Conditions: Gastric Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 530
Healthy volunteers: no

Brief summary:
Primary Objective:

\- To compare the 3-year progression free survival (PFS) in the two treatment arms.

Secondary Objectives:

* Overall survival (OS).
* Postoperative pathological stage and R0 (complete) resection rate.
* Safety: Toxicities associated with neoadjuvant chemotherapy, surgery, morbidity/mortality, toxicity of adjuvant chemotherapy.

Detailed description:
Participants in the neoadjuvant chemotherapy arm were treated for 3 cycles (1 cycle is 21 days) before surgery and treated for a year with S-1. Participants in the adjuvant chemotherapy arm underwent surgery and were treated for a year with S-1. All participants were followed during and after the study treatment until death or disease progression, whichever comes first.

Arms:
arm 1: Participants underwent surgery within 2 weeks after randomization followed by adjuvant chemotherapy with S-1 \[(Gimeracil) + Oxo (Oteracil)\] 40 milligrams per square meter (mg/m\^2) administered orally twice daily, from Day 1 to 28 of each cycle for 1 year, and were followed-up after End-of-Treatment (EOT) until disease progression or death or study cut-off date, whichever comes first (maximum duration: up to 10 years). arm 2: Participants received neo-adjuvant chemotherapy with Docetaxel 50 mg/m\^2 intravenously (IV) for greater than or equal to (\>=)1 hour (hr) on Day 1 of each treatment cycle plus Oxaliplatin 100 mg/m\^2 IV for \>=2 hr on Day 1 of each treatment cycle plus S-1 \[(Gimeracil) + Oxo (Oteracil)\] 40 mg/m\^2 administered orally twice daily from Day 1 to 14, of each treatment cycle followed by surgery approximately 1-3 weeks after completion of neo-adjuvant chemotherapy and adjuvant chemotherapy with S-1 \[(Gimeracil) + Oxo (Oteracil)\] 40 mg/m\^2 administered orally twice daily, from Day 1 to 28 of each cycle for 1 year, and were followed-up after EOT until disease progression or death or study cut-off date, whichever comes first (maximum duration: up to 10 years).

Interventions: intervention 1: Docetaxel (XRP6976) intervention 2: Oxaliplatin (SR96669) intervention 3: S-1 (1-(2-tetrahydrofuryl)-5-fluorouracil + 5-chloro-2, 4-dihydroxypyridine (CDHP) (Gimeracil) + Oxo (Oteracil)
Intervention descriptions: intervention 1: Pharmaceutical form:solution for infusion Route of administration: intravenous intervention 2: Pharmaceutical form:solution for infusion Route of administration: intravenous intervention 3: Pharmaceutical form:Tablet Route of administration: Oral

Protocol document:
Prot_002.pdf: 


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Name and address 
 
Coordinating investigator  
 
 
Study Manager  
 


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Study monitors  
 
 
Sanofi 
235 Banpodae-ro, Seocho-gu, Seoul 
Tel: 
 
Fax
 
 
 
 
 
 
 
Sponsor of the study 
 
 
 
Sanofi  
235 Banpodae-ro, Seocho-gu, Seoul, Korea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Information Manager  
 
 
Email: 
 
Fax: 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
1. 
CLINICAL TRIAL OUTLINE ............................................................................... 8 
2. 
FLOW CHART ....................................................................................................... 15 
2.1 
Study Design ............................................................................................................. 15 
2.2 
Study flow chart ........................................................................................................ 16 
3. 
ABBREVIATIONS ................................................................................................. 18 
4. 
INTRODUCTION AND THEORETICAL BACKGROUND ........................... 19 
5. 
STUDY OBJECTIVES .......................................................................................... 28 
5.1 
Primary objective ...................................................................................................... 28 
5.2 
Secondary objectives ................................................................................................ 28 
6. 
STUDY DESIGN .................................................................................................... 28 
6.1 
Description of protocol ............................................................................................. 28 
6.2 
Study period .............................................................................................................. 29 
6.3 
Steering Committee .................................................................................................. 30 
6.4 
Independent Data Monitoring Committee ................................................................ 30 
7. 
SUBJECT SCREENING ....................................................................................... 30 
7.1 
Prearranged sample size ........................................................................................... 30 
7.2 
Inclusion criteria ....................................................................................................... 30 
7.3 
Exclusion criteria ...................................................................................................... 31 
8 
STUDY PROCEDURE .......................................................................................... 32 
8.1 
Baseline .................................................................................................................... 32 
8.2 
Randomization .......................................................................................................... 34 
8.2.1 
Assignment of subjects to treatment groups ............................................................. 34 
8.3 
Treatment period ....................................................................................................... 34 
8.3.1 
Neo-adjuvant chemotherapy ..................................................................................... 34 
8.3.2 
Surgery ...................................................................................................................... 35 
8.3.3 
Adjuvant chemotherapy; S-1 .................................................................................... 36 
8.4 
End-of-Treatment (EOT) .......................................................................................... 37 
8.5 
Follow-up period after End-of-Treatment (EOT) ..................................................... 37 
8.6 
End of Study ............................................................................................................. 38 
8.7 
Progression of disease .............................................................................................. 38 
8.8 
Treatment after the last administration of study drugs ............................................. 38 
9 
Administration of the investigational product .......................................................... 39 
9.1 
Name and formulation .............................................................................................. 39 
9.2 
Preparation and administration ................................................................................. 39 
9.2.1 
Docetaxel .................................................................................................................. 39 


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9.2.2 
Oxaliplatin ................................................................................................................ 41 
9.2.3 
S-1 ............................................................................................................................. 42 
9.3 
Administration schedule ........................................................................................... 43 
9.3.1 
Neo-adjuvant chemotherapy (Neo DOS) - CSC Arm .............................................. 43 
9.3.2 
Adjuvant chemotherapy S-1 ..................................................................................... 44 
9.3.3 
Dose adjustment ....................................................................................................... 45 
9.4 
Storage ...................................................................................................................... 46 
9.5 
Handling and Disposal .............................................................................................. 47 
9.6 
Potential recall .......................................................................................................... 47 
9.7 
Combination therapy ................................................................................................ 48 
9.8 
Investigational product accountability management and compliance ...................... 49 
10 
SAFETY OF SUBJECTS ....................................................................................... 49 
10.1 
Safety endpoints ....................................................................................................... 49 
10.2 
Safety guidelines ....................................................................................................... 50 
10.2.1 
Physical examination ................................................................................................ 50 
10.2.2 
Clinical laboratory variables ..................................................................................... 50 
10.3 
Monitoring of adverse events ................................................................................... 50 
10.4 
Definition of adverse event (AE) and serious adverse event (SAE) ........................ 51 
10.5 
Investigator’s responsibility on safety report ........................................................... 51 
10.5.1 
Adverse event (AE) .................................................................................................. 51 
10.5.2 
Serious adverse event (SAE) .................................................................................... 52 
10.5.3 
Follow-up .................................................................................................................. 52 
10.6 
Pregnancy ................................................................................................................. 53 
10.7 
Overdose ................................................................................................................... 53 
10.8 
Responsibility of sponsor ......................................................................................... 54 
11 
TEMPORARY OR PERMANENT DISCONTINUATION OF TREATMENT AND 
MANAGEMENT OF THE DISCONTINUATION ............................................................ 54 
11.1 Permanent discontinuation of treatment with study drug ................................................. 54 
11.1.1 Criteria for permanent discontinuation of treatment ..................................................... 54 
11.1.2 Subject managemnet after permanent discontinuation of treatment ............................. 55 
Subject management ................................................................................................................. 55 
11.3 Results .............................................................................................................................. 56 
11.4 Definition of source data .................................................................................................. 56 
12 
STATISTICAL CONSIDERATIONS .................................................................. 56 
12.1 Statistical and analysis plan .............................................................................................. 56 
12.2 Sample size ....................................................................................................................... 56 
12.3 Analysis variables ............................................................................................................. 57 
12.3.1 Demographic and baseline characteristics ..................................................................... 57 
12.3.2 Efficacy variables .......................................................................................................... 57 
12.3.2.1 Primary efficacy variable: .......................................................................................... 57 
12.3.2.2 Secondary efficacy variables ...................................................................................... 58 
12.3.3 Safety variables .............................................................................................................. 58 
12.3.3.1 Adverse events ............................................................................................................ 58 


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12.3.3.2 Laboratory safety variables ........................................................................................ 59 
12.3.3.3 Blood pressure ............................................................................................................ 59 
12.3.3.4 Other safety variables ................................................................................................. 59 
12.4 Analysis sets ..................................................................................................................... 59 
12.4.1 Efficacy set .................................................................................................................... 59 
12.4.2 Safety analysis set .......................................................................................................... 60 
12.4.3 Characteristics of subjects ............................................................................................. 60 
12.5 Statistical method ............................................................................................................. 60 
12.5.1 Demographic and baseline characteristics ..................................................................... 60 
12.5.2 Level of treatment exposure and drug compliance ........................................................ 60 
12.5.3 Analysis of efficacy variables ........................................................................................ 61 
12.5.3.1 Analysis of the primary efficacy variable ................................................................... 61 
12.5.3.2 Analysis of secondary efficacy variables ................................................................... 61 
12.5.3.3 Analysis of additional efficacy variables .................................................................... 62 
12.5.4 Analysis of safety data ................................................................................................... 62 
12.5.4.1 Analysis of adverse events ......................................................................................... 62 
12.5.4.2 Analysis of laboratory variables ................................................................................. 63 
12.5.4.3 Analysis of blood pressure variables .......................................................................... 63 
12.5.4.4 Analysis of other safety variables ............................................................................... 63 
12.5.5 Analysis of pharmacokinetic and pharmacodynamic variables .................................... 63 
12.5.6 Analysis of health economic variables .......................................................................... 63 
12.6 Interim analysis ................................................................................................................. 64 
13 
ETHICS AND REGULATIONS ........................................................................... 64 
13.1 Ethical principles .............................................................................................................. 64 
13.2 Laws and regulations ........................................................................................................ 64 
13.3  
Informed consent ...................................................................................................... 64 
13.4 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) .................. 65 
14 
MONITORING ....................................................................................................... 65 
14.1 
Responsibilities of investigator(s) ............................................................................ 65 
14.2 
Responsibilities of sponsor ....................................................................................... 66 
14.3 
Source document requirements ................................................................................ 66 
14.4 
Preparation of case report form and other requests .................................................. 66 
14.5 
Use of computer system ........................................................................................... 67 
15 
ADMINISTRATIVE REGULATIONS ................................................................ 67 
15.1 
Curriculum Vitae ...................................................................................................... 67 
15.2 
Record retention in study site(s) ............................................................................... 67 
16 
CONFIDENTIALITY ............................................................................................ 67 
17 
PROPERTY RIGHTS ............................................................................................ 68 
18 
DATA PROTECTION ........................................................................................... 68 


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19 
COMPENSATION INSURANCE ........................................................................ 68 
20 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 69 
21 
EARLY DISCONTINUATION OF THE STUDY OR EARLY TERMINATION OF 
A SITE 69 
22 
RESULTS ................................................................................................................ 70 
23 
PUBLICATION AND RELEASE ......................................................................... 70 
24 
REVISION OF THE PROTOCOL ....................................................................... 70 
25 
REFERENCES ....................................................................................................... 72 
26 
APPENDICES ......................................................................................................... 77 
26.1 
Creatinine Clearance Calculation Method ................................................................ 78 
26.2 
ECOG Performance Status ....................................................................................... 79 
26.3 
Surgical Manual (v3.0_20120206) ........................................................................... 80 
26.4 
Participating Sites and Investigators ......................................................................... 86 
26.5 
AJCC TNM Classification (7th Edition) ................................................................... 87 


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1. CLINICAL TRIAL OUTLINE 
Drug substances: Docetaxel, Oxaliplatin, S-1 (Tegafur, Gimeracil, Oteracil) 
Clinical trial number: EFC13833 
Title 
 
A Phase III, Open-labelled, Randomised Study of Neoadjuvant Docetaxel+Oxaliplatin+S-1 (DOS) + 
Surgery + Adjuvant S-1 Versus Surgery + Adjuvant S-1 in Patients With Resectable Advanced Gastric 
Cancer 
Study 
objectives 
Primary objective:  
 
To compare the 3-year Progression-Free Survival (PFS) between two groups  
 
Secondary objectives:  
To assess and compare the followings between two groups: 
 
Overall survival (OS)  
 
Post-operative pathological stage 
 
R0 (complete) resection rate 
 
Safety assessment  
Study 
design 
A multicenter, open-label, randomized (1:1), phase 3 clinical study  
Study 
population
Key 
inclusion 
criteria: 
 
 
 
 
 
Key 
exclusion 
criteria: 
 
Inclusion criteria: 
1. Patients who provide voluntary written consent using the Informed Consent 
Form before participating in this study 
2. Patients with new histologically confirmed primary gastric or gastroesophageal 
junction adenocarcinoma amenable to curative resection 
3. Patients with TNM Stage T2,3/N (+) or any T4/N stage (according to the AJCC 
7th Edition) (lymph node positive: irrespective of the lymph node shape, if the 
short axis is ≥8 mm, it is defined as lymph node metastasis positive) 
 
Exclusion criteria: 
 
 
Methods 
1. 
Patients aged less than 20 years or over 76 years old (inclusive) 
2. 
Patients with the Eastern Cooperative Oncology Group (ECOG) Performance 
Status ≥2 
3. 
Patients with the past medical history of gastric cancer (gastroesophageal 
junction included) (including all of the following cases) 
- 
Patients who had surgery for gastric cancer (gastroesophageal junction included)
- 
Patients who received adjuvant chemotherapy, or pre-operative chemotherapy 
and/or radiotherapy and/or immunotherapy for treatment of gastric cancer 
(gastroesophageal junction included) 
4. 
Patients with the past medical history of other malignancy  
However, patients with the followings can be included in this study 
- 
Adequately treated basal cell or squamous cell carcinoma, in situ cervical 
carcinoma  
- 
Other cancer that exceeded 5 years after completion of chemotherapy and 
remained disease-free for 5 years or more  
5. 
Patients with a distant metastasis (M1) including a distant lymph node (retro-
pancreatic, para-aortic, peri-portal, retro-peritoneal, mesenteric lymph nodes) of 
gastric or gastroesophageal junction adenocarcinoma


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6. 
Patients who cannot undergo curative resection at the discretion of a surgeon  
- 
Patients with T4b with completely resectable involvement of the surrounding 
organ with no distant metastasis can be enrolled 
7. 
Patients who participated in another study or administered another 
investigational product within 30 days prior to signing the Informed Consent 
Form  
8. 
Patients who had any of the followings within 6 months prior to signing the 
Informed Consent Form: myocardial infarction, severe/unstable angina, 
coronary/peripheral artery bypass surgery, NYHA Class III or IV congestive 
heart failure, stroke or transient ischemic attack 
9. 
Patients who had deep vein thrombosis within 4 weeks prior to signing the 
Informed Consent Form  
10. Patients with the previous medical history of uncontrolled seizure, CNS or 
psychological disorder which is so clinically significant that it is impossible to 
obtain the Informed Consent Form or the severity may interfere with oral 
administration of medication 
11. Patients with uncontrolled active infection or sepsis, previously known acquired 
immune deficiency syndrome (AIDS), human immunodeficiency virus (HIV) 
infection, previously known active hepatitis B or C  
 
12. Patients with severe acute or chronic disease that may limit the ability to 
participate in the study or make it difficult to interpret results of the study  
13. Patients who have not fully recovered from other procedure  
14. Patients who may experience a problem with absorption after oral 
administration of the investigational product, as follows: 
- Patients with intolerability with oral administration, malabsorption, or absorption 
disorder 
- Patients who have not recovered from the lack of physical completeness of the 
upper gastrointestinal tract 
- Ileus 
- Chronic inflammatory bowel disease 
- Extensive small bowel resection and other diseases that limit drug absorption 
(example: gastric dumping syndrome, rapid intestinal transit, malabsorption after 
bowel surgery) 
15.  In case of female subjects of childbearing potential or male subjects with a 
female partner of childbearing potential, patients who do not consent to use of 
generally accepted effective contraception during the investigational product 
administration period or for at least 6 months after completion of the 
investigational product administration 
16. Breastfeeding or pregnant women. Women of childbearing potential with a 
positive pregnancy test 
 
 
 
Investigational product administration 
17. Inadequate bone marrow and organ function prior to administration of the investigational 
product: 
I. 
Absolute neutrophil count <1.5 x 109/L 
II. Platelet <100 x 109/L 
III. Hemoglobin ≤ 9 g/dL 
IV. AST >2.5 x ULN, ALT >2.5 x ULN 
V. ALP >2.5 x ULN  
VI. Total bilirubin >1.5 x ULN 
VII. Serum creatinine >1.5 x ULN 
Creatinine clearance is calculated by using the Cockcroft-Gault formula with 24 hr urine 
collection; patients with creatinine clearance <60 mL/min will be excluded.






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and surgical history, concomitant medication/treatment check, demographic data review, chest X-ray, 
abdominal-pelvic CT for clinical staging of advanced gastric cancer, and other tests to rule out M1 
should be conducted. 
 
Gastroduodenoscopy and histology findings for confirmation of advanced gastric adenocarcinoma 
within 3 months prior to randomization should be checked.  
 
Neo-adjuvant chemotherapy: DOS + surgery + S-1 treatment group only 
Within 7 days prior to start of each 3-week chemotherapy cycle, clinical examination (physical 
examination, blood pressure, body weight, ECOG PS) and clinical laboratory tests should be conducted. 
Radiological tests for tumor assessment (abdominal-pelvic CT and additional test at the discretion of the 
investigator) are conducted within 5 days of Cycle 2 initiation and after Cycle 3 completion, before 
surgery.  
 
Surgery:  
Within 14 days before surgery, clinical examination (physical examination, blood pressure, body weight, 
ECOG PS), clinical laboratory tests, 12-lead ECG, and chest X-ray should be conducted. Pathological 
stage and R0 resection should be confirmed after surgery. 
 
Adjuvant chemotherapy: 
Within 7 days prior to start of each 6-week chemotherapy cycle, clinical examination (physical 
examination, blood pressure, body weight, ECOG PS), clinical laboratory tests, and chest X-ray should 
be conducted. Total 8 cycles of treatment will be implemented for about 1 year. 
 
Adverse events should be continuously monitored from the time the subject signs the Informed Consent 
Form for this study, during the study treatment phase, and until 30 days after the last dose of the 
investigational product according to the NCI CTCAE v4.03. For details of assessment, see Study flow 
chart.  
 
Follow-up after the End-of-Treatment (EOT): 
Follow-up is conducted every 3 months for the first year after the End-of-Treatment (EOT), and 
subsequently, every 6 months up to 5 years after enrollment. Clinical examination (physical 
examination, blood pressure, ECOG PS) and survival status should be checked. As tumor assessment, 
physical examination, abdominal-pelvic CT, and gastroduodenoscopy will be conducted; abdominal-
pelvic CT will be conducted every 6 months (±2 weeks) and gastroduodenoscopy will be performed 
every 12 months (±2 weeks) from the date of surgery. In case of suspected disease progression at the 
discretion of the investigator, tests for tumor assessment can be immediately performed irrespective of 
the relevant schedule, and clinically necessary tests other than tumor assessment can be conducted. In 
case of following survival/death status only, follow the survival status with in-person visits or phone 
calls every 6 months. Subjects who have ended the study (End of Study) in a survival state can be 
further followed up for survival status by visits or phone calls, and the additionally collected information 
can be used only for exploratory evaluation. However, the entire follow-up shall end at the end of the 
study for subjects under follow-up (expected to be 5 years after the enrollment of the last subject). 
Statistical 
considerati
ons 
 
Analysis sets: 
Intent-to-treat (ITT) Set includes all randomized subjects. 
Full Analysis Set (FAS) is defined as all randomized subjects who satisfied the inclusion/exclusion 
criteria and had at least one tumor assessment after the Baseline visit. While the CSC (Chemotherapy + 
Surgery + Chemotherapy) Arm includes subjects who administered at least one dose of the DOS 
investigational products, the SC (Surgery + Chemotherapy) Arm will include subjects who had 
surgery. 
Per-Protocol (PP) Set includes all randomized subjects who have no major protocol deviation and satisfy 


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the following conditions. 
1) For the neo-adjuvant chemotherapy + surgery + adjuvant chemotherapy S-1 (CSC Arm), subjects 
who completed the entire total 3 cycles of DOS administration as neo-adjuvant chemotherapy, had 
surgery, and then started adjuvant chemotherapy (S-1) according to this protocol 
2) For the surgery + adjuvant chemotherapy (SC Arm), subjects who had surgery and then started 
adjuvant chemotherapy (S-1) according to this protocol 
Note: Subjects who intended to receive postoperative S-1 adjuvant chemotherapy but did not start it 
at the discretion of the investigator based on consideration of the patient’s medical condition such as 
toxicity will be included in the PP Set. Serious protocol deviations will be specified in the Statistical 
Analysis Plan (SAP). 
Main analysis will be conducted in the FAS and all efficacy analyses will be also conducted using the 
ITT Set and the PP Set to confirm robustness of this study. 
Safety Analysis Set includes subjects who administered at least one dose of the investigational product. 
Medication compliance/administration and all clinical safety data will be summarized using the Safety 
analysis set. All analyses using this population will be based on the actually administered drug. 
 
Efficacy analysis: 
The primary endpoint, 3-year Progression-Free Survival is compared between two treatment groups 
using a log rank test stratified by stratification factors (site, TNM stage (T2/N+, T3-4/N+, T4/N-) 
specified at randomization at the overall 5% significance level. Survival curve is estimated using the 
Kaplan-Meier estimate. Median and the corresponding 95% confidence interval, and the 3-year 
Progression-Free Survival will be presented by treatment group. 
Overall survival, a secondary endpoint, is analyzed in the same way as for PFS. For the postoperative 
stage and the R0 resection rate, frequency and percentage will be presented, and compared using a 
Cochran-Mantel-Haenszel test stratified by stratification factors (site, TNM stage (T2/N+, T3-4/N+, 
T4/N-) according to the AJCC 7th edition) specified at randomization. If the postoperative stage and the 
R0 resection rate are missing, the analysis is performed based on the Efficacy Set, and subjects with 
missing data will be excluded from the denominator when calculating the percentage. 
 
Safety analysis:  
For analysis of safety data, adverse events, hematological toxicity, routine physical examination, and 
laboratory data will be described and analyzed using the Safety analysis set defined in Section 12.4.2. 
Safety data will be also summarized by cycle (if applicable). For each safety variable, Baseline will be 
defined as the last level or assessment measured prior to the first treatment in the study. 
 
Interim analysis and final analysis: 
The interim analysis will be conducted upon occurrence of at least 122 PFS events (50% information 
rate). The efficacy boundaries will use the O’Brien-Fleming method, and the significance level to 
consider study completion based on the difference in efficacy at interim analysis will be 0.0031. If a 
statistically significant difference is observed between two groups at interim analysis, the study may be 
discontinued; otherwise, the study will continue until the final completion. 
 
Interim analysis will be conducted under supervision of the Independent Data Monitoring Committee 
(IDMC). 
 
The final analysis will be conducted once 244 PFS events occur or median follow-up reaches a 
minimum of 3 years, and the significance level to demonstrate superiority of the CSC Arm at final 
analysis is 0.0490.  


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OS will be compared between two groups in the same way as PFS.  
 
For the postoperative pathological stage and the R0 resection rate, frequency and percentage will be 
presented, and comparatively analyzed by using the Cochran-Mantel-Haenszel test stratified by the 
specified stratification factors (site, stage (T2/N+, T3-4/N+, T4/N-) at randomization. 
 
For all statistical tests, a two-sided significance level of 5% will be used. 
 
