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 で***となるため，処方変更水準が水準と判定した． 2.7.1.1.3 食事の影響試験の概観

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


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


**** ***** ****

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


**** ***** ****

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


**** ***** ****

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


* 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


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


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


AUC0-t area under the concentration-time curve from time 0 to the time (t) of the last

quantifiable concentrationt AUC


AUC


AUC

AUCinf area under the concentration-time curve from time 0 to infinity

AUC

CI confidence interval


CV coefficient of variation

CYP cytochrome P450 P450

FTD trifluridine


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


TPase thymidine phosphorylase


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


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


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


2.7.2.2.2.1.1-3 TAS-102 1 2 TPI TAS102-J001


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 (%

)


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


Perc

ent C

hang

e (%

)

-100

-80

-60

-40

-20

0

20


Perc

ent C

hang

e (%

)

-100

-80

-60

-40

-20

0


Perc

ent C

hang

e (%

)

WBC Neutrophil


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


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-


BSC best supportive care


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


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


TPase thymidine phosphorylase


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

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%


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


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


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



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


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 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



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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