An Open-label Randomized Multi-center Phase III Study of TAS-118 Plus Oxaliplatin Versus S-1 Plus Cisplatin as First-line Therapy in Patients With Advanced Gastric Cancer
Phase: PHASE3
Conditions: Gastric Cancer
Sponsor: Taiho Pharmaceutical Co., Ltd.

 
 
 
 
 
 
 
 
An open-label randomized multi-center phase III study of  
TAS-118 plus Oxaliplatin versus S-1 plus Cisplatin  
as first-line therapy in patients with advanced gastric cancer 
 
 
PROTOCOL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPONSOR : Taiho Pharmaceutical Co., Ltd. 
 
PROTOCOL No.: ********  
VERSION: P05 
DATE: 07 Nov 2019 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 The information contained in this document is the property of Taiho Pharmaceutical, Co., Ltd. and is 
provided for the use of the investigator and other designated site personal. It may also be distributed to 
appropriate Independent Ethics Committees/Institutional Review Boards/Regulatory Authorities upon 
notification of Taiho Pharmaceutical, Co., Ltd. These groups are also required to keep the enclosed 
information confidential. This document contained strictly confidential information and no part of this 
document may be published or disclosed, except as necessary to obtain consent form person who are 
considering participation in the study, without the prior written approval of Taiho Pharmaceutical, Co., 
Ltd. 
 
2 

 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ......................................................................................................... 3 
ABBREVIATIONS .................................................................................................................. 8 
PROTOCOL SYNOPSIS ...................................................................................................... 10 
1. Study Administrative Structure..................................................................................... 15 
1.1 Title of Protocol, Protocol Number and Date of Preparation ....................................... 15 
1.2 Sponsor ......................................................................................................................... 15 
1.3 Contract Research Organization................................................................................... 15 
2. Background Information................................................................................................ 16 
2.1 Background of disease ................................................................................................. 16 
2.2 Current standard treatment ........................................................................................... 16 
2.3 Introduction of novel anti-cancer therapy .................................................................... 17 
 TAS-118 ................................................................................................................ 17 
 Clinical Studies ......................................................................................................... 
2.3.2.1 
***************** .............................................................................................. 
2.3.2.2 
***************** .............................................................................................. 
2.3.2.3 
***************** .............................................................................................. 
2.3.2.4 
***************** .............................................................................................. 
2.4 Rationale for considering the new therapy as promising ............................................. 23 
3. GCP Compliance and Ethical Conduct of the Study ................................................... 24 
3.1 GCP Compliance .......................................................................................................... 24 
3.2 Protection of Subjects’ Privacy .................................................................................... 24 
3.3 Institutional Review Board/Independent Ethics Committee Approval ........................ 24 
4. Study Objectives ............................................................................................................. 25 
4.1 Primary objective ......................................................................................................... 25 
4.2 Secondary objective ..................................................................................................... 25 
5. Study Design .................................................................................................................... 25 
5.1 Endpoints...................................................................................................................... 25 
 Primary .................................................................................................................. 25 
 Secondary .............................................................................................................. 25 
5.2 Study Type .................................................................................................................... 25 
 Study Type by Objectives ..................................................................................... 25 
 Study Type by Design ........................................................................................... 25 
5.3 Description of Study Design ........................................................................................ 25 
5.4 Patient Numbering and Randomization ....................................................................... 26 
5.5 Blinding ........................................................................................................................ 26 
6. Study Procedures ............................................................................................................ 27 
6.1 Explanation of Study Schedule to Individual Subjects ................................................ 27 
 Definition of Study Period .................................................................................... 27 
7. Study Drug ....................................................................................................................... 28 
7.1 Study Drug ................................................................................................................... 28 
 TAS-118 ................................................................................................................ 28 
 S-1 ......................................................................................................................... 29 
7.2 Oxaliplatin (L-OHP) .................................................................................................... 30 
7.3 Cisplatin (CDDP) ......................................................................................................... 30 
 
3 
 

 
 
 
7.4 Packaging and Labeling of Study Drug ....................................................................... 30 
7.5 Delivery, Storage, Control, Retrieve of Study Drug .................................................... 30 
8. Criteria for Inclusion and Exclusion of Patients .......................................................... 31 
8.1 Inclusion Criteria .......................................................................................................... 31 
8.2 Exclusion Criteria ......................................................................................................... 32 
8.3 Informed Consent ......................................................................................................... 33 
 Procedure for obtaining informed consent ............................................................ 33 
9. Subject Registration ....................................................................................................... 34 
10. Administration ................................................................................................................ 35 
10.1 Dose, administration schedule ..................................................................................... 35 
 Dose ...................................................................................................................... 35 
10.1.1.1 Arm A (TAS-118/L-OHP) .............................................................................. 35 
10.1.1.2 Arm B (S-1/CDDP) ........................................................................................ 35 
 Administration schedule ....................................................................................... 37 
10.1.2.1 Arm A (TAS-118/L-OHP) .............................................................................. 37 
10.1.2.2 Arm B (S-1/CDDP) [CDDP on Day 1] (Korea) ............................................ 38 
10.1.2.3 Arm B (S-1/CDDP) [CDDP on Day 8] (Japan) ............................................. 39 
 Criteria for Modification of Treatment Schedule .................................................. 41 
10.1.3.1 Criteria for Dose Initiation in Each Cycle ..................................................... 41 
10.1.3.2 Criteria for Dose Interruption and Resumption within Treatment Cycle ...... 42 
10.1.3.3 Criteria for Dose Reduction (Arm A) ............................................................ 43 
10.1.3.4 Criteria for Dose Reduction (Arm B) ............................................................ 44 
 Criteria for Dose Increase ..................................................................................... 45 
10.2 Medication and Treatments Prohibited during Study................................................... 45 
 Medication and Treatments Prohibited during Study ........................................... 45 
 Concomitant Medications Requiring Precautions ................................................. 45 
 Expected Adverse Drug Reactions and Treatment Options .................................. 45 
10.3 Supportive therapy and other points to be considerd ................................................... 46 
10.4 Instruction to Patients for Handling Study Medication (TAS-118 or S-1) ................... 46 
11. Data Items and Schedule for Testing and Monitoring ................................................. 48 
11.1 Data Items and schedule for Testing and Monitoring .................................................. 48 
 Collection and Submission of Images ................................................................... 49 
11.2 Testing and Monitoring Schedule ................................................................................ 50 
11.3 Tests at Randomization or before Initiation of Study Treatment ................................. 52 
11.4 Tests during Study Treatment ....................................................................................... 52 
11.5 End of Treatment .......................................................................................................... 54 
11.6 Safety Follow-up .......................................................................................................... 54 
11.7 Tumor Follow-up ......................................................................................................... 55 
11.8 Survival Follow-up....................................................................................................... 55 
12. Pharmacokinetics and Pharmacogenomics .................................................................. 55 
13. Discontinuation of study ................................................................................................. 56 
13.1 Discontinuation criteria for individual subject ............................................................. 56 
 Study Treatment Discontinuation Criteria ............................................................ 56 
 Safety Follow-up Discontinuation Criteria ........................................................... 56 
 Tumor Follow-up Discontinuation Criteria .......................................................... 56 
 Survival Follow-up Discontinuation Criteria ........................................................ 56 
 
4 
 

 
 
 
13.2 Criteria for Discontinuation of Study in Individual Institutions .................................. 57 
13.3 Criteria for Termination of Entire Study ...................................................................... 57 
13.4 Post Treatment .............................................................................................................. 57 
14. Efficacy Assessment ........................................................................................................ 58 
14.1 Assessment of Antitumor Efficacy (RECIST Guideline Version 1.1) ......................... 58 
 Evaluation of lesions ............................................................................................. 58 
14.1.1.1 Measurement of Lesions ................................................................................ 58 
14.1.1.2 Tumor Definitions .......................................................................................... 58 
14.1.1.3 Evaluation of Response in Target Lesions ..................................................... 59 
14.1.1.4 Evaluation of Response in Non-Target Lesions ............................................. 60 
 Assessment of Overall Response .......................................................................... 61 
 Best Overall Response Assessment ....................................................................... 62 
14.2 Overall Response Rate (ORR) ..................................................................................... 62 
14.3 Disease Control Rate (DCR) ........................................................................................ 62 
14.4 Progression Free Survival (PFS) .................................................................................. 62 
14.5 Time to Treatment Failure (TTF) ................................................................................. 63 
14.6 Overall Survival (OS) .................................................................................................. 63 
15. Reporting Safety Information ........................................................................................ 64 
15.1 Adverse Events/Serious Adverse Events ..................................................................... 64 
 Adverse Events ..................................................................................................... 64 
 Adverse Drug Reactions ....................................................................................... 65 
 Serious Adverse Events (SAE) ............................................................................. 65 
 Disease Progression .............................................................................................. 66 
 Pregnancy .............................................................................................................. 67 
 Other Information ................................................................................................. 67 
 Breaking the Study Blind ...................................................................................... 67 
15.2 Laboratory Evaluations ................................................................................................ 67 
 Reporting and Evaluation of Laboratory Test Results .......................................... 67 
 Repeat Testing ....................................................................................................... 68 
15.3 Physical Examination and Performance Status ............................................................ 68 
15.4 Body Temperature, Blood Pressure and Body Weight ................................................. 68 
16. Statistical Analysis .......................................................................................................... 69 
16.1 Timing of Statistical analyses ...................................................................................... 69 
 Interim Analyses ................................................................................................... 69 
 Primary Evaluation ............................................................................................... 69 
 Final Evaluation .................................................................................................... 69 
16.2 Populations and Criteria for Handling Patient Data ..................................................... 69 
 Analysis Populations ............................................................................................. 69 
 Criteria for Handling Patient Data ........................................................................ 70 
16.3 Statistical Methods ....................................................................................................... 70 
 Patient Disposition, Baseline and Treatment Characteristics ................................ 71 
(1) Patient Disposition ................................................................................................... 71 
(2) Patient Baseline Characteristics ............................................................................... 71 
(3) Evaluation of Comparability .................................................................................... 71 
 Primary Endpoint Analyses ................................................................................... 71 
 Secondary Endpoints Analyses ............................................................................. 72 
 
5 
 

 
 
 
16.3.3.1 Efficacy Endpoints ......................................................................................... 72 
16.3.3.2 Treatment Status ............................................................................................ 72 
16.3.3.3 Safety Analyses .............................................................................................. 73 
16.4 Determination of Sample Size ..................................................................................... 73 
17. Case Report Form ........................................................................................................... 75 
17.1 Preparation of CRF ...................................................................................................... 75 
18. Protocol Compliance, Deviation and Amendment ....................................................... 76 
18.1 Protocol Compliance .................................................................................................... 76 
18.2 Protocol Deviation ....................................................................................................... 76 
18.3 Revision of Protocol, etc. ............................................................................................. 76 
19. Direct Access to Source Documents ............................................................................... 78 
19.1 Identification of Source Documents............................................................................. 78 
19.2 Method of Direct Access to Source Documents .......................................................... 79 
20. Quality Control and Quality Assurance for the Study ................................................ 80 
20.1 Conduct of the study .................................................................................................... 80 
20.2 Quality Control of the Study ........................................................................................ 80 
 Monitoring Procedures .......................................................................................... 80 
 Curriculum Vitae ................................................................................................... 80 
20.3 Sponsor’s Audits and Regulatory Inspections .............................................................. 80 
21. Archiving of Records ...................................................................................................... 81 
21.1 Archiving of Records ................................................................................................... 81 
 Investigator ............................................................................................................ 81 
 Sponsor .................................................................................................................. 81 
22. Compensation to Subjects and Investigators ............................................................... 81 
23. Confidentiality ................................................................................................................. 82 
24. Publication policy ............................................................................................................ 82 
25. Study Period .................................................................................................................... 82 
26. Rationales ........................................................................................................................ 83 
26.1 Validity of the clinical study design ............................................................................. 83 
26.2 Rationale for endpoints ................................................................................................ 83 
26.3 Rationale for doses ....................................................................................................... 83 
26.4 Rationale for administration methods .......................................................................... 84 
26.5 Rationale for inclusion criteria ..................................................................................... 85 
26.6 Rationale for exclusion criteria .................................................................................... 86 
26.7 Rationale for prohibited concomitant drugs and therapies .......................................... 87 
26.8 Rationale for precautions for concomitant drugs and therapies ................................... 87 
26.9 Rationale for contraception period ............................................................................... 87 
27. References ........................................................................................................................ 88 
 
 
 
 
 
 
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LIST OF IN-TEXT FIGURES 
Figure 6.1-1  Study period ................................................................................................. 27 
Figure 10.1.2.1-1  Study regimen of TAS-118/L-OHP ..................................................... 37 
Figure 10.1.2.1-2  Study regimen of TAS-118 .................................................................. 37 
Figure 10.1.2.2-1  Study regimen of S-1/CDDP ............................................................... 38 
Figure 10.1.2.2-2  Study regimen of S-1 (1) ..................................................................... 38 
Figure 10.1.2.2-3 Study regimen of S-1 (2) ...................................................................... 39 
Figure 10.1.2.2-4 Study regimen of S-1 (3) ...................................................................... 39 
Figure 10.1.2.3-1  Study regimen of S-1/CDDP ............................................................... 40 
Figure 10.1.2.3-2  Study regimen of S-1 (1) ..................................................................... 40 
Figure 10.1.2.3-3  Study regimen of S-1 (2) ..................................................................... 40 
Figure 10.1.2.3-4  Study regimen of S-1 (3) ..................................................................... 40 
 
 
LIST OF IN-TEXT TABLES 
Table 2.3.1-1  ******************************* ..........................................................  
Table 2.3.1-2  ******************************************************** ........  
Table 2.3.2.1-1  *********************************************** .......................  
Table 7.1.1-1  Description of TAS-118.............................................................................. 28 
Table 7.1.2-1  Description of S-1 ...................................................................................... 29 
Table 10.1.1.1-1  Initial Dose of TAS-118 ........................................................................ 35 
Table 10.1.1.2-1  Initial Dose of S-1 ................................................................................. 36 
Table 10.1.3.1-1  Dose initiation criteria in each cycle for TAS-118 and L-OHP (Arm A)
 ..................................................................................................................................... 41 
Table 10.1.3.1-2  Dose initiation criteria in each cycle for S-1 and CDDP (Arm B) ........ 41 
Table 10.1.3.2-1  Dose interruption criteria within treatment cycle .................................. 42 
Table 10.1.3.2-2  Dose resumption criteria within treatment cycle ................................... 42 
Table 10.1.3.3-1  Dose reduction criteria for TAS-118 and L-OHP .................................. 43 
Table 10.1.3.3-2  Dose reduction scheme for TAS-118 and L-OHP ................................. 43 
Table 10.1.3.3-3  Reduced dose of administration for TAS-118 ....................................... 43 
Table 10.1.3.4-1  Dose reduction criteria for S-1 and CDDP ............................................ 44 
Table 10.1.3.4-2  Dose reduction scheme for S-1 and CDDP ........................................... 44 
Table 10.1.3.4-3  Reduced dose of administration for S-1 ................................................ 44 
Table 11.1-1  Data items for testing and monitoring ......................................................... 48 
Table 11.2-1  A Study Schedule  Arm A (TAS-118/L-OHP) ........................................... 50 
Table 11.2-2  A Study Schedule Arm B (S-1/CDDP) ........................................................ 51 
Table 14.1.2-1  Time Point Response for Patients with Target (+/- Non-target) Disease . 61 
Table 14.1.2-2  Time Point Response for Patients with only Non-target Disease ............. 61 
Table 16.2.1-1  Definitions of Analysis Populations ......................................................... 70 
Table 16.4-1  Powers(%) at various situations where expected MSTs of each arm change
 ..................................................................................................................................... 74 
 
 
 
 
7 
 

 
 
 
ABBREVIATIONS 
Abbreviation 
Definition 
5,10-methylene-THF 5,10-methylene tetrahydrofolate 
5-FU 
5-fluoropyrimidine-2,4(1H, 3H)-dione 
5-fluorouracil, fluorouracil 
5-HT3 
5-hydroxytryptamine receptor subtype 3 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AT 
as-treated 
BID 
bis in die; twice a day  
BSA 
body surface area 
CA19-9 
carbohydrate antigen 19-9 
CDDP 
(SP -4-2)-diamminedichloroplatinum, Cisplatin 
CDHP 
5-chloro-2,4-dihydroxyprimidine, Gimeracil 
CEA 
carcinoembryonic antigen 
CI 
confidence intervals 
CPH 
cox proportional hazards 
CPT-11 
irinotecan hydrochloride hydrate  
CR 
complete response 
CRC 
clinical research coordinator 
CRO 
contract research organization 
CRP 
c-reactive protein  
CT 
computed tomography  
CTCAE 
common terminology criteria for adverse events 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DPD 
dihydropyrimidine dehydrogenase 
ECOG 
eastern cooperative oncology group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EU 
European Union 
FAS 
full analysis set  
FdUMP 
5-fluoro-2’-deoxyuridine-5’-monophosphate 
FT 
5-fluoro-1-[(2RS)-tetrahydrofuran-2-yl] uracil, Tegafur 
GCP 
good clinical practice 
G-CSF 
granulocyte colony stimulating factor 
GOT 
glutamic oxaloacetic transaminase 
GPT 
glutamic pyruvic transaminase 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
international conference on harmonization  
IDMC 
independent data monitoring committee  
IEC 
independent ethics committee  
IND 
investigational new drug  
IRB 
institutional review board  
IWRS 
interactive web response system 
 
8 
 

 
 
 
JCOG 
Japan clinical oncology group 
LDH 
lactate dehydrogenase  
LV 
calcium folinate (dl-LV), Leucovorin 
l-LV 
levofolinate calcium  
L-OHP 
(SP-4-2)-[(1R, 2R)-Cyclohexane-1, 2-diamine-κN, κN'] 
[ethanedioato(2-)-κO1, κO2] platinum, Oxaliplatin 
MASCC 
Multinational Association of Supportive Care in Cancer 
MRI 
magnetic resonance imaging  
MST 
median survival time  
MTS 
maximum tolerated schedule 
NCCN 
national comprehensive cancer network 
NCI 
national cancer institute  
NE 
not evaluable 
ORR 
overall response rate  
OS 
overall survival  
Oxo 
monopotassium 1,2,3,4-tetrahydro-2,4- dioxo-1,3,5-triazine-6-carboxylate, oteracil 
potassium 
PD 
progressive disease 
PFS 
progression free survival  
PS 
performance status  
PR 
partial response 
PT-INR 
prothrombin time international normalized ratio 
PTP 
press-through package 
QOL 
quality of life 
RD 
recommended dose 
RECIST 
response evaluation criteria in solid tumors 
RS 
recommended schedule 
RR 
response rate  
SAE 
serious adverse event  
SAP 
statistical analysis plan  
SD 
stable disease 
SOP 
standard operating procedures 
TR 
tumor response  
TS 
thymidylate synthase  
TTF 
time to treatment failure  
TTP 
time to progression  
UFT 
Tegafur･Uracil 
 
 
 
 
9 
 

 
 
 
PROTOCOL SYNOPSIS 
Title of Study: 
An open-label randomized multi-center phase III study of TAS-118 plus Oxaliplatin 
(L-OHP) versus S-1 plus Cisplatin (CDDP) as first-line therapy in patients with 
advanced gastric cancer 
Phase: 
Phase III 
Study Objectives: 
To compare the following endpoints for the TAS-118/L-OHP (experimental arm) 
with the S-1/CDDP (control arm) in patients with advanced gastric cancer: 
Primary 
- 
Overall Survival (OS) 
Secondary 
- 
Progression Free Survival (PFS) 
- 
Time to Treatment Failure (TTF) 
- 
Overall Response Rate (ORR) 
- 
Disease Control Rate (DCR) 
- 
Safety 
Indication: 
Advanced Gastric cancer 
Inclusion Criteria: 
Patients must fulfil all of the following criteria at the time of randomization in this 
study: 
(1) Histologically confirmed adenocarcinoma of the stomach or esophagogastric 
junction with metastatic or recurrent disease. 
(2) Measurable or evaluable metastatic lesion (s), according to RECIST version 1.1 
detected by CT or MRI for response evaluation within 21 days prior to 
randomization. 
(3) Negative or unknown for HER2 testing. 
(4) No prior treatment (e.g. radiotherapy, chemotherapy, hormonal therapy) for 
gastric cancer.  
・ Adjuvant chemotherapy is permitted if more than 180 days has elapsed 
between the end of adjuvant therapy and first recurrence. Adjuvant 
chemotherapy with platinum agent is not permitted. 
(5) ECOG PS of 0 to 1. 
(6) At least 20 years of age*1 at the time of informed consent. 
(7) The following bone marrow, liver, and kidney function parameters measured 
within 14 days prior to randomization: 
1) Neutrophil count ≥ 1500/mm3 *2  
2) Hemoglobin ≥ 8.0 g/dL *2 
3) Platelet count ≥ 100000/mm3 *2 
4) Total bilirubin ≤ 1.5 mg/dL 
5) AST, ALT levels ≤ 3 x ULN, or ≤ 5 x ULN in the presence of liver 
metastasis 
6) ALP levels ≤ 2.5 x ULN, or ≤ 5 x ULN in the presence of liver metastasis 
7) Creatinine clearance ≥ 60 mL/min *3 
(8) Life expectancy of at least 90 days after randomization. 
(9) Capable of oral intake. 
(10) Written informed consent to participate as a subject in this clinical study. 
 
*1: For 75 years of age or older patient, pay careful attention to manage adverse 
events. 
*2: If patients received blood transfusion or treatment with any blood product or 
hematopoietic factor such as G-CSF, it must be confirmed the data is obtained 
more than 14 days after the last blood transfusion or treatment. 
 