 
 
Sample size determination: 
Based on the assumption of the 3-year Progression-Free Survival (PFS) of 70% in the CSC Arm and 
60% in the SC Arm (i.e. HR=0.698), a total of 244 events and at least 238 subjects per group are 
required for comparison of PFS distribution between two groups with the 80% power. Given the dropout 
rate of 10%, a total of 530 subjects are required. This calculation was carried out by considering one 
interim analysis, using the group sequential approach with efficacy boundaries suggested by the 
O’Brien-Fleming alpha spending function.  
 
To compare the Progression-Free Survival (PFS) distribution between two groups, a two-sided 5% 
significance level and up to 7.5 years of follow-up were assumed, including 4.5 years of enrollment 
period.  
 
Therefore, in case superiority is not demonstrated at interim analysis, the database will be closed when 
the total number of events reaches a minimum of 244 or median follow-up reaches a minimum of 3 
years. 
Study 
period 
 
All subjects will be followed after EOT (End-of-Treatment) until death or study closing date, whichever 
is earlier. In case only survival/death status is followed, confirmation of disease progression, initiation of 
new anticancer treatment, and subject’s consent withdrawal on follow-up are included.  
 
The maximum study period and the final follow-up completion date for survival will be completed when 
a minimum of 244 recurrence or death occurs or the median follow-up reaches a minimum of 3 years. 
The duration of the study for a survival follow-up will be up to 5 years from randomization. However, 
subjects who have ended the study (End of Study) in a survival state can be further followed up for 
survival status by visits or phone calls. 






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Footnote for the study flow chart  
 
(a) Neo-adjuvant chemotherapy is administered to the CSC Arm only, and consists of the followings. For toxicity, it can be delayed for up to 3 weeks.  
 
Docetaxel 50 mg/m2 intravenous injection, Day 1 of each cycle 
 
Oxaliplatin 100 mg/m2 intravenous injection, Day 1 of each cycle 
 
S-1 40 mg/m2 oral, twice daily, Day 1-14 of each cycle 
(b) Surgery is scheduled 1~3 weeks after completion of neo-adjuvant chemotherapy for subjects in the CSC Arm, and within 2 weeks after randomization for subjects in the SC Arm. 
(c) Adjuvant chemotherapy starts within 3~6 weeks after surgery; S-1 40 mg/m2 is orally administered twice daily, Day 1~28 of each cycle. For toxicity, each cycle can be delayed for up to 3 
weeks. The actual dose follows the dose per BSA in the dose table in 9.2.2.3.  
(d) Within 7 days of randomization, neo-adjuvant chemotherapy Cycle 1 is initiated.  
(e) Clinical examination: Physical examination, blood pressure, height (at Baseline only), body weight (including body surface area calculation), ECOG PS 
(f) Clinical laboratory tests: To be conducted prior to initiation of treatment in each cycle 
Hematology: Hemoglobin, WBC, ANC, Platelet count.  
Blood chemistry: Sodium, Potassium, Calcium, BUN, Creatinine, Creatinine clearance, Total protein, Albumin, SGOT (AST), SGPT (ALT), Total bilirubin, Alkaline phosphatase, 
Glucose 
* Baseline test addition: Hematocrit, RBC, PMN, LYM, PT (INR), aPTT (sec),  
** Pre-operative test addition: Hematocrit, RBC, PMN, LYM, PT (INR), aPTT (sec)  
(g) Pregnancy test: Menopause is defined as maintenance of the menopausal condition for 1 year since the last menstruation.  
(h) Adverse events: Safety observation is recorded from the patient’s signature of the Informed Consent Form until 30 days (+1 week) after the last dose of the investigational product. During 
follow-up, all adverse events that occurred previously and are ongoing, and newly occurring adverse events related with the investigational product or determined by the investigator as having a 
reasonable possibility of being caused by the investigational product are recorded, and of these, serious adverse events are all reported. Serious adverse events ongoing at the time of completion 
of the investigational product administration will be followed during the follow-up period until resolved or stabilized irrespective of the relationship with the investigational product (see Section 
10.4). 
(i) Chest X-ray: During pre-operative and adjuvant chemotherapy, chest X-ray results within 14 days can be used, if available. 
(j) Tumor assessment: Tumor assessment will be conducted with (1) physical examination, (2) abdominal-pelvic CT scan, and (3) gastroduodenoscopy. In case of suspected M1, other protocol-
specified test can be conducted. Abdominal-pelvic CT scan will be conducted within 14 days prior to randomization, and subsequently, after neo-adjuvant chemotherapy Cycle 1 and before 
start of Cycle 2, after Cycle 3 before surgery, and subsequently, during the adjuvant chemotherapy period and follow-up, every 6 months (±2 weeks) from the date of surgery until progressive 
disease, upon development of suspected progressive disease, and at the follow-up completion visit. At each assessment, the same method will be used for follow-up. For the SC Arm, the same 
schedule will be implemented as the CSC Arm after surgery.  
 
(k) Survival status: In case of following only survival/death status, the survival status is followed with phone calls or in-person visits. For subjects who have ended the study (End of Study) in a 
survival state, information on survival/death may be additionally collected. 
 
* Visit window is based on calendar days 


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3. ABBREVIATIONS  
5-FU 
5-fluorouracil 
5-HT3 
5-hydroxytriptamine
AE 
Adverse event 
AESI 
Adverse event of special interest 
AGC 
Advanced gastric cancer
ALT 
Alanine aminotransferase
ALP 
Alkaline phosphatise
AST 
Aspartate aminotransferase
AUC 
Area under the curve
CDHP 
5-chloro-2, 4-dihydroxypyridine (gimestat)
CRF  
Case Report Form 
CSC 
Chemotherapy-Surgery-Chemotherapy
CSF 
Colony stimulating factor
CT 
Computed tomography
DOS 
Docetaxel, oxaliplatin and S-1
DPD 
Dihydropyrimidine dehydrogenase
DRF  
Discrepancy Resolution Form 
ECG  
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group
EUS 
Endoscopic ultrasound
FAS          
Full Analysis Set
FDA 
Food and Drug Administration
FT 
Tegafur
GI 
Gastrointestinal
ICF 
Informed consent form
ICH 
International Conference on Harmonisation
IDMC 
Independent Data Monitoring Committee
IRB/IEC  
Institutional Review Board/Independent Ethics Committee  
IRC 
Independent Review Committee
ITT 
Intent-to-treat
LYM 
Lymphocyte
NCI CTC
National Cancer Institute Common Terminology Criteria
ORR 
Objective response rate
OS 
Overall survival
Oxo 
Oteracil potassium
PFS 
Progression-Free Survival
PMN 
Poly-Morgho-Nuclear Leukocytes. Human Neutrophil
PP 
Per Protocol
SAE  
Serious adverse event 
SAP 
Statistical analysis plan
SC 
Surgery-Chemotherapy
TEAE 
Treatment emergent adverse event
ULN  
Upper limit of normal 


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4. INTRODUCTION AND THEORETICAL BACKGROUND  
Pre-operative anticancer adjuvant therapy and adjuvant chemotherapy for treatment of 
gastric cancer 
Gastric cancer remains the second leading cause of cancer deaths globally, with more than 
600,000 deaths caused by gastric cancer every year1-3. Surgery is a potentially curative 
treatment option in locally advanced gastric cancer (AGC) with no distant metastasis, and 
achievement of R0 resection (potentially curative resection in the absence of cancer cells at the 
margin) is necessary. However, prognosis is still poor for patients with locally advanced gastric 
cancer even after potentially curative resection, and the risk is high for recurrence at a local or 
distant site.4 
Globally, almost 60% of patients who had R0 resection experience recurrence, and according to 
several large-scale multinational studies, overall 5-year survival for resectable gastric cancer 
patients ranged 10%~71.4%5-7, 14, varying greatly in reported survival depending on the study 
method. While results from the meta analysis consistently suggest small but clear benefits of 
adjuvant chemotherapy in AGC patients8-13, such treatment effects in AGC still remain 
controversial. Nevertheless, well-designed, large-scale recent studies provided reliable data on 
the effects of adjuvant treatment in AGC. 
Three pivotal studies that investigated adjuvant treatment in AGC are the US Intergroup 
study (INT-0116)14 of the postoperative chemoradiotherapy, MAGIC study15 of pre-
operative/immediate postoperative chemotherapy, and a study in Japan16 that examined adjuvant 
chemotherapy using S-1 (ACTS-GC). 
The first study, i.e. the US Intergroup study (INT-0116) investigated the role of postoperative 
chemoradiotherapy, and reported significantly improved OS and RFS in patients in the 
chemoradiotherapy group compared to observation-only patients14. In the INT-0116 study, the 
5-year survival in the chemoradiotherapy group was 42%, which was not superior to 45~47% 
observed after the D1/D2 procedure only in a study in the Netherlands, and significantly inferior 
to 71.4%, survival achieved after the D2/D3 surgery only in the JCOG 9501 study17. Inferior 
results from the INT-0116 study were attributable to inappropriate surgery. Most patients were 
eligible for D0 (54%) or D1 (36%) surgery, and only 10% underwent the D2 procedure as 
originally planned. Therefore, while chemoradiotherapy is used as standard adjuvant treatment 
after curative resection for gastric cancer in the US, a number of oncologists in East Asia where 
the D2 procedure is a standard and frequently performed procedure, raise questions on the role 
of appropriate additional D2 postoperative chemoradiotherapy even though it may benefit 
patients who had inappropriate surgery (D0 or D1).  
 
The second one, the UK MAGIC study investigated the effect of pre-operative/immediately 
postoperative chemotherapy in operable gastroesophageal cancer patients. This study has clearly 
demonstrated the effect of pre-operative/immediate postoperative chemotherapy compared to 
surgery alone. Pre-operative/immediate postoperative chemotherapy group showed significantly 
improve results for 5-year OS and 5-year PFS compared to the surgery alone (5-year OS: 36% 
vs 23%, 5-year PFS 32% vs 15%).15 Based on such findings, pre-operative/immediate 
postoperative chemotherapy using chemotherapy became standard adjuvant treatment for 
operable advanced gastric cancer in the UK and several Western countries. However, this study 
faced similar criticism as that of the US Intergroup study. In other words, the 5-year survival of 


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the pre-operative/intra-operative/immediate postoperative chemotherapy group was only 36%. 
Such poor results were also attributable to the low percentage (38%) of patients who had the 
appropriate D2 procedure. Another criticism is feasibility of the proposed treatment. Overall, 
only 42% of patients completed 3 cycles of planned pre-operative/immediate postoperative 
chemotherapy, reflecting low tolerability of the platinum-containing triplet chemotherapy after 
gastric resection. The optimal timing for adjuvant chemotherapy (i.e. pre-operative, 
postoperative, or both pre- and postoperative) has not been established yet. Furthermore, in case 
of using pre-operative/immediate adjuvant chemotherapy, there is a risk that treatment may be 
excessive for a very early stage in operable gastric cancer patients. This is due to the incomplete 
accuracy of determination of the pre-operative clinical stage. In fact, approximately 13.5% of 
subjects in the MAGIC study (hereafter ‘subjects’) are estimated to have TNM Stage 1 gastric 
cancer. Six cycles of chemotherapy can obviously represent excessive treatment in such Stage 1 
gastric cancer patients.  
The third study, the ACTS-GC study in Japan included 1,059 Stage 2 and 3 (Japan 
classification) gastric cancer patients who received R0- resection after the D2 procedure, and 
assessed the effect of 1-year administration of adjuvant chemotherapy S-1 compared to the 
observation group16. This study was closed after the first interim analysis in 2006.06, since 
analysis results clearly showed significantly higher 3-year OS in the study group compared to 
the observation group (HR, 0.68; 95% CI, 0.52–0.87; p=0.0024). After results from this study 
were presented, adjuvant chemotherapy using S-1 became standard treatment after curative 
resection for gastric cancer in Japan and other Asian countries where the D2 procedure is 
performed.  
In summary, while the promising role of the adjuvant therapy in AGC was demonstrated, 
selected methods differed by region. While studies showed that chemoradiotherapy or pre-
operative/immediate adjuvant chemotherapy is recommended in the US and Europe where a 
limited procedure is the standard, it may be appropriate to use adjuvant chemotherapy only in 
Asian countries including Japan where more extensive procedures are frequently used. 
 
Based on these studies, it is required to investigate how to further improve the treatment 
effect of the standard adjuvant chemotherapy S-1 in Asian region in the future.  
 
First, the addition of radiotherapy such as the US Intergroup study can be considered; as 
mentioned previously, nevertheless, most oncologists are skeptical about adding another local 
therapy to effective local treatment such as the D2 procedure. However, a phase 3 study 
(ARTIST) has been conducted in one site in Korea for several years that compared adjuvant 
chemotherapy (XP) after the D2 procedure vs adjuvant chemotherapy (XP) + radiotherapy, and 
if the results are presented, it may be possible to reach a conclusion on whether additional 
radiotherapy is effective even after the D2 procedure.  
Next, intensity of adjuvant chemotherapy may be raised by adding platinum to S-1. 
Intensified adjuvant chemotherapy with combination of Fluoropyrimidine and platinum was 
compared with the observation only group in several previous phase 3 studies in Western 
countries; not only sample sizes were small but also no improved treatment effects were 
detected compared to the observation group. Such failure is attributable to intolerability of 
therapy including postoperative Cisplatin by most patients.  
The AMC 0201 study compared MMC administration followed by 3 months of Doxifluridine 
(Mf arm) with a group that added 6 doses of Cisplatin every 4 weeks and extended 


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administration of Doxifluridine for 12 months (MFP arm) in 855 Stage 2–4 (M0) gastric cancer 
patients who had R0-resection18. However, 3-year RFS and OS did not differ between these two 
groups. In other words, it was not effective to intensify adjuvant chemotherapy by simply 
adding Cisplatin or extending the treatment period. 
In addition, the US CALGB 80101 study investigated whether the intensified chemotherapy 
can improve the treatment effect by substituting chemotherapy with ECF therapy that added 
Epirubicin and Cisplatin to 5-FU in combination chemoradiotherapy using postoperative 5-FU 
Leucovorin (CCRT) for which effects were demonstrated in the previous Intergroup study. 
However, results presented at the 2011 ASCO suggested that this strategy was not effective at 
all.19  
In a recent CLASSIC study in Asian countries including Korea, 1035 patients after the D2 
procedure were compared by being divided into the observation group and 8 cycles of XELOX 
therapy (Capecitabine + Oxaliplatin); from the interim analysis results presented at the 2011 
ASCO, while effects were not demonstrated in terms of overall survival, the treatment group 
showed significant effects in the primary endpoint, 3-year disease free survival, so that XELOX 
was recognized as another effective adjuvant chemotherapy.20 
 However, from comparison of results between this study and the ACTS-GC study, almost the 
same treatment effect was shown, with a 13~14% improvement of the 3-year disease free 
survival in the treatment group (ACTS-GC 72%, CLASSIC 74%) compared to that of the 
control group (ACTS-GC 59.6%, CLASSIC 60%) in the patient population that had the almost 
same stage distribution (Stage 2 approximately 50%, Stage 3A approximately 30~36%, Stage 
3B 10~14%). Meanwhile, 170 of 517 patients in the S-1 treatment group of the ACTS-GC study 
discontinued treatment prior to 12 months; 143 of them discontinued due to side effects other 
than recurrence or consent withdrawal. In the CLASSIC study, 212 of 520 patients in the 
XELOX group discontinued treatment before the planned treatment period; other than 11 who 
discontinued due to recurrence, 201 discontinued due to treatment refusal or side effect or 
consent withdrawal. Such result may suggests inferior treatment compliance of XELOX therapy 
to S-1 monotherapy as expected.  
Unlike the AMC0201 study, the AMC 0101 study randomized 640 patients amenable to curative 
resection for whom tumor was determined to have involved the gastric serosa during surgery in 
the operating room, and in the study group (iceMFP arm), intraperitoneal chemotherapy using 
Cisplatin was conducted, adjuvant chemotherapy was started with MMC injection from the next 
day of surgery, 6 doses of Cisplatin was administered at 4-week intervals and Doxifluridine was 
administered for 12 months. In the control group, same as the AMC0201 study, MMC was 
injected 3 weeks after the surgery, followed by 3 months of Doxifluridine administration.21 In 
this AMC0101 study, in order to intensify adjuvant chemotherapy, Cisplatin was added, and 2 
more strategies were used compared to the AMC0201 study that used extended administration 
of Doxifluridine for 12 months: the first was the addition of intraperitoneal chemotherapy in 
order to lower the risk of peritoneal recurrence, and the second was early initiation of adjuvant 
chemotherapy, i.e. from the next day of surgery. As a result, unlike results from the AMC 0201 
study, the study group in the AMC 0101 study achieved a significantly improved treatment 
effect (RFS and OS) compared to the control group. The 3-year RFS was iceMFP group 60.2%, 
Mf group 50.0%, and HR was 0.695 (95% CI, 0.536–0.902; p=0,006). The 3-year OS was 
iceMFP group 71.2%, Mf group 59.6%, and HR was 0.710 (95% CI, 0.531–0.950; p=0.02). 
Along with negative findings from the AMC 0201 study, positive results of the AMC 0101 
study suggest that rather than simply adding Cisplatin or extending the treatment period, early 


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initiation of adjuvant chemotherapy or addition of intraperitoneal chemotherapy represents an 
effective strategy to improve the effect of adjuvant chemotherapy. 
Therefore, if early initiation of adjuvant chemotherapy is effective, it would be reasonable to 
consider neo-adjuvant chemotherapy as the adjuvant chemotherapy that starts earliest.  
 
Docetaxel  
Mechanism of action and pharmacokinetics 
The key mechanism of Docetaxel was increasing polymerization of tubulin into the stable 
microtubule while also reducing depolymerization, without changing the number of 
protofilaments in the microtubule during such actions. Pharmacokinetic characteristics are as 
follows: (1) Pharmacokinetic profile was established in a phase 1 study that treated cancer 
patients at 20~115 mg/m2, and (2) the response rate profile of Docetaxel is not dose-dependent. 
(3) Plasma concentrations followed the third order reaction rate, (4) Docetaxel’s half-life in 
blood was t½ = 4 min, t½ = 36 min, t½ = 11.1 hr, and (5) Docetaxel’s pharmacokinetics were 
not affected by age or sex of cancer patients.  
Docetaxel in treatment of gastric cancer 
Docetaxel has been demonstrated to be effective in AGC treatment. Activity of Docetaxel in 
this disease was known in the early 1990s, and Docetaxel monotherapy showed a 18-24% 
response rate as the first-line treatment, and similar results were also shown as the second-line 
treatment.22 
Investigation of combination therapy focused on the Docetaxel and Cisplatin and/or 5-FU 
combination therapy. The reasons were as follows: Pharmacological mechanisms did not 
overlap between drugs, there was no cross-resistance, and there were no overlapping side 
effects. In the study by Roth and Ajani,22 48 gastric cancer patients were treated with Docetaxel 
(85 mg/m2) and Cisplatin (75 mg/m2) combination therapy. The response rate was 56% 
(including 2 events of a complete response), median time to progression was 6.6 months, and 
median OS was 9 months. However, 9 patients developed substantial hematological toxicities 
and febrile neutropenia. Ridwelski et al. 23 conducted a phase 2 study of low dose Docetaxel 75 
mg/m2 and Cisplatin 75 mg/m2 treatment in 39 patients. While the 37.2% response rate was 
slightly lower than what was reported in the Roth et al. study, the time to progression (6.1 
months) and OS (10.4 months) were comparable. Hematological toxicity was significantly 
lower, and there was no febrile neutropenia. Nevertheless, 2 patients developed irreversible ear 
toxicity.  
In a recent phase 3 study, addition of Docetaxel to Cisplatin and 5-FU resulted in a significant 
improvement of the time to cancer progression (5.6 vs 3.7 months, P <0.001) and overall 
survival (Docetaxel, Cisplatin, 5-FU group 1-year survival 40% vs Cisplatin, 5-FU group 32%) 
compared to the Cisplatin and 5-FU only group.24 In 2006, based on results of this study, the 
Food and Drug Administration (FDA) approved combination therapy of Docetaxel with 
Cisplatin and 5-FU as treatment of AGC including gastroesophageal junction cancer. Such 
improved efficacy should be balanced with increased toxicity; for Docetaxel, Cisplatin, 5-FU 
triplet combination therapy, approximately 20% of patients experienced Grade 3 non-
hematological toxicities including lethargy, stomatitis, and diarrhea. The risk of infection was 
also high. Grade 3/4 neutropenia occurred in approximately 80% of patients and about 30% of 


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patients had neutropenic fever and infection. Therefore, despite improved efficacy, Docetaxel, 
Cisplatin, and 5-FU therapy was considered by many physicians as too toxic to be used in 
clinical settings.  
Other studies were also conducted that investigated methods other than the addition of 
Docetaxel to 5-FU and Cisplatin combination. A phase 1/2 study of Docetaxel, Capecitabine, 
Cisplatin triplet combination therapy was conducted in Korean advanced gastric patients.25 
Recommended doses of Docetaxel (60 mg/m2 on Day 1), Capecitabine (1,875 mg/m2/day on 
Day 1-14), and Cisplatin (60 mg/m2 on Day 1) were used for the 3-week cycle therapy of 
Docetaxel, Capecitabine, and Cisplatin. Docetaxel, Capecitabine, and Cisplatin combination 
therapy was highly active and tolerable as the first-line chemotherapy of AGC. Of 40 patients 
treated in the phase 2 part of this study, 4 patients showed a complete response, 23 reported a 
partial response, and the response rate was 68%. Median time to progression was 7.8 months 
and median OS was 16.9 months. Of subjects showing favorable responses, 10 had received 
resection of the primary gastric cancer, and achieved 4 pathological complete responses. What 
is more promising is the improved safety profile: 40% of patients had Grade 3/4 neutropenia 
and 10% experienced neutropenic fever. This represented much greater tolerability that what 
was reported for Docetaxel, Cisplatin, and 5-FU therapy24. Therefore, by reducing the Docetaxel 
and Cisplatin dose and replacing 5-FU with oral Fluoropyrimidine and Capecitabine, toxicities 
were remarkably reduced while maintaining efficacy of triplet combination therapy in advanced 
gastric cancer patients.  
Recently, Sym et al. reported a phase 2 study of neoadjuvant chemotherapy using the same 
Docetaxel, Capecitabine, and Cisplatin therapy in locally advanced unresectable or 
intraperitoneal metastatic gastric cancer patients.26 R0 resection rate in this patient population 
was 63%, and the toxicity profile was favorable. Only 4% of patients experienced febrile 
neutropenia.  
Oxaliplatin  
Mechanism of action and pharmacokinetics 
Oxaliplatin is a diaminocyclohexane platinum derivative with a similar molecular mechanism 
of action with Cisplatin: these two compounds form a DNA conjugate or DNA cross link 
between the Guanine base pairs (GG or GNG), or between Guanine and Adenine base pairs 
adjacent within the DNA single strand. Compared to Cisplatin, Oxaliplatin has a slightly wider 
spectrum of action, possibly due to its ability to form a conjugate in a different way, especially, 
coping with some mechanisms of platinum resistance based on mismatch repair deficiency and 
replication bypass.  
Pharmacokinetic characteristics are as follows: (1) After infusion for 2 hr, 15% of platinum 
remain in circulation, and the remaining 85% is promptly distributed into the tissue or 
eliminated via urine. (2) Half-life is determined by the natural regeneration period of RBC and 
serum albumin due to the irreversible binding with RBC and plasma binding in such distribution 
compartment between cells. (3) Accumulation of platinum was not observed in the ultrafiltrated 
plasma after administration of 85 mg/m2 every 2 weeks or 130 mg/m2 every 3 weeks. (4) 
Platinum is usually eliminated via the kidneys. Approximately 54% of the total dose was 
excreted via urine on Day 5, and less than 3% was eliminated via feces. (5) In case of limited 


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renal function, clearance may be clearly lowered from 17.6 ± 2.18 l/hr to 9.95 ± 1.91 l/hr, and 
the volume of distribution may greatly decrease from 330 ± 40.9 L to 241 ± 36.1 L. (6) The 
effect of seriously limited renal function on the plasma elimination rate has not been 
investigated.  
Oxaliplatin in treatment of gastric cancer 
Oxaliplatin is an anticancer agent approved for adjuvant chemotherapy in advanced colorectal 
cancer and colon cancer. In 5-FU-resistant tumor patients, Oxaliplatin monotherapy achieved a 
10% response rate.27,28 Oxaliplatin is also actively investigated in gastroesophageal cancer 
treatment. Various therapies were investigated in phase 2 studies and the response rate for all of 
them ranged 40~67%, and median survival was 8~15 months.28-36 
Therapeutic effects of Oxaliplatin in gastric cancer treatment was demonstrated in two phase 
3 studies.  
One of them was a study that compared Fluorouracil, Leucovorin, and Oxaliplatin 
combination therapy with 5-FU infusion + Cisplatin combination therapy; 220 advanced gastric 
cancer patients were randomized in this study. Time to progression was comparable between 
Fluorouracil, Leucovorin, and Oxaliplatin vs 5-FU infusion + Cisplatin (5.7 months vs 3.8 
months, log rank P = 0.081), and the response rate was 34% vs 24%, respectively. While 
Oxaliplatin containing therapy was associated with significantly lower grade nausea, alopecia, 
fatigue, and renal toxicity, more peripheral neuropathy events were reported as expected. In 
addition, compared to the 5-FU infusion + Cisplatin group, the Fluorouracil, Leucovorin, and 
Oxaliplatin group reported a slightly lower adverse event (AE) incidence. This study had an 
intent-to-treat design and was powered to test superiority of Fluorouracil, Leucovorin, and 
Oxaliplatin for the time to progression. 
As the other study, Cunningham et al. reported results of a randomized phase 3 study that 
compared Fluorouracil and Capecitabine combination vs Cisplatin and Oxaliplatin combination 
in 1002 treatment-naïve advanced gastroesophageal cancer patients.5 Compared to the standard 
therapy of Epirubicin, Cisplatin, and Fluorouracil, Epirubicin, Oxaliplatin, and Capecitabine 
therapy showed significantly better median OS as the first-line treatment of gastric cancer. 
Strength of such efficacy was associated with reduced Grade 3/4 neutropenia. Compared to 
Cisplatin, Oxaliplatin was associated with significantly less Grade 3 or 4 neutropenia and 
alopecia, but significantly more Grade 3 or 4 diarrhea and peripheral neuropathy. Compared to 
the Cisplatin group, the Oxaliplatin group tended to show a lower creatinine concentration 
elevation and a significantly lower rate of thromboembolic events. By adding the 3rd generation 
platinum compound Oxaliplatin and oral Fluoropyrimidine Capecitabine to Epirubicin, 
increased OS was achieved compared to standard therapy. Such data suggest that Oxaliplatin is 
as effective as Cisplatin in combination therapy for advanced gastroesophageal cancer subjects.  
S-1 
Mechanism of action and pharmacokinetics 
S-1 is an orally administered new anticancer agent consisting of Tegafur (FT), 5-chloro-2, 
4-dihydroxypyridine (gimestat [CDHP])], and Oteracil potassium (Oxo) at the 1:0.4:1 mole 
ratio. 




