Efficacy and Safety of Serplulimab Combined With Nab-paclitaxel and SOX as Neoadjuvant Treatment for Locally Advanced Gastric Cancer or Adenocarcinoma of Esophagogastric Junction: A Multicenter Randomized Controlled Trial
Phase: PHASE2
Conditions: Stomach Neoplasms, Immune Checkpoint Inhibitors
Sponsor: Xijing Hospital

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
Efficacy and Safety of Serplulimab Combined with SOX and
Nab-paclitaxel as Neoadjuvant Treatment for Locally
Advanced Gastric cancer or Adenocarcinoma of
Esophagogastric junction:
A Multicenter Randomized Controlled Trial
CLINICAL STUDY PROTOCOL
Registration Number:
Principle Investigator:
NCT06576921
Liu Hong, Ph.D.
Department of Digestive
surgery, Xijing Hospital of
Digestive Diseases, Air Force
Medical University, Xi' an,
China,710032.
Telephone: +86-13709284513
E-mail: hongliu180@126.com

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
TABLE OF CONTENTS
Abbreviations......................................................................................................................................... 1
SYNOPSIS............................................................................................................................................. 3
Study Plan...............................................................................................................................................8
1. Background...................................................................................................................................... 10
2. Objectives.........................................................................................................................................13
2.1 Primary Objective.................................................................................................................. 13
2.2 Secondary Objectives.............................................................................................................13
2.3 Exploratory Objective............................................................................................................13
2.4 Randomization, Blinding, and Unblinding ...........................................................................13
3. Study Design and Sample Size........................................................................................................ 14
3.1 Study Design.......................................................................................................................... 14
3.2 Study Schema.........................................................................................................................14
3.3 Study Duration....................................................................................................................... 14
3.4 Sample Size............................................................................................................................14
4. Study Population.............................................................................................................................. 15
4.1 Inclusion Criteria....................................................................................................................15
4.2 Exclusion Criteria...................................................................................................................15
4.3 Drop Out/Removal Criteria....................................................................................................16
4.4 Discontinue Criteria............................................................................................................... 16
5. Study Treatments..............................................................................................................................17
5.1 Handling and Storage.............................................................................................................17
5.2 Treatment................................................................................................................................17
5.3 Dose Modification..................................................................................................................18
5.3.1 Dose Modification for Serplulimab............................................................................ 18
5.3.2 Dose Modification for Chemotherapeutic Agents......................................................23
5.4 Concomitant Therapy.............................................................................................................25
6. Study Procedure............................................................................................................................... 26
6.1 Screening Period.................................................................................................................... 26
6.2 Treatment Period....................................................................................................................26
6.2.1 Neoadjuvant Treatment Period................................................................................... 27
6.2.2 Preoperative Assessments and Surgery...................................................................... 27
6.2.3 Adjuvant Treatment Period......................................................................................... 27
6.3 Follow-up Period....................................................................................................................28
6.4 Progression of Disease...........................................................................................................28
7. Efficacy Assessments....................................................................................................................... 29
8. Safety Assessments.......................................................................................................................... 30
8.1 Safety Endpoints.................................................................................................................... 30
8.2 Definition of Adverse Event and SeriousAdverse Event......................................................30
8.3 Recording and Follow-up of (Serious) Adverse Events........................................................ 31
9. Statistical Analysis Plan................................................................................................................... 32
9.1 Sample Size Considerations...................................................................................................32

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
9.2 Analysis Sets.......................................................................................................................... 32
9.3 Statistical Analysis................................................................................................................. 33
10. Data Management.......................................................................................................................... 33
10.1 CRF Completion Guidelines................................................................................................33
10.2 Data Lock............................................................................................................................. 34
10.3 Quality Control and Quality Assurance...............................................................................34
11. Ethics and Regulatory Considerations........................................................................................... 34
11.1 Local Regulations / Helsinki Declaration............................................................................ 34
11.2 Informed Consent.................................................................................................................35
11.3 Independent Ethics Committee/Institutional Review Board............................................... 35
11.4 Confidentiality Agreement...................................................................................................35
11.5 Record Storage..................................................................................................................... 35
11.6 Study Interruption.................................................................................................................36
11.7 Protocol Modification.......................................................................................................... 36
11.8 Protection of participants' Rights and Interests....................................................................36
References............................................................................................................................................ 37
Appendix 1 Mandard Regression Criteria........................................................................................... 40
Appendix 2 Pathological Staging System............................................................................................41
Appendix 3 Surgical Manual................................................................................................................43
Appendix 4 Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1..........................45
Appendix 5 ECOG Performance Status...............................................................................................47
Appendix 6 Classification of Surgical Complications.........................................................................48

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
Abbreviations
Abbreviations
Full names
AE
Adverse event
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase
ANC
Absolute neutrophil count
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BIL
Bilirubin
BSA
Body surface area
BUN
Blood urea nitrogen
CCr
Creatinine Clearance
CFDA
China Food and Drug Administration
CI
Confidence interval
Cr
Creatinine
CR
Complete response
CRF
Case Report Form
CT
Computed tomography
CTC AE
Common Terminology Criteria for Adverse Events
DLT
Dose Limiting Toxicity
DRQ
Data Request
ECG
Electrocardiography
ECOG
Eastern Cooperative Oncology Group
EORTC
The European Organization for Research and Treatment for
Cancer
FAS
Full Analysis Set
Fbg
Fibrinogen
GC
Gastric cancer
GCP
Good Clinical Practice
1

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
Glu
Glucose
Hb
Hemoglobin
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard Ratio
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IQR
Interquartile range
IRB
Institutional Review Board
irAE
Immune-related adverse event
ITT
Intention-to-treat
LAGC
Locally advanced gastric cancer
MPR
Major pathological response
MRI
Magnetic resonance imaging
MTD
Maximum Tolerated Dose
NMPA
National Medical Products Administration
NTAX
Nanoparticle albumin-bound-paclitaxel
NSCLC
Non-small Cell Lung Cancer
OB
Occult blood
ORR
Objective response rate
OS
Overall survival
pCR
Pathological complete response
PD
Progression disease
PD-1
Programmed cell death protein 1
PD-L1
Programmed cell death protein-ligand 1
PET
Positron emission tomography
PFS
Progression-free survival
PI
Principal Investigator
PLT
Platelets
2

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
PK
Pharmacokinetics
PPS
Per Protocol Set
PR
Partial response
PT
Prothrombin time
RBC
Red blood cell
RCCEP
Reactive cutaneous capillary endothelial proliferation
RECIST
Response Evaluation Criteria in Solid Tumor
RR
Respose Rate
SAE
Serious adverse event
SAS
Safty Analysis Set
SCr
Serum Creatinine
SD
Stable disease
TRG
Tumor regression grade
TSH
Thyroid-stimulating hormone
TT
Thrombin time
ULN
Upper limits of normal
VEGF
Vascular endothelial growth factor
WBC
White blood cell
3

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
SYNOPSIS
Title
Efficacy and Safety of Serplulimab Combined with SOX and Nab-
paclitaxel as Neoadjuvant Treatment for Locally Advanced Gastric or
Esophagogastric junction Cancer:
A Multicenter Randomized Controlled Trial
Study Subjects Patients
with
locally
advanced
gastric
cancer
(LAGC)
or
adenocarcinoma of esophagogastric junction (AEG)
Study Design
Multicenter, double-blind, randomized phase 2 clinical trial
Study
Objectives
Primary endpoint

Pathological complete response rate (pCR), postoperative
pathological response according to the Mandard tumor
regression grading system (TRG), TRG 1 is pCR.
Secondary endpoints

ORR，MPR, etc.

R0 resection rate

1/3-year PFS and OS

Safety of study drugs according to the NCI-CTCAE, version 5.0

Surgical safety: including morbidity, mortality, hospital stay, etc.

Patient reported outcomes: EORTC QLQ-C30 and QLQ-STO22
Number of
Patients
58 patients per group
Inclusion

Age older than 18 and younger than 80 years

Primary GC or AEG (Siewert II/III)confirmed pathologically by
endoscopic biopsy

Clinical stage T3/T4N+M0 disease as assessed by CT/MRI, PET-
CT, and laparoscopy, if feasible

At least one measurable lesion according to the RECIST, version
1.1

Eastern Cooperative Oncology Group (ECOG) performance
status of 0 or 1

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
Criteria

Surgical treatment after neoadjuvant chemotherapy is planned
according to clinical staging criteria.