10 
 

 
 
 
*3: A value obtained from a urine collection, if available. Otherwise an estimate by 
the Cockcroft-Gault formula: 
 
Estimated creatinine clearance (mL/min) 
= (140 - age) x Body weight (kg) / [72 x Serum creatinine (mg/dL)] 
For women, the obtained value is multiplied by a factor of 0.85. 
Exclusion 
Criteria: 
Patients who meet any of the following criteria at the time of randomization will be 
excluded from this study: 
(1) Serious hypersensitivity to any ingredients of S-1 or LV. 
(2) Treated with other investigational agents within 4 weeks before randomization. 
(3) Remain affected by a surgery performed before randomization. 
(4) Blood transfusion, treatment with blood products, or hematopoietic growth 
factors such as G-CSF within 2 weeks before randomization. 
(5) Ongoing treatment with flucytosine at the time of randomization. 
(6) Unmanageable Diarrhea (e.g. watery stool, difficulty in controlling bowel 
movements despite the medication, grade 2 or higher, 5 stools or more per day). 
(7) Current peripheral sensory neuropathy or paresthesia (grade 2 or higher). 
(8) Current or past severe lung disease (e.g. interstitial pneumonia, pulmonary 
fibrosis, or severe emphysema). 
(9) Any other active illness such as severe (e.g. grade 3 or higher) cardiac disease*1 
(e.g. myocardial infarction, angina pectoris, arrhythmia, or cardiac failure). Any 
of the following events within the 6 months prior to randomization: any episode 
of myocardial infarction or angina pectoris. 
(10) Diabetic patients who have poorly controlled despite the medication or severe 
diabetic complication. 
(11) Any other severe (e.g. Grade 3 or higher) complications (e.g. severe enteritis, 
severe stomatitis, gastrointestinal ulceration /perforation, ileus, renal failure, 
nephrosis syndrome, liver failure or cerebrovascular disorder). 
(12) Known human immunodeficiency virus (HIV) or active hepatitis. 
(13) Active infection, inflammatory diseases, or connective tissue disease (e.g. 
administration of intravenous antibiotics, fever of 38°C or higher). 
(14) Current use or anticipated need for continuous systemic steroid administration 
(oral or intravenous). 
(15) Active gastrointestinal bleeding (e.g. Grade 3 or higher). 
(16) Brain metastasis, present or suspected from clinical symptoms. 
(17) Extensive bone metastasis (e.g. whole pelvis, or 50% of spine). 
(18) Accumulation of pleural, ascitic, or pericardial fluid requiring drainage within 2 
weeks prior to randomization. 
(19) Other concurrent active cancer (synchronous double cancer or heterochronous 
double cancer with a disease-free interval of 5 years or shorter, excluding lesions 
consistent with intraepithelial cancer, i.e., carcinoma in situ, or intramucosal 
cancer that are assessed as cured by local treatment). 
(20) Pregnant, breast-feeding*2, possibly pregnant women or patients wishing to 
have children during the study period or a certain period (6 months) after 
stopping study treatment. Women of childbearing potential have to take a 
pregnancy test*3. 
(21) Concurrent mental disorder or psychiatric symptoms assessed as interfering 
with study participation. 
(22) Ineligible for participating in this study according to the investigator. 
 
*1: Patients with a cardiac pacemaker, or valve replacement are impossible to be 
randomized. 
*2: Women who stop breast-feeding are impossible to be randomized. 
*3: Women of childbearing potential are defined as any women who are 
 
11 
 

 
 
 
premenopausal, less than 1 year after last menses, more than 1 year with no 
menses due to medical causes, or not permanently sterilized and so on.   
 
Treatment 
Regimens: 
[Arm A (TAS-118/L-OHP)] 
L-OHP will be administered intravenously at dose of 85 mg/m2 on day 1, and 
TAS-118 will be administered 30-60 mg orally twice daily for 7 days (day 1 through 
day 7),  repeated  every 2 weeks. Treatment will be continued during the study 
period unless any of Study Treatment Discontinuation Criteria (see Section 13.1.1) is 
met. 
[Arm B (S-1/CDDP)] 
CDDP will be administered intravenously at dose of 60 mg/m2 on day 1 (Korea) or 
day 8 (Japan), and S-1 will be administered 40-60 mg orally twice daily for 21 days 
(day 1 through day 21), repeated every 5 weeks (rest period can be shorten from 14 
days to 7 days). Treatment will be continued during the study period unless any of 
Study Treatment Discontinuation Criteria (see Section 13.1.1) is met. 
Registration 
Central registration 
Study drugs 
TAS-118 (granules): 30 mg, 40 mg, 50 mg, 60 mg 
L-OHP (infusion solution): 100 mg 
S-1 (capsule): 20 mg, 25 mg 
CDDP (infusion solution): 50 mg 
Allocation 
Treatment assignment will be done centrally using a dynamic allocation method 
(minimization method) via an IWRS stratified by:  
- 
ECOG PS: (0, 1) 
- 
Measurable lesion: (Yes, No) 
- 
Country: (Japan, Korea) 
Observation/ 
examination items 
and study 
schedule 
See Tables in the following page. 
Evaluation 
method 
Evaluation of anti-tumor effects 
- 
RECIST criteria version 1.1 
Evaluation of adverse events 
- 
CTCAE version 4.03 
Planned Sample 
Size: 
686 patients will be enrolled in the study using a treatment allocation of 1:1 
(TAS-118/L-OHP: S-1/CDDP). 
Study period 
December 2014 to May 2020 
 
 
12 
 

 
 
 
Table 1  A Study Schedule  Arm A (TAS-118/L-OHP) 
Procedure 
Pretreatment Period 
Study Treatment Period 
Post-treatment Follow-up Period 
within 28 
days 
prior to 
randomiz
ation 
within 21 
days 
prior to 
randomiz
ation 
within 14 
days 
prior to 
randomiz
ation 
within 7 
days prior 
to 
Day 1 of 
the  first 
treatment 
cycle e 
Arm A 
End of 
Treatment j 
(+14 days) 
Safety 
Follow-up k 
30 days 
after last 
dose of 
study 
treatment 
(+14 days) 
Tumor 
Follow-up 
Every  6 
weeks 
(+/- 1 
week) 
Survival 
Follow-up 
Every  12 
weeks 
(+/-2 
weeks) 
Day 1 
Before 
Initiation of 
next treatment 
cycle h, i 
Day15 
(Day 14 to 18) 
TAS-118 treatment 
 
 
 
 
X f 
(Day 1 - 7) 
 
 
 
 
 
L-OHP treatment 
 
 
 
 
X f 
 
 
 
 
 
Signed ICF 
X 
 
 
 
 
 
 
 
Patient Background 
X 
 
 
 
 
 
 
 
Height 
 
 
X 
 
 
 
 
 
 
 
Pregnancy Test a 
 
 
X 
 
 
 
 
 
 
 
Weight 
 
 
X 
X 
→ g 
X 
X 
 
 
ECOG PS 
 
 
X 
X 
→ g 
X 
X 
 
 
Blood Pressure 
 
 
X 
X 
→ g 
→ g 
 
 
Body Temperature 
 
 
X 
X 
→ g 
→ g 
 
 
ECG 
 
X 
 
→ g 
→ g 
 
 
Physical 
Examination 
 
 
X 
X 
 
X 
X 
X 
 
 
Hematology 
 
 
X 
X 
 
X 
X 
X 
 
 
Serum Chemistry b 
 
 
X 
X 
 
X 
X 
X 
 
 
Urinalysis b 
 
 
X 
X 
 
X 
X 
X 
 
 
Tumor Markers c 
 
X 
→ 
→ 
→ 
→ 
→ 
X 
 
Tumor 
Measurements c 
 
X 
→ 
→ 
→ 
→ 
→ 
X 
 
Concomitant 
Medications d 
X 
→ 
→ 
→ 
→ 
X 
 
 
AE/SAE 
Assessment d 
X 
→ 
→ 
→ 
→ 
X 
 
 
Post Treatment 
 
 
 
 
 
 
 
 
 
X 
Survival Status 
 
 
 
 
→ 
→ 
→ 
→ 
→ 
X l 
 
a. 
If the patient is female and of childbearing potential, a pregnancy test (serum or urine) must be done and the results must be negative 
at baseline. 
b. 
Creatinine clearance is mandatory only at prior to randomization. 
c. 
Every 6 weeks starting on the day of randomization (the data may be collected within 1 week before or after the scheduled date). 
Patients without progressive disease (PD) defined by RECIST version 1.1 must be followed for tumor assessment. 
d. 
Monitor patients for any medications and untoward medical events from the time of signed ICF through the safety follow-up period. 
e. 
These data may be collected within 7 day prior to Day 1 of the first treatment cycle. These tests may be substituted by the data 
obtained within 14 days prior to randomization if screening data is obtained within 7 days prior to Day 1 of the first treatment cycle. 
f. 
Study drug administration is to be initiated within 8 days after randomization.  
g. 
If abnormalities are indicated by other physical examination or tests, it must be performed. 
h. 
These data may be collected 15 days after Day 1 (from Day 14 to Day 18 if not feasible on Day 15) of each treatment cycle. 
i. 
Every 1 week starting on Day 1 of each treatment cycle if the next treatment cycle is delayed (the data may be collected within 7 days 
before the scheduled date). Examination is mandatory on Day 1 or the day before starting the study treatment specified in this 
protocol. 
j. 
End of treatment assessments must be completed within 14 days from the date of last dose of study drug. 
k. 
These data may be collected 30 days after last dose of study drug or until the start of new anti-tumor therapy, whichever comes first. 
In cases an AE/SAE related to study drug is not resolving, the safety follow-up period will be extended. 
l. 
Obtain survival status (alive/ dead) at scheduled 12-week time intervals from randomization until death, and at the cutoff date for 
second interim analysis and primary evaluation (the data may be collected within 2 weeks before or after the scheduled date). 
 
 
 
 
13 
 

 
 
 
Table 2  A Study Schedule  Arm B (S-1/CDDP) 
Procedure 
Pretreatment Period 
Study Treatment Period 
Post-treatment Follow-up Period 
within 28 
days 
prior to 
randomiz
ation 
within 21 
days 
prior to 
randomiz
ation 
within 14 
days 
prior to 
randomiz
ation 
within 7 
days prior 
to 
Day 1 of 
the  first 
treatment 
cycle e 
Arm B 
End of 
Treatment m 
(+14 days) 
Safety 
Follow-up n 
30 days 
after last 
dose of 
study 
treatment 
(+14 days) 
Tumor 
Follow-up 
Every  6 
weeks 
(+/- 1 week) 
Survival 
Follow-up 
Every  12 
weeks 
(+/-2 
weeks) 
Day 1 
Day 8 i 
(Day 6 to 
15) 
(Japan) 
Day 15 j 
(Day 8 to 
22) 
Before 
Initiation of 
next treatment 
cycle k, l 
Day36 
(Day 29 to 43) 
S-1 treatment 
 
 
 
 
X f 
(Day 1 - 21) 
 
 
 
 
 
CDDP treatment 
(Korea) 
 
 
 
 
X f 
 
 
 
 
 
 
 
CDDP treatment 
(Japan) 
 
 
 
 
 
X g 
 
 
 
 
 
 
Signed ICF 
X 
 
 
 
 
 
 
 
 
 
Patient Background 
X 
 
 
 
 
 
 
 
 
 
Height 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test a 
 
 
X 
 
 
 
 
 
 
 
 
 
Weight 
 
 
X 
X 
→ h 
X 
X 
 
 
ECOG PS 
 
 
X 
X 
→ h 
X 
X 
 
 
Blood Pressure 
 
 
X 
X 
→ h 
→ h 
 
 
Body Temperature 
 
 
X 
X 
→ h 
→ h 
 
 
ECG 
 
X 
 
→ h 
→ h 
 
 
Physical 
Examination 
 
 
X 
X 
 
X i 
X 
X 
X 
X 
 
 
Hematology 
 
 
X 
X 
 
X i 
X 
X 
X 
X 
 
 
Serum Chemistry b 
 
 
X 
X 
 
X i 
X 
X 
X 
X 
 
 
Urinalysis b 
 
 
X 
X 
 
X i 
X 
X 
X 
X 
 
 
Tumor Markers c 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
Tumor 
Measurements c 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
Concomitant 
Medications d 
X 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
 
AE/SAE 
Assessment d 
X 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
 
Post Treatment 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival Status 
 
 
 
 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X o 
 
a. If the patient is female and of childbearing potential, a pregnancy test (serum or urine) must be done and the results must be negative at 
baseline. 
b. Creatinine clearance is mandatory only at prior to randomization. 
c. Every 6 weeks starting on the day of randomization (the data may be collected within 1 week before or after the scheduled date). 
Patients without PD defined by RECIST version 1.1 must be followed for tumor assessment. 
d. Monitor patients for any medications and untoward medical events from the time of signed ICF through the safety follow-up period. 
e. These data may be collected within 7 day prior to Day 1 of the first treatment cycle. These tests may be substituted by the data obtained 
within 14 days prior to randomization if screening data is obtained within 7 days prior to Day 1 of the first treatment cycle. 
f. 
Study drug administration is to be initiated within 8 days after randomization. 
g. CDDP administration shall be permitted within 2 days before and 7 days after the reference day. 
h. If abnormalities are indicated by other physical examination or tests, it must be performed. 
i. 
When administering CDDP, the examination on the day before administration or on the day of administration until the start of 
administration (hematology, serum chemistry, urinalysis, and physical examination) shall be mandatory. 
j. 
These data may be collected 15 days after Day 1 (from Day 8 to Day 22 if not feasible on Day 15) of each treatment cycle. Collect this 
data after the data of day8 and don’t put the data of day 8 together in Japan. 
k. These data may be collected 36 days (from Day 29 to Day 43 if not feasible on Day 36) after Day 1 of each treatment cycle.  
l. 
Every 1 week starting on Day 1 of each treatment cycle if the next treatment cycle is delayed (the data may be collected within 7 days 
before the scheduled date). Examination is mandatory on Day 1 or the day before starting the study treatment specified in this protocol. 
m. End of treatment assessments must be completed within 14 days from the date of last dose of study drug. 
n. These data may be collected 30 days after last dose of study drug or until the start of new anti-tumor therapy, whichever comes first. In 
cases an AE/SAE related to study drug is not resolving, the safety follow-up period will be extended. 
o. Obtain survival status (alive/ dead) at scheduled 12-week time intervals from randomization until death, and at the cutoff date for 
second interim analysis and primary evaluation (the data may be collected within 2 weeks before or after the scheduled date).  
 
14 
 

 
 
 
1. Study Administrative Structure 
1.1 Title of Protocol, Protocol Number and Date of Preparation 
Title of study: An open-label randomized multi-center phase III study of TAS-118 plus  
Oxaliplatin versus S-1 plus Cisplatin as first-line therapy in patients with  
advanced gastric cancer 
Protocol number: ******** (Ver.P05) 
Date: 07 Nov 2019 
 
1.2 Sponsor 
Company name: Taiho Pharmaceutical Co., Ltd. 
Location: 1-27, Kandanishiki-cho, Chiyoda-ku, Tokyo 
 
1.3 Contract Research Organization 
Company name: ICON Clinical Research Limited 
Location: South County Business Park, Leopardstown, Dublin 18, Ireland 
 
 
 
 
 
15 
 

 
 
 
2. Background Information 
2.1 Background of disease 
Gastric cancer is the third most common cancer on incidence of mortality worldwide 
(second common in Japan and third common in Korea)1. Surgical therapy is indicated for 
early gastric cancer. Based on the results of previously conducted clinical trials2,3,4which had 
shown the prolongation of overall survival (OS) in the chemotherapy group compared with 
the untreated group (Best Supportive Care: BSC), chemotherapy had been indicated for 
unresectable advanced, recurrent gastric cancer. 
 
2.2 Current standard treatment 
Chemotherapy for patients with unresectable, advanced/recurrent gastric cancer 
For chemotherapy in patients with unresectable, advanced/recurrent gastric cancer, 
5-fluorouracil (5-FU)-based combination therapy has been the most widely used.  
MacDonald et al. reported FAM therapy [the median survival time (MST), 5.5 months]5, a 
triple combination therapy with 5-FU, doxorubicin, and mitomycin C in 1980. The 
recommended treatment regimens vary from region to region. In the Europe, ECF 
[epirubicin/cisplatin 
(CDDP)/5-FU] 
therapy 
and 
EOX 
[epirubicin/oxaliplatin 
(L-OHP)/capecitabine] therapy are recommended, according to the result of the REAL2 
study6, which showed the non-inferiority of EOX therapy to ECF therapy. In the US, DCF 
(docetaxel/CDDP/5-FU) therapy is recommended, in accordance with the result of the V325 
study7, which showed the superiority of DCF therapy to CF (CDDP/5-FU) therapy. In 
regions other than Europe and the US, FP (5-FU/CDDP) therapy is recommended. 
Both in Japan and Korea, the combination therapy with fluoropyrimidine antitumor agents 
and platinum preparations is recommended as a standard therapy. The results of the 
JCOG9912 study8 (5-FU vs. CPT-11/CDDP vs. S-1) conducted in Japan showed that the OS 
of S-1 monotherapy was non-inferior to that of 5-FU continuous intravenous infusion, which 
was the standard therapy at that time. Moreover, in the SPIRITS study9 (S-1 vs. S-1/CDDP), 
S-1/CDDP combination therapy showed a significant prolongation of OS compared with S-1 
monotherapy. In addition, the ToGA study10 in patients with HER2 positive gastric cancer 
showed a significant OS prolongation when Trastuzumab, a molecular target agent, was 
added to capecitabine (or 5-FU)/CDDP therapy. On the basis of these results, the Japanese 
Gastric Cancer Treatment Guidelines (ver. 4) (revised in May 2014) 11  recommends 
capecitabine (or 5-FU)/CDDP/Trastuzumab therapy for patients with HER2-positive 
advanced/recurrent gastric cancer and S-1/CDDP combination therapy and S-1 monotherapy 
for patients with HER2-negative gastric cancer who can receive oral drugs. Clinical practice 
guidelines for gastric cancer in Korea published in 201412 recommends fluoropyrimidines 
(5-FU, capecitabine, or S-1)/CDDP combination therapy and (5-FU or capecitabine)/L-OHP 
combination therapy as a treatment regimen for first-line chemotherapy. 
Compared with L-OHP, CDDP requires hydration for the prevention of renal toxicity 
before treatment. Therefore replacement of CDDP by L-OHP requiring no hydration is under 
investigation. 
 
16 
 

 
 
 
As the REAL2 study (ECF vs. ECX vs. EOF vs. EOX)6 demonstrated the non-inferiority 
of OS in the L-OHP and CDDP groups, the efficacy of CDDP is considered to be similar to 
that of L-OHP. To evaluate non-inferiority of S-1/CDDP therapy to S-1/L-OHP therapy, the 
phase III clinical study (G-SOX study13,14) (S-1/CDDP vs. S-1/L-OHP) was performed in 
Japan. This result showed that the progression free survival (PFS) of S-1/L-OHP therapy was 
non-inferior to that of S-1/CDDP therapy but did not show the non-inferiority of OS. 
Oxaliplatin has not been approved for gastric cancer yet in Japan. 
 
2.3 Introduction of novel anti-cancer therapy 
 
TAS-118 
TAS-118 is an anti-cancer drug in which the components of TS-1 (S-1), i.e. tegafur (FT), 
gimeracil (CDHP), and oteracil potassium (Oxo), are combined with calcium folinate (dl-LV, 
hereafter LV). 
S-1 is a combination product containing FT, a prodrug of Fluorouracil (5-FU), and 2 
modulators, CDHP and Oxo, in a molar ratio of 1:0.4:1. CDHP increases 5-FU concentration 
by reversible inhibition of dihydropyrimidine dehydrogenase (DPD), an enzyme that 
degrades 5-FU, while Oxo, densely distributed in gastrointestinal tissues, prevents 
gastrointestinal toxicity of 5-FU by inhibiting its local activation. 
S-1 is an oral anticancer treatment, which has been developed by combining the three 
components to enhance therapeutic efficacy in comparison with conventional 5-FU products 
and also to reverse the resulting increase in adverse drug reactions. In Japan, the initial 
marketing authorization was granted in 1999 for S-1 capsules as a treatment for gastric 
cancer. Thereafter the indications have been extended to include head and neck cancer, 
colorectal cancer, non-small-cell lung cancer, unresectable or recurrent breast cancer, 
pancreatic cancer, and biliary tract cancer. In addition, fast-dissolving granules and orally 
disintegrating tablets were developed as an additional dosage form to provide a new option to 
diverse patients. S-1 is approved in Korea for the treatment of gastric cancer and head and 
neck cancer, in China for the treatment of advanced gastric cancer, in Singapore for 
postoperative adjuvant chemotherapy for locally advanced gastric cancer, in Taiwan for the 
treatment of gastric cancer and locally advanced or metastatic pancreatic cancer, in Hong 
Kong for postoperative adjuvant chemotherapy for locally advanced gastric cancer, in 
Thailand for treatment of advanced gastric cancer in adult by combination use with CDDP 
and use as monotherapy for adjuvant treatment for locally advanced gastric cancer, and in 
Malaysia for the treatment of advanced gastric cancer when given in combination with 
CDDP and postoperative adjuvant chemotherapy for locally advanced gastric cancer. In the 
EU, Norway, Iceland and Liechtenstein, S-1 has been approved in adults for the treatment of 
advanced gastric cancer when given in combination with CDDP. 
LV is an equal mixture of d- and l-diastereomers, among which the l-form is biologically 
active, e.g. in enhancing the antitumor efficacy of 5-FU. A number of basic studies have 
shown that coadministration of LV potentiates the inhibition by 5-FU of thymidylate synthase 
(TS), an enzyme that catalyzes thymidylate biosynthesis. LV is reduced to 5,10-methylene 
tetrahydrofolate (5,10-methylene-THF), which serves as a methyl donor in the pathway to 
 
17 
 

 
 
 
synthesize thymidylate, a substance essential for nucleic acid production, while 5-FU is 
phosphorylated to 2’-deoxy-5-fluorouridine-5’-monophosphate (FdUMP), which forms a 
stable ternary complex with TS and 5,10-methylene-THF, resulting in inhibition of nucleic 
acid synthesis. LV, when combined with 5-FU, is thus believed to enhance the formation of 
the ternary complex, and to thereby potentiate the antitumor efficacy of 5-FU. The benefits of 
combining 5-FU and LV in the treatment of colon cancer have been reported in many clinical 
researches, including a meta-analysis of more than 3000 subjects, which reported that 
coadministration of 5-FU and LV produced an increased response rate and prolonged survival 
in comparison with 5-FU alone15, and l-LV for injection has been in clinical use since being 
approved for “Enhancement of the antitumor efficacy of 5-FU for treatment of gastric cancer 
(unresectable or recurrent) and colorectal cancer” in Japan. In Korea, l-LV for injection has 
been approval for “advanced colorectal cancer with 5-FU” and “reduction of the toxicity of 
anti-folate agent”. Meanwhile, combination therapy with UFT, an oral agent, and oral LV was 
developed to improve ease of use in comparison with 5-FU/LV, and oral LV preparations 
were approved for “Enhancement of the antitumor efficacy of UFT for treatment of 
colorectal cancer” in Japan. In Korea, oral LV is approval for “reduction of the toxicity of 
anti-folate agent”. 
Given that LV has been shown to enhance the antitumor efficacy when coadministered 
with 5-FU or its prodrug, FT, LV was expected to produce a further enhancement in efficacy 
when combined with S-1, which also contains FT in combination with CDHP, a more potent 
DPD inhibitor than uracil, a component of UFT. 
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2.4 Rationale for considering the new therapy as promising 
Efficacy of TAS-118 and L-OHP against gastric cancer 
In the ******************** for patients with unresectable, advanced, recurrent gastric 
cancer conducted in Japan (see section 2.3.2.4), RR was highest at 66% for the 
S-1/LV/L-OHP group and PFS was 8.3 months, and OS was 18.4 months. On the other hand, 
RR was 46%, PFS was 5.6 months and OS was 12.6 months for one of the standard therapy, 
S-1/CDDP group, and S-1/LV/L-OHP group showed high efficacy. In addition, the efficacy 
of S-1/CDDP group was similar to other studies9, 13, 24. Therefore S-1/LV/L-OHP was 
suggested as promising regimen to show high efficacy. Regarding safety, tolerability was also 
 
23 
 

 
 
 
shown. From these results, TAS-118/L-OHP therapy using TAS-118 containing S-1 and LV is 
expected to be promising as the first-line therapy in patients with gastric cancer. 
 
