A Prospective Randomized Controlled Study of Immune Checkpoint Maintenance Therapy After Radiotherapy and Chemotherapy for Locally Advanced Head And Neck Tumors Based on Peripheral Blood CD8Tex Detection in Peripheral Blood
Phase: PHASE2
Conditions: Locally Advanced Head and Neck Squamous Cell Carcinoma
Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

A prospective randomized single blind
controlled study on maintenance therapy with
Sintilimab after radiotherapy and
chemotherapy for locally advanced head and
neck tumors based on peripheral blood
CD8TEX detection
Main researcher: Zhang Ting
Plan version number: 1.0 version
Date of formulation: January 25, 2024
Main research unit: Second Affiliated Hospital of Zhejiang University
1. Introduction to research background:
Head and neck squamous cell carcinoma (HNSCC) includes cancers of the mouth, oropharynx,
larynx and hypopharynx. The incidence rate ranks the sixth with a mortality rate of 40-50%. It is a serious
disability and life-threatening disease. Due to the unique anatomical location, the surgical disability rate of
HNSCC is high, which seriously affects the quality of life of patients. Radiation therapy is a very
important local treatment for malignant tumors. Radiation therapy not only protects organ function and has
cosmetic effects, but also has a long-term survival comparable to surgical treatment for early HNSCC
patients receiving radiation therapy. However, over 60% of HNSCC patients are initially diagnosed as
locally advanced. For patients with locally advanced stage who cannot undergo surgery, the current
standard treatment regimen is synchronous radiotherapy and chemotherapy (CRT) or synchronous targeted
treatment with cetuximab, followed by clinical follow-up. However, there are still relatively high rates of
local recurrence or distant metastasis in patients with locally advanced head and neck tumors after
radiotherapy and chemotherapy. The 3-year PFS rate is about 60%, 50% of relapses occur within 2 years
after radiotherapy and chemotherapy, 20% to 30% of patients experience distant metastasis, and the
overall 5-year survival rate is less than 50%. Therefore, it is necessary to further optimize the maintenance
treatment plan after radiotherapy and chemotherapy, in order to improve the clinical cure rate of patients
with locally advanced head and neck tumors.
Immunotherapy has achieved significant breakthroughs in recurrent and metastatic head and neck
tumors. Studies on various tumor models have shown that tumor infiltration of PD-1+CD8+depleted T
cells (CD8+TEX) is an important mechanism for the reduction of anti-tumor function and tumor
progression in the body. Immunotherapy can reactivate T cell responses by blocking the PD-1 pathway. A

clinical study by Checkmate 141 showed that anti PD-1 monoclonal antibodies showed long-lasting
efficacy in treating recurrent and metastatic HNSCC, with a nearly three fold increase in OS rate at 2 years
(16.9% vs 6.0%). Therefore, in 2016, the first anti PD-1 antibody was approved by the FDA for recurrent
or metastatic HNSCC that failed platinum chemotherapy. Radiation therapy can directly kill tumor cells
while also reshaping the local immune microenvironment of the tumor, including the release of
pro-inflammatory molecules and infiltration of immune cells. The subgroup analysis of KEYNOTE-001
and PEMBRO-RT studies found that patients who had previously undergone radiotherapy had better
immunotherapy efficacy after recurrence and metastasis. However, studies on immunotherapy in locally
advanced HNSCC have all failed, including the JAVELIN HEAD AND NECK 100 study comparing the
efficacy of Avelumab combined with CRT treatment and Avelumab maintenance therapy with CRT
standard treatment, and the GORTEC REACH study comparing the efficacy of Avelumab combined with
cetuximab combined with radiotherapy and Avelumab maintenance therapy with standard treatment. Both
studies used immunosynchronous therapy at the beginning of radiotherapy without adaptive screening, and
the PFS of both studies showed a trend of numerical benefits but no statistical significance. Therefore, can
better biomarkers be selected to screen suitable HNSCC patients for maintenance therapy after
synchronous radiotherapy and chemotherapy?
At present, there are no research reports on the changes of CD8+TEX cells in the tumor immune
microenvironment after radiotherapy. In our preliminary research, we found in the HNSCC mouse tumor
model that the proportion and quantity of PD-1+CD8+TEX cells in the tumor and peripheral blood
significantly increased with the prolongation of time after radiotherapy, and the combination of
immunotherapy at the end of radiotherapy or 7 days after radiotherapy had the best therapeutic effect. We
further tested the proportion of TEX in human peripheral blood and the expression level of PD1 during
and after synchronous radiotherapy and chemotherapy, and found a similar trend as in the mouse model.
So we speculate whether the proportion of peripheral blood CD8+TEX cells and the expression level of
PD1 can be used as a suitable screening for immunotherapy. In the early stage, we retrospectively
analyzed three patients who underwent immune maintenance therapy after synchronous radiotherapy and
chemotherapy, and found that they have been followed up for three years, and no PFS time has been
obtained. This study aims to ensure that patients receive standard treatment. By screening the proportion
of CD8+TEX cells in peripheral blood and the expression level of PD1, patients with upregulation of
CD8TEX in peripheral blood after radiotherapy or patients with PD1 expression levels higher than normal
were randomly divided into two groups: one group received maintenance therapy for immunity, and the
other group received placebo comparison to evaluate PFS time.
2.Research Purpose
2.1 Research Purpose:
A prospective randomized single blind controlled study on maintenance therapy with
Sintilimab after
radiotherapy and chemotherapy for locally advanced head and neck tumors
2.2 Main study endpoints:

