A Phase II Trial of Perioperative Chemotherapy With Leucovorin, Oxaliplatin, Docetaxel and S-1 (LOTS) For Patients With Locally Advanced Gastric or Gastroesophageal Junction Adenocarcinoma
Phase: PHASE2
Conditions: Gastric Cancer, Gastric Adenocarcinoma, Effects of Chemotherapy, Toxicity Due to Chemotherapy
Sponsor: National Cheng-Kung University Hospital

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Cover Page 
 
Title: 
A Phase II Trial of Perioperative Chemotherapy With Leucovorin, 
Oxaliplatin, Docetaxel and S-1 (LOTS) For Patients With Locally 
Advanced Gastric or Gastroesophageal Junction Adenocarcinoma 
 
NCT ID: 
not yet assigned 
 
Document date: 
07/Jul/2021 
 
 

LOTS-GC-01 version 4.0-07/Jul/2021 
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Abstract 
Background 
Gastric cancer ranks the third most deadly cancers worldwide. Adjuvant or 
perioperative chemotherapies improve the surgical outcome and reduce distant failure. 
Several perioperative chemotherapies are efficacious in patients with locally advanced 
gastric cancer. S-1 is an orally available fluoropyrimidine that demonstrates a good 
efficacy and synergistic effect with other chemotherapeutic partners. However, S-1, 
docetaxel and oxaliplatin triplet has not been investigated as perioperative therapy in 
locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. 
Objectives 
The aim of the trial is to investigate the clinical efficacy and toxicity of perioperative 
leucovorin, oxaliplatin, docetaxel and S-1 (LOTS) in patients with locally advanced 
gastric or GEJ adenocarcinoma who receive a curative surgery. The primary outcome 
is pathological response or curative resection rate. The secondary outcome includes 
recurrence-free survival, overall survival, disease control rate, protocol completion rate 
and adverse events. 
Study design and accrual 
The study is an open-label, single-arm and multi-center phase II investigator-initiated 
trial with Simon two-stage design. Subjects with ≥cT3 or N+ resectable gastric or GEJ 
adenocarcinoma who are eligible for curative D2 gastrectomy are included. A total of 
56 subjects will be enrolled. The minimal sample size is 23 when the treatment response 
is of the lower threshold. Trial accrual date is 01/Apr/2021. 
Treatment protocol 
LOTS (14 days as a cycle) 4 cycles every 2 weeks, followed by operation and another 
4 cycles every 2 weeks post-operatively. Leucovorin (30 mg) twice daily per oral on 
day 1 to 7, oxaliplatin (85 mg/m2) intravenously on day 1, docetaxel (40 mg/m2) 
intravenously on day 1 and S-1 (35 mg/m2) twice daily per oral on day 1 to 7. 
Anticipated results 
The study will prove the feasibility of perioperative LOTS in gastric or GEJ 
adenocarcinoma. The, provide an alternative to current regimens and warrant more 
clinical studies in the future. 
 
 
 
 

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SYNOPSIS 
Title of the 
study: 
Phase II trial of perioperative leucovorin, oxaliplatin, docetaxel 
and S-1 (LOTS) for patients with locally advanced gastric or 
gastroesophageal junction (GEJ) adenocarcinoma 
Drug supplier: 
S-1 (TS-1®), leucovorin (Folina®) and Oxaliplatin (Oxalip®) are 
supported by TTY Biopharm Co., Ltd, Taiwan. Docetaxel 
(Taxotere®) is supported by Sanofi-Aventis, France. 
Objectives: 
The objective of the study is to evaluate the following outcome 
parameters with perioperative LOTS and curative surgery in 
patients with resectable locally advanced (≥cT3, lymph node-
positive or both) gastric cancer. 
Primary outcome: 
▪ Pathological response (complete and partial) or curative 
resection rate (R0 resection). 
Secondary outcome: 
▪ Recurrence-free survival (RFS) 
▪ Overall survival (OS) 
▪ Disease control rate (objective response plus stable disease ≥ 3 
months) 
▪ Protocol completion rate 
▪ Adverse events related to protocol chemotherapy and/or curative 
surgery 
▪ Predictive biomarkers 
Design: 
The proposed study is an open-label, single-arm, single-country 
and multi-center phase II investigator-initiated trial with Simon 
two-stage design. 
Sample size: 
We assume the statistical power of 90% (β=0.1) and the 
probability of type I error by two-tailed α at 0.1, along with an 
estimated good response rate (P1) of 60% and a poor rate (P0) of 
35%. 
Stage 1: 14 subjects 
Stage 2: 25 subjects with a total of 39 subjects 
Minimal sample size: 23 subjects 
A total of 56 subjects will be enrolled under the assumption of a 
30% of drop-out and operation ineligibility rate per protocol. 
Criteria for 
inclusion: 
1. Subjects have histologically-confirmed gastric or GEJ
(classified as Siewert type III) adenocarcinoma with a clinical 
stage of T3 or above, lymph node involvement (N+) or both 

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according to American Joint Cancer Committee staging system, 
8th edition (AJCC 8th).  
2. Subjects present with at least one measurable lesion which can 
be accurately assessed by conventional techniques at least 2.0 cm 
or 1.0 cm by computed tomography (CT) or magnetic resonance 
imaging (MRI). 
3. Subjects have a lymph node-positive disease in which that at 
least one of the nodes with a diameter greater or equal to 0.8 cm 
in the long axis. If subjects do not have a node-positive disease, a 
clinical stage of T3 or above and a measurable tumor is required 
for inclusion. 
4. Subjects are above 20 years of age with an Eastern Cooperative 
Oncology Group (ECOG) performance status ≤1, have a life 
expectancy >3 months, have surgically resectable disease and are 
physically competent and willing to receive a curative operation.
5. Subjects have adequate organ functions, including bone 
marrow reserve with a leukocyte count ≥3,000 /µL and platelet 
count ≥100,000 /µL, hepatic reserve with a serum alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 
times of upper limits and total bilirubin ≤2.0 mg/dL, renal reserve 
with a creatinine clearance ≥60 mL/min and cardiac reserve with 
a left ventricular ejection fraction (LVEF) ≥50% by 
echocardiography at baseline. 
6. Subjects have, or agree to establish a vascular access that 
permits systemic intravenous chemotherapy and are capable of 
ingesting capsules per oral. 
7. Subjects with reproductive potentials are willing to accept 
contraceptive measures during the trial. 
8. Subjects are functionally and cognitively capable to be 
informed of the trial contents and objectives (including obtaining
blood and tumor tissue for the trial investigation), and agree to 
sign the written consent for enrollment. 
Criteria for 
exclusion: 
1. Subjects have metastatic (M1, including washing cytology 
positive 
for 
peritoneal 
carcinomatosis), 
recurrent 
gastric/gastroesophageal junction cancer (defined by an interval 
time less than five years from the current diagnosis to the prior 
initial disease), or any other underlying primary malignancies 
excluding carcinoma in situ or resectable skin cancer. 

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2. Subjects have received chemotherapies within 2 years, or a 
major abdominal surgery or radiotherapy within 4 weeks before 
the trial enrollment. 
3. Subjects are known to be allergic to any of the studied 
chemotherapeutics. 
4. Subjects have underlying chronic illnesses, including 
cardiopulmonary diseases, ischemic heart disease, inflammatory 
bowel disease, poorly-controlled diabetes mellitus, liver cirrhosis 
and/or peripheral neuropathy of any etiologies. 
5 Subjects have active bacterial, viral, fungal or mycobacterial 
infections that require systemic therapy, including active infection 
with human immunodeficiency virus (HIV), hepatitis B or C virus 
(HBV or HCV) (For details please refer to 5.2.5). 
6. Subjects are planning to conceive or already in pregnancy or 
breastfeeding. 
7. Subjects are currently participating in any other clinical trials 
or studies. 
Protocol 
treatment: 
Perioperative chemotherapy: 
LOTS (14 days as one cycle) 4 cycles every 2 weeks as 
preoperative therapy, followed by curative operation and another 
4 cycles every 2 weeks as postoperative therapy. 
 
