/F L/kg
TAS102-J004
16 9/7
35 mg/m2/
14 56301840 0.880.42 106475012 106485011 109435581 2.130.76 0.1060.056 0.3100.181 5.3.1.1.1
35 mg/m2/
14 35101380 1.320.93 98404247 98404247 100824593 1.720.58 0.1150.06 0.2600.102
Parameters Geometric Mean Ratio (Fed/Fasting)
90% CI Lower to Upper
Cmax 0.6074 0.5037 0.7323 AUC0-t* 0.9561 0.8566 1.0671 AUC0-12 0.9560 0.8566 1.0670 AUCinf 0.9559 0.8556 1.0680
-
2.7.1
15
2.7.1.4-4 TPI
*Secondary objective parameter
M/F
mg/m2/
TPI PK
N Cmax
ng/mL tmax
hr AUC0-t
nghr/mL AUC0-12
nghr/mL AUCinf
nghr/mL t1/2
hr CL/F
L/hr/kg Vd/F
L/kg
TAS102-J004
16 9/7
35 mg/m2/
14 13539 2.070.92 647281 647281 677309 2.190.66 0.7750.320 2.421.25 5.3.1.1.1
35 mg/m2/
14 76.826.3 2.791.37 361160 361160 384189 2.220.45 1.340.45 4.101.24
Parameters Geometric Mean Ratio (Fed/Fasting)
90% CI Lower to Upper
Cmax 0.5578 0.4732 0.6576 AUC0-t* 0.5526 0.4802 0.6358 AUC0-12 0.5526 0.4802 0.6358 AUCinf 0.5581 0.4872 0.6392
-
T15 T20
2 2CTD
2.7.2
-
2.7.2
2.7.2 .............................................................................................. 1 2.7.2.1 .................................................................................... 1
2.7.2.1.1 ........................................................ 1 2.7.2.1.2 ............................................................................... 1
2.7.2.2 .................................................................... 2 2.7.2.2.1 in vitro ........................................... 2 2.7.2.2.2 ............................................................................... 4
2.7.2.3 ........................................... 25 2.7.2.3.1 .......................................... 25 2.7.2.3.2 .................................................. 29
2.7.2.4 ...................................................................................... 31
-
2.7.2
5-CU 5-carboxyuracil5-
5-CdUrd 5-carboxy-2-deoxyuridine5--2-
6-HMU 6-hydroxymethyluracil6-
Ae urinary excretion rate
ATP adenosine triphosphate
AUC area under the concentration-time curve-
AUC0-t area under the concentration-time curve from time 0 to the time (t) of the last
quantifiable concentrationt AUC
AUC0-10 area under the concentration-time curve from time 0 to 10 hr 10
AUC
AUC0-12 area under the concentration-time curve from time 0 to 12 hr 12
AUC
AUCinf area under the concentration-time curve from time 0 to infinity
AUC
CI confidence interval
Cmax maximum plasma concentration
CV coefficient of variation
CYP cytochrome P450 P450
FTD trifluridine
FTY 5-(trifluoromethyl)uracil
GFR glomerular filtration rate
LC/MS/MS liquid chromatography-tandem mass spectrometry/
LOF lack of fit
MDR multidrug resistance protein
MRM multiple reaction monitoring
NA not applicable
Papp apparent permeability coefficient
P-gp P-glycoproteinP
PK pharmacokinetics
Rb blood / plasma concentration ratio/
t1/2 half-life
tmax maximum concentration time
TPase thymidine phosphorylase
TPI tipiracilthymidine phosphorylase inhibitor
-
2.7.2
FTD 2-deoxy-5-(trifluoromethyl)uridine
trifluridine
TPI 5-chloro-6-[(2-iminopyrrolidin-1-yl)
methyl]pyrimidine-2,4-(1H,3H)-dione
monohydrochloride
tipiracil hydrochloride
FTY 5-(trifluoromethyl)uracil
HN
NH
O
O
CF3
FTD
5-CU 5-carboxyuracil
HN
NH
O
O
O
OH
FTD
5-CdUrd 5-carboxy-2-deoxyuridine
O
OH
HO
N
HN
O
O
O
OH
FTD
6-HMU 6-hydroxymethyluracil
NH
HN
O
OHO
TPI
HN
NO
O
O
OH
HO
CF3
Cl
HN
NH
O
O
NHCl HN
-
2.7.2
dThd deoxythymidine
O
OH
HO
N
HN
O
O
CH3
-
2.7.2
1
2.7.2
2.7.2.1
2.7.2.1.1
FTDTPI
in vitro
2.6.4 FTD TPI
2.7.2.1.1-1
2.7.2.1.1-1 in vitro
5.3.2.3.1 ****** FTD TPI Caco-2
5.3.2.2.5 12DA17 FTD TPI P-gp
P-gp FTD TPI
5.3.2.1.1 ******** FTD
5.3.2.1.2 ******** TPI
5.3.2.2.4 12DA05 FTD
FTD
5.3.2.3.2 11DA34 FTD TPI
5.3.2.3.3 11DA38 FTD
5.3.2.3.4 ******** TPI
5.3.2.2.2 ******** FTD TPI CYP
5.3.2.2.3 11DA19 FTD TPI CYP
5.3.2.2.1 12DA18 FTD TPI
2.7.2.1.2
TAS102-J001 FTD TPI TAS102-J004
2 TAS102-J001
TAS102-J001 I TAS102-9804
I 5 TAS102-9801
TAS102-9805 5.3.3.2.2 5.3.3.2.6 2.7.6
TAS102-J001 TAS102-J004 FTDTPI
/LC/MS/MS
TAS-102 FTD
TPI
2.7.1.1.4.1 2.7.1.2.3
TAS-102 2.7.2.1.2-1
-
2.7.2
2
2.7.2.1.2-1 TAS-102
TAS102-J001 06DA01
5.3.3.2.1
28 1 1 2 5 2 2 14 3070 mg/m2/
21
TAS102-J004 11DA23
5.3.1.1.1
*
A B 1 2 1 1 1 5 A 1 2 B 1 2 35 mg/m2/
A 8 B 8
*
2.7.2.2
2.7.2.2.1 in vitro
2.7.2.2.1.1
2.7.2.2.1.1.1 Caco-2
Caco-2 FTD TPI 5.3.2.3.1 2550
800 mol/L FTD AB Papp
1.41.30.7 0.410-6 cm/sec BA Papp
3.12.92.4 1.110-6 cm/sec 2550 400 mol/L TPI A
B BA Papp 0.20.310-6 cm/sec AB
Papp 24.610-6 cm/sec AB Papp 0.310-6 cm/sec
FTD TPI Papp
2.6.4.3.1
2.7.2.2.1.1.2 PP-gpP-gp
P P-gp Sf9
MDR1 14C-FTD 14C-TPI
5.3.2.2.5 N-
MDR1 ATP N-
14C-FTD 14C-TPI
N- FTD5500 mol/L TPI2200 mol/L
P-gp
N- 99%FTD TPI
FTDTPI P-gp
-
2.7.2
3
2.7.2.2.1.2
2.7.2.2.1.2.1
14C-FTD 14C-TPI
5.3.2.1.1 5.3.2.1.2 FTD 14C-FTD
FTD0.55 50 g/mL TPI 96.9%97.3%
96.7%TPI5 g/mL 97.0%97.0% 96.4%
TPI 14C-FTD 14C-TPI0.050.5 5 g/mLFTD 50 g/mL
8%
2.7.2.2.1.2.2 FTD
FTD
5.3.2.2.4 FTD 99.0%
0.55 50 g/mL FTD 99.0%99.0% 98.8%FTD
FTD FTD
93.1% 1 10 g/mL 0.2
2 g/mL 0.1 1 g/mL 93.0% 93.0%93.6%
93.2%93.0% 93.9% FTD
2.7.2.2.1.2.3
14C-FTD 14C-TPI /Rb 5.3.2.3.2
FTD 0.5550 g/mL Rb 0.6110.596 0.619 TPI 10100
1000 ng/mL Rb 0.6610.598 0.581 FTD TPI Rb
FTD TPI
2.7.2.2.1.3
2.7.2.2.1.3.1
Dexter 14C-FTD 27 mg/kg
FTY 5-5-CU
1
TAS-102 35 mg/m2/ FTDFTY 5-CU
FTDAUCinfFTY5-CUAUCinf30%0.3%5.3.1.1.1
5--2-5-CdUrd
5.3.2.3.3 FTY FTD
TAS-102 3070 mg/m2/day
TPI 6-6-HMU
5.3.2.3.4 TPI
-
2.7.2
4
2.7.2.2.1.3.2 in vitro
FTD TPI 14C-FTD
FTY 5-CU 5-CdUrd
5.3.2.2.1 5-CdUrd
14C-TPI
14C-FTD TPI TPI FTD
80%FTD TPase
TPI
2.7.2.2.1.3.3 P450CYP
P450CYPCYP1A2CYP2A6CYP2B6
CYP2C8CYP2C9CYP2C19CYP2D6CYP2E1 CYP3A4/5 FTD TPI
5.3.2.2.2 FTD TPI 0.3300 mol/L
0.1100 mol/L FTD TPI CYP 50%
300 mol/L 100 mol/L
FTD TPI CYP
2.7.2.2.1.3.4 CYP
FTD TPI 3 phenacetin O-deethylaseCYP1A2
midazolam 1-hydroxylaseCYP3A4/5 5.3.2.2.3 FTD
0.55.0 50 g/mL TPI 0.010.1 1 g/mL
FTDTPICYP1A2CYP3A4/5
FTD TPI CYP
2.7.2.2.2
2.7.2.2.2.1 TAS102-J001
21 TAS-102 30405060 70 mg/m2/day 1
2 5 2 2
TPI TAS-102
2.7.2.2.2.1.1 TAS-102
Day 1 Day 12 Day 5 FTDFTYTPI
2.7.2.2.2.1.1-1 2.7.2.2.2.1.1-4 FTDFTY TPI
2.7.2.2.2.1.1-1 2.7.2.2.2.1.1-3
FTD -AUC
2.6 2.7.2.2.2.1.1-2Day 1 tmax
1.21.7 1.31.9
Cmax AUC
t1/2 Day 1 1.21.9 Day 12 1.52.4 2.7.2.2.2.1.1-1
-
2.7.2
5
FTY Cmax
2.7.2.2.2.1.1-2Day 1 tmax 1.52.1 1.22.3
2.7.2.2.2.1.1-2Cmax AUC t1/2 Day 1 1.21.6 Day 12
4.69.6 Day 1 4
TPI 2.7.2.2.2.1.1-3Day 1 tmax 1.72.7 Day 12 2.32.8 2.7.2.2.2.1.1-3t1/2 Day 1 1.52.3
Day 12 1.84.0
2 ng/mL TAS-102
4.38.0 Cmax8.232 ng/mL 2.7.2.2.2.1.1-4
Day 12 Cmax 68128 ng/mL Day 1 Cmax 7.8
AUC0-10 8.6 t1/2 2.810 TPI
TPase Cmax FTD Cmax
1/111/77 1/40
Day 1 TAS-102 10 FTDFTY TPI Ae%
FTD 4%
FTY 23%TPI 20%
-
2.7.2
6
+ : 30 mg/m2/day: 40 mg/m2/day: 50 mg/m2/day: 60 mg/m2/day: 70 mg/m2/day 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.2-1
2.7.2.2.2.1.1-1 TAS-102 1 2 FTD TAS102-J001
+ : 30 mg/m2/day: 40 mg/m2/day: 50 mg/m2/day: 60 mg/m2/day: 70 mg/m2/day 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.2-2
2.7.2.2.2.1.1-2 TAS-102 1 2 FTY TAS102-J001
-2 0 21
10
100
1000
10000
0 2 4 6 8 10Time (hr)
Plas
ma
conc
entra
tion
ng
/mL
1
10
100
1000
10000
0 2 4 6 8 10Time (hr)
Day 1 Day 5 Day 12
-2 0 21
10
100
1000
10000
0 2 4 6 8 10Time (hr)
Plas
ma
conc
entra
tion
ng
/mL
1
10
100
1000
10000
0 2 4 6 8 10Time (hr)
Day 1 Day 5 Day 12
-
2.7.2
7