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In a phase 1 clinical study, the once daily and twice daily (b.i.d.) dosing schedules were 
implemented for 28 continuous days. The maximum allowed dose was 150~200 mg/m2/day for 
once daily administration or 75~100 mg/m2/day for twice daily administration38.  
 
Pharmacokinetics were examined at 25, 50, 100, 150, and 200 mg/body. Results of this study 
were linear for unchanged S-1 after a single-dose, and the maximum plasma concentration and 
AUC of the active metabolite 5-FU were dose-dependent. Based on such results, the 
recommended dose for the phase 2a clinical study was determined as 75 mg/body twice daily 
for 28 consecutive days, followed by 14 days of wash-out (1 cycle). Phase 2a study was 
conducted at 50 or 75 mg/body39, and the recommended dose for the phase 2b study was 
determined as 80 mg/m2/day. Hirata et al. investigated pharmacokinetics for S-1 single dose 
(40mg/m2) and 8-day continuous administration (80 mg/m2/day, divided into 2 doses). Mean 
single dose per body surface area was 35.9 mg/m2 (31.7-39.7 mg/m2). Pharmacokinetic 
parameters for 5-FU in plasma were as follows: (1) maximum plasma concentration, 128.5 ± 
41.5 ng/mL, (2) time to the maximum plasma concentration, 3.5 ± 1.7 hr, (3) AUC0–14, 723.9 ± 
272.7 ng*h/mL, (4) t1/2, 1.9 ± 0.4 hr. (5) No variability or drug accumulation was observed for 
28-day continuous therapy. Such results suggest that pharmacokinetics of orally administered S-
1 are comparable to that of 5-FU administered with continuous intravenous infusion10.  
 
S-1 in treatment of gastric cancer 
From two phase 2 studies of S-1 monotherapy in Japan, a high objective response rate (ORR; 
44~49%) was observed after 4 weeks of 80 mg/m2/day administration, followed by 2 weeks of 
wash-out41,42 Such high objective response rate was not reproduced in the subsequent Korean 
study43.  
 
Based on the synergistic effect of S-1 and Cisplatin observed in a pre-clinical study, 
combination therapy of these two drugs was developed44-48. In a study conducted in Japan, 20 
patients administered S-1 for 2 weeks, followed by 1 week wash-out + Cisplatin (20 mg/m2) on 
Day 1 and Day 8, and achieved high ORR of 78%46. In a US study47,48, 42 patients administered 
S-1 50 mg/m2/day for 3 weeks, followed by 1 week wash-out + Cisplatin 75 mg/m2 on Day 1 of 
each 4-week cycle, and achieved ORR 48%, median Progression-Free Survival (PFS) 5.3 
months, and median OS 10.9 months. Toxicities of this therapy mostly developed in the third 
week of continuous administration, and in order to reduce such toxicities, a new administration 
schedule was developed. In other words, S-1 was continuously administered for 2 weeks during 
a 3-week cycle and the Cisplatin dose was 60 mg/m2. In a Korean study using this schedule, the 
recommended dose for S-1 was 90 mg/m2/day, and lowered to 80 mg/m2 to improve feasibility. 
In addition, Cisplatin was administered on Day 1. The resultant ORR was 48% and median PFS 
was 5.3 months45.  
 
Recently, results were reported from several phase 3 studies of S-1 in advanced gastric cancer 
treatment.8,49-51 Most of all, S-1 had comparable efficacy with intravenously infused 5-FU. 
Furthermore, addition of Cisplatin to S-1 resulted in a significant improvement of ORR and 
survival compared to S-1 monotherapy50; therefore in Japan, S-1 + Cisplatin combination 
therapy became standard treatment in advanced gastric cancer, and also in the Asian region 
including Korea, S-1 and Cisplatin combination therapy became standard therapy.  


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Docetaxel, Oxaliplatin, and S-1 combination therapy in gastric cancer 
In advanced gastric cancer patients, the role of Docetaxel, Oxaliplatin and/or S-1 combination 
chemotherapy was evaluated.  
Two phase 1/2 studies of Docetaxel and S-1 combination therapy were conducted in 
advanced gastric cancer patients. Yamaguchi et al.13 reported a 46% response rate and the 
tolerable toxicity profile (Docetaxel 40 mg/m2 on Day 1 + S-1 40 mg/m2 twice daily, Day 1-14 
of every 3 weeks) for this combination therapy. The most common Grade 3/4 toxicity was 
neutropenia (67% of subjects) which was predictable and manageable. In the other study, 48 
advanced gastric cancer patients administered intravenous Docetaxel 40 mg/m2 on Day 1 and 
oral S-1 80 mg/m2/day on Day 1~14 every 3 weeks. This study reported a 93.8% tumor 
suppression rate and tolerable toxicities52. This therapy showed moderate toxicity and promising 
activity in treatment of advanced gastric cancer. 
A phase 1/2 study of S-1 and fixed dose Oxaliplatin (130 mg/m2) combination therapy was 
conducted in Asian patients with advanced gastric cancer53. The recommended dose was 
determined as S-1 100 mg/m2/day on Day 1-14 and Oxaliplatin 130 mg/m2 on Day 1 of a 3-
week treatment cycle in Korean advanced gastric cancer patients. Pharmacokinetics of S-1 
ingredients or its active metabolite did not differ between S-1 monotherapy and combination 
with Oxaliplatin. For patient treatment, the objective response rate was observed as 61% (95% 
CI, 53~73%). Stable disease was achieved in 30% of patient and the median follow-up was 12.1 
months, median PFS was 6.5 months, and median OS was 12.2 months. Grade 3/4 toxicities 
included thrombocytopenia (39%), neutropenia (28%), anemia (17%), febrile neutropenia (8%), 
asthenia (8%), and decreased appetite (8%). Therefore, Oxaliplatin + S-1 combination therapy 
showed great activity in treatment of advanced gastric cancer, with a favorable toxicity profile 
in patients.  
 
Docetaxel + Oxaliplatin combination therapy was investigated for treatment of advanced 
gastric cancer. Kim et al.54 reported the efficacy and safety of Docetaxel + Oxaliplatin 
combination therapy in 42 treatment-naïve metastatic or recurrent measurable gastric cancer 
patients. Patients administered intravenous Docetaxel 65 mg/m2 + Oxaliplatin 120 mg/m2 on 
Day 1 based on a 3-week cycle. ORR was 45.2% and the median time to progression and 
median OS was 5.7 months. Richards et al.55 reported manageable toxicity after administration 
of Docetaxel 60 mg/m2, followed by Oxaliplatin 130 mg/m2 on Day 1 of each 3-week cycle. 
Results were promising, including the response rate 36%, the clinical benefit rate 40%, and 
mean survival 8.5 months, similar to that of standard first-line therapy. Furthermore, a phase 2 
study by Sym et al.26 demonstrated a favorable toxicity profile of the Docetaxel, Capecitabine 
and Cisplatin triplet adjuvant chemotherapy and achievement of the promising R0 resection rate 
in unresectable locally advanced gastric cancer or abdominal metastatic gastric cancer patients.  
 
A dose-finding study of Docetaxel, Oxaliplatin, and S-1 (DOS) was conducted in advanced 
gastric cancer patients. Docetaxel 52.5 mg/m2 and Oxaliplatin 105 mg/m2 on Day 1 and S-1 80 
mg/m2 on Day1-14 of each 21-day cycle were reported as the recommended dose of the 21-day 
cycle DOS therapy in advanced gastric cancer patients56. Most patients reported Grade 3/4 
neutropenia, and febrile neutropenia occurred at 56%. Most non-hematological toxicities were 
Grade 1/2 decreased appetite, diarrhea, neuropathy, and fatigue, and they were all reversible.  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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In a phase 2 study of Docetaxel (50 mg/m2), Oxaliplatin (100 mg/m2), and S-1 (80 mg/m2) 
neo-adjuvant chemotherapy in locally advanced gastric cancer or gastroesophageal cancer 
conducted by Dr. Kang, 39 events of R0 resection were reported from 41 advanced gastric 
cancer patients who received neo-adjuvant chemotherapy and surgery. Furthermore, 4 patients 
showed a pathological complete response after surgery. In this study, Grade 3 neutropenia 
(24%), Grade 3 thrombocytopenia (27%), and Grade 3 febrile neutropenia (10%) were reported 
as hematological toxicities of DOS. As non-hematological toxicities of DOS, Grade 3 decreased 
appetite (2%) and diarrhea (2%) were reported, so that a subsequent study could be conducted57.  
In conclusion, the role of neo-adjuvant chemotherapy in advanced gastric cancer is becoming 
increasingly important, and investigation of new therapy with a more favorable toxicity profile 
is crucial for the success of the approach to treatment. Given results of studies so far, the pre-
operative Docetaxel, Oxaliplatin, and S-1 triplet chemotherapy and postoperative S-1 alone 
chemotherapy are expected to present one of optimal treatment methods in advanced gastric 
cancer patients amenable to curative resection. 
 
  
5.  STUDY OBJECTIVES 
5.1 Primary objective 
To compare the 3-year Progression-Free Survival (PFS) between two groups in advanced gastric 
cancer patients amenable to curative resection who are randomized and treated in the pre-
operative DOS chemotherapy + surgery + adjuvant chemotherapy S-1 arm (hereafter CSC Arm) 
and the surgery + adjuvant chemotherapy S-1 arm (hereafter SC Arm).  
5.2 Secondary objectives 
To assess and compare the followings between two groups: 
 Overall survival (OS)  
 Post-operative pathological stage  
 R0 (complete) resection rate 
 Safety assessment (NCI CTCAE v4.03) 
 
6. 
STUDY DESIGN 
6.1 Description of protocol  
This is a randomized (1:1, CSC Arm and SC Arm), open-label, multicenter, comparative, phase 
3 clinical study in advanced gastric cancer patients amenable to curative resection. For details of 
the study procedure, see Section 8 Study procedure.  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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6.2 Study period  
Patients who signed the Informed Consent Form and are randomized are considered 
participating in this study. According to the Study diagram and the Study flow chart (Section 2.1 
and 2.2), the CSC Arm starts neo-adjuvant chemotherapy within 7 after randomization, 
administers the investigational product for a total of 3 cycles, and undergoes surgery within 1~3 
weeks, and the SC Arm undergoes surgery within 2 weeks after randomization; both groups will 
receive adjuvant chemotherapy for 8 cycles (for about 1 year) within 3~6 weeks after surgery, 
and have the safety assessment on Day 30 after the last dose of the investigational product, and 
follow-up (site visit every 3 months for the first year and subsequently, every 6 months, and 
after disease progression, only survival status will be checked with a phone call or in-person 
visit every 6 months).  
During the Baseline period, the relevant procedures (see Section 2 and Section 8) should be 
performed within specified periods (including Section 7.2 and Section 7.3 Inclusion/exclusion 
criteria review). 
Subjects in the CSC Arm will initiate neo-adjuvant chemotherapy within 7 days after 
randomization, receive treatment for a total of 3 cycles (1 cycle is 3 weeks, 2 weeks of 
administration + 1 week wash-out), and undergo surgery within 1~3 weeks after completion of 
neo-adjuvant chemotherapy. Administration of the investigational product should continue 
every 3 weeks unless the subject meets the administration discontinuation criteria described in 
Section 11. In case of unresolved toxicity, the study can be delayed for up to 3 weeks in each 
cycle. If disease progression is confirmed from pre-operative tumor assessment, the 
investigational product administration can be discontinued and surgery and other treatment can 
be considered. 
Subjects in the SC Arm will undergo surgery within 2 weeks after randomization. 
Both groups will receive S-1 adjuvant chemotherapy (1 cycle is 6 weeks, 4 weeks of 
administration + 2 weeks of wash-out) for 8 cycles (for about 1 year) within 3~6 weeks after 
surgery. Administration of the investigational product should continue every 6 weeks unless the 
subject meets the administration discontinuation criteria described in Section 11, and subjects 
should be followed for safety for at least 30 days after the last dose of the investigational 
product. In case of unresolved toxicity, the study can be delayed for up to 3 weeks in each cycle 
until the dose day in the next cycle, and any investigational product-related adverse event and 
any serious adverse event of subjects should be followed until resolved/stabilized. Adverse 
events possibly related with the investigational product recognized by the investigator should be 
reported to Monitoring Team at any time after discontinuation of the investigational product. 
All subjects will be followed after the End-of-Treatment (EOT) until death or study closing date, 
whichever is earlier. 
The study data cutoff date will be the day of occurrence of approximately 244 disease 
progression or death events or at least 3 years of median follow-up.  


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The duration of follow-up for survival status will be up to 5 years after subject enrollment. 
However, subjects who have ended the study (End of Study) in a survival state can be further 
followed up for survival status by visits or phone calls. 
6.3 Steering Committee  
Steering Committee will be involved in this study and provide scientific and strategic guidance 
for the study, and will assume the overall responsibility for the study design, conduct, and 
publication.  
In addition, the Steering Committee has the responsibility to assure high quality performance 
and management of the study.  
Steering Committee will approve the study criteria and guidelines before study initiation (e.g., 
protocol). 
Steering Committee will meet periodically to report and discuss the study progress. 
 
6.4 Independent Data Monitoring Committee  
The Independent Data Monitoring Committee (IDMC) consisting of independent external 
members not associated with the study conduct or other study Committees has the responsibility 
to periodically monitor safety of patients exposed to the investigational product and assess 
efficacy of the study at the interim analysis. DMC procedure will be fully described in the DMC 
charter and should be approved by DMC members. 
 
7. SUBJECT SCREENING 
7.1 Prearranged sample size  
Approximately 530 patients (265 per group) will be enrolled and treated in this study. It is 
planned that approximately 20 sites would enroll these subjects in about 54 months.  
7.2 Inclusion criteria 
Patients who satisfy all of the following criteria can be randomized in this study: 
 
1. Patients who provide voluntary written consent using the Informed Consent 
Form before participating in this study  
2. Patients with new histologically confirmed primary gastric or gastroesophageal 
junction adenocarcinoma amenable to curative resection  
Patients with TNM Stage T2,3/N (+) or any T4/N stage (according to the AJCC 7th 
Edition) (lymph node positive: irrespective of the lymph node shape, if the short 
axis is ≥8 mm, it is defined as lymph node metastasis positive) 
 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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7.3 Exclusion criteria 
Patients who satisfy any of the following criteria cannot be randomized in this study: 
 
 Methods 
1. 
Patients aged less than 20 years or over 76 years old (inclusive)  
2. 
Patients with the Eastern Cooperative Oncology Group (ECOG) Performance 
Status ≥2  
3. 
Patients with the past medical history of gastric cancer (gastroesophageal 
junction included) (including all of the following cases) 
– Patients who had surgery for gastric cancer (gastroesophageal junction included) 
– Patients who received adjuvant chemotherapy, or pre-operative chemotherapy 
and/or radiotherapy and/or immunotherapy for treatment of gastric cancer 
(gastroesophageal junction included) 
4. 
Patients with the past medical history of other malignancy 
However, patients with the followings can be included in this study. 
- 
Adequately treated basal cell or squamous cell carcinoma, in situ cervical 
carcinoma  
- 
Other cancer that exceeded 5 years after completion of chemotherapy and 
remained disease free for 5 years or more  
5. 
Patients with a distant metastasis (M1) including a distant lymph node (retro-
pancreatic, para-aortic, peri-portal, retro-peritoneal, mesenteric lymph nodes) 
of gastric or gastroesophageal junction adenocarcinoma  
6. 
Patients who cannot undergo curative resection at the discretion of a surgeon 
- 
Patients with T4b with completely resectable involvement of the surrounding 
organ with no distant metastasis can be enrolled  
7. 
Patients who participated in another study or administered another 
investigational product within 30 days prior to signing the Informed Consent 
Form  
8. 
Patients who had any of the followings within 6 months prior to signing the 
Informed Consent Form: myocardial infarction, severe/unstable angina, 
coronary/peripheral artery bypass surgery, NYHA Class III or IV congestive 
heart failure, stroke or transient ischemic attack 
9. 
Patients who had deep vein thrombosis within 4 weeks prior to signing the 
Informed Consent Form 
10. Patients with the previous medical history of uncontrolled seizure, CNS or 
psychological disorder which is so clinically significant that it is impossible to 
obtain the Informed Consent Form or the severity may interfere with oral 
administration of medication  
11. Patients with uncontrolled active infection or sepsis, previously known 
acquired immune deficiency syndrome (AIDS), human immunodeficiency 
virus (HIV) infection, previously known active hepatitis B or C  
 
12. Patients with severe acute or chronic disease that may limit the ability to 
participate in the study or make it difficult to interpret results of the study  
13. Patients who have not fully recovered from other procedure  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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14. Patients who may experience a problem with absorption after oral 
administration of the investigational product, as follows: 
- 
Patients with intolerability with oral administration, malabsorption, or 
absorption disorder 
- 
Patients who have not recovered from the lack of physical completeness of the 
upper gastrointestinal tract  
- 
Ileus  
- 
Chronic inflammatory bowel disease 
- 
Extensive small bowel resection and other diseases that limit drug absorption 
(example: gastric dumping syndrome, rapid intestinal transit, malabsorption 
after bowel surgery) 
15. In case of female subjects of childbearing potential or male subjects with a 
female partner of childbearing potential, patients who do not consent to use of 
generally accepted effective contraception during the investigational product 
administration period or for at least 6 months after completion of the 
investigational product administration  
16. Breastfeeding or pregnant women. Women of childbearing potential with a 
positive pregnancy test  
 
 Investigational product administration 
17. Inadequate bone marrow and organ function prior to administration of the 
investigational product: 
I. Absolute neutrophil count <1.5 x 109/L 
II. Platelet <100 x 109/L 
III. Hemoglobin ≤9 g/dL 
IV. AST >2.5 x ULN, ALT>2.5 x ULN 
V. ALP >2.5 x ULN  
VI. Total bilirubin >1.5 x ULN 
VII. Serum creatinine >1.5 x ULN 
Creatinine clearance is calculated by using the Cockcroft-Gault formula with 
24 hr urine collection; patients with creatinine clearance <60 mL/min will be 
excluded. 
18. Peripheral neuropathy with Grade ≥2 (NCI CTCAE v4.03) clinical symptoms  
19. Grade ≥2 (NCI CTCAE v4.03) hearing loss 
20. Grade ≥2 (NCI CTCAE v4.03) severe tumor bleeding  
21. Past medical history of the hypersensitivity reaction to the investigational 
product (Docetaxel, Oxaliplatin, S-1 (Tegafur, Gimeracil, Oteracil))  
22. Patients using immunosuppressants and prohibited concomitant medication  
 
8 STUDY PROCEDURE 
8.1 Baseline 
To determine eligibility for participation in this study, potential patients will be examined prior 
to start of the study. 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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 
Informed Consent Form should be necessarily signed by the patient prior to any 
study-related procedure. However, all Baseline tests can be substituted with results for 
the relevant test within the allowed window, if available. 
 
The following results should be confirmed within 14 days prior to randomization.  
o 
Inclusion/exclusion criteria check 
o 
Clinical examination: Physical examination, blood pressure, height and body weight 
for BSA calculation, ECOG PS 
o 
Clinical laboratory safety assessment: 
Hematology: Hemoglobin/Hematocrit, RBC, WBC, PMN, LYM, ANC, Platelet 
count 
Blood chemistry: Sodium, Potassium, Calcium, BUN, Creatinine, Creatinine 
clearance (using the Cockcroft-Gault calculation method), Total protein, Albumin, 
SGOT (AST), SGPT (ALT), Total bilirubin, Alkaline phosphatase, Glucose 
Coagulation test: PT (INR), aPTT (sec) 
For women of childbearing potential, pregnancy test: Urine β-hCG 
 
24 hr urine test: Creatinine in urine (optionally conducted for Creatinine Clearance 
calculation) 
o 
12-lead ECG 
o 
Demographics: Age, sex 
o 
Concomitant medication: For drugs that have been used from previously, record 
medications that are used as of 14 days prior to randomization. 
o 
Chest X-ray: Record abnormal pulmonary findings.  
o 
Tumor assessment: Abdominal-pelvic CT and the following tests for exclusion of M1 
can be used as source data at the discretion of the investigator, even if they were 
conducted at another site.  
 Brain MRI: In case of symptoms of suspected brain metastasis 
 Chest CT: In case of suspected a pulmonary metastasis from physical examination 
and chest X-ray 
 Laparoscopy: In case of suspected peritoneal dissemination from abdominal-
pelvic CT, confirm with laparoscopy at the discretion of the investigator (mini 
laparoscopy is also acceptable) 
 
Results of the following tests conducted within 3 months prior to randomization should be 
confirmed. 
o 
Gastric adenocarcinoma confirmation result: Gastroduodenoscopy results and 
histology results can be used as source data at the discretion of the investigator, if 
conducted at another site.  
 