Leucovorin 30 mg twice daily per oral on day 1 to 7. 
Oxaliplatin 85 mg/m2 on day 1. 
Docetaxel 40 mg/m2 on day 1. 
S-1 35 mg/m2 twice daily (daily total dose as determined by body 
surface area (BSA): <1.25 m2, 80 mg; 1.25-1.50 m2, 100 mg; 
≥1.50 m2, 120 mg) per oral on day 1 to 7. 
 
Operation: 
Radical total, subtotal or partial gastrectomy (laparotomic, 
laparoscopic or robotic) plus perigastric and celiac axial lymph 
node dissection (D2 at least) in a curative intent. 
 
Post perioperative treatment 
Patients who achieve a pathological complete response 
(ypT0N0M0) after the preoperative chemotherapy plus curative 
surgery in the absence of any residual tumors might omit the 

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postoperative therapy under the investigator’s discretion. 
 
After the postoperative chemotherapy per protocol (in a total of 8 
cycles), patients will be maintained by S-1 monotherapy on D1 to 
D14 every 21 days or D1 to D28 every 42 days for up to one year 
with the same dose in perioperative therapy according to the NHI 
practice and reimbursement guideline. 
 
Pre-medications: 
Intravenous antihistamine and serotonin receptor blocker 
with/without 10 mg of dexamethasone are administered before 
the intravenous chemotherapy. 
 
Therapeutic 
granulocyte 
stimulating 
factors 
(GCSF) 
or 
granulocyte-macrophage stimulating factors (GM-CSF) are 
allowed for grade 3 to 4 neutropenia or febrile neutropenia under 
the investigator’s discretion according to the NHI practice and
reimbursement guideline. Prophylactic GCSF or GM-CSF is not 
permitted. Antibiotic and supportive treatments for febrile 
neutropenia or infections are allowed according to the practice 
guidance. 
 
Pre-treatment preparation: 
After the enrollment, subjects are required to establish a viable 
vascular access for systemic chemotherapy, such as port-A or 
peripherally inserted central venous catheter. Chemotherapy will 
be initiated right after the access is established. 
 
 
 

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TRIAL SCHEMA 
A Phase II Trial of Perioperative Chemotherapy With Leucovorin, Oxaliplatin, 
Docetaxel and S-1 (LOTS) For Patients With Locally Advanced Gastric or 
Gastroesophageal Junction Adenocarcinoma 
 
 
Primary endpoint: pathological response (complete and partial) or curative resection 
rate 
 
 
 

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TABLE OF CONTENT 
 
List of abbreviations and definition of terms 
1. OBJECTIVES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙1 
2. BACKGROUNDS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙1 
3. STUDY DRUG INFORMATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙4 
3.1 Leucovorin∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙4 
3.2 Oxaliplatin∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙5 
3.3 Docetaxel∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙7 
3.4 S-1∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙9 
4. STAGING CRITERIA AND TOOLS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙10 
5. PATIENT SELECTION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙11 
6. STUDY DESIGN AND TREATMENT PLANS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙12 
7. STUDY SCHEDULE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙17 
8. EVALUATION OF THERAPEUTIC EFFICACY∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙19 
9. STATISTICAL CONSIDERATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙22 
10. REPORTING OF SEVERE ADVERSE EVENTS TO INSTITUTIONAL REVIEW 
BOARD (IRB) OF ETHICS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙22 
11. OTHERS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙23 
12. REFERENCES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙24 
 
 
 

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List of abbreviations and definition of terms 
 
AJCC 
American Joint Committee on Cancer 
ALT/AST 
alanine aminotransferase/aspartate aminotransferase 
ANC 
absolute neutrophil count 
CT 
computed tomography 
CCRT 
concurrent chemoradiotherapy 
eGFR 
estimated glomerular filtration rate 
ECOG 
Eastern Cooperative Oncology Group 
EGDscopy 
esophagogastroduodenoscopy 
ELISA 
enzyme-linked immunosorbent assay 
GCP 
Good Clinical Practice 
GCSF 
granulocyte colony stimulating factor 
GM-CSF 
granulocyte-macrophage stimulating factor 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficient virus 
LVEF 
left ventricular ejection fraction 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
RFS 
recurrence-free survival 
SAE 
serious adverse event 
SJS/TEN 
Steven-Johnson syndrome/toxic epidermal necrolysis 
SUSAR 
suspected unexpected serious adverse reactions 
TS 
thymidylate synthase 
TRG 
tumor regression grade 
PET 
positron emission tomography 
PLT 
platelet 
PSN 
peripheral sensory neuropathy 
 

 
1 
 
1. OBJECTIVES 
 
1.1 Objective of the study:  
To investigate the clinical efficacy and toxicity of perioperative chemotherapy of 
leucovorin, oxaliplatin, docetaxel and S-1 (LOTS) in patients with resectable and 
locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who 
receive a curative surgery. 
 
1.2 Primary objective: 
Pathological response (complete and partial) of study chemotherapy or curative 
resection rate. 
 
1.3 Secondary objectives: 
Recurrence-free survival (RFS), overall survival (OS), disease control rate (objective 
response plus stable disease ≥ 3 months), protocol completion rate, adverse events 
related to study chemotherapy or curative surgery and predictive biomarkers. 
 
2. BACKGROUNDS 
Adjuvant or perioperative chemotherapies in gastric cancer 
  Gastric cancer ranks the third most deadly cancers worldwide.1 Despite the 
improvements in the early detection and curative treatment, nearly two thirds of high-
risk patients still encounter a recurrence or progression of the disease.2 Adjuvant or 
perioperative chemotherapies have introduced substantial attentions for consolidating 
the surgical outcome and reducing distant failure.3-6 Indeed, operation alone in high-
risk patients, such as those who have an above T2 or nodal positive (N+) disease, is no 
longer a standard of treatment. Introduction of perioperative therapies, such as 
chemotherapies or concurrent chemoradiotherapies (CCRT), facilitates the optimal 
resection of the tumor and prolongs overall survival in the selected population.7,8 
However, given aggressive salvage therapies, patients with recurrent or advanced 
gastric cancer still have a dismal outcome with survival barely exceeds more than one 
year.9 
 
  The UK MAGIC trial investigated perioperative epirubicin, infusional fluorouracil 
(5-FU) and cisplatin (ECF) in stage II or higher gastric cancer and observed 
significantly prolonged progression-free and overall survival as compared with 
operation alone. The probability of curative resection (79.3% vs. 70.3%; p=0.03) and 
pathological staging of T1-2 tumors (51.7% vs. 36.8%; p=0.002) were more prevalent 
in patients who received perioperative ECF.3 Ychou and the French group also reported 

 
2 
 
a favorable curative resection rate (84% vs. 73%; p=0.04) and survival outcome with 
perioperative 5-FU and cisplatin (CF), at the cost of more treatment-related neutropenia 
(20.2%) but not operation-related morbidity.5 On the success of triplet regimens, the 
role of anthracycline had been questioned as an ideal partner due to a poor tolerability 
in perioperative therapies. In the phase II NeoFLOT trial, patients with clinical stage 
T3 or T4 and lymph node-positive disease received perioperative chemotherapy with a 
modified combination of 5-FU, leucovorin, oxaliplatin and docetaxel (FLOT). The 
pathological complete response rate (pCR) plus near complete histological remission 
(<10% residual tumor) was 40% with a median disease-free survival of 32.9 months.10 
The German group further investigated docetaxel-based triplet in comparison with 
anthracyclines in the similar group of high-risk patients in phase II/III FLOT4-AIO 
study. The results confirmed that the perioperative FLOT was superior to ECF in 
efficacy and comparable in tolerability.6 On the success of these clinical trials, 
perioperative chemotherapies have changed the paradigm in patients with resectable 
gastric cancer harboring high risk of recurrence. Although the ideal partners in the 
triplet combinations remain undetermined, emerging evidence has supported the 
anthracycline-free regimens with a favorable efficacy and comparable toxicity. 
 