+ : 30 mg/m2/day: 40 mg/m2/day: 50 mg/m2/day: 60 mg/m2/day: 70 mg/m2/day 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.2-3
2.7.2.2.2.1.1-3 TAS-102 1 2 TPI TAS102-J001
+ : 30 mg/m2/day: 40 mg/m2/day: 50 mg/m2/day: 60 mg/m2/day: 70 mg/m2/day 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.2-4
2.7.2.2.2.1.1-4 TAS-102 1 2 TAS102-J001
0
1
10
100
1000
-2 0 20
1
10
100
1000
0 2 4 6 8 10Time (hr)
Plas
ma
conc
entra
tion
ng
/mL
0
1
10
100
1000
0 2 4 6 8 10Time (hr)
Day 1 Day 5 Day 12
0
1
10
100
1000
-2 0 2
0
1
10
100
1000
0 2 4 6 8 10Time (hr)
Plas
ma
conc
entra
tion
ng
/mL
0
1
10
100
1000
0 2 4 6 8 10Time (hr)
Day 1 Day 5 Day 12
-
2.7.2
8
2.7.2.2.2.1.1-1 TAS-102 1 2 FTD TAS102-J001
Dose
(mg/m2/day) Day n
Cmax
(ng/mL)
tmax
(hr)
AUC0-10
(nghr/mL)
t
(hr)
Ae
%
30 1 6 1009491 1.71.3 2037773 1.390.38a) 3.593.82
12 6 1205421 1.60.7 54782849 2.441.57 NA
40 1 3 1840737 1.20.8 4347535 1.170.15 4.855.61
12 3 2747610 1.70.6 99942109 1.520.34 NA
50 1 3 24501021 1.50.9 42811380 1.490.59 7.644.49
12 3 27571173 1.30.6 8656b) 1.960.10 NA
60 1 3 36771459 1.20.8 82291441 1.880.73 0.963b)
12 3 54371685 1.30.6 236727844 2.331.26 NA
70 1 6 3338767 1.30.5 86781786a) 1.410.38 3.693.42a)
12 6 47521697 1.91.6 209502237 1.970.51 NA a) n=5b) n=2NANot applicable 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.2-9 11.4.4.1.2-10
2.7.2.2.2.1.1-2 TAS-102 1 2 FTY TAS102-J001
Dose
(mg/m2/day) Day n
Cmax
(ng/mL)
tmax
(hr)
AUC0-10
(nghr/mL)
t
(hr)
Ae
%
t1/2 increase
rate
30 1 6 24883 2.11.6 993392 1.340.30 21.29.6 NA
12 6 19849 2.30.8 1301524 4.572.74 NA 3.281.37
40 1 3 45391 1.70.6 1740172 1.320.40 25.33.4 NA
12 3 3984 2.00.0 2259411 4.552.90 NA 3.241.05
50 1 3 64523 1.50.9 1901316 1.180.18 25.34.2 NA
12 3 470174 1.70.6 2401b) 4.792.50 NA 4.051.88
60 1 3 753293 1.50.9 2653537 1.620.32 11.9b) NA
12 3 51241 1.20.8 3095538 9.605.31 NA 6.274.36
70 1 6 878228 2.00.0 3165341a) 1.570.38 27.27.0a) NA
12 6 56092 2.31.4 36221094 7.272.95 NA 4.551.58a) a) n=5b) n=2NANot applicablet1/2 increase ratet1/2 Day 1 Day 12 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.2-11 11.4.4.1.2-12
-
2.7.2
9
2.7.2.2.2.1.1-3 TAS-102 1 2 TPI TAS102-J001
Dose
(mg/m2/day) Day n
Cmax
(ng/mL)
tmax
(hr)
AUC0-10
(nghr/mL)
t
(hr)
Ae
%
30 1 6 25.814.7 2.61.6 11784 2.270.74 19.412.2
12 6 44.151.8 2.81.5 234283 2.890.83 NA
40 1 3 43.16.5 1.70.6 16629 1.530.17 22.95.1
12 3 41.814.7 2.71.2 16141 1.820.18 NA
50 1 3 54.228.5 1.70.6 21479 1.780.27 20.09.6
12 3 50.213.1 2.71.2 300b) 4.013.57 NA
60 1 3 13677 2.71.2 521338 1.660.37 20.0b)
12 3 99.643.8 2.71.2 447278 2.210.62 NA
70 1 6 76.632.1 2.30.8 28199a) 1.670.22 19.07.5a)
12 6 70.043.4 2.30.8 317182 2.370.93 NA a) n=5b) n=2NANot applicable 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.2-13 11.4.4.1.2-14
2.7.2.2.2.1.2
TAS-102 Day 1 FTD TPI Cmax AUC 2.7.2.2.2.1.2-1
2.7.2.2.2.1.2-2 2.7.2.2.2.1.2-1
2.7.2.2.2.1.2-2 Day 1 FTD TPI AUC0-10
2.7.2.2.2.1.2-3
Day 1Day 12 FTDTPICmaxAUC
2.7.2.2.2.1.2-1 2.7.2.2.2.1.2-2
LOF CmaxAUC
2.7.2.2.2.1.2-1FTD a Cmax AUC b
Cmax95% 0 AUC AUC0-10 0 FTD
Cmax AUC 95%
Cmax 1 AUC 1 FTD
FTD AUC0-10 4070 mg/m2/day
2.7.2.2.2.1.2-3
TPI Cmax AUC a b
95% 0
CmaxAUC
95% 1 2.7.2.2.2.1.2-2TPI
Day 1 FTD TPI AUC0-10
2.7.2.2.2.1.2-3TPI FTD 30 mg/m2/day
4070 mg/m2/day 70 mg/m2/day
-
2.7.2
10
normalized AUC0-10 30%CV12%32%
FTD AUC
AUC 4070 mg/m2/day
TPI
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.3-1
2.7.2.2.2.1.2-1 Day 1 FTD CmaxAUC0-10 AUCinfTAS102-J001
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.3-2
2.7.2.2.2.1.2-2 Day 1 TPI CmaxAUC0-10 AUCinfTAS102-J001
R2 = 0.623
0
1000
2000
3000
4000
5000
6000
0 10 20 30 40 50 60 70 80
Cm
ax(n
g/m
L)
Dose (mg/m2/day)
R2 = 0.818
0
2000
4000
6000
8000
10000
12000
0 10 20 30 40 50 60 70 80
AU
C 0-
10(n
g.hr
/mL)
Dose (mg/m2/day)
R2 = 0.793
0
2000
4000
6000
8000
10000
12000
0 10 20 30 40 50 60 70 80
AU
Cin
f(n
g.hr
/mL)
Dose (mg/m2/day)
R2 = 0.327
0
50
100
150
200
250
0 10 20 30 40 50 60 70 80
Dose (mg/m2/day)
Cm
ax (n
g/m
L)
R2 = 0.279
0
200
400
600
800
1000
0 10 20 30 40 50 60 70 80
Dose (mg/m2/day)
AU
C 0
-10 (
ng.h
r/mL)
R2 = 0.269
0
200
400
600
800
1000
0 10 20 30 40 50 60 70 80Dose (mg/m2/day)
AU
Cin
f (ng
.hr/m
L)
-
2.7.2
11
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.3-5
2.7.2.2.2.1.2-3 TAS-102 Day 1 FTD TPI AUC0-10 TAS102-J001
2.7.2.2.2.1.2-1 FTD TPI TAS102-J001
FTD
Parameter R2 Intercept Slope LOF
estimate 95%CI p-value estimate 95%CI p-value p-value
Cmax 0.623 -355 -1440734 0.503 56.3 35.377.4
-
2.7.2
12
2.7.2.2.2.1.2-2 FTD TPI TAS102-J001
FTD
Parameter R2 LOF
Estimate 95%CI p-value p-value
Cmax 0.697 1.33 0.9121.76
-
2.7.2
13
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.5-3
2.7.2.2.2.1.3-1 1 % Day 12 FTD CmaxTAS102-J001
-100
-80
-60
-40
-20
0
100 1000 10000Cmax (ng/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
100 1000 10000Cmax (ng/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
20
100 1000 10000Cmax (ng/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
100 1000 10000Cmax (ng/mL)
Perc
ent C
hang
e (%
)
p
-
2.7.2
14
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.5-4
2.7.2.2.2.1.3-2 1 % Day 12 FTD AUC0-10TAS102-J001
-100
-80
-60
-40
-20
0
1000 10000 100000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
1000 10000 100000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
20
1000 10000 100000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
20
1000 10000 100000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
p
-
2.7.2
15
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.5-5
2.7.2.2.2.1.3-3 1 % Day 12 TPI CmaxTAS102-J001
-100
-80
-60
-40
-20
0
10 100 1000Cmax (ng /mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
10 100 1000Cmax (ng /mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
20
10 100 1000Cmax (ng /mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
10 100 1000Cmax (ng /mL)
Perc
ent C
hang
e (%
)
Platelets Hemoglobin
WBC Neutrophil p
-
2.7.2
16
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.5-6
2.7.2.2.2.1.3-4 1 % Day 12 TPI AUC0-10TAS102-J001
-100
-80
-60
-40
-20
0
10 100 1000 10000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
10 100 1000 10000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
20
10 100 1000 10000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
20
10 100 1000 10000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
Platelets Hemoglobin
WBC Neutrophil
p
-
2.7.2
17
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.5-7
2.7.2.2.2.1.3-5 1 % Day 12 FTY CmaxTAS102-J001
-100
-80
-60
-40
-20
0
100 1000Cmax (ng/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
100 1000Cmax (ng/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
20
100 1000Cmax (ng/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
100 1000Cmax (ng/mL)
Perc
ent C
hang
e (%
)
WBC Neutrophil
Platelets Hemoglobin
p=0.312
p=0.249
p
-
2.7.2
18
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.5-8
2.7.2.2.2.1.3-6 1 % Day 12 FTY AUC0-10TAS102-J001
-100
-80
-60
-40
-20
0
100 1000 10000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
100 1000 10000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
20
100 1000 10000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
-100
-80
-60
-40
-20
0
100 1000 10000AUC0-10 (ng.hr/mL)
Perc
ent C
hang
e (%
)
WBC Neutrophil
Platelets Hemoglobin
p
-
2.7.2
19