Evaluation of progression free survival (PFS) and 1-year progression free survival (PFS) in two groups
of patients with locally advanced head and neck tumors after radiotherapy and chemotherapy (using
RECIST 1.1 criteria)
2.3 Secondary study endpoints:
Evaluation of overall survival (OS), safety and tolerability, changes in quality of life relative to baseline,
and time to deterioration in maintenance therapy with Xindilimab in patients with locally advanced head
and neck tumors after radiotherapy and chemotherapy (EORTC QLQ-C30 and H&N-35)
The primary safety analysis will be conducted based on subjects who experience toxicity (as defined by
CTCAE standards). CTCAE version 5.0 will be used to evaluate safety through reported adverse events.
The relationship between adverse events and drugs, onset time, duration of events, their resolution, and
any concomitant medication will be recorded. Adverse events (AEs) will be analyzed, including but not
limited to all AEs, SAEs, lethal AEs, and laboratory changes.
2.4 Exploratory study endpoint:
Explore biomarkers for predicting efficacy and adverse reactions, and obtain better guidance on the
combination therapy and safety of immunotumor drugs. In order to identify novel biomarkers, we
collected biological samples: 10-20ml of blood (before treatment and during efficacy evaluation) to
support the analysis of cellular components (such as DNA, proteins, etc.), such as whole exome gene
testing, TMB, PD-L1, MRD, etc.
3.Research design and methods:
3.1 Inclusion criteria:
(1) Male or female, age ≥18 years old, ≤75 years old.
(2) Localized advanced head and neck tumors with T3 or N+or above that have been histologically
confirmed as inoperable.
(3) Patients undergoing synchronous radiotherapy and chemotherapy
(4) ECOG physical fitness status ranges from 0 to 1 point.
(5) The expected lifespan is at least 12 weeks.
(6) At least one measurable lesion
(7) Hematology examination absolute neutrophil count (ANC)>1.5 × 109/L, hemoglobin>8g/dL and
platelets>100 × 109/L (based on the normal value of the clinical trial center).
(8) Prothrombin time (PT)<1.5 times the upper limit of normal value and normal thromboplastin time
(APTT)<1.5 times the upper limit of normal value.
(9) Laboratory tests show that serum creatinine is less than or equal to 1.5 times the upper limit of the
normal reference range (if serum creatinine increases, 24-hour urine must be collected, except for those
with a 24-hour creatinine clearance rate>50ml/min).

