Clinical trial NCT02322593
Conditions: Gastric Cancer
Keywords: Gastric Cancer Gastrointestinal Diseases Gastrointestinal Neoplasms First Line Treatment Antineoplastic Agents
Sponsor: Taiho Pharmaceutical Co., Ltd.
Start date: 2014-12-01; Completion date: 2020-05-01
Enrollment: 711 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this trial is to evaluate the efficacy of TAS-118 plus Oxaliplatin compared with S-1 plus Cisplatin in overall survival in patients with advanced gastric cancer.

Detailed description:

Arms: arm 1: TAS-118 plus Oxaliplatin arm 2: S-1 plus Cisplatin
Interventions: intervention 1: TAS-118 plus Oxaliplatin intervention 2: S-1 plus Cisplatin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
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 
 
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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 
 
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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 
 
 
 
 
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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. 
 
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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, 
 
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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． 
 
 
 
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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. 
 
 
 
 
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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. 
 
 
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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 
 
 
 
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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. 
 
87 
 


 
 
 
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. 
 
88 
 
 


 
 
 
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). 
 
89 
 
 


 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
90 
 
 


 
 
 
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. 
 
 
91 
 
 

SAP_001.pdf: 
TAS-118 Protocol: 
 
Page 1 / 41 
 
 
Statistical Analysis Plan 
Version 1.0 
 
 
 
 
Name of study drug 
TAS-118, Oxaliplatin 
Study title 
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 
 
Date of preparation or 
revision 
February 4, 2019 
Author 
 
 
 
 
 
Date and signature 
 
 
 
Month Day, Year 
 
 
 
 
 
Month Day, Year 
 
 
 
 


TAS-118 Protocol: 
 
Page 2 / 41 
 
 
 
Preparation and revision history 
Date 
Author 
Reason for preparation or revision 
February 4, 2019 
 
Prepared the first version 
 
 
 


TAS-118 Protocol: 
 
Page 3 / 41 
 
TABLE OF CONTENTS 
 
1. 
Scope and Objective ......................................................................................................................... 7 
1.1. 
Positioning of Statistical Analysis Plan ................................................................................... 7 
1.2. 
Study Objective ....................................................................................................................... 7 
1.3. 
Changes from Protocol ............................................................................................................ 7 
2. 
Main Statistical Considerations in the Study Design and Planned Sample Size ........................ 7 
2.1. 
Planned Sample Size ............................................................................................................... 7 
2.1.1. 
Planned Sample Size .................................................................................................... 7 
2.1.2. 
Rationale for Sample Size Determination Before Study Initiation ............................... 7 
2.1.3. 
Change in the Required Number of Events in the Analysis for Primary 
Evaluation ..................................................................................................................... 9 
2.2. 
Subject Registration and Randomization Method ................................................................. 10 
2.2.1. 
Randomization Method .............................................................................................. 10 
3. 
Data to Be Used in Statistical Analysis and Analysis Populations ............................................. 11 
3.1. 
Materials and Data Other Than Case Report Forms .............................................................. 11 
3.2. 
Analysis Populations ............................................................................................................. 12 
4. 
Timing of Analyses and Significance Level .................................................................................. 13 
5. 
Endpoints and Common Considerations for Statistical Analysis .............................................. 14 
5.1. 
Endpoints ............................................................................................................................... 14 
5.1.1. 
Efficacy Endpoints ..................................................................................................... 14 
 
OS ............................................................................................................................... 14 
 
PFS ............................................................................................................................. 14 
 
TTF ............................................................................................................................. 15 
 
Best Overall Response Assessment ............................................................................ 15 
5.1.1.4.1 
ORR ............................................................................................................................ 15 
5.1.1.4.2 
DCR ............................................................................................................................ 16 
5.1.1.4.3 
Duration of Overall Response .................................................................................... 16 
5.1.1.4.4 
Duration of Complete Response ................................................................................. 16 
5.1.1.4.5 
Tumor Shrinkage Rate ................................................................................................ 16 
5.1.2. 
Safety Endpoints ......................................................................................................... 16 
 
Adverse Events and Adverse Drug Reactions ............................................................ 16 
5.1.3. 
Compliance Endpoints ................................................................................................ 17 
 
Total Dose................................................................................................................... 17 
 
Dose Intensity ............................................................................................................. 17 
5.2. 
Common Considerations for Statistical Analysis .................................................................. 18 
5.2.1. 
Data Handling ............................................................................................................. 18 
 
Handling of Longitudinal Data ................................................................................... 18 
5.2.1.1.1 
Calculation of Number of Days and Period ................................................................ 18 
5.2.1.1.2 
Calculation of Number of Years, Months, and Weeks ............................................... 18 
5.2.1.1.3 
Acceptable Time Window .......................................................................................... 19 
 
Handling of Missing Data and Abnormal Values ....................................................... 19 
 
Handling of Treatment Arms ...................................................................................... 20 
5.2.2. 
Patient Baseline Characteristics .................................................................................. 20 
5.2.3. 
Statistical Methods ..................................................................................................... 22 
 
Summary Statistics for Continuous Data .................................................................... 22 
 
Proportion ................................................................................................................... 22 
 
Test Methods .............................................................................................................. 22 


TAS-118 Protocol: 
 
Page 4 / 41 
 
Model Analysis ........................................................................................................... 24 
 
Estimation Methods .................................................................................................... 24 
5.2.4. 
Sample Code ............................................................................................................... 25 
 
Stratified Log-Rank Test ............................................................................................ 25 
 
Log-Rank Test ............................................................................................................ 25 
 
Cox Proportional Hazards Model ............................................................................... 25 
 
Cox Proportional Hazards Model (by Baseline Characteristic Factor) ...................... 25 
 
Restricted Mean Survival Time (RMST) ................................................................... 26 
 
95% Confidence Interval of Between-Group Difference in MST by Bootstrap 
Method ........................................................................................................................ 27 
 
Stratified Cox Proportional Hazards Model ............................................................... 27 
 
Comparison of Proportions Between Treatment Arms ............................................... 28 
 
Confidence Interval of Proportion .............................................................................. 28 
 
Wilcoxon Test (Two-Sample) .................................................................................... 28 
 
Confidence Interval of Median ................................................................................... 28 
 
Log-Rank Test Using Recalculated α ......................................................................... 28 
 
Cochran–Mantel–Haenszel Test ................................................................................. 31 
5.2.5. 
Software to Be Used ................................................................................................... 31 
5.2.6. 
Dictionaries to Be Used .............................................................................................. 31 
6. 
Primary Endpoint Analyses........................................................................................................... 33 
6.1. 
Primary Analysis for Primary Objective ............................................................................... 33 
6.2. 
Sensitivity Analyses of Primary Analysis ............................................................................. 33 
6.3. 
Secondary Analyses of Primary Endpoint ............................................................................. 33 
7. 
Secondary Endpoint Analysis ........................................................................................................ 35 
7.1. 
Efficacy Analyses .................................................................................................................. 35 
7.1.1. 
Antitumor Activity ..................................................................................................... 35 
 
Best Overall Response ................................................................................................ 35 
 
ORR ............................................................................................................................ 35 
 
DCR ............................................................................................................................ 35 
 
Time to Response ....................................................................................................... 35 
 
Duration of Overall Response .................................................................................... 35 
7.1.2. 
PFS ............................................................................................................................. 35 
7.1.3. 
TTF ............................................................................................................................. 36 
7.1.4. 
Tumor Shrinkage Rate ................................................................................................ 36 
7.2. 
Safety Analysis ...................................................................................................................... 36 
7.2.1. 
Adverse Events and Adverse Drug Reactions ............................................................ 36 
7.2.2. 
Deaths ......................................................................................................................... 37 
7.3. 
Composition of Analysis Populations ................................................................................... 37 
7.4. 
Deviation ............................................................................................................................... 37 
7.5. 
Analyses of Patient Baseline Characteristics ......................................................................... 37 
7.6. 
Compliance Analyses ............................................................................................................ 37 
7.6.1. 
Dose Intensity ............................................................................................................. 37 
7.6.2. 
Compliance ................................................................................................................. 37 
7.6.3. 
Discontinuation ........................................................................................................... 37 
7.6.4. 
Cumulative Dose/Duration of Treatment ................................................................... 37 
7.6.5. 
Treatment Completion ................................................................................................ 38 
7.6.6. 
Treatment Cycle ......................................................................................................... 38 
7.6.7. 
Proportion of Outpatient Visits ................................................................................... 38 
7.7. 
Concomitant Medications ...................................................................................................... 38 


TAS-118 Protocol: 
 
Page 5 / 41 
7.8. 
Subsequent Therapy .............................................................................................................. 39 
7.9. 
Laboratory Values ................................................................................................................. 39 
7.10. 
Clinical Findings ................................................................................................................... 40 
7.11. 
Tumor Markers ...................................................................................................................... 40 
7.12. 
Vital Signs and ECOG PS ..................................................................................................... 40 
8. 
Review and Revision of Statistical Analysis Plan ........................................................................ 40 
9. 
Development of Output Plan ......................................................................................................... 40 
10. References ....................................................................................................................................... 40 
 
 
 
 


TAS-118 Protocol: 
 
Page 6 / 41 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The abbreviations and terms used in this statistical analysis plan are defined below. 
 
Abbreviation 
(term) 
Explanation (definition) 
BSA 
Body surface area 
CDDP 
(SP-4-2)-Diamminedichloroplatinum, cisplatin 
CR 
Complete response (response associated with antitumor activity) 
CRP 
C-reactive protein 
DCR 
Disease control rate 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
Full analysis set 
HR 
Hazard ratio 
IDMC 
Independent data monitoring committee 
IWRS 
Interactive web response system 
L-OHP 
(SP-4-2)-[(1R, 2R)-Cyclohexane-1, 2-diamine-κN, κN'] 
[ethanedioato(2-)-κO1, κO2]platinum: oxaliplatin (JAN) 
MedDRA 
Medical Dictionary for Regulatory Activities 
MST 
Median survival time 
NE 
Not evaluable (response associated with antitumor activity) 
ORR 
Overall response rate 
OS 
Overall survival  
PD 
Progressive disease (response associated with antitumor activity) 
PFS 
Progression-free survival 
PR 
Partial response 
PS 
Performance status 
RECIST 
Response evaluation criteria in solid tumors1) 
RMST 
Restricted mean survival time 
SD 
Stable disease (response associated with antitumor activity) 
SOC 
System organ class 
TTF 
Time to treatment failure 


TAS-118 Protocol: 
 
Page 7 / 41 
1. Scope and Objective 
1.1. Positioning of Statistical Analysis Plan 
This statistical analysis plan provides the details of the statistical analyses to be conducted in the 
primary and final evaluations in “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” 
. 
1.2. Study Objective 
To compare the following endpoints for TAS-118/oxaliplatin (L-OHP) (study arm) with S-1/cisplatin 
(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 
1.3. Changes from Protocol 
The full analysis set (FAS) is defined as “patients in as-treated (AT) population who have gastric 
cancer at randomization” in the protocol version 3.0, but the definition is changed to “patients in AT 
population who have advanced gastric cancer at randomization” in this statistical analysis plan. Since 
this study involves patients with advanced gastric cancer as specified in the primary objective, the 
protocol has not been revised, and the detailed definition of FAS is specified in the statistical analysis 
plan as determined in the discussion with medical advisor and the statistical advisor. 
 