S-1 in gastric cancer 
  S-1 is an oral chemotherapeutic composed of tegafur (a prodrug of 5-FU), gimeracil 
(preventing dihydropyrimidine dehydrogenase-mediated degradation of 5-FU) and 
oteracil (reducing the toxic effects of 5-FU) with excellent bioavailability and efficacy 
in various types of cancers.11,12 S-1 has been shown to improve the outcome in gastric 
cancer patients who have received optimal gastrectomy with D2 dissection and 
approved in several Asian countries rather than in the US.4 Yoshida et al. reported that 
adjuvant S-1 plus docetaxel prolonged the RFS and OS in stage III gastric cancer with 
few additional safety concerns.13 A combination of S-1 with cisplatin or oxaliplatin has 
also been intensively investigated in resectable gastric cancer as neoadjuvant or 
adjuvant alternatives to capecitabine/oxaliplatin (XELOX) and other platinum-based 
doublets.14-17 In the phase III JCOG0501 trial, patients with linitis plastica or large 
ulcero-invasive gastric cancer in whom that the prognosis is dismal, received 
neoadjuvant S-1 plus cisplatin and followed by adjuvant S-1 postoperatively. The 
results indicated a shorter operation time and a similar morbidity as compared to those 
not receiving neoadjuvant chemotherapy.18 In general, S-1-based doublets were well-
tolerated without active warning toxicities and yielded some potentials for the 
development of a three-drug combination. 
 
  To date, the optimal S-1-based triplet chemotherapies have not been well-established. 

 
3 
 
In the phase II KDOG1001 trial, neoadjuvant docetaxel, cisplatin and S-1 (DCS) 
contributed to a pathological response of 57.5% and a grade 3 histological remission of 
8% in patients with high-risk locally advanced gastric cancer.19 Similar results can also 
be observed in the phase III PRODIGY trial, in which that neoadjuvant docetaxel, 
oxaliplatin and S-1 (DOS) followed by adjuvant S-1 correlated with a significantly 
prolonged PFS as compared with adjuvant S-1 alone.20 However, the role of S-1 in 
perioperative therapies are not yet delineated in patients with borderline resectable and 
advanced gastric cancer who have a greater risk of recurrence, progression or failure on 
margin-free resection. Ongoing clinical studies are investigating the addition of 
immune checkpoint inhibitors to standard perioperative chemotherapies.21-23 However, 
the predictive biomarkers for efficacy and treatment response are still under 
investigations. More clinical trials are warranted to demonstrate the role of S-1 as an 
ideal partner in triplet perioperative chemotherapy.24 
 
The proposed trial: perioperative LOTS 
  S-1 is a feasible companion chemotherapeutic in various cancers. In the preclinical 
studies, the combination of S-1 and leucovorin enhances the antineoplastic activity as 
compared with S-1 alone.25 S-1 plus leucovorin has also been confirmed of the 
therapeutic efficacy in patients with metastatic colorectal cancer in several phase II 
trials, as an alternative to intravenous 5-FU.26-28 Furthermore, The oral formulation of 
the agents provides significantly favorable clinical convenience and accessibility as 
compared with prolonged intravenous infusions of high-dose 5-FU. A meta-analysis 
incorporating Asian patients with advanced gastrointestinal cancers indicated that S-1 
was an ideal alternative to intravenous 5-FU due to comparable efficacy and better 
tolerability.29 
 
  In addition to gastric cancer, a combination of S-1, leucovorin, oxaliplatin and 
gemcitabine (SLOG) has been evaluated in advanced pancreatic adenocarcinoma and 
concluded that the dosage of S-1 at 35 mg/m2 BID per oral in Asian population was 
acceptable.30 The grade 3 to 4 adverse events were less than 5% in the absence of 
warning toxicities other than anemia, neutropenia, diarrhea and mucositis. In the phase 
II TCOG T1211 study, SLOG demonstrated good efficacy in chemotherapy-naïve 
metastatic pancreatic adenocarcinoma.31 Furthermore, SLOG had been investigated as 
a frontline therapy in the advanced biliary tract cancer comparing with 
gemcitabine/cisplatin.32 Given the success and feasibility of the regimen, LOTS is a 
promising novel combination in locally advanced gastric cancer. 
 
  The proposed trial will investigate the triplet S-1, oxaliplatin, docetaxel and 

 
4 
 
leucovorin as perioperative chemotherapy for resectable and clinical stage of above T3 
and nodal-positive gastric cancer. The study will evaluate the therapeutic efficacy, such 
as pathological tumor response, curative resection, protocol completion, tolerability and 
potential adverse reactions. In the published literature, the triplet FLOT was considered 
an optimal regimen in the dosage of docetaxel no more than 50 mg/m2 and oxaliplatin 
at 85 mg/m2 biweekly, with an acceptable tumor response and toxicity in high-risk 
resectable gastric cancer.6 The dosage and treatment schedule will be carefully 
incorporated in the proposed trial. Together the results will prove the feasibility of S-1-
containing triplet perioperative therapies in gastric cancer, provide an alternative to 
current standard of treatment and warrant more clinical studies in the future.  
 
3. STUDY DRUG INFORMATION 
 
3.1 Leucovorin:  
3.1.1 Mechanism of action: 
Leucovorin calcium (Folina tab, TTY Biopharm) is utilized to reverse the 
hematological and metabolic toxicities to normal cells by methotrexate and other 
antifolate-metabolites. It serves as a reduced folate cofactor in the de novo production 
of 
thymidylate 
from 
dUMP 
upon 
intracellular 
conversion 
to 
5,10-
methylenetetrahydrofolate (CH2FH4). Administration of leucovorin enhances the 
stability of the covalent complex of fluorodeoxyuridine monophosphate (FdUMP) and 
thymidylate synthase (TS) and thus sensitizes the antineoplastic activity of 5-FU and 
its derivatives. 
 
3.1.2 Adverse events: 
Allergic reactions such as anaphylactoid response or urticaria, have been reported 
following both oral and parenteral administration of leucovorin with an incidence lower 
than 1%. The co-administration of leucovorin and 5-FU may augment the toxicity 
confined to 5-FU. 
 
3.1.3 Clinical formulation: 
Leucovorin calcium is commercially available as “Folina® tab” containing 15 mg of 
calcium folinate per tablet. It is recommended that Folina® is administered orally twice 
daily for every 6 hours in concordance with the administration of 5-FU and its 
derivatives. The pregnancy safety category of leucovorin is “C”. 
 
3.2 Oxaliplatin:  
3.2.1 Mechanism of action: 

 
5 
 
Oxaliplatin is a diaminocyclohexane (DACH) carrier ligand-based platinum compound 
that inhibits DNA synthesis and repair. The major antineoplastic action involves in the 
formation of intra-strand platinum-DNA adducts by a cross-link between activated 
platinum species and specific base sequences, such as two adjacent guanine residues or 
guanine-adenine bases. Oxaliplatin also produces inter-strand cross-links but it 
accounts for less than 5% in the total platinum-DNA adducts. The features of the 
adducts resemble that of other platinum chemotherapeutics such as cisplatin and 
carboplatin but the disruption of DNA synthesis and cytotoxicity are more prevalent 
with the oxaliplatin-mediated DACH-platinum adducts as compared with other 
platinums. The bulky DACH carrier ligand of oxaliplatin contributes to the enhanced 
antineoplastic activity in the absence of cross-resistance with other platinums. 
Oxaliplatin administration also compromises DNA repair by preventing the assembly 
of the repair machinery proteins, notably mismatch repair enzyme complex, and thereby 
sensitizes the DNA breakage and subsequent cell death. 
 