(10) When there is no liver metastasis, ALT or AST is less than or equal to 2.5 times the upper limit of
the normal reference range, and serum total bilirubin is less than or equal to 1.5 times the upper limit of
the normal reference range; For patients with liver metastasis, ALT or AST is less than or equal to 5
times the upper limit of the normal reference range, and serum total bilirubin is less than or equal to 3
times the upper limit of the normal reference range.
(11) Women of childbearing age must be willing to use adequate contraceptive measures during the
study drug treatment period.
(12) Signed informed consent form.
(13) At the end of radiotherapy, the proportion of peripheral blood PD1+CD8T cells is greater than 10%,
or more than twice the baseline
3.2 Exclusion criteria:
(1) Active autoimmune diseases that require systemic treatment (i.e. the use of disease relieving drugs,
corticosteroids, or immunosuppressants) have occurred within the past 2 years. Alternative therapies
(such as thyroid hormone, insulin, or physiological corticosteroid replacement therapy for adrenal or
pituitary insufficiency) are not considered systemic treatments.
(2) Diagnosed as immunodeficiency or undergoing systemic steroid therapy or any other form of
immunosuppressive therapy within 7 days prior to the first administration of the trial treatment. After
consulting with the sponsor, the use of physiological doses of corticosteroids may be approved.
(3) It is known that there are other malignant tumors that are progressing or require active treatment.
Excluding skin basal cell carcinoma, skin squamous cell carcinoma, or cervical carcinoma in situ that
have already undergone curative treatment.
(4) Active infections that require systemic treatment.
(5) There is a possibility of confusing the trial results, obstructing the participant's full participation in
the study due to medical history or evidence of illness, abnormal treatment or laboratory values, or the
researcher believing that participating in the study is not in the best interest of the participant.
(6) It is known that there are mental or substance abuse disorders that may affect compliance with the
trial requirements.
(7) Female subjects who are pregnant or breastfeeding, or expected to conceive during the planned trial
period or 180 days after the last dose of study treatment, or male subjects whose spouses are preparing to
conceive.
(8) Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibody) infection.
3.3 Research Design:
This study is a prospective single blind randomized controlled clinical trial of maintenance therapy with
Xindilimab based on peripheral CD8TEX screening after standard radiotherapy and chemotherapy for
locally advanced head and neck tumors. Synchronous radiotherapy and chemotherapy are routine
standard treatments and do not require the use of immunotherapy drugs in this study. Blood samples
were collected before and after radiotherapy, and participants were screened and evaluated according to
the inclusion and exclusion criteria of the protocol within 28 days before randomization. Patients who

agree to participate in this study will sign an informed consent form (ICF) prior to the screening process.
After completing all screening activities, eligible participants can start receiving study treatment.
According to the estimated sample size, a total of 104 patients are planned to be enrolled and randomly
assigned equally to the experimental group and control group. The treatment cycle for the study is 21
days. The experimental group starts treatment within one month after the end of radiotherapy and
chemotherapy. On the first day of each cycle, intravenous treatment with
Sintilimab is given, with a
cycle of 21 days. It is expected to be administered for a total of 18 cycles, or until the disease progresses;
The control group received placebo treatment. The experimental group underwent routine blood tests,
liver and kidney function, myocardial enzyme spectrum, thyroid function, electrocardiogram every 2
cycles, and CT scans every 4 cycles to evaluate toxic side effects; The control group underwent the same
frequency of follow-up and observation. The study started on January 1, 2024 and ended on January 1,
2027, to explore the efficacy of maintenance therapy with Xindilimab after radiotherapy and
chemotherapy for locally advanced head and neck tumors.
Research plan:
Intravenous infusion of
Sintilimab, D1, once every 3 weeks
3.4 Research Evaluation Plan
3.4.1 Baseline evaluation
3.4.2 Pre medication evaluation of treatment plan (starting from d1, once every 6 weeks, completed
each time before administration)
Inspection items
Inspection time and related instructions
Physical examination, medical history
Medical history collection
Physical examination items must include: heart
rate, blood pressure, respiratory rate, body
temperature, height, weight, and neurological
examination
Emphasis should be placed on inquiring about
possible adverse reactions of
Sintilimab
Peripheral blood routine
The blood routine test must include: red blood
cell count (RBC), hemoglobin (Hb), white
blood cell count (WBC), and white blood cell
classification count (absolute neutrophil and
lymphocyte counts are required), hematocrit
(HCT), and platelet count (PLT).
Blood biochemical examination
The blood biochemistry items must include:
blood electrolytes (K Na Ca Mg Cl HCO3- is
necessary), ALT, AST, γ- GT, total bilirubin,
direct bilirubin, amylase, lipase, creatinine, urea
T nitrogen, serum albumin, blood glucose
thyroid function
Thyroid function items must include: T3, T4,

fT3, fT3, TSH
urinalysis
Urine routine items must include: urine specific
gravity (SG), urobilinogen (URO), occult blood
(BLD), white blood cells (WBC), urine protein
(PRO), urine glucose (GLU), bilirubin (BIL),
ketone bodies (KET), urine red blood cells
(RBC), and urine color (COL).
Electrocardiogram examination
Twelve lead electrocardiogram
Blood
and
tissue
specimens
for
biomarker
research
Before treatment
and
before
each
efficacy
evaluation (blood samples
3.4.3
Efficacy evaluation
Inspection items
Inspection time and related instructions
Imaging examination
Complete baseline assessment within 1
month before treatment, and treat every 3
months
Chest and abdominal CT examination evaluation
3.4.4 Testing items and time after discontinuation/withdrawal from the study (once every 9 weeks since
the last medication use)
Inspection items
Inspection time and related instructions
Telephone follow-up
Telephone follow-up every two months
3.5 Treatment of subjects
3.5.1
Intervention measures