2. Main Statistical Considerations in the Study Design and Planned 
Sample Size 
2.1. Planned Sample Size 
2.1.1. Planned Sample Size 
Target number of patients at study initiation: 686 subjects (TAS-118/L-OHP arm: 343 subjects, S-
1/CDDP arm: 343 subjects); target number of patients included in the FAS: 650 subjects (TAS-118/L-
OHP arm: 325 subjects, S-1/CDDP arm: 325 subjects) 
2.1.2. Rationale for Sample Size Determination Before Study Initiation 
In a randomized phase II study of S-1/leucovorin (LV) therapy, S-1/LV/L-OHP (SOL) therapy, and 
S-1/CDDP therapy in patients with unresectable, advanced/recurrent gastric cancer (
 
 the median survival time (MST) was 12.6 months in the S-1/CDDP arm and 18.4 months 
in the SOL arm. In the SOS trial, which was conducted in Japan and Korea,4) the MST was 13.9 months 
in the S-1/CDDP (5-week interval) arm (15.5 months in Japanese subjects). Taking into account the 
ratio of the sample size between Japan and Korea and the target population in the present study, the 
MST is assumed to be 14.5 months in the S-1/CDDP arm and 19.33 months in the TAS-118/L-OHP 
arm (hazard ratio of TAS-118/L-OHP versus S-1/CDDP, 0.75). 
With an overall significance level of 5% (two-sided) in the entire study, the Lan and DeMets alpha 
spending function (O’Brien-Fleming type)5) was used to split the significance level for one benefit 


TAS-118 Protocol: 
 
Page 8 / 41 
evaluation in an interim analysis. Assuming that test statistics in the interim analysis and the primary 
analysis for the primary evaluation would follow a bivariate normal distribution, the boundaries zα1 
and zα2 that meet the formula below are 2.9627 and 1.9687, respectively, and the corresponding 
nominal significance levels are 0.305% and 4.899% (two-sided), respectively, in the interim analysis 
and the primary analysis for the primary evaluation. The information faction is assumed to be 0.5 
because the interim analysis will be conducted when half the specified number of events have been 
observed. 
P(𝑍1 ≥𝑧𝛼1) = 2 × {1 − Φ (
𝑍1−𝛼
2
√𝑡)} = 0.001525 
P(𝑍1 ≥𝑧α1, 𝑍2 ≥𝑧α2) = 0.025 
𝛼1: one‐ sided significance level in an interim analysis, 
𝛼2: one‐ sided significance level in the primary analysis for the primary evaluation, 
𝑡: information fraction, 𝛼: overall one‐ sided significance level 
 
On the condition that the survival time is exponentially distributed in both arms, with a two-sided 
significance level of 4.899% as calculated above and 85% power, 437 events will be required to test 
whether TAS-118/L-OHP is superior to S-1/CDDP with respect to survival time in the primary 
evaluation, as calculated using the Schoenfeld method below:6) 
Required number of events =
(𝑍1−𝛼
2 + 𝑍1−𝛽)
2
𝑟1 × 𝑟2 × (log(Λ))2 
𝛼: two‐ sided significance level, 1‐ 𝛽: power, Λ: hazard ratio, 
𝑟1: randomization ratio in Arm A, 𝑟2: randomization ration in Arm B 
 
Assuming that patients would be uniformly accumulated for an accrual period of 17 months and be 
followed up for 19 months, the target sample size is estimated to be 650 patients according to the 
formula below.7) In this case, approximately 38 patients need to be enrolled per month; however, the 
accrual period is set at 19 months because accrual may be slower than required and approximately 5% 
of patients may be additionally excluded from the FAS, and therefore, the total sample size is 
calculated to be 686 patients in the overall two groups. 
Target sample size = Required number of events/ ∑𝑟𝑖(1 −e−𝜆𝑖𝑌(1 −e−𝜆𝑖𝑋)
𝜆𝑖𝑋
)
𝑖
 
𝑖: arm, 𝑟𝑖: randomization ratio in Arm 𝑖, 𝜆𝑖: hazard in Arm i, 
𝑋: accrual period, 𝑌: follow‐up period 
 
Subjects can be additionally enrolled when death events occur less frequently than expected. If the 
number of subjects to be enrolled is increased above 686 subjects, the sponsor will determine the final 
planned sample size in the discussion with the statistical advisor. 
 
Null and alternative hypotheses in statistical tests are as follows: 
• 
Null hypothesis H0: λ𝑇/λ𝐶 = 1 
• 
Alternative hypothesis H1: λ𝑇/λ𝐶 ≠ 1 
• 
λ𝐶: Hazard with S-1/CDDP 
• 
λ𝑇: Hazard with TAS-118/L-OHP 
 
A list of powers provided when expected MST is changed in each arm is shown in Table 2-1. 
 
 
 


TAS-118 Protocol: 
 
Page 9 / 41 
Table 2-1 Changes in power (%) in the final analysis when expected MST is changed 
MST (months) in TAS-
118/L-OHP arm 
MST (months) in S-1/CDDP arm 
12 
13 
14 
14.5 
15 
16 
17 
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 
 
The powers were calculated with a total number of events of 437 and a two-sided significance level 
of 4.899%. 
The power selected in this study is underlined. 
 
The overall power (a probability that the test is significant under the alternative hypothesis either in 
the interim analysis or the primary evaluation) is 85.1% in this study, including the interim analysis. 
This power was calculated using logarithmic transformation and normal approximation of the expected 
hazard ratio according to the following formulas: 
Total power = 1 −Pr (𝑍1 > 𝑧𝛼1
2
, 𝑍2 > 𝑧𝛼2
2
) 
(
𝑍1
𝑍2
) ~N
(
 
 
 
 
(
 
 
 log(𝛬) × √𝑁1
4
log(𝛬) × √𝑁2
4
 
)
 
 
 
,
(
 
 
 1
√𝑁1
𝑁2
√𝑁1
𝑁2
1
)
 
 
 
)
 
 
 
 
,  
𝛼1: two‐ sided significance level in an interim analysis, 
𝛼2: two‐ sided significance level in the primary analysis for the primary evaluation, 
𝑁1: required number of events in an interim analysis, 𝑁2: required number of events in the final analysis 
 
2.1.3. Change in the Required Number of Events in the Analysis for Primary Evaluation 
Ramucirumab was approved in Japan in March 2015 and Korea in April 2015. As of March 2017, 
when the independent data monitoring committee (IDMC) emergency meeting was held, an application 
was filed for the approval of partial changes to marketing approval matters on the indication of 
nivolumab for gastric cancer in Japan in December 2016, and early use of nivolumab was expected. 
Using these drugs, which were not considered at the time of study initiation, in subsequent therapy 
may prolong OS and reduce the power assumed before study initiation. The IDMC was therefore 
consulted for that concern in the IDMC emergency meeting in March 2017 and recommended that the 
required total number of events be changed to 491 events. Accordingly, the protocol was revised on 
April 12, 2017, to change the required number of events to 491 in the analysis for the primary 
evaluation. 


TAS-118 Protocol: 
 
Page 10 / 41 
2.2. Subject Registration and Randomization Method 
2.2.1. Randomization Method 
Subjects will be randomized in a 1:1 ratio to TAS-118/L-OHP (study arm, Arm A) or S-1/CDDP 
(control arm, Arm B). 
Treatment assignment will be performed via an interactive web response system (IWRS) using a 
dynamic allocation method (minimization method) stratified by the following allocation adjustment 
factors: 
• 
Measurable lesion: (yes, no) 
• 
Eastern Cooperative Oncology Group (ECOG) performance status (PS): (0, 1) 
• 
Country: (Japan, Korea) 
 
 
 


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3. Data to Be Used in Statistical Analysis and Analysis Populations 
3.1. Materials and Data Other Than Case Report Forms 
A list of materials and data required for statistical analysis other than the case report form (CRF) is 
presented in Table 3-1. 
Table 3-1 Materials and data required for statistical analysis other than the CRF 
Parameters 
Materials or data 
Remarks 
Randomization 
True allocation key 
To identify the treatment randomized to each 
subject. 
Data at 
randomization 
Patient baseline characteristics 
information, such as the 
allocation adjustment factors 
used for patient randomization, 
that is provided with the true 
allocation key by the trial 
registration office 
To summarize the information using both data 
at randomization and CRF data. 
Coding to MedDRA 
terms 
Corresponding table between 
terms of adverse events, medical 
history, and complications 
recorded by the investigator and 
MedDRA terms 
To summarize the proportion of subjects with 
adverse events by using unified terms. 
Name of 
concomitant 
medications and 
therapies 
Corresponding data between 
terms of concomitant 
medications recorded by the 
investigator and WHO Drug 
Dictionary 
To summarize concomitant medications by 
using unified terms. 
Inclusion of subjects Flag of the inclusion of each 
subject in each analysis 
population 
To identify which analysis population each 
subject is included in. 
Significance level in 
the primary analysis 
for the primary 
evaluation 
Significance level calculated and 
information in interim analyses 
To calculate the significance level in the 
primary analysis. 
Information on 
follow-up censoring 
Date of follow-up censoring 
To reflect the date of follow-up censoring as 
the date of censoring in survival analysis in 
subjects whose consent to survival 
information follow-up cannot be confirmed. 
Information on 
deviations 
Nature of deviation and 
important deviation flag 
To provide a list of deviated subjects. 
Institutional normal 
range 
Institutional normal range of 
laboratory values 
To determine whether laboratory values are 
normal or abnormal or evaluate the change in 
CTCAE grade. 
 
 
 


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3.2. Analysis Populations 
A list of the name and definition of analysis populations is presented in Table 3-2. 
If there are any problems with the inclusion of subjects in each analysis population except the 
criteria listed below, the sponsor will determine in which population the subject should be included 
before analysis in the discussion with the medical advisor. 
 
Table 3-2 Definitions of analysis populations 
Analysis populations 
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 advanced gastric cancer at 
randomization 
Tumor response-evaluable 
population 
Patients in FAS population who have measurable lesions (at least one 
target lesion) at baseline and are evaluated for tumor responses at least 
once during treatment with the study drug 
 
 
 


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4. Timing of Analyses and Significance Level 
In this study, two interim analyses were planned and implemented before the analysis for the primary 
evaluation. Based on the results of the two interim analyses and IDMC reviews, the timing of the 
analysis for the primary evaluation is defined in Table 4-1. 
In the analysis for the primary evaluation, whether TAS-118/L-OHP is superior to S-1/CDDP with 
respect to OS will be tested in the FAS population. As the test method, a stratified log-rank test will be 
conducted according to the following allocation adjustment factors: measurable lesion (yes, no), ECOG 
PS (0, 1), and country (Japan, Korea). 
 