Prior medical history, surgical history, and other comorbidities should be confirmed within 6 
months prior to obtaining the informed consent. 
 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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8.2 Randomization  
A subject who consents to participation in this study will complete all Baseline procedures, and 
based on the results, the investigator will determine eligibility of the relevant subject and then 
the subject will be randomized. Subject will be randomized 1:1 to the CSC Arm or the SC Arm.  
 
8.2.1 Assignment of subjects to treatment groups  
Subjects will be assigned to treatment groups by the IWRS (Interactive Web-Response System) 
according to the computer-generated randomization list. Subjects who satisfy all 
inclusion/exclusion criteria will be randomized 1:1 to the CSC Arm or the SC Arm, with the site 
and TNM stage according to the AJCC 7th Edition (T2/N+, T3-4/N+, T4/N-) as stratification 
factors. The investigator should record it in the Case Report Form, and it is the investigator’s 
responsibility to ensure that subjects assigned to each group receive the planned treatment for 
the assigned group.  
 
8.3 Treatment period 
8.3.1 Neo-adjuvant chemotherapy 
Administration of the neo-adjuvant chemotherapy is initiated within 7 days after randomization. 
During this period, subject will administer DOS at a 3-week interval (for the detailed 
administration method, see Section 9.2). 
 
The following tests to be conducted in each cycle should be performed within 7 days prior to 
start of each cycle. 
 
Clinical examination before each cycle: ECOG PS, physical examination, blood 
pressure, body weight 
 
Concomitant medication  
 
All adverse events 
 
Clinical laboratory safety assessment: 
Hematology: Hemoglobin, WBC, ANC, Platelet count 
Blood chemistry: Sodium, Potassium, Calcium, BUN, Creatinine, Creatinine 
clearance (using the Cockcroft-Gault calculation method), Total protein, Albumin, 
SGOT (AST), SGPT (ALT), Total bilirubin, Alkaline phosphatase, Glucose. 
 
Other tests as clinically necessary  
 
* Tumor assessment: To follow the target lesion confirmed at Baseline, pre-operative 
abdominal-pelvic CT will be conducted within 5 days prior to start of Cycle 2 and after 
completion of Cycle 3; additional tumor assessment can be conducted at any time if disease 
progression is clinically suspected. Abdominal-pelvic CT at Baseline and after neo-adjuvant 
chemotherapy will be read by a central reviewer. If tumor progression is demonstrated, the 
subject will complete administration of the investigational product.  
If tumor progression is demonstrated with tumor assessment during the neo-adjuvant 
chemotherapy period, it will be recorded in the Case Report Form, the investigational product 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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treatment will be discontinued, and then (1) surgery or (2) other anticancer treatment not 
applicable to contents of this study will be instituted at the discretion of the investigator, among 
treatments established at the relevant site. In this case, the investigator should inform the patient 
of tumor progression, and the subject should voluntarily determine continuation or 
discontinuation of participation in this study.  
Nevertheless, discontinuation of the investigational product administration does not mean 
discontinuation of participation in this study, and the further process will be implemented 
according to the follow-up plan in the protocol. In this study, discontinuation of study 
participation only refers to the case that the patient voluntarily withdraws consent on study 
participation.    
 
8.3.2  Surgery  
Subjects in the SC Arm will undergo surgery within 2 weeks after randomization. Subjects in 
the CSC Arm will complete the entire total 3 cycles of neo-adjuvant chemotherapy (3 weeks per 
cycle), and then will undergo surgery within 1~3 weeks. 
 
Pre-operative assessment (within 14 days before surgery)  
The following tests should be conducted within 14 days before surgery.  
 
Pre-operative clinical examination: ECOG PS, physical examination, blood pressure, 
body weight 
 
Concomitant medication  
 
All adverse events 
 
Clinical laboratory safety assessment: 
Hematology: Hemoglobin/Hematocrit, RBC, WBC, PMN, LYM, ANC, Platelet  
Blood chemistry: Sodium, Potassium, Calcium, BUN, Creatinine, Total protein, 
Albumin, SGOT (AST), SGPT (ALT), Total bilirubin, Alkaline phosphatase, 
Glucose. 
Coagulation test: PT (INR), aPTT (sec) 
 
12-lead EGG 
 
Chest X-ray 
 
Other tests as clinically necessary  
 
Surgery  
The goal of the surgery is complete resection (R0). Tumor condition is explained according to 
the Residual Tumor (R) Classification: 
 
R0; No residual cancer (negative cross-section) 
 
R1; Microscopically observed residual cancer (positive cross-section) 
 
R2; Macroscopically observed residual cancer  
 
While the surgery method would be determined at the discretion of the investigator, it is 
recommended to be based on the Surgical Manual presented in this study (Appendix 26.3).  
 


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Post-operative assessment 
 Confirmation of the postoperative stage and the R0 resection rate: TNM pathological 
stage will be determined according to standardized histopathology and the AJCC 7th 
Edition. 
 In case of postoperative histological finding of R1 or finding of R2 at the operating 
room, it is considered as the progressive disease, the case will be handled as the End-
of-Treatment (EOT), and then, the patient will receive standard treatment at each site 
and subsequently followed for survival/death status. However, in case of R1, one 
resurgery will be allowed for R0 resection, and depending on the resurgery result, the 
final resection (R status) will be determined. 
 Post-operative adverse events: Post-operative adverse event is determined as an event 
that occurs within 30 days after surgery, and an adverse event that can develop as part 
of the surgical procedure will be reported only when considered by the investigator as 
an adverse event (for an intraoperative or postoperative adverse event, see Appendix 
26.3 Surgical Manual presented in this study.) 
 
8.3.3 Adjuvant chemotherapy; S-1 
As the adjuvant chemotherapy, S-1 will be administered from 3-6 weeks by which the patient 
would have recovered from surgery, and total 8 cycles (for about 1 year) will be implemented 
with 6 weeks per cycle (4 weeks of S-1 administration, followed by 2 weeks of wash-out). 
During this period, subjects will visit the site every 6 weeks and get prescription of the 
investigational product (for the detailed administration method, see Section 9.2.).  
 
In the SC Arm, if the TNM stage is confirmed by postoperative histology as one of T1/N0, 
T1/N1, or T2N0 according to the AJCC 7th Edition, the investigator should fully discuss and 
determine with the subject the subsequent treatment by necessarily including the following two 
items, and the subject can determine whether or not to administer S-1, the postoperative 
adjuvant anticancer treatment presented in this study.  
1) There is no international treatment guideline established for postoperative adjuvant 
anticancer treatment at the relevant stage. 
2) In this case, even if the patient does not receive adjuvant chemotherapy in this study, 
this does not represent discontinuation of participation in this study, and disease 
progression and survival follow-up will be performed as specified in the protocol.  
  
Tests conducted during this period are as follows (within 7 days prior to start of each cycle). 
 
Clinical examination before start of each cycle: ECOG PS, physical examination, 
blood pressure, body weight 
 
Concomitant medication  
 
All adverse events 
 
Chest X-ray 
 
Clinical laboratory safety assessment:  
Hematology: Hemoglobin, WBC, ANC, Platelet count 
Blood chemistry: Sodium, Potassium, Calcium, BUN, Creatinine, Total protein, 
Albumin, SGOT (AST), SGPT (ALT), Total bilirubin, Alkaline phosphatase, 
Glucose. 


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 
Tumor assessment: From the date of surgery, tumor assessment will be conducted with 
abdominal-pelvic CT every 6 months (±2 weeks) and gastroduodenoscopy every 12 
months (±2 weeks) (see 2.2 Study flow chart). However, in case of clinically 
suspected progressive disease, additional evaluation can be performed irrespective of 
the relevant period 
 
Other tests as clinically necessary  
 
8.4 End-of-Treatment (EOT) 
The following tests should be conducted at least 30 days (+1 week) after the last dose of the 
investigational product.  
 
Clinical examination: ECOG PS, physical examination, blood pressure, body weight 
 
Concomitant medication  
 
All adverse events 
 
Clinical laboratory safety assessment: 
Hematology: Hemoglobin, WBC, ANC, Platelet count 
Blood chemistry: Sodium, Potassium, Calcium, BUN, Creatinine, Total protein, 
Albumin, SGOT (AST), SGPT (ALT), Total bilirubin, Alkaline phosphatase, 
Glucose. 
 
Other tests as clinically necessary  
 
However, for a subject for whom treatment was discontinued prior to the investigational product 
administration or for whom treatment was discontinued after the investigational product 
administration due to the progressive disease, the study withdrawal date will be the day when 
treatment discontinuation was determined. In such cases, the End-of-Treatment (EOT) visit will 
be conducted, and the visit date, physical examination, and clinical laboratory tests will be 
implemented at the discretion of the investigator within the extent of checking the subject’s 
safety, depending on the reason for study withdrawal. 
 
8.5 Follow-up period after End-of-Treatment (EOT)  
At the follow-up visit, the following assessment will be conducted every 3 months for the first 
year from the End-of-Treatment, and subsequently, every 6 months until the End-of-Study, or 
up to 5 years after enrollment. 
 
Follow-up every 3 months for the first year and subsequently every 6 months 
 
Clinical examination: ECOG PS, physical examination, blood pressure 
 
Adverse events: AEs ongoing at the completion of the investigational product 
administration and newly occurring AEs during follow-up and related with the 
investigational product will be recorded until recovery or stabilization of progression or 
initiation of additional anticancer treatment. 
 
Other tests as clinically necessary 
 In case only survival/death status is checked, in-person visit or phone call follow-up 
every 6 months  
 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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* Tumor assessment: To be conducted with physical examination, abdominal-pelvic CT, or 
gastroduodenoscopy. Physical examination will be conducted every 3 months for the first year 
of the End-of-Treatment(EOT) and subsequently, every 6 months. The following tests will be 
scheduled based on the date of surgery, irrespective of the follow-up visit date; abdominal-
pelvic CT will be conducted every 6 months (± 2 weeks), and gastroduodenoscopy will be 
conducted every 12 months (± 2 weeks).  
Follow-up will continue after the End-of-Treatment until death or study closing date, whichever 
is earlier. In case only the survival/ death status is followed, if disease progression is confirmed 
or new anticancer treatment is initiated, withdrawal of the subject’s consent on follow-up 
assessment will be included. The investigator should do one’s best to follow the subject’s 
disease progression and survival status.  
 
8.6  End of Study  
The following test will be conducted after the follow-up visit, or for subjects who have no 
further follow-up. Subjects who have ended the study (End of Study) in a survival state can be 
further followed up for survival status by visits or phone calls. 
 
Survival status check 
8.7 Progression of disease 
If any of the following criteria is met, it is defined as the progressive disease. 
 
1. Determination as the progressive disease according to the RECIST 1.1 
2. Finding of a distant metastasis or reporting of a distant metastasis from pathology, 
irrespective of intraoperative curative resection  
3. Persistence of visually observed cancer cells at the resection margin during surgery that could 
not be further removed (R2) 
4. Persistence of cancer cells at the resection margin from postoperative histology (R1) 
5. Finding of a recurrence/distant metastasis during follow-up after R0 complete resection  
 
For a subject determined to have disease progression, administration of the investigational 
product will be discontinued according to Section 11.1.1 Permanent treatment discontinuation 
criteria. Cases that are censored although not meeting the disease progression criteria are 
described in 12.3.2.1 Primary efficacy variable.  
 
8.8 Treatment after the last administration of study drugs 
Treatment after discontinuation of the investigational product administration is determined at the 
discretion of the investigator. If the subject or the investigator wants to discontinue the 
investigational product administration and change to other treatment without disease 
progression, the case will be censored, and unless the subject voluntarily withdraws consent on 
study participation, only survival status will be continuously followed according to the protocol.  


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9 
Administration of the investigational product  
9.1 
Name and formulation 
The investigational products (Docetaxel, Oxaliplatin, and S-1) are packaged, provided, and 
labeled by the sponsor. Contents in the label will follow domestic regulations and requirements. 
 
Docetaxel 
Brand name: Taxotere injection, 20 mg and 80 mg 
Brand name: Taxotere 1-vial injection, 20 mg and 80 mg 
Oxaliplatin  
Brand name: Eloxatin injection 5 mg/ml (Oxaliplatin), 50 mg/10 mL and 100 mg/20 mL 
concentrated solution 
S-1 (Tegafur, Gimeracil, Oteracil) 
Brand name: TS-1 capsule 20 and TS-1 capsule 25 
9.2 Preparation and administration 
For Docetaxel, Oxaliplatin, and S-1, a Mosteller method is used for the BSA formula as follows: 
(height (cm) is rounded off to an integer and body weight (kg) is rounded to the first decimal 
point)  
 
BSA (m²) = ([Height (cm) x Weight (kg)]/ 3600)½ 
 
Dose is determined based on the BSA measured at the start of each chemotherapy Cycle 1. 
However, if the BSA on Day 1 of each treatment cycle differs from the BSA at the initiation of 
Cycle 1 by ≥ +/-10%, the re-measured BSA will be used.  
 
 
9.2.1 
 Docetaxel 
One of the following 2 types of Docetaxel will be supplied to sites. One is a package (2 vials) in 
which the Docetaxel study drug and solvent are separately provided to be diluted and mixed at 
the site, and the other (1 vial) is a form that is previously diluted and mixed at the factory.  
The package consisting of the study drug and solvent should be provided to subjects after the 
following process. If the vials were refrigerated, leave the required Taxotere®  package at 
ambient temperature for 5 min. Hold the vial at an angle, take the entire content in the solvent 
vial with a syringe and a needle using an aseptic technique, and infuse solvent into the 
Taxotere® vial. Carefully invert this stock solution upside down for at least 45 sec, and 
necessarily allow to stand at ambient temperature for 5 min. This stock solution contains 
Docetaxel 10 mg/mL, and should be used immediately for preparation of the infusion fluid.  


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Several stock solution vials may be required to obtain the appropriate dose (mg) for the subject. 
This stock solution is infused into a 200 mL injection bag or an injection bottle containing 5% 
dextrose or 0.9% sodium chloride.  
Docetaxel 50mg/m2 is intravenously administered on Day 1 of each 3-week cycle over ≥1 hr. 
Rounding off of the calculated dose is determined at the discretion of the investigator at the site. 
Pretreatment with Dexamethasone (8 mg) should be concurrently administered in accordance 
with Section 9.3 Pretreatment to prevent the hypersensitivity reaction and pulmonary/peripheral 
edema, and reduce and/or delay Docetaxel-related skin toxicity and fluid retention, as follows. 
Hypersensitivity reaction may develop irrespective of pretreatment. 
Treatment of the hypersensitivity reaction to Docetaxel: 
When infusing Docetaxel, it is necessarily infused using an instillation (dropping) method for 
the first 5 min. The administrator should stay beside the patient’s bed, and while monitoring the 
patient’s general conditions during the first dose, check the blood pressure and pulse, if possible. 
In case of an adverse event, emergency resuscitation should be performed immediately.  
As the device and treatment for emergency resuscitation, antihistamine, corticosteroid, 
aminophyline, and epinephrine should be readily available beside the patient.  
In case of the hypersensitivity reaction during Docetaxel administration, appropriate emergency 
treatment should be instituted depending on the symptom. For severity and corresponding 
treatment of the hypersensitivity reaction, see the following table.  
Mild symptom: Local 
adverse events of 
pruritus, flushing, and 
rash 
Reduce the infusion rate until the patient’s condition is recovered. 
Stay available next to the patient. 
If the patient’s condition recovers, infuse again at the initially planned rate.  
For subsequent cycles, infuse at the planned pretreatment and infusion rate.  
Moderate symptom: 
Abnormal symptom not 
listed in mild or severe 
symptoms, generalized 
pruritus, flushing, rash, 
dyspnea, hypotension 
with systolic blood 
pressure >80 mm Hg  
Discontinue Docetaxel infusion.  
After intravenous infusion of Dexamethasone 10 mg, administer intravenous 
infusion of Diphenhydramine 50 mg.  
Infuse Docetaxel again after recovery of symptoms.  
For subsequent cycles, after the planned pretreatment and 1 hr before Docetaxel 
infusion 1 hr, administer intravenous infusion of Dexamethasone 10 mg, 
intravenous infusion of Diphenhydramine 50 mg, and then infuse Docetaxel. 
Severe symptom: 
Bronchospasm, 
generalized urticaria, low 
blood pressure (systolic 
blood pressure 
<80mmHg), angioedema 
Discontinue Docetaxel infusion.  
Administer intravenous infusion of Dexamethasone 10 mg, followed by 
intravenous infusion of Diphenhydramine 50 mg. Infuse Epinephrine as 
necessary.  


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(periocular edema)  
After symptom recovery, infuse Docetaxel within 3 hr, or within 72 hr, administer 
intravenous infusion of Dexamethasone 10mg, intravenous infusion of 
Diphenhydramine 50 mg, and then infusion Docetaxel 1 hr later. 
For subsequent cycles, (1) in the evening of the Docetaxel infusion day, 
administer Dexamethasone 20 mg orally, (2) in the morning of the Docetaxel 
infusion day, administer Dexamethasone 20 mg orally 1 hr before, (3) in the 
morning of the Docetaxel infusion day, administer intravenous infusion of 
Diphenhydramine 50 mg 1 hr before, and then infuse Docetaxel. 
In case of recurrence of the severe symptom, the patient will be excluded from 
treatment. 
Anaphylaxis (NCI 
CTCAE Grade 4) 
Discontinue treatment.  
  
 Note: Docetaxel is an anticancer agent, and as with other potential toxic chemicals, attention 
should be paid to handling and preparation of the Docetaxel solution. The investigator should 
wear gloves, and in case of skin contact with the Docetaxel stock solution, pre-mix solution or 
injection solution, should immediately wash thoroughly with soap and ample quantity of 
running water.  
9.2.2 
Oxaliplatin 
Oxaliplatin is diluted with 250 to 500 mL of 5% dextrose solution to obtain the final 
concentration of 0.2 mg/mL or higher. 
Oxaliplatin 100 mg/m2 is administered with intravenous administration over ≥2 hr on Day 1 of 
every 3-week cycle. Rounding off of the calculated dose is determined at the discretion of the 
investigator at the site. 
In case of extravasation, administration should be immediately discontinued, and after removing 
a needle, keep the injection site higher than the heart to minimize the extent of tissue damage.  
In case of acute throat paresthesias during or after 2 hr instillation of Oxaliplatin during a 
treatment cycle, extend the next Oxaliplatin injection time to 6 hr. Patient should be carefully 
monitored for paresthesias during injection, and should be advised in advance to avoid cold 
stimulus.  
 
 Note 1: Neurological toxicity - Neurological toxicity is classified into 2 types, i.e. acute 
paresthesias within several hours or days after treatment and accumulative sensory nerve 
damage occurring after several treatment cycles. The incidence of hypoesthesia in extremities 
and/or paresthesias after Oxaliplatin instillation is 85~90%. It may or may not be accompanied 
by convulsion, caused by coldness, and symptoms are resolved between two treatment cycles. 
The acute paresthesias syndrome of the throat has the incidence of 1~2%, occurs within several 
hours after administration, and is caused by coldness. Symptoms are characterized by subjective 
dysphagia and dyspnea. However, even though the objective evidence of dyspnea is not 






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Oxaliplatin  
To prevent nausea and vomiting, antiemetics (e.g.: 5-HT 3 antagonists) should be administered 
with Dexamethasone or Methylprednisolone. Antiemetic administration can be prescribed 
according to the practice at the relevant site. 
 
S-1  
Pretreatment is not required. 
 Use of recombinant granulocyte colony stimulating factors (G-CSFs): Use for prophylaxis or 
simple neutropenia is not recommend; it is recommended to follow the ASCO guideline 58. 
 
 Neo DOS schedule adjustment: Cycle delay and dose interruption  
One cycle consists of 3 weeks, and a total of 3 cycles will be performed. In case of unresolved 
toxicity, it is acceptable to delay administration for up to 3 weeks, and the new administration 
cycle cannot be initiated until the investigational product-related toxicity recovers to ≤ Grade 1 
or Baseline or is stabilized (except for alopecia, skin hyperpigmentation, and nail ridging). In 
case of dose delay due to any one of the relevant drugs, the entire treatment cycle should be 
delayed.  
If the neo-adjuvant chemotherapy exceeds 3 weeks per cycle or in case of dose adjustment, the 
next phase, i.e. surgical treatment can be selected for any reason, at the discretion of the 
investigator or at the request of the subject.  
However, unless the investigational product discontinuation criteria are met, the maximum of 3 
cycles should be all administered.  
 
9.3.2 Adjuvant chemotherapy S-1 
Adjuvant chemotherapy is administered from 3-6 weeks after surgery. One cycle consists of 6 
weeks, and after 4 weeks of S-1 40 mg/m2 twice daily oral administration, 2 weeks of wash-out 
will follow, and a total of 8 cycles will be implemented for about 1 year. 
 S-1 schedule adjustment: Cycle delay and dose interruption  
The investigational product should be administered for all 8 cycles, unless the administration 
discontinuation criteria are met. 
In case of unresolved investigational product-related toxicity during the adjuvant chemotherapy 
period, it is acceptable to delay administration for up to 3 weeks, and the new administration 
cycle cannot be initiated until recovery to ≤ Grade 1 or Baseline or stabilization (except for 
alopecia, skin hyperpigmentation, and nail ridging). However, for Grade 2 neutropenia during 
adjuvant chemotherapy, S-1 can be administered after reducing dose as presented in Table 4, at 
the discretion of the investigator.  
In case of dose delay for ≥ 3 weeks for the investigational product-related toxicity, adjuvant 
chemotherapy should be discontinued, and unless the subject withdraws consent on 
participation in this study, the study will continue, except for discontinuation of the relevant 
adjuvant chemotherapy.  
 






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Taxotere injection should be stored at 2C~25C and protected from light. In the case of 
Taxotere injection, physicochemical test results indicate the pre-mix solution prior to use is 
stable for 8 hr at 2C~8C or room temperature, but the pre-mix solution should be used 
immediately for preparation of the infusion solution. Taxotere injection should be used within 4 
hr, including 1 hour of injection time, at ambient temperature under normal lighting conditions 
after preparation of the infusion solution. 
As with any parenteral drug, the Docetaxel infusion solution and the pre-mix solution must be 
visually inspected prior to use, and should be discarded if there is any precipitate or 
discoloration.  
 
Oxaliplatin 
It should be stored at 1°C~25°C. 
Prepared infusion solution: From a physicochemical perspective, a solution diluted with 5% 
dextrose solution is stable at 2°C~8°C for 48 hours or at 25°C for 24 hours. From a 
microbiological perspective, the injection solution should be used immediately. In case of not 
using the solution immediately, the responsibility of the storage period and storage conditions 
prior to use lies with the user. However, it should not be stored for ≥ 24 hours at 2°C~8°C 
except for dilution under controlled and approved aseptic conditions.  
 
S-1 (Tegafur, Gimeracil, Oteracil) 
It should be stored at 1C~30C.  
9.5 Handling and Disposal 
Subjects will not discard but return unused blisters remaining after administration. 
All unused, partially used, or used investigational products will be checked for accurate 
accountability, signed by the investigator, and the returned to and destroyed by the sponsor. 
The investigator (or clinical trial pharmacist) will complete a detailed administration log of the 
investigational product, and the investigator’s Monitoring Team will co-sign the log.  
The investigator will not destroy the investigational product without the sponsor’s written 
approval.  
All materials used for dilution and administration can be disposed according to the standard 
procedure at the relevant site. 
9.6 Potential recall 
The investigational product can be recalled if there is a potential quality defect. In this case, the 
investigator has the responsibility to promptly respond to the sponsor’s request for the 
investigational product recall and elimination of the potential risk.  


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9.7 Combination therapy 
Concomitant therapy refers to any type of treatment continued from 14 days before 
randomization, during the study administration period, and until 30 days after the last dose, or 
all treatment initiated since the first dose of the investigational product. Such treatment should 
be carefully and accurately documented in the Case Report Form and source data.  
Any concomitant therapy during the study should be minimized to avoid the influence on results 
of this study. However, concomitant therapy can be implemented if determined by the 
investigator as not affecting the investigational product and necessary for the patient’s welfare. 
In this case, it should be necessarily recorded in the Case Report Form.  
It is recommended to use G-CSF according to the ASCO guideline58.  
Supportive treatment such as analgesics or blood products may be administered as necessary, 
based on a medical judgment.  
 