1.0 版
7
Sintilimab treatment regimen
drug
Dosage
Administration
frequency
Usage
method
treatment cycle
Sintilimab
According
to the
recommende
d dosage in
the manual
Q3W
Intravenous
infusion
Cycle every 21 days, administered on
the first day
The use of
Sintilimab (IBI308)
The main active ingredient of IBI308 is a recombinant human monoclonal antibody against
programmed cell death receptor 1, with a concentration of 10 mg/mL. This product is a clear,
colorless liquid, free from foreign objects, flocculent substances, and precipitates. The excipients
include 140 mmol/L mannitol, 25 mmol/L histidine, 20 mmol/L sodium citrate dihydrate, 50
mmol/L sodium chloride, 0.02 mmol/L disodium edetate (ethylenediaminetetraacetic acid
disodium), 0.2 mg/mL polysorbate 80, pH 6.0.
The minimum packaging unit for IBI308 is a box, with each box containing one injection of
Sintilimab packaged in a penicillin bottle. The packaging box is printed with the drug name,
dosage form, specifications, drug code, production batch number, expiration date, storage
conditions, and information about the sponsor. The label of the penicillin bottle and the packaging
box have the same information printed on them, but there is no information on the dosage form,
precautions, and dosage on the penicillin bottle label. All packaging boxes and penicillin bottles
are labeled as "for clinical research purposes only". The finished product of Sintilimab is stored in
a dark place at 2-8 ℃and has a shelf life of 24 months. If there are quality problems such as
turbidity and precipitation in the injection, it should be immediately sealed and Xinda
Biopharmaceutical (Suzhou) Co., Ltd. (hereinafter referred to as "Xinda Biotech") should be
notified immediately.
The intravenous infusion time of IBI308 should be within 30-60 minutes. Do not administer

1.0 版
8
through intravenous injection or single rapid intravenous injection.
The guidance for dilution of drugs before administration is as follows:

Solution preparation and infusion

Do not shake the medicine bottle.

Restore the medication bottle to room temperature (25 ° C or below) before use.

After removing the medicine bottle from the refrigerator, it can be left at room temperature
(25 ° C or below) for a maximum of 24 hours before dilution.

Before administration, the injection medication should be visually inspected for the presence
of suspended particles and discoloration. This product is a clear to slightly milky, colorless to
light yellow liquid with no foreign objects. If visible particles are observed, the medicine
bottle should be discarded.

Extract 2 bottles of this product injection (200mg) and transfer them to an intravenous
infusion bag containing 9mg/ml (0.9%) sodium chloride solution. Prepare a final
concentration range of 1.5-5.0mg/ml. Gently flip the diluent and mix well.

From a microbiological perspective, this product must be used immediately upon dilution and
should not be frozen. The stability study of this product shows that it can be stored in dark at
2-8 ° C for 24 hours, including a maximum of 6 hours under indoor light at 20-25 ° C (6
hours including administration time). After refrigeration, the medication bottle and/or
intravenous infusion bag must be restored to room temperature before use. The infusion tube
used during infusion must be equipped with a sterile, heat free, low protein binding infusion
tube filter (pore size 0.2) μ m) . The infusion time is within 30-60 minutes.

Do not use the same infusion tube to administer medication simultaneously with other
medications.

This product is for one-time use only. Any unused medication remaining in the medication
bottle must be discarded.
Medication adjustment of
Sintilimab

1.0 版
9
Throughout the entire research process, it is not allowed to adjust the dosage of Xindilimab.
The principles of suspending and permanently stopping Xindilimab administration are shown in
the table below.
3.5.2 信迪利单抗暂停给药和永久停药原则
Adverse
events
with Sintilimab
Severity
Dose
adjustment
pneumonia
Grade 2
Suspend
administrationa
Grade 3 or 4 or recurrent level 2
Permanent
discontinuation
of medication
Diarrhea/Colitis
Grade 2 or 3
Suspend
d i i
i
a
Grade 4
Permanent
hepatitis
For subjects with normal baseline ALT, AST, or TBIL, level 2
AST, ALT (3-5 times ULN), or TBIL (1.5-3 times ULN) were
elevated; For subjects with baseline AST, ALT, or TBIL>ULN, an
increase of ≥
50% in AST, ALT, or TBIL (meeting level 2
requirements) and a duration of<7 days is required
Suspend
administrationa