Table 4-1 Timing of each analysis and significance level 
 
Timing of analysis 
Significance level 
at sample size 
determination 
First interim analysis 
When the number of death events reaches 
100 (Date: April 22, 2016) 
Not tested 
Second interim 
analysis 
When the number of death events reaches 
219 (Date: November 30, 2016) 
0.305% 
Analysis for the 
primary evaluation 
When the required number of death 
events, 491, is confirmed 
4.899% 
 
These significance levels were calculated using the Lan and DeMets method (O’Brien-Fleming type) 
at the time of sample size determination. The significance levels to be spent will be recalculated in the 
interim analyses and the analysis for the primary evaluation. The procedures for recalculation are 
presented in Section “5.2.4.12 Log-Rank Test Using Recalculated α” 


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5. Endpoints and Common Considerations for Statistical Analysis 
5.1. Endpoints 
The definition of efficacy, safety, and compliance is presented below. 
Based on the data cutoff date decision record created according to the data cutoff procedures, the 
range of entry data will be identified. In the primary analysis, the cutoff date is handled as the event 
date in the 491st subject. 
5.1.1. Efficacy Endpoints 
The efficacy endpoints in this study are the primary endpoint of OS and the secondary endpoints of 
PFS, TTF, ORR, and DCR, as well as the duration of overall response, the duration of complete 
response, and tumor shrinkage rate. 
 OS 
Overall survival is defined as the time (in months) from the date of randomization to the date of 
death due to any cause. In the primary analysis, subjects who are not known to be dead or are alive as 
of the cutoff date will be censored at the date of the last survival confirmation or the cutoff date, 
whichever comes first. 
The OS cutoff date used for the analysis is defined as the event date in the 491st subject in the FAS 
population. In the analyses in the enrolled population, the cutoff date is defined as the event date in the 
491st subject in the enrolled population. 
A list of the definition of OS events is presented in Table 5-1. 
 
Table 5-1 Definition of OS events 
 
Case 
Date 
Event 
Subjects died before the cutoff date. Date of death 
Censoring 
Subjects failed to be followed up for 
death or are alive as of the cutoff 
date. 
Date of the last survival confirmation*1 or the cutoff date, 
whichever comes first 
*1: The latest date among the dates recorded in all pages of the CRF 
 PFS 
Progression-free survival is defined as the time (in months) from the date of randomization until the 
date of the investigator-assessed disease progression or death due to any cause, whichever comes first. 
Subjects who start to receive subsequent therapy before disease progression assessment will be 
censored at the date of the last progression-free assessment before subsequent therapy is initiated. A list 
of the definition of PFS events is presented in Table 5-2. 
Subjects who are progression-free and alive as of the cutoff date will be censored at the date of the 
last progression-free assessment. 
 
 


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Table 5-2 Definition of PFS events 
 
Case 
Date 
(if multiple cases apply, the earliest date is used) 
Event 
Progressive disease (PD) before the 
data cutoff date 
Date of PD confirmation 
 
Death (PD not observed) 
Date of death*1 
Censoring 
Non-PD or non-death at the time of 
data cutoff 
Date of the last tumor assessment 
 
Unknown date of PD 
Date of the last tumor assessment 
 
No tumor assessment after 
randomization 
Date of randomization 
 
Another subsequent therapy for any 
reason other than PD 
Date of the last tumor assessment before the start of 
subsequent therapy 
 
Evaluated as not evaluable (NE) 
Date of the last tumor assessment immediately before 
evaluation 
 
Other 
Date of the last tumor assessment 
*1: If no tumor is assessed on the date of imaging assessment specified after the date of the last 
study treatment and a death event occurs before the acceptable limit of the imaging assessment 
day (the specified assessment day + 1 week), the event will be handled as a PFS event. If a 
death event occurs after the acceptable limit, the event is not handled as a PFS event. 
 TTF 
Time to treatment failure is defined as the time (in months) from the date of randomization until the 
date of the last study treatment. Subjects who are still on study treatment as of the cutoff date will be 
censored at the date of the last study treatment or the cutoff date, whichever comes first. A list of the 
definition of TTF events is presented in Table 5-3. 
 
Table 5-3 Definition of TTF events 
 
Case 
Date 
Event 
Discontinued study treatment 
Date of the last study treatment 
Censoring 
Other cases 
Date of data cutoff 
 Best Overall Response Assessment 
Best overall response as per RECIST 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 if SD (or non-CR/non-PD) is confirmed as the best overall response, the criteria 
for SD (or non-CR/non-PD) must be met in a test conducted at least 6 weeks after entry (acceptable 
within 1 week before and after the scheduled date). 
5.1.1.4.1 ORR 
Overall response rate is defined as the proportion of subjects with the best overall response of CR or 
PR in the tumor response-evaluable population. 
 
ORR (%): (CR + PR) / (Number of subjects in the tumor response-evaluable population) × 100 


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5.1.1.4.2 DCR 
The assessment of DCR will be parallel that of ORR, with DCR defined as the proportion of subjects 
with objective evidence of CR, PR, or SD. 
 
DCR (%): (CR + PR + SD) / (Number of subjects in the tumor response-evaluable population) × 100 
5.1.1.4.3 Time to Overall Response 
Time to overall response is defined as the time (days) from the date of study drug administration to 
the first overall response of CR or PR. The time to overall response will not be calculated if CR or PR 
is not evident. 
Time to overall response: Date of first overall response of CR or PR – Date of study drug 
administration + 1 
5.1.1.4.4 Time to Complete Response 
Time to complete response is defined as the time (days) from the date of study drug administration to 
the first overall response of CR. The time to complete response will not be calculated if CR is not 
evident. 
Time to complete response: Date of first overall response of CR – Date of study drug administration 
+ 1 
5.1.1.4.5 Tumor Shrinkage Rate 
The sum of the longest diameters of target lesions at the time of imaging assessment 𝑙= 0,1, ⋯, 𝐿 
(𝑙= 0 at predose, 𝑙≥1 after the first dose and on and before the start date of subsequent therapy) is 
defined as 𝑅𝑙. Tumor shrinkage rate at the time of imaging assessment l  in each subject is defined by 
the following expression: 
100(𝑅𝑙−𝑅0)
𝑅0
 
 
Maximum tumor shrinkage rate in each subject is defined by the following expression: 
Min1≤𝑙≤𝐿(100(𝑅𝑙−𝑅0)
𝑅0
) 
5.1.2. Safety Endpoints 
 Adverse Events and Adverse Drug Reactions 
An adverse event (AE) is any untoward medical condition sign, symptom, or disease that occurs in a 
subject while participating in this study and does not necessarily have a causal relationship with the 
study drug. 
Treatment-emergent adverse events are AEs that occur from the initiation of any study medication 
administration and do not necessarily have a causal relationship with the study drug. 
Any untoward medical sign, symptom, or disease that occurs outside the period of safety follow-up 
(30 days after the last dose of study medication or until the start of new antitumor therapy, whichever 
comes first) is not considered an AE. If any AEs are observed after the safety follow-up period has 
ended, only those AEs suspected to have a causal relationship with the study drug will be recorded in 
the CRF. 
The analysis of AEs will be based on treatment-emergent adverse events. 


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Adverse drug reactions in this study are defined as adverse events (including laboratory 
abnormalities) determined to have a reasonable possibility of a causal relationship with the study drug. 
5.1.3. Compliance Endpoints 
 Total Dose 
The dose in each cycle 𝑙= 1,2, … , 𝐿 (the cycle of the last study treatment 𝑙= 𝐿) is defined as 𝑑𝑙. 
The definition of 𝑑𝑙 in each arm is presented below. 
 
A (TAS-118) 
The 𝑑𝑙 in Arm A (TAS-118) is defined by the following formula, where the number of doses of 
30, 40, 50, and 60 mg is 𝑛1, 𝑛2, 𝑛3 and 𝑛4, respectively: 
𝑑𝑙= 30𝑛1 + 40𝑛2 + 50𝑛3 + 60𝑛4 
If an unspecified dose is administered, the 𝑑𝑙 in Arm A (TAS-118) is defined by the following 
formula, where the dose is A and the number of doses is 𝑚: 
𝑑𝑙= 30𝑛1 + 40𝑛2 + 50𝑛3 + 60𝑛4 + ∑𝐴𝑖𝑚𝑖 
 
A (L-OHP) 
The 𝑑𝑙 in Arm A (L-OHP) is defined as the actual dose [mg/body] administered in each cycle. 
 
B (S-1) 
The 𝑑𝑙 in Arm B (S-1) is defined by the following formula, where the number of doses of 40, 50, 
and 60 mg is 𝑛1, 𝑛2, and 𝑛3, respectively: 
𝑑𝑙= 40𝑛1 + 50𝑛2 + 60𝑛3 
If an unspecified dose is administered, the 
ld  in Arm B (S-1) is defined by the following 
formula, where the dose is A  and the number of doses is 𝑚: 
𝑑𝑙= 40𝑛1 + 50𝑛2 + 60𝑛3 + ∑𝐴𝑖𝑚𝑖 
 
    B (CDDP) 
The 𝑑𝑙 in Arm B (CDDP) is defined as the actual dose [mg/body] administered in each cycle. 
 
The total dose is the sum of doses administered from the start of Cycle 1 study treatment through the 
discontinuation of study treatment and is defined by the following formula: 
𝐷= ∑𝑑𝑙
𝐿
𝑙=1
 
 Dose Intensity 
The definition of actual dose intensity and relative dose intensity is presented in Tables 5-4 and 5-5, 
respectively. 
 
 
 


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Table 5-4 Definition of actual dose intensity 
Arm 
Definition 
Unit 
A 
TAS-118 
(Total dose [mg] / BSA [m2] at entry) / ((Start date of the last cycle 
treatment – Start date of Cycle 1 treatment + 14) / 7) 
[mg/m2/week] 
 
L-OHP 
(Total dose [mg] / BSA [m2] at entry) / ((Start date of the last cycle 
treatment – Start date of Cycle 1 treatment + 14) / 7) 
B 
S-1 
(Total dose [mg] / BSA [m2] at entry) / ((Start date of the last cycle 
treatment – Start date of Cycle 1 treatment + 35) / 7) 
 
CDDP 
(Total dose [mg] / BSA [m2] at entry) / ((Start date of the last cycle 
treatment – Start date of Cycle 1 treatment + 35) / 7) 
 
Table 5-5 Definition of relative dose intensity 
Arm 
Definition 
Unit 
A 
TAS-118 
100 × Actual dose intensity [mg/m2/week] / 
((Initial dose [mg] × 2 × 7 / BSA [m2] at entry) / 2 [week]) 
[%] 
 
L-OHP 
100 × Actual dose intensity [mg/m2/week] / 
((Initial dose [mg/body] / BSA [m2] at entry) / 2 [week]) 
B 
S-1 
100 × Actual dose intensity / 
((Initial dose [mg] × 2 × 21 / BSA [m2] at entry) / 5 [week]) 
 
CDDP 
100 × Actual dose intensity [mg/m2/week] / 
((Initial dose [mg/body] / BSA [m2] at entry) / 5 [week]) 
5.2. Common Considerations for Statistical Analysis 
5.2.1. Data Handling 
 Handling of Longitudinal Data 
5.2.1.1.1 Calculation of Number of Days and Period 
In this statistical analysis plan, the number of days and period will be consistently calculated using 
the following formulas unless otherwise specified: 
• 
After the reference date 
Day n = target date – reference date + 1 
• 
Before the reference date 
Day n = target date – reference date 
Accordingly, the start date of treatment is Day 1, the day following the start of treatment is Day 2, 
and the day before the start of treatment is Day −1. The period is 1 day when the target date is just the 
reference date and 2 days when the target date is the date following the reference date. 
If the month is missing in a date used for the calculation, the number of days and period is regarded 
as missing. If only the day is missing, it is replaced with the first day before calculation (e.g., April xx, 
2016 → April 1, 2016). Only when the date of death is missing (year and month observed) and the date 
of the last survival confirmation in the same year and month is known, the date of death is regarded as 
the date following the last survival confirmation. 
5.2.1.1.2 Calculation of Number of Years, Months, and Weeks 
In this statistical analysis plan, the number of years, months, and weeks will be consistently 
calculated using the following formulas: 
• 
Number of years = Number of days / 365.25 
• 
Number of months = Number of days / 30.4375 
• 
Number of weeks = Number of days / 7 
The number of years, months, or weeks will not be rounded unless indicated. 