Life expectancy of at least 3 months

Acceptable bone marrow, hepatic, and renal function, including:
1.Blood routine examination(No blood transfusion within 14 days; No
granulocyte colony-stimulating factor (G-CSF) or other
hematopoietic stimulating factors were used): white blood cell
count ≥3.5 ×109/L, neutrophils ≥1.5 × 109/L, platelet count >100
× 109/L, and hemoglobin ≥90 g/L;
2. Hepatic function: alanine aminotransferase (ALT) and aspartate
aminotransferase (AST), ALT and AST≤2.5×ULN; total bilirubin
(TBIL) ≤1.5×ULN (Gilbert syndrome patients, ≤3×ULN);
3. Renal function: serum creatinine (Cr) ≤1.5×ULN or
creatinine clearance (Ccr) ≥60mL/ min;
4. Coagulation function: activated partial thromboplastin time
(APTT), international standardized ratio (INR), prothrombin
time (PT) ≤1.5×ULN;

Written informed consent
Exclusion
Criteria

Squamous cell carcinoma, adenosquamous cell carcinoma, small
cell carcinoma, and undifferentiated gastric cancer were
confirmed by pathology

Positive Her-2 detection (IHC3+ or IHC2+ amplified by FISH
detection)

Prior chemotherapy, radiotherapy, hormone therapy, targeted
therapy, or immunotherapy

Contraindications for surgical treatment or chemotherapy

Presence of distant metastasis

History of other malignant disease within the past 5 years,
except: basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or in situ cervical cancer that have been

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
treated radically and have shown no signs of disease for at least 5
years

Any active or history of autoimmune disease, or history of
syndrome that required systemic steroids or immunosuppressive
medications, except for subjects with vitiligo or resolved
childhood asthma/atopy

History
of
immunodeficiency
diseases,
including
human
immunodeficiency virus (HIV), or other acquired or congenital
immune-deficient disease, or transplantation

Severe mental disorder

Presence of digestive tract obstruction, jaundice, acute infectious
diseases, inflammatory bowel disease, Crohn's disease,
ulcerative colitis, chronic diarrhea, active tuberculosis

Immunosuppressive drugs are required for 2 weeks or within 2
weeks or during the study period, excluding the following: a)
intranasal, inhaled, topical or topical steroid injections (e.g. intra-
articular injections); b) Physiological dose of systemic
corticosteroids (≤10mg/ day prednisone or equivalent dose); c)
Short-term (≤7 days) use of steroids for the prevention or
treatment of non-autoimmune allergic diseases;

Patients who have undergone major surgery or received live
virus vaccine within 4 weeks

Pregnant or breast-feeding women, subjects who are unwilling to
receive effective contraception during treatment and within 6
months after the end of treatment (including male subjects who
have the ability to impregnate women and female subjects and
their male partners)

Evidence of bleeding tendency or receiving thrombolytics or
anticoagulants

According to the criteria of the term Common Adverse Events
(NCI-CTCAE V5.0), the corresponding symptoms have been
diagnosed;

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024

Hepatitis B or hepatitis C virology tests at the time of screening
meet any of the following: a) HBsAg positive and HBV-DNA
titer ≥104 copy number /mL or ≥2000IU/mL (hepatitis B carriers
should ask researchers for appropriate antiviral treatment); b)
Active hepatitis C: HCV antibody positive and HCV-RNA higher
than the lower detection limit of the assay;

Allergic to study drugs

The investigator believes that the subjects have other conditions
that may affect their adherence to the protocol and evaluation of
the study indicators, and the subjects are not suitable to participate
in the study.
Drop
out/removal
criteria

Use of NMPA-approved modern traditional Chinese medicine
agents for the treatment of gastric cancer

Concurrent radiotherapy or other local treatments during the
study periods

Medication, dosing, and treatment methods do not follow the
study protocol
Treatment
end/termi
nation
Criteria

The patient has completed the treatment prescribed in the
protocol;

Withdrawn of the informed consent

Progression disease (PD) or death

Unbearable toxicity after dose reductions

When an adverse event (AE) or serious adverse event (SAE)
occurs, the patient does not wish to continue treatment or has an
unexpected and unacceptable adverse drug reaction;

Loss to follow up

Investigator’s decision that stopping treatment was in the best
interest of the patient
Study Duration

Planned start date: September 1, 2024

Planned enrollment completion date: September 1, 2025

Planned study end date: September 31, 2025

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
Treatment
Regimens
Neoadjuvant treatment
Treatment group (S-P-SOX):

Serplulimab, 4.5 mg intravenously on day 1;

Nap-paclitaxel, 260 mg/m2 intravenously on days 1;

Oxaliplatin (OXA), 130mg/ /m2, intravenously on days 1;

Tigio (S-1), 40-60 mg orally twice daily on days 1 to 14.
Control group (P-SOX):

Nap-paclitaxel, 260 mg/m2 intravenously on days 1;

Oxaliplatin (OXA), 130mg/ m2, intravenously on days 1;

Tigio (S-1), 40-60 mg orally twice daily on days 1 to 14.
The dose of S-1 is based on body surface area (BSA):
BSA
Dose
The above treatments will be administered every 3 weeks for three
preoperative cycles. Dose adjustment is not allowed and delayed
dosing is allowed.
Surgery
Surgery was scheduled 3 to 4 weeks after completion of the last cycle
of neoadjuvant treatment. All surgical procedures are performed
according to the guidelines of the Japanese Research Society for the
Study of Gastric Cancer.
Adjuvant treatment
Adjuvant treatment started 3 to 8 weeks after surgery. Patients will
receive three to five 3-week cycles of adjuvant treatment with S-P-
SOX or P-SOX according to the preoperative regimen.
< 1.25m2
40mg× 2/day
1.25m2 - 1.5m2
50mg× 2/day
> 1.5m2
60mg× 2/day

Serplulimab for G/EGJ cancer Protocol (Version 1.1) Date: Oct 8, 2024
Statistical
Consideration
Full analysis set (FAS) included all patients who are randomly
assigned according to the intention-to-treat (ITT) principle. This
population will be used for the efficacy analyses. Baseline data were
analyzed by FAS.
Per-protocol set (PPS) included patients in the ITT population
who did not present major deviations from the protocol. We pre-
specified that participants who received surgery after administration
of neoadjuvant S-P-SOX or P-SOX are included in this set. This
population will be also used for the efficacy analyses.
Safety analysis set (SAS) included patients who received at least
one dose of allocated treatment. This population will be also used for
the safety analyses.
Sample size
determination
Based on results and data from previous similar studies, the pCR
rate of nap-paclitaxel combined with SOX is known to be 7%, and
the pCR rate of the Serplulimab combined with nap-paclitaxel and
SOX is expected to be 25%. A sample size of 58 patients per group
was required to detect improvement with 80% power and a one-sided
alpha level of 0.05, including a 15% dropout rate.
Version
1.1

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
Study Plan
Items
Screening Period
Randomization
Neoadjuvant Treatment Period
Surgery
Adjuvant Treatment
Period
Follow-
up[16]
Before 2
weeks of
enrollment
Before 1
week of
enrollment
Cycle 1
Cycle 2
Cycle 3
Before
1 week
of
surgery
After 1
week of
surgery
Cycle 4-6
Day 14
Day 1
Day 14
Day 1
Day 14
Day 1
Day 14
Baseline characters
Informed consent
√
Demographics data
√
Medical history
√
Vital signs and
physical[1]
√
√
√
√
√
√
√
√
√
√
√
Assessments
Blood routine[2]
√
√
√
√
√
√
√
√
√
√
√
Urinary routine[3]
√
√
√
√
√
Fecal routine
√
√
√
√
√
Biochemistry[4]
√
√
√
√
√
√
√
√
√
√
√
Coagulation test[5]
√
√
√
√
√
Thyroid function test[6]
√
√
Tumor markers[7]
√
√
√
√
√
√
√
Myocardial zymogram
√
√
Pituitary-adrenal axis
examination[8]
√
HBV/HCV/HIV[9]
√
√
Tumor sample[10]
√
√
Gastroduodenoscopy
√
12-lead ECG
√
√
√
√
√
Echocardiography[11]
√
√
Imaging examination[12]
√
√
√
ECOG status
√
√
√
√
√
√
√
√
√
√
Blood pressure
monitoring[13]
√
√
√
√
√
√
√
√
√
√
Adverse events[14]
√
√
√
√
√
√
√
√
√
8

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
Others
Concomitant treatments
√
√
√
√
√
√
√
√
√
√
Drug compliance
√
√
√
√
Surgical record[15]
√
Drug suspension and dose
adjustment
√
√
√
√
√
√
√
√
Pathological efficacy
evaluation
√
[1]
Including vital signs (blood pressure, pulse, and temperature), height (at baseline only), weight, and physical examination (especially abdominal examination).
[2]
Including hemoglobin, hematocrit, RBC, WBC, ANC, and platelet count.
[3]
Including urinary protein and urine occult blood.
[4]
Including bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatinine, blood urea nitrogen (BUN), glucose, calcemia, sodium, and potassium.
[5]
Including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen.
[6]
Including thyroid-stimulating hormone (TSH), free T3, and free T4.
[7]
Including carcinoembryonic antigen (CEA), carbohydrate antigen (CA)19-9, CA125, CA153, etc.
[8]
Pituitary-adrenal axis examination: adrenocorticotropin, cortisol
[9]
Including hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV).
[10] Central evaluation of programmed death-ligand 1 (PD-L1) expression and microsatellite instability (MSI) in pretreatment specimens, tumor regression grade in surgical specimens, and exploring the the
mechanisms of response and resistance to S-P-SOX.
[11] Echocardiography must be examined during screening. During the study period, ECG abnormalities of significant clinical significance should be supplemented by Echocardiography
[12] Including chest, abdomen and pelvis CT or MRI.
[13] Blood pressure monitoring is completed by the patient and recorded in a diary card. Blood pressure should be measured at least 3 times a week for the first 3 cycles. For patients with abnormal blood
pressure, blood pressure should be measured every day. At each visit, blood pressure should be measured by the investigator. Each blood pressure measurement should be taken ipsilateral.
[14] Adverse events are recorded from randomization until 30 days after the last dose of the investigational product. During follow-up, all adverse events that occur 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.
[15] Surgical record: including operative time, intraoperative bleeding, surgical approach, postoperative complications, postoperative outcomes, surgical costs, and pathological result.
[16] Patients are followed up postoperatively by physical examination, laboratory tests, and imaging examination every 3 months for 2 years, every 6 months during years 3-5, and annually thereafter.
Endoscopy is recommended annually.
9