1.0 版
10
For subjects with normal baseline ALT, AST, or TBIL, grade 3 or 4
AST, ALT (>5x ULN), or TBIL elevation (>3x ULN); For subjects
with baseline AST, ALT, or TBIL>ULN, AST, ALT, or TBIL
increase ≥50% (meeting level 3 or 4 requirements) and duration
≥7 days
Permanent
discontinuation
of medication
nephritis
Grade 2 or Grade 3 elevated blood creatinine
Suspend
administrationa
Grade 4 elevated blood creatinine
Permanent
discontinuation
Endocrine
disorders
Symptomatic grade 2 or 3 hypothyroidism
Grade 2 or 3 hyperthyroidism
Grade 2 or 3 pituitary inflammation
Grade 2 adrenal insufficiency
Grade 3 hyperglycemia or type 1 diabetes
Suspend
administrationa
Grade 4 hypothyroidism
Grade 4 hyperthyroidism
Grade 4 pituitary inflammation
3rd or 4th grade adrenal insufficiency
Grade 4 hyperglycemia or type 1 diabetes
Permanent
discontinuation
of medication
Skin
adverse
reactions
Grade 3
Suspend
administrationa
Level 4, Stevens Johnson syndrome (SJS) or toxic epidermal
necrolysis (TEN)
Permanent
discontinuation
thrombocytopenia
Grade 3
Suspend
Grade 4
Permanent

1.0 版
11
Other
immune
related
adverse
reactions
Level 3 or 4 elevated blood amylase or lipase
Grade 2 or 3 pancreatitis
Grade 2 myocarditis c
Other immune related adverse reactions that occur for the first time
at level 2 or 3
Suspend
administrationa
Grade 4 pancreatitis or any level of recurrent pancreatitis
Grade 3 or 4 myocarditis
Grade 3 or 4 encephalitis
Other immune related adverse reactions that first occurred at level 4
Permanent
discontinuation
of medication
Recurrent
or
persistent adverse
reactions
Recurrent grade 3 or 4 (excluding endocrine disorders)
Grade 2 or 3 adverse reactions within 12 weeks after the last
administration
Not improved to level 0-1 (excluding endocrine diseases)
Failure of corticosteroids to decrease to ≤10mg/day prednisone
equivalent dose within 12 weeks after the last administration
Permanent
discontinuation
of medication
Table: Suspension and permanent discontinuation of Sintilimab regimen
a: Resumption of medication after symptom improvement to level 0-1 or baseline level.
b: Pituitritis, adrenocortical insufficiency, thyroid insufficiency/hypothyroidism and type 1
diabetes can be re used when they are fully controlled and only need physiological hormone
replacement treatment.
c: For abnormal results in Level 4 laboratory tests, the decision to terminate medication should be
based on accompanying clinical symptoms/signs and the researcher's clinical judgment.
The maximum interval allowed for drug suspension is 12 weeks. If the subject cannot recover to a
state where they can reuse Sintilimab within 12 weeks, they will permanently discontinue
Sintilimab and enter the follow-up phase. Excluding the following two situations:
1) Due to the use of glucocorticoids in the treatment of irAE, the process of reducing
glucocorticoids resulted in the suspension of Sintilimab for more than 12 weeks. In this case, it is

1.0 版
12
necessary to discuss with the medical manager of the sponsor to decide whether to continue
treatment with Sintilimab. The imaging examination for evaluating the therapeutic effect is carried
out according to the plan and is not affected by the suspension of medication.
2) Due to the treatment of AE unrelated to Xindilimab, Xindilimab was temporarily suspended for
more than 12 weeks. In this case, it is necessary to discuss with the sponsor to decide whether to
continue treatment with Sintilimab. The imaging examination for evaluating the therapeutic effect
is carried out according to the plan and is not affected by the suspension of medication.
The principle of restoring Sintilimab
When resuming the use of Sintilimab, relevant AEs need to be restored to level 0-1 or baseline,
with an ECOG PS score of 0-1.
Management of infusion reactions related to Sintilimab
Xindilizumab may cause severe or life-threatening infusion reactions, including severe
hypersensitivity or allergic reactions. Signs and symptoms usually appear during or shortly after
drug infusion, and can usually be completely resolved within 24 hours of completion of infusion.
The management guidelines for infusion reactions associated with Sintilimab are shown in Table
2.
NCI CTCAE
classification
Treatment
Perform pre-treatment
medication during subsequent
administration
Grade 1
Mild reactions; No need
to interrupt infusion; No
intervention required
According to the patient's
medical indications, strengthen
monitoring of their vital signs until
the researchers believe that the
subject's condition is stable.
None