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5.2.1.1.3 Acceptable Time Window 
For each evaluation time point, data obtained within the time window specified below will be used. 
If multiple observations or measurements are available within a time window, data outside the time 
window will be excluded, and then the data obtained on the day closest to the scheduled day will be 
used for each parameter of observation or measurement. If measurement days before and after the 
scheduled day are shifted by the same number of days, the data obtained after the scheduled day will be 
used. 
 
[Imaging assessment (overall response)] The reference day is the randomization day. 
Time point 
Scheduled day 
Time window 
6 weeks after 
randomization 
Day 43 
Randomization day ≤ measurement day ≤ Day 50 
n × 6 weeks after 
randomization 
Day (n × 42 + 1) 
Day (n × 42 – 6) ≤ measurement day ≤ Day (n × 42 + 8) 
 
[Sum of diameters of target lesions/laboratory values/tumor markers/vital signs (including 
height/weight/BSA)] 
Time point 
Scheduled day 
Time window 
Baseline 
Start date of study 
treatment 
Measurement day ≤ start date of study treatment 
 
[Cycles used for the analyses] 
Relationship between the start date of treatment in each cycle 
and the assessment day 
Cycle used for the analysis 
Start date of treatment in Cycle x < assessment day < start date 
of treatment in Cycle x + 1 
Cycle x 
Start date of treatment in Cycle x = assessment day and 
assessed after treatment 
Cycle x 
Start date of treatment in Cycle x = assessment day and 
examined before treatment 
Cycle x − 1 
If x = 1, then baseline is used. 
Start date of treatment in Cycle x < assessment day (with no 
next cycle) within the cycle decision period* 
Cycle x 
Start date of treatment in Cycle x < assessment day (with no 
next cycle) outside the cycle decision period* 
After safety follow-up 
*Data obtained on the date of the last study treatment + 30 days or the start date of subsequent 
therapy, whichever comes first (including the day), will be included in the cycle decision period. Data 
obtained within this period after the date of the last study treatment will be included in the last cycle. 
When data are collected in each cycle that is not specified in the list, all cycles except those after 
safety follow-up will be included in the analysis. 
 Handling of Missing Data and Abnormal Values 
No imputation of missing data will be performed. All data accepted at each time point will be used 
for the analysis. The proportion of subjects with adverse events and other proportions will be calculated 
using the analysis population as the denominator. 
All data measured will be used for the analysis unless the cause of abnormalities is obvious, such as 
laboratory abnormalities caused by hemolysis during blood collection. If there are abnormalities to be 


TAS-118 Protocol: 
 
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excluded from the analysis, these values will be identified, and the reason for exclusion will be 
justified. 
 Handling of Treatment Arms 
Analyses in the FAS and the tumor response-evaluable population will be based on the randomized 
treatment arm in principle. 
Analyses in the AT population will be based on the actual treatment given to each subject. 
5.2.2. Patient Baseline Characteristics 
A list of patient baseline characteristics to be measured at entry is presented in Table 5-6. 
For ECOG PS, both data obtained at randomization and data entered in “Vital Signs and ECOG (At 
the time of Randomization)” of the CRF will be used. 
For the presence or absence of measurable lesions, both data obtained at randomization and data 
entered in “Tumor Imaging (Baseline)” of the CRF will be used. In the data from “Tumor Imaging 
(Baseline),” a measurable lesion is determined as being present when a target lesion is present, and a 
measurable lesion is determined as being absent when a target lesion is absent. 
The number of metastatic organs is defined as the number of “sites of lesions” recorded in “Target 
Lesion” and “Non-target Lesion” at predose. However, “Stomach” will not be treated as a metastatic 
organ because all stomach lesions are primary lesions. The number of metastatic organs will be counted 
as one if multiple metastases are recorded in the same organ, and regional lymph nodes and distant 
lymph nodes are counted as the same organ. Metastatic organs recorded as “Other” will also be counted 
respectively in “Number of metastatic organs.” 
If multiple measurements are available before treatment initiation, the most recent data before 
treatment initiation will be used. 
Among the patient characteristic factors listed in Table 5-6, the factors used for efficacy analysis are 
presented in Table 5-7, and the details of categories of each factor are presented in Table 5-8. 
If data are missing, the category will be indicated as “Missing.” Missing data will be excluded from 
the denominator used to calculate proportions and from statistical tests. 
 
Table 5-6 Characteristic factors 
Parameter 
Factor 
Patient baseline 
characteristics 
Sex, age, race, country, height, weight, BSA, ECOG PS 
Disease characteristics 
Presence/absence of primary lesion, primary site, histological type, 
detail of diffuse type, detail of intestinal type, HER2, clinical stage, 
presence/absence of measurable lesion, sum of diameters of target 
lesions, category of the number of metastatic organs, metastatic organ 
category, presence/absence of liver metastasis, peritoneum metastasis, 
ascites, and lymph node metastasis, JCOG Index* 
Prior treatment 
Neoadjuvant chemotherapy (yes/no, regimen, detail of chemotherapy), 
adjuvant chemotherapy (yes/no, regimen, detail of chemotherapy), prior 
gastrectomy (yes/no, detail of surgery, outcome), other therapy (yes/no) 
Laboratory values 
Hemoglobin, white blood cell count, neutrophil count, lymphocyte 
count, platelet count, AST, ALT, ALP, albumin, bilirubin, creatinine, 
creatinine clearance, Na, K, corrected Ca, CRP, LDH, urine protein, 
CEA, CA19-9 
 
*JCOG Index: Number (0 to 4) of conditions that apply to a patient among the following risk factors: 
ECOG PS ≥ 1, number of metastatic organs ≥ 2, no prior gastrectomy, and ALP deviation from the 
institutional upper limit of normal (ULN).11) 
 


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Table 5-7 Factors used for analysis of each characteristic factor 
Parameter 
Factor 
Patient baseline 
characteristics 
Sex, age category 1, age category 2, country, BSA category, ECOG PS 
Disease characteristics 
Presence/absence of primary lesion, primary site, histological type, 
detail of diffuse type, detail of intestinal type, HER2, clinical stage, 
presence/absence of measurable lesion, category of the number of 
metastatic organs, metastatic organ category, presence/absence of liver 
metastasis, peritoneum metastasis, ascites, and lymph node metastasis 
Prior treatment 
Neoadjuvant chemotherapy (yes/no), adjuvant chemotherapy (yes/no), 
prior gastrectomy (yes/no), other therapy (yes/no) 
Laboratory values 
CEA category, CA19-9 category 
 
 
 


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Table 5-8 Details of categories 
Category 
Details 
Sex 
Male, female 
Age category 1 
<65 years, ≥65 years 
Age category 2 
<75 years, ≥75 years 
Country 
Japan, Korea 
BSA category 
<1.250, ≥1.250 to <1.500, ≥1.500 
ECOG PS 
0, 1 
Primary site 
Stomach, gastroesophageal junction 
Histological type 
Diffuse type, intestinal type, unknown 
Detail of diffuse type 
Poorly differentiated adenocarcinoma, signet-ring cell carcinoma, 
mucinous adenocarcinoma 
Detail of intestinal type 
Well-differentiated tubular adenocarcinoma, moderately differentiated 
tubular adenocarcinoma, papillary adenocarcinoma 
HER2 
Negative, positive (IHC 3+), positive (IHC 2+ / FISH+), unknown 
Clinical stage 
Stage IV, recurrent 
Category of the number of 
metastatic organs 
1, 2, ≥3 
Metastatic organ category 
Liver, lung, regional lymph nodes, distant lymph nodes, peritoneum, 
ascites, pleura, pleural effusion, bone, bone marrow, brain, skin, adrenal 
glands, esophagus, colon and rectum, ovary, pancreas, other 
JCOG Index 
Good risk (0 or 1), moderate risk (2 or 3), poor risk (4) 
Neoadjuvant/adjuvant 
chemotherapy 
Chemotherapy, chemoradiotherapy, radiotherapy 
Detail of chemotherapy 
Paclitaxel, Abraxane, docetaxel, irinotecan, S-1, capecitabine, 5-FU, 
UFT, oxaliplatin, cisplatin, leucovorin, trastuzumab, other 
CEA category 
≤ institutional ULN, > institutional ULN 
CA19-9 category 
≤ institutional ULN, > institutional ULN 
5.2.3. Statistical Methods 
 Summary Statistics for Continuous Data 
Summary statistics for continuous data, if indicated, include the sample size, minimum, maximum, 
median, first quartile, third quartile, mean, and standard deviation. 
 Proportion 
Proportions will be calculated using the following formula: 
 
Proportion (%) =
Number of relevant subjects
Number of subjects in each arm in the analysis population × 100 
 
 Test Methods 
(1) Patient baseline characteristics 
The test methods used to investigate whether patient baseline characteristics are biased between the 
treatment arms are presented in Table 5-9. 