3.2.2 Adverse effects: 
3.2.2.1 Neurotoxicity: 
The dose and duration-limiting toxicity of oxaliplatin is sensory neuropathy. 
Oxaliplatin related peripheral sensory neuropathy (PSN) presents with two distinctive 
forms. The first features by tingling of the face and extremities and may be subsided 
spontaneously. Cumulative administrations of oxaliplatin correlate with the increase 
severity and duration of PSN. Severe PSNs, such as laryngopharyngeal spasm/vocal 
cord palsy, temperature dysesthesia and hyperesthesia are observed in 1 to 2% of 
patients treated with oxaliplatin. The symptoms may resolve with prolongation or 
discontinuation of oxaliplatin infusion and the related mortality is extremely rare. The 
second form involves solely on the extremities and augments with accumulative dosing. 
Persistent irreversible functional impairment, including disability of fine sensor-motor 
executive actions or neuropathic pain, requires a dose reduction, delay and event 
permanent discontinuation of oxaliplatin. The risk of oxaliplatin related PSN at a 
cumulative dose of 780 mg/m2 is reported 10% while of 1,170 mg/m2 is 50%, 
respectively. 
 
3.2.2.2 Nephrotoxicity: 
Oxaliplatin is relatively renal-sparing as compared with other platinums. Drug related 
renal insufficiency was reported 3% in of all treated populations and grade 3 to 4 events 
were less than 1%. In addition, pharmacokinetic studies revealed that oxaliplatin does 
not increase the risk of renal toxicity or impair the metabolite clearance in patients with 
moderate renal insufficiency (eGFR 30 to 60 ml/min). 

 
6 
 
 
3.2.2.3 Hepatic toxicity: 
A transient elevation of liver enzymes may occur in patients treated with oxaliplatin. 
However, clinically relevant hepatotoxicity has not been reported to be a dose-limiting 
event from oxaliplatin administrations. 
 
3.2.2.4 Gastrointestinal toxicity: 
Nausea and vomiting were observed in patients treated with oxaliplatin but could be 
managed by conventional medications, such as 5-HT3 (serotonin) antagonists. 
Oxaliplatin is recognized as moderately emetogenic as compared with cisplatin, and 
does not cause delayed emesis. Diarrhea was reported in 41% of patients but the grade 
3 to 4 events were fewer than 5%. Mucositis occurs in only 4% of patients and does not 
require additional managements. 
 
3.2.2.5 Hematological toxicity: 
Myelosuppression is reported less than 5% in oxaliplatin monotherapy. However, the 
risk of hematological toxicity is increased in combinatorial regimens. The 
myelosuppressive effects are short in durations, potentially reversible and does not lead 
to significant complications such as neutropenic sepsis or bleeding. 
 
3.2.2.6 Allergic reactions: 
Infrequent allergic reactions have been described. Anaphylactic reactions are reported 
in 0.5% of patients treated with oxaliplatin but may require permanent discontinuation. 
 
3.2.3 Clinical formulation: 
Oxaliplatin (Oxalip®) is produced by TTY Biopharma. It is available in the form of 
vials of sterile solution. Each vial contains 50/100 mg of oxaliplatin in 10/20 ml solution. 
The concentration of oxaliplatin in the solution is 5 mg/ml. It is recommended that 
oxaliplatin should be diluted for infusion in 250 ml to 500 ml of 5% glucose solution. 
The chemical and physical stability of the reconstituted solution have been 
demonstrated for 48 hours at 2-8 degree and 30 degree Celsius. Oxaliplatin should not 
be mixed or administered with saline or other chloride-containing solutions or alkaline 
media such as basic solutions of 5-FU. The pregnancy safety category of oxaliplatin is 
“D”. 
 
 
3.3 Docetaxel:  
3.3.1 Mechanism of action: 

 
7 
 
Docetaxel is an antimitotic chemotherapeutic against various types of cancer. It binds 
to free tubulin, then promotes the polymerization of tubulin into stable microtubules 
and inhibits microtubule disassembly, resulting in blockade of cellular mitotic and 
interphase functions. Consequently, docetaxel promotes tumor cell death by interfering 
the mitotic division process and demonstrates cell-cycle dependent cytotoxicity. Unlike 
paclitaxel and other taxanes in clinical application, docetaxel does not alter the number 
of protofilaments in the bound microtubules and therefore is not cross-resistant with 
paclitaxel. 
 
3.3.2 Adverse effects: 
3.3.2.1 Hematological toxicity: 
The drug-limiting toxicity of docetaxel is myelosuppression. The maximal tolerable 
dose of docetaxel monotherapy is 100 mg/m2. The incidence of neutropenia is reported 
76% in all grades and 52% in grade 3 to 4 events as monotherapy. Severe treatment-
related anemia (8.9%) and thrombocytopenia (0.2%) are also noticed in the phase I/II 
trials. The associated neutropenic sepsis accounts for less than 5% in patients treated 
with docetaxel but few cases are reported to have clinically relevant thrombocytopenic 
bleeding. The risk of myelosuppression is increased when docetaxel incorporates other 
combinatorial chemotherapeutics, such as fluoropyrimidines, anthracyclines and 
platinums. Prophylactic or therapeutic growth factor treatment is recommended given 
in high-risk settings. The risk of treatment-related deaths associated with 
myelosuppression is rare and reported less than 1%.  
 
3.3.2.2 Gastrointestinal toxicity: 
Diarrhea, anorexia and mucositis are observed in patients treated with docetaxel but can 
be safely managed by conventional measures. The incidence of grade 3 to 4 mucositis 
is 5.3%, diarrhea 4.0%, anorexia 4.0% and vomiting 0.8% at a dose of 100 mg/m2, 
respectively. However, the events rarely result in the discontinuation or dose reduction 
of docetaxel and no toxicity-related deaths are reported. 
 
3.3.2.3 Hepatic toxicity: 
Docetaxel is associated with a risk of transient elevations in hepatocellular enzymes 
and bilirubin. The incidence of grade 3 to 4 hepatotoxicity is 5% in hyperbilirubinemia 
and less than 3% in transaminitis of in patients treated with docetaxel at a dose of 100 
mg/m2. However, the hepatotoxic reaction is idiosyncratic and does not positively 
correlate with the dosage. 
 
3.3.2.4 Allergic reactions: 

 
8 
 
Allergic reactions such as anaphylaxis, bronchospasm, angioedema, hypotension and 
generalized skin rashes are reported. The risk is exponentially higher in the first infusion 
of docetaxel. Grade 1 to 2 reactions can be managed by slower infusion rate, 
corticosteroid and/or antihistamine treatments. Although the risk of grade 3 to 4 
reaction is low (less than 1%), medical personnel should prepare emergent management 
and procedures for life-threatening anaphylaxis prior to the administrations. If the 
patient encounters an above grade 3 allergic event, discontinuation of docetaxel is 
required. 
 
3.3.2.5 Neurotoxicity: 
Docetaxel is associated with an increased risk of PSN. The incidence of grade 3 to 4 
PSN is 3% to 4% in patients treated with docetaxel. Rare cases of ageusia and anosmia 
are reported but the incidence is lower than 0.1%. Generally, grade 1 to 2 PSN improves 
spontaneously after the completion of treatment. However, persistent irreversible PSN, 
including hyperesthesia or neuropathic pain, requires a dose reduction, delay and event 
permanent discontinuation of docetaxel. 
 
3.3.2.6 Vesicant reactions: 
Docetaxel is a moderate vesicant and irritant and should be carefully managed when 
extravasation occurs. Local ice packing for 15 minutes every hour by 3 to 5 hours and 
hyaluronidase 150 unit local injections to the affected site are suggested to alleviate the 
symptoms. 
 
3.2.2.7 Cardiovascular toxicity: 
Docetaxel has been reported to be associated with fluid retentions such as pleural, 
pericardial and peritoneal effusions. However, such reactions are only seen in few 
scattered reports. 
 