1.0 版
13
Grade 2
Treatment or interruption
of infusion is necessary, but
symptomatic treatment (such
as antihistamines, nonsteroidal
anti-inflammatory drugs
[NSAIDs], anesthetics,
intravenous infusion) should
be carried out as soon as
possible to quickly generate a
response; Preventive
medication should be taken
for ≤24 hours
Stop infusion and monitor
symptoms.
Other appropriate drug
treatments may include, but are not
limited to: intravenous
antihistamines
NSAIDS
Acetaminophen anesthesia
According to the patient's
medical indications, strengthen
monitoring of their vital signs until
the researchers believe that the
subject's condition is stable.
If the symptoms improve within
one hour after stopping drug
infusion, the infusion can be
restarted at 50% of the original
infusion rate (such as reducing from
100 mL/h to 50 mL/h). Otherwise,
medication should be suspended
until symptoms improve, and
subjects should receive
pre-treatment medication before the
next planned administration.
For subjects who still exhibit
level 2 toxicity despite receiving
sufficient pre-treatment medication,
further study drug treatment should
be permanently discontinued.
Subjects receiving anti
PD1/PDL1 monotherapy
Within 1.5 hours (± 30
minutes) prior to treatment, the
following pre-treatment
medications can be accepted:
Oral administration of 50
mg diphenhydramine (or
equivalent dose of
antihistamine).
Oral administration of
500-1000 mg of acetaminophen
(or an equivalent dose of
antipyretic).

1.0 版
14
Grade 3/4
Grade 3：
Long duration (i.e.
failure to respond quickly
after symptomatic medication
and/or brief interruption of
infusion); Symptom
recurrence after initial
improvement; Hospitalization
is required due to other
clinical sequelae such as
kidney damage and lung
infiltration
Grade 4：
Endangering life;
Require vasopressor
medication or ventilation
support
Stop infusion.
Other appropriate drug
treatments may include but are not
limited to: adrenaline * *
intravenous infusion antihistamines
NSAIDS
Acetaminophen anesthesia
Oxygen boosting drugs
Corticosteroids are used to
strengthen monitoring of the
patient's vital signs based on their
medical indications, until researchers
believe that the subject's condition is
stable.
Hospitalization may be required
for treatment.
**If an allergic reaction occurs,
adrenaline should be used
immediately.
Subjects should permanently
discontinue further study drug
treatment。
No subsequent
administration
Appropriate first aid equipment should be equipped in the ward and physicians should be
available at all times during medication administration.
For further information, please refer to the Common Terminology Standard for Adverse Events
(CTCAE) version 4.03
（http://ctep.cancer.gov ）

1.0 版
15
3.6 Accompanying treatment
Allowing accompanying treatment
Medications that have been determined by the researchers to comply with the protocol (such as
those used to treat disease-related symptoms and accompanying treatments for various AEs).
Subjects who need long-term medication due to basic diseases such as hypertension and diabetes
can continue to use medication.
Allow local corticosteroid medication, such as topical use, eye drops, nasal spray, inhalation, etc.
Prohibited concomitant therapy
During the treatment period of this study, participants were prohibited from receiving the
following treatments:
Biotherapy with anti-tumor effect (excluding cytokine drugs used to treat adverse events
caused by chemotherapy drugs), and traditional Chinese patent medicines and simple preparations
with anti-tumor effect
Drugs with immunomodulatory effects, including but not limited to non-specific
immunomodulators (such as thymosin, interferon, interleukin, immunoglobulin, gamma globulin)
and traditional Chinese patent medicines and simple preparations with immunomodulatory effects
Chemotherapy not specified in this plan
Live vaccine administration within 30 days prior to the first administration of Sintilimab and
during the study process. Live vaccines include, but are not limited to, the following: measles,
mumps, rubella, chickenpox, yellow fever, rabies, BCG vaccine, typhoid fever (oral) vaccine.
Allow receiving inactivated virus vaccines for seasonal influenza; However, it is not allowed to
receive attenuated live influenza vaccines administered intranasally.