2.7.2.2.2.1.3-1 1 % Day 12 TAS102-J001
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.5-3
Compound PK Parameter Percent Change of Hematorogic Parameters - Course 1Neutrophil WBC Platelets Hemoglobin
FTD Course 1, Day 12 (AM Dose)AUC0-10 (ng.hr/mL)
N 20 20 20 20R -0.753 -0.610 -0.440 -0.187
p-value 0.0001 0.0043 0.0520 0.431
Cmax (ng/mL)N 21 21 21 21R -0.678 -0.536 -0.309 -0.144
p-value 0.0007 0.0122 0.173 0.532
FTY Course 1, Day 12 (AM Dose)AUC0-10 (ng.hr/mL)
N 20 20 20 20R -0.675 -0.546 -0.348 -0.265
p-value 0.0011 0.0127 0.133 0.259
Cmax (ng/mL)N 21 21 21 21R -0.611 -0.485 -0.232 -0.263
p-value 0.0033 0.0259 0.312 0.249
TPI Course 1, Day 12 (AM Dose)AUC0-10 (ng.hr/mL)
N 20 20 20 20R -0.570 -0.558 -0.541 -0.446
p-value 0.0087 0.0106 0.0138 0.0487
Cmax (ng/mL)N 21 21 21 21R -0.631 -0.600 -0.535 -0.347
p-value 0.0022 0.0040 0.0125 0.124
p
-
2.7.2
20
2.7.2.2.2.1.3-2 1 % Day 12 TAS102-J001
5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.5-5
2.7.2.2.2.1.4 TPI
TPI 6-HMU
5.3.2.3.45070 mg/m2/day 2 8 12 ng/mL 6-HMU
010 6-HMU 50 ng/mL
TAS-102 50 mg/m2/day 70 mg/m2/day
UV MS
TPI
Compound PK Parameter Percent Change of Hematorogic Parameters - Course 1Neutrophil WBC Platelets Hemoglobin
FTD Course 1, Day 12 (AM Dose)AUC0-10 (ng.hr/mL)
N 20 20 20 20R -0.781 -0.653 -0.584 -0.295
p-value
-
2.7.2
21
2.7.2.2.2.2 TAS102-J004
FTD TPI 2.7.1.2.1
TAS-102
2 2 16
A B 2
1 35 mg/m2 TAS-102 12
4
FTD TPI B 2
2.7.2.2.2.2.1
FTD TPI 2.7.2.2.2.2.1-1 FTY 5-CU
2.7.2.2.2.2.1-2 2.7.2.2.2.2.1-1
FTD Cmax 2.7.2.2.2.2.1-1Cmax
FTD AUC
2.7.2.2.2.2.1-1 Cmax
AUC FTD
TPI Cmax AUC 2.7.2.2.2.2.1-1
FTY Cmax 2.7.2.2.2.2.1-2Cmax FTY
AUCinf 2.7.2.2.2.2.1-1
5-CU Cmax AUC 2.7.2.2.2.2.1-2
FTDFTY 5-CU AUCinf 109432972 32 nghr/mL
2.7.2.2.2.2.1-1FTD AUCinf FTY 5-CU AUCinf
30% 0.3%
FTD AUC0-12AUCinf AUC0-t/ 90%
0.81.25FTD CmaxTPI Cmax TPI AUC
90%
FTD
TPI tmax
FTD AUC FTD CmaxTPI Cmax AUC
40%
TAS-102 FTD AUC
FTD TPI TAS-102
TAS102-J001 FTD
Cmax Cmax
TAS-102
-
2.7.2
22
Linear scale
Logarithmic scale
+ : n=14: n=14 5.3.1.1.1 TAS102-J004 CSR 11.4.2.1-1 11.4.2.1-2
2.7.2.2.2.2.1-1 TAS-102 FTD TPI TAS102-J004
-
2.7.2
23
Linear scale
Logarithmic scale
+ : n=14: n=14 5.3.1.1.1 TAS102-J004 CSR 11.4.2.2-1 11.4.2.2-2
2.7.2.2.2.2.1-2 TAS-102 FTY 5-CU TAS102-J004
-
2.7.2
24
2.7.2.2.2.2.1-1 TAS-102 TAS102-J004
Food
condition
n Cmax
ng/mL
tmax
hr
AUC0-t
nghr/mL
AUC0-12
nghr/mL
AUCinf
nghr/mL
t1/2
hr
FTD Fasting 14 56301840 0.880.42 106475012 106485011 109435581 2.130.76
Fed 14 35101380 1.320.93 98404247 98404247 100824593 1.720.58
TPI Fasting 14 13539 2.070.92 647281 647281 677309 2.190.66
Fed 14 76.826.3 2.791.37 361160 361160 384189 2.220.45
FTY Fasting 14 860207 1.430.51 2899838 2900837 2972868 2.410.61
Fed 14 728186 1.961.01 3011856 3011855 3121941 2.080.69
5-CU Fasting 14 2.931.69 4.431.79 168 178 328a) 3.910.60a)
Fed 14 2.320.57 4.861.29 147 157 2910b) 4.841.18b)
a) n=4b) n=5 5.3.1.1.1 TAS102-J004 CSR 11.4.2.1-5 11.4.2.1-6 11.4.2.1-7 11.4.2.1-8 11.4.2.2-5 11.4.2.2-6 11.4.2.2-7 11.4.2.2-8
2.7.2.2.2.2.2 FTD
TAS102-J004 FTD UV-VIS
LC/MS/MS TAS-102 UV MS
TAS-102 5.3.2.3.3 UV
FTY Multiple Reaction MonitoringMRM
5-CU 5-CdUrd FTY
FTD Selected Ion Monitoring Precursor Ion
Scan FTD
FTY 5-CU 5-CdUrd
5.3.2.3.3 No. 11DA38 Fig.A
2.7.2.2.2.2.2-1 FTD TAS102-J004
O
OH
HO
N
HN
O
O
COOH
HN
NH
O
O
CF3HN
NH
O
O
COOH
FTD 5-CdUrd
FTY 5-CU
O
OH
HO
N
HN
O
O
CF3
-
2.7.2
25
2.7.2.3
2.7.2.3.1
TAS102-J001 I TAS102-9804
TAS102-9804 5060 80 mg/m2/day
50 60 mg/m2/dayTAS-102FTDTPI
tmaxCmaxAUC t1/2 2.7.2.3.1-1 3070
mg/m2/day 5080 mg/m2/day Day 1 Day 12 FTD
TPI Cmax AUC 2.7.2.3.1-1 2.7.2.3.1-2Day 1
Day 12 FTD TPI
FTD AUC
TAS102-J001 1 1 TAS102-9801
TAS102-9802 Day 1 2.7.2.3.1-2 FTD
FTY TPI
I
-
2.7.2
26
2.7.2.3.1-1 TAS-102 50 60 mg/m2/day 1 2
TAS102-J001 TAS102-9804 Day Compound Dose Country n PK parameters
mg/m2/day tmaxhr Cmax
ng/mL
AUC
nghr/mLa)
t1/2
(hr)
1 FTD 50 Japan 3 1.50.9 24501021 42971387 1.490.59
USA 7 1.20.6 23211067 46601165b) 1.100.27 b)
60 Japan 3 1.20.8 36771459 84351645 1.880.73
USA 3 1.00.9 44002090 65991337 1.400.57
FTY 50 Japan 3 1.50.9 64523 1915327 1.180.18
USA 7 1.40.5 691225 2263420 1.200.17
60 Japan 3 1.50.9 753293 2710559 1.620.32
USA 3 1.20.8 978237 3011560 1.170.25
TPI 50 Japan 3 1.70.6 54.228.5 22279 1.780.27
USA 7 2.71.3 71.839.4 277174b) 1.570.33 b)
60 Japan 3 2.71.2 13677 542360 1.660.37
USA 3 1.70.6 83.322.3 310102 1.900.18
12 FTD 50 Japan 3 1.30.6 27571173 8656c) 1.960.10
USA 7 1.00.5 46731368 147613892 1.620.49
60 Japan 3 1.30.6 54371685 236727844 2.331.26
USA 3 1.70.6 4293880 209122028 1.800.81
FTY 50 Japan 3 1.70.6 470174 2401 c) 4.792.50
USA 7 1.50.6 49552 2820562 3.250.86
60 Japan 3 1.20.8 51241 3095538 9.605.31
USA 3 1.70.6 527110 3867804 5.343.52
TPI 50 Japan 3 2.71.2 50.213.1 300c) 4.013.57
USA 7 2.01.0 69.131.4 266134b) 3.300.98 b)
60 Japan 3 2.71.2 99.643.8 447278 2.210.62
USA 3 2.00.0 54.014.2 25848 2.630.27
a) Day 1 AUCinfDay 12 AUC0-10 AUC0-12 b) n=6 c) n=2 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.2-9 11.4.4.1.2-14 2.7.6.6.4.7.1 p157p159 2.7.6.6.4.7.1-1 2.7.6.6.4.7.1-3
-
2.7.2
27
2.7.2.3.1-2 TAS-102 Day 1 % TAS102-J001 TAS102-9801 TAS102-9802
Dose
mg/m2/day
n FTD FTY TPI
Japan 30 6 3.593.82 21.29.6 19.412.2
(0-10 hr)a) 40 3 4.855.61 25.33.4 22.95.1
50 3 7.644.49 25.34.2 20.09.6
60 2 0.963 11.9 20.0
70 5 3.693.42 27.27.0 19.07.5
USA b) 50 6 5.724.64 17.75.3 19.211.4
(0-24 hr)a) 60 4 5.246.92 33.429.9 50.430.3
100 2 1.00d) 6.46 2.46
USA c) 50 2 2.18 24.2 32.6
(0-24 hr) a) 70 6 2.231.40 30.610.7 21.08.4
80 2 3.01 25.2 29.5
90 3 3.463.29 18.57.6 31.413.8
100 4 6.905.60 19.310.5 16.37.3
110 2 2.80 14.6 24.0
a) b) TAS102-9801 c) TAS102-9802 d) n=1, 5.3.3.2.2 TAS102-9801 PK/PD Report Appendix 5 Table 16.5 % 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.6-2
-
2.7.2
28
3070 mg/m2/day
30 mg/m2/day FTD 4/5 FTD AUCinf 4/5 1 TPI 5/6 24 mg/m2/day
5080 mg/m2/day 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.6-1
2.7.2.3.1-1 TAS-102 1 2 Day 1 TAS102-J001 TAS102-9804
0
50
100
150
200
250
0 10 20 30 40 50 60 70 80
Dose (mg/m2/day)
Cm
ax (n
g/m
L)
0
200
400
600
800
1000
1200
0 10 20 30 40 50 60 70 80Dose (mg/m2/day)
AU
Cin
f (ng
.hr/m
L)
0
2000
4000
6000
8000
10000
12000
0 10 20 30 40 50 60 70 80Dose (mg/m2/day)
Cm
ax (n
g/m
L)
02000400060008000
10000120001400016000
0 10 20 30 40 50 60 70 80Dose (mg/m2/day)
AU
Cin
f (ng
.hr/m
L)
FTD, Cmax FTD, AUCinf
TPI, AUCinf TPI, Cmax
-
2.7.2
29
3070 mg/m2/day
30 mg/m2/day 5/6 24 mg/m2/day
5080 mg/m2/day a) AUC0-10AUC0-12 5.3.3.2.1 TAS102-J001 CSR 11.4.4.1.6-2
2.7.2.3.1-2 TAS-102 1 2 Day 12 TAS102-J001 TAS102-9804
2.7.2.3.2
2.7.2.3.2.1
TAS-102
FTD
( 2.6.4.6.3 ) 5.3.2.1.1 FTD
TPI
2.6.4.6.3 TPI FTD
FTD
020406080
100120140160
0 10 20 30 40 50 60 70 80Dose (mg/m2/day)
Cm
ax (n
g/m
L)
0100200300400500600700800900
0 10 20 30 40 50 60 70 80Dose (mg/m2/day)
AU
C (n
g.hr
/mL)
010002000300040005000600070008000
0 10 20 30 40 50 60 70 80Dose (mg/m2/day)
Cm
ax (n
g/m
L)
0
500010000
15000
20000
2500030000
35000
0 10 20 30 40 50 60 70 80Dose (mg/m2/day)
AU
C (n
g.hr
/mL)
FTD, Cmax FTD, AUCa)
TPI, Cmax TPI, AUCa)
-
2.7.2
30
TAS-102
TAS-102
TAS-102 4.2.3.2.2 4.2.3.2.10
2.7.2.3.2.2
2.7.2.3.2.2.1
TAS102-J004 TAS-102 FTD AUC
FTD CmaxTPI Cmax AUC 40%
FTD AUC FTD TPI
TAS-102
TAS102-J001 FTD Cmax
Cmax TAS-102
2.7.2.3.2.2.2
TAS-102 FTD FTY 5-CU
FTD AUCinf FTY 5-CU AUCinf 30% 0.3%FTY
