Toripalimab Plus Etoposide and Platinum-based Chemotherapy in First-line Treatment of Locally Advanced or Metastatic Genitourinary Small Cell Carcinoma：A Multicenter, Prospective, Open Label, Single-arm, Phase II Study
Phase: PHASE2
Conditions: Toripalimab, First-line Treatment
Sponsor: Sun Yat-sen University

Toripalimab plus etoposide and Platinum-based chemotherapy
in first-line treatment of locally advanced or metastatic
genitourinary small cell carcinoma：A multicenter, prospective,
open label, single-arm, phase II study
Research center：Sun Yat-sen University Cancer Center
Principal Investigator：Shi yanxia
Phone number：020-87343874
Version：1.0
Version date：2022.10.15
Sun Yat-sen University Cancer Center
2022.10.15

1
1 Background
1.1 Background
Small cell carcinoma of the urinary system is very rare, including bladder,
prostate, ureter, etc. Among them, small cell carcinoma of the bladder accounts for
about 1% of bladder tumors. According to the US SEER database, the incidence of
small cell carcinoma of the bladder is increasing, from 0.05/100,000 in 1991 to
0.14/100,000 in 2005[1].Most patients with small cell carcinoma of the bladder are
often at an advanced stage of the disease when they are diagnosed, and are prone to
distant metastasis. Compared with urothelial carcinoma, small cell carcinoma of the
bladder is more aggressive and has a worse prognosis[2]. Small cell carcinoma of the
prostate is a rare prostate tumor with high malignancy and strong invasiveness. About
50% of small cell carcinoma of the prostate is mixed with adenocarcinoma, and the
rest are pure small cell carcinoma.The effect of comprehensive treatment is not good,
and the median survival time is less than one year[3]. Small cell carcinoma of the
ureter is also very rare, accounting for about 0.5% of ureteral tumors. Its onset is
insidious, and it is usually advanced when it is diagnosed. The median survival time
varies greatly among different case reports.[4]. In summary, small cell carcinoma of
the urinary system is rare but has a poor prognosis.
Small cell carcinoma of the urinary system has no treatment recommendations
based on randomized clinical trials, only a few retrospective studies have explored
treatment options, and some experts believe that small cell carcinoma outside the lung
can be treated with similar chemotherapy regimens as small cell lung cancer[5],
Including the combination of etoposide and cisplatin (EP) regimen. Although patients
with metastatic small cell carcinoma of the bladder and small cell carcinoma of the
prostate can achieve a high response rate, the median survival time is only 7-13
months[6]. However, the remission period of patients is often very short-lived, most
patients will relapse after treatment, and the data on chemotherapy for small cell
carcinoma of the urinary system are limited. A prospective trial included 12 patients
with stage IV small cell carcinoma of the bladder at the time of diagnosis. These

2
patients received IA regimen (ifosfamide + doxorubicin) and EP regimen alternately,
and 3 patients completely recovered. Remission, and received surgical consolidation
therapy. Median OS in this cohort was 13 months, but only 1 patient remained
disease-free at 28 months after initial treatment[7].A French multicenter retrospective
study found that the first-line EP regimen in advanced metastatic patients had longer
overall survival than etoposide combined with carboplatin (EC) regimen[8], However,
only 3 patients received immunotherapy in this study, therefore, the role of
immunotherapy in SCBC remains to be further explored. The treatment of small cell
carcinoma of the prostate and small cell carcinoma of the ureter is mostly based on
case reports and analysis. Gene profile analysis has found that small cell carcinoma of
the prostate and small cell carcinoma of the bladder have certain similarities. Most of
them refer to small cell lung cancer for comprehensive treatment based on
radiotherapy and chemotherapy[9]. After EP treatment, there is no standard
maintenance treatment plan. Currently, there is no second-line recommended plan for
patients with disease progression after EP treatment. Some treatment centers have
published relevant treatment experience, but only case reports with a small sample
size[10]. Therefore, for patients with effective EP, the appropriate maintenance
regimen to delay disease progression needs further exploration.
Immunotherapy has been explored in urothelial carcinoma of the bladder and
small cell lung cancer. The KEYNOTE-045 study enrolled 542 patients with
advanced
urothelial
carcinoma
who
had
relapsed
or
progressed
after
prior
platinum-based chemotherapy, and compared the efficacy of pembrolizumab with
chemotherapy (paclitaxel, docetaxel, vinblastine) , the results showed that the median
OS of the pembrolizumab group was 10.3 months, and the ORR was 21.1%; the
median OS of the chemotherapy group was 7.4 months, and the ORR was 11.0%, the
differences were statistically significant[11]；The Checkmate-275 study found that the
second-line overall ORR of nivolumab in patients with advanced urothelial cancer
was 19.6%, and the median OS was 8.74 months[12]. PD-L1 monoclonal antibody
also has certain curative effect on patients with metastatic urothelial carcinoma, and