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
1. Background
Gastric Cancer (GC) is the fifth most common malignancy globally and the third
leading cause of cancer death. Half of the world's cases occur in eastern Asia [1], which
has the highest mortality rate. According to the latest data released by the National
Tumor Registration Center, it is estimated that in 2015, there were 679,000 new cases
of gastric cancer in China, and 498,000 deaths, ranking second in both incidence and
fatality rate among malignant tumors [2]. The overall prognosis is poor, posing a
serious threat to human health.
Environmental and genetic factors play an important role in the development of
gastric cancer, with common risk factors including age, male gender, smoking,
radiation and family history. Specific risk factors for gastric cancer include
Helicobacter pylori infection and dietary factors [3]. Helicobacter pylori (H.pylori)
infection often leads to chronic gastritis, gastric atrophy, and then intestinal metaplasia,
abnormal hyperplasia and gastric cancer [4-6]. Dietary factors include low intake of
fruits and vegetables, high salt, and intake of smoked foods.
Radical surgical resection is still the main treatment for non-metastatic gastric
cancer, but the postoperative recurrence and metastasis rate is as high as 40-80%, and
the 5-year survival rate is 30-60%[7-8]. The treatment mode of neoadjuvant
chemotherapy + surgery + adjuvant chemotherapy (perioperative treatment) is an
important part of the comprehensive treatment of gastric cancer at present. A number of
studies have proved that compared with surgery alone, this treatment mode can reduce
the tumor stage, increase the R0 resection rate, and improve the overall survival,
without increasing postoperative complications and mortality. The purpose of
neoadjuvant chemotherapy is to reduce tumor load and increase the possibility of R0
resection [9], so as to improve the pathological complete response rate. Neoadjuvant
chemotherapy can measure a patient's sensitivity to chemotherapy drugs and therefore
predict a patient's response to subsequent chemotherapy. At present, it has been
confirmed that pathological complete response rate is correlated with overall survival
[10]. On September 28, 2019, at the ESMO Conference , Chinese scholars announced
the results of the RESOLVE Phase III study on perioperative treatment of locally
10

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
advanced gastric cancer [11], adding new evidence-based medical evidence for
perioperative treatment of such patients. The RESOLVE study is A three-arm,
randomized, multicenter, open-label Phase III trial comparing the efficacy and safety of
using XELOX (Group A) or SOX (Group B) after radical D2 surgery versus
perioperative use of SOX (group C). Finally, 1022 cases of ITT population were
included in the analysis. In the perioperative group (group C), the R0 resection rate
(92.88%) and the proportion of D2 lymph node dissection (95.59%) showed an
increasing trend. The R0 removal rates of group A and group B were 86.47% and
87.83%, respectively.
In
patients
with locally advanced
gastric cancer,
SOX
chemotherapy during perioperative period improved 3-year disease-free survival
(62.02% vs 54.78%, P=0.045, HR=0.79, 95%CI 0.62-0.99) compared with XELOX
adjuvant. Results of a multicenter Phase III clinical study in France [12] showed that
preoperative neoadjuvant chemotherapy with PF regimen significantly increased R0
resection rate compared with surgery alone (84% vs 73%, P=0.04). For initially treated
locally advanced gastroesophageal cancer, XELOX regimen has been proven to be as
effective as cisplatin combined with fluorouracil regimen [13]. Results of a Chinese
study showed that for patients with advanced gastric cancer, the ORR of neoadjuvant
chemotherapy with FOLFOX regimen was 70%[14], and the R0 resection rate was
significantly improved compared with surgery alone (86% vs 55%, P=0.011). A study
from Japan showed [15] that neoadjuvant chemotherapy with SP protocol is safe and
effective for stage II and III gastric cancer with lymph node metastasis, with ORR of
75.5% and R0 removal rate of 87.8%. Chinese researchers have found [16] that SOX
neoadjuvant application in advanced gastric cancer has an ORR of 68.5%, and the R0
removal rate is also significantly higher than that of operation alone (81.3%vs 73.5%,
P=0.040). The results of the recent FLOT4 study [17] showed that the perioperative
regimen of 5-fluorouracil + docetaxel + oxaliplatin + calcium folinate (FLOT) was
superior to the perioperative regimen of epirubicin + cisplatin + 5-fluorouracil or
capecitabine (ECF/ECX) in terms of R0 removal rate (85% vs 78%). P=0.0162).
At present, the recommended preoperative chemotherapy for gastric cancer mainly
includes: Epirubicin combined with Cisplatin and
fluorouracil (ECF) and its
modification, cisplatin combined with fluorouracil (PF), oxaliplatin combined with
11

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
13
capecitabine (XELOX), oxaliplatin combined with fluorouracil (FOLFOX), Cisplatin
combined with S-1 (SP), oxaliplatin combined with S-1 (SOX), FLOT (5-fluorouracil +
docetaxel + oxaliplatin + calcium folinate).
The evaluation of neoadjuvant chemotherapy regimen and cycle selection as well
as clinical efficacy for advanced gastric cancer is summarized as follows. For whether
combined immunotherapy drugs are needed, further randomized controlled trials are
needed to verify their advantages and value.
Table 1 Phase II clinical trials of neoadjuvant chemotherapy for advanced GC
Items
sample
treatment
Cycle
cRR
pRR
Chen et al.
113
OXA /5-FU/ calcium
folinate
/
/
17/87(19)
Epirubicin/OXA/capecit
abine
/
/
10/26(38)
Yoshiaki et al.
49
S-1/ cisplatin
2
25/49(51)
23/49(47)
Takaki et al.
83
S-1/ cisplatin
2/4
19/41(46)
17/41(42）
paclitaxel / cisplatin
11/42(26)
14/42(33)
2 cycles
14/42(33)
15/42(36)
4 cycles
16/41(39)
16/41(39)
Migita et al.
59
S-1/ cisplatin /
Docetaxel
1-2
44/59(74)
42/59(71)
Aoyama et al.
132
S-1/ cisplatin
2/4
12/62(19）
S-1/ cisplatin /
Docetaxel
10/65(15)
2 cycles
10/64(15)
4 cycles
12/63(19)
As a highly heterogeneous malignant tumor, gastric cancer is an extremely
complex process in which the immune microenvironment plays an important role, and
the inhibitory immune microenvironment and immune escape have received more and
more attention. programmed death receptor-1 (PD-1) and programmed death ligand-1
(PD-L1) belong to the B7/CD28 superfamily and are very important negative co-
stimulatory molecules discovered in recent years. It can negatively regulate the activity
of immune cells [18]. PD-1 is the main immunosuppressive molecule on the surface of
T cells and B cells. PD-1 has two ligands, PD-L1 and PD-L2. PD-L1 is widely

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
14
expressed in activated T cells, B cells, macrophages, dendritic cells, and tumor cells.
PD-L1 expressed by tumor cells and PD-1 expressed by tumor Infiltrating Lymphocytes
(TILs) (mainly CD8+T cells) bind to activate the PD-1/PD-L1 signaling pathway and
inhibit the activation of tumor infiltrating lymphocytes. Reduced T cell reactivity leads
to T cell incapacitated, induces T cell apoptosis, provides a suitable microenvironment
for the development of tumor cells, mediates tumor immune escape, and promotes
tumor growth [19]. Blocking the PD-1/PD-L1 signaling pathway can reverse the tumor
immune microenvironment and enhance the endogenous anti-tumor immune effect. PD-
L1 is highly expressed in various solid malignant tumors [20-21], including non-small
cell lung cancer, melanoma, renal cell carcinoma, prostate cancer, breast cancer,
stomach cancer, etc., and its expression level varies according to different tumor types.
At present, the relationship between PD-L1 expression and prognosis in gastric cancer
is still controversial.
In December 2018, the Phase II trial results of the Asian Attract-04 study [22]
were published. The study was designed to explore the safety and efficacy of
Nivolumab in combination with SOX (Ticeo and oxaliplatin) or XELOX (capecitabine
and oxaliplatin) in first-line treatment of advanced, unresectable, or recurrent
gastric/gastroesophageal junctional adenocarcinoma. The randomized ratio was 1:1, and
the median OS follow-up was not reached in the FAS population (NR (11.9, NR) and
NR (11.2, NR), respectively). Median PFS were 9.7 months (5.8-NR) and 10.6 months
(5.6-12.5), respectively. The ORR of Nivolumab combined with SOX was 57.1%, and
that of Nivolumab combined with XELOX was 76.5%.
In March 2019, the results of KEYNOTE-059 study [23] Cohort 2 and cohort 3
Phase II clinical trials were published. The study cohort 2 and cohort 3 were designed
to explore the safety and efficacy of Pembrolizumab± chemotherapy in first-line
treatment of advanced gastric or gastroesophageal junction adenocarcinoma. In cohort 2,
25 patients received Pembrolizumab combined with chemotherapy. All patients had an
ORR of 60.0%, including 73.3% ORR in the PD-LI positive group and 37.5% ORR in
the PD-LI negative group, with a median OS of 13.8 months (8.6-NR). The median PFS
was 6.6 months (5.9-10.6). In cohort 3, 31 PD-L1 positive (CPS ≥1) patients who

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15
received Pembrolizumab monotherapy had an ORR of 25.8%, a median OS of 20.7
months (9.2-20.7), and a median PFS of 3.3 months.
At the American Society of Clinical Oncology Symposium (ASCO) in June 2019,
Merck presented the results of the KEYMAT-062 Phase III study [24], which
randomized untreated PD-L1-positive advanced gastric or gastroesophageal junction
adenocarcinoma into three groups, group 1 being Pembrolizumab monotherapy (Group
P). Pembrolizumab combined with chemotherapy in group 2 (P+C) and placebo
combined with chemotherapy in group 3 (C) had primary endpoints of PFS in people
with PD-L1 CPS≥1 and OS in people with PD-L1 CPS≥1 and CPS≥10. The results
suggest that Pembrolizumab combined with chemotherapy is not superior to
chemotherapy for OS and PFS in any population. From the perspective of ORR alone,
in patients with CPS≥1, the ORR in group P vs group C vs group P+C was 14.8% vs
37.2% vs 48.6%; In patients with CPS≥10, the ORR in group P vs C vs P+C was
25.0% vs 37.8%vs 52.8%. In terms of safety, the P vs C group had better safety, with
the incidence of any grade of AE in the P+C vs C group being 94% vs 92%, and the
incidence of grade 3-4 TRAE being 71% vs 68%, with no unexpected adverse events.
On November 5, 2022, at the CSCO Annual Meeting, Professor Huang Jing
reported on the research related to the treatment of advanced esophageal cancer with
Srulizumab - ASTRO-007: In the whole population, the median PFS in the srulizumab
and placebo groups was 5.8 months vs5.3 months (HR=0.60, P < 0.0001), and the
median OS was 15.3 months vs 11.8 months (HR=0.68, P=0.0020). Among those with
PD-L1 CPS ≥10, the median PFS for both groups was 7.1 months vs 5.3 months
(HR=0.48, P < 0.0001), and the median OS was 18.6 months vs 13.9 months (HR=0.59,
P=0.0082). The study also confirmed the significance of srulizumab combined with
chemotherapy in the first-line treatment of advanced esophageal cancer, especially in
those with CPS > 10.
Table 2 First-line PD-1 antibody combined with chemotherapy for GC
Items
Treatment
Sample
ORR
ATTRACTION-04
SOX
21
57.1
XELOX
18
76.5