5.3.1.1.1 FTD FTY 5-CU
5-CdUrd FTD
FTY5-CU 5-CdUrd 5-CdUrd 5.3.2.2.1
FTD TPI 80% TPase
TAS-102 FTD FTY
4% 23%FTD 5.3.3.2.1
FTD FTY TAS-102
TPI 6-HMU
TPI 6-HMU 5.3.3.2.1
TAS-102 TPI 20%TPI
FTDTPICYP1A2CYP2A6CYP2B6
CYP2C8CYP2C9CYP2C19CYP2D6CYP2E1 CYP3A4/5
5.3.2.2.2 FTD TPI CYP1A2 CYP3A4/5
FTD TPI CYP
P-gp Sf9 MDR1
FTD TPI P-gp 5.3.2.2.5
FTD TPI P-gp FTD
TPI P-gp
FTD 96.4%97.3%FTD
5.3.2.1.1 in vitro FTD
5.3.2.2.4 FTD
-
2.7.2
31
FTD FTD
TAS-102 TPI
TAS-102 70 mg/m2/day
Day 1 0.331 L/hr/kg 5.3.3.2.1 TPI 8%
5.3.2.1.2
GFR 0.125 L/hr/kg TPI
GFR 2 TPI
2.7.2.4
-
T15 T20
2 2CTD
2.7.3
-
2.7.3
2.7.3 .............................................................................................. 1 2.7.3.1 .................................................................................... 1 2.7.3.2 .................................................................... 4
2.7.3.2.1 TAS102-J003 II ...................................................................................................... 4
2.7.3.2.2 TAS102-J001 I ...................................... 9 2.7.3.3 ........................................... 13
2.7.3.3.1 ............................................................................. 13 2.7.3.3.2 .............................................. 19 2.7.3.3.3 .................................................. 26
2.7.3.4 .................................... 40 2.7.3.5 ...................................................................... 40 2.7.3.6 ................................................................................................. 41
-
2.7.3
5-FU 5-fluorouracil5-
AUC area under the concentration-time curve-
BSC best supportive care
Cmax maximum plasma concentration
CPT-11 irinotecan hydrochloride
CR complete response
DCR disease control rate
DLT dose limiting toxicity
ECOG Eastern Cooperative Oncology Group
EGFR epidermal growth factor receptor
FAS full analysis set
FOLFIRI LV/5-FU/CPT-11/5-/
FOLFOX LV/5-FU/L-OHP/5-/
FTD trifluridine
FTY 5-(trifluoromethyl)uracil
KRAS v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
MST median survival time
MTD maximum tolerated dose
NE not evaluable
ORR overall response rate
OS overall survival
PD progressive disease
PFS progression free survival
PGx pharmacogenomics
PR partial response
PS performance status
RECIST Response Evaluation Criteria in Solid Tumors
SD stable disease
TK thymidine kinase
tmax maximum concentration time
TPase thymidine phosphorylase
TPI tipiracilthymidine phosphorylase inhibitor
TTF time to treatment failure
-
2.7.3
1
2.7.3
2.7.3.1
II TAS102-J003 1
I
TAS102-J001 TAS102-J003
TAS102-J003
2.7.3.1-1 *******
CPT-11
I TAS102-J002
1.5.4.1 II TAS102-9806
2.7.3.6
2.7.3.1-1 TAS-102
mg/m2/day
TAS102-
J003 II
28 1 5 2 2 14 1 2 70
TAS-102,
OS
PFSTTFORRDCR,
KRAS
PGx
169
TAS102-
J001 I
28 1 5 2 2 14 1 2 30, 40, 50, 60, 70
TAS-102
OSPFS TTF
ORR
21 *
* 21 18 OS: PFS: TTF: ORR: DCR: PGx:
TAS-102 FTDTPI
KM20C
5-5-FUCPT-11
*****
I 5
TAS102-9801 TAS102-9802 TAS102-9803 TAS102-9804 TAS102-9805
28 1 1 2 5 2
2 14
106 43 SD
-
2.7.3
2
1 42 5-FU
5-FU
*******
I TAS102-J001
70 mg/m2/day35 mg/m21 2
85.7%18/21 3.4
26 3 4 III
TAS-102 3 5070 mg/m2/day
12 OS 10.9
OS 5-FU
CPT-11
TAS102-J001 FOLFOX
FOLFIRI 3 2
CPT-11 3
TAS-102 OS
II TAS102-J003
TAS102-J003 TAS-102 OS OS
TAS-102 9.0 6.6 0.5695% 0.39
0.81p = 0.0011
2.7.3.1-2
2.7.3.1-2 TAS102-J003 TAS102-J001
OS
PFSTTFORRDCR
OSPFSTTFORR
RECIST Version 1.0 1.1 Version 1.0 Version 1.1
RECIST Version 1.0
RECIST
OS
12
121
OS
*********
-
2.7.3
3
TAS102-J003 TAS102-J001 ******** PFS PD
PD
PD ********* RECIST********
********
*******
PFS PD PD PD PD PD
PD PD PD
PD
TTF PD
TTF
PD PD
PD
(1) CR PR
PD
(2) CR PD
1 PD
(1) CR PR
PD
(2) CR PD
OS: PFS: TTF: ORR: DCR: RECIST:Response Evaluation Criteria in Solid TumorsPD: CR: PR:
-
2.7.3
4
2.7.3.2
2.7.3.2.1 TAS102-J003 II
2.7.3.2.1.1
1
2 CPT-11
3
TAS-102 70 mg/m2/day35 mg/m21 2
II
TAS-102 21
Eastern Cooperative Oncology Group performance statusECOG PS012
2
20 ECOG PS 02
3
TAS-102 28 1 1 2
5 2 2 14
Response Evaluation Criteria in Solid TumorsRECIST 12 4
8
4
OS
best supportive careBSC
III CO.17 3OS 6.1 4.6
BSC III 20020408 4OS
6.4 6.3 TAS-102 I
TAS102-J001 3 5070 mg/m2/day OS
10.9 TAS102-J001 85.7%
3.4 26
III
OS
II I
II
CPT-11 3
OS
TAS102-J001 OS *******
-
2.7.3
5
1.13.1 OS
*******************************************************************************
********************************
*******************************************************************************
************************************
PFSTTF
ORRDCR
PGx KRAS
TK1 TPase
%tail DNA
5
FAS 1
FAS OS 10%
Kaplan-Meier
MST 80% Cox
80%MST
95%
aPFS
FAS Kaplan-Meier
PFS PFS 95%
Cox 95%
bTTF
FAS Kaplan-Meier
TTF TTF 95%
Cox 95%
cORR
FAS ORR 95% Fisher
FAS
dDCR
CRPR SD
6
-
2.7.3
6
FAS DCR 95% Fisher
FAS
e
FAS
2.7.3.2.1.2
172 TAS-102 114 58
TAS-102 1 TAS-102
113 58 1
FAS TAS-102 112 57 KRAS
TAS-102 99 50 2.7.3.2.1.2-1
5.3.5.1.1 TAS102-J003 CSR 10.1.1-1
2.7.3.2.1.2-1 TAS102-J003
KRAS TAS-102 99 54 45
50 24 26 2.7.3.2.1.2-1
All Enrolled Patients 172
TAS-102 Placebo 114 58
Ineligible Patients Ineligible Patients 1 0
Eligible Patients Eligible Patients 113 58
Eligible but Untreated Eligible but Untreated 1 1
FAS FAS 112 57
-
2.7.3
7
2.7.3.2.1.2-1 KRAS TAS102-J003
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.6.1-1
2.7.3.2.1.3
TAS-102
63.0 2880 62.0 3979 1.5630 m21.1472.078 m2
1.5740 m21.2771.929 m2 64 57.1% 28
49.1% 48 42.9% 29 50.9%ECOG PS 0 72 64.3% 35 61.4%
ECOG PS 1 37 33.0% 21 36.8%ECOG PS 2 3 2.7% 1 1.8%
108 96.4% 57 100.0%
2.7.3.2.1.4
TAS-102 63 56.3% 36
63.2% 49 43.8% 21 36.8% 47 42.0% 29
50.9% 65 58.0% 28 49.1% 1
2 111 55 7466.1%
33 57.9% 31 27.7% 17 29.8%
95 84.8% 49 86.0%
TAS-102 10392.0% 50 87.7%
54 48.2% 15 26.3%EGFR
71 63.4% 36 63.2% 87
KRAS TAS-102(N= 112) Placebo(N= 57) Inspection Method Mutation N (%) N (%) P Value *
Total Wild 58 (51.8) 28 (49.1) F:0.743 Mutation 51 (45.5) 28 (49.1)
Scorpion arms Total 99 (88.4) 50 (87.7) Wild 54 (54.5) 24 (48.0) F:0.490 Mutation 45 (45.5) 26 (52.0) Gly12Ala 1 (1.0) 1 (2.0) Gly12Asp 23 (23.2) 12 (24.0) Gly12Cys 1 (1.0) 2 (4.0) Gly12Ser 2 (2.0) 2 (4.0) Gly12Val 7 (7.1) 6 (12.0) Gly13Asp 11 (11.1) 3 (6.0)
Direct Sequence Total 46 (41.1) 26 (45.6) Wild 21 (45.7) 14 (53.8) Mutation 24 (52.2) 12 (46.2)
ARMS-PCR Total 5 (4.5) 5 (8.8) Wild 2 (40.0) 2 (40.0) Mutation 3 (60.0) 3 (60.0)
ARMS-Clumping Total 0 (0.0) 0 (0.0) Wild 0 0 Mutation 0 0
Others Total 6 (5.4) 6 (10.5) Wild 1 (16.7) 2 (33.3) Mutation 5 (83.3) 4 (66.7)
Analysis Set: FAS*:Fisher's Exact Test
-
2.7.3
8
77.7% 47 82.5%TAS-102
2 17 15.2% 13 22.8%3
46 41.1% 16 28.1%4 30 26.8% 12 21.1%
FOLFOXFOLFIRI
CPT-11+ 50%
2.7.3.2.1.5
TAS-102 34.7 16.4 25.0
10.0 3647.4 1743.2 mg 2592.5 1100.0 mg
2.7.3.2.1.6 Dose Intensity
TAS-102 Actual Dose Intensity 142.28
165.54 mg/m2/week 147.35 168.61 mg/m2/week Relative Dose Intensity
83.24 97.00 mg/m2/week 85.71 100.00 mg/m2/weekRelative Dose
Intensity 80% 81 72.3% 54 94.7%
2.7.3.2.1.7
*********TAS-102
108 96.4% 57 100.0%
99 56
2.7.3.2.1.8 OS
*******TAS-102 7567.0%
48 84.2%
OS TAS-102 9.0 95% 7.311.3
6.6 95% 4.98.0 TAS-102
0.5695% 0.390.81p = 0.0011
OS ECOG PS 0 TAS-102 10.3
8.0 0.5595% 0.340.89p = 0.013ECOG PS 1
2 TAS-102 7.2 3.7
0.5495% 0.300.96p = 0.033
2.7.3.2.1.9 PFS
PFS TAS-102 2.0
1.0 0.4195% 0.280.59p < 0.0001
PFS TAS-102 2.7 1.0