3. GCP Compliance and Ethical Conduct of the Study 
3.1 GCP Compliance 
It is mandatory that all considerations regarding the protection of human subjects be 
carried out in accordance with the protocol, Good Clinical Practices (GCP), ICH Guidelines, 
the ethical principles that have their origin in the Declaration of Helsinki, and all applicable 
regulatory requirements. 
 
3.2 Protection of Subjects’ Privacy 
When processing and archiving personal data pertaining to the investigator and or to the 
patients, the sponsor or its representatives shall take all appropriate measures to safeguard 
and prevent access to this data by any unauthorized third party. 
 
3.3 Institutional Review Board/Independent Ethics Committee Approval 
The study must be approved by an appropriately constituted Institutional Review Board 
(IRB)/ Independent Ethics Committee (IEC), as required in Chapter 3 of the ICH E6 
Guidelines. 
The IRB/IEC must provide written approval of the study. The written approval/favorable 
opinion should include protocol (title, protocol number and version number), list of 
documents reviewed (e.g., protocol, ICF, IB, curriculum vitae, etc), and the date of the 
review. 
The investigator is required to submit a copy of the written and dated IRB/IEC 
approval/favorable opinion to the sponsor or its representative prior to initiation of this study. 
Investigational product will not be released to the trial site and the investigator will not 
start the trial until this written IRB/IEC approval/favorable opinion is received by the sponsor 
or its representative. 
The investigator is responsible for obtaining renewal of approval throughout the duration 
of the study. Timeframes for renewal will be based on IRB/IEC requirements but renewal at 
least annually is required by regulations. 
At the end of the trial, the IRB/IEC will be notified of the conclusion of the trial and its 
outcome. 
 
 
24 
 

 
 
 
4. Study Objectives 
4.1 Primary objective 
To compare the overall survival (OS) in patients with advanced gastric cancer treated with 
TAS-118/L-OHP versus S-1/CDDP. 
 
4.2 Secondary objective 
To compare the efficacy and safety of TAS-118/L-OHP versus S-1/CDDP in patients with 
advanced gastric cancer． 
 
5. Study Design 
5.1 Endpoints 
 
Primary 
Overall Survival：OS 
 
Secondary 
Progression Free Survival：PFS 
Time to Treatment Failure：TTF 
Overall Response Rate：ORR 
Disease Control Rate：DCR 
Safety 
 
5.2 Study Type 
 
Study Type by Objectives 
Type: Confirmatory trial 
Objectives: Assessment of the evidence of efficacy 
 
 
Study Type by Design 
Multinational, multicenter, open-label, active-controlled, randomized, parallel-group, 
comparative study using central registration 
 
5.3 Description of Study Design 
This trial is confirmatory trial to evaluate the superiority of TAS-118/L-OHP therapy 
against S-1/CDDP therapy in the OS. 
Patients with advanced gastric cancer will be enrolled using the central registration 
method on a multicenter basis, randomized to two treatment groups, and treated/evaluated on 
 
25 
 

 
 
 
an open-label basis. 
 
5.4 Patient Numbering and Randomization 
Once patient have been confirmed to be eligible, patients will be centrally randomized in a 
1:1 ratio to TAS-118/L-OHP (experimental arm) or S-1/CDDP (control arm) via an 
Interactive Web Response System (IWRS) based on a dynamic allocation method 
(minimization method). Detailed instructions for randomization are provided as a separate 
document. 
The IWRS will assign a unique patient number as well as identification corresponding to 
the patient’s treatment assignment. 
No patients will be replaced at any time during this study. 
Patient will be stratified by the following factors: 
- 
ECOG PS: (0, 1) 
- 
Measurable lesion: (Yes, No) 
- 
Country: (Japan, Korea) 
 
5.5 Blinding 
This is an open-label study. 
Maintenance of blinding would require a double-dummy design because of the difference 
between treatment procedures, but in this study with cancer patients, double-dummy blinding 
may reduce treatment compliance of subjects and thereby affect the assessment of efficacy 
and safety. Therefore an open-label design was selected. 
 
 
 
 
26 
 

 
 
 
6. Study Procedures 
6.1 Explanation of Study Schedule to Individual Subjects 
 
Figure 6.1-1  Study period 
 
 
 
Definition of Study Period 
Study periods for each patient are defined below: 
・ Pretreatment Period:  Commences on the day the ICF is signed and lasts until the day 
prior to initiation study treatment. 
・ Study Treatment Period:  Commences on the day of initiation study treatment and lasts 
until the day the patient meets any of the study treatment discontinuation criteria (see. 
13.1.1 Study Treatment Discontinuation Criteria). 
・ Safety Follow-up Period:  Defined as the day after the end of study treatment (i.e. last 
dose of study drug) until 30 days or until the start of new anti-tumor therapy, whichever 
comes first. (see. 13.1.2 Safety Follow-up Discontinuation Criteria). 
・ Tumor Follow-up Period:  Applicable only to patients who have had no progressive 
disease (PD) defined by RECIST version 1.1 until the end of study treatment and defined 
as the day after the end of study treatment until patients meet tumor follow-up 
discontinuation criteria (see. 13.1.3 Tumor Follow-up Discontinuation Criteria). 
・ Survival Follow-up Period:  Defined as the day after the end of study treatment until 
patients meet survival follow-up discontinuation criteria (see. 13.1.4 Survival Follow-up 
Discontinuation Criteria). The patient will be followed for survival and the use of new 
anti-tumor therapy. 
・ Post-Treatment Follow-up Period:  Defined as the day after the end of study treatment. 
 
 
Adm. Reco
very
Adm. Reco
very
Reco
very
Adm.
≤7days
*Adm.: administration
≤28days
Tumor Follow-up Period
≤14days
≤21days
Survival Follow-up Period
≤30days
Pretreatment Period
Study treatment Period
Post-treatment Follow-up Period
Safety Follow-up
Period
IC
Randomization
Tumor Follow-up Period
Discontinuation
Survival Follow-up Period
Discontinuation
Study treatment
Discontinuation
Safety Follow-up Period
Discontinuation
Day1
Screening
Screening
(CT･MRI)
 
27 
 

 
 
 
7. Study Drug 
The sponsor will supply TAS-118 (30, 40, 50, 60 mg), S-1 (20, 25 mg), L-OHP (100 mg), 
CDDP (50 mg) during study period.  
TAS-118 will be packed in sachet packages in a box. S-1 will be packed in a press through 
package (PTP) in a box. 
7.1 Study Drug 
 
TAS-118 
TAS-118 is an anti-cancer drug in which the components of S-1, i.e. tegafur (FT), 
gimeracil (CDHP), and oteracil potassium (Oxo), are combined with calcium folinate (LV). 
Physical and chemical characteristics of the active ingredients are shown in Table 7.1.1-1. 
 
Table 7.1.1-1  Description of TAS-118 
Code name 
TAS-118 
Generic 
name 
Tegafur 
Gimeracil 
Oteracil 
potassium 
Calcium Folinate 
Chemical 
name 
5-fluoro-1- 
[(2RS)-tetrahydrof
uran-2-yl]uracil 
5-chloro-2,4- 
dihydroxypyr
idine 
monopotassium 
1,2,3,4-tetrahyd
ro-2,4- 
dioxo-1,3,5-tria
zine-6- 
carboxylate 
monocalcium 
N-{4-[(2-amino-5-formyl-4-ox
o-1,4,5,6,7,8-hexahydropteridi
n- 
6-yl)methylamino]benzoyl}-L-
glutamate 
Chemical 
structure 
 
 
 
 
 
 
 
 
and enantiomer 
 
 
 
Molecular 
formula 
C8H9FN2O3 
(200.17) 
C5H4ClNO2 
(145.54) 
C4H2KN3O4 
(195.17) 
C20H21CaN7O7 
(511.50) 
Dosage form 
Combination granules 
Description 
TAS-118 (30 mg): 
white granules and white to yellowish 
white granules in one pack 
TAS-118 (40 mg): 
white granules and white to yellowish 
white granules in one pack 
TAS-118 (50 mg): 
white granules and white to yellowish 
white granules in one pack 
TAS-118 (60 mg): 
white granules and white to yellowish 
white granules in one pack 
Compounds 
and unit dose 
TAS-118 (30 mg): 
*****************************************************
*****************************************************
******** 
TAS-118 (40 mg): 
*****************************************************
*****************************************************
******** 
N H 
N O 
F 
O 
O 
H 
N 
O H 
C l 
O H 
N
NH
H
N
O
O
KO2C
H
N
N
N
H
N
O
H2N
H
N
H
N
CO2
O
H
CO2
Ca2+
O
H
 
28 
 

 
 
 
TAS-118 (50 mg): 
*****************************************************
*****************************************************
******** 
TAS-118 (60 mg): 
*****************************************************
*****************************************************
******** 
Composition 
TAS-118 is a combination of S-1 and LV. S-1 is a combination of FT, CDHP and Oxo 
with a molar ratio of 1: 0.4: 1. S-1 (as FT 30mg, 40 mg, 50 mg and 60 mg) is combined 
with LV 25 mg (as folinate). TAS-118 drug product is immediate release granules 
packed in a sachet. 
**********************************************************************. 
Storage 
condition 
Room temperature (1-30°C) 
Package form 
30mg/dose          1 pack: TAS-118 (30) x 14 (Color: pink) 
40mg/dose          1 pack: TAS-118 (40) x 14 (Color: yellow) 
50mg/dose          1 pack: TAS-118 (50) x 14 (Color: blue) 
60mg/dose          1 pack: TAS-118 (60) x 14 (Color: gray) 
Two aluminum pouches with desiccant in a box 
 
 
S-1 
S-1 is an anti-tumor nucleoside drug that combines Tegafur, Gimeracil and Oteracil 
potassium. Physical and chemical characteristics of the active ingredients are shown in Table 
7.1.2-1. 
 
Table 7.1.2-1  Description of S-1 
Code name 
S-1 
Generic 
name 
Tegafur 
Gimeracil 
Oteracil potassium 
Chemical 
name 
5-fluoro-1- 
[(2RS)-tetrahydrofuran-2-
yl]uracil 
5-chloro-2,4- 
dihydroxypyridine 
monopotassium 
1,2,3,4-tetrahydro-2,4- 
dioxo-1,3,5-triazine-6- 
carboxylate 
Chemical 
structure 
 
 
 
 
 
 
 
 
and enantiomer 
 
 
Molecular 
formula 
C8H9FN2O3 
(200.17) 
C5H4ClNO2 
(145.54) 
C4H2KN3O4 
(195.17) 
Dosage form 
Capsule 
Description 
S-1 (20mg): 
An opaque, hard-shell capsule with a white cap and white body containing 
white powder and granules 
S-1 (25mg): 
An opaque, hard-shell capsule with an orange cap and white body 
containing white powder and granules 
Compounds 
S-1 (20mg):  
Tegafur (20 mg), gimeracil (5.8 mg) and oteracil potassium (19.6 mg) 
N H 
N O 
F 
O 
O 
H 
N 
O H 
C l 
O H 
N
NH
H
N
O
O
KO2C
 
29 
 

 
 
 
and unit 
dose 
S-1 (25mg): 
Tegafur (25 mg), gimeracil (7.25 mg) and oteracil potassium (24.5 mg) 
Composition 
S-1 is an immediate release dosage form contained in a capsule in which FT, CDHP, and 
Oxo are combined at a molar ratio of 1:0.4:1. The capsule excipients are lactose 
monohydrate and magnesium stearate. 
Storage 
condition 
room temperature (1-30°C) 
Package form 
(1) 
40 mg/dose 
1 sheet:S-1 (20) x 2 CAP x 2 x 7 (PTP board color: copper) 
50 mg/dose 
1 sheet:S-1 (25) x 2 CAP x 2 x 7 (PTP board color: blue) 
60 mg/dose 
1 sheet:S-1 (20) x 3 CAP x 2 x 7 (PTP board color: silver) 
Four sheets in a box 
Package form 
(2) 
40 mg/dose 
1 sheet:S-1 (20) x 2 CAP x 2 x 7 (PTP board color: copper) 
50 mg/dose 
1 sheet:S-1 (25) x 2 CAP x 2 x 7 (PTP board color: blue) 
60 mg/dose 
1 sheet:S-1 (20) x 3 CAP x 2 x 7 (PTP board color: silver) 
Three sheets in a box 
 
7.2 Oxaliplatin (L-OHP) 
Oxaliplatin will be provided in this clinical study. See the current package insert for 
handling, treatment, and storage of L-OHP. 
 
7.3 Cisplatin (CDDP) 
Cisplatin will be provided in this clinical study. See the current package insert for 
handling, treatment, and storage of CDDP. 
 
7.4 Packaging and Labeling of Study Drug 
Required information will be printed on the label(s) according to local regulatory 
requirements. 
 
7.5 Delivery, Storage, Control, Retrieve of Study Drug 
In accordance with International Conference on Harmonization (ICH) and local regulatory 
requirements, the investigator and/or the person responsible for dispensing study drug must 
be able at all times to account for all study drug provided to the site. The study drug 
administrator of the study site follows “study drug management procedures”. Record the use 
of all study drug on the appropriate Drug Accountability Record. 
Dose reductions, interruptions, and reasons for these actions must be recorded in the 
patient’s source documents. 
At the conclusion of the study, all unused study drug shipped to the investigator must be 
returned to the sponsor or its representative. 
No study drug is to be used outside of this study. 
 
30 
 

 
 
 
 
8. Criteria for Inclusion and Exclusion of Patients 
8.1 Inclusion Criteria 
Patients must fullfil all of the following criteria at the time of randomization in this study: 
The rationale is provided in “26.5 Rationale for inclusion criteria”. 
(1) Histologically confirmed adenocarcinoma of the stomach or esophagogastric junction 
with metastatic or recurrent disease. 
(2) Measurable or evaluable metastatic lesion(s), according to RECIST version 1.1 detected 
by CT scan or MRI for response evaluation within 21 days prior to randomization. 
(3) Negative or unknown for HER2 testing. 
(4) No prior treatment (e.g. radiotherapy, chemotherapy, hormonal therapy) for gastric 
cancer. 
・ Adjuvant chemotherapy is permitted if more than 180 days has elapsed between the 
end of adjuvant therapy and first recurrence. Adjuvant chemotherapy with platinum 
agent is not permitted. 
(5) ECOG PS of 0 to 1. 
(6) At least 20 years of age*1 at the time of informed consent. 
(7) The following bone marrow, liver, and kidney function parameters measured within 14 
days prior to randomization: 
1) Neutrophil count ≥ 1500/mm3 *2 
2) Hemoglobin ≥ 8.0 g/dL *2 
3) Platelet count ≥ 100000/mm3 *2 
4) Total bilirubin ≤ 1.5 mg/dL 
5) AST, ALT levels ≤ 3 x ULN, or ≤ 5 x ULN in the presence of liver metastasis 
6) ALP levels ≤ 2.5 x ULN, or ≤ 5 x ULN in the presence of liver metastasis 
7) Creatinine clearance ≥ 60 mL/min *3 
(8) Life expectancy of at least 90 days after randomization. 
(9) Capable of oral intake. 
(10)  Written informed consent to participate as a subject in this clinical study. 
 
1*：For 75 years of age or older patient, pay careful attention to manage adverse 
events. 
2*：If patients received blood transfusion or treatment with any blood product or 
hematopoietic factor such as G-CSF, it must be confirmed the data is obtained 
more than 14 days after the last blood transfusion or treatment. 
3*：A value obtained from a urine collection, if available. Otherwise an estimate by 
the Cockcroft-Gault formula: 
Estimated creatinine clearance (mL/min) 
= (140 - age) x Body weight (kg) / [72 x Serum creatinine (mg/dL)] 
For women, the obtained value is multiplied by a factor of 0.85. 
 
31 
 

 
 
 
8.2 Exclusion Criteria 
Patients who meet any of the following criteria at the time of randomization will be 
excluded from this study: 
The rationale is provided in “26.6 Rationale for exclusion criteria”. 
(1) Serious hypersensitivity to any ingredients of S-1 or LV. 
(2) Treated with other investigational agents within 4 weeks before randomization. 
(3) Remain affected by a surgery performed before randomization. 
(4) Blood transfusion, treatment with blood products, or hematopoietic growth factors such 
as G-CSF within 2 weeks before randomization. 
(5) Ongoing treatment with flucytosine at the time of randomization. 
(6) Unmanageable Diarrhea (e.g. watery stool, difficulty in controlling bowel movements 
despite the medication, grade 2 or higher, 5 stools or more per day). 
(7) Current peripheral sensory neuropathy or paresthesia (grade 2 or higher). 
(8) Current or past severe lung disease (e.g. interstitial pneumonia, pulmonary fibrosis, or 
severe emphysema). 
(9) Any other active illness such as severe (e.g. grade 3 or higher) cardiac disease*1 (e.g. 
myocardial infarction, angina pectoris, arrhythmia, or cardiac failure). Any of the 
following events within the 6 months prior to randomization: any episode of myocardial 
infarction or angina pectoris. 
(10)  Diabetic patients who have poorly controlled despite the medication or severe diabetic 
complication. 
(11)  Any other severe (e.g. Grade 3 or higher) complications (e.g. severe enteritis, severe 
stomatitis, gastrointestinal ulceration/perforation, ileus, renal failure, nephrosis 
syndrome, liver failure or cerebrovascular disorder). 
(12)  Known human immunodeficiency virus (HIV) or active hepatitis. 
(13)  Active infection, inflammatory diseases, or connective tissue disease (e.g. 
administration of intravenous antibiotics, fever of 38°C or higher). 
(14)  Current use or anticipated need for continuous systemic steroid administration (oral or 
intravenous). 
(15)  Active gastrointestinal bleeding (e.g. Grade 3 or higher). 
(16)  Brain metastasis, present or suspected from clinical symptoms. 
(17)  Extensive bone metastasis (e.g. whole pelvis, or 50% of spine). 
(18)  Accumulation of pleural, ascitic, or pericardial fluid requiring drainage within 2 weeks 
prior to randomization. 
(19)  Other concurrent active cancer (synchronous double cancer or heterochronous double 
cancer with a disease-free interval of 5 years or shorter, excluding lesions consistent 
with intraepithelial cancer, i.e., carcinoma in situ, or intramucosal cancer that are 
assessed as cured by local treatment). 
(20)  Pregnant, breast-feeding*2, possibly pregnant women or patients wishing to have 
children during the study period or a certain period (6 months) after stopping study 
treatment. Women of childbearing potential have to take a pregnancy test*3. 
 
32 
 

 
 
 
(21)  Concurrent mental disorder or psychiatric symptoms assessed as interfering with study 
participation. 
(22)  Ineligible for participating in this study according to the investigator. 
 
*1： Patients with a cardiac pacemaker, or valve replacement are impossible to be 
 
randomized. 
*2： Women who stop breast-feeding are impossible to be randomized.  
*3： Women of childbearing potential are defined as any women who are 
premenopausal, less than 1 year after last menses, more than 1 year with no 
menses due to medical causes, or not permanently sterilized and so on. 
 
8.3 Informed Consent 
Patients will indicate their consent to participate in the study by signing and dating an ICF 
prior to study procedures. 
Patients must be provided a signed and dated copy of the ICF prior to any study-related 
procedures that are outlined in the consent. 
 
 
Procedure for obtaining informed consent 
Obtaining informed consent must be done according to the guidelines provided in the 
Declaration of Helsinki, ICH E6 Guideline for GCP, and local regulations. 
The investigator (according to applicable regulatory requirements) or a person designated 
by the investigator should fully inform patients of all pertinent aspects of the clinical trial. All 
participants should be informed to the fullest extent possible about the study in a language 
and in terms they are able to understand. 
Prior to participation in the trial, the written ICF is to be signed and personally dated by 
the patient and the person who conducted the ICF discussion. A copy of the signed and dated 
ICF will be provided to the patient. The ICF used must have had prior approval by the IRB/ 
IEC. 
 
 
 
 
33 
 

 
 
 
9. Subject Registration 
All subjects will be enrolled into this study using the central registration (IWRS). 
(1) The investigator (subinvestigator) evaluates and verifies the eligibility of each subject 
candidate according to the inclusion and exclusion criteria. 
(2) The subject will be centrally randomized to one of the two treatment arms and received 
the subject number via an IWRS. 
(3) The subject number will be "TAS-118 GC-" and 3 digits; these 3 digits will be 
consecutive number for study (not each site). 
(4) The subject number will be maintained throughout the study and will not be reassigned. 
(5) Study drug administration should be initiated within 8 days of randomization. 
(6) If the investigator (subinvestigator) does not enroll any patient for more than 6 months 
from initial supply of study drug to the site, randomization procedure can not be 
performed in the site. 
 