3.3.2.8 Alopecia: 
Docetaxel may induce clinically significant alopecia. 
 
3.3.3 Clinical formulation: 
Docetaxel (Taxotere®) is produced by Sanofi-Aventis, France. It is available in the 
form of vials in sterile solution. Each vial contains 20 mg or 80 mg of docetaxel in 1.0 
to 4.0 ml anhydrous ethanol since the content is lipophilic. The concentration of 
docetaxel in the solution is 20 mg/ml. Patients who are allergic to the excipient 
polysorbate 800 should avoid the infusion of docetaxel. It is recommended that 
docetaxel not to be infused or diluted with polyene (PVC) bags. The chemical and 

 
9 
 
physical stability of the reconstituted solution have been demonstrated for 48 hours at 
2-8 degree and 30 degree Celsius. The pregnancy safety category of docetaxel is “D”. 
 
3.4 S-1: 
3.4.1 Mechanism of action:  
S1 is an orally available fluoropyrimidine chemotherapeutic based on a biochemical 
modulation of 5-FU. S-1 contains tegafur, a prodrug of 5-FU; gimeracil, an inhibitor of 
dihydropyrimidine dehydrogenase which prevents the rapid degradation of 5-FU; 
oteracil, which inhibits the phosphorylation of 5-FU and thereby facilitates the 
clearance of toxic metabolites and reduces the gastrointestinal toxicity, by a molar ratio 
of 1:0.4:1, respectively.  
 
3.4.2 Adverse events 
3.4.2.1 Hematological toxicity: 
The maximal tolerable dose of S-1 is 150 mg per day according to the phase I clinical 
study. However, pharmacogenetic variations are reported in different ethnical 
backgrounds, as the Caucasian patients require robust dose reductions to 75 mg per day 
due to the heterogeneous activity of cytochrome 2A6 (CYP2A6) as compared with 
Asian. The dose limiting toxicity of S-1 is myelosuppression. The incidence of 
myelosuppression is reported 78% in all grades and 20% in grade 3 to 4 events at a dose 
of 80 mg/m2 per day. Among the hematological reactions, neutropenia is the most 
common event with an incidence of 39%, followed by anemia of 31%, and 
thrombocytopenia of 11%. The phase III ACTS-GC trial incorporated 529 patients to 
receive S-1 monotherapy at a dose of 80 mg/m2 with the maximum of 120 mg daily and 
concluded that the grade 3 to 4 hematological events were neutropenia (1.2%), anemia 
(1.2%) and thrombocytopenia (0.2%), in the absence of neutropenic infections or severe 
bleeding. There were no treatment-related deaths associated with myelosuppression and 
all the events can be managed safely by conventional measures.  
 
3.4.2.2 Gastrointestinal toxicity: 
Diarrhea, anorexia and vomiting are observed in patients treated with S-1 and require 
no dose delays or reductions. The incidence of gastrointestinal toxicity is reported in 
the phase I/II studies, in which that mucositis (24%), diarrhea (12%) and 
anorexia/vomiting (12%) are the most prevalent events. In the ACTS-GC trial, grade 3 
to 4 anorexia (6.0%), nausea (3.7%), diarrhea (3.1%) and mucositis (0.2%) are reported 
and safely managed by conventional measures.  
 
3.4.2.3 Nephrotoxicity: 

 
10 
 
S-1 has not been reported to be associated with clinically relevant renal toxicity. 
However, scattered cases of grade 3 to 4 proteinuria are reported but the incidence is 
lower than 0.5%. 
 
3.4.2.4 Dermatotoxicity: 
S-1 has not been reported to be associated with severe dermatotoxicity such as Steven-
Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). However, 16% of the 
patients treated with S-1 developed drug-related allergic dermatitis in the phase I/II 
trials. Grade 3 to 4 allergic dermatitis accounts for only 1%. In addition, skin 
hyperpigmentation is observed in 22% to 37% in patients receiving S-1 but it does not 
require medical attentions other than cosmetic issues. 
 
3.4.2.5 Hepatic toxicity: 
A transient elevation of liver enzymes may occur in patients treated with S-1. Grade 3 
to 4 transaminitis are reported 1.2% to 1.7% in large-scale phase III trials. However, 
clinically relevant hepatotoxicity has not been reported to be a dose-limiting event in 
the literature. 
 
3.4.3 Clinical formulation:  
S-1 (Taiho Pharmaceutical) is commercially available as a capsule containing 20 mg of 
tegafur. The tegafur component is utilized as the dose level representative of S-1. It is 
recommended that S-1 is administered orally once or twice daily after meals. S-1 should 
be taken orally by swallowing and not be divided, grinded or dissolved in solution for 
feeding tube administration. The pregnancy safety category of oxaliplatinS-1 is “D”. 
 
4. STAGING CRITERIA AND TOOLS 
The TNM staging system, including the clinical, pathological or re-staging definitions 
which are described in American Joint Committee on Cancer Manual for Staging of Cancer 
(8th edition), will be used. A supplementary staging system incorporating Japanese 
Classification of Gastric Cancer, 3rd English edition is also utilized but not mandatory for 
stratification and analysis. 
 
5. PATIENT SELECTION 
 
5.1 Inclusion criteria 
5.1.1. Subjects have histologically-confirmed gastric or gastroesophageal junction 
(classified as Siewert type III) adenocarcinoma with a clinical stage of T3 or above, 
lymph node involvement (N+) or both according to American Joint Cancer Committee 

 
11 
 
staging system, 8th edition (AJCC 8th).  
 
5.1.2. Subjects present with at least one measurable lesion which can be accurately 
assessed by conventional techniques in one dimension at least 2.0 cm or 1.0 cm by 
computed tomography or magnetic resonance imaging. 
 
5.1.3. Subjects have a lymph node-positive disease in which that at least one of the 
nodes with a diameter greater or equal to 0.8 cm in the long axis. If subjects do not have 
a node-positive disease, a clinical stage of T3 or above and a measurable tumor is 
required for inclusion (5.1.1 and 5.1.2). 
 
5.1.4. Subjects are above 20 years of age with an Eastern Cooperative Oncology Group 
(ECOG) performance status ≤1, have a life expectancy >3 months, have surgically 
resectable disease and are physically competent and willing to receive a curative 
operation. 
 
5.1.5. Subjects have adequate organ functions, including bone marrow reserve with a 
leukocyte count ≥3,000 /µL and platelet count ≥100,000 /µL, hepatic reserve with a 
serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 times 
of upper limits and total bilirubin ≤2.0 mg/dL, renal reserve with a creatinine clearance 
≥60 mL/min and cardiac reserve with a left ventricular ejection fraction (LVEF) ≥50% 
by echocardiography at baseline. 
 
5.1.6. Subjects have, or agree to establish a vascular access that permits systemic 
intravenous chemotherapy and are capable of ingesting capsules per oral. 
 
5.1.7. Subjects with reproductive potentials are willing to accept contraceptive 
measures during the trial. 
 
5.1.8. Subjects are functionally and cognitively capable to be informed of the trial 
contents and objectives (including blood and tumor tissue for the trial investigation), 
and agree to sign the written consent for enrollment. 
 
5.2 Exclusion criteria 
5.2.1. Subjects have metastatic (M1, including washing cytology positive for peritoneal 
carcinomatosis), recurrent gastric/gastroesophageal junction cancer (defined by an 
interval time less than five years from the current diagnosis to the prior initial disease), 
or any other underlying primary malignancies excluding carcinoma in situ or resectable 

 
12 
 
skin cancer. 
 
5.2.2. Subjects have received chemotherapies within 2 years, or a major abdominal 
surgery or radiotherapy within 4 weeks before the trial enrollment. 
 
5.2.3. Subjects are known to be allergic to any of the studied chemotherapeutics. 
 
5.2.4. Subjects have underlying chronic illnesses, including cardiopulmonary diseases, 
ischemic heart disease, inflammatory bowel disease, poorly-controlled diabetes 
mellitus, liver cirrhosis and/or peripheral neuropathy of any etiologies. 
 