0.3495% 0.240.49p < 0.0001
2.7.3.2.1.10 TTF
TTF TAS-102 1.9
1.0 0.4095% 0.280.56p < 0.0001
-
2.7.3
9
TTF TAS-102 2.7 1.0
0.3495% 0.240.49p < 0.0001
2.7.3.2.1.11 ORRDCR
TAS-102 PR 1
ORR 0.9%95% 0.04.9
DCRTAS-10243.8%95%34.453.4
10.5%95% 4.021.5p < 0.0001
DCR TAS-102 54.5%95% 44.863.9 14.0%
95% 6.325.8p < 0.0001
2.7.3.2.1.12
*********
TAS-102 109 56
TAS-102 PR 1
0 CR
0 TAS-102
80.0 2472 29.0 14184 p < 0.0001
2.7.3.2.1.13
OS TAS-102
9.0 95 % 7.311.3 6.6 95% 4.98.0 TAS-102
0.5695% 0.390.81
p = 0.0011
OS TAS-102
9.0 6.0
2.7.3.2.2 TAS102-J001 I
2.7.3.2.2.1
1
TAS-102 1 2 5 2 2 14
I
54 3 6 24
2.7.3.2.2.1-1
-
2.7.3
10
2.7.3.2.2.1-1 TAS102-J001 1 30 mg/m2/day 2 40 mg/m2/day 3 50 mg/m2/day 4 60 mg/m2/day
4 10 mg/m2/day
DLT
3 DLT 3 1
3
1 DLT 3 2 46 2
MTD 1
MTD MTD
2.7.3.2.2.1-2
2.7.3.2.2.1-2 TAS102-J001
DLT MTD
0/3 1/3
2/3 MTD 1/6
2/6 MTD
2
ECOG PS 02 20 74
3
28 1 TAS-102 1 2 5 2
2 14
RECIST46
4
DLT 2.7.6.2.6
OSPFSTTFDCR
5
FAS 1
DLT DLT
-
2.7.3
11
aOS
FAS Kaplan-Meier MST 95%
bPFS
FAS Kaplan-Meier PFS PFS
cTTF
FAS Kaplan-Meier TTF TTF
d
FAS ORR
FAS ORR
2.7.3.2.2.2
21 130 mg/m2/day 2
40 mg/m2/day 350 mg/m2/day 460 mg/m2/day 570 mg/m2/day
1 5 6 3 21
1 DLT 1
2.7.3.2.2.3
FAS 21 14 7 59.0 3868
1.5460 m2 1.1042.050 m2 TAS-102
52.11 mg/m2/day 27.271.9 mg/m2/dayECOG PS 0 16 76.2%ECOG PS 1
4 19.0%ECOG PS 2 1 4.8% 19 90.5%
2.7.3.2.2.4
4 19.0% 17 81.0%
6 28.6% 12 57.1% 1 4.8% 1 4.8%
1 4.8% 6 28.6%
12 57.1% 2 9.5% 1 4.8%
2.7.3.2.2.5
TAS-102 30.2 30.0 10100
2464.8 mg 1755.0 mg 3008955 mg
-
2.7.3
12
2.7.3.2.2.6 Dose Intensity
TAS-102Dose Intensity111.52 mg/m2/week120.94 mg/m2/week
Relative Dose Intensity 90.45 mg/m2/week 97.67 mg/m2/week Relative
Dose Intensity 80% 17 81.0%
2.7.3.2.2.7
2.7.3.2.2.8 OS
***********Kaplan-Meier FAS 21 OS
10.0 95% 7.612.0 1
2 3 4 5 3.8 95% 2.411.3 10.3
95% 9.512.8 10.0 95% 4.312.8 13.7 95%
9.4 10.4 95% 7.612.0
29.595% 2.811.33 10.9
95% 9.012.8
18 OS 9.8 95% 7.612.0
6 12 12.5 95% 9.5
14.7 8.3 95% 4.310.3
2.7.3.2.2.9 PFSTTF
PFS TTF
FAS 21 PFS 1 2 3 4 5
36.0 57.0 71.0 99.0 96.0 2 3
47.0 92.5
2.7.3.2.2.10
FAS 21 SD 11 PD 10 ORR 0%
1 2 3 4 5 SD
2 1 1 3 4 PD 4 2 2 0 2
CR PRDCR CRPR
SD 6
FAS 21 DCR 52.4% 1 2
3 4 5 33.3%33.3%33.3%100.0% 66.7%
2.7.3.2.2.11
CR PR
2.7.3.2.2.12
FAS 21 CR 0 PR 0
SD 11 PD 10 NE 0 DCR 52.4%
-
2.7.3
13
PFS 2 3 47.0 92.5
TAS102-9804 50 mg/m2/day
3 2 PFS
OS 10.0 2 3
3 2 OS
18 85.7% 3.4
26 5-FU CPT-11
3
2.7.3.3
TAS102-J003 TAS102-J001
18
TAS102-J003
2.7.3.3.1
2.7.3.3.1.1
1TAS102-J003
TAS-102
63.0 2880 62.0 3979 1.5630 m21.1472.078 m2
1.5740 m21.2771.929 m2 64 57.1% 28
49.1% 48 42.9% 29 50.9%ECOG PS 0 72 64.3% 35 61.4%
ECOG PS 1 37 33.0% 21 36.8%ECOG PS 2 3 2.7% 1 1.8%
108 96.4% 57 100.0%
2.7.3.3.1.1-1
-
2.7.3
14
2.7.3.3.1.1-1 TAS102-J003
5.3.5.1.1 TAS102-J003 CSR 11.2-1
TAS-102(N= 112) Placebo(N= 57)N (%) N (%) P Value *
Gender Male 64 ( 57.1) 28 ( 49.1) F:0.333 Female 48 ( 42.9) 29 ( 50.9) Age(years) N 112 57 t:0.771 Mean(S.D.) 62.0(9.8) 62.4(8.6) Median 63.0 62.0 Range[Min , Max] [28,80] [39,79] Age Category 1(years)
-
2.7.3
15
2TAS102-J001
18 12 6 59.5 3868
1.5365 m2 1.2622.050 m2ECOG PS 0 14 77.8%ECOG
PS 1 4 22.2% 16 88.9% 2.7.3.3.1.1-2
2.7.3.3.1.1-2 TAS102-J001
5.3.5.4.1 TAS102-J001 CTD 11.1-1
2.7.3.3.1.2
1TAS102-J003
TAS-102 63 56.3% 36
63.2% 49 43.8% 21 36.8% 47 42.0% 29
50.9% 65 58.0% 28 49.1% 1
2 111 55 7466.1%
33 57.9% 31 27.7% 17 29.8%
95 84.8% 49 86.0%
2.7.3.3.1.2-1
N (%) N (%) N (%) N (%) N (%) N (%)Gender 4 (80.0) 3 (100.0) 2 (66.7) 1 (50.0) 2 (40.0) 12 (66.7) 1 (20.0) 0 (0.0) 1 (33.3) 1 (50.0) 3 (60.0) 6 (33.3)
Age (years)N 5 3 3 2 5 18 Mean (S.D.) 56.8 (5.9) 57.7 (8.3) 51.0 (12.1) 60.5 (4.9) 63.4 (4.0) 58.2 (7.6) Median 56.0 55.0 53.0 60.5 63.0 59.5 Range (Min - Max) 48-64 51-67 38-62 57-64 59-68 38-68
Age Category (years)65 5 (100.0) 2 (66.7) 3 (100.0) 2 (100.0) 3 (60.0) 15 (83.3)65 0 (0.0) 1 (33.3) 0 (0.0) 0 (0.0) 2 (40.0) 3 (16.7)
Height (cm)N 5 3 3 2 5 18 Mean (S.D.) 167.72 (9.56) 167.83 (5.46) 165.53 (5.95) 158.40 (10.47) 150.42 (7.86) 161.53 (10.43) Median 170.60 166.30 164.00 158.40 149.20 162.90 Range (Min - Max) 153.8-177.3 163.3-173.9 160.5-172.1 151.0-165.8 142.8-161.1 142.8-177.3
Weight (kg)N 5 3 3 2 5 18 Mean (S.D.) 68.78 (6.52) 69.30 (24.88) 55.97 (9.13) 58.40 (5.66) 48.78 (5.58) 60.02 (13.42) Median 69.00 67.80 55.10 58.40 52.30 57.75 Range (Min - Max) 60.4-77.4 45.2-94.9 47.3-65.5 54.4-62.4 40.0-52.7 40.0-94.9
BSA (m2)N 5 3 3 2 5 18 Mean (S.D.) 1.7334 (0.1116) 1.7260 (0.3182) 1.5670 (0.1442) 1.5530 (0.1344) 1.3838 (0.0989) 1.5873 (0.2067) Median 1.7570 1.7140 1.5270 1.5530 1.3900 1.5365 Range (Min - Max) 1.546-1.838 1.414-2.050 1.447-1.727 1.458-1.648 1.262-1.495 1.262-2.050
BSA Category (m2)1.250 1.500 0 (0.0) 1 (33.3) 1 (33.3) 1 (50.0) 5 (100.0) 8 (44.4)1.500 1.750 2 (40.0) 1 (33.3) 2 (66.7) 1 (50.0) 0 (0.0) 6 (33.3)1.750 3 (60.0) 1 (33.3) 0 (0.0) 0 (0.0) 0 (0.0) 4 (22.2)
PS0 4 (80.0) 2 (66.7) 3 (100.0) 2 (100.0) 3 (60.0) 14 (77.8)1 1 (20.0) 1 (33.3) 0 (0.0) 0 (0.0) 2 (40.0) 4 (22.2)
Complications 0 (0.0) 1 (33.3) 0 (0.0) 1 (50.0) 0 (0.0) 2 (11.1) 5 (100.0) 2 (66.7) 3 (100.0) 1 (50.0) 5 (100.0) 16 (88.9)
Anamnesis 2 (40.0) 1 (33.3) 2 (66.7) 1 (50.0) 3 (60.0) 9 (50.0) 3 (60.0) 2 (66.7) 1 (33.3) 1 (50.0) 2 (40.0) 9 (50.0)
Analysis Set: FAS (Full Analysis Set
Level 1 (N= 5) Level 2 (N= 3) Level 3 (N= 3) Level 4 (N= 2) Level 5 (N= 5) Total (N= 18)
-
2.7.3
16
2.7.3.3.1.2-1 TAS102-J003
5.3.5.1.1 TAS102-J003 CSR 11.2-2
2TAS102-J001
18 2 11.1% 16 88.9%
6 33.3% 12 66.7%
6 33.3% 12 66.7%
2.7.3.3.1.2-2
TAS-102(N= 112) Placebo(N= 57) N (%) N (%) P Value *
Diagnosis 63 ( 56.3) 36 ( 63.2) F:0.413 49 ( 43.8) 21 ( 36.8) Stage 47 ( 42.0) 29 ( 50.9) F:0.327 65 ( 58.0) 28 ( 49.1) Histological Type 31 ( 27.7) 17 ( 29.8) C:0.459 74 ( 66.1) 33 ( 57.9) 6 ( 5.4) 5 ( 8.8) 1 ( 0.9) 2 ( 3.5) Primary Lesion No 95 ( 84.8) 49 ( 86.0) F:1.000 Yes 17 ( 15.2) 8 ( 14.0) Number of Metastatic Organs (Investigator , RECIST 1.0) 1 25 ( 22.3) 11 ( 19.3) W:0.216 2 43 ( 38.4) 20 ( 35.1) 3 27 ( 24.1) 12 ( 21.1) 4 14 ( 12.5) 5 ( 8.8) 5-< 3 ( 2.7) 9 ( 15.8) Metastatic Organ (Investigator , RECIST 1.0) 65 ( 58.0) 38 ( 66.7) 87 ( 77.7) 44 ( 77.2) 42 ( 37.5) 20 ( 35.1) 19 ( 17.0) 11 ( 19.3) 6 ( 5.4) 5 ( 8.8) 11 ( 9.8) 17 ( 29.8) () 1 ( 0.9) 0 ( 0.0) 32 ( 28.6) 21 ( 36.8) Analysis Set: FAS* F: Fisher's exact test, W: Wilcoxon's rank sum test, C: Chi-square test : Multiple answers allowed
-
2.7.3
17
2.7.3.3.1.2-2 TAS102-J001
5.3.5.4.1 TAS102-J001 CTD 11.1-2
2.7.3.3.1.3
1TAS102-J003
TAS-102 10392.0% 50 87.7%
54 48.2% 15 26.3% EGFR 71
63.4% 36 63.2% 87 77.7% 47 82.5%
TAS-102
2 17 15.2% 13 22.8%3 46 41.1%
16 28.1%4 30 26.8% 12 21.1%
FOLFOXFOLFIRICPT-11+
50% 2.7.3.3.1.3-1
N (%) N (%) N (%) N (%) N (%) N (%)
0 (0.0) 0 (0.0) 0 (0.0) 1 (50.0) 1 (20.0) 2 (11.1) 5 (100.0) 3 (100.0) 3 (100.0) 1 (50.0) 4 (80.0) 16 (88.9) 2 (40.0) 1 (33.3) 0 (0.0) 2 (100.0) 1 (20.0) 6 (33.3) 3 (60.0) 2 (66.7) 3 (100.0) 0 (0.0) 4 (80.0) 12 (66.7)
0 (0.0) 1 (33.3) 2 (66.7) 0 (0.0) 3 (60.0) 6 (33.3) 5 (100.0) 2 (66.7) 1 (33.3) 2 (100.0) 2 (40.0) 12 (66.7)
0 (0.0) 0 (0.0) 0 (0.0) 1 (50.0) 1 (20.0) 2 (11.1) 5 (100.0) 3 (100.0) 3 (100.0) 1 (50.0) 4 (80.0) 16 (88.9)
5 (100.0) 3 (100.0) 3 (100.0) 2 (100.0) 5 (100.0) 18 (100.0) 3 (60.0) 1 (33.3) 1 (33.3) 2 (100.0) 3 (60.0) 10 (55.6) 4 (80.0) 2 (66.7) 3 (100.0) 1 (50.0) 3 (60.0) 13 (72.2) 2 (40.0) 1 (33.3) 1 (33.3) 1 (50.0) 0 (0.0) 5 (27.8) 1 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6) 2 (40.0) 1 (33.3) 0 (0.0) 1 (50.0) 1 (20.0) 5 (27.8)