 
 
 
 
34 
 

 
 
 
10. Administration 
10.1 Dose, administration schedule 
 
Dose 
10.1.1.1 
Arm A (TAS-118/L-OHP) 
For the initial dose, TAS-118 shall be administered orally twice daily after breakfast and 
after dinner according to the reference daily dose in the following table depending on the 
body surface area (See Table 10.1.1.1-1).  
Even if body weight change at subsequent cycle, dose of TAS-118 is not modified. 
 
Table 10.1.1.1-1  Initial Dose of TAS-118 
Body Surface Area 
(m2) 
Dosage in each 
dose 
Number of sachet 
package 
Total daily dose 
(Number of sachet packages) 
< 1.25 
40 mg 
Morning: 1 
Evening: 1 
80 mg (2) 
≥ 1.25 – < 1.5 
50 mg 
Morning: 1 
Evening: 1 
100 mg (2) 
≥ 1.5 
60 mg 
Morning: 1 
Evening: 1 
120 mg (2) 
 
L-OHP shall be administered via intravenous drip for 2 hours on Day 1 of each cycle, with 
an initial dose of 85 mg/m2 (acceptable within ± 10%). 
5-HT3 receptor antagonist and steroid are recommended to be administered as 
pretreatment. However, for patients considered inappropriate for steroid treatment, such as 
patients with hepatitis virus infection or diabetes mellitus, steroid treatment is not essential. 
See the current package insert for other precautions for the preparation and treatment of 
L-OHP. 
The dose shall not be recalculated by body weight fluctuation in principle, but for 10% or 
higher fluctuation of body weight, recalculation is possible at the discretion of the 
investigator (or subinvestigator). When recalculation, the body surface area (BSA) will be 
calculated using the DuBois formula. 
 
10.1.1.2 
Arm B (S-1/CDDP) 
For the initial dose, S-1 shall be administered orally twice daily after breakfast and after 
dinner according to the reference daily dose in the following table depending on the body 
surface area (See Table 10.1.1.2-1). 
Even if body weight change at subsequent cycle, dose of S-1 is not modified. 
 
 
35 
 

 
 
 
Table 10.1.1.2-1  Initial Dose of S-1 
Body Surface Area 
(m2) 
Dosage in each 
dose 
Number of capsules 
Total daily dose 
(Number of 
capsules) 
20 mg 
(white) 
25 mg 
(orange/white) 
< 1.25 
40 mg 
Morning: 2  
Evening: 2  
Morning: -  
Evening: -  
80 mg (4) 
≥ 1.25 – < 1.5 
50 mg 
Morning: -  
Evening: -  
Morning: 2  
Evening: 2  
100 mg (4) 
≥ 1.5 
60 mg 
Morning: 3  
Evening: 3  
Morning: -  
Evening: -  
120 mg (6) 
 
CDDP shall be administered via intravenous drip for 2 hours or longer on Day 1 (Korea) 
or Day 8 (Japan) of each cycle, with an initial dose of 60 mg/m2 (acceptable within ± 10%). 
Before and after treatment of CDDP, hydration shall be performed to maintain sufficient 
urinary volume, and 5-HT3 receptor antagonist, Neurokinin (NK)1 receptor antagonist, and 
steroid are recommended to be administered as pretreatment for nausea and vomiting. Care 
must be taken to avoid overhydration for patients with suspected heart disease or with pleural 
effusion or ascites. Pretreatment with steroid are not recommended for the patients who are 
inappropriate for administration of steroid (e.g. active hepatitis or diabetes mellitus). 
See the current package insert for other precautions for the preparation and treatment of 
CDDP. 
The dose shall not be recalculated by body weight fluctuation in principle, but for 10% or 
higher fluctuation of body weight, recalculation is possible at the discretion of the 
investigator (or subinvestigator). When recalculation, the BSA will be calculated using the 
DuBois formula. 
 
 
 
 
36 
 

 
 
 
 Administration schedule 
The administration schedule for each treatment group is shown below. The administration 
period is until 31 Jan 2020. 
10.1.2.1 
Arm A (TAS-118/L-OHP) 
L-OHP will be administered on Day 1, and TAS-118 will be administered orally twice 
daily in a administration period from Day 1 through Day 7 followed by a recovery period 
from Day 8 through Day 14. This regimen is to be repeated every 2 weeks until study 
treatment discontinuation criteria (Section 13.1.1). If TAS-118 administration is initiated 
from evening on Day 1, it will be continued until morning on Day 8, and recovery period will 
be from evening on Day 8 through morning on Day 15 (see Figure 10.1.2.1-1). 
・ A recovery period is not allowed to be shortened (e.g. even if the dosing is interrupted 
due to some reasons, such as adverse events after the morning of Day 6, the 
subsequent dosing should be started as a new treatment cycle after the 
morning/evening meal on Day 15). 
・ Any unused doses are not allowed to be administered in a recovery period (see Figure 
10.1.2.1-2). 
・ If any of dose initiation criteria (see Table 10.1.3.1-1) for L-OHP did not meet, 
administration of L-OHP may be skipped and start each treatment cycle only with 
TAS-118. 
 
 
Figure 10.1.2.1-1  Study regimen of TAS-118/L-OHP 
 
  
Figure 10.1.2.1-2  Study regimen of TAS-118 
 
 
 
L-OHP (Day1)
Day
1
7
8
14
Morning
Evening
L-OHP (Day1)
Day
1
8
15
Morning
Evening
Recovery Period
Administration Period (TAS-118)
Administration Period (TAS-118)
Recovery Period
   
Day
1
7
8
14
Morning
Evening
Dose interruption 
TAS-118 should only be given  in administration 
period from Day 1 to Day 7
TAS-118 administration into the  recovery
period  is  not  permitted.
Administration
Recovery period
Admini
stration
All of dose resumption criteria withintreatment 
cycle are met
Any of dose interruption criteria within 
treatment cycle are met
 
37 
 

 
 
 
10.1.2.2 
Arm B (S-1/CDDP) [CDDP on Day 1] (Korea) 
CDDP will be administered on Day 1, and S-1 will be administered orally twice daily in a 
administration period from Day 1 through Day 21 followed by a recovery period from Day 
22 through Day 35. This regimen is to be repeated every 5 weeks until study treatment 
discontinuation criteria (Section 13.1.1). If S-1 administration is initiated from evening on 
Day 1, it will be continued until morning on Day 22, and recovery period will be from 
evening on Day 22 through morning on Day 36 (see Figure 10.1.2.2-1). 
・ A recovery period may be shortened down to 7 days after the administration period 
which has been finished either without AE/SAE related to study drug or with AE/SAE 
related to study drug that are of no safety concern and assessed as allowing the 
subsequent recovery period to be shortened (see Figure 10.1.2.2-2Figure 10.1.2.2-3). 
・ Any unused doses are not allowed to be administered in a recovery period (see Figure 
10.1.2.2-3). 
・ If the dose interruption continues 14 days and over in the administration period, drug 
administration has to be discontinued in the cycle. After confirmation of being met 
criteria for starting new treatment cycle (see Table 10.1.3.1-2), drug administration can 
be restarted as the next treatment cycle (see Figure 10.1.2.2-4). 
・ If any of dose initiation criteria for CDDP(see Table 10.1.3.1-2) did not meet, 
administration of CDDP may be skipped and start each treatment cycle only with S-1. 
 
  
Figure 10.1.2.2-1  Study regimen of S-1/CDDP 
 
   
Figure 10.1.2.2-2  Study regimen of S-1 (1) 
 
CDDP (Day1)
Day
1
21
22
35
Morning
Evening
CDDP (Day1)
Day
1
22
23
36
Morning
Evening
Administration Period (S-1)
Administration Period (S-1)
Recovery Period
Recovery Period
Day
1
21
22
1
Morning
Evening
Administration period (21days)
Recovery 
for at least 7days
A recovery period may be shortened
down to minimum 7 days 
Recovery period
Administration as a 
new treatment cycle
Administration Period
All of dose initiation criteria are met
 
38 
 

 
 
 
 
 
Figure 10.1.2.2-3  Study regimen of S-1 (2) 
 
 
Figure 10.1.2.2-4  Study regimen of S-1 (3) 
 
10.1.2.3 
Arm B (S-1/CDDP) [CDDP on Day 8] (Japan) 
CDDP will be administered on Day 8 (Day 6 to Day 15), and S-1 will be administered 
orally twice daily in a administration period from Day 1 through Day 21 followed by a 
recovery period from Day 22 through Day 35. This regimen is to be repeated every 5 weeks 
until study treatment discontinuation criteria (Section 13.1.1). If S-1 administration is 
initiated from evening on Day 1, it will be continued until morning on Day 22, and recovery 
period will be from evening on Day 22 through morning on Day 36 (see Figure 10.1.2.3-1). 
・ A recovery period may be shortened down to 7 days after the administration period 
which has been finished either without AE/SAE related to study drug or with AE/SAE 
related to study drug that are of no safety concern and assessed as allowing the 
subsequent recovery period to be shortened (see Figure 10.1.2.3-2).  
・ Any unused doses are not allowed to be administered in a recovery period (see Figure 
10.1.2.3-3). 
・ If the dose interruption continues 14 days and over in the administration period, drug 
administration has to be discontinued in the cycle. After confirmation of being met 
criteria for starting new treatment cycle (see Table 10.1.3.1-2), drug administration can 
be restarted as the next treatment cycle (see Figure 10.1.2.3-4).  
・ If any of dose initiation criteria (see Table 10.1.3.1-2) for CDDP did not meet, 
administration of CDDP may be skipped and start each treatment cycle only with S-1. 
 
Day
1
21
22
35
Morning
Evening
S-1 should only be given in administration 
period from Day 1 to Day21
Administration
Dose interruption
Admini
stration
S-1 administration into the  recovery
period  is  not  permitted.
Recovery period
Any of dose interruption criteria within 
treatment cycle are met
All of dose resumption criteria withintreatment 
cycle are met
Day
1
Morning
Evening
Dose interruption
(14.0 days or more)
All of dose initiation criteria are met
Administration as a new treatment cycle
Administration
Administration period (21days)
 
39 
 

 
 
 
  
Figure 10.1.2.3-1  Study regimen of S-1/CDDP 
 
 
 
Figure 10.1.2.3-2  Study regimen of S-1 (1) 
 
   
Figure 10.1.2.3-3  Study regimen of S-1 (2) 
 
 
Figure 10.1.2.3-4  Study regimen of S-1 (3) 
 
 
 
 
   CDDP (Day8)
Day
1
8
21
22
35
Morning
Evening
   CDDP (Day8)
Day
1
8
22
23
36
Morning
Evening
Administration Period (S-1)
Administration Period (S-1)
Recovery Period
Recovery Period
Day
1
21
22
1
Morning
Evening
Administration period (21days)
Recovery 
for at least 7days
A recovery period may be shortened
down to minimum 7 days 
Recovery period
Administration as a 
new treatment cycle
Administration Period
All of dose initiation criteria are met
Day
1
21
22
35
Morning
Evening
S-1 should only be given in administration 
period from Day 1 to Day21
Administration
Dose interruption
Admini
stration
S-1 administration into the  recovery
period  is  not  permitted.
Recovery period
Any of dose interruption criteria within 
treatment cycle are met
All of dose resumption criteria withintreatment 
cycle are met
Day
1
Morning
Evening
Dose interruption
(14.0 days or more)
All of dose initiation criteria are met
Administration as a new treatment cycle
Administration
Administration period (21days)
 
40 
 

 
 
 
 
Criteria for Modification of Treatment Schedule 
10.1.3.1 
Criteria for Dose Initiation in Each Cycle 
Cycle 1 will be started after completion of the scheduled examination and the 
confirmation of being met all of dose initiation criteria in each cycle (Table 10.1.3.1-1, Table 
10.1.3.1-2), which may be substituted by the test at randomization performed within 7 days 
prior to Day 1 treatment start. Cycle 2 and later cycles will be started if the results of the 
scheduled examination on or one day before Day 1 meet all the following criteria (Table 
10.1.3.1-1, Table 10.1.3.1-2). No treatment cycle can be started if any of these criteria are not 
met. Even if a subject meets all the following criteria, dose initiation can be postponed at the 
investigator’s discretion. Even if all of dose initiation criteria were met, administration of 
L-OHP or CDDP may be skipped and each treatment cycle can be started only with TAS-118 
or S-1 at the investigator’s discretion. 
 
Table 10.1.3.1-1  Dose initiation criteria in each cycle for TAS-118 and L-OHP (Arm A) 
Item 
TAS-118 
L-OHP 
Neutrophil count 
≥ 1000 /mm3  
（≤ Grade2）*1 
≥ 1500 /mm3  
（≤ Grade1）*1 
Platelet count 
≥ 75000 /mm3（≤ Grade1）*2 
Serum creatinine*3 
< 1.5 mg/dL 
(1.2 -< 1.5 mg/dL: 1 level down） 
- 
Infection 
No infection with fever (< 38°C) 
Diarrhea, Stomatitis, Anorexia 
≤ Grade1 
Peripheral sensory neuropathy 
－ 
≤ Grade2*4 
*1：If the patients received G-CSF, it must be confirmed the data is obtained more than 48 hours after the last 
administration. 
*2：If the patients received platelet transfusion, it must be confirmed the data is obtained more than 48 hours after the last 
transfusion. 
*3：New treatment cycle would be initiated with creatinine clearance ≥ 50 mL/min, as a reference. 
*4：Even if the grade is ≤ 2, administration of L-OHP may be skipped at the investigator’s discretion. 
 
Table 10.1.3.1-2  Dose initiation criteria in each cycle for S-1 and CDDP (Arm B) 
Item 
S-1 
CDDP 
Neutrophil count 
≥ 1000 /mm3  
(≤ Grade2)*1 
≥ 1500 /mm3  
(≤ Grade1)*1 
Platelet count 
≥ 75000 /mm3 (≤ Grade1)*2 
Serum Creatinine*3 
< 1.5 mg/dL 
(1.2 -< 1.5 mg/dL:  
1 level down） 
< 1.5 mg/dL 
( 1.2 – < 1.5 mg/dL: 10 mg/mm2 
reduction from previous cycle) 
Infection 
No infection with fever (< 38°C) 
Diarrhea, Stomatitis, Anorexia 
≤ Grade1 
*1：If the patients received G-CSF, it must be confirmed the data is obtained more than 48 hours after the last 
administration. 
*2：If the patients received platelet transfusion, it must be confirmed the data is obtained more than 48 hours after the last 
transfusion. 
*3：New treatment cycle would be started with creatinine clearance ≥ 50 mL/min, as a reference. 
 
 
41 
 

 
 
 
10.1.3.2 
Criteria for Dose Interruption and Resumption within Treatment Cycle 
The study treatment must be interuppted if any of the following dose interruption criteria 
(Table 10.1.3.2-1) is met during administration period of the study agent (TAS-118 or S-1), 
and will be resumed after the confirmation of being met all the following dose resumption 
criteria (Table 10.1.3.2-2). After dose resumption, the dose must be the same as before dose 
interruption. 
 
Table 10.1.3.2-1  Dose interruption criteria within treatment cycle 
Item 
Criterion 
Neutrophil count  
< 1000/mm3 (Grade 3 ≤) 
Platelet count 
< 50000/mm3 (Grade 3 ≤) 
Infection 
Infection with fever (≥ 38°C) 
Diarrhea, Stomatitis 
Grade 3 ≤ 
Other 
Difficulty in continuing treatment as assessed by the investigator 
(subinvestigator) 
 
Table 10.1.3.2-2  Dose resumption criteria within treatment cycle 
Item 
Criterion 
Neutrophil count  
≥ 1000/mm3 (≤ Grade 2)*1 
Platelet count 
≥ 50000/mm3 (≤ Grade 2)*2 
Serum Creatinine*3 
< 1.5 mg/dL 
Infection 
No infection with fever (< 38°C) 
Diarrhea, Stomatitis 
≤ Grade 1 
Other 
Acceptability of resuming treatment as assessed by the investigator 
(subinvestigator) 
*1：If the patients received G-CSF, it must be confirmed the data is obtained more than 48 hours after the last 
administration. 
*2：If the patients received platelet transfusion, it must be confirmed the data is obtained more than 48 hours after the last  
transfusion. 
*3：The study treatment would be resumed with creatinine clearance ≥ 50 mL/min, as a reference. 
 
 
 
 
 
42 
 

 
 
 
10.1.3.3 
Criteria for Dose Reduction (Arm A) 
If the patients suffered any adverse drug reaction that meets any of the following dose 
reduction criteria, a new treatment cycle will be started after confirmation that the subject 
meets “Section 10.1.3.1 criteria for dose initiation in each cycle”, with the dose of TAS-118 
or L-OHP reduced 1 level in each step according to the scheme for dose reduction criteria. 
Dose reduction is not allowed in the same treatment cycle. 
Table 10.1.3.3-1  Dose reduction criteria for TAS-118 and L-OHP 
Item 
Criterion 
TAS-118 
L-OHP 
Neutrophil count  
< 500/mm3 
(Grade 4) 
Worst grade observed in last cycle 
1 step 
1 step 
Platelet count 
< 25000/mm3 
(Grade 4) 
1 step 
1 step 
Febrile neutropenia 
Grade 3 ≤ 
1 step 
1 step 
Stomatitis 
Grade 3 ≤ 
1 step 
- 
Diarrhea 
Grade 3 ≤*1 
1 step 
- 
Peripheral sensory 
neuropathy 
Grade 3 ≤*2 
- 
1 step 
Serum creatinine 
1.2 - < 1.5 
mg/dL 
The value observed before the 
initiation of new treatment cycle 
1 step 
- 
Others*3 
Difficulty in continuing treatment without reducing the study drug dose as 
assessed by the investigator (subinvestigator) 
*1: In the event of a Grade 3 or greater adverse drug reaction in spite of the best treatment possible.  
*2: Even if the grade is ≤ 2, the dose can be reduced at the investgator’s discretion. 
*3: If the patient suffers from anorexia or other remarkable adverse drug reactions, the dose can be reduced at the 
investigator’s discretion. 
 
Table 10.1.3.3-2  Dose reduction scheme for TAS-118 and L-OHP 
Investigational product 
Initial dose 
Step 1 
Step 2 
Step 3 
TAS-118 
60 mg/dose 
50 mg/dose 
40 mg/dose 
30 mg/dose 
50 mg/dose 
40 mg/dose 
30 mg/dose 
None* 
40 mg/dose 
30 mg/dose 
None* 
None* 
L-OHP 
85 mg/m2 
65 mg/m2 
50 mg/m2 
None* 
*：In this case, the dose reduction cannot be done for the subjects, but there is no necesssity that the study treatment is 
terminated. After confirmation that the patients meet all of dose resumption criteria, the study treatment can be restarted at 
minimum dose. 
 
Table 10.1.3.3-3  Reduced dose of administration for TAS-118 
Dosage in each dose 
Number of sachet package 
Total daily dose 
(Number of sachet packages) 
30 mg 
Morning: 1 
Evening: 1 
60 mg (2) 
40 mg 
Morning: 1 
Evening: 1 
80 mg (2) 
50 mg 
Morning: 1 
Evening: 1 
100 mg (2) 
 
43 
 

 
 
 
10.1.3.4 
Criteria for Dose Reduction (Arm B) 
If the patients suffered any adverse drug reaction that meets any of the following dose 
reduction criteria, a new treatment cycle will be started after confirming that the subject 
meets “Section 10.1.3.1 criteria for dose initiation in each cycle”, with the dose of S-1 or 
CDDP reduced 1 level in each step according to the scheme for dose reduction criteria. 
Dose reduction is not allowed in the same treatment cycle. 
 
Table 10.1.3.4-1  Dose reduction criteria for S-1 and CDDP 
Item 
Criterion 
S-1 
CDDP 
Neutrophil count  
< 500/mm3 
(Grade 4) 
Worst grade observed in 
last cycle 
1 step 
Reduced by 
10 mg/m2 
Platelet count 
< 25000/mm3 
(Grade 4) 
1 step 
Reduced by 
10 mg/m2 
Febrile neutropenia 
Grade 3 ≤ 
1 step 
Reduced by 
10 mg/m2 
Stomatitis 
Grade 3 ≤ 
1 step 
- 
Diarrhea 
Grade 3 ≤*1 
1 step 
- 
Serum creatinine 
1.2 - < 1.5 mg/dL 
The value observed before 
the initiation of new 
treatment cycle 
1 step 
Reduced by 
10 mg/m2 
Others*2 
Difficulty in continuing treatment without reducing the study drug dose as 
assessed by the investigator (subinvestigator) 
*1: In the event of a Grade 3 or greater adverse drug reaction in spite of the best treatment possible. 
*2: If the patient suffers from anorexia or other remarkable adverse drug reactions, the dose can be reduced at the 
investigator’s discretion. 
 
Table 10.1.3.4-2  Dose reduction scheme for S-1 and CDDP 
Investigational product 
Initial dose 
Step 1 
Step 2 
S-1 
60 mg/dose 
50 mg/dose 
40 mg/dose 
50 mg/dose 
40 mg/dose 
None* 
40 mg/dose 
None* 
None* 
CDDP 
60 mg/m2 
Reduced by 10 mg/m2 
*：In this case, the dose reduction cannot be done for the subjects, but there is no necessity that the study treatment is 
terminated. After confirmation that the patients meet all of dose resumption criteria, the study treatment can be restarted at 
minimum dose. 
 
Table 10.1.3.4-3  Reduced dose of administration for S-1 
Dosage in each dose 
Number of capsules 
Total daily dose 
(Number of capsules) 
20 mg 
(white) 
25 mg 
(orange/white) 
40 mg 
Morning: 2 
Evening: 2 
Morning: - 
Evening: - 
80 mg (4) 
50 mg 
Morning: - 
Evening: - 
Morning: 2 
Evening: 2 
100 mg (4) 
 
44 
 

 
 
 
 
 
Criteria for Dose Increase 
The dose of study drugs (TAS-118, L-OHP, S-1, and CDDP) must not be increased even 
after dose reduction. 
 