The following concomitant therapy is not allowed during administration of the investigational 
product in this study.  
 
 
Other investigational product 
 
Administration of other types of anticancer agent including conventional therapy or 
herbal medicine and/or radiotherapy 
 
Drugs excluded due to possible drug-drug interactions with S-1 during the study drug 
administration period (Table 5) 
 
Treatment with warfarin or other coumarin class anticoagulants  
 
Table 5. List of drugs that should be used with care or are prohibited due to potential 
drug-drug interactions with S-1 
 
Drug name 
Prohibited from 
concurrent use 
Fluoropyrimidine anti-malignant tumor agent 
Fluorouracil 
Tegafur, Uracil compound 
Tegafur 
Doxifluridine 
Capecitabine (Xeloda) 
Camofur
Folinate, Tegafur, Uracil therapy (e.g., UZEL/UFT, etc.) 
Levofolinate, Fluorouracil therapy (e.g., Isovorin/5-FU, 
etc.)
Fluoropyrimidine antifungal agent 
Flucytosine
Attention required 
for concurrent use  
Phenytoin 
Warfarin potassium
Other anti-malignant tumor agent, radiation, etc.
*TS-1Ⓡ Capsule 20, 25, Insert Paper dated 25Apr2015; 359 


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If use of prohibited concomitant medication or treatment is required for a subject, administration 
of the investigational product should be necessarily discontinued. Such cases should be 
necessarily reported as a reason for the investigational product discontinuation.  
 
9.8 Investigational product accountability management and compliance 
The investigator or the clinical trial pharmacist should check the inventory of all investigational 
product shipments, and confirm their receipt. The investigational product should be stored in a 
locked place with limited access, and stored and handled according to the manufacturer’s 
guideline. 
Administration of the investigational product is supervised by the investigator or the 
subinvestigator. 
The investigational product dispensing personnel should appropriately document all 
investigational products. Not only the total number of vials or tablets administered or dispensed 
to a patient per cycle but also Lot No. should be recorded in the Case Report Form or the 
Investigational Product Accountability Log. 
The person in charge of drug administration to a subject should accurately record the dosing 
date. 
 
The study monitor should periodically check the quantity of the investigational product retained 
by the investigator or the clinical trial pharmacist to confirm the accountability records of all 
used investigational products. Unless there is a method approved by the sponsor, all unused 
investigational products and all drug containers should be returned to the sponsor. The sponsor 
should check the final report of the Investigational Product Accountability Log, and confirm 
retention in the Investigator Study File. 
 
 
10  SAFETY OF SUBJECTS  
10.1 Safety endpoints 
In this study, clinical adverse events and data from conducted tests will be graded according to 
the NCI CTCAE v4.03.  
 
The investigator will collect information on the following variables and record in the Case 
Report Form. 
 
 
 Clinical examination including body weight, blood pressure, and ECOG PS 
 
 Clinical laboratory data 
o Total blood count and clinical chemistry  
o Other tests as clinically necessary 
 
Adverse events and serious adverse events 
 
Concomitant medication and concomitant therapy 
 
Reasons for administration discontinuation and the last dose date 
 
Adverse events that occurred prior to initiation of the investigational product are 
summarized separately. 


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 
For adverse events that occurred before and during administration, type, frequency, 
and cycle are assessed according to the Medical Dictionary for Regulatory Activities, 
and severity, seriousness and relationship, and abnormal levels of the conducted tests 
are evaluated according to the NCI CTCAE v4.03. 
 
10.2 Safety guidelines 
10.2.1 Physical examination 
Physical examination includes the tests including but not limited to the followings.  
 
Blood pressure 
 
Height (Baseline only), body weight 
 
ECOG PS 
In case of an abnormal finding or worsening from Baseline, it should be documented in the 
Adverse Event page of the Case Report Form. If such finding meets the serious adverse event 
criteria, the appropriate reporting procedure should be followed, as described in Section 10.5. 
Height is recorded at Baseline only. Body weight and ECOG PS are recorded prior to start of 
each administration cycle, and every 3 months or 6 months during follow-up until death or End-
of-Study (EOS), whichever is earlier.  
 
10.2.2 Clinical laboratory variables 
Clinical laboratory tests are conducted at the clinical laboratory of each site. Baseline findings 
should be necessarily performed and recorded to determine eligibility for enrolment, and 
protocol-specified tests should be conducted and the results should be confirmed and 
documented prior to starting administration of the investigational product at each cycle.  
 
Normal ranges of tests to be conducted at each site laboratory should be forwarded to the 
sponsor before starting this study. In case of abnormal and clinically significant findings based 
on these ranges, the relevant findings should be documented in the relevant section of the Case 
Report Form, and depending on the findings, a corresponding and appropriate medical action 
should be taken promptly. Data on test findings will be analyzed according to the Sanofi Test 
Result Data Processing and Reporting Guideline.  
 
Note: In case it is necessary to make a decision on permanent discontinuation of the 
investigational product due to abnormal findings of laboratory or ECG parameters, re-
measurement should be performed immediately to confirm the relevant test result, before 
determining permanent discontinuation of the investigational product. 
 
10.3 Monitoring of adverse events  
All adverse events will be managed and reported in compliance with applicable regulations, and 
included in the final result report. 
 


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10.4 Definition of adverse event (AE) and serious adverse event (SAE)  
An adverse event is any untoward and unintended sign (e.g.: abnormal laboratory findings), 
symptom, or disease occurring in a subject who administered the investigational product and 
does not necessarily have a causal relationship with the relevant investigational product.  
The protocol-specified efficacy endpoint is not considered an adverse event. However, this is 
not applicable in case the event is considered exceptional in the medical judgment of the 
investigator due to the course, severity, or other characteristics of the case.  
For an intra-operative or postoperative adverse event, if the event can occur as part of the 
surgical procedure or represents a usual postoperative adverse event, it does not have to be 
collected, at the discretion of the investigator. However, all other adverse events (see Appendix 
26.3 Surgical Manual Table 1) should be necessarily collected and reported according to the 
seriousness criteria.  
A serious adverse event is an adverse event or adverse drug reaction at any dose of the 
investigational product that corresponds to one of the following: 
1) Resulting in death or is life-threatening; 
2) Requiring in-patient hospitalization or prolongation of existing hospitalization; 
3) Resulting in persistent or significant disability of dysfunction; 
4) Resulting in congenital anomaly or birth defect; 
5) Important medical event: Medical and scientific judgment is required to determine necessity 
of expedited reporting for other cases such as a medical event that is not immediately life-
threatening or does not result in death or hospitalization but may jeopardize the subject or 
requires intervention to prevent one of other outcomes defined above. 
Such cases are usually considered serious. 
Note: Examples of such events are allergic bronchospasm, blood dyscrasias, convulsion 
requiring intensive care at an emergency room or home, or ALT elevation ≥ 10xULN, 
development of drug dependence or drug abuse that is asymptomatic but not resulting in 
hospitalization. 
Planned hospitalization for the surgery included in the process of this study is not considered a 
serious adverse event.  
10.5 Investigator’s responsibility on safety report 
10.5.1 Adverse event (AE) 
The safety observation period starts from the moment that a subject signs the Informed Consent 
Form for this study. 
 


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Adverse event that occurred while the subject was not being exposed to the investigational 
product is considered an adverse event only if it persisted until the initial dose of the 
investigational product or was serious, and should be recorded in the relevant page of the Case 
Report Form. 
 
All adverse events that occurred from the initial dose of the investigational product to 30 days 
after the last dose should be recorded in the relevant page of the Case Report Form, irrespective 
of seriousness or the causal relationship with the investigational product.  
 
For follow-up, see Section 10.5.3. 
 
Adverse event symptoms should be grouped as one syndrome or diagnosis. The investigator 
should record the adverse event onset date, severity, action taken for the investigational product, 
treatment, results of additionally conducted tests, outcome, and his/her opinion on the causality 
with the investigational product in the relevant pages. 
Abnormal blood pressure or ECG findings are recorded as an adverse event only when 
considered medically relevant, such as the followings: 
- Symptomatic or requiring correctional treatment; 
- Resulting in discontinuation/dose adjustment of the investigational product and/or 
satisfying the seriousness criteria. 
 
Abnormal clinical laboratory findings are recorded as an adverse event if they result in 
discontinuation or dose adjustment of the investigational product and/or are considered 
clinically relevant. 
 
10.5.2 Serious adverse event (SAE) 
In case of a serious adverse event(SAE), the investigator should report as follows. 
 Send the relevant Case Report Form page signed and dated to the Monitoring Team 
representative whose name, address, and fax number are specified in the protocol. It 
should be sent within 24 hr after the date that SAE was recognized.  
 
Email: 
 
 
Fax: 
 
 
Attach a copy of all conducted tests and test dates. Care should be taken to ensure that 
the subject’s identity is protected and the subject identification number is 
appropriately specified on the copy of all source documents provided to the sponsor 
(e.g.: de-identify the subject name). For laboratory results, the laboratory normal 
range should be included. 
 Follow-up of all SAEs resulting in death or are life-threatening should be additionally 
provided within one week. 
 
10.5.3 Follow-up 
 
The investigator should take all actions as medically appropriate to ensure safety of 
subjects. In particular, the investigator should follow all adverse events (e.g., clinical 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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signs, test results) until the subject’s condition recovers to the NCI CTCAE v4.03 ≤ 
Grade 1 or Baseline or is stabilized.  
 
In case of a serious adverse event, the subject should be followed until complete 
clinical recovery, and recovery of laboratory results to Baseline or stabilization of 
progression. This means that the subject may be followed until reaching these 
conditions even after the subject discontinues the study, and further investigations can 
take place at the request of Monitoring Team. 
 
For an adverse event occurring at any time after the investigational product 
discontinuation that is related with the investigational product or possibly caused by 
the investigational product at the discretion of the investigator, it should be recorded 
in the case report and reported to Monitoring Team if it is serious.  
 
10.6 Pregnancy 
Pregnancy is considered a serious adverse event only if it meets the seriousness criteria. 
However, even if it not meets the seriousness criteria, administration of the investigational 
product should be discontinued and the SAE Form and/or DEVP (Drug Exposure Via Parents) 
Form should be completed and submitted to the Monitoring Team representative whose name, 
address, and fax number are specified in the protocol (Email. 
 / Fax. 
) or the sponsor within 24 hr (expedited reporting). The investigator should discuss 
with the subject about the pregnancy, necessarily explain risks involved in case the pregnancy is 
maintained and possible effects on the fetus, and immediately discontinue administration of the 
investigational product, and implement follow-up as planned in this study.  
 
This would remain effective until 90 days after completion of the investigational product 
administration, and the subject’s pregnancy status monitoring and follow-up will be necessarily 
performed during this period. 
 
For a male subject, if the partner gets pregnant, it should be reported to the investigator and the 
sponsor. Partner of the relevant subject should get medical consultation and be followed as 
described above.  
 
10.7 Overdose 
Overdose of the investigational product is defined as administration of 30% or more from the 
planned dose in case of Docetaxel and Oxaliplatin, and administration of 30% or more from the 
allowed dose in case of S-1. Accidental or intentional overdose with symptoms of the 
investigational product should be reported to the sponsor within 24 hr (expedited reporting) 
regardless of seriousness criteria, and the circumstances of the overdose should be clearly 
recorded and the reason should be fully documented. In case of an asymptomatic case resulting 
from overdose, it should be recorded in a separate AE Form.  
 


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10.8 Responsibility of sponsor  
During the study, the sponsor will promptly report all SAEs that are suspected to be related with 
the investigational product and unexpected (i.e. SUSAR) to applicable relevant authorities, 
IRB/IEC, and the investigator.  
In addition, the sponsor may promptly report all expected SAEs that are suspected to be related 
with the investigational product to relevant authorities according to applicable local regulations.  
In this study, serious adverse events that are determined to be related with the underlying 
disease are considered unexpected only when they are deemed exceptional in light of the 
medical context according to the medical decision of the investigator, based on the course or 
severity or other characteristics of such events.  
 
Adverse events other than the expected adverse events in the Investigator’s Brochure and this 
protocol are considered unexpected adverse events.  
The sponsor will report all safety information observed during the conduct of this study in the 
Clinical Study Report (CSR). 
 
11 TEMPORARY OR PERMANENT DISCONTINUATION OF TREATMENT AND 
MANAGEMENT OF THE DISCONTINUATION  
Administration of the investigational product should continue according to the protocol, if 
possible. In case of discontinuing administration of the investigational product, it should be 
checked if it represents temporary interruption. Permanent administration discontinuation should 
be carefully considered, and should be necessarily recorded in the Case Report Form. In case of 
pregnancy, administration of the investigational product should be necessarily discontinued 
permanently.  
11.1 Permanent discontinuation of treatment with study drug 
11.1.1 Criteria for permanent discontinuation of treatment 
In following cases, the subject’s investigational product administration can be discontinued. 
However, unless the subject withdraws consent on participation in this study, assessment and 
follow-up planned in this study will be continuously performed:  
 
 
The subject may request for discontinuation of the investigational product 
administration at one’s wish, at any time, irrespective of the reason. For a subject who 
is not capable of voluntary self-expression, administration of the study drug can be 
discontinued at the request of the subject’s legally acceptable representative. “Legally 
acceptable representative” refers to an individual or legal or other entity authorized to 
provide consent on the subject’s participation in study-related procedure on behalf of 
the subject according to applicable laws. 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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 
Continuous administration of the investigational product may be harmful to the 
subject as follows, at the discretion of the investigator: 
(Example)  
- Disease progression defined in Section 8.7; 
- Unacceptable adverse event not controlled with symptomatic treatment, dose delay, or 
dose adjustment that interferes with subsequent administration of the investigational 
product;  
- Finding of a second primary cancer during the study, so that the study-specific 
treatment cannot be continued at the discretion of the investigator, and the subject 
agrees with this decision;  
 
Intercurrent disease that makes it impossible to administer the investigational product; 
 
Pregnancy; 
 
At the special request of the sponsor; 
 
Subject lost to follow-up. 
 
For all cases, the reason and date of discontinuation should be documented in the Case Report 
Form and the subject’s medical record. The subject should be followed to determine if the 
relevant reason represents an adverse event, and if it is an adverse event, it should be reported 
according to the adverse event reporting procedure. 
 
11.1.2 Subject managemnet after permanent discontinuation of treatment 
In case of permanent discontinuation of the investigational product administration, it should be 
recorded in the relevant page of the Case Report Form. 
 
Then, the subject will have an End-of-Treatment (EOT) visit as described in the protocol and 
enter follow-up subsequently. For a subject who cannot make an in-person visit to the relevant 
site, the investigator should do one’s best to contact the subject to identify the health condition 
of the relevant subject including survival status. And such attempts should be documented in the 
patient log (e.g., phone contact attempt date, registered mail receipt, etc.)  
 
If the subject does not withdraw consent on follow-up of this study even after the End-of-
Treatment (EOT), follow-up should be implemented as specified in the protocol. In addition, 
subjects who have ended the study (End of Study) in a survival state can be further followed up 
for survival status by visits or phone calls. 
 
Subject management  
A subject may discontinue follow-up of this study according to one’s voluntary decision at any 
time, for any reason. This is also possible at the discretion of the investigator.  
  
 
If follow-up is discontinued, this should be necessarily recorded in the relevant page 
of the protocol. 
 
It will be specified in the Statistical Analysis Plan (SAP) how to consider the primary efficacy 
endpoint of subjects who are lost to follow-up.  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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11.3 Results 
A subject who discontinued treatment in this study cannot re-enter this study, and the selection 
and treatment number of such subject should not be reused. However, a subject may be re-
selected in the study in exceptional cases that the subject has previously satisfied all 
inclusion/exclusion criteria at Baseline, was not randomized, and with the discussion of the 
investigator and the sponsor. Meanwhile, it will be determined whether the subject can be re-
tested for Baseline by the discussion of the investigator and the sponsor.  
 
11.4 Definition of source data 
Source data include clinical results, observations, and all information included in the original 
and certified copy of other activities required for reconstruction and assessment of the study. 
Source data are in source documents. Source documents are original documents, data, and 
records related to the study (e.g.: hospital note, clinical and administrative chart, laboratory note, 
memo, subject diary or assessment checklist, pharmacy dispensing record, data recorded in an 
automated machine, printout or copy certified after accuracy and integrity check, microfiches, 
film negative, microfilm or magnetic media, X-ray, subject file, pharmacy record, laboratory 
record, Medical-Technical Department record). Source documents should be maintained to 
support information from the Case Report Form.  
 
12 STATISTICAL CONSIDERATIONS  
12.1 Statistical and analysis plan 
Section 12 of this protocol will serve as the basis of the Statistical Analysis Plan for this study. 
This plan can be revised during the course of the study to reflect protocol amendments, and to 
address unexpected problems to the study conduct and data that may affect the planned analysis. 
Such revisions will be reviewed with the study and data kept as blind, and the final plan will be 
issued prior to the database lock for the interim analysis. 
12.2 Sample size  
The primary assessment of efficacy is based on the 3-year Progression-Free Survival (PFS). 
Results from the following previous studies were used as reference for sample size calculation.  
 
Reference 
Treatment 
3-year Relapse-
Free Survival 
N ENGL MED 2007;357:1810-2016) 
Surgery+S-1 
72% 
ASCO 2008, Gastrointestinal Cancer 
Symposium, abstracts No.6, 18)
Surgery+MFP or MF 
60%, 50% 
J Clin Oncol 26: 2008 (May 20 suppl; abstr 
LBA4511) 21)
Surgery+iceMFP or MF 
64%, 67% 
  
In a prior study of the postoperative adjuvant anticancer treatment (S-1) in Japanese gastric 
cancer patients, the 3-year Relapse-Free Survival to recurrence or death was 72%, and in 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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another study of the postoperative adjuvant anticancer treatment, it was approximately 
50%~67%. A study of S-1 in Japanese patients showed a much superior 3-year RFS to other 
study results, and the 3-year RFS of other adjuvant chemotherapy was 60%. Given the 
difference with subjects of this study since all these studies were conducted by randomly 
assigning subjects who had tumor resection, the 3-year Progression-Free Survival (PFS) in the 
SC Arm was assumed as 60%, and the 3-year PFS in the CSC Arm was calculated by assuming 
a 10% improvement from this level.  
Based on the assumption of the 3-year PFS of 70% in the CSC Arm and 60% in the SC Arm (i.e. 
HR=0.698), a total of 244 events and at least 238 subjects per group are required for comparison 
of PFS distribution between two groups with the 80% power. Given the dropout rate of 10%, a 
total of 530 subjects are required. This calculation was carried out by considering one interim 
analysis, using the group sequential approach with efficacy boundaries suggested by the 
O’Brien-Fleming alpha spending function. Two-sided 5% significance level and a total of 7.5 
years of follow-up were assumed, including 4.5 years of enrollment period. This study is 
completed upon observation of at least the target number of 244 events at the final analysis or 
reaching the median follow-up of 3 years.  
The software used for sample size calculation is nQuery Advisor 6.0, and the significance level 
for interim analysis and final analysis was calculated with PASS11. 
 
12.3 Analysis variables 
12.3.1 Demographic and baseline characteristics 
Standard demographic characteristics and Baseline characteristics (age, sex, body weight, and 
height included), relevant medical history, cancer diagnosis, prior anticancer agent treatment, 
pre-existing signs and symptoms will be collected at Baseline.  
Baseline efficacy variables and other prognostic variables such as tumor assessment will be also 
evaluated. At this time, Baseline is defined as the last level or assessment prior to administration 
of the first dose in the study. 
12.3.2 Efficacy variables 
12.3.2.1 Primary efficacy variable:  
The primary efficacy variable is the 3-year Progression-Free Survival (3-year PFS) defined as 
the time from randomization to demonstration of progressive disease (PD) or death.  
Progressive disease is defined as follows according to the RECIST1.1 Criteria and the time to 
progression is calculated until the first date of demonstration of progression. 
 
1. In the CSC Arm, PD is determined according to the RECIST 1.1 Criteria during the 
neo-adjuvant chemotherapy period. In case of PD determination based on the sum 
of diameters of target lesions, the date of such determination is defined as the last 
tumor assessment date of target lesions; PD based on apparent progression of a 
non-target lesion is defined as the relevant tumor assessment date. 
2. Irrespective of curative resection, if an intraoperative distant metastasis is observed 
or a distant metastasis is reported from pathology, it is considered PD, and the date 
of surgery is defined as the progression demonstration date.  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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3. If residual cancer cells were visually identified at the resection margin during 
surgery but could not be completely resected (R2), it is considered PD, and the date 
of surgery is defined as the progression demonstration date.  
4. If residual cancer cells are finally confirmed at the resection margin during 
postoperative histology (R1), it is considered PD, and the date of surgery is defined 
as the progression demonstration date.  
5. In case of finding a recurrence/distant metastasis or a new lesion during follow-up 
after R0 complete resection, it is defined as the first tumor assessment date when it 
was observed. 
 
In case of not being applicable to disease progression, the study will be censored on the 
following date, whichever is the earliest. 
 
1. For a subject lost to follow-up or disease progression or death is not confirmed 
until the End-of-Study, the last tumor progression status assessment date 
2. In case of finding a second primary cancer other than gastric adenocarcinoma at 
any time during the study, the last tumor progression status assessment date 
3. In case of receiving treatment other than the planned treatment without tumor 
recurrence, the last tumor progression status assessment date  
4. In case of no tumor assessment after randomization, the randomization date 
5. Study completion date 
    
 
12.3.2.2 Secondary efficacy variables 
Secondary efficacy variables are overall survival (OS), the postoperative stage, and the R0 
resection rate. 
OS is defined as the time from randomization to death for any cause. In case it is not clear 
whether the subject is dead or not, the survival period is calculated based on the last day that the 
subject is known to be alive or the study completion date, whichever is earlier. 
Post-operative stage and the R0 resection rate will be collected. 
12.3.3 Safety variables 
The following safety data will be collected: adverse events, hematological toxicity, clinical 
examination (physical examination, blood pressure, BSA, body weight, ECOG PS), special tests 
(chest X-ray, ECG), and laboratory data 
12.3.3.1 Adverse events 
Toxicity profile will be determined based on the NCI CTCAE v4.03 and collected at each visit 
after Baseline. 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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12.3.3.2 Laboratory safety variables 
Hematology and blood chemistry data will be collected at each visit during the treatment period. 
 