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
16
KEYNOTE-062
CPS≥1
257
48.6
CPS≥10
99
52.8
KEYNOTE-059
Cohort 2
25
60.0
Innovent
F cohort
20
85
HOTWELL
43
44
In other cancers, such as triple negative breast cancer and head and neck squamous
cell carcinoma, Pembrolizumab combined with neoadjuvant chemotherapy has shown
promising antitumor activity and clinical efficacy. At present, immunotherapy is also
being explored in the perioperative period of gastric cancer, such as the phase III
clinical study of KEYKEYNOTE 585 perioperative chemotherapy for gastric cancer
combined with or without PD-1 inhibitor, and the clinical study of mFOLFOX
combined with PD-1 inhibitor for the treatment of gastroesophageal conjoint
adenocarcinoma or gastric adenocarcinoma in perioperative period (NCT03488667), etc.
In order to provide a new clinical thinking for the treatment of locally advanced gastric
cancer.
2. Objectives
2.1 Primary Objective
To assess the efficacy of Serplulimab combined with nab-paclitaxel plus SOX
versus nab-paclitaxel plus SOX alone as neoadjuvant treatment for locally advanced
GC or AEG, as measured by pCR according to the the Mandard tumor regression
grading criteria.
2.2 Secondary Objectives
To assess and compare the followings between the two groups:

ORR，MPR, etc.

R0 resection rate

1/3-year PFS and OS

Safety of study drugs according to the NCI-CTCAE, version 5.0

Surgical safety: including morbidity, mortality, hospital stay, etc.

Patient reported outcomes: EORTC QLQ-C30 and QLQ-STO22
2.3 Exploratory Objective

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17
To assess the associations between the primary endpoint and several tumor
biomarkers (including but not limited to PD-L1 expression and MSI status), and explore
the mechanisms of response and resistance to S-P-SOX.
2.4 Randomization, Blinding, and Unblinding
A randomized, double-blind design is employed in this trial. This study employed
block randomization to allocate subjects in a 1:1 ratio to either the experimental or
control group. To ensure balance in sample size between the groups, the randomization
sequence was generated using SAS 9.4 software. The randomization list was generated
by an independent statistician and securely stored in a password-protected computer
system, with corresponding envelopes prepared. The research team remained blinded to
the group assignments, and subjects were instructed to open the envelopes according to
their enrollment order.:

Arm A (S-P-SOX): Serplulimab + Nap-paclitaxel + S-1 + Oxaliplatin

Arm B (P-SOX): placebo + Nap-paclitaxel + S-1 + Oxaliplatin
During the study, the subjects, the investigator, the sponsor, and the designees are
not aware of the randomized allocation, except in the event of emergency unblinding.
During the course of treatment with the study drug, if the investigator determines
that the study drug is related to a life-threatening situation of the subject, and the
investigator considers that knowing the medication of the subject is conducive to the
handling of adverse events, an emergency unblinding is allowed. The decision to
unblind in an emergency is the responsibility of the investigator and will not be delayed
or declined by the sponsor; however, the investigator may contact the sponsor or its
designees to discuss the unblinding and the protocol that is in the best interest of the
subject prior to unblinding. The investigator shall ensure that unblinding is performed
in strict accordance with the protocol. The investigator shall inform the sponsor of the
circumstances of and reasons for emergency unblinding as soon as possible, and record
these details clearly on the subject’s source document. Two sets of sealed blind
envelopes were prepared. In the event of an emergency unblinding, the identification
number will be used to open the retained envelope to complete the unblinding process.
If deemed necessary, the unblinding shall only apply to the affected subject.

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18
The study will be unblinded overall after the last subject completed the study visit.
The study shall remain blinded unless there is an emergency medical condition
(emergency treatment is only possible when being informed of the randomized
medication) or unblinding is requested by the regulatory authorities. Only when all data
have been input into the database, all data queries have been resolved and subjects have
been allocated into analysis sets, can the random codes be unblinded.
3. Study Design and Sample Size
3.1 Study Design
This is a multicenter, double-blind, randomized, phase 2 trial to investigate the
efficacy and safety of Serplulimab combined with nab-paclitaxel plus SOX versus nab-
paclitaxel plus SOX alone as neoadjuvant treatment for locally advanced GC or AEG. It
will be conducted in 5 medical centers in China. Eligible patients were randomly
assigned to receive Serplulimab (4.5 mg intravenously on day 1) combined with
chemotherapy (nap-paclitaxel 260 mg/m2 intravenously on days 1, OXA 130mg/ /m2,
intravenously on days 1, and S-1 40 to 60 mg orally twice daily depending on BSA on
days 1 to 14) or chemotherapy alone every 3 weeks for 3 preoperative cycles followed
by 3-5 postoperative cycles. All patients will be followed for survival.
3.2 Study Schema
3.3 Study Duration
The total duration for enrollment is expected to be 12 months, beginning with the
first patient in September 1, 2024, and ending with the last patient in September 1, 2025.
The initial analyses for the primary endpoint are planned in September 31, 2025. The
total duration of the study is expected to be 4 years, including a follow-up period of 3

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
19
years. The final analyses for OS and PFS are planned in the third quarter of 2028.
3.4 Sample Size
Based on results and data from previous similar studies, the pCR rate of nap-
paclitaxel combined with SOX is known to be 7%, and the pCR rate of the Serplulimab
combined with nap-paclitaxel and SOX is expected to be 25%. A sample size of 58
patients per group was required to detect improvement with 80% power and a one-sided
alpha level of 0.05, including a 15% dropout rate.
4. Study Population
4.1 Inclusion Criteria

Age older than 18 and younger than 80 years

Primary GC or AEG (Siewert II/III)confirmed pathologically by endoscopic biopsy

Clinical stage T3/T4N+M0 disease as assessed by CT/MRI, PET-CT, and laparoscopy, if
feasible

At least one measurable lesion according to the RECIST, version 1.1

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Surgical treatment after neoadjuvant chemotherapy is planned according to clinical staging
criteria.

Life expectancy of at least 3 months

Acceptable
bone
marrow,
hepatic,
and
renal
function,
including:
a)Blood
routine
examination(No blood transfusion within 14 days; No granulocyte colony-stimulating factor
(G-CSF) or other hematopoietic stimulating factors were used): white blood cell count ≥3.5
×109/L, neutrophils ≥1.5 × 109/L, platelet count >100 × 109/L, and hemoglobin ≥90 g/L;
b)Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST),
ALT and AST≤2.5×ULN; total bilirubin (TBIL) ≤1.5×ULN (Gilbert syndrome patients, ≤
3×ULN); c)Renal function: serum creatinine (Cr) ≤1.5×ULN or creatinine clearance (Ccr) ≥
60mL/
min;
d)Coagulation
function:
activated
partial
thromboplastin
time
(APTT),
international standardized ratio (INR), prothrombin time (PT) ≤1.5×ULN;

Written informed consent
4.2 Exclusion Criteria

Squamous cell carcinoma, adenosquamous cell carcinoma, small cell carcinoma, and
undifferentiated gastric cancer were confirmed by pathology

Positive Her-2 detection (IHC3+ or IHC2+ amplified by FISH detection)

Prior chemotherapy, radiotherapy, hormone therapy, targeted therapy, or immunotherapy

Contraindications for surgical treatment or chemotherapy

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
20

Presence of distant metastasis

History of other malignant disease within the past 5 years, except: basal cell carcinoma of the
skin, squamous cell carcinoma of the skin, or in situ cervical cancer that have been treated
radically and have shown no signs of disease for at least 5 years

Any active or history of autoimmune disease, or history of syndrome that required systemic
steroids or immunosuppressive medications, except for subjects with vitiligo or resolved
childhood asthma/atopy

History of immunodeficiency diseases, including human immunodeficiency virus (HIV), or
other acquired or congenital immune-deficient disease, or transplantation

Severe mental disorder

Presence of digestive tract obstruction, jaundice, acute infectious diseases, inflammatory bowel
disease, Crohn's disease, ulcerative colitis, chronic diarrhea, active tuberculosis

Immunosuppressive drugs are required for 2 weeks or within 2 weeks or during the study
period, excluding the following: a) intranasal, inhaled, topical or topical steroid injections (e.g.
intra-articular injections); b) Physiological dose of systemic corticosteroids ( ≤10mg/ day
prednisone or equivalent dose); c) Short-term (≤7 days) use of steroids for the prevention or
treatment of non-autoimmune allergic diseases;

Patients who have undergone major surgery or received live virus vaccine within 4 weeks

Pregnant or breast-feeding women, subjects who are unwilling to receive effective
contraception during treatment and within 6 months after the end of treatment (including male
subjects who have the ability to impregnate women and female subjects and their male
partners)

Evidence of bleeding tendency or receiving thrombolytics or anticoagulants

According to the criteria of the term Common Adverse Events (NCI-CTCAE V5.0), the
corresponding symptoms have been diagnosed;