1.0 版
16
Corticosteroids. Allow the use of inhaled steroids as part of fixed treatment for asthma or chronic
obstructive pulmonary disease (COPD). Corticosteroids allowed for handling adverse events with
potential immune causes. After consulting with the sponsor, the use of physiological doses of
corticosteroids can be approved.
Note: The use of prophylactic corticosteroids is allowed to avoid allergic reactions (such as
pre-treatment of intravenous contrast agents or chemotherapy drugs).
According to the evaluation of the researchers, subjects who need to use any of the above
treatment methods for clinical treatment should be excluded from the trial. The subjects may
accept other medication treatments deemed medically necessary by the researchers. It is important
for researchers to review each medication (prescription and over-the-counter) received by
participants before the start of the study and during each study visit.
During each visit, the subject must be asked about any new medications they have received.
To reduce the risk of adverse drug interactions, all measures must be taken to limit the number of
concomitant medications that are truly necessary.
During administration, drugs with hepatotoxicity should be avoided (i.e. drugs with hepatotoxicity
are warned in the product manual). Encourage researchers to review each potential hepatotoxic
drug by searching the website www.livertox.nih. gov.
3.7 This study excluded the inclusion of vulnerable groups, such as individuals with mental illness,
critically ill patients, pregnant women, illiterate individuals, minors, cognitive impairment
individuals, students of PI or researchers, subordinates of PI or co researchers, employees of
research institutions or sponsors.
3.8 Data Management and Confidentiality
The data collected during the study period will be recorded in the subject's personal case
report form. Each subject is assigned a unique subject number in the case report form for

1.0 版
17
identification. Any data modifications made by data entry personnel in the case report form system
will be automatically recorded through the system's "audit trail" function.
The data entry personnel should fill out the case report form as soon as possible after
follow-up, and any questions should be answered as soon as possible to maintain the latest data.
The case report form should be completed, reviewed, and signed by the researcher as soon as
possible after the last follow-up of the subjects. Each subject who has signed the ICF and passed
all screening steps must have a completed case report form. If the subject did not receive treatment,
the reason must be recorded in the case report form. All data outside of the case report form
(laboratory tests, imaging examinations) will be integrated with the relevant data in the subject's
case report form. The subject number and date of participation in the study should be recorded by
the researcher in the subject's medical/research file along with the study code. Researchers should
also record the following information in their medical/research records: written and oral
confirmation of informed consent, clinical status of the subjects, dates of each study follow-up,
dates of study drug administration, concomitant medications, copies of all relevant reports and
laboratory test results, opinions on the results, and any AEs mentioned. The researcher completes
electronic signatures through the system in the case report form, which indicate that the researcher
has checked or reviewed the data, data questions, and research center notices on the case report
form, and agrees to the relevant content. All information and other materials used by subjects and
researchers must use clear and understandable vocabulary and language.
The medical records, imaging data, drug use registration form, subject code table, serious
adverse event report form and other data of the subjects are kept confidential, and these materials
are not disclosed to the public outside the scope permitted by relevant laws and/or regulations. The
drug regulatory department, the sponsor, and their authorized supervisory personnel, as well as the
ethics committee, have the right to access relevant trial data and original records with the consent
of the main researchers involved in the trial.
4. Informed consent

1.0 版
18
Before participants participate in the study, the researcher is responsible for fully explaining
the research purpose, methods, expected benefits, and potential hazards to the participants, in
order to further obtain voluntary written consent from the participants or their guardians (if
permitted by local regulations). The legal representative refers to an individual or institution who,
in accordance with legal requirements and with the authorization of the subject or the law, can
make consent on behalf of the subject to participate in clinical research. ICF should be written in
the native language of the potential subject population.
Researchers should comply with relevant regulatory requirements, GCP, and ethical
principles derived from the Helsinki Declaration to obtain written consent from participants.
Before providing ICF and its revised versions to potential subjects, approval from IEC/IRB should
be obtained. Researchers should ensure that each participant is informed that they can voluntarily
terminate the study at any time, and that each participant has the opportunity to ask questions and
have time to reflect on the information obtained.
The ICF should be obtained before the participants participate in the study and the consent
form should be kept in the research center as a document. The ICF should be signed by the subject
themselves or their legal representative (if permitted by local regulations), as well as the
researcher's name and date. The original signed ICF should be kept at the research center and a
copy of the signed consent form should be provided to the subject or their legal representative.
The date of obtaining informed consent should be recorded in the medical records and original
records.
If the subject or their legal representative (if permitted by local regulations) lacks reading
ability, a fair witness should be present throughout the informed consent discussion process.
Witnesses should sign the ICF after the subject or their legal representative agrees to participate in
the study and signs the ICF (if possible). Signing the ICF indicates that the witness confirms that
they have fully explained the information and any other written information in the ICF to the
subject or their legal representative, that they have clearly understood the information, and that the
subject or their legal representative agrees to sign the written ICF.