10.2 Medication and Treatments Prohibited during Study 
 
Medication and Treatments Prohibited during Study 
The following concomitant therapies are not permitted during the study treatment period. 
(1) Any other anti-tumor therapy, including chemotherapy, radiotherapy, immunotherapy, 
biological response modifiers (BRMs) with antitumor effect, or endocrine therapy 
(2) Other investigational drugs 
(3) Uracil, Cimetidine and Calcium folinate 
(4) Flucytosine 
(5) Prophylactic use of G-CSF 
 
 
Concomitant Medications Requiring Precautions 
(1) Warfarin potassium 
Changes in coagulation profile should be monitored e.g. by INR when relevant 
abnormalities are indicated by other tests or findings, and the warfarin dose should be 
adjusted as needed. 
(2) Phenytoin 
Subjects receiving phenytoin should be monitored. If abnormalities are noted, 
appropriate measures should be taken including dose reduction or discontinuation. 
(3) Aminoglycoside antibiotics, vancomycin hydrochloride, and furosemide (Arm B: 
S-1/CDDP therapy only) 
(4) Amphotericin B for injection (Arm B: S-1/CDDP therapy only) 
(5) Piretanide (Arm B: S-1/CDDP therapy only) 
 
 
Expected Adverse Drug Reactions and Treatment Options 
The following medications may be given concomitantly under the following guidelines. In 
case that dose reduction should be taken, see section 10.1.3-3 or 10.1.3-4. 
(1) Neutrophil count decrease: Appropriate measures, such as dose change (reduction) or 
dose interruption, should be taken. Any accompanying fever should be treated with 
appropriate agent (e.g. antibiotics). 
(2) Stomatitis: Severe Stomatitis interfering with continuation of oral drug treatment should 
be managed by appropriate measures such as dose change (reduction) or dose 
interruption. 
(3) Nausea/vomiting: Severe nausea/vomiting interfering with continuation of oral drug 
treatment should be treated by appropriate agent (e.g. antiemetics). 
 
45 
 

 
 
 
(4) Anorexia: Appropriate measures, such as dose change (reduction) or dose interruption, 
should be taken. Taken actions for causal disease of Anorexia such as Nausea/vomitings 
should be taken as well. 
(5) Diarrhea: Severe diarrhea should be managed by dose interruption of TAS-118 and S-1 
and appropriate fluid replacement as needed while adequately monitoring fluid and 
electrolyte balance. Antidiarrheal treatment (e.g. loperamide hydrochloride) should be 
considered while diarrhea is still mild if prevention of its exacerbation is required on the 
basis of careful monitoring. 
(6) Skin eruption: Skin eruption should be managed by appropriate measures such as dose 
reduction or dose interruption. 
(7) Platelet decrease: Appropriate measures, such as dose change (reduction) or dose 
interruption, should be taken. 
(8) Peripheral sensory neuropathy: Paresthesia or dysesthesia of hands, feet or area 
surrounding the mouth and lips (peripheral neuropathy) occurs in almost all patients 
from immediately after the administration of L-OHP. Carefully observe the patient’s 
state because a constricted feeling of the larynx and pharynx (dysesthesia of the larynx 
and pharynx) may appear, and take appropriate measures such as dose 
reduction/interruption if such abnormalities occur. 
(9) Hypersensitivity: Appropriate measures, such as antihistamic agent or steroid, should be 
taken. 
(10) Renal disorder: Before and after treatment with CDDP, adequate hydration and 
coadministration of diuretics to maintain sufficient urinary volume shall be performed in 
order to prevent renal disorder. When renal insufficiency occurs, careful fluid 
management, electrolyte replacement, and if required, renal dialysis shall be performed 
to restore urinary volume. 
 
10.3 Supportive therapy and other points to be considerd 
・ Therapies required for study drug (L-OHP or CDDP) administration (supportive 
therapies) 
- 
administration of 5-HT3 receptor antagonist, NK1 receptor antagonist, and steroid as 
prophylaxis of nausea and vomiting 
- 
hydration for prophylaxis of renal disorder 
・ In patients with past medical history of Hepatitis B infection, attention should be paid to 
signs or symptoms of the reactivation of Hepatitis B, and regular monitoring for liver 
function tests or viral markers are recommended. 
 
10.4 Instruction to Patients for Handling Study Medication (TAS-118 or 
S-1) 
The patient must be instructed in the handling of study medication as follows: 
・ To store the study medication at room temperature 
・ To only open the indicated sachet at the time of dosing (TAS-118) 
・ To only take out the indicated dose from the PTP sheet at the time of dosing (S-1) 
 
46 
 

 
 
 
・ Not to take out study drugs in advance of the next scheduled dosing 
・ Take the study drugs within 1 hour after the morning and evening meals, and to keep at 
least about 8 hours between the two meals 
・ To make every effort to take doses on schedule 
・ Not to take any missed doses, and report it 
・ If the patient vomits after taking study medication, the patient should not take another 
dose 
・ To take study medication after completing a meal (morning and evening meal) with a 
glass of water 
・ To keep study medication in a safe place and out of reach of children 
・ To bring all unused study medication to the site at each visit 
 
 
 
 
47 
 

 
 
 
11. Data Items and Schedule for Testing and Monitoring 
11.1 Data Items and schedule for Testing and Monitoring 
Table 11.1-1  Data items for testing and monitoring 
 
 
 
Data items for testing and monitoring 
Informed consent 
Date of informed consent 
Patient background 
Sex, age, country, race, past medical history, complications, date of first 
diagnosis, site of primary lesion, clinical stage, distant metastasis, 
histological type, whether or not past treatment included any of the 
following: gastrectomy (surgical site, procedure, date, outcome); previous 
treatment (regimen, start/end dates), HER2 status 
Height,  
body temperature, 
blood pressure 
Height (only at randomization),  
body temperature,  
blood pressure (systolic/diastolic) 
ECOG PS, weight 
ECOG PS, body weight 
Hematology 
Hemoglobin, white blood cell count, white blood cell fractions (percentages 
of neutrophils and lymphocytes), platelet count 
Serum chemistry 
Serum AST (GOT), serum ALT (GPT), serum ALP, serum albumin, total 
serum bilirubin, serum creatinine, creatinine clearance (only at 
randomization), LDH, serum CRP, serum electrolytes (Na, K, Ca) 
Urinalysis 
Urine protein (qualitative) 
Physical examination 
Stomatitis, diarrhea, anorexia, peripheral sensory neuropathy 
Electrocardiography 
Resting 12-lead electrocardiography 
Pregnancy test 
Pregnancy test 
Tumor measurement 
CT, MRI  
Tumor markers 
CA19-9, CEA 
Compliance with study 
treatment 
Compliance with treatment, missed doses, non-compliance e.g. with dose 
level, discontinuation (dose interruption) during treatment cycle, changes in 
recovery period 
Concomitant 
medications/regimen 
Concomitant medications (regimen, reason) 
Post treatment 
Whether or not a post treatment is performed (if yes, regimen and start date 
and end date) 
Hospitalization 
Date of admission, reason for admission, date of discharge 
Survival status 
Survival date, date of death, cause of death 
 
48 
 

 
 
 
 
Collection and Submission of Images 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination when both methods have been 
used to assess the antitumor effect of treatment. All measurements should be recorded. 
Contrast enhanced CT is the preferred method for tumor assessments. If contrast agent is 
contraindicated in a patient, obtain a non-contrast chest CT and magnetic resonance imaging 
(MRI) of the abdomen and pelvis. Spiral CT should be performed using a 5 mm or less 
continuous reconstruction algorithm. Images must be acquired of the chest, abdomen and 
pelvis at each time point. Only CT and MRI may be used for tumor measurement. 
Imaging data of baseline and requested for submission by sponsor must be captured 
according to the format of Digital Imaging and Communication in Medicine (DICOM) be 
submitted to the sponsor. 
 
 
 
 
49 
 

 
 
 
11.2 Testing and Monitoring Schedule 
Table 11.2-1  A Study Schedule  Arm A (TAS-118/L-OHP) 
Procedure 
Pretreatment Period 
Study Treatment Period 
Post-treatment Follow-up Period 
within 28 
days 
prior to 
randomiz
ation 
within 21 
days 
prior to 
randomiz
ation 
within 14 
days 
prior to 
randomiz
ation 
within 7 
days prior 
to 
Day 1 of 
the  first 
treatment 
cycle e 
Arm A 
End of 
Treatment j 
(+14 days) 
Safety 
Follow-up k 
30 days 
after last 
dose of 
study 
treatment 
(+14 days) 
Tumor 
Follow-up 
Every  6 
weeks 
(+/- 1 
week) 
Survival 
Follow-up 
Every  12 
weeks 
(+/-2 
weeks) 
Day 1 
Before 
initiation of 
next cycle h, i 
Day15 
(Day 14 to 
18) 
TAS-118 treatment 
 
 
 
 
X f 
(Day 1 - 7) 
 
 
 
 
 
L-OHP treatment 
 
 
 
 
X f 
 
 
 
 
 
Signed ICF 
X 
 
 
 
 
 
 
 
Patient Background 
X 
 
 
 
 
 
 
 
Height 
 
 
X 
 
 
 
 
 
 
 
Pregnancy Test a 
 
 
X 
 
 
 
 
 
 
 
Weight 
 
 
X 
X 
→ g 
X 
X 
 
 
ECOG PS 
 
 
X 
X 
→ g 
X 
X 
 
 
Blood Pressure 
 
 
X 
X 
→ g 
→ g 
 
 
Body Temperature 
 
 
X 
X 
→ g 
→ g 
 
 
ECG 
 
X 
 
→ g 
→ g 
 
 
Physical 
Examination 
 
 
X 
X 
 
X 
X 
X 
 
 
Hematology 
 
 
X 
X 
 
X 
X 
X 
 
 
Serum Chemistry b 
 
 
X 
X 
 
X 
X 
X 
 
 
Urinalysis b 
 
 
X 
X 
 
X 
X 
X 
 
 
Tumor Markers c 
 
X 
→ 
→ 
→ 
→ 
→ 
X 
 
Tumor 
Measurements c 
 
X 
→ 
→ 
→ 
→ 
→ 
X 
 
Concomitant 
Medications d 
X 
→ 
→ 
→ 
→ 
X 
 
 
AE/SAE 
Assessment d 
X 
→ 
→ 
→ 
→ 
X 
 
 
Post Tratment 
 
 
 
 
 
 
 
 
 
X 
Survival Status 
 
 
 
 
→ 
→ 
→ 
→ 
→ 
X l 
 
a. 
If the patient is female and of childbearing potential, a pregnancy test (serum or urine) must be done and the results must be negative 
at baseline. 
b. 
Creatinine clearance is mandatory only at prior to randomization. 
c. 
Every 6 weeks starting on the day of randomization (the data may be collected within 1 week before or after the scheduled date). 
Patients without PD defined by RECIST version 1.1 must be followed for tumor assessment. 
d. 
Monitor patients for any medications and untoward medical events from the time of signed ICF through the safety follow-up period. 
e. 
These data may be collected within 7 day prior to Day 1 of the first treatment cycle. These tests may be substituted by the data 
obtained within 14 days prior to randomization if screening data is obtained within 7 days prior to Day 1 of the first treatment cycle. 
f. 
Study drug administration is to be initiated within 8 days after randomization.  
g. 
If abnormalities are indicated by other physical examination or tests, it must be performed. 
h. 
These data may be collected 15 days after Day 1 (from Day 14 to Day 18 if not feasible on Day 15) of each treatment cycle. 
i. 
Every 1 week starting on Day 1 of each treatment cycle if the next treatment cycle is delayed (the data may be collected within 7 days 
before the scheduled date). Examination is mandatory on Day 1 or the day before starting the study treatment specified in this 
protocol. 
j. 
End of treatment assessments must be completed within 14 days from the date of last dose of study drug. 
k. 
These data may be collected 30 days after last dose of study drug or until the start of new anti-tumor therapy, whichever comes first. 
In cases an AE/SAE related to study drug is not resolving, the safety follow-up period will be extended. 
l. 
Obtain survival status (alive/ dead) at scheduled 12-week time intervals from randomization until death, and at the cutoff date for 
second interim analysis and primary evaluation (the data may be collected within 2 weeks before or after the scheduled date). 
 
 
 
 
50 
 

 
 
 
Table 11.2-2  A Study Schedule Arm B (S-1/CDDP) 
Procedure 
Pretreatment Period 
Study Treatment Period 
Post-treatment Follow-up Period 
within 28 
days 
prior to 
randomiz
ation 
within 21 
days 
prior to 
randomiz
ation 
within 14 
days 
prior to 
randomiz
ation 
within 7 
days prior 
to 
Day 1 of 
the  first 
treatment 
cycle e 
Arm B 
End of 
Treatment m 
(+14 days) 
Safety 
Follow-up n 
30 days 
after last 
dose of 
study 
treatment 
(+14 days) 
Tumor 
Follow-up 
Every  6 
weeks 
(+/- 1 week) 
Survival 
Follow-up 
Every  12 
weeks 
(+/-2 
weeks) 
Day 1 
Day 8 i 
(Day 6 to 
15) 
(Japan) 
Day 15 j 
(Day 8 to 
22) 
Before 
Initiation of 
next treatment 
cycle k, l 
Day36 
(Day 29 to 43) 
S-1 treatment 
 
 
 
 
X f 
(Day 1 - 21) 
 
 
 
 
 
CDDP treatment 
(Korea) 
 
 
 
 
X f 
 
 
 
 
 
 
 
CDDP treatment 
(Japan) 
 
 
 
 
 
X g 
 
 
 
 
 
 
Signed ICF 
X 
 
 
 
 
 
 
 
 
 
Patient Background 
X 
 
 
 
 
 
 
 
 
 
Height 
 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test a 
 
 
X 
 
 
 
 
 
 
 
 
 
Weight 
 
 
X 
X 
→ h 
X 
X 
 
 
ECOG PS 
 
 
X 
X 
→ h 
X 
X 
 
 
Blood Pressure 
 
 
X 
X 
→ h 
→ h 
 
 
Body Temperature 
 
 
X 
X 
→ h 
→ h 
 
 
ECG 
 
X 
 
→ h 
→ h 
 
 
Physical 
Examination 
 
 
X 
X 
 
X i 
X 
X 
X 
X 
 
 
Hematology 
 
 
X 
X 
 
X i 
X 
X 
X 
X 
 
 
Serum Chemistry b 
 
 
X 
X 
 
X i 
X 
X 
X 
X 
 
 
Urinalysis b 
 
 
X 
X 
 
X i 
X 
X 
X 
X 
 
 
Tumor Markers c 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
Tumor 
Measurements c 
 
X 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
Concomitant 
Medications d 
X 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
 
AE/SAE 
Assessment d 
X 
→ 
→ 
→ 
→ 
→ 
→ 
X 
 
 
Post Treatment 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival Status 
 
 
 
 
→ 
→ 
→ 
→ 
→ 
→ 
→ 
X o 
 
a. 
If the patient is female and of childbearing potential, a pregnancy test (serum or urine) must be done and the results must be negative 
at baseline. 
b. 
Creatinine clearance is mandatory only at prior to randomization. 
c. 
Every 6 weeks starting on the day of randomization (the data may be collected within 1 week before or after the scheduled date). 
Patients without PD defined by RECIST version 1.1 must be followed for tumor assessment. 
d. 
Monitor patients for any medications and untoward medical events from the time of signed ICF through the safety follow-up period. 
e. 
These data may be collected within 7 day prior to Day 1 of the first treatment cycle. These tests may be substituted by the data 
obtained within 14 days prior to randomization if screening data is obtained within 7 days prior to Day 1 of the first treatment cycle. 
f. 
Study drug administration is to be initiated within 8 days after randomization. 
g. 
CDDP administration shall be permitted within 2 days before and 7 days after the reference day. 
h. 
If abnormalities are indicated by other physical examination or tests, it must be performed. 
i. 
When administering CDDP, the examination on the day before administration or on the day of administration until the start of 
administration (hematology, serum chemistry, urinalysis, and physical examination) shall be mandatory. 
j. 
These data may be collected 15 days after Day 1 (from Day 8 to Day 22 if not feasible on Day 15) of each treatment cycle. Collect 
this data after the data of day8 and don’t put the data of day 8 together in Japan. 
k. 
These data may be collected 36 days (from Day 29 to Day 43 if not feasible on Day 36) after Day 1 of each treatment cycle.  
l. 
Every 1 week starting on Day 1 of each treatment cycle if the next treatment cycle is delayed (the data may be collected within 7 days 
before the scheduled date). Examination is mandatory on Day 1 or the day before starting the study treatment specified in this 
protocol. 
m. 
End of treatment assessments must be completed within 14 days from the date of last dose of study drug. 
n. 
These data may be collected 30 days after last dose of study drug or until the start of new anti-tumor therapy, whichever comes first. 
In cases an AE/SAE related to study drug is not resolving, the safety follow-up period will be extended. 
o. 
Obtain survival status (alive/ dead) at scheduled 12-week time intervals from randomization until death, and at the cutoff date for 
second interim analysis and primary evaluation (the data may be collected within 2 weeks before or after the scheduled date). 
 
 
51 
 

 
 
 
11.3 Tests at Randomization or before Initiation of Study Treatment 
The investigator (subinvestigator) should obtain written informed consent from each 
subject candidate before randomization. Then the investigator (subinvestigator) or the CRC 
prepares the following findings and test results, and verifies the eligibility of the candidate. In 
addition to the inclusion and exclusion criteria, the results of tests such as CT or MRI should 
be included in the eligibility assessment on an as-needed basis. The results of unscheduled 
tests performed before informed consent, if available, may be used as the basis for 
randomization. Participation of a patient being treated in another hospital/department at the 
time of randomization should be notified to his or her attending physician. 
Eligibility for randomization in this study will be determined from review of results of the 
baseline assessments in relation to the inclusion/exclusion criteria (see Section 8.1, 8.2). 
Obtain the following at baseline: 
(1) Within 28 days prior to randomization 
・ Informed consent, patient background, AE/SAE assessment, concomitant 
medications 
(2) Within 21 days prior to randomization 
・ Tumor measurement, AE/SAE assessment, concomitant medications 
(3) Within 14 days prior to randomization 
・ Height, weight, body temperature, blood pressure, ECOG PS, hematology
, 
serum chemistry
, urinalysis, tumor markers, pregnancy test, electrocardiography
, 
physical examination, AE/SAE assessment, concomitant medications 
(4) Within 7 days prior to Day 1 of the first treatment cycle    
・ Weight, body temperature, blood pressure, ECOG PS, hematology
, serum 
chemistry
, urinalysis, physical examination, AE/SAE assessment, concomitant 
medications 
・ These tests may not be needed, if it is overlapped with the test date which is “(3) 
within 14 days prior to randomization”. 
 
11.4 Tests during Study Treatment 
Arm A
 (TAS-118/L-OHP) 
(1) Before initiation of next treatment cycle (Day15) (from Day 14 to Day 18 if not 
feasible on Day 15) 
・ Hematology
, serum chemistry
, urinalysis, physical examination, AE/SAE 
assessment, concomitant medications 
・ Examination is mandatory on Day1 or the day before starting study treatment 
specified in this protocol. 
(2) If initiation of next treatment cycle is postponed 
 Hematology
, serum chemistry
, urinalysis, physical examination, AE/SAE 
assessment, concomitant medications 
・ Every 1 week starting on Day 1 of each treatment cycle (the data may be 
collected within 7 days before the scheduled date). 
(3) If any of abnormality is suspected (if necessary) 
・ Weight, body temperature, blood pressure, ECOG PS, electrocardiography 
 
52 
 

 
 
 
(4) Every 6 weeks from the day of randomization (within 1 week before or after the 
scheduled date) 
・ Tumor measurement, tumor markers 
 
 If PD  is  strongly  suspected  by any symptoms  or signs,  preform  extra  tumor 
measurement  objectively  at  the  discretion  of  the  investigator  (or  subinvestigator) 
even if not the scheduled date. 
In  case  of  performing  extra  tumor  measurement,  the  measurement  of  the  tumor 
marker is not mandatory. 
 
Arm B (S-1/CDDP) [CDDP on Day1] (Korea) 
(1) Day 15 in each cycle (from Day 8 to Day 22 if not feasible on Day 15) 
・ Physical examination, hematology
, serum chemistry
, urinalysis, AE/SAE 
assessment, concomitant medications 
(2) Before initiation of next treatment cycle (Day36) (from Day 29 to Day 43 if not 
feasible on Day 36) 
・ Hematology
, serum chemistry
, urinalysis, physical examination, AE/SAE 
assessment, concomitant medications 
・ Examination is mandatory on Day1 or the day before starting study treatment 
specified in this protocol. 
(3) If initiation of next treatment cycle is postponed 
 Hematology
, serum chemistry
, urinalysis, physical examination, AE/SAE 
assessment, concomitant medications 
 Every 1 week starting on Day 1 of each treatment cycle if the next treatment 
cycle is delayed (the data may be collected within 7 days before the scheduled 
date). 
(4) If any of abnormality is suspected (if necessary) 
・ Weight, body temperature, blood pressure, ECOG PS, electrocardiography 
(5) Every 6 weeks from the day of randomization (within 1 week before or after the 
scheduled date) 
・ Tumor measurement, tumor markers 
 
 If PD  is  strongly  suspected  by any symptoms  or signs,  preform  extra  tumor 
measurement  objectively  at  the  discretion  of  the  investigator  (or  subinvestigator) 
even if not the scheduled date. 
In  case  of  performing  extra  tumor  measurement,  the  measurement  of  the  tumor 
marker is not mandatory. 
 