1 (20.0) 1 (33.3) 1 (33.3) 1 (50.0) 4 (80.0) 8 (44.4) 4 (80.0) 2 (66.7) 2 (66.7) 1 (50.0) 1 (20.0) 10 (55.6)Analysis Set: FASFull Analysis Set
Level 3 (N= 3) Level 4 (N= 2) Level 5 (N= 5) Total (N= 18)
1 2
Level 1 (N= 5) Level 2 (N= 3)
Primary Lesion
Histological Type
Stage
Metastatic Lesion
Number of Metastatic Lesion
-
2.7.3
18
2.7.3.3.1.3-1 TAS102-J003
5.3.5.1.1 TAS102-J003 CSR 11.2-3
2TAS102-J001
3.4 26 16
88.9% 2 11.1% 7 38.9%
11 61.1% 2.7.3.3.1.3-2
2.7.3.3.1.3-2 TAS102-J001
5.3.5.4.1 TAS102-J001 CTD 11.1-1
TAS-102(N= 112) Placebo(N= 57) N (%) N (%) P Value *
Chemotherapy Yes 112 (100.0) 57 (100.0) F:-Surgical History No 9 ( 8.0) 7 ( 12.3) F:0.410 Yes 103 ( 92.0) 50 ( 87.7) Postoperative Adjuvant Chemotherapy No 58 ( 51.8) 42 ( 73.7) F:0.0079 Yes 54 ( 48.2) 15 ( 26.3) Radiotherapy No 94 ( 83.9) 49 ( 86.0) F:0.824 Yes 18 ( 16.1) 8 ( 14.0) Other Treatment History No 104 ( 92.9) 50 ( 87.7) F:0.269 Yes 8 ( 7.1) 7 ( 12.3) Containing Anti-EGFR Monoclonal Antibody Therapeutics No 41 ( 36.6) 21 ( 36.8) F:1.000 Yes 71 ( 63.4) 36 ( 63.2) Containing Bevacizumab Therapeutics No 25 ( 22.3) 10 ( 17.5) F:0.550 Yes 87 ( 77.7) 47 ( 82.5) Number of Chemotherapy 2 17 ( 15.2) 13 ( 22.8) W:0.631 3 46 ( 41.1) 16 ( 28.1) 4 30 ( 26.8) 12 ( 21.1) 5 7 ( 6.3) 7 ( 12.3) 6 9 ( 8.0) 4 ( 7.0) 7 1 ( 0.9) 2 ( 3.5) 8 1 ( 0.9) 2 ( 3.5) 9 1 ( 0.9) 1 ( 1.8) Analysis Set: FAS* F: Fisher's exact test, W: Wilcoxon's rank sum test
N (%) N (%) N (%) N (%) N (%) N (%)
2 0 (0.0) 1 (33.3) 0 (0.0) 1 (50.0) 0 (0.0) 2 (11.1)3 2 (40.0) 1 (33.3) 0 (0.0) 0 (0.0) 3 (60.0) 6 (33.3)4 1 (20.0) 0 (0.0) 1 (33.3) 1 (50.0) 0 (0.0) 3 (16.7)5 1 (20.0) 1 (33.3) 0 (0.0) 0 (0.0) 0 (0.0) 2 (11.1)6 0 (0.0) 0 (0.0) 2 (66.7) 0 (0.0) 1 (20.0) 3 (16.7)7 1 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.6)9 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (20.0) 1 (5.6)
2 1 (20.0) 2 (66.7) 0 (0.0) 1 (50.0) 0 (0.0) 4 (22.2)3 2 (40.0) 1 (33.3) 0 (0.0) 0 (0.0) 3 (60.0) 6 (33.3)4 1 (20.0) 0 (0.0) 1 (33.3) 1 (50.0) 2 (40.0) 5 (27.8)5 1 (20.0) 0 (0.0) 1 (33.3) 0 (0.0) 0 (0.0) 2 (11.1)6 0 (0.0) 0 (0.0) 1 (33.3) 0 (0.0) 0 (0.0) 1 (5.6)
Adjuvant 3 (60.0) 1 (33.3) 2 (66.7) 2 (100.0) 3 (60.0) 11 (61.1) 2 (40.0) 2 (66.7) 1 (33.3) 0 (0.0) 2 (40.0) 7 (38.9)
Operation History 0 (0.0) 0 (0.0) 0 (0.0) 1 (50.0) 1 (20.0) 2 (11.1) 5 (100.0) 3 (100.0) 3 (100.0) 1 (50.0) 4 (80.0) 16 (88.9)
Analysis Set: FAS (Full Analysis Set
Level 2 (N= 3) Level 3 (N= 3) Level 4 (N= 2) Level 5 (N= 5) Total (N= 18)
Total Number of PriorTherapy
Total Number ofRegimen
Level 1 (N= 5)
-
2.7.3
19
2.7.3.3.2
2.7.3.3.2.1 OS
1TAS102-J003
OS TAS-102 9.0 6.6 TAS-102
0.5695% 0.39
0.81p = 0.0011 2.7.3.3.2.1-1
5.3.5.1.1 TAS102-J003 CSR 11.4.1.1-1
2.7.3.3.2.1-1 TAS102-J003
Group Time (Months) 0 3 6 9 12 15 TAS-102 Number of Patient At Risk 112 104 77 55 23 6 Cumulative survival(%) 100.0 92.9 68.8 50.0 36.7 21.1 Placebo Number of Patient At Risk 57 46 31 18 4 1 Cumulative survival(%) 100.0 80.7 54.4 31.6 15.8 11.9
Allocation Adjustment Factors : PS (0 : 0 , 1 : 1 or 2)OS(Months) Stratified logrank test
Group N Event Median 95% CI Statistics P ValueTAS-102 112 75 9.0 [7.3 , 11.3] Chi-square=10.693 0.0011Placebo 57 48 6.6 [4.9 , 8.0] df=1
Parameter Standard Hazard Ratio* Chi-Variable N Estimate Error Unit HR 95% CI square df P Value
Group(1 : TAS-102 , 0 : Placebo) 169 -0.576 0.186 1 0.56 [0.39 , 0.81] 9.541 1 0.0020PS (0 : 0 , 1 : 1 or 2) 169 0.400 0.185 1 1.49 [1.04 , 2.15] 4.648 1 0.031Analysis Set: FASIf confidence interval could not be calculated,'-' is indicated.Months in the Figure indicate the survival days divided by 30.4375.1 year corresponds to 12 months.* : Covariate adjusted hazard ratio
-
2.7.3
20
OS ECOG PS 0 TAS-102 10.3
8.0 0.5595% 0.340.89p = 0.013ECOG PS
1 2 TAS-102 7.2 3.7
0.5495% 0.300.96p = 0.033 2.7.3.3.2.1-2
5.3.5.1.1 TAS102-J003 CSR 11.4.1.1-3
2.7.3.3.2.1-2 TAS102-J003
2TAS102-J001
Kaplan-Meier 18 6 12
2.7.3.3.2.1-3 18 OS 9.8 95%
7.612.0 12.5 95% 9.5
14.7 8.3 95% 4.310.3
PS Group Time (Months) 0 3 6 9 12 15 0 TAS-102 Number of Patient At Risk 72 68 50 40 16 3 Cumulative Survival (%) 100.0 94.4 69.4 55.6 41.8 20.9 Placebo Number of Patient At Risk 35 33 23 14 1 Cumulative Survival (%) 100.0 94.3 65.7 40.0 14.5
1 or 2 TAS-102 Number of Patient At Risk 40 36 27 15 7 3 Cumulative Survival (%) 100.0 90.0 67.5 39.8 27.7 18.5 Placebo Number of Patient At Risk 22 13 8 4 3 1 Cumulative Survival (%) 100.0 59.1 36.4 18.2 18.2 12.1
OS(Months) Hazard Ratio logrank test PS Group N Event Median 95% CI HR 95% CI Statistics P Value0 TAS-102 72 45 10.3 [7.8 , 13.0] 0.55 [0.34 , 0.89] Chi-square=6.202 0.013 Placebo 35 29 8.0 [5.4 , 10.1] df=1
1 or 2 TAS-102 40 30 7.2 [6.1 , 10.3] 0.54 [0.30 , 0.96] Chi-square=4.526 0.033 Placebo 22 19 3.7 [2.6 , 6.8] df=1
Analysis Set: FASIf confidence interval could not be calculated,'-' is indicated.Months in the Figure indicate the survival days divided by 30.4375.1 year corresponds to 12 months.
-
2.7.3
21
FAS 6 MST12.5 95% 9.514.7 FAS 12 MST8.3 95% 4.310.3 FAS 18 MST9.8 95% 7.612.0
5.3.3.2.1 TAS102-J001 CSR 11.4.1.1-3
2.7.3.3.2.1-3 TAS102-J001
2.7.3.3.2.2 PFS
1TAS102-J003
PFS TAS-102 2.0
1.0 0.4195% 0.280.59p < 0.0001 2.7.3.3.2.2-1
-
2.7.3
22
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.4.1-1
2.7.3.3.2.2-1 TAS102-J003
PFS TAS-102 2.7 1.0
0.3495% 0.240.49p < 0.0001 2.7.3.3.2.2-2
Group Time (Months) 0 3 6 9 12 TAS-102 Number of Patient At Risk 112 31 17 4 1 Cumulative Event Free Rate(%) 100.0 34.5 20.3 6.3 2.1 Placebo Number of Patient At Risk 57 4 1 Cumulative Event Free Rate(%) 100.0 10.0 2.5
Allocation Adjustment Factors : PS (0 : 0 , 1 : 1 or 2)PFS(Months) Stratified logrank test
Group N Event Median 95% CI Statistics P ValueTAS-102 112 91 2.0 [1.9 , 2.8] Chi-square=22.899
-
2.7.3
23
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.4.2-1
2.7.3.3.2.2-2 TAS102-J003
2TAS102-J001
18 PFS 2.4 95% 1.52.8
3.4 95% 2.54.6 1.6 95%
1.02.6 2.7.3.3.2.2-3
Group Time (Months) 0 3 6 9 12 15 TAS-102 Number of Patient At Risk 112 46 25 11 4 2 Cumulative Event Free Rate(%) 100.0 41.1 22.3 9.8 3.6 3.6 Placebo Number of Patient At Risk 57 5 1 Cumulative Event Free Rate(%) 100.0 9.4 1.9
Allocation Adjustment Factors : PS (0 : 0 , 1 : 1 or 2)PFS(Months) Stratified logrank test
Group N Event Median 95% CI Statistics P ValueTAS-102 112 109 2.7 [1.9 , 3.2] Chi-square=35.271
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2.7.3
24
5.3.5.4.1 TAS102-J001 CTD 11.3-4.1-2
2.7.3.3.2.2-3 TAS102-J001
2.7.3.3.2.3 ORRDCR
1TAS102-J003
TAS-102PR 1
ORR 0.9%95% 0.04.9
DCR TAS-102 43.8%95% 34.453.4
10.5%95% 4.021.5p < 0.0001 2.7.3.3.2.3-1
Colon Cancer : N=6 Event=6 Censored=0 Median=3.4 months (95%CI 2.54.6)Rectal Cancer : N=12 Event=12 Censored=0 Median=1.6 months (95%CI 1.02.6)Total : N=18 Event=18 Censored=0 Median=2.4 months (95%CI 1.52.8)
Colon Cancer Rectal Cancer TotalCumulative Cumulative CumulativeProgression Progression Progression
Time at Risk free rate at Risk free rate at Risk free rate(month) % % %
0 6 100.0 12 100.0 18 100.03 3 50.0 2 16.7 5 27.86 - - 1 8.3 1 5.6
Analysis Set: FASIf confidence interval could not be calculated,'-' is displayed.PFS month in the figure is days divided by 30.4375.1 year is 12 months.