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Table 5-9 Test methods for patient baseline characteristics 
Test method 
Parameter 
Factor 
t test (homogeneity of 
variance) 
Patient baseline 
characteristics 
Age, height, weight, BSA 
 
Disease 
characteristics 
Sum of diameters of target lesions 
 
Laboratory 
values 
Hemoglobin, white blood cell count, neutrophil count, 
lymphocyte count, neutrophil/lymphocyte count ratio, platelet 
count, AST, ALT, ALP, albumin, bilirubin, creatinine, 
creatinine clearance, Na, K, corrected Ca, CRP, LDH, urine 
protein, CEA, CA19-9 
Fisher’s exact test 
Patient baseline 
characteristics 
Sex, age category 1, age category 2, country, ECOG PS 
 
Disease 
characteristics 
Presence/absence of primary lesion, primary site, clinical 
stage, presence/absence of measurable lesion, 
presence/absence of liver metastasis, peritoneal metastasis, 
ascites, and lymph node metastasis 
 
Prior treatment Presence/absence of neoadjuvant chemotherapy, 
presence/absence of adjuvant chemotherapy, prior 
gastrectomy, other therapy 
 
Laboratory 
values 
CEA category, CA19-9 category 
χ2 test 
(Pearson chi-squared test 
without continuity correction) 
Patient baseline 
characteristics 
– 
Disease 
characteristics 
Histological type, HER2 
 
Prior treatment – 
Wilcoxon test 
(normal approximation 
with continuity correction) 
Patient baseline 
characteristics 
BSA category 
 
Disease 
characteristics 
Category of the number of metastatic organs, JCOG Index 
 
Laboratory 
values 
Urine protein 
To be tested after it is converted into numbers as follows: 
−1: − 
0: +− 
1: + 
2: 2+ 
3: 3+ 
4: 4+ 
 
(2) Survival analysis 
A stratified log-rank test or log-rank test will be used to compare the distribution of survival times 
between the treatment arms. The endpoints of OS, PFS, and TTF will be evaluated. 
 
(3) Comparison of proportions 
Fisher’s exact test will be used to compare the proportion of subjects between the treatment arms. 
The endpoints of ORR and DCR will be evaluated. For the endpoints of ORR and DCR, a Cochran–
Mantel–Haenszel test stratified by the allocation adjustment factors will also be conducted. 
 
 
 


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 Model Analysis 
(1) Cox proportional hazards model 
A Cox proportional hazards model will be used to estimate the hazard ratio. The hazard function at 
time t is defined as follows: 
𝜆(𝑡; 𝐗) = 𝜆0(𝑡) exp(𝐗𝛃), 
where 𝜆0(𝑡) is a baseline hazard function, 𝐗 is a covariate, and 𝛃 is a regression coefficient. 
 Estimation Methods 
(1) Confidence interval of proportions 
The confidence interval of ORR, DCR, and the proportion of subjects with adverse events will be 
calculated using the F distribution-based method proposed by Clopper and Pearson (1934).8) 
The upper limit of confidence interval PU and the lower limit of confidence interval PL will be 
estimated using the following formulas, where P is a proportion, X is the number of subjects with 
events, N is the number of subjects in the analysis population, and 𝛼 is a two-sided significance level: 
𝑃=  𝑋/𝑁 
𝑃𝑈=
𝜈1𝐹𝜈1,𝜈2(𝛼/2)
𝜈2 + 𝜈1𝐹𝜈1,𝜈2(𝛼/2) , 𝜈1 = 2(𝑋+ 1), 𝜈2 = 2(𝑁−𝑋) 
𝑃𝐿=
𝜈2
𝜈2 + 𝜈1𝐹𝜈1,𝜈2(𝛼/2) , 𝜈1 = 2(𝑁−𝑋+ 1), 𝜈2 = 2𝑋 
 
(2) Estimation of survival curves 
The survival time function 𝑆(𝑡𝑗) will be estimated using the following formula based on the 
Kaplan–Meier method, where 𝑡1 < 𝑡2 < ⋯< 𝑡𝑁 is the time of event onset in subject 𝑗= 1, … , 𝑁, 𝑛𝑗  
is the number of subjects at risk at time 𝑡𝑗, and 𝑑𝑗 is the number of subjects with events: 
𝑆̂(𝑡𝑁) = ∏(1 −𝑑𝑗
𝑛𝑗
)
𝑁
𝑗=1
 
 
(3) Confidence interval of MST 
The confidence interval of MST will be calculated using the method based on the sign test for 
censored data.9) 
The standard error of survival time function 𝑆(𝑡𝑗) will be estimated using the following formula: 
𝜎̂ (𝑆̂(𝑡𝑁)) = 𝑆̂(𝑡𝑁)√∑
𝑑𝑗
𝑛𝑗(𝑛𝑗−𝑑𝑗)
𝑁
𝑗=1
 
The confidence interval of MST is defined as the time of event onset within the following interval, 
where 𝛼 is a two-sided significance level: 
{𝑡: (1 −𝑆̂(𝑡) −0.5)
2 ≤𝜒1
2(𝛼)𝜎̂2 (𝑆̂(𝑡))} 
 
(4) Confidence interval of hazard ratios 
The covariance matrix of a regression coefficient estimate 𝛃̂ is expressed using the following 
formula, where 𝑙(𝛃) is a log-likelihood function: 
𝐕̂(𝛃̂) = −[𝜕2𝑙(𝛃̂)
𝜕𝛃𝜕𝛃′ ]
−1
 
 
Ties in survival time, if any, will be processed using the Breslow method. 
The confidence interval of a hazard ratio estimate of the pth covariate, exp(𝛽̂𝒑), will be estimated 
using the following expression,10) where 𝛼 is a two-sided significance level and 𝐕̂𝑝(𝛃̂) is the pth 
diagonal element in the covariance matrix 𝐕̂(𝛃̂): 


TAS-118 Protocol: 
 
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exp (𝛽̂𝑝± 𝑍𝛼/2 √𝐕̂𝑝(𝛃̂)) 
5.2.4. Sample Code 
 Stratified Log-Rank Test 
proc lifetest data = TargDS method = KM conftype = linear; 
  TIME TimeVAR * CensorVAR(1); 
  STRATA StratifiedVARs / Group = TrtVAR; 
  ods output HomTests = hom; 
run; 
 
/* Explanation of variables (the same applies hereinafter) */ 
/* TargDS: dataset to be analyzed */ 
/* TimeVAR: variable with the time to event or time to censoring */ 
/* CensorVAR: variable that provides event or censoring, in the sample above, 1 = censoring */ 
/* StratifiedVARs: variables handled as strata or subgroups such as allocation factors, more than one 
variable is possible. */ 
/* TrtVAR: treatment arm [1: A(TAS-118/L-OHP), 0: B(S-1/CDDP)] */ 
 
 Log-Rank Test 
proc lifetest data = TargDS method = KM 
                conftype = linear; 
  TIME TimeVAR * CensorVAR(1); 
  STRATA TrtVAR; 
  ods output Quartiles = qua; 
  ods output ProductLimitEstimates = est; 
run; 
 Cox Proportional Hazards Model 
proc phreg data = TargDS;  
  class TrtVAR  StratifiedVARs; 
  model TimeVAR * CensorVAR(1) = TrtVAR  StratifiedVARs 
           / rl TIES = BRESLOW; 
  hazardratio TrtVAR / CL = Wald; 
run; 
 Cox Proportional Hazards Model (by Baseline Characteristic Factor) 
proc phreg data = TargDS;  
  class TrtVAR  StratifiedVAR; 
  model TimeVAR * CensorVAR(1) = TrtVAR  StratifiedVAR  TrtVAR * StratifiedVAR 
           / rl TIES = BRESLOW; 
  hazardratio TrtVAR / CL = Wald; 
run; 
 
/* More than one StratifiedVAR is prohibited. */ 
/* To create a forest plot in each Subgroup, use the following results: */ 


TAS-118 Protocol: 
 
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/* p-value of interaction: p-value of TrtVAR * StratifiedVAR */ 
/* HR and confidence interval in each Subgroup: HR of each category of StratifiedVAR */ 
 Restricted Mean Survival Time (RMST) 
The boundary time τ is assumed to be 36 months. For the calculation of the number of years, see 
Section 5.2.1.1.2. 
For variance, standard output data from SAS will be used. 
For the details of the calculation method, refer to “Measures to evaluate time-to-event responses—
To understand restricted mean survival time (RMST),” which is provided by the Japan Pharmaceutical 
Manufacturers Association.11) 
 
/* Step1 If survival time is longer than 36 months, then change all subjects to censoring. */ 
data TargDS2; 
  set TargDS; 
  if TimeVAR > 36 then CensorVAR = 1; 
run; 
 
/* Step2 Calculate RMST */ 
proc lifetest data = TargDS2 conftype = linear timelim = 36; 
  time TimeVAR * CensorVAR(1);   /* Day * Censored or not (value at the time of censoring) */ 
  strata TrtVAR; 
  ods output   Means = pre_RMST /* Obtain RMST */ 
             ; 
run; 
 
/* Step3 Calculate the confidence interval in each arm and the difference in RMST and its 95% 
confidence interval */ 
data rmst; 
  set pre_RMST; 
  CI_low = Mean - quantile('NORMAL', .975) * StdErr; /* Lower confidence limit */ 
  CI_up = Mean + quantile('NORMAL', .975) * StdErr; /* Upper confidence limit */ 
run; 
 
/* Step 4 Calculate the between-group difference in RMST and its 95% confidence interval */ 
data rmstdiff; 
  merge pre_RMST(where = (TrtVAR = "A(TAS-118/L-OHP)")  
keep = TrtVAR Mean StdErr  
rename = (Mean = Mean_A StdErr = StdErr_A)) 
        pre_RMST(where = (TrtVAR = "B(S-1/CDDP)")  
keep = TrtVAR Mean StdErr  
rename = (Mean = Mean_B StdErr = StdErr_B)); 
  diff = Mean_A - Mean_B; /* Difference in RMST */ 
  CIdiff_low = diff - quantile('NORMAL', .975) * sqrt(StdErr_A ** 2 + StdErr_B ** 2); /* Lower 
confidence limit */ 
  CIdiff_up = diff + quantile('NORMAL', .975) * sqrt(StdErr_A ** 2 + StdErr_B ** 2); /* Upper 
confidence limit */ 
run; 
 


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 95% Confidence Interval of Between-Group Difference in MST by Bootstrap 
Method 
/* Step1 Run 2000 repetitions of sampling with replacement for the number of subjects to be 
analyzed in each arm. */ 
  proc surveyselect data = TargDS method = urs rep = 2000 
     rate = 1 seed = 20181122 out = out OUTHITS;   
strata TRT01P; 
  run; 
proc sort data = out; 
  by Replicate; 
run; 
 
/* Step2 Calculate MST in each arm in each repetition */ 
proc lifetest data = out method = KM 
                conftype = linear; 
  TIME AVAL * CNSR(1); 
  STRATA TRT01P; 
  by Replicate; 
  ods output Quartiles = qua; 
run; 
 
/* Step3 Calculate the between-group difference in MST in each repetition */ 
data MST; 
  merge qua(where = (TRT01P = "A(TAS-118/L-OHP)" and Percent = 50) keep = Replicate 
TRT01P Percent Estimate rename = (Estimate = Estimate_A)) 
        qua(where = (TRT01P = "B(S-1/CDDP)" and Percent = 50) keep = Replicate TRT01P 
Percent Estimate rename = (Estimate = Estimate_B)); 
  by Replicate; 
  mstdiff = Estimate_A - Estimate_B; 
run; 
 
proc sort data = MST; 
  by mstdiff; 
run; 
 
/* Step4 Calculate the 2.5th percentile (lower confidence limit) and 97.5th percentile (upper 
confidence limit) */ 
proc univariate data = MST; 
  var mstdiff; 
  output out = MST_CI pctlpre = P pctlpts = 2.5 97.5; 
run; 
 Stratified Cox Proportional Hazards Model 
proc phreg data = TargDS;  
  class TrtVAR  StratifiedVARs; 
  model TimeVAR * CensorVAR(1) = TrtVAR  
           / rl TIES = BRESLOW; 
  strata StratifiedVARs; 


TAS-118 Protocol: 
 
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  hazardratio TrtVAR / CL = Wald; 
run; 
 
 Comparison of Proportions Between Treatment Arms 
proc freq data = TargDS; 
  tables StratifiedVARs * TrtVAR / chisq fisher; 
run; 
 Confidence Interval of Proportion 
proc freq data = TargDS; 
  tables KubunVAR / binomial; 
run; 
/* KubunVAR: variable that provides a category in which a proportion is calculated */ 
 
Wilcoxon Test (Two-Sample) 
proc npar1way data = TargDS Wilcoxon; 
  class TrtVAR; 
  var  StratifiedVAR; 
run; 
 
Note: To avoid errors in ranking internally processed in SAS, the variance used in VAR statement 
will be rounded off to the ninth decimal place. 
 