Arm B (S-1/CDDP) [CDDP on Day8] (Japan) 
(1) Day 8 in each cycle (on the day before administration or on the day of 
administration until the start of administration) (from Day 6 to Day 15 if not feasible 
on Day 8) 
・ Physical examination, hematology
, serum chemistry
, urinalysis, AE/SAE 
assessment, concomitant medications   
 
53 
 

 
 
 
(2) Day 15 in each cycle (from Day 8 to Day 22 if not feasible on Day 15) 
・ Physical Examination, Hematology
, serum chemistry
, urinalysis, AE/SAE 
assessment, concomitant medications 
(3) Before initiation of next treatment cycle (Day36) (from Day 29 to Day 43 if not 
feasible on Day 36) 
・ Hematology
, serum chemistry
, urinalysis, physical examination, AE/SAE 
assessment, concomitant medications 
・ Examination is mandatory on Day1 or the day before starting study treatment 
specified in this protocol. 
(4) If initiation of next treatment cycle is postponed 
 Hematology
, serum chemistry
, urinalysis, physical examination, AE/SAE 
assessment, concomitant medications   
 Every 1 week starting on Day 1 of each treatment cycle if the next treatment 
cycle is delayed (the data may be collected within 7 days before the scheduled 
date). 
(5) If any of abnormality is suspected (if necessary) 
・ Weight, body temperature, blood pressure, ECOG PS, electrocardiography 
(6) Every 6 weeks from the day of randomization (within 1 week before or after the 
scheduled date) 
・ Tumor measurement, tumor markers 
 
 If PD  is  strongly  suspected  by any symptoms  or signs,  preform  extra  tumor 
measurement  objectively  at  the  discretion  of  the  investigator  (or  subinvestigator) 
even if not the scheduled date. 
In  case  of  performing  extra  tumor  measurement,  the  measurement  of  the  tumor 
marker is not mandatory. 
 
11.5 End of Treatment 
An end of treatment visit will be conducted at the date of last dose of study drug (+14 
days). 
Perform the following assessments: 
・ ECOG PS, weight, physical examination, hematology
, serum chemistry
, urinalysis, 
AE/SAE assessment, concomitant medications (including new anti-tumor therapy) 
As needed (when abnormalities are indicated): 
・ Body temperature, blood pressure, electrocardiography 
 
11.6 Safety Follow-up 
A
 Safety Follow-up visit will be conducted 30 days (+ 14 days) after the last dose of study 
drug. Moreover, if an adverse drug reaction due to the study drug occurs after the end of the 
safety follow-up period, this information should be reported. If the patient starts new 
anti-tumor therapy within 30 days of the last dose of study treatment, the Safety Follow-up 
Visit should be performed prior to the start of new anti-tumor therapy
. If the patient is unable 
to return to the site prior to the initiation of new treatment, a follow-up phone call can be 
 
54 
 

 
 
 
conducted by the site to collect any new safety information that occurred between the “11.5 
End of Treatment Visit” and the initiation of the new treatment. 
Perform the following assessments: 
・ ECOG PS, weight, physical examination, hematology, serum chemistry, urinalysis, 
AE/SAE assessment, concomitant medications (including new anti-tumor therapy) 
As needed (when abnormalities are indicated): 
・ Body temperature, blood pressure, electrocardiography 
 
11.7 Tumor Follow-up 
For patients who discontinued treatment for reasons other than radiologic disease 
progression defined by RECIST version 1.1, tumor follow-up visit will be performed every 6 
weeks (+/-1 week) from randomization until the patient develops radiologic disease 
progression defined by RECIST version 1.1, or initiation of new anti-tumor therapy. 
Perform the following assessments: 
・ Tumor measurement, tumor markers 
 
11.8 Survival Follow-up 
All treated patients will be followed for survival status (alive/dead) and new anti-tumor 
therapy at scheduled 12-week (+/- 2 weeks) time intervals from randomization until death, 
and at the cutoff date for second interim analysis and primary evaluation. Patients will be 
followed until the target number of events (deaths) is met. The investigator (subinvestigator) 
should make every effort to contact the patient or primary caregiver to determine his/her 
survival status. Survival information must be documented in the patient’s records. If patient 
wishes to discontinue the study treatment (including withdrawal of consent), survival 
follow-up will be continued.  
 
12. Pharmacokinetics and Pharmacogenomics 
Not included in this study. 
 
 
 
 
55 
 

 
 
 
13. Discontinuation of study 
13.1 Discontinuation criteria for individual subject 
 
Study Treatment Discontinuation Criteria 
Discontinue the study treatment if any of the following occur: 
∙ Disease progression defined by RECIST version 1.1 
∙ Patient has an adverse event (AE) that in the opinion of the investigator 
(subinvestigator) requires the study treatment to be discontinued 
∙ Patient has not taken the study drug for more than 28 consecutive days 
∙ Application for curative surgery due to tumor shrinkage 
∙ Patient has a critical protocol deviation 
∙ Pregnancy 
∙ Patient request to discontinue the study treatment 
∙ The investigator (subinvesitigator) concludes that the patient needs to discontinue 
the study treatment 
∙ Study is completed 
 
Safety Follow-up Discontinuation Criteria 
In the case of follows, safety follow-up is discontinued.  
∙ 30 days after the last dose study treatment 
∙ The start of new anti-tumor therapy 
∙ Patient meets one of the survival follow-up discontinuation criteria 
∙ Safety follow-up becomes impossible due to changing hospital or other reasons 
∙ Patient wishes to discontinue the safety follow up (including withdrawal of 
consent) 
If an AE/SAE related to study drug occurs after the end of the safety follow-up period, this 
information should be reported. 
 
Tumor Follow-up Discontinuation Criteria 
Only patients who discontinued study treatment without PD defined by RECIST version 
1.1 will be followed for tumor assessments every 6 weeks (+/- 1 week) from randomization 
until one of the following occurs: 
∙ Disease progression defined by RECIST version 1.1 
∙ The starts of new anti-tumor therapy 
∙ Patient meets one of the survival follow-up discontinuation criteria 
∙ Patient wishes to discontinue the imaging and tumor marker measurement 
∙ Tumor follow-up becomes impossible due to changing hospital or other reasons 
∙ The investigator (subinvestigator) judges it necessary to discontinue the imaging 
for the safety of the patient 
 
Survival Follow-up Discontinuation Criteria 
A patient is considered “Discontinued from Survival Follow-up” only if one of the 
following occurs: 
∙ Patient dies 
 
56 
 

 
 
 
∙ Study is completed or terminated by the sponsor or regulatory agencies. 
 
13.2 Criteria for Discontinuation of Study in Individual Institutions 
The sponsor may discontinue the study in a study institution where significant or 
continued non-compliance with GCP or the study protocol by an investigator 
(subinvestigator) is found to be compromising the proper conduct of the study. In that case, 
the sponsor will notify the discontinuation of the study to the investigator and the head of the 
institution in question. 
If an investigator takes the initiative to discontinue the study, he/she should notify his or 
her intention and reasons in writing to the head of the study institution, who should then 
forward the notified intention and reasons for discontinuation/interruption in writing to the 
Institutional Review Board. 
 
13.3 Criteria for Termination of Entire Study 
The sponsor may terminate the study either entirely or partially at any time for whatever 
reason. In that case, the sponsor will notify the termination of the study and reasons in 
writing to the heads of the institutions, who should then forward the notification of 
termination and reasons to the Institutional Review Boards and investigators. The 
investigators (subinvestigators) should immediately advise subjects of the termination of the 
study, and initiate another treatment. The sponsor should notify the regulatory authorities of 
the termination of the study. 
 
13.4 Post Treatment 
Post treatments depend on investigator’s choice. 
 
 
 
 
57 
 

 
 
 
14. Efficacy Assessment 
14.1 Assessment of Antitumor Efficacy (RECIST Guideline Version 1.1) 
 
Evaluation of lesions 
14.1.1.1 
Measurement of Lesions 
The diameters of individual lesions, the long axis for non-nodal lesions and the short axis 
for nodal lesions, should be measured (in mm) using objective diagnostic techniques. 
 
14.1.1.2 
Tumor Definitions 
(1) Measurable Lesions 
Measurable tumor lesions: Lesions that can be accurately measured in at least 1 dimension 
with the longest diameter (to be recorded) ≥10 mm by CT or MRI scan if using slice 
thickness of 5 mm or less, or at least double the slice thickness of CT or MRI scan if 
the slice thickness is >5 mm. 
Measurable malignant lymph nodes: A lymph node must be considered pathologically 
enlarged with high suspicion of metastasis and measure ≥15 mm in the short axis 
when assessed by CT or MRI scan. The short axis is defined as the longest linear 
dimension perpendicular to the node’s longest diameter as assessed within the same 
plane that the scan was acquired. 
Only measurable lesions can be selected as target lesions. 
 
(2) Non-measurable Lesions 
Non-measurable lesions include: 
・ Small metastatic tumor lesions that have a longest dimension less than 10 mm or if 
slice thickness is greater than 5 mm less than twice the slice thickness. 
・ Abnormal and suspected metastatic lymph nodes that are ≥10 mm to <15 mm in the 
short axis. 
・ Truly non-measurable lesions (e.g., ascites). 
・ Primary lesion (in case primary lesion is not able to be evaluated as non-measurable 
lesion, evaluation of the lesion will not be performed.) 
All non-measurable lesions can only be selected as non-target lesions. 
 
(3) Target Lesions 
・ All measurable lesions up to a maximum of 2 lesions/organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions. 
・ Target lesions should be selected on the basis of their size (visceral lesion with the 
longest diameter and lymph node with the measurement of short axis), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. 
・ When recording tumor measurements the longest diameter will be measured for 
 
58 
 

 
 
 
tumor lesions. For pathological lymph nodes, the short axis will be measured. 
・ Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded, even if the nodes regress to below 10mm on study. This 
means that when lymph nodes are included as target lesions, the sum of lesions may 
not be zero even if complete response (CR) criteria are met. 
・ The sum of the diameters for all target lesions at beseline will be calculated as the 
beseline sum. The baseline sum will be used as a reference for follow-up tumor 
assessment. 
・ An option of ‘Not Assessable’ for a lesion will only apply to lesions that cannot be 
read due to technical reasons, for example: 
・ CT artifact. 
・ Patient positioning where the lesions are obstructed or cannot be seen. 
・ Lesion that may not be seen in their entirety due to CT slice thickness. 
・ In cases where a lesion divides into 2 lesions, the longest diameters of the 
fragmented portions should be added together to calculate the target lesion sum. 
・ In cases where 2 lesions coalesce, a plane between them may be maintained that 
would aid in obtaining maximal diameter measurements of each individual lesion. If 
the lesions have truly coalesced such that they are no longer separable, the vector of 
the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.  
 
(4) Non-target Lesions 
・ Non-target lesions include all non-measurable lesions and measurable lesions that 
have not been selected as target lesions. 
・ Lymph nodes that have a short axis <10 mm are considered non-pathological and 
should not be recorded. 
・ All lesions (or sites of disease) other than target lesions, including pathological 
lymph nodes, should be identified as non-target lesions and should also be recorded 
at baseline. Measurements are not required, but their presence, absence, or 
unequivocal progression should be followed until tumor follow-up discontinuation. 
・ It is possible to record multiple non-target lesions involving the same organ as a 
single item on the eCRF (e.g., multiple enlarged pelvic lymph nodes or multiple 
liver metastases). 
 
14.1.1.3 
Evaluation of Response in Target Lesions 
The response in target lesions should be evaluated using the 5-grade scale shown below. 
 
Complete Response (CR): 
Complete disappearance of non-nodal target lesions, and the short axes of all nodal target 
lesions below 10 mm (an assessment of CR with the sum of diameters being above 0 is 
possible if nodal lesions have been included in target lesions before the study treatment). 
Partial Response (PR): 
 
59 
 

 
 
 
A decrease of at least 30% in the sum of the diameters of target lesions in comparison 
with the baseline value. 
Stable Disease (SD): 
The absence not only of tumor shrinkage corresponding to CR or PR but also of tumor 
growth corresponding to PD. 
Progressive Disease (PD): 
An increase of at least 20% and at least 5 mm in length in the sum of the diameters of 
target lesions in comparison with the smallest value among the sums obtained previously 
(including the baseline value). 
Not Evaluable (NE): 
Lack of examination for any reason; response corresponding to none of CR, PR, SD, and 
PD. 
 
The diameters of target lesions should have their actual measurements recorded even 
when they have become very small (e.g. 2 mm). When the diameter has become “too small to 
measure”, the measurement should be recorded as 0 mm if the lesion is considered to have 
disappeared, or a default value of 5 mm should be assigned if the lesion is believed to be 
present. 
 
14.1.1.4 
Evaluation of Response in Non-Target Lesions 
The response in non-target lesions should be evaluated using the 4-grade scale shown 
below. 
 
Complete Response (CR): 
Complete disappearance of non-nodal non-target lesions, the short axes of all nodal 
non-target lesions below 10 mm, and all tumor marker levels at or below the institutional 
upper normal limits. 
Non-Complete Response/Non-Progressive Disease (Non-CR/non-PD): 
The presence of at least one non-nodal non-target lesion; or the short axis not less than 
10 mm in at least one nodal non-target lesion; or any tumor marker levels above the 
institutional upper normal limits. 
Progressive Disease (PD): 
Clear progression of existing non-target lesions, where “clear progression” is, in the 
presence of target lesions, an increase in overall tumor volume which is assessed as 
warranting discontinuation of the study treatment despite SD or PR in the target lesions 
but does not apply to a “modest increase” in tumor volume, and in the presence of only 
non-measureable lesions, e.g. a 73% increase in tumor volume (equivalent to a 20% 
increase in the diameters of measurable lesions). 
Not Evaluable (NE): 
 
60 
 

 
 
 
Lack of examination for any reason; response corresponding to none of CR, 
Non-CR/non-PD, and PD. 
 
Examination of Pleural, Ascitic, and Pericardial Fluids: Any fluid in body cavities that has 
collected or increased in the absence of progression in both target and non-target lesions 
should be examined for cytology as needed, and assessed to determine whether its 
collection/increase represents an adverse event or PD. 
Although this protocol specifies no procedures for confirmation of the appearance of new 
lesions, it is advisable that any findings suggesting development of new lesions be promptly 
investigated using appropriate diagnostic instruments. 
 
 
Assessment of Overall Response 
Assessments will be based on the definitions provided in Table 14.1.2-1 and Table 
14.1.2-2 below. 
 
Table 14.1.2-1  Time Point Response for Patients with Target (+/- Non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR * 
CR 
Non-CR/Non-PD or 
Not all evaluated 
No 
PR 
PR 
Non-PD or Not all 
evaluated 
No 
PR 
SD 
Non-PD or Not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* For CR, tumor marker must have been under upper limit of normal. 
 
Table 14.1.2-2  Time Point Response for Patients with only Non-target Disease 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR * 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* For CR, tumor marker must have been under upper limit of normal. 
 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
 
61 
 

 
 
 
change the assigned time point response. 
 
 
Best Overall Response Assessment 
The best overall response as per RECIST Criteria (version 1.1) is the best response 
recorded from the start of the study treatment until the end of tumor follow-up period. The 
confirmation of tumor response for CR or PR is not required, but the duration of SD (or 
Non-CR/Non-PD) is set as 6 weeks from randomization (the data may be collected within 1 
week before or after the scheduled date). 
 
14.2 Overall Response Rate (ORR) 
ORR is defined as the proportion of patients with the best overall response of CR or PR in 
tumor response evaluable population. 
 
14.3 Disease Control Rate (DCR) 
The assessment of DCR will parallel that of ORR, with DCR defined as the proportion of 
patients with objective evidence of CR, PR, or SD. 
 
14.4 Progression Free Survival (PFS) 
Progression free survival is defined as the time (in months) from the date of randomization 
until the date of the investigator-assessed radiological disease progression or death due to any 
cause, whichever comes first. Patients who receive post treatment before disease progression 
will be censored at the date of the last evaluable tumor assessment before post treatment is 
initiated.Patients who are alive with no disease progression at the time of the analysis will be 
censored at the date of the last confirmation as non-PD. 
 
Event / Censoring 
Case 
Event date 
Event 
PD 
the date of disease 
progression 
Death (without PD) 
the date of death 
Censoring 
Non-PD at the time of analysis 
the date of the last 
tumor assessment 
The date of PD is unknown 
the date of the last  
tumor assessment 
Patient 
without 
any 
tumor 
assessment 
after 
randomization 
the date of  
randomization 
Patient receive other post treatment for a reason other 
than PD 
the date of the last  
tumor assessment 
Other 
the date of the last  
tumor assessment 
 
62 
 

 
 
 
14.5 Time to Treatment Failure (TTF) 
Time to treatment failure is defined as the time from the date of randomization until the 
date of last dose of study treatment. Patients who are still on study treatment as of the cut-off 
date will be censored at the last date of study treatment, or the cut-off date, whichever is 
earlier. 
 
14.6 Overall Survival (OS) 
Survival is defined as the time from the date of randomization to the date of death due to 
any cause. In the absence of death confirmation or for patients alive as of the cut-off date, 
patient will be censored at the date of last study follow-up, or the cut-off date, whichever is 
earlier. 
 
 
63 
 

 
 
 
15. Reporting Safety Information 
15.1 Adverse Events/Serious Adverse Events 
 
Adverse Events 
An adverse event (AE) is any untoward medical condition that occurs in a patient while 
participating in a clinical study and does not necessarily have a causal relationship with the 
use of the product. 
Treatment emergent adverse events are AEs that occur from the initiation of any study 
medication administration, and do not necessarily have a causal relationship to the use of the 
study medication. 
Provide a complete and specific clinical diagnosis as an AE term. If a diagnosis is not 
available, then report physical examination. The National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE version 4.03) terms are to be used to 
assess severity/provide the grade for each adverse event that is reported. 
Refer to Sections 15.1.5 and 15.1.6 for definitions and reporting of pregnancy, medication 
errors, and overdose, respectively. 
Symptoms or laboratory or instrumental (e.g., electrocardiographic) abnormalities of a 
pre-existing disease, such as cancer or other disease, should not be considered an AE. 
However, occurrences of new symptoms as well as worsening of pre-existing medical 
conditions are considered AEs. In addition, a new laboratory or instrumental abnormality that 
has a clinical impact on a patient (e.g., resulting in study medication dose reduction, 
treatment delay, treatment discontinuation, requires treatment due to abnormal values, or is 
considered medically important by the investigator) is considered an AE, unless it is 
considered part of clinical manifestations to a clinical diagnosis that is already reported as an 
AE. 
AEs will be reported from the time a patient signs informed consent through the period of 
patient follow-up (30 days after the last dose of study medication or until the start of new 
anti-tumor therapy, whichever is earlier). Document all AEs in the source documents. 
Documentation should include onset and resolution dates, severity/grade, relationship to 
study medication, and outcome of the event. 
Any untoward medical event that occurs outside the period of patient follow-up (30 
days after the last dose of study medication or until the start of new antitumor therapy, 
whichever is earlier) is not considered an AE. If any AEs are observed after the patient 
follow-up period has ended, only those AEs determined to have a causal relationship with the 
investigational drug will be recorded in the case report form. 
 
Causal relationship: 
(1) 
Related: The AE is related if it follows a reasonable temporal sequence from 
administration of study medication. 
(2) 
Not related: The AE is not related when there is no reasonable possibility that the 
study medication caused the event. For the purposes of safety reporting, “no 
 
64 
 

 
 
 
reasonable possibility” means there is no evidence to suggest a causal relationship 
between the drug and the adverse event and one or more of the following conditions 
are true: 
・Disease Under Study 
・Medical Condition(s) 
・Previous or Concomitant Medication 
・Protocol-related Procedure 
・Other 
 
Outcome: 
∙ Resolved without sequelae 
∙ Resolved with sequelae 
∙ Resolving (Should be used only in the reporting SAE) 
∙ Unresolved 
∙ Death 
∙ Unknown 
 
Any ongoing AEs should be followed until the earliest occurrence of one of the following: 
∙ AE has resolved 
∙ Although the AE has not yet resolved, the Investigator considers that the AE is 
stable or no further improvement is expected. An AE cannot be considered 
stabilized while the patient is on study medication. Ongoing AEs must be 
assessed for stabilization 30 days post after the last dose of study medication 
∙ The start of new anti-tumor therapy 
∙ Patient meets one of the survival follow-up discontinuation criteria 
∙ Safety follow-up becomes impossible due to changing hospital or other reasons 
∙ Patient wishes to discontinue the safety follow up (including withdrawal of 
consent) 
 
 
Adverse Drug Reactions 
Adverse drug reactions are concern noxious and unintended responses to a medicinal 
product within adverse events. 
 
 
Serious Adverse Events (SAE) 
A Serious Adverse Event (experience) or reaction is any untoward medical occurrence that 
at any dose: 
(a) 
Results in death. 
(b) 
Is life-threatening. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an 
event in which the patient was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it 
were more severe. 
 
65 
 

 
 
 
(c) 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
The following are not considered hospitalizations for the purposes of 
assessing seriousness: 
∙ Emergency room visits less than 24 hours. 
∙ Hospitalizations for preplanned procedures. 
∙ Hospitalization for study-related treatment and procedures. 
(d) 
Results in persistent or significant disability or incapacity. 
(e) 
Is a congenital anomaly/birth defect. 
(f) 
Is any other important medical event. 
∙ Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition 
above. These should also usually be considered serious. 
∙ Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse. 
 
Serious adverse events must be reported to Taiho Drug Safety or designee within 24 hours 
from the time the investigator first becomes aware of the SAE. The SAE reporting process 
and contact information for reporting SAEs are provided in the CRF and SAE Completion 
Guidelines. 
After the initial SAE notification to Taiho Drug Safety or designee, follow-up SAE 
information will be submitted each time that important follow-up information (e.g., diagnosis, 
outcome, causality assessment, results of specific investigations) becomes available. 
All SAEs within the follow-up window (e.g., within 30 days after the last dose of study 
medication or until the start of new anti-tumor therapy, whichever is earlier) established in 
the protocol will be reported to Taiho Drug Safety or designee. 
If serious medical occurrences including deaths outside the follow-up window established 
by the protocol are reported to or observed by the investigator that he/she believes are related 
to the administration of the investigational product, it is the investigator’s responsibility to 
report this occurrence to Taiho Drug Safety or designee. 
 
 
Disease Progression 
Disease progression is not an acceptable AE term. In cases of disease progression the 
relevant signs, symptoms and complications should be reported as an AE unless they meet 
the serious criteria. If any of the signs, symptoms and complications meets any of the serious 
criteria, they should be reported as an SAE. In both cases it should be indicated whether the 
signs, symptoms and complications are related to disease progression. 
In cases of death due to clinical disease progression, clinical disease progression may only 
be reported as an SAE term if none of the relevant signs or symptoms support a fatal 
 
66 
 

 
 
 
outcome. 
Radiological disease progression without relevant signs, symptoms and complications will 
not be reported as an AE or SAE. 
 