Hepatitis B or hepatitis C virology tests at the time of screening meet any of the following: a)
HBsAg positive and HBV-DNA titer ≥104 copy number /mL or ≥2000IU/mL (hepatitis B
carriers should ask researchers for appropriate antiviral treatment); b) Active hepatitis C: HCV
antibody positive and HCV-RNA higher than the lower detection limit of the assay;

Allergic to study drugs

The investigator believes that the subjects have other conditions that may affect their
adherence to the protocol and evaluation of the study indicators, and the subjects are not
suitable to participate in the study.
4.3 Drop Out/Removal Criteria

Use of NMPA-approved modern traditional Chinese medicine agents for the treatment of
gastric cancer

Concurrent radiotherapy or other local treatments during the study periods

Medication, dosing, and treatment methods do not follow the study protocol

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
21
4.4 Treatment end/termination Criteria

The patient has completed the treatment prescribed in the protocol;

Withdrawn of the informed consent

Progression disease (PD) or death

Unbearable toxicity after dose reductions

When an adverse event (AE) or serious adverse event (SAE) occurs, the patient does not wish
to continue treatment or has an unexpected and unacceptable adverse drug reaction;

Loss to follow up
Investigator’s decision that stopping treatment was in the best interest of the patient
5. Study Treatments
5.1 Handling and Storage
Study drugs must be stored in a secure area under the appropriate physical
conditions. Access to and administration of the study drugs will be limited to the
investigators and authorized site staff. The investigators must complete storage,
handling, dispensing, and infusion information for the study drugs in time. The trial
agents were not allowed to be used in other treatments.
The management, distribution and withdrawal of drugs in this study shall be the
responsibility of the investigator designated person, and the investigator must ensure
that all drugs in the study are only used for participants in the clinical study, and their
dosage and administration are in accordance with the trial protocol. Surplus or expired
drugs should be returned to the pharmaceutical company for destruction, and clinical
drugs should not be transferred to any non-clinical study participants.
A drug receipt must be signed at the time of drug receipt, signed by two persons
and kept by the research center. When the remaining drugs are recovered, both parties
sign a drug recovery form. Each drug release and recall should be recorded in a timely
manner on a special record sheet.
5.2 Treatment
The study drugs that are used in this trial are outlined below in Table 3.
Table 3. Study drugs.

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
22
Product name
Serplulimab
Nap-paclitaxel
S-1
Oxaliplatin
Dosage form
Lyophilized powder
Lyophilized powder
Capsule
Lyophilized powder
Unit dose strength
4.5 mg
100 mg
20 mg
50 mg
Route of administration
IV infusion
IV infusion
Oral
IV infusion
Storage requirements
2-8℃. Protect from
light and freezing.
<25℃. Protect
from light.
20-30℃. Protect
from light.
<25℃. Protect
from light.
Treatment will be assigned to eligible patients after signed consent forms:

Serplulimab is to be administered initially at 4.5 mg as a 60-minute IV infusion
every 3 weeks for 2 preoperative cycles followed by 6 postoperative cycles.

Nap-paclitaxel is to be administered initially at 260 mg/m2 as a 30-minute IV
infusion every 3 weeks for 2 preoperative cycles followed by 6 postoperative
cycles.

Oxaliplatin is to be administered initially at 130 mg/m2 as a 120-minute IV infusion
every 3 weeks for 2 preoperative cycles followed by 6 postoperative cycles.
S-1 is to be administered initially at 40-60 mg orally twice daily on days 1 to 14
every 3 weeks for 2 preoperative cycles followed by 6 postoperative cycles.
Table 4. Dose of S-1 depending on BSA.
BSA
Dose
< 1.25m2
40mg× 2/day
1.25m2 - 1.5m2
50mg× 2/day
> 1.5m2
60mg× 2/day
5.3 Dose Modification
Dose modification will be performed based on the severity of toxicities according
to the NCI-CTCAE, version 5.0. Reasons for dose interruption, delay, or reduction, the
supportive measures, and the outcomes will be documented. Dose interruptions are
permitted for reasons apart from toxicities, such as medical/surgical events or logistical
reasons (e.g., unrelated medical events or elective surgery).
For participants treated with S-P-SOX, if a toxicity is considered to be due solely
to one investigational agent (i.e., Serplulimab or chemotherapeutic agents), the dose of
that agent should be interrupted or delayed in accordance with the guidelines below and
the treatment with other agents can continue as scheduled at the discretion of the
investigator.
When
the
attribution
of
toxicity
is
uncertain,
interruption
of

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23
chemotherapeutic agents is done first. If one agent is discontinued due to unacceptable
toxicity, patients are able to continue the study with the other agent.
5.3.1 Dose Modification for Serplulimab
Toxicities associated or possibly associated with Serplulimab may represent an
immunologic etiology. For suspected immune-related AEs (irAEs), ensure adequate
evaluation to confirm etiology or exclude other causes.
In general, administration of Serplulimab may be continued in the presence of
most grade 1 irAEs. For grade 2-4 irAEs, Serplulimab is usually discontinued and can
be resumed once irAEs resolve to ≤grade 1. Serplulimab should be permanently
discontinued if the irAE cannot resolve within 12 weeks of the last dose or
corticosteroids cannot be reduced to ≤10 mg/day prednisone or equivalent within 12
weeks. Permanent discontinuation of Serplulimab should be considered for any severe
or life-threatening events.
The use of corticosteroids is the mainstay of management of irAEs. For severe and
life-threatening irAEs, corticosteroids should be initiated intravenously first followed
by oral administration. With improvement to ≤grade 1, initiate corticosteroid taper and
continue to taper over at least 1 month. Other immunosuppressive treatment should be
initiated if irAEs cannot be controlled by corticosteroids within 3-5 days.
Dose reduction is not permitted for Serplulimab. Dose modification is shown in table 5.
Table 5. Dose modification guidelines for Serplulimab.
Toxicity
Grade
Timing for
Resumption
Toxicity Treatment
Pneumonitis
Grade 2
Withhold
Serplulimab
Administer corticosteroids at a dose of
1 mg/kg/day prednisone equivalents.
Grade 3
Resolution for
≤grade 2 toxicity
Administer corticosteroids at a dose of
2-4 mg/kg/day prednisone equivalents
followed by corticosteroid taper.
Grade 4 or
reoccurrence
Permanently
discontinue
Diarrhea and colitis
Grade 2
Resolution for
≤grade 1 toxicity
Administer corticosteroids at a dose of
0.5-1 mg/kg/day prednisone equivalents
followed by corticosteroid taper for
colitis of more than 5 days duration.

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24
if worsening or no improvement occurs
despite initiation of corticosteroids,
increase dose to 1-2 mg/kg/day
prednisone equivalents.
Grade 3
Resolution for
≤grade 1 toxicity
Administer corticosteroids at a dose of
1-2 mg/kg/day prednisone equivalents
followed by corticosteroid taper for
grade 3-4 colitis.
Grade 4 or
reoccurrence
Permanently
discontinue
Grade 2
Resolution for
≤grade 1 toxicity
Administer corticosteroids at a dose of
0.5-1 mg/kg/day prednisone equivalents
for grade 2 transaminase elevations.
Hepatitis
Grade 3
Resolution for
≤grade 1 toxicity
Administer corticosteroids at a dose of
1-2 mg/kg/day prednisone equivalents
followed by corticosteroid taper for
grade 3-4 transaminase elevations, with
or without concomitant elevation in
total bilirubin.
Grade 4 or
reoccurrence
Permanently
discontinue
Nephritis and
Renal Dysfunction
Grade 2-3
Resolution for
≤grade 1 toxicity
Administer corticosteroids at a dose of
0.5-1 mg/kg/day prednisone equivalents
for grade 2-3 increased serum
creatinine.
if worsening or no improvement occurs,
increase dose of corticosteroids to 1-2
mg/kg/day prednisone equivalents.
Grade 4
Permanently
discontinue
Administer corticosteroids at a dose of
1-2 mg/kg/day prednisone equivalents
followed by corticosteroid taper.
Endocrinopathies
Grade 2-3
Resolution for
≤grade 1 toxicity
Administer hormone-replacement
therapy for hypothyroidism
Initiate medical management for control
of hyperthyroidism.
Other endocrinopathies include
hypophysitis, adrenal insufficiency,
type 1 diabetes mellitus, etc. Monitor
patients for signs and symptoms and
provide specialist treatment.
Grade 4
Permanently
discontinue
specialist treatment
Skin Adverse
Reactions
Grade 3
Resolution for
≤grade 2 toxicity
Administer corticosteroids at a dose of
1 to 2 mg/kg/day prednisone

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
25
equivalents followed by a corticosteroid
taper.
Grade 4
Permanently
discontinue
Other Immune-
mediated Adverse
Reactions
Grade 3 or 4
serum amylase or
lipase elevation
Grade 2 or 3
pancreatitis
Grade 2
myocarditis
Other adverse
reactions that occur
for the first time in
grade 2 or 3
Resolution for
≤grade 1 toxicity
Based on the severity of the adverse
reaction, administer high-dose
corticosteroids, upon improvement to
≤grade 1, initiate corticosteroid taper
and continue to taper over at least 1
month.
Grade 4 pancreatitis
or any grade of
reoccurrence
pancreatitis
Grade 3 or 4
myocarditis
Grade 3 or 4
encephalitis
Other adverse
reactions that occur
for the first time at
grade 4
Permanently
discontinue
specialist treatment
Infusion Reactions
Grade 1-2
Symptom relief
Interrupt or slow the rate of infusion in
patients
Grade 3-4
Resolution for
≤grade 2 toxicity
Suspension or delay of administration
5.3.1 Dose Modification for chemotherapeutic agents
For intolerable grade 2 AEs, chemotherapeutic agents (nap-paclitaxel, oxaliplatin, and
S-1) should be interrupted until resolution to ≤grade 1. For grade 3-4 AEs,
chemotherapeutic agents should be interrupted until resolution to ≤grade 1 or 2, then
resume treatment with one dose or two dose reductions, or permanently discontinue
treatment which is based on investigator judgement. A maximum of two dose
reductions are permitted for chemotherapeutic agents. Permanently discontinue
chemotherapeutic agents in the presence of grade 3 or 4 AEs after two dose reductions.
However, exception will be permitted in the best interest of the patients. Dose
escalation is not permitted. Dose modification of chemotherapeutic agents guidelines
are provided in Table 5. The dose modifications must be performed as clinically
indicated at the discretion of the investigator.
Table 5. Dose modification guidelines for chemotherapeutic agents.