5.2.5 Subjects have active bacterial, viral, fungal or mycobacterial infections that 
require systemic therapy, including active infection with human immunodeficiency 
virus (HIV) (defined as positive immunoblotting confirmatory test for HIV) hepatitis B 
or C virus (HBV or HCV) (defined as positive HBV surface antigen (HBs Ag) with a 
viral load ≥500 IU/mL obtained within 28 days prior to the study in the absence of any 
anti-HBV therapies; positive HCV antibody with a detectable viral load obtained within 
28 days prior to the study in the absence of any anti-HCV therapies). However, patients 
with positive HBs Ag, a viral load <500 IU/mL and are treated with anti-HBV therapies 
for at least 14 days, positive HCV antibody with an undetectable viral load and positive 
HIV testing with peripheral blood CD4 T cells ≥350 cells/µL, a viral load <400 IU/mL 
and are treated with anti-retroviral therapies for at least 28 days do not preclude from 
the enrollment. 
 
5.2.6. Subjects are planning to conceive or already in pregnancy or breastfeeding. 
 
5.2.7. Subjects are currently participating in any other clinical trials or studies. 
 
6. STUDY DESIGN AND TREATMENT PLANS 
The study is an open-label, single-arm, single-country and multi-center phase II 
investigator-initiated trial with Simon two-stage design. The primary objective is to 
investigate the therapeutic efficacy of perioperative chemotherapy LOTS in resectable 
locally advanced gastric cancer. The primary endpoint is the treatment response rate, as 
in pathological partial or complete response. The secondary objectives are to evaluate 
the survival outcome, such as RFS, OS, the treatment duration, protocol completion, 
adverse events and predictive biomarkers for efficacy.  
 
Enrolled subjects will receive the protocol therapies until its completion, disease 

 
13 
 
progression, death at any causes, intolerable toxicities, subject’s refusal, investigator’s 
discretion or the trial termination according to the major study principal investigator. 
 
6.1 Overall protocol 
6.1.1 Perioperative LOTS 
LOTS (14 days as one cycle) 4 cycles every 2 weeks as preoperative therapy, followed 
by curative operation and another 4 cycles every 2 weeks as postoperative therapy. 
 
Leucovorin 30 mg twice daily as a fixed dose per oral on day 1 to 7. 
 
Oxaliplatin 85 mg/m2 in 250 mL of 5% dextrose water, administered as a 3-hour 
intravenous infusion on day 1. 
 
Docetaxel 40 mg/m2 in 250 mL of normal saline, administered as a 1.5-hour intravenous 
infusion on day 1. 
 
S-1 35 mg/m2 twice daily (daily total dose as determined by body surface area (BSA): 
<1.25 m2, 80 mg; 1.25-1.50 m2, 100 mg; ≥1.50 m2, 120 mg) per oral on day 1 to 7. 
 
6.1.2 Operation 
Radical total, subtotal or partial gastrectomy (laparotomic, laparoscopic or robotic) plus 
perigastric and celiac axial lymph node dissection (D2 at least) in curative intent. 
 
6.1.3 Post perioperative treatment 
Patients who achieve a pathological complete response (ypT0N0M0) after the 
preoperative chemotherapy plus curative surgery in the absence of any residual tumors 
might omit the postoperative therapy under the investigator’s discretion. 
 
After the postoperative chemotherapy per protocol (in a total of 8 cycles), patients will 
be maintained by S-1 monotherapy on D1 to D21 every 28 days or D1 to D28 every 42 
days for up to one year with the same dose in perioperative therapy according to the 
NHI practice and reimbursement guideline. 
 
6.2 Pre-medication and preparation 
6.2.1 Pre-medications before the chemotherapy 
Intravenous antihistamine and serotonin receptor blocker with/without 10 mg of 
dexamethasone are administered before the intravenous chemotherapy. 
 

 
14 
 
Therapeutic granulocyte stimulating factors (GCSF) or granulocyte-macrophage 
stimulating factors (GM-CSF) are allowed for grade 3 to 4 neutropenia or febrile 
neutropenia under the discretion of the investigator according to the NHI Taiwan 
reimbursement criteria and guidance. Prophylactic GCSF or GM-CSF is not permitted. 
Antibiotic and supportive treatments for febrile neutropenia or infections are allowed 
according to the practice guidance. 
 
6.2.2 Pre-treatment preparation 
After the enrollment, subjects are required to establish a viable vascular access for 
systemic chemotherapy, such as port-A or peripherally inserted central venous catheter. 
Chemotherapy will be initiated right after the access is established. 
 
6.3 Dose modification and treatment delay  
6.3.1 Treatment requirement:  
Subjects will receive perioperative LOTS (leucovorin, oxaliplatin, docetaxel and S-1) 
chemotherapy every 2 weeks for a total of 8 times (4 preoperative and 4 postoperative 
administrations). Each cycle of treatment will be administered only when the peripheral 
hemogram (within 72 hours), and physical conditions meet the following requirements: 
absolute neutrophil count (ANC) ≥1,500/µL, platelet count ≥100×103/µL and all the 
treatment-related adverse events recover to less than or equal to grade 1.  
 
6.3.2 Treatment delay: 
If subjects fail to meet the aforementioned requirements, the scheduled cycle of LOTS 
can be delayed for one consecutive week. The maximum of treatment delay should not 
exceed 4 consecutive weeks. 
 
6.3.2 Dose reduction and level: 
In addition to dose delays, investigators may adjust the dose level of the next cycle of 
treatment according to the table below. A maximum of two dose reductions is allowed. 
If the subject fails to tolerate the least dose level (Level -2), the treatment is 
discontinued and subject withdrawn from the study. Only dose reductions are allowed 
but not escalations. A discontinuation of a single chemotherapeutic is permitted outside 
of the dose level restrictions only when it is recognized as the inciting drug responsible 
for the specific event as described below but the guidance for dose levels is still 
maintained per protocol. In that if only single agent is preserved in the regimen 
excluding leucovorin, the subject is also withdrawn from the study. 
 
Dose levels of LOTS 

 
15 
 
Dose level 
0 (standard) 
-1 
-2 
leucovorin 
30 mg BID
30 mg BID
30 mg BID 
oxaliplatin 
85 mg/m2
60 mg/m2
45 mg/m2 
docetaxel 
40 mg/m2
30 mg/m2
20 mg/m2 
S-1 
35 mg/m2 BID
35 mg/m2 BID
20 mg/m2 BID 
 
6.3.3 Specific considerations by adverse events: 
6.3.3.1 Neutropenia 
In the presence of grade 3 neutropenia (ANC 500-1000/µL) or febrile neutropenia for 
5-7 days, reduce the dose to Level -1, followed by Level -2 and then discontinue 
docetaxel. In the presence of grade 4 neutropenia (ANC <500/µL) or febrile 
neutropenia for >7 days, reduce the dose to Level -2, and then discontinue docetaxel. If 
the subject still fails to meet the requirements, the subject is withdrawn from the study. 
 
6.3.3.2 Thrombocytopenia 
In the presence of grade 3 to 4 thrombocytopenia (PLT <50/µL), reduce the dose to 
Level -2 and then followed by discontinuation of oxaliplatin. If the subject still fails to 
meet the requirements, the subject is withdrawn from the study. 
 
6.3.3.3 Renal impairment 
Cockcroft & Gault formula (eGFR (ml/min) = (140-age) x (weight in kg) x (0.85 if 
female) / (72 x serum Cr in ug/dL) is utilized to calculate creatinine clearance. If 
eGFR=40 to 60 ml/min, reduce the dose to Level -1. If eGFR<40 ml/min, reduce the 
dose to Level -2 and then followed by discontinuation of oxaliplatin. If the subject still 
fails to meet the requirements, the subject is withdrawn from the study. 
 
6.3.3.4 Hepatic impairment 
If the serum bilirubin is 2 to 3 times of the upper normal limits, reduce the dose to Level 
-1. If the serum bilirubin is 3 times more than the upper normal limits, reduce the dose 
to Level -2. If the serum hepatic aminotransferases are 5 to 20 times of the upper normal 
limits, reduce the dose to Level -1. If the serum hepatic aminotransferases are more 
than 20 times of the upper normal limits, reduce the dose to Level -2. If the subject still 
fails to meet the requirements, the subject is withdrawn from the study. However, 
adequate management for obstructive cholestasis and evaluation of acute hepatitis are 
required. 
 