 
Pregnancy 
If a patient becomes pregnant while in the study, the study treatment must be immediately 
discontinued. Pregnancy information for a female patient or for the female partner of the 
male patient should be reported within 24 hours from the time the investigator first becomes 
aware of a pregnancy or its outcome. This should be performed by completing a Pregnancy 
Form and emailing or faxing it to Taiho Drug Safety or designee. 
New and/or corrected information regarding the pregnancy obtained after submitting the 
Pregnancy Form must be submitted by emailing or faxing an updated Pregnancy Form to 
Taiho Drug Safety or designee. 
If outcome of the pregnancy is a stillbirth, congenital anomaly/birth defect, or a serious 
event in the mother, report as an SAE to Taiho Drug Safety or designee. 
 
 
Other Information 
Any information about overdose, or medication error, which was defined below, should be 
forwarded to the sponsor regardless of whether it is associated with an adverse event (even if 
not fulfilling seriousness criterion). 
∙ 
Overdose: Administration at a dose above the dose specified in “section 10.1 
Dose, administration method, and administration period”; 
∙ 
Medication error: Any errors in administration of the study treatment, 
including the wrong agent, wrong route of administration, wrong dose/dosing 
interval, and accidental ingestion; 
 
 
Breaking the Study Blind 
This is an open-label study. Both investigators and patients will be aware of which 
treatment regimen the patient is receiving, TAS-118/L-OHP or S-1/CDDP. 
 
15.2 Laboratory Evaluations 
 
Reporting and Evaluation of Laboratory Test Results 
Laboratory tests are to be performed as required per protocol. All laboratory values that 
are out of the normal range are to be evaluated for their clinical significance before exposing 
the patient to the next dose of study medication. 
The laboratory must provide normal reference ranges. 
Any laboratory abnormality that is clinically significant, e.g., results in delay of study 
 
67 
 

 
 
 
medication dosing, study discontinuation, requires treatment due to abnormal values, or is 
considered by the investigator to be medical important, must be reported as an AE, unless it 
is considered a supporting lab to a clinical diagnosis that is already reported as an AE. All 
laboratory data will be analyzed using NCI CTCAE grade criteria (version 4.03). 
 
 
Repeat Testing 
Repeat the evaluation of any clinically significant laboratory test, as clinically indicated, 
until the value returns to the baseline level or clinically stabilizes, or until new anti-tumor 
therapy is given. 
 
15.3 Physical Examination and Performance Status 
Perform physical examinations and performance status evaluations as described in the 
Study Procedures section of the protocol. If changes are observed, determine whether they 
meet the definition of an AE. Document all observations and evaluations. 
 
15.4 Body Temperature, Blood Pressure and Body Weight 
Verify and document body temperature, blood pressure (systolic/diastolic) and body 
weight. If a clinically significant change is observed, repeat the measurement as clinically 
indicated and evaluate for its clinical relevance and whether it meets the definition of an AE. 
 
 
 
 
68 
 

 
 
 
16. Statistical Analysis 
The data obtained during this clinical trial will be analyzed following the details provided 
below. In addition to this document, we will also prepare a Statistical Analysis Plan (SAP), 
which will include further technical details and descriptions of the planned statistical 
analyses and summaries of the results. 
16.1 Timing of Statistical analyses 
Four analyses will be performed at the times of two interim analyses, time of primary 
evaluation, and time of final analysis as follows. 
 
Interim Analyses 
The Independent Data Monitoring Committee (IDMC) will perform two interim analyses. 
In order to evaluate the safety data, first interium analysis will be performed by the IDMC. At 
second interim analysis, the IDMC will evaluate the safety and efficacy data based on these 
analyses. The IDMC will propose whether the trial should stop earlier based on the results 
obtained to that point. Further details of the role and responsibility of IDMC and the review 
process are provided in the IDMC charter. The interim analyses will be performed with the 
data gathered up to following cutoff point. 
(1) Data cutoff for the first interim analysis 
・In safety analyses, the cutoff data will be defined on the basis of the date when 100 death 
events are confirmed. 
 (2) Data cutoff for second interim analysis 
・The cutoff date for primary endpoint is the date when 219 death, which is the 50% 
required number of death events, are confirmed. 
・In safety analyses, the cutoff data will be defined on the basis of the date when 219 death 
events are confirmed. 
 
Primary Evaluation 
The primary analysis will be performed when the cutoff date is determined, and CRFs, 
dispositions and adoptions of all patients are fixed again. 
(1) Data cutoff for primary evaluation 
・The cutoff date for primary endpoint will be set at the date when 491 death events are 
confirmed, representing the final number of events required. 
・In safety analyses, the cutoff data will be defined on the basis of the date when 491 death 
events are confirmed. 
 
Final Evaluation 
At the end of the trial, statistical analyses will be performed using all the data gathered to 
this point. 
16.2 Populations and Criteria for Handling Patient Data 
 
Analysis Populations 
The analysis populations are defined in Table 16.2.1-1. 
 
69 
 

 
 
 
The sponsor, in collaboration with the medical specialists, will determine the overall 
disposition of the patients if there are any problems except the following criteria for patient’s 
disposition. 
FAS will be included only in the primary analysis. 
 
Table 16.2.1-1  Definitions of Analysis Populations 
Analysis Population 
Definition 
Enrolled Population 
All patients enrolled in this trial. 
As Treated (AT) Population 
Enrolled patients who received at least one dose of the study drug. 
Full Analysis Set (FAS) 
Patients in AT population who have gastric cancer at randomization. 
Tumor 
Response 
(TR) 
Evaluable Population 
Patients in FAS population presenting measurable lesions (at least one 
target lesion), evaluated for tumor responses at least once during 
treatment with the study drug. 
 
 
Criteria for Handling Patient Data 
The criteria for handling patient data are described below. 
The sponsor, in collaboration with the medical specialists, will determine the approach to 
handle data if there are problematic patients for handling except the criteria listed below:  
(1) Handling of missing values and abnormal values 
・No specific measures will be implemented. Analyses will be performed using all the data 
gathered for each time frame. For each analysis proportions will be estimated on the 
basis of the whole population analyzed. 
・The analyses will include all data points unless the laboratory tests, such as the effect of 
hemolysis during blood collection, showed obvious abnormal values. In the presence of 
excluding abnormal laboratory results from analysis, these values will still be provided 
and the reasons for exclusion clearly stated. 
(2) Patients with violations of study drug randomization 
・For those analyses involving the AT population, the data of patients who have been 
administered study drug of different treatment arm from allocated treatment arm will be 
treated as that arms based on actual administored study drug. 
・In the analyses for FAS or TR population, data will be treated as allocated treatment arm. 
 
16.3 Statistical Methods 
The main statistical methods to evaluate the primary and secondary objectives of the trial 
are described below. 
All the details of the analyses performed in the trial are described in the statistical analysis 
 
70 
 

 
 
 
plan and a report analysis plan will be separately developed.   
 
Patient Disposition, Baseline and Treatment Characteristics 
(1) Patient Disposition 
The number of patients included in each population, the reasons for exclusion, and any 
randomization and/or stratification errors will be summarized schematically. 
(2) Patient Baseline Characteristics 
The distribution of data such as main patient background characteristics, disease 
characteristics, and baseline laboratory values will be summarized. 
(3) Evaluation of Comparability 
Deviation between study drugs will be evaluated using the appropriate statistical test 
depending on the characteristics of the data. 
 
 
Primary Endpoint Analyses 
Main methods of primary endopoint (OS) analysis are shown below. 
(1) Primary analysis 
・ OS in the FAS will be compared between the two study treatment arms using stratified 
log-rank test by three stratification factors (significance level is 5% for 2 sided test). 
0.305% and 4.899% are set at the time of second interim and main evaluation respectively 
by alpha spending function with O’Brien-Fleming form and considering correlation 
between each test statistic to maintain significance level throughout the study less than or 
equal to 5%. Superiority of efficacy of TAS-118/L-OHP arm to S-1/CDDP arm is 
statistically considered valid when either p-values are less than or equal to each 
significance level in each statistical test. Also, a confirmation of the superiority in the first 
interim analysis will not be done. 
(2) Sensitivity analyses of primary analysis 
・ OS in the FAS will be compared between the two study treatment arms using unstratified 
log-rank test. In addition, Cox Proportional Hazard (CPH) model will be performed with 
the study drug as covariate. 
(3) Secondary analysis of primary endpoint 
Following analyses will be performed in FAS population. 
・ Hazard ratio of OS with 95% confidence interval will be estimated by CPH model with 
the study drug and three stratification factors as covariates. 
・ In each study treatment, survival curves of OS will be estimated and Median Survival 
Time (MST) with 95% confidence interval using the Kaplan-Meier method will be 
presented. Otherwise the number at risk and cumulative event free rate every three months 
will be presented. 
 
71 
 

 
 
 
・ In each stratification factor and each study treatment, survival curves of OS will be 
estimated and MST with 95% confidence interval using the Kaplan-Meier method will be 
presented. Otherwise the number at risk and cumulative event free rate every three months 
will be presented. 
 
 
Secondary Endpoints Analyses 
Main methods of secondary endpoints analyses are shown below. 
16.3.3.1 
Efficacy Endpoints 
(1) Overall Response Rate (ORR) 
Following analyses will be performed in TR population. 
・ In each study treatment, best overall responses will be summarized and ORRs with 95% 
confidence interval will be estimated. The treatment comparison will be done using 
Fisher’s exact test. 
・ In each study treatment, onset date, duration of response (duration of overall response and 
duration of overall complete response) for antitumor effect will be summarized in patients 
with responses. 
(2) Disease Control Rate (DCR) 
・ In each study treatment and TR population, DCR based on the best overall response will 
be estimated. The treatment comparison will be done by Fisher’s exact test. 
(3) Progression Free Survival (PFS) 
・ In each study treatment and FAS population, survival curves of PFS will be estimated and 
MST with 95% confidence interval using the Kaplan-Meier method will be presented. 
Otherwise the number at risk and cumulative event free rate every three months will be 
presented. 
・ PFS in the FAS will be compared between the two study treatment arms using stratified 
log-rank test by three stratification factors. In addition, hazard ratio of PFS with 95% 
confidence interval will be estimated by CPH model with the study drug as covariates. 
(4) Time to Treatment Failure (TTF) 
・ In FAS population, TTF analyses will be performed by the same ways as PFS analyses. 
16.3.3.2 
Treatment Status 
(1) Treatment discontinuation 
・ For each study treatment and FAS population, treatment discontinuations and their reasons 
will be summarized. 
(2) Dose Intensity 
 
72 
 

 
 
 
・ For each study treatment and FAS population, actual dose intensity and relative dose 
intensity of each patient will be summarized. 
 
16.3.3.3 
Safety Analyses 
Following analyses will be performed in AT population. However, same analyses will be 
done in FAS population if AT population doesn’t correspond to FAS population. 
(1) Adverse event 
・ Rate of adverse event will be summarized. 
・ For maximum grade of each adverse event in each patient, the number of patient and rate 
of adverse event by grade will be summarized. 
・ For all adverse events between onset of study drug administration and end of the trial, 
tables of their class, grade, onset date, causal relationship, outcome and treatment contents 
will be described. 
(2) Adverse drug reaction 
・ For adverse drug reaction, same analyses as adverse events will be performed. 
(3) Laboratory test 
・ Transition of main hematological laboratory values (White Blood Cell, Lymphocyte, 
Neutrophil, Hemoglobin, Platelet) at each point of each patient will be described as graph. 
(4) Clinical findings 
・For clinical findings (stomatitis, anorexia, diarrhea, peripheral sensory neuropathy), onset 
date of each patient, date of occurrence for maximum grade, first date of condition with 
grade 3 or higher, and time to recovery will be presented as list in each study treatment 
arm. 
 
16.4 Determination of Sample Size 
Number of target patients: 686 subjects  
(TAS-118/L-OHP arm: 343 subjects, S-1/CDDP arm: 343 subjects)  
Number of target patients as FAS: 650 subjects 
(TAS-118/L-OHP arm: 325 subjects, S-1/CDDP arm: 325 subjects) 
In a randomized phase II study of S-1/LV therapy, S-1/LV/L-OHP therapy, and S-1/CDDP 
therapy in patients with unresectable, advanced, recurrent gastric cancer (********* 
********), MST of the S-1/LV/L-OHP therapy was 18.4 months and MST of S-1/CDDP 
therapy was 12.6 months, respectively. In SOS trial which conducted in Japan and Korea, 
 
73 
 

 
 
 
MST of the S-1/CDDP (5-week-interval administration) was 13.9 months, although the 
Japanese subgroup showed an MST of 15.5 months. Taking the difference on the ratio of 
target number of randomized patient between Japan and Korea and on the target popuration 
in this trial into consideration, MST of the S-1/CDDP is assumed to be 14.5 months for this 
trial and MST of TAS-118/L-OHP is set 19.33 months (hazard ratio : 0.75). 
In the condition that MST is exponentially distributed and 2-sided 4.899% significance 
level and 85% power, the required number of death events is 437 for logrank test in the 
primary analysis which compares OS of TAS-118/L-OHP arm with of S-1/CDDP for primary 
evaluation. In the case that patients are uniformally enrolled in accrual period of 19 months 
and follow-up period is 19 months, the total required number of patients can be estimated 
686 including expectation of 5% exclusion from FAS. Patients can be additionally enrolled 
when the number of events is less than expectation in the evaluation during the trial. The 
sponsor will determine, in collaboration with the statistics advisor, the final number of 
patients if the number of patient increases. 
Null and alternative hypotheses of statistial test are as follows 
Null hypothesis H0： 
1
=
C
T λ
λ
 
Alternative hypothesis H1： 
1
≠
C
T λ
λ
 
C
λ ：Hazard of S-1/CDDP arm 
T
λ ：Hazard of TAS-118/L-OHP arm 
Powers at various situations where expected MSTs of each arm change are shown in Table 
16.4-1. 
 
Table 16.4-1  Powers(%) at various situations where expected MSTs of each arm change 
 
MST of S-1/CDDP arm  
12 
13 
14 
14.5 
15 
16 
17 
MST of 
TAS-118/L-OHP arm 
17 
95.3 
79.8 
52.4 
38 
25.4 
9.1 
2.4 
18 
98.8 
92.4 
74.5 
61.5 
47.5 
23 
8.5 
19 
99.8 
97.7 
88.9 
80.4 
69.2 
43.2 
21 
19.33 
99.9 
98.5 
92 
85 
75.2 
50.3 
26.6 
20 
100 
99.4 
96.1 
91.8 
85 
64.2 
39.4 
21 
100 
99.9 
98.8 
97.1 
93.9 
80.9 
59.5 
22 
100 
100 
99.7 
99.2 
97.9 
91.3 
76.6 
Note: Powers are estimated in the condition that the number of death events are 437 and 
2-sided significance level is 4.899%. The underline is the power set in this trial． 
 
 
 
74 
 

 
 
 
17. Case Report Form 
17.1 Preparation of CRF 
The investigator shall be provided with standardized eCRFs and shall ensure that all data 
from patient visits are promptly entered into the eCRFs in accordance with the specific 
instructions given. 
Investigators will be provided with detailed eCRF Completion Guidelines that will 
identify the required data points to be collected, how to document them, and when the data 
should be documented. 
It is the responsibility of the investigator to maintain adequate and accurate eCRFs to 
record (according to the eCRF Completion Guidelines) all observations and other data 
pertinent to the clinical trial obtained during scheduled or unscheduled visits. All eCRFs 
should be fully completed to ensure accurate data interpretation. 
The investigator should record all the data on eCRFs in accordance with time limit in the 
following items (Except the sponsor request to stop recording the data); 
・ Patient background：Within 14 days after randomization 
・ Administration record：Within 14 days after last administration of each cycle 
・ Hematology, serum chemistry, urinalysis：Within 14 days after the test date 
・ Survival, post treatment：14 days after getting the information 
・ Other items：Within 14 days after end of treatment 
 
The computerized handling of the data by the sponsor after receipt of the eCRFs may 
generate additional requests via electronic queries or other means to which the investigator is 
obliged to respond by confirming or modifying the data questioned. These requests with their 
responses will be appended to the eCRFs held by the investigator and the sponsor. 
 
 
 
 
75 
 

 
 
 
18. Protocol Compliance, Deviation and Amendment 
18.1 Protocol Compliance 
(1) The investigator agrees with the sponsor the contents of a sample of the protocol and the 
case report form; in addition, to certify that he/she has agreed with compliance with this 
protocol, the investigator shall, together with the sponsor, sign and/or seal and date the 
protocol or other document in lieu of the protocol. 
(2) In the event of revision of a sample of the protocol and the case report form, and in the 
event of revision of a sample of the protocol and the case report form pursuant to the 
instructions of the head of the medical institution in accordance with the institutional 
review board, the same as mentioned in above (1) shall apply. 
 
18.2 Protocol Deviation 
In attempting to change a protocol, the investigator and subinvestigators shall agree in 
writing in advance to obtain written approval in accordance with pre-review of the IRB.  
The investigator must report promptly every change of the protocol that will have a 
significant effect on the conduct of the study or will increase the hazard to study subjects to 
the sponsor, the head of the medical institution and the IRB via the head of the medical 
institution.  Where there is some medically compelling reason such as to eliminate an 
immediate hazard to a study subject, the investigator or subinvestigator may make a 
deviation from or a change of the protocol without prior written agreement with the sponsor 
and without prior approval of the IRB.  In such a case, the investigator shall promptly report 
the content of deviation or change and the reason for it to the sponsor and the head of the 
medical institution, and submit the report to the IRB via the head of the medical institution to 
obtain written approval of the IRB. 
The investigator is to record any deviation from the protocol, irrespective of any reasons 
whatsoever. 
 
18.3 Revision of Protocol, etc. 
(1) When the sponsor deems it necessary to revise the samples of the protocol and the case 
report form, the sponsor will provide the investigator with the proposed revisions of the 
protocol and the case report form. 
(2) The investigator will fully consider the proposed revisions. 
(3) In revising the samples of the protocol and the case report form, the sponsor shall obtain 
agreement of the investigator on the contents of the revised protocol and the case report 
form. 
(4) The sponsor shall promptly submit the revised protocol and case report form to the head 
of the medical institution and obtain the approval of the IRB via the head of the medical 
institution. 
 
 
76 
 

 
 
 
However, when the revisions are made to the protocol, etc., due to the changes in 
administrative aspects of the study (e.g., change in organization or structure of the sponsor, 
change in name or name of diagnosis and treatment department of other medical institutions, 
change in location or telephone number(s) of other medical institutions and the sponsor, 
change in the title of the investigator, change in monitors, change in layout of a sample of the 
case report form, etc.), no new agreements are required. 
 
 
 
 
77 
 

 
 
 
19. Direct Access to Source Documents 
The investigator and the head of the medical institution must provide direct access to all 
the study related records including source documents during monitoring and auditing relating 
to the study, and at the investigations by the IRB and regulatory authorities. 
19.1 Identification of Source Documents 
Items listed in (1) through (7) below will be handled as source documents related to the 
present study. Items (8) through (12) will be handled as “data that should be directly entered 
in the case report form and regarded as source data.”  A list of source documents, etc. 
stipulated in the monitoring plan will be prepared at each medical institution based on the 
prior confirmation by the investigator or subinvestigator and their copy will be submitted to 
the investigator and subinvestigators. 
(1) Medical records (chart): registration form, informed consent form, records for oral 
consent, patient background characteristics examined, subjective symptoms and 
objective findings, vital signs, height, body weight, PS, records for concomitant 
medication/therapy (other than reasons for concomitance), start date and contents of 
post-treatment performed, records of incharge and out discharge from the hospital, 
and outcomes. 
(2) Examination reports (pathological examinations, image analysis): Name of 
histopathological diagnosis and evaluation of lesions (results of cytological diagnosis 
of ascites/pleural effusion). 
(3) Diagnostic images including CT, MRI, X-ray, echo, etc. 
(4) Recording data of automated apparatuses (blood chemistry tests, urinalysis, etc.) and 
clinical laboratory values or clinical laboratory results 
(5) Electrocardiogram waves: Electrocardiography 
(6) Records of dosing of study drug 
(7) Drug accountability log, delivery forms of study drug, receipt of study drug returned 
(8) Pre-dosing subjective symptoms and objective findings/grades 
(9) Records for images evaluation 
(10) Reasons for concomitance, concomitant medication/therapy prescribed at other 
hospitals 
(11) Presence or absence of adverse events, name of adverse events, serious/non-serious, 
clinical course (date, grade, outcome, etc.), treatment on study therapy, causal 
relationship with study drug, and reasons for terminating follow-up. 
(12) Reasons for incharge and discharge from the hospital, reasons for discontinuation 
or termination from the study, and reasons for death. 
 
 
 
78 
 

 
 
 
 
19.2 Method of Direct Access to Source Documents 
The monitor of the sponsor should cross-check the entries in the case report forms and 
source documents to confirm that descriptions are accurate with regard to the following.  If 
there are any discrepancies between the entries in case report forms, etc., and source 
documents, the monitor will obtain from the investigator records explaining such 
discrepancies. 
(1) Data required by the protocol have been accurately recorded in the case report form and 
the report on serious adverse events, and are consistent with the descriptions in the source 
documents. 
(2) All changes in dosage regimen or treatment method, if any, have been recorded in the 
case report form for each patient. 
(3) Adverse events have been recorded in the case report form in accordance with the 
protocol. 
(4) All discontinued or drop-out cases among registered patients have been recorded in the 
case report form together with the reasons for discontinuation or drop-out. 
 