Confidence Interval of Median 
proc univariate data = TargDS cipctldf; 
  var ady; 
run; 
/* Calculate a distribution-free confidence interval using the cipctldf option. */ 
 
Log-Rank Test Using Recalculated α 
The log-rank test will be conducted according to the following procedures in this study: 
• 
Using Proc Seqdesign, derive a boundary p-value for the primary evaluation at the time of sample 
size determination. 
• 
Derive estimated maximum information to establish a boundary at the time of analysis. 
• 
Based on the maximum information as derived above, use Proc Seqdesign to calculate a boundary 
at the time of each testing. 
• 
In the second interim analysis, use Proc Lifetest to calculate rank-order statistics/covariance 
matrix in a log-rank test for actual accumulated data. 
• 
Edit the results of Proc Lifetest for Proc Seqtest. 
• 
Using Proc Seqtest, conduct a test based on the boundary calculated by Proc Seqdesign and the 
edited log-rank test statistics and calculate a boundary used in the analysis for the primary 
evaluation. 
• 
In the analysis for the primary evaluation, use Proc Lifetest to calculate rank-order 
statistics/covariance matrix in a log-rank test for actual accumulated data. 
• 
Edit the results of Proc Lifetest for Proc Seqtest. 
• 
Using Proc Seqtest, conduct a test based on the boundary calculated by Proc Seqtest in the second 
interim analysis and the edited log-rank test statistics. 
 
/* Derive a boundary p-value for the primary evaluation at the time of sample size determination. */ 


TAS-118 Protocol: 
 
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proc seqdesign altref=-0.287682072 errspend boundaryscale = pvalue; 
/* The value of altref is the logarithmic value of 0.75, a hazard ratio of TAS-118/L-OHP to S-
1/CDDP as specified in the protocol. */ 
 
  TwoSidedErrorSpending: design  
  method(alpha) = errfuncobf /* O'Brien-Fleming type alpha spending function */ 
 
  info = cum(0.5, 1) 
  /* The value of info = cum is information fraction. */ 
  /* The value is 0.5 when half of all events are accumulated, */ 
  /* and the value of 1 when all events are accumulated. */ 
 
  alpha   = 0.05           /* Significance level */ 
  nstages = 2              /* Number of tests */ 
  alt     = twosided       /* Two-sided test */ 
  stop    = reject; 
  samplesize model = twosamplesurvival 
  (nullhazard = 0.047803254 acctime = 19 foltime = 19);  
  /* Into t in an exponential distribution S(t) = exp(−λt), */ 
  /* substitute an estimated MST of 14.5 in the S-1/CDDP arm as specified in the protocol to 
calculate λ. */ 
  /* Acctime and foltime are the accrual period and the follow-up period, respectively, as defined in 
the protocol. */ 
ods output Boundary = boundpre; 
run; 
 
/* Derive estimated maximum information to establish a boundary at the time of analysis. */ 
data maxinfo; 
  set boundpre;  
  where _Stage_ = 2;  
  theta = log(0.75); /* Estimated logarithmic hazard ratio */ 
  alpha = Bound_LA; 
  /* Estimated boundary p-value for the primary evaluation */ 
  /* (Value derived by Proc Seqdesign: 0.0244997106 ) */ 
 
  inva = quantile("normal",1-alpha); 
  beta =0.15; * power in the primary analysis; 
  invb = quantile("normal",1-beta); 
 
  maxinfo = ((inva + invb) / theta) ** 2; /* Estimated maximum information */ 
  required = maxinfo * 4;          /* For reference: required number of events */ 
 
  call symput("maxinfo",strip(put(maxinfo,best.))); 
  /* Convert the estimated maximum information used in Proc Seqdesign to a macro variable. */ 
run; 
 
/* Calculate a boundary at the time of analysis using the converted maximum information. */ 
proc seqdesign altref=-0.287682072 errspend   maxinfo = &maxinfo; 
  TwoSidedErrorSpending: design  


TAS-118 Protocol: 
 
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  method(alpha) = errfuncobf   info = cum(0.5, 1)   alpha = 0.05   nstages = 2 
  alt = twosided   stop = reject; 
  samplesize model = twosamplesurvival 
  (nullhazard = 0.047803254 acctime = 19 foltime = 19);  
  ods output ErrSpend = ErrSpend; 
  ods output Boundary = bound_surv; 
run; 
 
 
/* Stratified log-rank test (the second interim analysis) */ 
/* MLIWN PSIWN CNTRYIWN means the allocation adjustment factors. */ 
/* Presence/absence of measurable lesion, ECOG PS, country */ 
/* TRT01P is an assigned treatment arm. */ 
proc lifetest data = ADTTE method = KM conftype = linear; 
  time AVAL * CNSR(1); 
  strata MLIWN PSIWN CNTRYIWN / Group = TRT01P; 
  ods output HomStats = outs; 
  ods output LogrankHomCov = outv; 
run; 
 
/* Edit the results of Proc Lifetest for Proc Seqtest. */ 
data logrank_result; 
  merge outs outv; 
  by TRT01P; 
  keep Variable _Scale_ _Stage_ StdErr Estimate; 
  Variable = 'Arm'; 
  _Scale_ = "Score"; 
  _Stage_ = 1; /* Designate which number is this test among the planned tests. */ 
  /* Obtain a standard error from the element in the first row and the first column (= variance) of a 
2 × 2 covariance matrix for the log-rank test. */ 
  if _n_ = 1 then do; 
    StdErr = sqrt(A_TAS_118_L_OHP_);  
    Estimate = LogRank; 
    output; 
  end; 
run; 
 
/* Conduct a test using */ 
/* the boundary calculated by Proc Seqdesign and the edited log-rank test statistics. */ 
proc seqtest boundary = bound_surv boundaryscale = pvalue 
  parms(testvar = Arm) = logrank_result 
  errspendadj = errfuncobf /* O'Brien-Fleming type alpha spending function */ 
  order = stagewise; 
  ods output test = test_surv1; /* Use as a boundary in the analysis for the primary evaluation. */ 
run; 
 
/* Stratified log-rank test (analysis for the primary evaluation) */ 
proc lifetest data = ADTTE method = KM conftype = linear; 
  TIME AVAL*CNSR(1); 


TAS-118 Protocol: 
 
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  strata MLIWN PSIWN CNTRYIWN / Group = TRT01P; 
  ods output HomStats = outs2; 
  ods output LogrankHomCov = outv2; 
run; 
 
/* Edit the results of Proc Lifetest for Proc Seqtest. */ 
data logrank_result2; 
  merge outs2 outv2; 
  by TRT01P; 
  keep Variable _Scale_ _Stage_ StdErr Estimate; 
  Variable = 'Arm'; 
  _Scale_ = "Score"; 
  _Stage_ = 2; /* Designate which number is this test among the planned tests. */ 
  /* Obtain a standard error from the element in the first row and the first column (= variance) of a 
2 × 2 covariance matrix for the log-rank test. */ 
  if _n_ = 1 then do; 
    StdErr = sqrt(A_TAS_118_L_OHP_);  
    Estimate = LogRank; 
    output; 
  end; 
run; 
 
/* Conduct a test using the boundary calculated in the second IDMC */ 
/* and the log-rank test statistics in the analysis for the primary evaluation. */ 
ods graphics on;  
proc seqtest boundary = test_surv1  boundaryscale=pvalue 
  parms(testvar=Arm) = logrank_result2 
  errspendadj = errfuncobf  
  order = stagewise; 
  ods output test = test_surv2; 
run; 
 
Cochran–Mantel–Haenszel Test 
proc freq data = TargDS; 
  tables StratifiedVARs * TrtVAR * KubunVAR / cmh; 
run; 
/* KubunVAR: variable that provides a category in which a proportion is calculated */ 
 
5.2.5. Software to Be Used 
The software to be used and the version are presented in Table 5-10. 
Table 5-10 Software to be used and version 
 
Software and version 
Operating system 
Microsoft Windows 7 
Statistical analysis software 
SAS 9.4 or later 
5.2.6. Dictionaries to Be Used 
The dictionaries to be used in analyses are presented in Table 5-11. 


TAS-118 Protocol: 
 
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Table 5-11 Dictionaries to be used 
Term 
Dictionary 
Remarks 
Adverse event 
term 
MedDRA/J 
• System organ class will be coded by MedDRA System Organ Class 
(SOC) and symptoms by MedDRA Preferred Term (PT). 
• SOC will be sorted in the order of SOC codes, if presented. 
• PT will be sorted in the order of PT codes, if presented. 
• The latest version will be used whenever possible. 
Concomitant 
medication name 
WHO Drug 
Dictionary 
• Medications will be tabulated using Generic Medication Names. 
• Medications will be sorted in the order of Generic Medication 
Names. 
• The latest version will be used whenever possible. 
 
 
 


TAS-118 Protocol: 
 
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6. Primary Endpoint Analyses 
The details of the primary analysis and an overview of its sensitivity analyses and the secondary 
analyses of the primary endpoint are presented below. 
6.1. Primary Analysis for Primary Objective 
• 
The superiority of TAS-118/L-OHP to S-1/CDDP with respect to OS will be tested in the FAS 
population. As the test method, a stratified log-rank test will be conducted according to the 
following allocation adjustment factors: ECOG PS (0, 1), measurable lesion (1: yes, 0: no), and 
country (1: Japan, 0: Korea). If the data on ECOG PS and measurable lesion at randomization 
differ from the data entered in the CRF, the data obtained at randomization will be used. 
6.2. Sensitivity Analyses of Primary Analysis 
• 
In the FAS population, a stratified log-rank test will be conducted according to the allocation 
adjustment factors entered in the CRF. 
• 
Using a log-rank test without any allocation adjustment factors, the analysis will be conducted. 
• 
In the enrolled population, the primary analysis will be conducted. 
6.3. Secondary Analyses of Primary Endpoint 
• 
With the date of observed death as the event date and the date of the last survival confirmation as 
the censoring date, without consideration of the cutoff date, the same analysis as the primary 
analysis will be conducted. 
 