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
26
Toxicity
Grade
Timing for
Resumption
Toxicity Treatment
Hematological
toxicity
Grade 3-4
Resolution for
≤grade 1 toxicity
1st occurrence:
75% of Nap-paclitaxel starting dose
75% of Oxaliplatin starting dose
75% of S-1 starting dose
2nd occurrence:
50% of Nap-paclitaxel starting dose
50% of Oxaliplatin starting dose
50% of S-1 starting dose
Mucositis/stomatitis,
diarrhea, and
anorexia
Grade 2
Resolution for
≤grade 1 toxicity
1st occurrence: maintain the same dose
2nd occurrence:
75% of Oxaliplatin starting dose
75% of S-1 starting dose
3rd occurrence:
50% of Oxaliplatin starting dose
50% of S-1 starting dose
Grade 3
Resolution for
≤grade 1 toxicity
1st occurrence:
75% of Oxaliplatin starting dose
75% of S-1 starting dose
2nd occurrence:
50% of Oxaliplatin starting dose
50% of S-1 starting dose
Grade 4
Resolution for
≤grade 1 toxicity
1st occurrence:
50% of Oxaliplatin starting dose and
50% of S-1 starting dose or
permanently discontinue
Peripheral
neuropathy
Grade 2 (cannot
resolve to ≤grade 1
despite supportive
care
Resolution for
≤grade 1 toxicity
1st occurrence:
75% of Nap-paclitaxel starting dose
2nd occurrence:
50% of Nap-paclitaxel starting dose
Grade 3-4
Resolution for
≤grade 1 toxicity
1st occurrence:
75% of Nap-paclitaxel starting dose
2nd occurrence:
50% of Nap-paclitaxel starting dose
Other non-
hematological
toxicity
Grade 2
Resolution for
≤grade 1 toxicity
1st occurrence: maintain the same dose
2nd occurrence:
75% of Nap-paclitaxel starting dose
75% of Oxaliplatin starting dose
75% of S-1 starting dose

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
27
3rd occurrence:
50% of Nap-paclitaxel starting dose
50% of Oxaliplatin starting dose
50% of S-1 starting dose
Grade 3
Resolution for
≤grade 1 toxicity
1st occurrence:
75% of Nap-paclitaxel starting dose
75% of Oxaliplatin starting dose
75% of S-1 starting dose
2nd occurrence:
50% of Nap-paclitaxel starting dose
50% of Oxaliplatin starting dose
50% of S-1 starting dose
Grade 4
Resolution for ≤
grade 1 toxicity
1st occurrence:
50% of Nap-paclitaxel, Oxaliplatin, and
S-1 starting dose or permanently
discontinue
5.4 Concomitant 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 study drugs. Such treatment should
be carefully and accurately documented in the Case Report Forms (CRFs).
6. Study Procedure
6.1 Screening Period
The following items are completed within 2 weeks before randomization:

Demographics data: age, gender, date of birth, height, weight, etc.

Tumor data: date of diagnosis, histological classification, clinical stage, etc.

Medical history: comorbidities, previous medication/surgery, etc.

Imaging examination: chest, abdomen and pelvis CT or MRI.
After admission, patients who meet the eligibility criteria are screened out. For these
patients, the investigator introduces this trial in detail, and the patients sign informed
consent if they agree to participate.
The following items are completed within 1 week before randomization:

ECOG performance status.

Vital signs: heart rate, breathing rate, temperature, and blood pressure.

Physical examination: head, skin, lymph nodes, eyes, ears, nose, throat, mouth,

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respiratory
system,
cardiovascular
system,
abdomen,
genitourinary
system,
musculoskeletal system, and nervous system.

Blood routine: hemoglobin, hematocrit, RBC, WBC, ANC, and platelet count.

Urinary routine: urinary protein and urine occult blood, and a 24-hour urinary
protein quantification test should be performed in the presence of urine protein ≥2+.

Stool routine: fecal occult blood.

Biochemistry: bilirubin, ALT,AST, ALP, creatinine, BUN, glucose, calcemia,
sodium,and potassium.

Coagulation test: PT, APTT, TT, and fibrinogen.

Thyroid function test: TSH, fT3, and fT4.

Pituitary-adrenal axis examination: adrenocorticotropin, cortisol.

Myocardial zymogram

Tumor markers: CEA, CA19-9, CA125, CA153, etc.

HBV, HCV, and HIV tests.

Pretreatment tumor samples.

12-lead ECG.

Echocardiography.
6.2 Treatment Period
6.2.1 Neoadjuvant Treatment Period
Administration of the neoadjuvant treatment is initiated within 7 days after
randomization. The following items are completed during the neoadjuvant treatment:

Physical examination, vital signs, ECOG performance status, tumor markers,
Urinary routine, Fecal routine, Coagulation test, and ECG are performed on day 1
of cycles 2 and 3. If cardiac pains or palpitations occur, myocardial enzyme
spectrum (creatine kinase, lactate dehydrogenase), and cardiac ultrasound should
be immediately performed.

Blood routine and biochemistry are performed on day 14 of cycle 1 and days 1, 14
of cycles 2 and 3.

Imaging examination is performed after completion of cycle 3 and before 1 week
of surgery.

AEs during the treatment period should be recorded and graded according to the
CTCAE, version 5.0.
ECOG status and blood pressure monitoring are performed by the patient and
recorded in a diary card.

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6.2.2 Preoperative Assessments and Surgery
After completion of the last cycle of neoadjuvant treatment, 1 week before surgery,
blood
routine,
biochemistry,
stool
routine,
urine
routine,
12-lead
ECG,
echocardiography, coagulation test, thyroid function test, myocardial zymogram, tumor
markers,
and
imaging
examination
are
performed.
Without
clear
surgical
contraindications and with the patients’ consent, surgery will be performed. If the
disease progresses, laparoscopic exploration is recommended. The following items are
completed after surgery:

Blood routine, biochemistry, tumor markers.

Surgical outcomes: operation time, intraoperative bleeding, surgical approach,
intraoperative complications (e.g. major bleeding), postoperative complications and
management, postoperative hospital stay, etc.

Tumor data: tumor regression grade, residual tumor (R) classification, etc.

Surgical specimens.
6.2.3 Adjuvant Treatment Period
Adjuvant treatment started 3-8 weeks after surgery. The following items are
completed during the adjuvant treatment:

Physical examination, vital signs, ECOG status, urinary routine, fecal routine,
coagulation test, tumor markers, and ECG are performed on day 1 of cycles 4-6. If
cardiac pains or palpitations occur, myocardial enzyme spectrum (creatine kinase,
lactate dehydrogenase), and cardiac ultrasound should be immediately performed.

Blood routine and biochemistry are performed on days 1, 14 of cycles 4-6.

Imaging examination is performed every 3 months.

AEs during the treatment period should be recorded and graded according to the
NCI-CTCAE, version 5.0.

Blood pressure monitoring is performed by the patient and recorded in a diary card.
6.3 Follow-up Period
After completion of the last administration of study drugs, patients enter follow-up
period. All patients are followed up with every 3 months (± 2 weeks) during the first 2
years and then every 6 months (± 2 weeks) beyond the third year. Data on survival

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status and disease progression are recorded in the follow-up tables.
Assessments during the follow-up period include physical examination, blood
routine, biochemistry, tumor markers, abdominal ultrasound, and chest, abdomen and
pelvis CT. Gastroscopy is recommended to performed once a year.
6.4 Progression of Disease
If any of the following criteria is met, it is defined as the progressive disease:

Determination as PD according to the RECIST, version 1.1 during the neoadjuvant
treatment

Reporting of a distant metastasis from pathology

R1 or R2 resection

Finding of a recurrence/distant metastasis during follow-up after R0 resection
For a subject determined to have disease progression, administration of the study drugs
will be discontinued and other anti-tumor treatment will be administered at the
discretion of the investigator.
7. Efficacy Assessments

Pathological Response
TRG is evaluated centrally using the Mandard regression criteria, which are based on
the percentage of vital tumor cells in the tumorous area and include the following
categories: TRG 1 (no residual tumor cells, including lymph nodes, staging ypT0N0-
M0), TRG 2 (Only single or small focal residual tumor cells), TRG 3 (residual tumor
less than fibrotic interstitium tissue), TRG 4 (residual tumor more than fibrotic
interstitium tissue), and TRG 5 (tumor did not change or even progress). The pCR rate
is defined as the proportion of patients with TRG1 in resection specimens. More details
are provided in Appendix 1.

Radiologic Response
Radiologic response is evaluated using RECIST (version 1.1), which is based on CT or
MRI findings and includes complete response (CR), partial response (PR), stable disease
(SD), and progressive disease (PD). The objective response rate (ORR) was defined as
the proportion of patients with CR and PR, and the disease control rate (DCR) was
defined as the proportion of patients with CR, PR, and SD. More details are provided in
Appendix 4.
In a comparison between the pretreatment and posttreatment clinical staging, T

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31
downstaging, N downstaging are compared between the two groups based on the CT
findings.

Surgical Margin
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
R0 resection rate is defined as the proportion of patients who achieve the R0 resection.