1.0 版
19
The following vulnerable groups with informed consent were excluded from this study, such as:
(1) Patients, especially hospitalized and mentally ill patients with serious illnesses: those who have
no capacity for behavior shall have their legal guardians sign.
(2) Prisoners, pregnant women, intellectually disabled individuals, and other individuals who may
be economically or educationally disadvantaged
(3) Children: must obtain an informed consent form signed by their legal guardian; When children
can actually make a decision to agree to participate in the study, they must obtain their consent
(4) Students, staff members of this institution, etc.: Participating in research conducted by their
management personnel shall not have any additional benefits, and shall not be forced to
participate;
(5) Notes on obtaining informed consent for patients with mental/cognitive impairments:
7. Reporting of Adverse Events
7.1 Definition of Adverse Events
Adverse Event (AE) is defined as any adverse medical event that occurs in a clinical study after a
subject receives treatment with a certain drug, regardless of whether it is causally related to the
investigational drug. AE includes but is not limited to the following situations:

The worsening of the original medical condition/disease (including symptoms, signs, and
laboratory test abnormalities) before entering clinical trials;

Any newly occurring adverse medical conditions (including symptoms, signs, newly

1.0 版
20
diagnosed diseases);

Abnormal laboratory test values or results with clinical significance.
7.2 Definition of serious adverse events
Serious Adverse Event (SAE) refers to an adverse event that meets at least one of the following
criteria:

Causing death, excluding deaths caused by disease progression based on research indications.

Life threatening (defined as "life-threatening" refers to an AE where the subject is at risk of
death when it occurs, but does not include an AE that could potentially cause death if the
event worsens).

Hospitalization treatment or extended hospital stay is required, excluding the following
situations:
Rehabilitation institutions
Sanatorium
Routine emergency room admission
Same day surgery (such as outpatient/same day/non bed rest surgery)
Hospitalization treatment or prolonged hospital stay that is not related to the
deterioration of AE itself is not an SAE.For example, if admitted due to an
existing disease, there have been no new adverse events or worsening of the
existing disease (such as in order to check for laboratory test abnormalities that
have persisted since the trial); Hospitalization for management reasons (such as
annual routine physical examinations); Hospitalization specified in the trial
protocol during the clinical trial period (such as operating according to the
requirements of the trial protocol); Selective hospitalization unrelated to the
worsening of adverse events (such as elective surgery); The scheduled treatment
or surgical procedure should be included in the entire trial protocol and/Or record
in the baseline data of the individual subject; Admitted solely for the use of blood

1.0 版
21
products.
Causing permanent or severe disability/loss of ability.
Causing congenital abnormalities/birth defects.
Other important medical events: defined as events that harm subjects or require
medical intervention to prevent the occurrence of any of the above situations.
7.3 Evaluation of Adverse Events
Researchers will evaluate all adverse events according to the NCI Common Terminology for
Adverse Events (CTCAE) version 5.0. Any adverse events that change the CTCAE level will be
recorded in the adverse event case report form/worksheet.
All adverse events, regardless of CTCAE level, must be evaluated for severity.
Various adverse events: Take timely measures to handle and record in the case report form.
Serious adverse events (SAE): Take timely measures to handle, record in the case report form,
decide to stop or reduce medication by the researcher, immediately report to the ethics committee,
drug clinical trial institution, and sponsor, and report to the national and provincial food and drug
regulatory authorities within 24 hours. SAE must log in to the "Non Responsibility Reporting
System for Adverse Events and Similar Errors within the Hospital" to report. Specific process: see
the following figure
Serious adverse events occur (requiring hospitalization, prolonged hospitalization, disability,
affecting work ability, endangering life or death, causing congenital malformations, etc.)

1.0 版
22