The following secondary analyses of the primary endpoint will be conducted in the FAS population: 
• 
The survival curve, MST, and 95% confidence interval will be estimated in each treatment arm. 
The between-group difference in MST and its 95% confidence interval (by the bootstrap method) 
will also be calculated. The RMSTs and their 95% confidence intervals will be estimated, with 
an RMST boundary of 3 years (36 months). In addition, the between-group difference in RMST 
and its 95% confidence interval will be calculated. 
• 
The number of subjects at risk at 3-month intervals, cumulative event-free rate, and median 
follow-up period (time to censoring) and its 95% confidence interval will also be presented. 
• 
Using a Cox proportional hazards model with the allocation adjustment factors of study treatment 
(1: TAS-118/L-OHP, 0: S-1/CDDP), ECOG PS (0, 1) at randomization, measurable lesion (1: yes, 
0: no) at randomization, and country (1: Japan, 0: Korea) as covariates and a stratified Cox 
proportional hazards model according to the allocation adjustment factors, the hazard ratio for 
each covariate and its confidence interval will be estimated. To estimate the confidence interval 
of the hazard ratio corresponding to the primary analysis, the confidence level of the stratified 
Cox proportional hazards model is defined as follows: 100–significance level (%) used for the 
primary analysis. The 95% confidence interval will also be estimated. 
• 
Using a Cox proportional hazards model with the allocation adjustment factors of study treatment 
(1: TAS-118/L-OHP, 0: S-1/CDDP), ECOG PS (0, 1) entered in the CRF, measurable lesion (1: 
yes, 0: no) entered in the CRF, and country (1: Japan, 0: Korea) as covariates and a stratified Cox 
proportional hazards model according to the allocation adjustment factors, the hazard ratio for 
each covariate and its 95% confidence interval will be estimated. 
• 
Using a Cox proportional hazards model with study treatment (1: TAS-118/L-OHP, 0: S-
1/CDDP) as a covariate, the hazard ratio for the covariate and its 95% confidence interval will 
also be estimated. 
• 
For each allocation adjustment factor, the survival curve, MST, and 95% confidence interval will 
be estimated in each treatment arm. The between-group difference in MST and its 95% confidence 
interval (by the bootstrap method) will also be calculated. The RMSTs and their 95% confidence 
intervals will be estimated, with an RMST boundary of 3 years (36 months). In addition, the 
between-group difference in RMST and its 95% confidence interval will be calculated. 
• 
The number of subjects at risk at 3-month intervals, cumulative event-free rate, and median 
follow-up period (time to censoring) and their 95% confidence intervals will also be presented. 
Among the allocation adjustment factors, ECOG PS and presence/absence of measurable lesion 
will be analyzed using both data obtained at randomization and data entered in the CRF. 


TAS-118 Protocol: 
 
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• 
For each allocation adjustment factor, using a Cox proportional hazards model with study 
treatment alone as a covariate and a Cox proportional hazards model with the allocation 
adjustment factors that have not been used for subgrouping and study treatment as covariates, the 
hazard ratio between study treatments and its 95% confidence interval will be estimated. 
Furthermore, the distribution of survival time will be compared between the treatment arms by a 
log-rank test and a stratified log-rank test according to the allocation adjustment factors that have 
not been used for subgrouping. Among the allocation adjustment factors, ECOG PS and 
presence/absence of measurable lesion will be analyzed using both data obtained at randomization 
and data entered in the CRF. 
• 
For each baseline characteristic factor listed in Table 5-7 in Section “5.2.2 Patient Baseline 
Characteristics” and each allocation adjustment factor, the MST and its 95% confidence interval 
will be presented in each treatment arm, and the hazard ratio and its 95% confidence interval will 
be estimated by a Cox proportional hazards model. The covariate of the model will be study 
treatment only.The confidence interval of the hazard ratio between the treatment arms will be 
illustrated in a forest plot, and the p-value of interaction between treatment response and each 
baseline characteristic factor will be presented to check the uniformity among the strata.The 
following three covariates will be used to calculate the p-value of interaction in the Cox 
proportional hazards model: study treatment, baseline characteristic factor, and interaction 
between study treatment and baseline characteristic factors. 
• 
A breakdown of events and censoring will be tabulated in each treatment arm, and the same 
analysis will also be conducted by country. 
• 
If the assigned treatment differs from the actual treatment given to a subject, a stratified log-rank 
test will also be conducted by handling the actual treatment given to the subject as the treatment 
arm. 
 
 
 


TAS-118 Protocol: 
 
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7. Secondary Endpoint Analysis 
An overview of the main analyses of the secondary endpoints is presented below. 
To compare with data from literatures, a confidence coefficient of 95% will be used to present the 
confidence interval. 
7.1. Efficacy Analyses 
The following analyses will be conducted for the endpoints of antitumor activity in the tumor 
response-evaluable population and for PFS and TTF in the FAS population. For the selected endpoints, 
the same analyses will also be conducted by country. 
7.1.1. Antitumor Activity 
 Best Overall Response 
• 
The proportion of subjects with each best overall response will be calculated in each treatment 
arm. 
 ORR 
• 
The ORR and its 95% confidence interval will be estimated in each treatment arm. 
• 
The ORR will be compared between the treatment arms by Fisher’s exact test and Cochran–
Mantel–Haenszel test stratified by the allocation adjustment factors. For the allocation adjustment 
factors, data entered in the CRF will be used. 
• 
For each baseline characteristic factor listed in Table 5-7 in Section “5.2.2 Patient Baseline 
Characteristics,” the ORR and its 95% confidence interval will be estimated in each treatment 
arm. 
• 
The ORR analyses specified above will also be conducted by country. 
In the stratified Cochran–Mantel–Haenszel test, the allocation adjustment factors other than the 
country will be used as strata. 
 DCR 
• 
The DCR will be analyzed in each treatment arm in the same manner as specified in Section 
“7.1.1.2 ORR.” 
 Time to Response 
• 
Cycles in which overall response has first been determined to be CR or PR after the start of study 
treatment will be tabulated, and the summary statistics of the number of days to CR or PR will be 
presented in each treatment arm. 
 Duration of Overall Response 
• 
The following analyses will be conducted in subjects with the best overall response of CR or PR 
in the tumor response-evaluable population: 
• 
The survival curve of the duration of overall response, MST, and 95% confidence interval will be 
estimated in each treatment arm. 
In addition, the number of subjects at risk at 3-month intervals, cumulative event-free rate, and 
median follow-up period and their 95% confidence intervals will be presented, and the analyses 
specified above will also be conducted by country. 
Duration of complete response 
• 
In subjects with the best overall response of CR in the tumor response-evaluable population, the 
analyses specified in Section “7.1.1.5 Duration of Overall Response” will be conducted. 
7.1.2. PFS 
• 
Progression-free survival will be analyzed in the same manner as specified in Section “6. Primary 
Endpoint Analyses” (excluding the analyses of RMST and between-group difference in MST). In 


TAS-118 Protocol: 
 
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the analyses using the allocation adjustment factors, only data entered in the CRF will be used 
with a confidence level of 95% for all confidence intervals. 
• 
In the enrolled population, the same analyses will be conducted. 
7.1.3. TTF 
• 
Time to treatment failure will be analyzed in the same manner as specified in Section “6. Primary 
Endpoint Analyses” (excluding the analyses in the enrolled population and the analyses of RMST 
and between-group difference in MST). In the analyses using the allocation adjustment factors, 
only data entered in the CRF will be used with a confidence level of 95% for all confidence 
intervals. 
7.1.4. Tumor Shrinkage Rate 
• 
The distributions of maximum tumor shrinkage rate and tumor shrinkage rate at 6 and 12 weeks 
after entry will be illustrated in a waterfall plot in each treatment arm. 
• 
The summary statistics will be presented for the maximum tumor shrinkage rate, tumor shrinkage 
rates at 6 and 12 weeks after entry and at the last imaging assessment, and tumor shrinkage rate 
at the last imaging assessment in subjects who discontinued the study because of PD in each 
treatment arm. The maximum tumor shrinkage rate will be compared between the treatment arms 
by a Wilcoxon test. 
• 
The proportion of subjects with tumor shrinkage of ≥20% at 6 weeks after entry will be presented 
and compared between the treatment arms by Fisher’s exact test. 
7.2. Safety Analysis 
The following analyses will be conducted in the AT population. These analyses except listings will 
also be conducted by country. The listings will be provided in the enrolled population. 
7.2.1. Adverse Events and Adverse Drug Reactions 
• 
The number and proportion of subjects with adverse events and adverse drug reactions will be 
calculated by MedDRA SOC and PT and grade in each treatment arm. For grade 2 or higher 
events, grade 3 or higher events, and events with an incidence of ≥10% in either arm (an incidence 
of ≥5% for adverse drug reactions), the number and proportion of subjects will also be calculated 
by MedDRA SOC and PT and grade. 
• 
According to ECOG PS entered in the CRF and age (<75 years), the number and proportion of 
subjects with adverse events and adverse drug reactions will be calculated by MedDRA SOC and 
PT and grade in each treatment arm. 
• 
The number and proportion of subjects with adverse events leading to discontinuation (subjects 
with adverse events recorded in “Treatment Discontinuation” of the CRF) will be calculated by 
MedDRA SOC and PT in each treatment arm. 
• 
The number and proportion of subjects with adverse events leading to interruption of TAS-118 
or S-1 within a cycle will be tabulated by MedDRA PT in each treatment arm. 
• 
The number and proportion of subjects with adverse events leading to the interruption of L-OHP 
or CDDP will be tabulated by MedDRA SOC and PT in each treatment arm. 
• 
The number and proportion of subjects with adverse events leading to a skip of L-OHP or CDDP 
will be tabulated by MedDRA SOC and PT in each treatment arm. 
• 
The number and proportion of subjects with adverse events leading to dose reduction in TAS-118, 
S-1, L-OHP, or CDDP will be tabulated by MedDRA SOC and PT in each treatment arm. 
• 
The number and proportion of subjects with adverse events leading to prolongation of the TAS-
118 or S-1 recovery period will be tabulated by MedDRA SOC and PT in each treatment arm. 
• 
The number and proportion of subjects with serious adverse events will be tabulated by MedDRA 
SOC and PT in each treatment arm. Serious adverse drug reactions will also be analyzed in the 
same manner. 
• 
A list of adverse event type, grade, time of onset, causality, course, treatment, and other 
information will be created in the enrolled population. 
• 
For serious adverse events, a list of grade, outcome, date of outcome, seriousness, causality, and 
other information will be created in the enrolled population. 


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7.2.2. Deaths 
• 
In subjects in the enrolled population who died within 90 days after entry or before the end of the 
safety follow-up period, a list will be created for the reason for death, start date of treatment, end 
date of treatment, date of death, number of days from entry to death, number of days from 
treatment completion to death, and other information. 
7.3. Composition of Analysis Populations 
The following analyses will be conducted in all subjects. These analyses except listings will also be 
conducted by country. 
 