Hematology: Hemoglobin, WBC, ANC, Platelet count 
 
Blood chemistry: Sodium, Potassium, Calcium, BUN, Creatinine, Total protein, 
Albumin, SGOT (AST), SGPT (ALT), Total bilirubin, Alkaline phosphatase, Glucose 
* Creatinine clearance (using the Cockcroft-Gault calculation method): Collected at 
Baseline and during the neo-adjuvant chemotherapy period only 
 
12.3.3.3 Blood pressure 
Normal/abnormal result for blood pressure is collected at each visit. 
12.3.3.4 Other safety variables 
Routine physical examination is evaluated before and after administration. 
12.4 Analysis sets 
12.4.1 Efficacy set 
Intent-to-treat (ITT) Set includes all randomized subjects. 
Full Analysis Set (FAS) is defined as all randomized subjects who satisfied the 
inclusion/exclusion criteria and had at least one tumor assessment after the Baseline visit. While 
the CSC Arm includes subjects who administered at least one dose of the DOS investigational 
products, the SC Arm will include subjects who had surgery. 
Per-Protocol (PP) Set includes all randomized subjects who have no major protocol deviation 
and satisfy the following conditions. 
1) For the CSC Arm, subjects who completed the entire total 3 cycles of DOS administration as 
neo-adjuvant chemotherapy and then started adjuvant chemotherapy (S-1) according to this 
protocol  
2) For the SC Arm, subjects who had surgery and then started adjuvant chemotherapy (S-1) 
according to this protocol  
Note: Subjects who intended to receive postoperative S-1 adjuvant chemotherapy but did not 
start it at the discretion of the investigator based on consideration of the patient’s medical 
condition such as toxicity will be included in the PP Set. 
Serious protocol deviations will be specified in the Statistical Analysis Plan (SAP).  
Main analysis will be conducted in the FAS and all efficacy analyses will be also conducted 
using the ITT Set and the PP Set to confirm robustness of this study.  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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12.4.2 Safety analysis set 
Safety analysis set includes subjects who administered at least one dose of the investigational 
product. Medication compliance/administration and all clinical safety data will be summarized 
using the Safety analysis set. All analyses using this population will be based on the actually 
administered drug. 
12.4.3 Characteristics of subjects 
Subjects who entered Baseline are defined as all subjects who completed the Informed Consent 
Form and had assessment for enrollment eligibility criteria confirmation during the Baseline 
period.  
Randomized subjects are defined as all subjects who satisfied the enrollment eligibility criteria 
and randomized to one of two treatment groups. 
In addition, reasons for treatment discontinuation and study discontinuation will be presented 
for randomized subjects by treatment group. 
12.5 Statistical method 
Categorical data will be summarized in a table for frequency and the corresponding percentage 
by treatment group. Categorical data will be summarized by treatment group using frequency, 
mean, standard deviation, median (if applicable), minimum, and maximum. Descriptive analysis 
will be summarized for Baseline characteristics by treatment group and overall.  
Descriptive summary of the time to event data includes a Kaplan-Meier method, median time to 
event, and corresponding 95% confidence interval. 
All statistical tests will be conducted at an overall two-sided significance level of 5%.  
12.5.1 Demographic and baseline characteristics 
Demographics, medical history, and diagnosis at the Baseline visit will be tabulated using the 
ITT Set. Continuous variables, i.e. age, body weight, and height, and qualitative variables, i.e. 
sex, medical history, anticancer agent treatment history, diagnosis, and underlying signs and 
symptoms will be summarized as appropriate for characteristics of each data as explained 
previously, and will be compared for the between-group difference. 
12.5.2 Level of treatment exposure and drug compliance  
Extent of exposure will be assessed using the Safety analysis set. 
Number of treated subjects, number of administered cycles, dosing period (week), accumulated 
dose (mg/m2), dose intensity (mg/m2/week), and relative dose intensity (%) will be summarized 
by group.  
Dose delay and dose reduction will be also analyzed.  
S-1 compliance will be assessed based on the S-1 administration diary. 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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12.5.3 Analysis of efficacy variables  
12.5.3.1 Analysis of the primary efficacy variable  
The primary analysis will be conducted using the FAS as described in Section 12.4.1.  
The efficacy analysis is to compare the Progression-Free Survival (PFS). If h1(t) is a risk 
function of the CSC Arm and h0(t) is a risk function of the SC Arm, the null and alternative 
hypotheses for the main analysis are as follows and therefore, this study aims to demonstrate 
superiority of the CSC Arm to the SC Arm.  
 
H0:   h0(t) = h1(t)   vs 
H1:  h0(t)  h1(t) 
 
Progression-Free Survival is compared between two treatment groups using a log rank test 
stratified by stratification factors (site, TNM stage (T4/N-, T2/N+, T3-4/N+) according to the 
AJCC 7th Edition) specified at randomization at the overall 5% significance level. Survival 
curve is estimated using the Kaplan-Meier estimate. Median and the corresponding 95% 
confidence interval, and the 3-year Progression-Free Survival will be presented by treatment 
group.  
 
The final PFS analysis is conducted upon observation of at least 244 events or reaching median 
follow-up of at least 3 years. One PFS interim analysis was planned for efficacy confirmation 
upon occurrence of approximately 122 PFS events (50% of all events). Using group sequential 
approach with the O’Brien-Fleming alpha spending function and the overall significance level 
of 5%, the significance level for the final analysis is 0.049 (for details of the interim analysis, 
see Section 12.6). 
The analysis described above will be repeated for the PP Set defined in Section 12.4.1. 
 
12.5.3.2 Analysis of secondary efficacy variables  
Overall survival is analyzed in the same way as the PFS. At the overall 5% significance level, 
survival experiences are compared between two treatment groups using a log rank test stratified 
by stratification factors (site, TNM stage (T2/N+, T3-4/N+, T4/N-) according to the AJCC 7th 
Edition) specified at randomization. Survival curve is estimated using the Kaplan-Meier 
estimate. Median and the corresponding 95% confidence interval will be presented by treatment 
group.  
 
For the postoperative stage and the R0 resection rate, frequency and percentage will be 
presented, and compared using a Cochran-Mantel-Haenszel test stratified by stratification 
factors (site, TNM stage (T2/N+, T3-4/N+, T4/N-) according to the AJCC 7th Edition) specified 
at randomization.  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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In case the postoperative stage and the R0 resection rate are missing, analysis will be conducted 
using the Efficacy Set, and subjects with missing data will be excluded from the denominator 
when calculating percentage.  
 
12.5.3.3 Analysis of additional efficacy variables  
Additional explorative analysis can be considered and will be fully presented in the SAP. For 
example, a Cox proportional hazard model can be used to investigate the effect of various 
prognostic factors on PFS and OS. Hazard ratio assessment and the corresponding 95% 
confidence interval can be presented using the Cox proportional hazard model stratified by the 
same stratification factors as used for the aforementioned log rank test, if data satisfy conditions 
for a Cox proportional hazard model. In addition, OS can be analyzed exploratorily by including 
data on survival status, additionally collected after the end of the study (End of Study). 
 
12.5.4 Analysis of safety data 
For analysis of safety data, adverse events, hematological toxicity, routine physical 
examination, and laboratory data will be described and analyzed using the Safety analysis set 
defined in Section 12.4.2. Safety data will be also summarized by cycle (if applicable). For each 
safety variable, Baseline will be defined as the last level or assessment measured prior to the 
first treatment in the study. 
 
12.5.4.1 Analysis of adverse events  
Adverse events will be described using the total number of subjects who experienced toxicity or 
an adverse event. For comparison of safety between two groups, adverse events will be 
summarized by treatment group, and the number and percentage of subjects with an adverse 
event will be presented. For the CSC Arm, adverse events reported during the pre-operative 
DOS period will be presented separately from postoperative adverse events, and adverse events 
reported postoperatively will be compared between the CSC Arm and the SC Arm using 
frequency analysis.  
 
Baseline adverse event is defined as an adverse event that developed or worsened during 
Baseline.  
Treatment-emergent adverse event (TEAE) is defined as an adverse event that developed or 
worsened during the treatment period (from the investigational product administration to 30 
days after the last dose of the investigational product). However, in case a subject used an 
anticancer agent other than the investigational product during the treatment period, the adverse 
event after using concomitant medication will be excluded from analysis.  
All adverse events will be classified using the MedDRA and summarized as grades determined 
according to the NCI CTCAE v4.03. MedDRA version retained by Sanofi at the time of analysis 
will be used. Severity of adverse events will be summarized as the highest grade experienced by 
the subject. For the following adverse events, frequency and percentage will be presented by 
System Organ Class and Preferred Term in the Safety analysis set. 


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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 
All adverse events classified by System Organ Class and TEAEs possibly related with 
the investigational product, in descending order of frequency  
 
All TEAEs and TEAEs possibly related with the investigational product by severity 
and System Organ Class 
 
Serious adverse events: All and possibly related serious TEAEs classified by 
seriousness criterion  
 
Serious adverse events: All and possibly related TEAEs classified by System Organ 
Class 
 
Death: All and possibly related TEAEs classified by System Organ Class  
 
Study discontinuation: All and possibly related TEAEs  
 
Other significant adverse events: All and possibly related TEAEs according to the 
“Other significant” adverse event criteria  
12.5.4.2 Analysis of laboratory variables  
Hematological toxicity will be assessed based on laboratory findings. Worst NCI CTCAE grade 
for leukocytopenia, neutropenia, thrombocytopenia, and anemia will be calculated according to 
the NCI Common Terminology Criteria.  
Hematological toxicity will be summarized with quantitative and qualitative results. Qualitative 
data (worst NCI CTCAE grade) will be summarized by cycle and subject. 
Biochemistry will be analyzed using the worst NCI CTCAE grade calculated from laboratory 
findings, if applicable (laboratory normal range, other). 
 
12.5.4.3 Analysis of blood pressure variables  
Change from Baseline in blood pressure will be descriptively analyzed. 
 
12.5.4.4 Analysis of other safety variables  
Descriptive statistics for clinical examination (physical examination, blood pressure, height, 
body weight, ECOG PS) and special tests (gastroduodenoscopy, laparoscopy) will be presented 
by visit, and change from Baseline will be summarized. 
 
12.5.5 Analysis of pharmacokinetic and pharmacodynamic variables  
There was no plan for pharmacokinetic and pharmacodynamic analysis. 
12.5.6 Analysis of health economic variables  
Health economic analysis was not conducted in this study.  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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12.6 Interim analysis 
The objective of the interim analysis is to provide IDMC members with a methodological 
rationale and decision making rules for continuation of the study as planned or recommendation 
of early study discontinuation in case of demonstrating efficacy based on the previously 
described boundary area. Further details will be described in the IDMC Charter.  
The interim analysis will be conducted upon occurrence of approximately 122 PFS events (50% 
information rate). O’Brien-Fleming α-spending function will be used for interim analysis of 
efficacy. Under this suggestion, a total of 244 events are required along with the interim analysis 
upon occurrence of approximately 122 PFS events. At the interim analysis, the boundary for 
early study discontinuation with the absolute efficacy of CSC would be the significance level of 
0.0031. 
 
13 ETHICS AND REGULATIONS 
13.1 Ethical principles 
This study will be conducted according to the principles set out at the 18th World Medical 
Association (Helsinki, 1964), all applicable revisions at World Medical Association meetings, 
and the International Conference on Harmonisation Good Clinical Practice Guideline (ICH 
GCP). 
 
13.2 Laws and regulations 
This study is conducted in compliance with all international laws and regulations, local laws 
and regulations in the country where the study is conducted, and applicable guidelines.  
13.3  Informed consent 
The investigator (according to applicable regulatory requirements) or a person designated by 
the investigator should fully inform a subject of all study-related aspects, including information 
on the Approval/Approval with Correction Letter (favorable opinion) of the IRB/IEC, under the 
responsibility of the investigator. All participants should receive as much information as 
possible on the study, in the language and terms they can understand.  
Prior to the subject’s study participation, the subject or subject’s legally acceptable 
representative, and the person who conducted the informed consent process should sign the 
Informed Consent Form and other relevant documents according to local laws and regulation, 
and personally sign and date them. A copy of the signed and dated Informed Consent Form is 
provided to the subject. 
The Informed Consent Form used by the investigator to obtain consent of the subject should be 
reviewed and approved by the sponsor before being submitted for approval/approval with 
correction of the relevant IRB/IEC.  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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13.4 Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
The investigator or the sponsor should submit the protocol to the relevant IRB/IEC and provide 
the Approval Letter/Approval with Correction Letter dated and signed by the Ethics Committee 
Chairperson to the sponsor. 
 
The study (study number, protocol title, and version number), reviewed documents (e.g., 
protocol, Informed Consent Form, Investigator’s Brochure, investigator’s Curriculum Vitae), 
voting member list and qualification, and the review date should be clearly mentioned in the 
Approval Letter/Approval with Correction Letter of the relevant IRB/IEC. 
 
The investigational product cannot be supplied to the site nor can the study be initiated before 
the sponsor receives the dated Approval Letter/Conditional Approval Letter. 
 
During the study, all revisions or amendments of the protocol should be submitted to the 
IRB/IEC. In addition, any matter that may affect subject safety and continuous conduct of the 
study, in particular, safety-related change should be reported during the course of the study. All 
revised Investigator’s Brochures are to be submitted to the IRB/IEC. 
 
If requested, a study progression report is to be submitted to the IRB/IEC every year, and 
summarized study results are to be submitted at study completion. 
 
14 MONITORING  
14.1 Responsibilities of investigator(s) 
The investigator conducts the study according to this protocol, the International Conference on 
Harmonisation Good Clinical Practice Guideline (ICH GCP), and applicable laws regulation. 
 
The investigator should comply with all protocol-required procedures and all study procedures 
provided by the sponsor (confidentiality principle included). The investigator should provide 
reliable data and all protocol-required information (using the Case Report Form (CRF), 
Discrepancy Report Form (DRF), or other applicable tool) according to the provided guideline 
in an accurate and legible manner, and allow the sponsor’s representative to have direct access 
to source documents. 
 
The investigator may designate other person according to the protocol if deemed appropriate as 
a subinvestigator to support the study conduct. All subinvestigators are to be designated in a 
timely manner and recorded in a list. The subinvestigator is under the supervision and 
responsibility of the investigator. The investigator is to provide the subinvestigator with the 
protocol and a copy of all necessary documents.  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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14.2 
Responsibilities of sponsor 
Sponsor of this study has the responsibility to take any reasonable action to guarantee 
appropriate conduct of and compliance with the protocol in relation to the ethical aspect and 
integrity and validity of Case Report Form entries to public health authorities. Therefore, the 
major responsibility of Monitoring Team is to support the investigator and the sponsor to 
maintain high ethical, scientific, technical, and legal standards in all aspects of the study. 
 
Monitoring Team representative will periodically conduct site visits during the study via 
monitoring visits, letters, or phone calls to review the study progress status, compliance of the 
investigator and subjects with protocol requirements, and any emergent issue. During such 
monitoring visits, the following matters (not minor issues) will be closely examined with the 
investigator: Informed Consent Form, subject eligibility, subject enrollment and follow-up, 
serious adverse event recording and reporting, investigational product dispensing, subject’s 
compliance with the protocol and investigational product treatment, investigational product 
accountability check, use of concomitant medication, and data quality level.  
14.3 
Source document requirements  
According to the International Conference on Harmonisation Good Clinical Practice Guideline 
(ICH GCP), Monitoring Team should compare Case Report Form entries with source 
documents, except for source data that are to be directly recorded in the Case Report Form as 
specified previously. Informed Consent Form includes a statement that the subject allows the 
sponsor’s formally designated representative, IRB/IEC, and relevant authorities to have direct 
access to source documents (e.g., subject’s medical records, appointment table, original of 
laboratory test reports) that support the Case Report Form. All such people bound by 
professional confidentiality should maintain confidentiality of all personal or medical 
information according to the confidentiality principle. 
14.4 Preparation of case report form and other requests  
It is the responsibility of the investigator to maintain the Case Report Form designed by Sanofi 
(according to the Sanofi guideline) to capture all observations and other clinical test-related 
data in an appropriate and accurate manner (depending on the used method). All Case Report 
Forms should be completed in a clear and legible manner to allow accurate data interpretation. 
 
Corrected information should not obscure the original entry. The corrected information is to be 
recorded by an authorized person next to the previous entry, and the person who made the 
correction is to sign and date.  
 
NCR Form is used for the Case Report Form, and an original and a copy will be collected by 
the monitor. The original form will be sent to Statistical Department for analysis and the first 
copy will be retained at Sanofi. The last and second copy should be maintained at the site.  


STUDY N° EFC13833                                                                                                                            VERSION: V9.0  
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14.5 
Use of computer system  
A computer system will be used to develop, correct, maintain, save, and, search a database of 
all data collected from this study. 
 
15 ADMINISTRATIVE REGULATIONS  
15.1 Curriculum Vitae 
The original Curriculum Vitae reflecting the latest details of the career, qualification, and 
education of each investigator and subinvestigator should be provided to the sponsor prior to 
study initiation. 
15.2 Record retention in study site(s)  
The investigator should maintain all study records as confidential, and take action to prevent 
accidental or premature destruction of these documents.  
 
Unless separately specified in the Investigator Agreement according to standards and/or laws of 
the relevant country, the investigator is recommended to retain study records for 15 years after 
study completion or discontinuation. 
 
However, if a longer period is required by applicable regulations, it should be followed.  
 
The investigator should inform the sponsor prior to destruction of key study documents after 
study completion or discontinuation. 
 
In case further retention cannot be ensured due to the investigator’s personal situation, the 
investigator should inform the sponsor and transfer relevant documents to a mutually agreed 
delegate.  
 
16 CONFIDENTIALITY 
All information disclosed or provided by the sponsor (or a company/site working on behalf of 
the sponsor) or generated during the study is confidential, including the protocol, Case Report 
Form, Investigator’s Brochure, and results obtained during the course of the study. The 
investigator and all subinvestigators under the supervision of the investigator should agree to 
confidentiality and no disclosure of information to any other site without the sponsor’s prior 
written approval. 
 
However, it is clearly acceptable to submit this protocol and other necessary documents to the 
IRB/IEC, and IRB/IEC members are also bound by the same confidentiality obligation. 
 


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The subinvestigator has the same obligation as the investigator. The investigator should inform 
the subinvestigator of the confidentiality principle of the study. 
 
The investigator and the subinvestigator should use such information only for the study purpose, 
but not for one’s own or a third site’s interests.  
 
17 PROPERTY RIGHTS 
Any information, document, and investigational product provided by the sponsor or its 
representative are the exclusive property of the sponsor. 
 
The investigator should not mention the information or the investigational product associated 
with a patent or any other intellectual property. 
 
In any form, any result, document, or details of intervention derived directly or indirectly from 
the study represent an exclusive property of the sponsor.  
 
The sponsor can use or utilize all results at the sponsor’s own discretion, without any restriction 
in the ownership (area, field, persistency). The sponsor shall not have any responsibility for 
other use of the patent, development, marketing, or study results. 
 
18 DATA PROTECTION 
Personal information of the subjects and the investigator that may be included in the sponsor’s 
database will be handled according to applicable laws and regulations.  
During retention and processing of personal information related to the investigator and/or the 
subject, the sponsor should take all appropriate actions to prevent and protect from 
unauthorized access to such data.  
 
19 COMPENSATION INSURANCE  
The sponsor ensures subscription to a liability insurance policy covering all studies supported 
by the sponsor. This insurance policy is to comply with laws and regulation of the relevant 
country. The obligation of the investigator and cooperators to maintain their own liability 
insurance policy cannot substitute the insurance taken out by the sponsor. In a country that 
requires such document, a copy of the insurance certificate is to be submitted to the IRB/IEC or 
relevant authorities. 
 


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20 SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
To ensure compliance with the protocol, Good Clinical Practice (GCP) and applicable 
regulatory requirements, the investigator should accept an audit by the sponsor or its 
representative and an inspection by applicable regulatory authorities. 
The investigator should agree to allow an auditor/inspector bound by professional 
confidentiality to have direct access to study records for a review, and this would not result in 
disclosure of personal identity or personal medical information. 
The investigator will do his/her best to support the audit and inspection by allowing access to 
any necessary facilities, data, and documents. 
Upon being notified of the inspection from authorities, the investigator is to immediately inform 
the sponsor and authorize the sponsor to attend the inspection. Priority will be given to 
confidentiality of validated data and protection of subjects during implementation of such 
inspection. 
 
The investigator should immediately inform the sponsor of all results and information raised 
from the inspection by regulatory authorities. 
 
The investigator should take an appropriate action as requested by the sponsor to correct any 
problem found during the audit or inspection. 
 
21 EARLY DISCONTINUATION OF THE STUDY OR EARLY TERMINATION OF A 
SITE 
At the decision of the sponsor: 
 
In case of a suspected benefit/risk ratio from information on the product; 
 
In case the investigator has not enrolled any subject after a mutually agreed 
appropriate period, after having received all investigational products, methods, and 
information required for the study conduct from the sponsor; 
 
In case the study results do not appear scientifically reliable to the sponsor (for 
example, based on results of the planned futility analysis); 
 
In case the study objective is outdated or not relevant anymore; 
 
In case the investigator violated the basic responsibilities in this contract including but 
not limited to the protocol deviation, and the International Conference on 
Harmonisation Good Clinical Practice Guideline (ICH GCP); 
 
In case of recruiting the target number of subjects earlier than expected. 
In any case, the sponsor will inform the investigator of such decision in writing.  
At the decision of the investigator: 
The investigator should inform the sponsor of the decision and the reason in writing (at least 30 
days prior to discontinuation). 


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In any case (whether decided by the sponsor or the investigator), the relevant IRB/IEC and 
public health authorities will be informed.  
 
22 RESULTS 
The sponsor has the right to complete the Clinical Study Report (CSR). 
The sponsor will transfer study results to the investigator after sufficiently analyzing data from 
all sites; 
 
23 PUBLICATION AND RELEASE 
The investigator has the obligation not to make any publication or presentation in relation to this 
study and/study results before getting the sponsor’s written consent, and this is based on the 
understanding that the sponsor would not unduly postpone such approval.  
 
Since this study is conducted in multiple sites, the sponsor agrees that the first presentation or 
publication of results of this study will be based on results obtained from all sites conducting 
this protocol to be in line with scientific standards. However, if multicenter publication is not 
implemented or there is no such plan within 12 months after completion of this study at all sites, 
the investigator has the right to independently publish or present results from this study 
according to the review procedure established herein. The investigator should provide a copy of 
all such presentations or publications derived from this study at least 45 (calendar) days, or a 
copy of an abstract at least 30 days prior to submission for such presentation or publication to 
the sponsor to get a review and opinions. In addition, at the request of the sponsor, submission 
for presentation or publication should be postponed for a limited period not exceeding 90 days 
for patent application or other action as determined appropriate for establishment and retention 
of the sponsor’s property right.  
 
The investigator should not use the name of the sponsor or its employee in an advertisement or 
promotion material or publication without getting the prior written approval of the sponsor. The 
sponsor shall not use the name of the investigator and/or co-investigator in an advertisement or 
promotion material or publication without getting the prior written approval of the investigator 
and/or co-investigator. 
 
The sponsor has the right to publish results of this study at any time.  
 
24 REVISION OF THE PROTOCOL 
All appendices attached to and referenced in this document are treated as part of this protocol. 
 


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The investigator cannot violate the protocol or implement the protocol amendment before the 
sponsor’s consent and documentation of the result of the IRB/IEC review and 
approval/approval with correction (favorable opinion) for the amendment, unless it is necessary 
to eliminate the immediate hazard to subjects or in case of an amendment involving only a 
logistical or administrative aspect of the study. Contents of all agreed amendments will be 
documented, the investigator and the sponsor will sign the written amendment version, and the 
signed amendment version will be filed with this protocol. 
 
All protocol amendments require the Approval Letter/Conditional Approval Letter of IRB/IEC 
before implementation, unless there is a prioritized safety issue. 
 
In some cases, it may be necessary to revise the Informed Consent Form due to amendment. 
The investigator should get written approval/conditional approval of IRB/IEC for the revised 
Informed Consent Form before implementing the amendment.  


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25 REFERENCES 
 
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25. Kang Y, Kim T, Chang H, Ryu M, Yook J, Oh S et al. Phase I/II study of a combination of 
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cisplatin (DXP) in patients with unresectable locally advanced or metastatic gastric cancer. Ann 
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oxaliplatin, fluorouracil, and folinic acid in locally advanced or metastatic gastric cancer 
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37. Shirasaka T, Shimamato Y, Ohshimo H, Yamaguchi M, Kato T, Yonekura K et al. 
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S-1 alone in advanced gastric cancer (JCOG9912). J Clin Oncol (Meeting Abstracts) 2007; 25 
(18 suppl), LBA4513. 
50. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M et al. S-1 + cisplatin vesus S-
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52. Yoshida K, Ninomiya M, Takakura N, Hirabayashi N, Takiyama W, Sata Y et al. Phase II study 
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55. Richards D, McCollum D, Wilfong L, Sborov M, Boehm KA, Zhan F et al. Phase II study of 
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59. TS-1Ⓡ Capsule 20, 25, Insert Paper dated 25Apr2015; 3 
 


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26 APPENDICES 
26.1 Creatinine Clearance Calculation Method 
26.2 ECOG Performance Status 
26.3 Surgical Manual (v3.0_20120206) 
26.4 Participating Sites and Investigators 
26.5 AJCC TNM Classification (7th Edition) 
 
 
 


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26.1 Creatinine Clearance Calculation Method 
 
 Use the Cockcroft-Gault calculation method  
 
 
Female:                                                                               X 0.85 
             
 
 
 
Male:  
 
 
 


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26.2 ECOG Performance Status 
 
 
ECOG PERFORMANCE STATUS*
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, e.g., light house work, office work
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982.  
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the scale, please 
cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
 
 
 


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26.3 Surgical Manual (v3.0_20120206) 
<Surgical Manual > 
In this study, the basic purpose of surgery is curative resection. Curative resection is as 
follows.  
 