6.3.3.5 Diarrhea 
In the presence of grade 3 to 4 diarrhea, S-1 is reduced to Level -2 (20 mg/m2 BID) but 

 
16 
 
other chemotherapeutics are rather maintained. A further discontinuation of S-1 is 
suggested in the absence of recovery. If the subject still fails to meet the requirements, 
the subject is withdrawn from the study. 
 
6.3.3.6 Neurologic toxicity 
In the presence of grade 3 to 4 PSN, a dose reduction to Level -2 is required, and 
followed by discontinuation of oxaliplatin. If the subject still fails to meet the 
requirements, the subject is withdrawn from the study. 
 
6.3.3.7 Mucositis 
In the presence of grade 2 mucositis, S-1 is reduced to Level -2 (20 mg/m2 BID) but 
other chemotherapeutics are rather maintained. A further discontinuation of S-1 is 
suggested in the absence of recovery. If the subject still fails to meet the requirements, 
the subject is withdrawn from the study. 
 
6.3.3.8 Dermatitis 
In the presence of grade 3 to 4 dermatitis, such as SJS/TEN, the treatment is 
discontinued regardless of the dose levels and subject withdrawn from the study.  
 
6.3.3.9 Allergic reactions 
In the presence of grade 3 to 4 allergic events, such as anaphylaxis, angioedema or 
bronchospasm, the inciting agent is permanently discontinued regardless of the dose 
levels. If the research team fails to identify the specific inciting agent, or in 
combinatorial reactions for the severe allergic events, the subject is withdrawn from the 
study. 
 
6.4 Off-study criteria 
Subjects who meet any one of the following conditions will be withdrawn from the 
study, 
▪ Imaging or tissue evidence of disease progression or recurrence 
▪ Delayed recovery of treatment-related toxicities, which prohibits the protocol 
treatment for 28 days since the inciting treatment. 
▪ Unacceptable or unanticipated toxicity 
▪ Subject’s death 
▪ Subject’s refusal 
▪ Investigator’s discretion to stop the protocol treatment 
▪ Available and potentially better alternative treatments at the discretion of the 
investigator 

 
17 
 
 
7. STUDY SCHEDULE 
 
7.1 Pre- and Post-treatment Investigations 
The following tests are performed within one week before the initiation of therapy (as 
the baseline data) and then repeated as scheduled and described below 
. 
7.1.1 The first and screening computed tomographic (CT) or magnetic resonance 
imaging (MRI) scans must be done within 2 weeks prior to the initiation of therapy and 
then followed by every 8 weeks (including one exam after pre-operative chemotherapy 
prior to operation and one exam before post-operative chemotherapy after surgery) for 
4 times, and then followed by every 12 weeks for 6 times. 
 
7.1.2 Esophagogastroduodenoscopy (EGDscopy) will be conducted within 2 weeks 
prior to the initiation and 4 weeks after the completion of the protocol therapies. 
EGDscopy-directed local therapies for hemostasis, biopsy and removal of other non-
tumoral lesions are permitted but not the local antineoplastic therapy for the tumor. 
However, an interim EGDscopy can be arranged when patients are suspicious of local 
recurrence or progression. 
 
7.1.3 Physical examinations (including body weight), comprehensive medical history, 
performance status by Eastern Cooperative Oncology Group (ECOG) and peripheral 
hemogram will be examined every 2 weeks before each infusion within 72 hrs. 
 
7.1.4 Serum creatinine level will be examined and calculated for eGFR (eGFR (ml/min) 
= (140-age) x (weight in kg) x (0.85 if female) / (72 x serum Cr in ug/dL)) every 2 
weeks before each infusion within 72 hrs. 
 
7.1.5 Liver functional tests (albumin, bilirubin direct/indirect, AST/ALT, and alkaline 
phosphatase) and routine electrolytes (Na, K and Ca) will be examined every 2 weeks 
before each infusion within 72 hrs. 
 
7.1.6 CEA and CA19-9 will be evaluated by enzyme-linked immunosorbent assay 
(ELISA) at baseline and every 8 weeks of the protocol for 4 times (including one exam 
after pre-operative chemotherapy prior to operation and one exam before post-operative 
chemotherapy after surgery), and then followed by every 12 weeks for 6 times. 
 
7.1.7 Chest roentgenogram will be examined at baseline and at every 2 weeks of the 

 
18 
 
protocol. Chest CT will only be done when patients are suspicious of lung metastasis. 
 
7.1.8 Positron emission tomography (PET) and Tc-99m bone scintigraphy will only be 
arranged when patients are suspicious of distant metastasis. 
 
7.1.9 Serum samples (8 mL) will be collected at study entry and then followed by every 
8 weeks (including one exam after pre-operative chemotherapy prior to operation and 
one exam before post-operative chemotherapy after surgery) for 4 times, and then 
followed by every 12 weeks for 6 times. 
 
7.1.10 20 paired pre and post-treatment tumoral and peri-tumoral microscopic slides 
(4-10 µm) are obtained and prepared for immunohistochemical staining, tissue 
microarray and whole/targeted-exome sequencing following next-generation 
sequencing procedures and practice guidelines. 
 
7.2 Time table for examinations 
 
Baseline 
Q2W
Q4W
Q8W 
Additional 
PE (including BW) 
X 
X 
 
 
 
Performance status, ECOG 
X 
X 
 
 
 
Hemogram 
X 
X 
 
 
 
LFT and Lytes 
X 
X 
 
 
 
Serum creatinine (eGFR) 
X 
X 
 
 
 
CEA, CA19-9 
X 
 
 
X 
Xa, b 
PT/aPTT/INR 
X 
X 
 
 
 
Chest roentgenogram 
X 
X 
 
 
 
CT or MRI of abdomen 
X 
 
 
X 
Xa, b 
PET or bone scintigraphy 
 
 
 
 
Xc 
Serum samples 
X 
 
 
X 
Xa, b 
Tumoral/peritumoral tissue 
X 
 
 
 
Xd 
a. one exam after pre-operative chemotherapy prior to operation and one exam before post-operative 
chemotherapy after surgery. If the time interval between the additional exam to the scheduled one is less 
than 4 weeks, the investigator may omit one of the exams. 
b. the scheduled exams for 4 times, and then followed by every 12 weeks for 6 times 
c. only when in suspicion of distal metastasis. 
d. pre and post-treatment paired samples without a defined time interval. 
 
7.3 Serum and tumor sample collections 

 
19 
 
7.3.1 Serum samples 
In each sampling, 15.0 ml of peripheral blood will be drawn for plasma collection, 
which is stored in 3 separate vials after centrifugation. Buffy coat-rich plasma will also 
be collected for the storage of peripheral blood mononuclear cells (PBMCs). All 
samples will be collected by research nurses of the participating institutes at -20 degree 
Celsius and sent to NCKUH Biobank, Tainan in dry ice batches for further 
investigations, such as cell-free tumor DNAs, circulating tumor cells, inflammatory 
cytokines and other serum biomarkers. 
 
7.3.2 Tumor and peritumor samples 
Tumor/peritumor slides will be prepared for Hematoxylin & Eosin and IHC staining. 
Tumor infiltrating immune cells will be evaluated and quantified via IHC stains. Tumor 
DNA will be extracted from the formalin-fixed paraffin-embedded tissue (FFPE) 
samples (archival or fresh) and sent for whole/targeted-exome sequencing with a list of 
cancer- or immune-related genes. Tumor mutation burdens will be quantified via tumor-
specific mutation loads deducted by germline ones as defined by the PBMCs from an 
identical subject. 
 
8. EVALUATION OF THERAPEUTIC EFFICACY 
 
8.1 Tumor response evaluation 
8.1.1 Specification by methods of measurements: 
The identical assessment methods should be implemented to each lesion at baseline, 
during the protocol treatment and in the follow-up periods. Image-based evaluation 
tools are preferred than clinical ones for the accurate measurement of treatment effect. 
In addition, pathological response of the complete resected tumor will be evaluated. 
 