• 
The inclusion of subjects in each analysis population will be tabulated in each treatment arm. The 
reason for exclusion will also be tabulated. 
7.4. Deviation 
The following analyses will be conducted in the enrolled population. These analyses except listings 
will also be conducted by country. 
 
• 
The presence or absence and nature of deviation will be tabulated in each treatment arm. 
7.5. Analyses of Patient Baseline Characteristics 
The following analyses will be conducted in the AT and FAS populations. These analyses except 
listings will also be conducted by country. 
 
• 
For the baseline characteristic factors listed in Table 5-6 of Section “5.2.2 Patient Baseline 
Characteristics,” the number and proportion of subjects and summary statistics will be presented 
in each treatment arm. 
7.6. Compliance Analyses 
The following analyses will be conducted in the AT and FAS populations. These analyses except 
listings will also be conducted by country. 
7.6.1. Dose Intensity 
• 
The summary statistics of actual dose intensity and relative dose intensity and the number and 
proportion of subjects with each category of relative dose intensity (<80%, ≥80% to <90%, ≥90%) 
will be presented in each treatment arm. 
7.6.2. Compliance 
• 
The number and proportion of subjects with dose reduction, interruption, skip (only for L-OHP 
and CDDP), and prolongation of the recovery period (only for TAS-118 and S-1) will be 
calculated in each treatment arm. These analyses will be conducted for each cycle and for the 
overall cycles. 
7.6.3. Discontinuation 
• 
The presence or absence of study discontinuation and the reason for discontinuation will be 
tabulated in each treatment arm. 
• 
A list of adverse events leading to discontinuation will be created in the enrolled population. 
7.6.4. Cumulative Dose/Duration of Treatment 
• 
The summary statistics of the total duration of treatment and cumulative dose will be presented 
by treatment arm and study drug. The total duration of TAS-118 and S-1 treatment will be 
calculated by dividing the sum of the number of doses by 2; the total duration of L-OHP and 
CDDP treatment will be the sum of the number of doses. 


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7.6.5. Treatment Completion 
• 
The number of subjects who completed the treatment in each cycle will be tabulated by treatment 
arm. Subjects who received doses of each drug that are not less than the doses specified below in 
one cycle are regarded as those who completed the treatment and otherwise as those who did not 
complete the treatment. The doses required for completion are presented in Table 7-1. 
Table 7-1 Doses required for completion 
TAS-118 
14 packages 
S-1 
84 capsules (at a dose of 40  or 50 mg at 
the start of cycle) 
126 capsules (at a dose of 60 mg at the 
start of cycle) 
L-OHP and CDDP 
1 dose 
7.6.6. Treatment Cycle 
• 
The summary statistics of the number of subjects in each cycle and the last cycle number in each 
subject will be presented by treatment arm. 
7.6.7. Proportion of Outpatient Visits 
• 
The summary statistics of the proportion of outpatient visits will be presented by treatment arm. 
The proportion of outpatient visits will be calculated as follows. In this calculation, the cutoff date 
is defined as the data cutoff date recorded in the data cutoff date decision record. The definition 
of hospitalization and the last dose is presented in Table. 7-2. 
Proportion of outpatient visits: 100% −
Duration of hospitalization
Duration of treatment
× 100 
Duration of hospitalization: End date of hospitalization – Start date of hospitalization + 1 
(If a subject experienced more than one hospitalization, add up the durations of hospitalization) 
Duration of treatment: Date of the last treatment – Start date of Cycle 1 treatment + 1 
 
Table 7-2 Definition of hospitalization and last treatment 
Start date of 
hospitalization 
If a subject is hospitalized before the start date of Cycle 1 treatment, the duration is 
defined as the time from the start date of Cycle 1 treatment. 
End date of 
hospitalization 
In a subject who discontinued the treatment and is still hospitalized after the date of the 
last treatment, the date of the last treatment is defined as the end date of hospitalization. 
In a subject who continues to receive the study drug as of the data cutoff date, the data 
cutoff date is defined as the end date of hospitalization. 
Date of the last 
treatment 
In a subject who continues to receive the study drug as of the data cutoff date, the data 
cutoff date is defined as the date of the last treatment. 
7.7. Concomitant Medications 
• 
The use of concomitant medications will be tabulated by Generic Medication Name of WHO 
Drug Dictionary in each treatment arm. 
 
 


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7.8. Subsequent Therapy 
• 
The number and proportion of subjects who used subsequent therapies listed in Table 7-3 will be 
tabulated in each treatment arm. This analysis will also be conducted by country. 
Table 7-3 Subsequent therapy 
Category 
Details 
Subsequent therapy 
No, yes 
Type of subsequent therapy 
Chemotherapy, chemoradiotherapy, radiotherapy, immune/hormonal 
therapy, surgery, other 
Detail of chemotherapy 
Paclitaxel, Abraxane, docetaxel, irinotecan, S-1, capecitabine, 5-FU, 
UFT, oxaliplatin, cisplatin, leucovorin, trastuzumab, ramucirumab, 
nivolumab, other 
Intent of surgery 
Palliative, curative 
7.9. Laboratory Values 
The following analyses will be conducted in the AT population. These analyses except listings will 
also be conducted by country. The listings will be based on the enrolled population. 
 
• 
The change in laboratory values over time from the start of each cycle in each subject will be 
graphed by treatment arm. 
Laboratory values to be evaluated are hemoglobin, white blood cell count, neutrophil count, 
lymphocyte count, and platelet count. 
• 
The minimum level of laboratory tests at predose and at each cycle in each subject will be 
identified by treatment arm, the summary statistics will be presented, and the levels will be 
summarized by grade. 
Laboratory tests to be evaluated are hemoglobin, white blood cell count, neutrophil count, 
lymphocyte count, platelet count, albumin, Na, K, and corrected Ca. 
• 
The maximum level of laboratory tests at predose and at each cycle in each subject will be 
identified by treatment arm, the summary statistics will be presented, and the levels will be 
summarized by grade. 
Laboratory tests to be evaluated are AST, ALT, ALP, bilirubin, creatinine, Na, K, and corrected 
Ca. 
• 
The worst level of urine protein at predose and at each cycle in each subject will be identified by 
treatment arm and summarized by category. 
• 
The minimum level of laboratory tests throughout the study period in each subject will be 
identified by treatment arm, and the summary statistics will be presented for predose level, 
minimum level, the number of days to the minimum level, and cycle with the minimum level. 
Laboratory tests to be evaluated are hemoglobin, white blood cell count, neutrophil count, and 
platelet count. 
• 
The summary statistics will be presented for the minimum level of laboratory tests in subjects 
with grade 3 or higher reduction, the number of days from the start date of onset cycle to the 
minimum level, and the number of days required for recovery to grade 2 or less from the minimum 
level within an onset cycle in each treatment arm. 
Laboratory tests to be evaluated are hemoglobin, white blood cell count, neutrophil count, and 
platelet count. 
If grade 3 or higher reduction is observed in more than one cycle in the same subject, both 
decreased levels will be used for calculating the summary statistics. 
 
Subjects who meet any of the following criteria will be regarded as those who are not recovered: 
1. After grade 3 or higher reduction, grade 2 or less is not measured within the same cycle. 
2. Measurement date of grade 2 or less reduction in laboratory values – date of the last study 
treatment ≥ 30 days 
When the start date of subsequent therapy ≤ date of the last study treatment + 30 days is met, the 
following criterion will be used: 
Measurement date of grade 2 or less reduction in laboratory values ≥ start date of subsequent 
therapy 


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• 
After “grade 3 or higher reduction” is replaced with “grade 2 or higher reduction” and “recovery 
to grade 2 or less” is replaced with “recovery to grade 1 or less,” the same analyses as specified 
above will be conducted. 
7.10. Clinical Findings 
The following analyses will be conducted in the AT population. These analyses except listings will 
also be conducted by country. The listings will be based on the enrolled population. 
 
• 
The summary statistics will be presented for the number of days from the start of Cycle 1 
treatment to the first onset of clinical findings of grade 1 or higher, the number of days to the 
worst grade, the number of days from the first onset to the outcome of recovery, and the number 
of days from clinical findings of grade 3 or higher to recovery to grade 2 or less in each treatment 
arm. 
Clinical findings to be evaluated are stomatitis, anorexia, diarrhea, peripheral sensory neuropathy, 
nausea, and fatigue. 
• 
A list will be created for the time of onset of the clinical findings to be analyzed in each subject, 
the time of worst grade, the time of grade 3 or higher, and the time required for recovery in each 
treatment arm. 
7.11. Tumor Markers 
The following analyses will be conducted in the AT population. These analyses except listings will 
also be conducted by country. The listings will be based on the enrolled population. 
 
• 
The change in tumor markers over time will be graphed in each treatment arm. 
7.12. Vital Signs and ECOG PS 
The following analyses will be conducted in the AT population. These analyses except listings will 
also be conducted by country. The listings will be based on the enrolled population. 
 
• 
The summary statistics of measured weight and change from baseline at the time of 
discontinuation will be presented in each treatment arm. 
• 
A cross table of ECOG PS will be created at baseline and discontinuation in each treatment arm. 
8. Review and Revision of Statistical Analysis Plan 
This statistical analysis plan will be finalized as version 1 before the receipt of CRF data or a true 
allocation key used to create the results of statistical analysis. If a change or addition is required after 
the finalization of version 1, a revised version will be prepared after the background, and the reason for 
changes are clarified. Newly planned analyses will be separated from the preplanned analyses and 
included in the change record. 
9. Development of Output Plan 
This statistical analysis plan provides the representative analyses only. All analyses to be conducted 
are presented in a separate output plan. 
10. References 
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evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45:228-247. 
2) 
 


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3) 
4) 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). 
5) Lan KKG, DeMets DL. Discrete Sequential Boundaries for Clinical Trials. Biometrika. 
1983;70:659-663. 
6) Schoenfeld D. The asymptotic properties of nonparametric tests for comparing survival 
distributions. Biometrika. 1981;68:316-319. 
7) Shuster JJ. Power and Sample Size for Phase III Clinical Trials of Survival. In: Crowley J, 
Pauler Ankerst D, editors. Handbook of Statistics in Clinical Oncology. 2nd ed. Boca Raton: 
Chapman & Hall/CRC. 2006;289-333. 
8) Clopper CJ, Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the Case of 
the Binomial. Biometrika. 1934;26:404-413. 
9) Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. Biometrics. 
1982;38:29-41. 
10) Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. 2nd ed. New York: 
Wiley. 2002;99-104. 
11) Takahari D, Boku N, Mizusawa J, Takashima A, Yamada Y, Yoshino T, et al. Determination of 
prognostic factors in Japanese patients with advanced gastric cancer using the data from a 
randomized controlled trial. Oncologist. 2014;19:358-366. 
12) Summary measures to evaluate time-to-event responses—To understand restricted mean 
survival time (RMST)— (in Japanese). Available from: 
http://www.jpma.or.jp/medicine/shinyaku/tiken/allotment/pdf/rmst.pdf.