1. No distant metastasis.  
2. No infiltration to surrounding organs, or in case of infiltration, curative combined resection 
should be performed. 
3. No macroscopic residual cancer.  
4. D2 or greater resection is necessarily required.  
5. No infiltration of cancer cells on both margins from histopathology.  
 
Minimum qualifications of the surgeon should satisfy the following conditions  
1) Investigator at a site that performs at least 60 gastric cancer operations per year  
2) Investigator with at least 2 years of career experience in gastric cancer surgery  
3) Investigator who has performed at least 100 gastric cancer operations  
 
Methods of the surgery are as follows. 
 
1. Gastrectomy methods depending on the tumor location 
The scope of gastrectomy can be determined at the discretion of the investigator depending 
on the location of tumor. 
 
1) Total gastrectomy 
Tumor located in upper 1/3 or upper/middle 1/3 of the stomach 
2) Subtotal gastrectomy 
i) Tumor located in lower/middle 1/3 of the stomach  
ii) 
Tumor located in lower 1/3 of the stomach irrespective of gastric pylorus or 
duodenum involvement 
 
2. Surgical resection margin 
 
1) The recommended distance from the tumor to the resection margin is at least 3 cm for 
Borrmann type I or II and at least 5 cm for Borrmann type III or IV.  
2) In case it is difficult to secure the specified safety margin, conduct frozen biopsy, and 
resection can be performed after confirming negative pathological findings on the 
resection area. 
3) For total gastrectomy, if the tumor margin is close to the gastroesophageal junction, at 
least 3 cm proximal safety resection distance is required, and it should be confirmed 
that there are no tumor cells with frozen biopsy. 
 
3. Guideline on the lymph node resection based on D2 resection 




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2) Omentobursectomy may be performed if necessary, at the discretion of the investigator. 
3) For total gastrectomy, both pancreatic conservation surgery and splenic conservation 
surgery can be conducted to remove the #10 lymph node. 
 
5. Reconstruction method after gastrectomy 
Any of the suggested reconstruction methods can be performed as preferred by the 
investigator.  
 
A. Total gastrectomy 
1. Roux-en-Y esophagojejunostomy 
2. Jejunal interposition 
3. Double tract method  
 
B. Subtotal gastrectomy 
1. Billoroth I gastroduodenostomy 
2. Billoroth II gastrojeunostomy 
3. Roux-en-Y gastrojejunostomy 
4. Jejunal interposition 
 
6. Recording after resection  
CRF record and photo documentation are recommended as they enable confirmation of 
the resection scope after surgery. For photo documentation, 2 or 3 pictures should be 
taken, and the following areas should be necessarily included. 
1) Pancreatic head including #6 and #14 lymph nodes 
2) Superior border of the pancreas with exposed portal vein, hepatic artery, celiac 
trunk, and splenic vein  
3) The area including the origin of the left gastroepiploic vessel  
 
7. Reporting of postoperative complications 
For reporting of adverse events of the postoperative complications, adverse events developing 
during surgery and within 30 days after surgery should be reported, and it is not necessary to 
report usually occurring postoperative complications as adverse events, at the discretion of the 
investigator. However, it is recommended to report complications other than usually occurring 
complications according to the following examples and the CTCAE criteria (Table 1). 
 










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26.5  AJCC TNM Classification (7th Edition) 
 
 
 
 
 

SAP_003.pdf: 
The information in this document is the property of sanofi-aventis and is confidential. Neither the document nor the information 
contained therein may be reproduced or disclosed outside Aventis without the written consent of the company. 
STATISTICAL ANALYSIS PLAN 
A Phase III, Open-labelled, Randomised Study of Neoadjuvant Docetaxel+Oxaliplatin+S-1 
(DOS) + Surgery + Adjuvant S-1 versus Surgery + Adjuvant S-1 in Patients with resectable 
Advanced Gastric Cancer  
EFC13833 (V 9.0) 
PRODIGY 
Prepared by 
 Name: 
 
Date of issue: 
21 December 2021 
Document version number: 
Addendum 2 
NCT01515748


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TABLE OF CONTENTS 
ABBREVIATIONS AND DEFINITIONS ......................................................................................................... 4 
SIGNATURE PAGE ........................................................................................................................................ 5 
1 
OVERVIEW ..................................................................................................................................... 6 
1.1 
OBJECTIVES .................................................................................................................................... 6 
1.1.1 
Primary Objectives ............................................................................................................................. 6 
1.1.2 
Secondary Objectives .......................................................................................................................... 6 
1.1.3 
Safety ................................................................................................................................................ 6 
1.2 
MODIFICATIONS FROM THE STATISTICAL SECTION IN THE PROTOCOL ................................. 6 
2 
INVESTIGATIONAL PLAN ............................................................................................................ 7 
2.1 
STUDY DESIGN AND RANDOMIZATION ....................................................................................... 7 
2.2 
SAMPLE SIZE JUSTIFICATION ....................................................................................................... 8 
3 
STATISTICAL AND ANALYTICAL PROCEDURES ................................................................... 10 
3.1 
ANALYSIS VARIABLES ................................................................................................................ 10 
3.1.1 
Efficacy Variables ............................................................................................................................ 10 
3.1.1.1 
Primary Efficacy variable .................................................................................................................. 10 
3.1.1.2 
Secondary efficacy variables ............................................................................................................. 11 
3.1.2 
Safety Variables ............................................................................................................................... 11 
3.1.2.1 
Adverse Events................................................................................................................................. 11 
3.1.2.2 
Laboratory Safety Variables .............................................................................................................. 11 
3.1.2.3 
Creatinine clearance(Cockcroft-Gault Formula) .................................................................................. 11 
3.1.2.4 
Blood Pressure ................................................................................................................................. 12 
3.1.2.5 
Other Safety Variables ...................................................................................................................... 12 
3.2 
ANALYSIS POPULATIONS ............................................................................................................ 13 
3.2.1 
Efficacy Populations ......................................................................................................................... 13 
3.2.1.1 
Intent -to-Treat (ITT) and Full Analysis Set Population........................................................................ 13 
3.2.1.2 
Per-protocol Population ..................................................................................................................... 13 
3.2.2 
Safety Population ............................................................................................................................. 14 
3.3 
STATISTICAL METHODS .............................................................................................................. 14 
3.3.1 
Demographics and Baseline Characteristics ........................................................................................ 14 
3.3.1.1 
Variables Related to Demographics and Baseline Characteristics .......................................................... 15 
3.3.2 
Discontinuations and Dropouts .......................................................................................................... 15 


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3.3.3 
Extent of Exposure and Compliance ................................................................................................... 15 
3.3.3.1 
Variables of Extent of Exposure and Compliance ................................................................................ 16 
3.3.4 
Concomitant Treatment ..................................................................................................................... 17 
3.3.4.1 
Prior and Concomitant Medication ..................................................................................................... 17 
3.3.4.2 
Past and Current Medical History ....................................................................................................... 17 
3.3.5 
Efficacy analyses .............................................................................................................................. 17 
3.3.5.1 
Primary efficacy analysis................................................................................................................... 17 
3.3.5.2 
Secondary efficacy analyses .............................................................................................................. 18 
3.3.5.3 
Additional efficacy analyses .............................................................................................................. 19 
3.3.5.4 
Subgroup Analysis ............................................................................................................................ 19 
3.3.6 
Safety Analyses ................................................................................................................................ 20 
3.3.6.1 
Adverse Events................................................................................................................................. 20 
3.3.6.2 
Laboratory Safety Variables .............................................................................................................. 21 
3.3.6.3 
Other Safety Variables ...................................................................................................................... 23 
3.4 
DATA HANDLING CONVENTIONS ............................................................................................... 24 
3.4.1 
Baseline Definitions .......................................................................................................................... 24 
3.4.2 
Missing Data .................................................................................................................................... 24 
3.4.2.1 
Missing data of Efficacy Variable ...................................................................................................... 24 
3.4.2.2 
Missing data of Safety Variable ......................................................................................................... 24 
3.4.3 
Handling of Incomplete Data ............................................................................................................. 24 
3.4.4 
Character Values of Clinical Laboratory Evaluation ............................................................................ 25 
3.4.5 
Decimals .......................................................................................................................................... 25 
3.4.6 
Pooling of Centers for Statistical Analyses .......................................................................................... 25 
3.4.7 
Statistical Technical Issues ................................................................................................................ 25 
4 
INTERIM ANALYSIS .................................................................................................................... 26 
5 
SOFTWARE DOCUMENTATION ................................................................................................ 27 
LIST OF APPENDICES................................................................................................................................. 28 
REFERENCES .............................................................................................................................................. 28 
APPENDIX A: SUMMARY OF STATISTICAL ANALYSES ........................................................................ 29 
APPENDIX B: UNIT CONVERSION TABLE ............................................................................................... 31 


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ABBREVIATIONS AND DEFINITIONS 
 
BSA: Body surface area 
CSC: Neoadjuvant Docetaxel+Oxaliplatin+S-1 (DOS) + Surgery + Adjuvant S-1 arm 
ECOG PS: Eastern Cooperative Oncology Group Performance status 
HR: Hazard ratio 
IDMC: Independent data monitoring committee 
ITT: Intention-to-treat 
IWRS: Interactive web response system 
KPS: Karnofsky Performance Score 
MedDRA: the Medical Dictionary for Regulatory Activities Terminology 
NA: Not applicable 
NCI CTCAE: National cancer institute common terminology criteria for adverse events 
OS: Overall Survival 
PD: Progressive disease 
PFS: Progression free survival 
RECIST: Response Evaluation Criteria in Solid Tumors 
SC: Surgery + Adjuvant S-1 
SI units: International system of units 
TEAE: Treatment emergent adverse event 
WHO drug: World health organization drug 


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SIGNATURE PAGE 
 
 
Prepared by: 
 
 
 
Date(dd-mmm-yyyy) 
 
Signature 
 
Reviewed by LSK Global PS:  
 
 
 
 
 
 
 
Date(dd-mmm-yyyy) 
 
Signature 
 
 
Approved by Sanofi 
 
 
 
 
 
 
 
 
 
Date(dd-mmm-yyyy) 
 
Signature 
 
 
 


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1 
OVERVIEW 
 
The statistical analysis process to be performed in the clinical trial is based on the clinical trial protocol 
and this statistical analysis plan (SAP), and evaluates the demographic and medical information, as well 
as the efficacy and safety data. This SAP may be changed during the trial in order to reflect the changes 
in the clinical trial protocol and to accept unexpected problems in the study implementation and data 
affecting the planned analysis. These changes will be examined in the blinded state of the trial and data. 
 
The statistical software, SAS (Version 9.4 or higher, SAS Institute, Cary, NC, USA) will be used for the 
statistical analysis. 
 
1.1 
OBJECTIVES 
1.1.1 
Primary Objectives 
 
To compare a 3-year progression free survival (PFS) in patients with resectable advanced gastric cancer 
who are randomly assigned into either Neoadjuvant Docetaxel+Oxaliplatin+S-1 (DOS) + Surgery + 
Adjuvant S-1 (hereinafter, CSC arm) or Surgery + Adjuvant S-1 (hereinafter, SC arm). 
1.1.2 
Secondary Objectives 
 
The following endpoints are evaluated and compared in the two treatment arms: 
• 
Overall Survival (OS)  
• 
Postoperative Pathological Stage  
• 
R0 (Complete) Resection Rate 
1.1.3 
Safety 
 
The following data are evaluated and compared in the two treatment arms: 
• 
Adverse Event: Reported and evaluated according to NCI CTCAE v4.03 
• 
Hematology, biochemistry, and urinalysis laboratory data 
• 
Other safety test results 
1.2 
MODIFICATIONS FROM THE STATISTICAL SECTION IN THE PROTOCOL 
 
NA  


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2 
INVESTIGATIONAL PLAN 
2.1 
STUDY DESIGN AND RANDOMIZATION 
 
This study is a randomized (1:1), open-label, multicenter, comparative, phase III clinical trial, in which 
patients with resectable advanced gastric cancer are randomly assigned to either the CSC or SC arm. 
Patients who signed the informed consent form and were randomly assigned are considered eligible to 
participate in this trial. Based on the clinical trial flowchart below, the trial is conducted as follows: CSC 
arm starts neoadjuvant chemotherapy within 7 days after randomization and undergoes surgery within 1 
to 3 weeks after 3 cycles of investigational product dosing. SC arm undergoes surgery within 2 weeks 
after randomization. After the surgery, both arms are administered adjuvant chemotherapy for 8 cycles 
(approximately 1 year) within 3 to 6 weeks after the surgery and safety evaluation is carried out on day 
30 after the final investigational product dosing and follow-up (every 3 months for the first 1 year and 
thereafter every 6 months by visiting the site; after disease progression, survival status is checked by 
telephone call or visit every 6 months for up to 5 years from enrollment ). Subjects who have ended the 
study (End of Study) in a survival state can be further followed up for survival status by visits or phone 
calls, and the additionally collected information can be used only for exploratory evaluation. However, 
the entire follow-up shall end at the end of the study for subjects under follow-up (expected to be 5 years 
after the enrollment of the last subject). 
The clinical trial data deadline shall be the date on which approximately 244 cases of disease progression 
or death have occurred or the median follow-up period has reached a minimum of three years.  
Subjects are assigned with a treatment arm by the Interactive Web Response System (IWRS) according to 
a computer-generated randomization list. By having the site and TNM stage (T2/N+, T3-4/N+, and T4/N-) 
based on the AJCC 7th edition as the stratification factors, the subjects who met the inclusion/exclusion 
criteria will be randomly assigned to either the CSC or SC arm at a ratio of 1:1.  
 
 


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Figure 1 Outline of Study Design 
 
 
2.2 
SAMPLE SIZE JUSTIFICATION  
 
The primary evaluation for efficacy is based on a 3-year progression free survival (PFS). 
If the rates of a 3-year progression free survival (PFS) is assumed to be 70% in the CSC arm and 60% in 
the SC arm (i.e., HR = 0.698), a total of 244 events and at least 238 subjects per group are required for 
comparison of PFS distribution between two arms with the 80% power. A total of 530 subjects are 
required when assuming a dropout rate of 10%. This calculation was made considering a single interim 
analysis with a group sequential approach by using efficacy boundaries suggested by the O’Brien-
Fleming alpha spending function.   
A 5% significance level for two-sided tests and a total of 7.5 years of follow-up period, including a 
recruitment period of 4.5 years, were assumed. This clinical trial is terminated if at least 244 events are 
observed at the time of the final analysis or at least 3 years in the median follow-up period. The duration 
of the study for a survival follow-up will be up to 5 years from randomization. However, subjects who 
have ended the study (End of Study) in a survival state can be further followed up for survival status by 
visits or phone calls 
The software used for the calculation of the sample size was nQuery Advisor 6, and the significance 
levels at the interim and final analyses were calculated by using PASS 11. 
An interim analysis is performed during the 122 PFS events (50% information rate). O’Brien-Fleming 
alpha-spending function is used for the interim analysis of efficacy. Based on this suggestion, the required 
total number of events is 244, in addition to the interim analysis to be performed at the time of occurrence 


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of 122 PFS events. In the interim analysis, the boundary of early termination of the trial with an 
overwhelming efficacy of CSC will be at a significance level of 0.0031. 


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3 
STATISTICAL AND ANALYTICAL PROCEDURES 
3.1 
ANALYSIS VARIABLES 
3.1.1 
Efficacy Variables 
3.1.1.1 
Primary Efficacy variable 
 
The primary efficacy variable is the 3-year PFS rates, defined as the period from randomization date to 
progressive disease (PD) or proof of death. 
PD is defined according to RECIST1.1 criteria as follows, and the time to progression is calculated based 
on the first date the progression is proven. 
1. PD is determined based on the RECIST 1.1 criteria during the neoadjuvant chemotherapy period 
in the CSC arm. When PD is determined based on the sum of the diameters of target lesions, the 
determination date is defined as the final tumor assessment day for the target lesions, and the 
determination date of PD due to the clear progression of non-target lesions is defined as the 
corresponding tumor assessment day. 
2. Regardless of radical resection, it is considered as PD when distant metastasis is observed 
during surgery or reported in the pathological examination. The date of operation is defined as 
progression confirmation day.  
3. The case where cancer cells are visibly remaining in the resection margin during surgery but 
cannot be completely resected (R2) is considered PD, and the date of operation is defined as 
progression confirmation day. 
4. The case where the remaining cancer cells in the resection margin are finally confirmed in the 
histological examination after surgery (R1) is considered as PD, and the date of operation is 
defined as progression confirmation day. 
5. The case where there is a recurrent/distant metastasis found during follow-up after the R0 
complete resection or a new lesion is found, it is defined as the first tumor assessment day. 
 
If the condition does not meet the criteria for PD, censoring is carried out based on the earlier time point 
among the dates specified as follows : 
1. The last day of evaluating the progression of tumor for the subjects whose follow-up has failed, 
or whose disease progression or death has not been confirmed until the end of the trial 


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2. The last day of evaluating the progression of tumor if a second primary cancer is found that is 
different from gastric adenocarcinoma at any time during the trial 
3. The last day of evaluating the progression of tumor if the patient receives treatment other than 
the scheduled treatment without the recurrence of tumor 
4. Randomization date if no tumor assessment information is available after randomization 
5. The deadline of the clinical trial 
3.1.1.2 
Secondary efficacy variables 
 
The secondary efficacy variables include the overall survival (OS), postoperative pathological stage, and 
R0 resection rate. 
The OS is defined as the period from the randomization date to the proof of death regardless of the cause. 
If death is not confirmed, the survival time is based on the earlier time point between the last known date 
of survival and the deadline of the clinical trial. 
After surgery, the stage of disease and R0 resection rate are collected.  
3.1.2 
Safety Variables 
 
Safety data include adverse events, hematological toxicity, clinical examination (e.g., physical examination, 
blood pressure, BSA, body weight, and ECOG PS), special tests (e.g., chest x-ray and ECG), and 
laboratory data.  
3.1.2.1 
Adverse Events 
 
Toxicity profiles are determined based on NCI CTCAE v4.03 and collected at each visit after the baseline. 
3.1.2.2 
Laboratory Safety Variables 
 
Hematology and blood chemistry data are collected at each visit during the treatment period. 
Hematology: Hemoglobin, WBC, ANC, Platelet count, 
Blood Chemistry: Sodium, Potassium, Calcium,  BUN, Creatinine,  Total protein, Albumin, SGOT 
(AST), SGPT (ALT), Total bilirubin, Alkaline phosphatase, Glucose 
3.1.2.3 
Creatinine clearance(Cockcroft-Gault Formula)  
: Collected Only at Baseline and Neoadjuvant Chemotherapy Period Other Safety Variables 


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3.1.2.4 
Blood Pressure 
 
The normal/abnormal status of the blood pressure is collected at each visit. 
3.1.2.5 
Other Safety Variables 
General physical examinations are evaluated before and after the treatment. 


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3.2 
ANALYSIS POPULATIONS 
3.2.1 
Efficacy Populations 
 
All efficacy analyses are performed on the FAS as a main analysis, while ITT and PP set are also analyzed 
in order to check the robustness of this trial. 
3.2.1.1 
Intent -to-Treat (ITT) and Full Analysis Set Population 
 
Intent-to-treat (ITT) set includes all randomized subjects. That is, all subjects assigned to the treatment 
arms by randomization are included, regardless of whether the subject received the study drug or a study 
drug different from the one that was randomly assigned. The subjects included in the ITT group will be 
analyzed according to their randomized treatment arm. 
Full analysis set (FAS) is defined as all randomized subjects who have met the inclusion/exclusion criteria, 
and those who have received at least one tumor assessment since the baseline visit. In addition, the CSC 
arm will include those who have received DOS investigational products at least once, while the SC arm 
will include the subjects who underwent surgery. 
3.2.1.2 
Per-protocol Population 
 
Per-Protocol (PP) Set includes all randomized subjects who have no major protocol deviation and satisfy 
the following conditions. 
1) The CSC arm will include the subjects who started postoperative adjuvant chemotherapy (S-1) as 
planned in this protocol after completing all three cycles of DOS treatment as neoadjuvant 
chemotherapy and undergoing surgery 
2) The SC arm will include the subjects who started postoperative adjuvant chemotherapy (S-1) as 
planned in this protocol after undergoing surgery. 
However, subjects who intended to receive postoperative S-1 adjuvant chemotherapy but did not start it at 
the discretion of the investigator based on consideration of the patient’s medical condition such as toxicity 
will be included in the PP Set. 
 
Critical Protocol Violation 
- Inclusion/exclusion criteria violation  
- Randomization Error: The case of assigning the patient into a treatment arm other than the one 
assigned by the IWRS (this is not the case of randomization stratification factor error)   


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- Administration of contraindicated medications 
- Cross-administration of the study drug 
- Start of dosing before randomization 
- Randomization before obtaining written consent 
- Dose modification error or malpractice deviating 80% to 120% from the scheduled dose 
 
3.2.2 
Safety Population 
 
Safety set includes the subjects who received at least one dose of the investigational product. Medication 
compliance/administration and all clinical safety data are summarized using the safety set. All analyses 
using this population are based on the drug that was actually administered. 
 
3.3 
STATISTICAL METHODS 
 
Categorical data will be summarized in the table showing the frequencies and corresponding proportion 
for each treatment arm. Continuous data will be summarized for each treatment arm using number of 
subjects, mean, standard deviation, median (if applicable), and minimum and maximum. Descriptive 
analysis will be summarized for the description of pre-treatment characteristics for each treatment arm 
and total number of subjects.  
A descriptive summary of the time-to-event data includes the Kaplan-Meier method, the median time to 
event, and its 95% confidence interval. 
In general, all statistical tests will be performed at a two-sided significance level of 5% unless otherwise 
noted. 
3.3.1 
Demographics and Baseline Characteristics 
 
The demographic characteristics, medical history, and diagnosis at baseline visit will be tabulated based 
on the ITT set. For continuous and qualitative variables, t-tests (or Wilcoxon rank sum tests) and chi-
square tests (or Fisher's exact tests) will be used to compare the treatment arms. The statistical analysis 
for data at the baseline visit will be done entirely in an exploratory manner. When there is a difference 
between the two treatment arms (p < 0.05), additional analysis will be performed in order to determine 
how the imbalance of baseline visit data affected the primary efficacy endpoint. 
The difference between the two treatment arms will be tested for the variables specified in 3.3.1.1 below. 


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3.3.1.1 
Variables Related to Demographics and Baseline Characteristics 
 
Demographic Characteristics 
 
Age is calculated in the unit of ‘year’ as follows, and the value of the decimal point is discarded: 
Number of Months of (Date of Informed Consent Form – Date of Birth) / 12Gender (Male/Female) 
 
Tumor Assessment 
 
Endoscopy Evaluation (Yes/No) 
 
Site (gastroesophageal junction, body, pylorus, greater curvature, posterior wall, fundus, antrum, 
duodenum, lesser curvature, anterior wall, and others) 
 
Histological Type (Adenocarcinoma, etc.) 
 