8.1.2 Tumor response criteria 
Tumor response will be evaluated by Response Evaluation Criteria in Solid Tumors 
(RECIST) Guidelines version 1.1.33 Pathological response will be assessed by 
Chevallier system with tumor regression grading (TRG) according to the guidance 
described by Mandard et al..34,35 
 
8.1.3 Definition of measurable disease 
At baseline, tumor lesions will be categorized as measurable and non-measurable. 
 
Measurable: Lesions that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as U ≥20 mm with conventional techniques or as ≥10 mm with 

 
20 
 
CT, MRI or PET images. 
 
Non-measurable: All other lesions excluding measurable ones (longest diameter <20 
mm with conventional techniques or <10 mm with CT, MRI or PET images). 
 
8.1.4 "Target" and "Non-target" lesions. 
Target lesions: All measurable lesions up to a maximum of 2 per organ or up to 5 in 
total that represent all the involved organs at baseline. Target lesions should be based 
on their sizes (in the longest diameter) and the reproducibility for repeated 
measurements. A sum of the longest diameter for all target lesions will be calculated as 
the baseline sum and be utilized as a reference for the calculation of objective response. 
 
Non-target lesions: All other lesions (or sites of disease) should be identified as non-
target lesions and should also be recorded at baseline. Measurements of these lesions 
are not mandatory, but the presence or absence of each should be recorded in the follow-
up periods alone with their responses. 
 
8.1.5 Image response Criteria 
8.1.5.1 Evaluation of target lesions. 
Complete response (CR): The disappearance of all target lesions. 
 
Partial response (PR): At least a 30% decrease in the sum of the longest diameter of 
target lesions. 
 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor increase to 
qualify for PD. 
 
Progressive disease (PD): At least a 20% increase in the sum of the longest diameter of 
target lesions plus an increased diameter of any of the target lesions at least 0.5 cm, the 
development of at least one new measurable lesion, the reappearance of lesions that 
were previously disappeared, or frank deteriorations of any assessable disease. 
 
8.1.5.2 Evaluation of non-target lesion 
Complete response (CR): The resolution of all non-target lesions. 
Incomplete response/stable disease (iCR/SD): The persistence of at least one non-target 
lesion. 
Progressive disease (PD): The development of at least one new lesion and progression 
of pre-existing non-target lesions. 

 
21 
 
 
8.1.5.3 Evaluation of best overall response 
The assignment of the best overall response is defined by both the measurement and 
confirmation criteria. An overall response will be recorded when the assessment is 
performed every 8 weeks for 4 times and consists of all combinations of tumor 
responses in target and non-target lesions. When a status of PR or CR is assigned, it 
requires the tumor response to last at least 4 weeks and be confirmed by the subsequent 
assessment by any time intervals. In cases of SD, the clinical status must fulfill the SD 
criteria at a minimal interval of 4 weeks. 
 
Overall response criteria 
Target lesion 
Non-target 
lesion 
New lesion
Overall response 
CR 
CR 
No 
CR 
CR 
iCR/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No
PD 
Any 
PD 
Yes or No
PD 
 
8.1.6 Pathological response criteria 
Pathological complete response (pCR): defined as the complete resolution of all the 
tumor and negative lymph nodes, as classified by tumor regression grade 1 (TRG 1). 
 
Pathological partial response (pPR): defined as presence of any residual tumor cells 
with partial tumor regression, as classified by TRG 2 to 4. 
Pathological no response (pNR): defined as absence of any regressions or changes of 
the tumor, as classified by TRG 5. 
 
9. STATISTICAL CONSIDERATION 
In the proposed study, a Simon two-stage design is utilized for calculation of the optimal 
sample size. We assume a statistical power of 90% (β=0.1) and the probability of type 
I error by two-tailed α at 0.1. According to the published studies, the response rate of 
preoperative chemotherapies for locally advanced gastric cancer were 30% to 40%. We 
estimate a good treatment response rate (P1) of 60% and a poor rate (P0) of 35%. In the 
optimum model, 14 subjects will be enrolled in the stage 1. A maximum of 5 subjects 
is required to reject the futility of the trial in stage 1. In the stage 2, an additional 25 
subjects (39 in total) will be enrolled with a maximum of 18 in total to reject the futility 

 
22 
 
of the trial. The minimal estimated sample size is 23 if the treatment response is poor 
(P0). In summary, a total of 56 subjects will be enrolled under the assumption of a 30% 
of drop-out and operation ineligibility rate per protocol, respectively. The treatment 
completion rate of the published trials is presented below, along with the estimated 
subjects in the proposed trial. 
 
Treatment completion in the literature and estimated subjects in the proposed trial 
 
Enrolled 
patients, n
Preoperative 
CT 
completion, n (%)
Operation 
completion, n (%)
Postoperative CT 
completion, n (%)
MAGIC: ECF arm3 
250
215 (86)
209 (84)
104 (42)
FNCLCC-FFCD: CF 
arm5 
113
105 (93)
101 (89)
54 (48)
AIO-FLOT46 
  FLOT arm 
  ECX/EFX arm 
356
360
352 (99)
353 (98)
345 (97)
341 (95)
213 (60)
187 (52)
Pooled completion rate 
-
(95)
(88)
(50)
Proposed trial: LOTS 
arm 
56
53 
49  
28 
 
10. 
REPORTING 
OF 
SEVERE 
ADVERSE 
EVENTS 
TO 
INSTITUTIONAL REVIEW BOARD (IRB) OF ETHICS 
 
10.1 Reporting events to IRB 
All investigators must receive adequate professional training according to the Good 
Clinical Practice (GCP) guideline, be approved by the IRB, abide to the related 
obligations and be accredited for clinical trial investigations. Serious adverse 
events/Suspected unexpected serious adverse reactions/Unanticipated problems 
(SAE/SUSAR/UP) must be reported in written form to the PI immediately. The PI will 
then report to IRB within 72 hours. The events are defined as any of those described in 
sections 10.1.1 to 10.1.6 below. However, serious events occurring after the subject is 
withdrawn from the study do to warrant mandatory reporting under the investigator’s 
discretion. Events which are anticipated morbidities associated with malignancy and 
chemotherapy are waived from the reporting. 
 
10.1.1 Causes death 
Study-specific clinical outcomes of death because of disease progression are excluded 
from the reporting unless the investigator deems the death related to the study treatment. 
 

 
23 
 
10.1.2 Are life-threatening. 
 
10.1.3 Causes severe or permanent disability. 
 
10.1.4 Causes prolonged inpatient hospitalization. 
Hospitalization for study drug administration or hospitalization due to anticipated 
morbidity related to chemotherapy and malignancy is waived from the reporting. 
Therefore, hospitalization due to therapy-related myelosuppression, fever, nausea, 
vomiting, weight loss, fatigue, electrolyte disturbance, pain management, anxiety, or 
palliative care is waived from the reporting. However, investigator is authorized to 
report events in which the severity inconsistent with anticipated risks. 
 
10.1.5 Causes congenital anomaly. 
 
10.1.6 Is significant for any other reasons. 
 
11. OTHERS 
 
11.1 All patients must have a signed Informed Consent form and an on-study 
(confirmation of eligibility) form filled out and signed by a responsible investigator 
before entry. 
 
11.2 The responsible study investigators and research nurses must approach each 
patient prior to study drug administration. All required pre-treatment and interim 
information should be available and the investigators must decide if a re-evaluation is 
needed and the grade of treatment-related toxicity if presents. 
 
11.3 Data must be recorded before a course of therapy can be given. A brief explanation 
for required but missing data should be recorded as a comment. 
 
11.4 Data from patients enrolled at the Cooperative Ward of the Cancer Clinical 
Research Center (CCRC) of National Health Research Institutes (NHRI) will be entered 
into the Clinical Data Management System of CCRC. 
 
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