 
 
 
79 
 

 
 
 
20. Quality Control and Quality Assurance for the Study 
20.1 Conduct of the study 
The sponsor/CRO will implement and maintain quality control and quality assurance 
(QA) procedures with written standard operating proceduers (SOPs). 
20.2 Quality Control of the Study 
 
Monitoring Procedures 
The sponsor will control the quality of the study by performing the main services as the 
follows in accordance with each study-related SOP and the monitoring plan of the study. 
・To hold a briefing on study protocol for the investigator, subinvestigators, or clinical 
research coordinators to explain the method of screening subjects, examination on efficacy 
or safety, the methods of evaluation thereof. 
・To perform periodic monitoring of participating medical institutions, in order to confirm the 
performance of the study in compliance with the protocol and GCP. 
・To inspect the source documents so that the entries into the CRFs are accurate. To prepare a 
guidance for change or revision in the CRFs; if any CRF requires any change or revision, 
to request the investigator (subinvestigator) or clinical research coordinators to revise the 
relevant CRF. 
・To check the entries into CRFs. 
・To confirm whether required documents to be stored at the medical institutions are properly 
stored. 
・To record or report the management of the study, data collection, data control, statistical 
analysis, analysis on adverse events, etc., in accordance with the sponsor’s SOP, and check 
and confirm the foregoing. 
 
Curriculum Vitae 
All investigators and any subinvestigator(s) must provide Taiho Pharmaceutical Co., Ltd. 
with current signed and dated copies of their own curriculum vitae listing the experience, 
qualifications, and training prior to the beginning of the study. 
20.3 Sponsor’s Audits and Regulatory Inspections 
For the purpose of ensuring compliance with the protocol, GCP and applicable regulatory 
requirements, the investigator will permit auditing by the sponsor or its representative and 
inspections by regulatory authorities. 
The investigator agrees to allow the auditors and inspectors to have direct access to the 
study records for review. The people performing these activities will not disclose any 
personal identity or personal medical information assessed. 
The investigator will make every effort to help with the performance of the audits and 
inspections, giving access to all necessary facilities, data and documents pertaining to the 
clinical trial. As soon as the investigator is notified of a planned inspection by the regulatory 
authorities or IRB/IEC, the investigator will inform the sponsor. Any results arising from 
 
80 
 

 
 
 
such inspections will be immediately communicated by the investigator to the sponsor. The 
investigator shall take appropriate measures required by the sponsor to take corrective actions 
for all problems found during audits and or inspections. 
 
21. Archiving of Records 
21.1 Archiving of Records 
 
Investigator 
The investigator is responsible for the retention of all study documents according to 
institutional policies, local laws and ICH Parts 4.9.4 and 4.9.5 and for studies conducted 
under an Investigational New Drug (IND) application. 
The investigator agrees to inform Taiho Pharmaceutical Co., Ltd. in writing of the 
intention to remove or destroy any study-related records. Prior to contacting Taiho 
Pharmaceutical Co., Ltd., the investigator must ensure that institutional and local 
requirements (for example, ICH Guidelines) have been satisfied. Taiho Pharmaceutical Co., 
Ltd. will provide authorization for destruction of such records to the investigator in writing. 
In the event that all retention of records requirements have been fulfilled, but Taiho 
Pharmaceutical Co., Ltd. requests that the investigator maintain the records for a longer 
period of time, additional arrangements will be made. 
 
Sponsor 
The sponsor must retain all sponsor-specific essential documents in conformance with the 
applicable regulatory requirements of the countries where the product is approved, and where 
the sponsor intends to apply for approvals. 
If the sponsor discontinues the clinical development of an investigational product (i.e. for 
any or all indications, routes of administration, or dosage forms), the sponsor must maintain 
all sponsor-specific essential documents in conformance with the applicable regulatory 
requirements. 
 
22. Compensation to Subjects and Investigators 
If required by the applicable regulatory requirements, Taiho Pharmaceutical Co., Ltd. 
should provide insurance or should indemnify (legal and financial coverage) the 
investigator/the institution against claims arising from the trial, except for claims that arise 
from malpractice and/or negligence. 
Taiho Pharmaceutical Co., Ltd.’s policies and procedures should address the costs of 
treatment of patients in the event of trial-related injuries in accordance with the applicable 
regulatory requirements. 
When patients receive compensation, the method and manner of compensation should 
comply with applicable regulatory requirements. 
 
81 
 

 
 
 
23. Confidentiality 
All information provided to the investigator by the sponsor or sponsor’s representatives, 
information produced during the clinical trial included, but not limited to the protocol, CRF, 
IB, and the results obtained during the course of the trial is confidential. Taiho 
Pharmaceutical Co., Ltd. has exclusive rights to access and use the data regarding this trial. 
The members of the research team agree not to discuss such information in any way without 
prior written permission from Taiho Pharmaceutical Co., Ltd. 
However, the submission of the protocol and necessary documentation to the IRB/IEC is 
permitted. The IRB/IEC members have the same obligation of confidentiality. 
The patient’s personal data and investigator’s personal data which may be included in the 
sponsor’s database shall be treated in compliance with all applicable laws and regulations. 
When processing and archiving personal data pertaining to the investigator and or to the 
patients, the sponsor or its representatives shall take all appropriate measures to safeguard 
and prevent access to this data by any unauthorized third party. 
 
24. Publication policy 
All unpublished documentation (including the protocol, CRF, and IB) given to the 
investigator is strictly confidential. All recipients must agree not to disclose the information 
contained herein to any person without the prior written authorization of Taiho 
Pharmaceutical Co., Ltd. The submission of these documents to the IRB/IEC is permitted. 
The investigator agrees that Taiho Pharmaceutical Co., Ltd. maintains the right to use the 
results of this study in their original form and/or in a global report for submission to 
governmental and regulatory authorities of any country. 
The results of the study may be presented during scientific symposia or published in a 
scientific journal only after review by Taiho Pharmaceutical Co., Ltd. in accordance with the 
guidelines set forth in the applicable publication or financial agreement. 
The steering committee and sponsor discuss and determine the first presenter and time of 
the primary results at a major medical meeting in this study. 
 
25. Study Period 
Study period (Plan): December 2014 to May 2020 
Patient recruitment period (Plan): December 2014 to June 2016 
Study treatment period: Until 31 Jan 2020 
 
 
 
82 
 

 
 
 
26. Rationales 
26.1 Validity of the clinical study design 
Rationale for setting S-1/CDDP combination therapy as the control group 
The standard first-line treatment for unresectable, with HER2-negative advanced recurrent 
gastric cancer was S-1/CDDP therapy in the 2014 Japanese Gastric Cancer Treatment 
Guidelines (ver. 4)11. In the 2014 Korean guidelines12, the recommended regimen listed for 
patients previously untreated with chemotherapy is (5-FU, Capecitabine or S-1)/CDDP 
combination therapy or (5-FU or Capecitabine) /L-OHP combination therapy. From the 
above, it was determined appropriate to set the control group as S-1/CDDP therapy, the 
recommended regimen in both Japan and Korea. 
Furthermore, the results of the Japanese-Korean phase III clinical study (SOS 
study16)(S-1/CDDP therapy: 3-week-interval administration vs. 5-week-interval 
administration) have been published and MST for S-1/CDDP therapy (5-week-interval 
administration) was reported to be 13.9 months. The MST for S-1/CDDP therapy in the 
Japanese SPIRITS study was 13.0 months. Since the repeatability was fairly high for results 
on clinical performance obtained in different countries, it was determined appropriate to set 
the control group as S-1/CDDP therapy. The standard schedule for CDDP administration is 
commonly on Day 8 in Japan, whereas it is on Day 1 in Korea in dailiy practice. Almost all 
treatment methods (dose of S-1 and CDDP, schedule of S-1 administration) except for the 
schedule of CDDP administration are same between Japan and Korea. In addition, there were 
no difference in S-1/CDDP treatment group of SOS study between two countries in terms of 
efficacy and toxicity to be ignorable for conducting multinational trial. Therefore the CDDP 
administration day was set differently for each country. 
Rationale for allocation adjustment factors 
・ PS (0, 1): PS is generally considered to be a factor that greatly affects the prognosis of 
patients. 
・ Measurable lesion (Yes, No): The difference of tumor volume between mesualable lesion 
and non-measurable lesion may affects the prognosis of patients. 
・ Country (Japan, Korea): Country was estimated due to multinational study.  
 
26.2 Rationale for endpoints 
According to the Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in 
Japan, survival rate or OS is recommended as primary endpoint in phase III trial to evaluate 
the clinical usefulness of antitumor agent. 
Secondary endpoints used for this study are commonly used endpoints for the evaluation 
of the safety and efficacy of anticancer drugs. 
 
26.3 Rationale for doses 
 (1) Rationale for TAS-118 dose selection 
 
83 
 

 
 
 
TAS-118 is a preparation containing S-1 and LV. Because LV alone has no antitumor 
effect, it is considered important to not reduce but to maintain the blood concentration of 
5-FU, which is the active body of S-1, in the combination therapy of S-1 and LV in order to 
maintain the RR of S-1 alone and enhance the effect of LV. Therefore, S-1 will be 
administered at the usual dose in this study. The single dose of 25 mg of LV was considered 
appropriate on the basis of the experiences of the combination treatment with UFT, an oral 
fluoropyrimidine drug similar to S-1. 
(2) Rationale for L-OHP dose selection 
For regimens, including L-OHP used in foreign countries (FOLFOX, etc.), the 
recommended dose (RD) is usually 85 mg/m2 every 2 weeks, which is the same as the 
approved dose of L-OHP for corolectal cancer in Japan. For the combination regimen of 
three drugs, S-1, LV, and L-OHP, the RD was also 85 mg/m2 every 2 weeks; therefore, the 
dose of L-OHP in this study was also set at 85 mg/m2 every 2 weeks. 
(3) Rationale for CDDP dose selection 
The RD of CDDP was 60 mg/m2 in the phase I/II study of S-1 combined with CDDP in 
patients with gastric cancer17; and the phase III study (SPIRITS study9), the SOS study24,  
G-SOX13, 14 study, and the phase II study (*******************) were performed using the 
same RD. Thus, the same dose of CDDP will also be used in this study. 
 
26.4 Rationale for administration methods 
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For S-1/CDDP therapy, S-1 shall be administered for 21 days followed by 14 days rest and 
CDDP shall be administered on Day 8 of each cycle, similarly to the regimens in the phase 
I/II study25, phase II study**, and phase III study9, 13 of S-1/CDDP in patients with gastric 
 
84 
 

 
 
 
cancer. The CDDP administration day was set differently for each country (Day 1 in Korea 
and Day 8 in Japan). The standard schedule for CDDP administration is commonly on Day 8 
in Japan, whereas it is on Day 1 in Korea in dailiy practice. Almost all treatment methods 
(dose of S-1 and CDDP, schedule of S-1 administration) except for the schedule of CDDP 
administration are same between Japan and Korea. In addition, there were no difference in 
S-1/CDDP treatment group of SOS study between two countries in terms of efficacy and 
toxicity to be not ignorable for conducting multinational trial. Therefore the CDDP 
administration day was set differently for each country. 
 
26.5 Rationale for inclusion criteria 
(1) As it is stated that “the confirmation of malignancy with histological examination or 
cytology is necessary” in the Guidelines for Clinical Evaluation Methods of Anti-Cancer 
Drugs in Japan, this criterion has been established as an inclusion criterion to select the 
target disease of this study. 
(2) In the Guidelines for Clinical Evaluation Methods of anti-cancer Drugs in Japan, it is 
stated that “RECIST guideline is recommended to be used as a standard for assessment of 
antitumor efficacy, and appropriate guideline is necessary to be used for more appropriate 
assessment of the investigational drug taking scientific progress into account.” 
(3) To evaluate the efficacy of the study drugs appropriately, this criterion has been 
established. 
(4) To evaluate the efficacy of the study drugs appropriately, this criterion has been 
established. 
(5) To evaluate the safety of the study drugs as appropriate as possible, patients are included 
with reference to the Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in 
Japan. 
(6) In the Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in Japan, it is 
stated that “the age of subjects is not limited in principle, but it shall be determined based 
on physiological functions and ability to give consent.” Therefore, patients aged 20 years 
or older are included based on the ability to give consent. Besides, an annotation is set 
referring to the criteria of SOS study24 and the phase II study (*******************) 
which showed higher rate of treatment discontinuation due to adverse event in the group 
consist of the subject who were 75 years or higher at randomization compare with other 
group. 
(7) Since it is described that “it is necessary that the physiological functions (such as 
hematopoietic, cardiac, pulmonary, hepatic and renal functions) of patients are retained 
sufficiently” in the Guidelines for Clinical Evaluation Methods of Anti-Cancer Drugs in 
Japan, this criterion has been established to evaluate the safety of the study drugs as 
appropriately as possible. The criteria for each laboratory data are established based on 
Phase II (******************), investigator’s brochure, and package insert. 
(8) Expected survival duration of 90 days or longer is determined as the inclusion criterion 
because the period is considered to be necessary to evaluate the efficacy and safety of the 
study drugs, with reference to the Guidelines for Clinical Evaluation Methods of 
Anti-Cancer Drugs in Japan. 
 
85 
 

 
 
 
(9) Since TAS-118 and S-1 are oral drugs, this criterion has been established to include 
patients who are able to take drugs orally. 
(10)This criterion is established according to the guideline for ICH-GCP. 
 
26.6 Rationale for exclusion criteria 
(1) Since serious drug hypersensitivity may affect the evaluation of the safety of study drugs, 
this criterion has been established. 
(2) This criterion has been established to exclude the effect of another study drug which 
safery evaluation have not been done. 
(3) This criterion has been established because the inclusion of those patients is considered to 
be inappropriate to ensure the safety of subjects and to evaluate the safety of the study 
drugs. 
(4) This criterion has been established because the inclusion of those patients is considered to 
be inappropriate to ensure the safety of subjects and to evaluate the safety of the study 
drugs. 
(5) This criterion has been established because the inclusion of those patients is considered to 
be inappropriate to ensure the safety of subjects and to evaluate the safety of the study 
drugs. 
(6) This criterion has been established because the inclusion of those patients is considered to 
be inappropriate to ensure the safety of subjects and to evaluate the safety of the study 
drugs. 
(7) This criterion has been established because the inclusion of those patients is considered to 
be inappropriate to ensure the safety of subjects and to evaluate the safety of the study 
drugs. 
(8) Since patients with those severe complications may not have stable physiological 
function and such patients are considered to be inappropriate for evaluating the safety of 
the study drugs, this criterion has been established. 
(9) Since patients with those severe complications may not have stable physiological 
function and such patients are considered to be inappropriate for evaluating the safety of 
the study drugs, this criterion has been established. 
(10)Since patients with those severe complications may not have stable physiological 
function and such patients are considered to be inappropriate for evaluating the safety of 
the study drugs, this criterion has been established. 
(11)Since patients with those severe complications may not have stable physiological 
function and such patients are considered to be inappropriate for evaluating the safety of 
the study drugs, this criterion has been established. 
(12)Since patients with those severe complications may not have stable physiological 
function and such patients are considered to be inappropriate for evaluating the safety of 
the study drugs, this criterion has been established. 
(13)This criterion has been established because the inclusion of those patients is considered 
to be inappropriate to ensure the safety of subjects and to evaluate the safety of the study 
drugs. 
(14)This criterion has been established because the inclusion of those patients is considered 
to be inappropriate to ensure the safety of subjects and to evaluate the safety of the study 
drugs. 
 
86 
 

 
 
 
(15)This criterion has been established because the inclusion of those patients is considered 
to be inappropriate to ensure the safety of subjects and to evaluate the safety of the study 
drugs. 
(16)This criterion has been established because the inclusion of those patients is considered 
to be inappropriate to evaluate the efficacy and safety of the study drugs. 
(17)Since patients with those severe complications may not have stable physiological 
function and such patients are considered to be inappropriate for evaluating the safety of 
the study drugs, this criterion has been established. 
(18)Since the PS of those patients is expected to be worsened and such patients are 
considered to be inappropriate for evaluating the efficacy and the safety of the study 
drugs, this criterion has been established. 
(19)This criterion has been established because the inclusion of those patients is considered 
to be inappropriate to evaluate the efficacy and safety of the study drugs. 
(20)This criterion has been established because the teratogenicity of S-1 has been observed in 
nonclinical studies. 
(21)This criterion has been established from ethical aspects for subjects. 
(22)This criterion has been established to exclude other inappropriate subjects to ensure the 
safety of subjects and evaluate the efficacy and safety of the study drugs appropriately. 
 
26.7 Rationale for prohibited concomitant drugs and therapies 
(1) The use of those drugs is considered inappropriate to evaluate the efficacy of the study 
drugs. 
(2) Safety information is not available for drug-drug interactions between the study treatment 
and other study drugs. This criterion has been established to ensure the safety of subjects. 
(3) Those drugs may enhance the side effect of TAS-118 and S-1. 
(4) Those drugs may enhance the side effect of TAS-118 and S-1. 
(5) The use of those therapies is considered inappropriate to evaluate the efficacy of the 
study drugs. 
 
26.8 Rationale for precautions for concomitant drugs and therapies 
(1) Tegafur may enhance the effect of warfarin potassium. 
(2) Tegafur may inhibit the metabolism of phenytoin to increase the blood phenytoin 
concentration, so that phenytoin toxicities may occur (such as queasy/vomiting, 
nystagmus, and movement disorder). 
(3) Concomitant administration of these drugs with CDDP may enhance renal disorder and 
ototoxicity. 
(4) Concomitant administration of the drug with CDDP may enhance renal disorder. 
(5) Concomitant administration of the drug with CDDP may enhance ototoxicity. 
 
26.9 Rationale for contraception period 
Since the teratogenicity of S-1 has been observed in nonclinical studies, the same 
contraception period as that generally used for an antitumor agent known to be teratogenic is 
set in this study. 
 
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27. References 
1 International Agency for Research on Cancer, World Health Organization. GLOBOCAN 
2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Available 
from: http://globocan.iarc.fr/fact-sheets-population.aspx. 
2 Pyrhönen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, 
epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care 
alone in patients with non-resectable gastric cancer. Br J Cancer.1995; 71: 587-591. 
3 Murad AM, Santiago FF, Petroianu A, Rocha PRS, Rodrigues MAG, Rausch M. Modified 
therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. 
Cancer. 1993;72:37-41. 
4 Glimelius B, Hoffman K, Haglund U, Nyrén O, Sjödén PO. Initial or delayed 
chemotherapy with best supportive care in advanced gastric cancer. Ann Oncol. 1994; 5: 
189-190. 
5 MacDonald JS, Schein PS, Woolley PV, Smythe T, Ueno W, Hoth D, et al. 5-fluorouracil, 
doxorubicin, and mitomycin (FAM) combination chemotherapy for advanced gastric 
cancer. Ann Intern Med. 1980;93:533-536. 
6 Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, et al. Capecitabine and 
Oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008;358:36-46. 
7 Cutsem EV, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, et al. Phase III 
study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil 
as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin 
Oncol. 2006;24:4991-4997. 
8 Boku N, Yamamoto S, Fukuda H, Shirao K, Doi T, Sawaki A, et al. Fluorouracil versus 
combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a 
randomised phase 3 study. Lancet Oncol. 2009;10:1063-1069. 
9 Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, et al. S-1 plus cisplatin 
versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase 
III trial. Lancet Oncol. 2008;9:215-221. 
10 Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. 
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment 
of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 
3, open-label, randomised controlled trial. Lancet. 2010;376:687-697. 
11 The Japanese Gastric Cancer Treatment Guidelines Revised in May 2014 (ver. 4), edited 
by the Japanese Gastric Cancer Association, Kanehara & Co., Ltd. 
12 Lee JH, Kim JG, Jung HK, Kim JH, Jeong WK, Jeon TJ, et al. Clinical Practice 
Guidelines for Gastric Cancer in Korea:An Evidence-Based Approach. J Gastric Cancer. 
2014;14:87-104. 
 
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13 Higuchi K, Koizumi W, Yamada Y, Nishikawa K, Gotoh M, Fuse N, et al. Randomized 
phase III study of S-1 plus oxaliplatin versus S-1 plus cisplatin for first-line treatment of 
advanced gastric cancer. J Clin Oncol. 2013;31 (suppl 4; abstr 60). 
14 Gotoh M, et al; Abstract PD7-7, The 86th Annual Meeting of Japanese Gastric Cancer 
Association 2014.  
15 Thirion P, Michiels S, Pignon JP, Buyse M, Braud AC, Carlson RW, et al. Modulation of 
fluorouracil by leucovorin in patients with advanced colorectal cancer: an updated 
meta-analysis. J Clin Oncol. 2004;22:3766-3775. 
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16 Ryu MH, Baba E, Lee KH, Boku N, Park YI, Hyodo I, et al. Phase III trial of a 3-weekly 
versus 5-weekly schedule of S-1 plus cisplatin (SP) combination chemotherapy for 
first-line treatment of advanced gastric cancer (AGC): SOS study. J Clin Oncol. 2013;31 
(suppl; abstr LBA4024). 
 
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17 Koizumi W, Tanabe S, Saigenji K, Ohtsu A, Boku N, Nagashima F, et al. Phase I/II study 
of S-1 combined with cisplatin in patients with advanced gastric cancer. Br J Cancer. 
2003;89:2207-2212. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 1. Definition of EGJ 
The area extending 2 cm above to 2 cm below the esophagogastric junction (EGJ) is 
designated the EGJ area. Tumors having their epicenter in this area are designated EGJ 
carcinomas irrespective of histological type. 
 
Appendix 2. Definition of HER2 status11 
HER2 status 
Criteria 
Positive 
(Meet either criteria) 
1．Score as 3+ on immunohistochemistry (IHC) 
2．Score as 2+ on IHC and Positive on fluorescence in situ 
hybridization (FISH) 
Negative 
Other 
Using Silver in situ hybridization (SISH) or other tests instead of FISH test for confirmation of HER2 
status are allowed. 
 
Appendix 3. Cockcroft-Gault formula 
The Cockcroft-Gault formula: 
Estimated creatinine clearance (mL/min) 
  = (140 - age) x Body weight (kg) / [(72 x Serum creatinine (mg/dL)] 
For women, the obtained value is multiplied by a factor of 0.85. 
 
Appendix 4. Du Bois formula 
The BSA will be calculated by the IWRS using the following DuBois formula. All BSA 
calculations are rounded down, so the number must be set to 2 decimal places. 
BSA (m²) =  ( [Body Weight (kg) ]0.425 x [Height (cm)]0.725) x 0.007184 
 
Appendix 5. ECOG Performance status (PS) 
GRADE 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. 
Cannot carry on any self-care. 
Totally confined to bed or chair 
5 
Dead 
From: Oken MM, Creech, RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group.  Am J Clin Oncol 1982;5:649-55. 
 
 
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