Survival
OS is defined as the time between randomization and the death date. Patients alive at
last report will be considered censored at the endpoint. Alive patients will be censored
at the last date known to be alive, either during study treatment period or during follow-
up period.
PFS is defined as the time between disease progression (see Section 6.4) or death
irrespective of cause and censored at the date of last contact.
8. Safety Assessments
8.1 Safety Endpoints
Data on all AEs, whether volunteered by the subject, discovered by investigator
questioning, or detected through physical examination, laboratory test or other means,
will be collected, recorded, and followed as appropriate.
The investigator will collect information on the following variables and record in
the CRFs:

Surgical
safety:
operation
time,
blood
loss,
intraoperative
complications,
postoperative morbidity, mortality, postoperative hospital stay, time to ambulation,
time to first flatus, and time to first liquid intake etc.
Postoperative morbidity is evaluated according to the Clavien-Dindo classification
(Appendix 6)

Study drug safety: AEs and serious AEs (SAEs)
All AEs should be recorded by it duration, regulatory seriousness criteria, suspected
relationship to the study drug, and actions taken. AEs are evaluated according to the
CTCAE, version 5.0.

Details on drug modification caused by AEs

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See 5.3 for details.
8.2 Definition of Adverse Event and Serious Adverse Event
An AE is defined as any new untoward medical occurrence or worsening of a
preexisting medical condition in a clinical investigation participant administered study
drug and that does not necessarily have a causal relationship with this treatment. An AE
can therefore be any unfavorable and unintended sign (such as an abnormal laboratory
finding), symptom, or disease temporally associated with the use of study drugs,
whether or not considered related to the study drugs. The causal relationship to study
drug is determined by a physician and should be used to assess all AEs.
The casual relationship can be one of the following:
- Definitely: An AE which has a timely relationship to the administration of the
study drugs, follows a known pattern of response, for which no alternative cause is
present.
- Probably: An AE, which has a timely relationship to the administration of the
study drugs, follows a known pattern of response, but for which a potential alternative
cause may be present.
- Unlikely: An AE which does not have a timely relationship to the administration
of the study drugs, follows no known pattern of response, does not reappear or worsen
after re-administration of the study drugs (if applicable), and for which there is
evidence that it is related to a cause other than the study drugs.
- Unrelated: An AE, for which there is evidence that it is definitely related to a
cause other than the study drugs. In general, there is no timely relationship to the
administration of the study drugs, or if there is a timely relationship, the event does not
follow a known pattern of response, and there is an alternative cause.
A SAE is an AE not classified as serious that, at any time, fulfills one or more of
the following criteria:
- Results in death
- Is life threatening
- Requires in-patient hospitalization or prolongation of existing hospitalization
- Results in persistent or significant disability/incapacity
- Results in congenital anomaly/birth defect
- Any important medical event that may not be immediately life threatening or

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33
result in death or hospitalization but, based upon appropriate medical judgment, may
endanger the patient or may require intervention to prevent one of the other outcomes
listed in the definition above.
- Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic)
via the study drug is an SAE.
- Any component of a study endpoint that is considered related to study therapy
should be reported as an SAE (e.g. death is an endpoint, if death occurred due to
anaphylaxis, anaphylaxis must be reported).
Events initially reported as an AE may also become serious.
8.3 Recording and Follow-up of (Serious) Adverse Events
AEs and SAEs will be recorded from time of signature of informed consent,
throughout the treatment period and including 30 days after the last dose of study drugs
(SAEs will be collected for 90 days after discontinuation of treatment). During the
course of the study all AEs and SAEs should be followed up for each patient. Every
effort should be made to obtain a resolution for all events, even if the events continue
after discontinuation or study completion.
The investigator is requested to assess the relationship between the study drugs
and the occurrence of each (S)AE. The investigator will use clinical judgment to
determine the relationship. Alternatives causes, such as natural history of the underlying
diseases, concomitant therapy, other risk factors, and the temporal relationship of the
event to the investigational product will be considered and investigated.
All SAEs occurring to any patient on this study, regardless of attribution, should
be reported to the Institutional Review Board and regulatory authority within 24 hours
of the investigator’s knowledge of the events. The report of SAE should be consistent
with standard SAE reporting guidelines.
9. Statistical Analysis Plan
9.1 Sample Size Considerations
Based on results and data from previous similar studies, the pCR rate of nap-
paclitaxel combined with SOX is known to be 7%, and the pCR rate of the Serplulimab
combined with nap-paclitaxel and SOX is expected to be 25%. A sample size of 58
patients per group was required to detect improvement with 80% power and a one-sided
alpha level of 0.05, including a 15% dropout rate.

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9.2 Analysis Sets
FAS included all patients who are randomly assigned according to the ITT
principle. This population will be used for the efficacy analyses. Baseline data were
analyzed by FAS.
PPS included patients in the ITT population who did not present major deviations
from the protocol. We pre-specified that participants who received surgery after
administration of neoadjuvant S-P-SOX or P-SOX are included in this set. This
population will be also used for the efficacy analyses.
SAS included patients who received at least one dose of allocated treatment. This
population will be also used for the safety analyses
9.3 Statistical Analysis
Baseline characteristics and demographic variables will be summarized in the
mITT set. Surgical and pathology results will be summarized in the per-protocol set.
Nonsurgical AEs will be summarized in the safety analysis set. Continuous variables
are presented as medians and interquartile ranges (IQRs) or means and standard
deviations (SDs) and are compared using the Wilcoxon rank sum test or t test.
Categorical variables are presented as frequencies and percentages and are compared
using the χ2 test or Fisher’s exact test.
The efficacy analysis will be performed using both the mITT and per-protocol sets.
The efficacy endpoints, including the pCR rate, R0 resection rate, ORR, DCR, and
survival, are compared using the Fisher’s exact test. The pCR rate, R0 resection rate,
ORR, and DCR will be summarized (i.e., number of patients [%]) and 95% confidence
intervals (CIs) for the objective response rate will be provided. Medians and 95% CIs
for OS and PFS will be calculated. Kaplan-Meier plots of OS and PFS will be presented.
Hazard ratio assessment and the corresponding 95% CIs can be presented using the Cox
proportional hazard model.
The relationship between biomarkers (including but not limited in PD-L1
expression and MSI status) and the pCR rate will be presented for a subset of patients in
the efficacy evaluable population who are available for these biomarkers.
The safety analysis will be done on the safety analysis set. All AEs will be
presented as frequencies and percentages in each category. If a patient experiences the
same AE multiple times during the treatments, the event will be counted only once and

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35
by the greatest severity.
10. Data Management
10.1CRF Completion Guidelines
For each participant, CRF should be completed by the investigator. The
investigator is responsible for ensuring that data recorded in the CRFs are complete,
accurate, and legible. The CRF will be served as the original records, and should not be
changed. Any correction must not be made on the original records, but an additional
narrative can be used for recording the change, the investigator should sign and date for
any change made. All data in the CRFs must come from and be consistent with the
source documents, i.e. patient’s file or medical records.
The CRFs should be completed before reviewing by the Monitor. For any
questionable data in the case report form, the Monitor will issue the Data Request
(DRQ) to query the investigator, the investigator should answer it as soon as possible
and return.
10.2Data Lock
After validating the data correction under blinding review, the principle
investigator and statistical analysis personnel will lock the data. The locked database is
no longer to be changed.
10.3Quality Control and Quality Assurance
Investigational personnel must be physicians through training of clinical study and
who will work under the guidance of the principal investigator.
Prior to the study initiation, the pre-study qualification is needed to ensure the
facility is equipped with all rescue equipment and meets the standard requirements.
Recommendations to study nurses who will administer study medications to
subjects, have a good understanding of the drug administration, and ensuring the
compliance of study subjects.
Each study center must strictly conduct in accordance with the study protocol, and
complete CRFs faithfully.
The Monitor will monitor the clinical study according to the Good Clinical
Practice and the Standard Operating Procedure, ensure the data recording and reporting
is correct and intact, all CRFs will be completed correctly and be verified with the

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36
original documents, and ensure the study can be conducted according to the study
protocol.
11. Ethics and Regulatory Considerations
11.1Local Regulations / Helsinki Declaration
The study was performed in accordance with the Helsinki Declaration of 1964 and
later versions, Guidelines for Good Clinical Practice, and Chinese law.
11.2Informed Consent
The investigator must explain to subjects that their participation is voluntary and
that they may withdraw at any study stage at any time, and will not affect their medical
treatment and interest; they also can continue to receive other kind of treatments after
withdrawal. Subjects must be informed that their participation and their personal
information in the study are confidential. Subjects must be informed of the study nature,
the study objectives, anticipated benefits, potential hazards or inconveniences, other
available treatments, and subject rights and obligations that meet the Declaration of
Helsinki, etc. Subjects should be given sufficient time to consider whether or not they
will participate the trial. The signature of the participant is needed on the informed
consent form. If new safety information changes the risk/benefit assessments, the
informed consent may be modified as necessary. If any modification is made, all
subjects (including those who have received treatment) will be notified of the new
information and given a revised consent form to continue their participation in the study.
11.3Independent Ethics Committee/Institutional Review Board
Before the study begins, all participating centers should submit the study protocol
and relevant documents (CRFs, consent forms, and other documents that may be
required) to the Independent Ethics Committee (IEC)/Institutional Review Board (IRB).
The study can only start after obtaining approval from the IEC/IRB. Any amendments
to the study protocol must be submitted to the IEC/IRB in accordance with local laws
and regulations.
11.4Confidentiality Agreement
Data obtained by this study is confidential, and disclosure to third parties other