-
2.7.3
25
2.7.3.3.2.3-1 TAS102-J003
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.1.1-1
DCR TAS-102 54.5%95% 44.863.9
14.0%95% 6.325.8p < 0.0001 2.7.3.3.2.3-2
2.7.3.3.2.3-2 TAS102-J003
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.1.2-1
waterfall plot 2.7.3.3.2.3-1
TAS-102(N= 112) Placebo(N= 57)N (%) N (%) P Value *
CR 0 ( 0.0) 0 ( 0.0)PR 1 ( 0.9) 0 ( 0.0)SD 48 ( 42.9) 6 ( 10.5)PD 53 ( 47.3) 44 ( 77.2)NE 10 ( 8.9) 7 ( 12.3)Response Rate(CR+PR) 1 ( 0.9) 0 ( 0.0) 1.00095%CI(%) [ 0.0, 4.9] [ 0.0, 6.3]Disease Control Rate(CR+PR+SD) 49 ( 43.8) 6 ( 10.5)
-
2.7.3
26
Analysis Set: FAS Change From Baseline (%) = min ( (value at each date - baseline value) / baseline value 100) RECIST Ver.1.0
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.2-1
2.7.3.3.2.3-1 waterfall plotTAS102-J003
2TAS102-J001
18 SD PD 9
1 2 3 4 5 SD 2 1 1 2
3 PD 3 2 2 0 2
DCR 50.0% 1 2 3 4
5 40.0%33.3%33.3%100.0% 60.0% 2.7.3.3.2.3-3
2.7.3.3.2.3-3 TAS102-J001
5.3.5.4.1 TAS102-J001 CTD 11.3-1.1-6
2.7.3.3.3
TAS102-J003
2.7.3.3.3.1
FAS 169 TAS-102 112 57 OS
forest plot 2.7.3.3.3.1-1
TAS-102
0.2395% 0.051.00
1.1295% 0.572.20
Level 1 (N= 5) Level 2 (N= 3) Level 3 (N= 3) Level 4 (N= 2) Level 5 (N= 5) Total (N= 18)Response N (%) N (%) N (%) N (%) N (%) N (%)CR 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)PR 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)SD 2 (40.0) 1 (33.3) 1 (33.3) 2 (100.0) 3 (60.0) 9 (50.0)PD 3 (60.0) 2 (66.7) 2 (66.7) 0 (0.0) 2 (40.0) 9 (50.0)NE 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)Disease Control Rate(CR+PR+SD) 2 (40.0) 1 (33.3) 1 (33.3) 2 (100.0) 3 (60.0) 9 (50.0)95%CI(%) Width of 95%CI Analysis Set: FAS
48.080.1 80.1 89.7 89.7 84.2 5.3 - 85.3 26.0 - 74.014.7 - 94.7 15.8 - 100.0 0.8 - 90.6 0.8 - 90.6
-
2.7.3
27
6, 7, 8, 9, 10, 11TAS-102
DNA
EGFR
TAS-102
-
2.7.3
28
5.3.5.1.1 TAS102-J003 CSR 11.4.2.8-1
2.7.3.3.3.1-1 TAS102-J003
TAS-102 Placebo Hazard Ratio N N HR 95%CIGender Male 64 28 0.68 [0.41 , 1.13] Female 48 29 0.49 [0.29 , 0.83]Age Category1(years)
-
2.7.3
29
PFS
forest plot 2.7.3.3.3.1-2 TAS-102
-
2.7.3
30
5.3.5.1.1 TAS102-J003 CSR 11.4.2.8-2
2.7.3.3.3.1-2 TAS102-J003
TAS-102 Placebo Hazard Ratio N N HR 95%CIGender Male 64 28 0.55 [0.33 , 0.91] Female 48 29 0.30 [0.17 , 0.53]Age Category1(years)
-
2.7.3
31
2.7.3.3.3.2 KRAS
TAS102-J003 PGx KRAS 12 13
KRAS TAS-102
1
KRAS 2.7.3.3.3.2-1
2.7.3.3.3.2-1 KRAS KRAS TAS102-J003
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.6.2-1
KRAS Wild KRAS MutationTAS-102(N= 54) Placebo(N= 24) TAS-102(N= 45) Placebo(N= 26)
N (%) N (%) N (%) N (%)Gender Male 33 ( 61.1) 11 ( 45.8) 25 ( 55.6) 13 ( 50.0) Female 21 ( 38.9) 13 ( 54.2) 20 ( 44.4) 13 ( 50.0)Age(years) N 54 24 45 26 Mean(S.D.) 62.8(10.0) 61.1(9.1) 61.3(10.0) 64.4(8.8) Median 64.0 61.0 64.0 66.0 Range[Min , Max] [28,79] [42,78] [33,80] [39,79] Age Category 1(years)
-
2.7.3
32
2
KRAS 2.7.3.3.3.2-2
TAS-102 34 63.0% 16
66.7% 24 53.3% 15 57.7% 20 37.0% 8
33.3% 21 46.7% 11 42.3% TAS-102
1 2
47 87.0% 22 91.7% 37 82.2%
20 76.9%
2.7.3.3.3.2-2 KRAS KRAS TAS102-J003
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.6.2-2
3
KRAS 2.7.3.3.3.2-3
KRAS TAS-102
EGFR 90%
KRAS Wild KRAS MutationTAS-102(N= 54) Placebo(N= 24) TAS-102(N= 45) Placebo(N= 26)
N (%) N (%) N (%) N (%)Diagnosis 34 ( 63.0) 16 ( 66.7) 24 ( 53.3) 15 ( 57.7) 20 ( 37.0) 8 ( 33.3) 21 ( 46.7) 11 ( 42.3)Stage 28 ( 51.9) 12 ( 50.0) 26 ( 57.8) 12 ( 46.2) 26 ( 48.1) 12 ( 50.0) 19 ( 42.2) 14 ( 53.8)Histological Type 13 ( 24.1) 10 ( 41.7) 14 ( 31.1) 6 ( 23.1) 34 ( 63.0) 11 ( 45.8) 31 ( 68.9) 17 ( 65.4) 6 ( 11.1) 3 ( 12.5) 0 ( 0.0) 1 ( 3.8) 1 ( 1.9) 0 ( 0.0) 0 ( 0.0) 2 ( 7.7)Primary Lesion No 47 ( 87.0) 22 ( 91.7) 37 ( 82.2) 20 ( 76.9) Yes 7 ( 13.0) 2 ( 8.3) 8 ( 17.8) 6 ( 23.1)Number of Metastatic Organs (Investigator , RECIST 1.0) 1 9 ( 16.7) 8 ( 33.3) 11 ( 24.4) 1 ( 3.8) 2 20 ( 37.0) 6 ( 25.0) 19 ( 42.2) 14 ( 53.8) 3 14 ( 25.9) 5 ( 20.8) 11 ( 24.4) 6 ( 23.1) 4 9 ( 16.7) 2 ( 8.3) 4 ( 8.9) 2 ( 7.7) 5-< 2 ( 3.7) 3 ( 12.5) 0 ( 0.0) 3 ( 11.5)Metastatic Organ (Investigator , RECIST 1.0) 17 ( 31.5) 7 ( 29.2) 12 ( 26.7) 10 ( 38.5) 34 ( 63.0) 17 ( 70.8) 26 ( 57.8) 17 ( 65.4) 39 ( 72.2) 13 ( 54.2) 38 ( 84.4) 25 ( 96.2) 4 ( 7.4) 5 ( 20.8) 6 ( 13.3) 9 ( 34.6) 3 ( 5.6) 4 ( 16.7) 2 ( 4.4) 0 ( 0.0) 28 ( 51.9) 9 ( 37.5) 9 ( 20.0) 6 ( 23.1) 12 ( 22.2) 4 ( 16.7) 4 ( 8.9) 3 ( 11.5) () 0 ( 0.0) 0 ( 0.0) 1 ( 2.2) 0 ( 0.0)Analysis Set: KRAS Evaluable Patients : Multiple answers allowed
-
2.7.3
33
2.7.3.3.3.2-3 KRAS KRAS TAS102-J003
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.6.2-3
4
KRAS 2.7.3.3.3.2-4
2.7.3.3.3.2-4 KRAS KRAS TAS102-J003
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.6.2-4
KRAS Wild KRAS MutationTAS-102(N= 54) Placebo(N= 24) TAS-102(N= 45) Placebo(N= 26)
N (%) N (%) N (%) N (%)Chemotherapy Yes 54 (100.0) 24 (100.0) 45 (100.0) 26 (100.0)Surgical History No 5 ( 9.3) 2 ( 8.3) 3 ( 6.7) 5 ( 19.2) Yes 49 ( 90.7) 22 ( 91.7) 42 ( 93.3) 21 ( 80.8)Postoperative Adjuvant Chemotherapy No 33 ( 61.1) 19 ( 79.2) 22 ( 48.9) 18 ( 69.2) Yes 21 ( 38.9) 5 ( 20.8) 23 ( 51.1) 8 ( 30.8)Radiotherapy No 45 ( 83.3) 21 ( 87.5) 39 ( 86.7) 22 ( 84.6) Yes 9 ( 16.7) 3 ( 12.5) 6 ( 13.3) 4 ( 15.4)Other Treatment History No 51 ( 94.4) 20 ( 83.3) 41 ( 91.1) 24 ( 92.3) Yes 3 ( 5.6) 4 ( 16.7) 4 ( 8.9) 2 ( 7.7)Containing Anti-EGFR Monoclonal Antibody Therapeutics No 5 ( 9.3) 1 ( 4.2) 30 ( 66.7) 18 ( 69.2) Yes 49 ( 90.7) 23 ( 95.8) 15 ( 33.3) 8 ( 30.8)Containing Bevacizumab Therapeutics No 18 ( 33.3) 7 ( 29.2) 6 ( 13.3) 3 ( 11.5) Yes 36 ( 66.7) 17 ( 70.8) 39 ( 86.7) 23 ( 88.5)Number of Chemotherapy 2 5 ( 9.3) 2 ( 8.3) 11 ( 24.4) 10 ( 38.5) 3 25 ( 46.3) 9 ( 37.5) 16 ( 35.6) 5 ( 19.2) 4 12 ( 22.2) 5 ( 20.8) 12 ( 26.7) 5 ( 19.2) 5 5 ( 9.3) 4 ( 16.7) 2 ( 4.4) 2 ( 7.7) 6 5 ( 9.3) 1 ( 4.2) 3 ( 6.7) 3 ( 11.5) 7 1 ( 1.9) 2 ( 8.3) 0 ( 0.0) 0 ( 0.0) 8 1 ( 1.9) 0 ( 0.0) 0 ( 0.0) 1 ( 3.8) 9 0 ( 0.0) 1 ( 4.2) 1 ( 2.2) 0 ( 0.0)Analysis Set: KRAS Evaluable Patients
KRAS Wild KRAS MutationTAS-102 Placebo TAS-102 Placebo
(mg) (mg) (mg) (mg)Total Treatment Days*
N 54 24 45 26 Mean(S.D.) 31.8( 28.5) 14.9( 11.0) 38.0( 27.3) 18.3( 15.1) Median 20.0 10.0 30.0 10.0 Range[Min , Max] [ 3 , 130 ] [ 6 , 50 ] [ 1 , 100 ] [ 10 , 60 ]
Cumulative DoseN 54 24 45 26 Mean(S.D.) 3405.8( 3003.2) 1620.4( 1274.1) 3931.9( 2825.1) 1902.9( 1579.4) Median 2300.0 1100.0 3245.0 1100.0 Range[Min , Max] [ 250 , 14000 ] [ 605 , 5580 ] [ 100 , 10800 ] [ 720 , 6600 ]
Analysis Set: KRAS Evaluable Patients* The number of days on which drug were used( drug interrupted period were not included) .