Tumor staging (T4 N- / T2 N+ / T3-4 N+ / Others) 
 
Physical Examination 
 
Body Weight (kg) 
 
Height (cm) 
 
Systolic Blood Pressure (mmHg) 
 
Diastolic Blood Pressure (mmHg) 
 
ECOG Performance Status (0 1 / 2 / 3 / 4) 
 
12-Lead ECG (Normal / Abnormal NCS / Abnormal CS) 
 
Chest X-Ray (Normal / Abnormal NCS / Abnormal CS) 
3.3.2 
Discontinuations and Dropouts 
 
The frequencies and percentages of the subjects who have completed the trial and those who have dropped 
out are presented. In case of a dropout, frequency analysis will be performed. 
3.3.3 
Extent of Exposure and Compliance 
 
For the number of administered cycles, dosing period (week),accumulated dose (mg/m2), dose intensity 
(mg/m2/week), percentage of projected dose intensity (%), and average percentage of projected drug 
intensity (%), continuous variables will be summarized with descriptive statistics (e.g., number of 
subjects, mean, standard deviation, median, and minimum and maximum), and t-tests (or Wilcoxon rank 
sum tests) will be used to compare the treatment arms. 


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The results will be summarized for the safety analysis set. The findings of the CSC arm will be presented 
by dividing them into neoadjuvant chemotherapy and postoperative adjuvant chemotherapy periods. The 
findings of the SC arm are presented for the postoperative adjuvant chemotherapy period. 
3.3.3.1 
Variables of Extent of Exposure and Compliance 
 
Number of administered cycles : 
The frequencies and percentages of the study drug administration cycles until the end of treatment are 
presented.  
 
Dosing period (week) is calculated as follows: 
For the neoadjuvant chemotherapy period, 
(Final dosing date of docetaxel – Initial dosing date of docetaxel + 21) / 7 
(Final dosing date of oxaliplatin – Initial dosing date of oxaliplatin + 21) / 7 
(Preoperative final dosing date of S-1 – Initial dosing date of S-1 + 8 [since S-1 is administered for 14 
days]) / 7 
 
For postoperative adjuvant chemotherapy period,  
(Final dosing date of S-1 – Postoperative final dosing date of S-1 + 15 [since S-1 is administered for 28 
days]) / 7 
 
Accumulated dose (mg/m2) is calculated by adding the total doses of all cycles where the study drug is 
administered. 
 
Dose intensity (mg/m2/week) (%) is calculated as follows: 
 
For each subject, 
g
do
of
duration
Total
n
i
i
BSA
i
cycle
at
given
dose
Total
sin
1
/

=
 
 
Here, BSAi is BSA at ith cycle, and n is the maximum number of cycles in which the subject underwent 
treatment. 
 
Percentage of projected dose intensity (%) is calculated as follows: 
 
Actual dose intensity for each patient / Projected dose intensity for the regimen  
 
Here, projected dose intensity (mg/m2/week) is calculated as follows:  
 
For the neoadjuvant chemotherapy period, (intended dose per cycle) / 3 
For the postoperative adjuvant chemotherapy period, (intended dose per cycle) / 6 
 
Average percentage of projected drug intensity for all drugs (%) is calculated as follows: 
 
For the neoadjuvant chemotherapy period, 


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(Percentage of projected dose intensity of docetaxel + Percentage of projected dose intensity of 
oxaliplatin + Percentage of projected dose intensity of S1) / 3 
 
For the postoperative adjuvant chemotherapy period, the average percentage of projected drug intensity 
for S-1 is not calculated because there is only one drug used. 
 
Dose Modification: 
The frequency and percentage of the subjects with dose modification after the last visit are presented by 
treatment arm and by each cycle. 
 
3.3.4 
Concomitant Treatment 
3.3.4.1 
Prior and Concomitant Medication 
 
As for the analysis by classification, concomitant medication is standardized with “Anatomical 
Category” and “Therapeutic Category” by using the latest version of the ATC code, while the number of 
subjects (%) and the number of events are presented for each treatment arm. A summary of the 
concomitant medications will be presented for the ITT analysis set. In addition, chi-square tests or 
Fisher's exact tests will be performed in order to find the difference between the arms in the proportion 
of subjects with concomitant medications. 
Combination therapy is any type of treatment that lasts from three weeks before the screening to the 
investigational product dosing period, and one month after the final dosing date, or any treatment initiated 
after the first investigational product dosing. 
 
3.3.4.2 
Past and Current Medical History 
 
Past/current comorbid diseases will be classified according to the continuity status collected in the case 
report form. The medical history selected as “ongoing” is considered as the current medical history. 
All comorbid diseases will be standardized with “System Organ Class” and “Preferred Term” by using the 
latest version of MedDRA, and the number of subjects (%) and number of events will be presented for 
each arm. A summary of the past and current medical history will be presented for the ITT analysis set. In 
addition, chi-square tests or Fisher’s exact tests will be conducted in order to find the difference between 
the arms in the proportion of subjects with past/current comorbid diseases. 
 
3.3.5 
Efficacy analyses 
3.3.5.1 
Primary efficacy analysis 
 


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The primary efficacy analysis is used to compare the progression free survival (PFS). When h1(t) is the risk 
function of the CSC arm and h0(t) is the risk function of the SC arm, the null hypothesis and the alternative 
hypothesis in the main analysis are as follows. Therefore, this study intends to prove the superiority based 
on the comparison between the CSC and SC arms.  
 
H0:   h0(t) = h1(t) 
 vs 
H1:  h0(t) ≠ h1(t) 
 
PFS is compared between the two treatment arms by using a stratified log-rank test by stratification 
factors (site and TNM stage [T2/N+, T3-4/N+, and T4/N-]) according to the specified at randomization  
at the overall significance level of 5%. Survival curves are estimated by using the Kaplan-Meier 
estimator. The median PFS time, 95% confidence interval, and 3-year PFS rate are presented for each 
treatment arm. 
The final PFS analysis ends when at least 244 events are observed, or when the median follow-up period 
reaches at least three years. A single PFS interim analysis is planned to identify the efficacy upon the 
occurrence of approximately 122 PFS events (50% of entire events). The significance level of 0.049 will 
be used at the final analysis by using the O’Brien-Fleming alpha spending function and group sequential 
approach with the significance level of 5%. (Please see section 4 for details on the interim analysis.) 
If the date of death, disease progression confirmation date, or the last follow-up date is unclear and no 
more information can be collected, i.e., ‘month’ or ‘day’ is not collected, the ‘month’ or ‘day’ will be 
considered as January or the 1st day for the analysis. If the date is entirely unclear, not partially, i.e., if 
the year, month, and day are unidentifiable, censoring will be performed at the last date among the dates 
collected. (If the last date is equal to or earlier than the randomization date, the randomization date will 
be used.) 
The main analysis is performed for the FAS, and the ITT and PP set are also analyzed. 
3.3.5.2 
Secondary efficacy analyses 
 
Overall survival (OS) is analyzed in the same way as PFS. The survival experience is compared between 
the two treatment arms with the stratified log-rank test by stratification factors (e.g., site and TNM stage 
[T2/N+, T3-4/N+, and T4/N-]) specified at the time of randomization at the overall significance level of 
5%. Survival curves are estimated by using the Kaplan-Meier estimator. The median OS survival time 
and corresponding 95% confidence interval are presented for each treatment arm. 
In addition, OS can be analyzed exploratorily by including data on survival status, additionally collected 
after the end of the study (End of Study) , method of analysis  is consistency with previous mentioned 
one. For the postoperative stage and R0 resection rate, frequencies and percentages are presented, and 


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comparison is performed by using the Cochran-Mantel-Haenszel test stratified by stratification factors 
(site and TNM stage [T2/N+, T3-4/N+, and T4/N-]) specified at the time of randomization.  
In case the postoperative stage and R0 resection are missing, the analysis will be based on the efficacy 
analysis set, and the subject whose data is missing when calculating the proportion will be excluded from 
the denominator. 
The main analysis is performed for the FAS, and the ITT and PP set are also analyzed. 
3.3.5.3 
Additional efficacy analyses 
For the CSC arm, the proportion and two-sided 95% confidence intervals of complete remission (CR), 
partial remission (PR), and stable disease (SD) are presented in the preoperative tumor assessment. The  
proportion is defined as the number of subjects who were assessed to have CR, PR, or SD, respectively, 
divided by the number of subjects with measurable lesions. 
The mean, standard deviation, median, and minimum and maximum are used to analyze the time from 
the operation date to the start of the postoperative adjuvant chemotherapy. The differences between the 
two treatment arms are compared by using t-tests or Wilcoxon rank sum tests. 
Additional efficacy analyses are performed on the FAS.  
3.3.5.4 
Subgroup Analysis 
PFS, OS, and R0 resection rate are analyzed for the following subgroups. Subgroup analysis is done for the 
FAS. 
- TNM Stage at Randomization: T2/N+ vs T3-4/N+ vs T4/N- 
- Age: Below 65 years vs. 65 years or older 
- Gender: Male vs. Female 
- T Stage: T0 vs. T1 vs. T2 vs. T3 vs. T4 
- N Stage: N0 vs. N1 vs. N2 vs. N3 
- Histological Type: Intestinal vs. Diffuse vs. Mixed 
- Postoperative Adjuvant Chemotherapy: Complete vs. Incomplete 
- Response at CSC Arm: CR vs. Non-CR 
 
For the PFS and OS, survival curves, median survival time, and 95% confidence interval using the 
Kaplan-Meier estimator are presented for each subgroup and each treatment arm. If the data meet the 
Cox proportional assumption, the hazard ratio and 95% confidence interval will be presented by using 


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the Cox proportional hazard model stratified with the stratification factor (TNM stage [T2/N+, T3-4/N+, 
and T4/N-]) at the time of randomization. 
The frequency and percentage of R0 resection are presented for each subgroup and each treatment arm. 
Additional subgroup analysis can be performed for exploratory purposes in the future. 
3.3.6 
Safety Analyses 
 
For the safety data analysis, adverse events, hematological toxicity, general physical examination, and 
laboratory data are described, and all safety analyses are performed in the safety set. For each safety 
variable, the pre-treatment level is defined as the last value or assessment value measured before the first 
treatment in the trial, and the final evaluation is based on the final value evaluated during the study drug 
dosing period. 
3.3.6.1 
Adverse Events 
 
Adverse events are described by the total number of subjects who experienced toxicity or adverse events. 
In order to compare the safety of the two arms, the adverse events are summarized for each treatment 
arm, and the number of subjects (incidence rate) and the number of events are presented. 
In the CSC arm, the adverse events reported during the preoperative DOS period are presented 
separately from the postoperative adverse events, and the postoperative adverse events will be compared 
by using the frequency analysis between the CSC and SC arms. In addition, adverse events in the whole 
period and postoperative adjuvant chemotherapy cycle 1 will also be summarized. Adverse events are 
divided into two types as follows according to the time of onset. 
 
Pre-treatment adverse events are defined as adverse events that appear or worsen during the pre-
treatment period. 
 
Treatment emergent adverse events (TEAEs) are defined as adverse events that appear or worsen 
during the treatment period (up to 30 days after the last dose of the investigational product). However, if 
the subject is administered other anticancer drugs, in addition to the investigational product, during the 
treatment period, the adverse events after the administration of combined anticancer drugs will be 
excluded from the analysis. 
 
For TEAEs, adverse drug reactions, serious adverse events, and CTCAE grade 3 or higher, the number 
of subjects who experienced the event, incidence rate (%), number of events, and 95% confidence 
interval of the incidence rate are presented. The statistical significance of the incidence rate between the 


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treatment arms is examined by using chi-square tests or Fisher’s exact tests. If the Fisher's exact test is 
performed for the comparison of the treatment arms, the 95% exact confidence interval for the incidence 
rate is presented. 
If there are same adverse events with different CTCAE grade and causality, they will be considered as 
one case when calculating the number of subjects, and they will be treated as having the greatest CTCAE 
grade and causality. The total number of subjects in each treatment arm is used in calculating the 
incidence rate. In the calculation of the number of events, the above cases are considered as different 
adverse events. 
 
All adverse events are classified with MedDRA and summarized with the grade determined by NCI 
CTCAE v4.03. At the time of the analysis, the latest version of MedDRA owned by Sanofi is used. 
 
The number of subjects (incidence rate) and the number of events of the following adverse events are 
presented in the safety setg by system organ class (SOC) and preferred term (PT). However, 3) and 8) 
are presented in the list of subjects. 
1) All adverse events and TEAEs that are likely to be related to the investigational products, which 
are classified by SOC in order of frequency 
2) All TEAEs and TEAEs that are likely to be related to the investigational products, which are 
classified by SOC and by severity 
3) Serious Adverse Events: All serious and possibly related serious TEAEs, which are classified by 
seriousness 
4) Serious Adverse Events: All and possibly related TEAEs, which are classified by SOC 
5) Death: All and possibly related TEAEs, which are classified by SOC  
6) Study Discontinuation: All and possibly related TEAEs  
7) Other Significant Adverse Events: All and possibly related TEAEs based on “other significant*” 
adverse event criteria 
8) Discontinuation or Change of Treatment: All and possibly related TEAEs, which led to the 
discontinuation or change** of the investigational product dosing 
 
* Other Significant: Defined as other medically important events in the seriousness criteria 
** Action Taken: 2. Delayed, 3. Dose reduced, 4: Delayed and reduced, and 5: Interrupted. 
3.3.6.2 
Laboratory Safety Variables 
 
If the laboratory test values are measured in unit other than the one recorded in the CRF, the unit should 
be converted according to the International System of Units (SI) given in the table in Appendix B. 
Hematological toxicity is assessed based on the laboratory test results. Worst NCI CTCAE grades of 
leukopenia, neutropenia, thrombocytopenia, and anemia are calculated according to the NCI common 
terminology standards. 


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Qualitative and quantitative results for hematological toxicity and biochemistry tests are summarized.  
For the quantitative analysis, descriptive statistics (e.g., number of subjects, mean, standard deviation, 
median, and minimum and maximum) are presented for each cycle and changes before and after dosing 
by treatment arm. The pre-treatment level is defined as the last value or assessment value measured prior 
to the first treatment in the trial, and the final evaluation is based on the last value evaluated during the 
study drug dosing period. 
 
For the qualitative data (worst NCI CTCAE grade or Normal [or NCS]/CS), the frequency is presented 
by treatment arm using the calculated worst NCI CTCAE grade or Normal (or NCS)/CS in a shift table 
for the change after the investigational product dosing compared to the baseline. 
 
In addition, if the status was Normal/NCS at baseline, but showed a change into CS after the 
investigational product dosing, the results of each cycle of the subject are presented according to the time 
of measurement, and treatment information, subject identification number, gender, age, measurement time, 
measurement date, Lab item, baseline result, result of each time point, and information on normality are 
listed. 
 
 
Hematological Test (Unit) 
 
Haemoglobin (g/dL) 
 
Hematocrit (%) 
 
WBC (ⅹ109/L) 
 
PMN (%) 
 
LYM (%) 
 
ANC (ⅹ109/L) 
 
Platelet (ⅹ109/L) 
 
PT (INR) 
 
aPTT (sec) 
 
Biochemistry Test (Unit) 
 


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Sodium (mmol/L) 
 
Potassium (mmol/L) 
 
Calcium (mmol/L) 
 
 
BUN (mg/dL) 
 
Creatinine (mg/dL) 
 
Total protein (g/dL) 
 
Albumin (g/dL) 
 
SGOT(AST) (U/L) 
 
SGPT(ALT) (U/L) 
 
Total bilirubin (mg/dL) 
 
ALP (U/L) 
 
Glucose (mg/dL) (fasting / non-fasting) 
 
Creatinine clearance (mL/min) 
 
3.3.6.3 
Other Safety Variables 
 
The descriptive statistics (e.g., number of subjects, mean, standard deviation, median, and minimum and 
maximum) of the physical examinations (e.g., body weight, blood pressure, and ECOG PS) are presented 
on a visit basis, and the changes before and after dosing are summarized. In addition, the frequencies of 
special tests (e.g., chest x-ray and ECG) are presented using Normal (or NCS)/CS in a shift table for the 
change after the investigational product dosing compared the baseline. 
Weight (kg) 
 
SBP (mmHg) 
 
DBP (mmHg) 
 
ECOG Performance Status (0 / 1 / 2 / 3 / 4) 
 
Chest X-Ray (Normal / Abnormal, not clinically significant / Abnormal, clinically significant) 
 
ECG (Normal / Abnormal, not clinically significant / Abnormal, clinically significant) 
 


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3.4 
DATA HANDLING CONVENTIONS 
 
The rules for data processing are as follows. 
3.4.1 
Baseline Definitions 
 
Overall, the baseline values of the analysis variables are defined as pre-treatment or preoperative last 
observation values.  
3.4.2 
Missing Data 
 
3.4.2.1 
Missing data of Efficacy Variable 
 
Overall, no imputation method for missing data is used. The following are the basic methods for handling 
missing data.  
• Categorical Data: When calculating the proportion for a categorical variable, the subjects whose data 
is missing in the calculation of the ratio are excluded from the denominator. 
• Continuous Data: Observed data are based on the analysis and summary of continuous variables, and 
the number of subjects with missing data is presented. 
• Time-to-Event Data: If there are missing data, the censoring rule shall be followed. The information 
on censoring is described in the analysis variable section. 
 
3.4.2.2 
Missing data of Safety Variable 
 
In the safety data, if a subject has withdrawn prior to the end of the trial or has a missing data, the case is 
treated as missing without imputation. 
 
3.4.3 
Handling of Incomplete Data 
 
If part of a day or month is missing from the start or end date of medical history, concomitant medication, 
adverse event, etc., and collected as unknown, the date is compared only to the unit collected without 
replacing the date. If the entire start date is missing, it is considered to be prior to the first dose of the 
investigational product, and if the end date is missing, it is considered to be ongoing or being 
administered. 
However, if the date of death, disease progression confirmation date, which are related to the primary 
efficacy analysis, or last follow-up date, is unclear, and no further information can be collected, i.e., 
‘month’ or ‘day’ is not collected, ‘month’ or ‘day’ is considered as January or the 1st day. If the entire date 


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is unclear, not partially, i.e., if all the year, month, and day are unidentifiable, censoring is done at the last 
date collected. (If the last date is equal to or earlier than the randomization date, the randomization date is 
used.) 
 
3.4.4 
Character Values of Clinical Laboratory Evaluation 
 
If any of the measurements, including inequality signs, of the clinical laboratory results are collected, the 
data are summarized by replacing as follows. When presenting a list of subjects, the recorded values in 
the case report form are presented. 
- If the result is recorded as not less than or over (i.e., > =100 or > 100), replace it with a minimum 
value (i.e., 100) 
- If the result is recorded as not more than or below (i.e., < = 4 or < 4), replace it with a maximum value 
(i.e., 4) 
 
3.4.5 
Decimals 
 
Descriptive statistics (e.g., mean, standard deviation, median, and minimum and maximum) for continuous 
data are presented to the second decimal place for the efficacy data and demographic information. 
Laboratory results are rounded to the significant digit, i.e., the digit below the maximum decimal point for 
each item. When presenting the ratio of categorical data, the values are presented to the second decimal 
place, and the p-value is summarized to the fourth decimal place. If the calculated p-value is below 0.0001, 
it will be presented as < .0001. 
 
3.4.6 
Pooling of Centers for Statistical Analyses 
 
Not applicable 
 
3.4.7 
Statistical Technical Issues 
 
Not applicable 
 
 


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4 
INTERIM ANALYSIS 
 
The purpose of the interim analysis is to provide IDMC members with methodological theoretical 
rationale and decision rules for recommending the continuation of the trial as planned or early 
termination of the trial because the efficacy has already been proven based on the pre-described 
boundaries. Additional details will be described in the IDMC Charter. 
 
A single interim analysis is planned, and IDMC members will review the primary efficacy and safety. 
An independent statistician will perform the analysis during the interim analysis, and the trial will not be 
interrupted. The interim analysis results are reported only to IDMC members during this trial. IDMC will 
regularly monitor the safety of the subjects who are exposed to the investigational products, while TEAE, 
hematological toxicity, and biochemical toxicity will be summarized by using descriptive statistics. 
If the IDMC review result falls under any of the following, early termination of the trial will be 
considered: 
 
Early Evidence of Superiority 
In order to prevent the increase of type I error due to a single interim analysis, the O’Brien-Fleming 
alpha spending function is used.  
An interim analysis is conducted at the time of occurrence of about 122 PFS events (50% information 
rate). If there is a significant difference in PFS between the two arms at the significance level of 0.0031, 
the trial will be discontinued, and a planned final analysis will be performed. Otherwise, follow-up is 
conducted until the total number of PFS events reaches 244 or more, and the final analysis for efficacy 
will be performed at the significance level of 0.049. 
 
Problem with AEs 
Discontinuation of the trial may be considered later if hematological or biochemical toxicity is more 
serious than anticipated.  
 
Details about the interim analysis will be described in the other SAP for interim analysis. 


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5 
SOFTWARE DOCUMENTATION 
 
For all result summaries and statistical analyses, SAS (version 9.4 or higher, SAS Institute, Cary, NC, 
USA) will be used. 
 


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LIST OF APPENDICES 
Appendix A: 
Summary of statistical analyses 
Appendix B: 
Unit conversion table 
REFERENCES 
 
Group sequential methods with applications to Clinical Trials by Chritopher Jennison and Bruce W. 
Turnbull CHAPMAN & Hall/CRC. 
Group sequential, sample size re-estimation and two-stage adaptive designs in clinical trials: A comparison 
by Weichung Joe Shih, Statistics in Medicine, 2006:25;933-941 
The calculation of actual or received dose intensity: a comparison of published methods by Don L. Longo 
et al., Journal of Clinical Oncology, Vol9, No 11(November), 1991: 2042-2051  
Guidance for Clinical Trial Sponsors-Establishment and Operation of Clinical Trial Data Monitoring 
Committees 
 
 
 
 
 
 
 
 
 






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APPENDIX B: UNIT CONVERSION TABLE  
 
Variable 
Sex 
Unit 
Conversion Factor 
SI unit 
Hemoglobin 
Both 
mg/dL 
ⅹ0.01 
g/L 
Hemoglobin 
Both 
g/dL 
ⅹ10 
g/L 
Hematocrit 
Both 
% 
ⅹ0.01 
L/L 
WBC 
Both 
ⅹ103/mm3 
ⅹ1.0 
ⅹ109/L 
ANC 
Both 
ⅹ103/mm3 
ⅹ1.0 
ⅹ109/L 
Platelet 
Both 
ⅹ103/mm3 
ⅹ1.0 
ⅹ109/L 
Sodium 
Both 
mg/dL 
NA 
mmol.L 
Potassium 
Both 
mg/dL 
ⅹ0.2558 
mmol/L 
Potassium 
Both 
mEq/L 
ⅹ1.0 
mmol/L 
Calcium 
Both 
mg/dL 
ⅹ0.250 
mmol/L 
Calcium 
Both 
mEq/L 
ⅹ0.500 
mmol/L 
Phosphorus 
Both 
mg/dL 
ⅹ0.3229 
mmol/L 
Magnesium 
Both 
mg/dL 
ⅹ0.4114 
mmol/L 
Magnesium 
Both 
mEq/L 
ⅹ0.500 
mmol/L 
BUN 
Both 
mg/dL 
ⅹ0.357 
mmol/L 
Creatinine 
Both 
mg/dL 
ⅹ76.25 
μmol/L 


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Variable 
Sex 
Unit 
Conversion Factor 
SI unit 
Total protein 
Both 
g/dL 
ⅹ10 
g/L 
Albumin 
Both 
mg/dL 
ⅹ0.01 
g/L 
Albumin 
Both 
g/dL 
ⅹ10 
g/L 
SGOT (AST) 
Both 
μkat/L 
ⅹ59.988 
U/L 
SGPT (ALT) 
Both 
μkat/L 
ⅹ59.988 
U/L 
Total bilirubin 
Both 
mg/dL 
ⅹ17.1 
mol/L 
Total bilirubin 
Both 
mg/L 
ⅹ1.71 
mol/L 
ALP 
Both 
μkat/L 
ⅹ0.01667 
U/L 
Glucose 
Both 
mg/dL 
ⅹ0.05551 
mmol/L 
Creatinine clearance 
Both 
NA 
NA 
mL/min