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37
than the regulatory authority, the principle investigator, and study personnel is
prohibited.
11.5Record Storage
The investigator should arrange for the storage of the research files until the end of
the study. All records and documents pertaining to the conduct of this study and the
distribution of the study drugs, including CRFs, consent forms, laboratory test results,
and medical inventory records, must be retained by the principal investigator for at least
5 years.
11.6Study Interruption
The principal investigator can decide to discontinue this study at any time and for
any reason; the decision to discontinue the study will be communicated in writing to the
participating researchers. Likewise, if other participating researchers decide to
withdraw from the study, they must notify the company in writing.
11.7Protocol Modification
Any modification to the protocol will be recorded in a written revision and signed
by the principal investigator. A signed, revised version will be attached to the last
version of the protocol.
11.8Protection of participants' Rights and Interests
Ethics committee and informed consent are the main organizations and measures
to protect the rights and interests of subjects. Before the clinical study starts, the
research plan must be reviewed and approved by the Ethics Committee of Cancer
Hospital of Chinese Academy of Medical Sciences and signed before it can be
implemented. During the clinical study, any changes to the study protocol should be
approved by the Ethics Committee before implementation.
Clinical investigators must explain to subjects that participation in clinical research
is voluntary, and at any stage of the study have the right to withdraw from the study at
any time without discrimination and retaliation, their medical treatment and rights will
not be affected, and they can continue to receive other treatment methods and treatment
means. Subjects must be made aware that personal data relating to and participating in
the study are confidential. Subjects should also be informed of the nature of the clinical

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38
study, the purpose of the study, the expected possible benefits and possible risks and
inconveniences, the alternative treatment options available to them, and the rights and
obligations of the subjects in accordance with the Declaration of Helsinki, so that the
subjects have sufficient time to consider whether they are willing to participate in the
study and sign the informed consent.
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Appendix 1 Mandard Regression Criteria
Mandard Regression Criteria
Grade
Characteristic
TRG 1
Complete tumor regression without residual tumor
TRG 2
Only single or small focal residual tumor cells
TRG 3
Residual tumor less than fibrotic interstitium tissue
TRG 4
Residual tumor more than fibrotic interstitium tissue
TRG 5
tumor did not change or even progress
Note: The Mandard regression criteria are based on the comparison of residual tumor
cells and the degree of fibrosis in the cancer foci after neoadjuvant chemotherapy as a
grading index, which can describe the morphological changes of tumor treatment
response semi-quantitatively, and can objectively evaluate the degree of tumor
regression after treatment. TRG has a good performance in evaluating the efficacy of
neoadjuvant chemotherapy for gastric cancer.
Appendix 2 Pathological Staging System
American Joint Committee on Cancer (AJCC) TNM Staging Classification for
Carcinoma of the Stomach (8th ed, 2017)

Definition of Primary Tumor (T)
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis
Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria,
high-grade dysplasia
T1
Tumor invades lamina propria, muscularia mucosa or sub-mucosa
T1a
Tumor invades the lamina propria or muscularis mucosae
T1b
Tumor invades the sub-mucosa
T2
Tumor invades the muscularis propria
T3
Tumor penetrates the subserosal connective tissue without invasion of the visceral
peritoneum or adjacent structures

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42
T4
Tumor invades the serosa (visceral peritoneum) or adjacent structures
T4a
Tumor invades the serosa (visceral peritoneum)
T4b
Tumor invades adjacent structures/organs

Definition of Regional Lymph Node (N)
Nx Regional lymph node(s) cannot be assessed
N0 No regional lymph node metastasis
N1
Metastasis in one or two regional lymph nodes
N2
Metastasis in three to six regional lymph nodes
N3 Metastasis in seven or more regional lymph nodes
N3a Metastasis in seven to 15 regional lymph nodes
N3b Metastasis in 16 or more regional lymph nodes

Definition of Distant Metastasis (M)
M0
No distant metastasis
M1
Distant metastasis
Post-Neoadjuvant Therapy (ypTNM)
When T is...
And N is...
And M is...
Then the stage group is...
T1
N0
M0
I
T2
N0
M0
I
T1
N1
M0
I
T3
N0
M0
II
T2
N1
M0
II
T1
N2
M0
II
T4a
N0
M0
II
T3
N1
M0
II
T2
N2
M0
II
T1
N3
M0
II
T4a
N1
M0
III
T3
N2
M0
III
T2
N3
M0
III
T4b
N0
M0
III
T4b
N1
M0
III
T4a
N2
M0
III
T3
N3
M0
III
T4b
N2
M0
III
T4b
N3
M0
III
T4a
N3
M0
III
AnyT
AnyN
MI
IV
Appendix 3 Surgical Manual
In this study, the basic purpose of surgery is curative resection. Curative resection

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
43
is defined as follows:
- No distant metastasis.
- No infiltration to surrounding organs, or in case of infiltration, curative combined
resection should be performed.
- No macroscopic residual cancer.
- D2 or greater resection is necessarily required.
- No infiltration of cancer cells on both margins from histopathology.
Selection of gastrectomy The standard surgical procedure for clinically node-positive
(cN+) or T2-T4a tumors is either total or distal gastrectomy. Distal gastrectomy is
selected when a satisfactory proximal resection margin (see below) can be obtained.
When obtaining proximal resection margin is not possible, total gastrectomy isselected.
Resection margin A sufficient resection margin should be ensured when determining
the resection line in gastrectomy with curative intent. Proximal margin of at least 3 cm
is recommended for T2 or deeper tumors with an expansive growth pattern (types 1 and
2) and 5 cm for those with an infiltrative growth pattern (types 3 and 4). When these
rules cannot be satisfied, it is advisable to examine the whole thickness of proximal
resection margin by frozen section. For tumors invading the esophagus, resection
margin >5 cm is not necessarily required, but frozen section examination of the
resection line is preferable to ensure an R0 resection.
Definition of the D levels

Total gastrectomy
D0: Lymphadenectomy less than D1.
D1: No. 1-7.
D1+: D1 + No. 8a, 9, 11p.
D2: D1 + No. 8a, 9, 11p, 11d, 12a.
For tumors invading the esophagus, resection of No.110 should be added to D1+, and
resection of Nos. 19, 20, 110 and 111 to D2.
Appendix 4 Response Evaluation Criteria in Solid Tumors (RECIST),
Version 1.1
Measurability of tumor at baseline
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-
measurable as follows:

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
44
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest
diameter in the plane of measurement is to be recorded) with a minimum size of:
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm).
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately
measured with calipers should be recorded as non-measurable).
• 20 mm by chest X-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only
the short axis will be measured and followed.
Non-measurable
All other lesions, including small lesions (longest diameter <10 mm or pathological
lymph nodes with ≥10 to <15 mm short axis) as well as truly non-measurable lesions.
Lesions considered truly non-measurable include: leptomeningeal disease, ascites,
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement
of skin or lung, abdominal masses/abdominal organomegaly identified by physical
exam that is not measurable by reproducible imaging techniques.
Response criteria
This section provides the definitions of the criteria used to determine objective
tumour response for target lesions.

Evaluation of target lesions
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph
nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions,
taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target
lesions, taking as reference the smallest sum on study (this includes the baseline sum if
that is the smallest on study). In addition to the relative increase of 20%, the sum must
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or
more new lesions is also considered progression).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD, taking as reference the smallest sum diameters while on
study。

Evaluation of non-target lesions

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
45
This section provides the definitions of the criteria used to determine the tumour
response for the group of non-target lesions.
While some non-target lesions may actually be measurable, they need not be
measured and instead should be assessed only qualitatively at the time points specified
in the protocol.
Complete Response (CR): Disappearance of all non-target lesions and normalisation of
tumour marker level. All lymph nodes must be non-pathological in size (<10 mm short
axis).
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance
of tumour marker level above the normal limits.
Progressive Disease (PD): Unequivocal progression (see comments below) of existing
non-target lesions. (Note: the appearance of one or more new lesions is also considered
progression).
Appendix 5 ECOG Performance Status
According to the simplified performance status score scale developed by the ECOG, the
patients’ performance status can be classified into 6 levels, namely 0-5, as follows:
ECOG Performance Status
Grade
Characteristic
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 housework, office work.
2
Ambulatory and capable of all self-care but unable to carry
out any work activities. Up and about more than 50% of
waking hours.
3
Capable of only limited self-care, confined to bed or chair
more than 50% of waking hours.
4
Completely disabled. Cannot carry on any self-care. In
total, confined to bed or chair.
5
Dead.
Note: Patients at levels 3, 4 and 5 are generally considered to be unsuitable for surgical

Serplulimab for G/EGJ cancer Protocol (Version 1.0) Date: July 2, 2024
46
treatment or chemotherapy.
Appendix 6 Classification of Surgical Complications
Clavien-Dindo Classification
Grade
Characteristic
Grade I
Any deviation from the normal postoperative course without
the need for pharmacological treatment or surgical,
endoscopic, and radiological interventions. Allowed
therapeutic regimens are: drugs as antiemetics, antipyretics,
analgetics, diuretics, electrolytes, and physiotherapy. This
grade also includes wound infections opened at the bedside.
Grade II
Requiring pharmacological treatment with drugs other than
such allowed for grade I complications.
Grade III
Requiring surgical, endoscopic or radiological intervention
Grade IIIa: Intervention not under general anesthesia
Grade IIIb: Intervention under general anesthesia
Grade IV
Life-threatening complication requiring ICU management
Grade IVa: Single organ dysfunction (including dialysis)
Grade IVb: Multiorgan dysfunction
Grade V
Death of a patient.

Efficacy and Safety of Serplulimab Combined with SOX and
Nab-paclitaxel as Neoadjuvant Treatment for Locally
Advanced Gastric cancer or Adenocarcinoma of
Esophagogastric junction:
A Multicenter Randomized Controlled Trial
SUMMARY OF CHANGES.
Protocol Version History
Version Number
Version Date
Scientific and Substantive Revisions
v1.0
July 7, 2024
●Initial protocol
v1.1
Oct 8, 2024
●Add secondary objectives: Patient reported outcomes: EORTC
QLQ-C30 and QLQ-STO22