-
2.7.3
34
5OS
OS TAS-102 7.2 7.0
0.7095% 0.411.20p = 0.191OS 13.0
6.9 0.4495% 0.250.80p = 0.0056
2.7.3.3.3.2-1
KRAS
5 4 12, 13 KRAS
EGFR
KRAS
EGFR
TAS-102 KRAS KRAS
EGFR KRAS
KRAS EGFR
KRAS
KRAS
-
2.7.3
35
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.6.2.1-1
2.7.3.3.3.2-1 KRAS TAS102-J003
6PFS
PFS TAS-102
1.9 1.0 0.4095% 0.230.69p = 0.0004
PFS 2.8 1.0 0.3495%
0.190.61p < 0.0001 2.7.3.3.3.2-2
KRAS Mutation Group Time (Months) 0 3 6 9 12 15 Wild TAS-102 Number of Patient At Risk 54 48 34 23 6 1
Cumulative Survival (%) 100.0 88.9 63.0 42.6 22.2 16.7 Placebo Number of Patient At Risk 24 19 14 9 2 1 Cumulative Survival (%) 100.0 79.2 58.3 37.5 10.0 10.0
Mutation TAS-102 Number of Patient At Risk 45 44 35 26 14 4 Cumulative Survival (%) 100.0 97.8 77.8 59.9 52.9 24.2 Placebo Number of Patient At Risk 26 23 15 8 2 Cumulative Survival (%) 100.0 88.5 57.7 30.8 21.5
OS(Months) Hazard Ratio logrank test KRAS Mutation Group N Event Median 95% CI HR 95% CI Statistics P Value
Wild TAS-102 54 40 7.2 [6.1 , 10.3] 0.70 [0.41 , 1.20] Chi-square=1.710 0.191 Placebo 24 21 7.0 [3.4 , 9.4] df=1
Mutation TAS-102 45 27 13.0 [8.6 , 14.3] 0.44 [0.25 , 0.80] Chi-square=7.667 0.0056 Placebo 26 21 6.9 [5.2 , 8.6] df=1
Analysis Set: KRAS Evaluable PatientsIf confidence interval could not be calculated,'-' is indicated.Months in the Figure indicate the survival days divided by 30.4375.1 year corresponds to 12 months.
-
2.7.3
36
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.6.2.2-1
2.7.3.3.3.2-2 KRAS TAS102-J003
7 EGFR
****************EGFR
EGFR
2010 3
KRAS
KRAS KRAS KRAS
KRAS 2012 11
EGFR KRAS
EGFR KRAS OS PFS
a EGFR OS
EGFR OS TAS-102
7.17.40.7795%0.441.32p = 0.337
EGFR OS 13.0
6.9 0.4195% 0.210.84p = 0.011 EGFR
EGFR
KRAS Mutation Group Time (Months) 0 3 6 9 12 Wild TAS-102 Number of Patient At Risk 54 13 4 2 1
Cumulative Event Free Rate (%) 100.0 26.0 9.6 4.8 2.4 Placebo Number of Patient At Risk 24 1 Cumulative Event Free Rate (%) 100.0 6.7
Mutation TAS-102 Number of Patient At Risk 45 14 9 2 Cumulative Event Free Rate (%) 100.0 41.4 26.6 10.1 Placebo Number of Patient At Risk 26 2 Cumulative Event Free Rate (%) 100.0 10.0
PFS(Months) Hazard Ratio logrank test KRAS Mutation Group N Event Median 95% CI HR 95% CI Statistics P Value
Wild TAS-102 54 48 1.9 [1.1 , 2.8] 0.40 [0.23 , 0.69] Chi-square=12.475 0.0004 Placebo 24 21 1.0 [1.0 , 1.1] df=1
Mutation TAS-102 45 34 2.8 [1.9 , 4.7] 0.34 [0.19 , 0.61] Chi-square=15.819
-
2.7.3
37
EGFR
2.7.3.3.3.2-3
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.6.2.3-1
2.7.3.3.3.2-3 EGFR KRAS TAS102-J003
Anti-EGFR Monoclonal Antibody Therapeutics :Yes KRAS Mutation Group Time (Months) 0 3 6 9 12 15
Wild TAS-102 Number of Patient At Risk 49 43 30 19 5 1 Cumulative Survival (%) 100.0 87.8 61.2 38.8 25.2 16.8 Placebo Number of Patient At Risk 23 18 14 9 2 1 Cumulative Survival (%) 100.0 78.3 60.9 39.1 10.4 10.4
Mutation TAS-102 Number of Patient At Risk 15 14 9 7 3 Cumulative Survival (%) 100.0 93.3 60.0 53.3 45.7 Placebo Number of Patient At Risk 8 7 4 2 Cumulative Survival (%) 100.0 87.5 50.0 25.0
OS(Months) Hazard Ratio logrank test KRAS Mutation Group N Event Median 95% CI HR 95% CI Statistics P Value
Wild TAS-102 49 36 7.1 [5.7 , 10.3] 0.77 [0.44 , 1.32] Chi-square=0.923 0.337 Placebo 23 20 7.4 [3.4 , 9.4] df=1
Mutation TAS-102 15 9 9.1 [5.3 , 14.6] 0.53 [0.18 , 1.53] Chi-square=1.421 0.233 Placebo 8 6 6.1 [3.7 , -] df=1
Anti-EGFR Monoclonal Antibody Therapeutics :NoKRAS Mutation Group Time (Months) 0 3 6 9 12 15
Wild TAS-102 Number of Patient At Risk 5 5 4 4 1 Cumulative Survival (%) 100.0 100.0 80.0 80.0 20.0 Placebo Number of Patient At Risk 1 1 Cumulative Survival (%) 100.0 100.0
Mutation TAS-102 Number of Patient At Risk 30 30 26 19 11 4 Cumulative Survival (%) 100.0 100.0 86.7 63.3 56.5 27.1 Placebo Number of Patient At Risk 18 16 11 6 2 Cumulative Survival (%) 100.0 88.9 61.1 33.3 20.8
OS(Months) Hazard Ratio logrank test KRAS Mutation Group N Event Median 95% CI HR 95% CI Statistics P Value
Wild TAS-102 5 4 11.3 [5.9 , -]
-
2.7.3
38
b EGFR PFS
EGFR PFS TAS-102
1.9 1.0 0.4095% 0.230.70p =
0.0006 EGFR PFS
2.8 1.0 0.3295% 0.160.64p = 0.0004
EGFR EGFR
EGFR
2.7.3.3.3.2-4
-
2.7.3
39
5.3.5.1.1 TAS102-J003 CSR 11.4.1.2.6.2.3-2
2.7.3.3.3.2-4 EGFR KRAS TAS102-J003
2.7.3.3.3.3 DNA
TK1TPase
%tail DNA
2.7.6.8.3.8.2 2.7.6.8.3.8.3
Anti-EGFR Monoclonal Antibody Therapeutics :Yes KRAS Mutation Group Time (Months) 0 3 6 9
Wild TAS-102 Number of Patient At Risk 49 11 3 1 Cumulative Event Free Rate (%) 100.0 24.4 8.4 2.8 Placebo Number of Patient At Risk 23 1 Cumulative Event Free Rate (%) 100.0 7.2
Mutation TAS-102 Number of Patient At Risk 15 6 5 1 Cumulative Event Free Rate (%) 100.0 47.6 39.7 19.8 Placebo Number of Patient At Risk 8 1 Cumulative Event Free Rate (%) 100.0 15.6
PFS(Months) Hazard Ratio logrank test KRAS Mutation Group N Event Median 95% CI HR 95% CI Statistics P Value
Wild TAS-102 49 44 1.9 [1.1 , 2.7] 0.40 [0.23 , 0.70] Chi-square=11.656 0.0006 Placebo 23 20 1.0 [1.0 , 1.1] df=1
Mutation TAS-102 15 9 2.1 [1.0 , -] 0.40 [0.14 , 1.19] Chi-square=3.158 0.076 Placebo 8 7 1.0 [1.0 , 1.9] df=1
Anti-EGFR Monoclonal Antibody Therapeutics :No KRAS Mutation Group Time (Months) 0 3 6 9 12
Wild TAS-102 Number of Patient At Risk 5 2 1 1 1 Cumulative Event Free Rate (%) 100.0 40.0 20.0 20.0 20.0 Placebo Number of Patient At Risk 1 Cumulative Event Free Rate (%) 100.0
Mutation TAS-102 Number of Patient At Risk 30 8 4 1 Cumulative Event Free Rate (%) 100.0 38.1 19.0 4.8 Placebo Number of Patient At Risk 18 1 Cumulative Event Free Rate (%) 100.0 7.4
PFS(Months) Hazard Ratio logrank test KRAS Mutation Group N Event Median 95% CI HR 95% CI Statistics P Value
Wild TAS-102 5 4 2.8 [0.3 , -] 0.51 [0.05 , 5.74] Chi-square=0.302 0.583 Placebo 1 1 1.1 [- , -] df=1
Mutation TAS-102 30 25 2.8 [1.9 , 4.6] 0.32 [0.16 , 0.64] Chi-square=12.654 0.0004 Placebo 18 16 1.0 [1.0 , 2.0] df=1
Analysis Set: KRAS Evaluable PatientsIf confidence interval could not be calculated,'-' is indicated.Months in the Figure indicate the survival days divided by 30.4375.1 year corresponds to 12 months.RECIST Ver.1.0
-
2.7.3
40
2.7.3.4
5 I111TAS-102
2.7.3.4-1 TAS102-9804
28 1 1 2 5 2 2
14
50 mg/m2/day
2.7.3.4-1 I
* mg/m2/day % of patients
(median)
mg/m2/day
TAS102-9801
21 1 14 7 1 1
50, 60, 100 14
100.0% 4.0 50
TAS102-9802
28 1 5 2 2 14 1 1 50, 70, 80, 90, 100, 110
24 83.3% 3.5 100
TAS102-9803
21 1 5 16 1 1 100, 110, 120, 130, 140, 150, 160, 170, 180
39 82.1% 4.0 160
TAS102-9804
28 1 5 2 2 14 1 2 50, 60, 80
19 100.0% 5.0 50
TAS102-9805
28 1 5 2 2 14 1 3
60, 70, 80
15 60.0%
3.0 70
*
I TAS102-J001 I
28 1 1 2 5 2
2 14 MTD
21 30 mg/ m2/day 6 40 mg/m2/day 3 50 mg/m2/day 3 60 mg/m2/day
3 70 mg/m2/day 6 TAS-102 70 mg/m2/day 30
60 mg/m2/day 3 4 MTD
70 mg/m2/day II FTD TPI
tmaxCmax
-AUC TAS102-9804
II TAS102-J003 TAS-102 70 mg/m2/day35 mg/m2
1 2
2.7.3.2.1.13
2.7.3.5
TAS102-J003 TTF 2.7.3.2.1.10
2.7.3.2.1.12
-
2.7.3
41
TAS-102 112 2 79 70.5%
3.0 13 2.7.3.5-1
2.7.3.5-1
5.3.5.1.1 TAS102-J003 CSR 11.3.1.1-5
30
TAS-102
99/112
2.7.3.6
II TAS102-9806
2.7.3.6-1 TAS102-9806
mg/m2/day
TAS102-
9806 II
Simon 2
28 15 2 2 141 2 50
ORR
PFSOS
PGx
18
1 18 CR PR
mOS7.5 []
mPFS1.7 95% 1.31.9
SD3 16.7% PD15 83.3%
[] mPFS1.7 95%
1.31.8 SD1 5.6% PD17 94.4%
ORR: PFS: OS: PGx: CR: PR: m: SD: PD: 5.3.5.2.1 TAS102-9806 CSR
TAS-102(N=112) Placebo(N=57)N (%) N (%)
Number of Patients in each Course1 112 (100.0) 57 (100.0)2 79 ( 70.5) 18 ( 31.6)3 57 ( 50.9) 9 ( 15.8)4 44 ( 39.3) 6 ( 10.5)5 35 ( 31.3) 5 ( 8.8)6 24 ( 21.4) 1 ( 1.8)7 20 ( 17.9) 0 ( 0.0)8 14 ( 12.5) 0 ( 0.0)9 8 ( 7.
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