3
the median OS of atezolizumab second-line treatment is 7.9 months[13]. In the
exploration of first-line combination chemotherapy, PD-1 and PD-L1 immunotherapy
have also achieved encouraging results in urothelial carcinoma. At present, nivolumab,
pembrolizumab, and atezolizumab have been approved abroad for the first-line
treatment of metastatic urothelial carcinoma. However, no immunotherapy has been
explored in non-urothelial carcinoma. In extensive-stage small cell lung cancer,
chemotherapy
combined
with
PD-L1
monoclonal
antibody
(atezolizumab,
durvalumab) has been confirmed by a large number of studies to improve the overall
survival of patients[14, 15]. It has been confirmed by a large number of studies that it
can improve the overall survival of patients. Maintenance therapy with PD-L1
monoclonal antibody after combination therapy has filled the gap in maintenance
therapy for small cell lung cancer and is one of the major advances in the treatment of
small cell lung cancer in recent years. However, in small cell carcinoma outside the
lung, there is not much evidence for immune combination chemotherapy, and the
choice of immune checkpoint inhibitors needs further exploration. Toripalimab is a
PD-1 antibody independently developed by my country, which has been approved by
the Chinese FDA for the first-line and later-line treatment of recurrent and metastatic
nasopharyngeal carcinoma and melanoma[16, 17], Exploration of toripalimab in other
cancers such as esophageal cancer is underway[18].
According to the current domestic and foreign literature, immunotherapy
combined
with
chemotherapy
has
achieved
great
success
in
lung
cancer,
nasopharyngeal carcinoma and other tumor types, and other tumor types are also
exploring its efficacy through clinical trials. Therefore, this study aims to explore an
effective salvage chemotherapy regimen for small cell carcinoma of the urinary
system, using the standard EP regimen combined with toripalimab, which is expected
to increase the efficacy of the EP regimen and provide options for subsequent
maintenance therapy for patients. For patients whose EP regimen is effective,
toripalimab is used as maintenance therapy until disease progression or unacceptable
side effects, which further provides a new way to improve the curative effect of

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patients with small cell carcinoma of the urinary system.
1.2 Research Principles
According to the clinical dose data of triplatin, etoposide and cisplatin /
carboplatin in small cell cancer, we selected the doses of 240mg/, etoposide
100mg/m2, D1-3 and cisplatin 25mg/m2, D1-3 as the dose of this study, every 21
days as a course of treatment.
For patients with cisplatin intolerance, we use carboplatin instead of cisplatin.
The criteria for cisplatin intolerance are as follows:
(1) Renal dysfunction calculated serum creatinine clearance < 30-60mL/min
according to CG formula (Annex 2);
(2) ECOG score is 2;
(3) Hearing impairment: difficulty in communication due to hearing aids, or
hearing loss greater than 25 decibels twice in a row.
(4) Other concomitant diseases are not suitable for cisplatin chemotherapy.
Note: if the patient is accompanied by two or more of the above conditions, the
researchers need to evaluate in detail whether they can tolerate combined
chemotherapy.
For patients with cisplatin intolerance, EC regimen combined with toripalimab
was used for treatment, toripalimab 240mg/time, etoposide 100mg/m2, d1-3,
Carboplatin is calculated according to AUC=5 (ivgtt, d1) based on renal function
After entering the group, the patients were treated with triplizumab combined
with EP or EC for 4 to 6 courses, and the efficacy was evaluated by imaging every 2
courses. If there is a chance of local treatment, they will participate in a
multidisciplinary discussion to determine the next step of treatment. After local
treatment, they will continue to use triplizumab to maintain treatment until the disease
progresses or intolerable toxicity occurs, and the maximum duration of maintenance
treatment is 2 years. If the patient's efficacy was evaluated as complete remission
(CR), partial remission (PR) or disease stability (SD) after 4 to 6 courses of treatment,
maintenance therapy with triplizumab 240mg/ every 21 days until the disease

5
progressed or intolerable toxicity developed for up to 2 years. If the patient has
disease progression or intolerable side effects in the course of treatment, the patient
will be withdrawn from the group. The patients in the withdrawal group entered the
follow-up period.
1.3 Risk/Benefit
1.3.1 Risk
Subjects will receive toripalimab, etoposide, and cisplatin/carboplatin therapy
after enrollment. According to preclinical and clinical research reports and a large
number of clinical application evidences, treatment with toripalimab, etoposide,
cisplatin, and carboplatin may cause myelosuppression, hair loss, rash, peripheral
neurotoxicity, blurred vision, fatigue, and nausea , anemia, decreased appetite, fever,
diarrhea, constipation, vomiting, back pain, increased blood thyroid-stimulating
hormone, decreased white blood cell count, cough, itching, hypothyroidism,
decreased
appetite,
increased
blood
sugar,
and
increased
blood
bilirubin
,
transaminase elevation and other toxic reactions; in addition, due to possible leakage
of chemotherapy drugs during administration (varies from person to person), serious
adverse events such as skin damage or even necrosis around the injection port may
occur. During the trial, the researchers will closely monitor any adverse events and
risks that may occur to ensure that the subjects receive timely examination and
treatment, and if necessary, reduce or stop the use of related drugs, or even terminate
the subjects from continuing to participate in the trial.
1.3.2 Benefit
Subjects will receive good medical services during the study period. According
to relevant clinical research reports, subjects may benefit from drug effects such as
delayed disease progression and life extension, but we cannot guarantee or promise
that all subjects will benefit. In addition, if the subjects are successfully enrolled, they
will receive good medical treatment. After the subjects are successfully enrolled,
participating in this study will receive free medicines for all courses of toripalimab,
and the costs of chemotherapy drugs and related examinations will be borne by the

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subjects themselves.
2 Research purposes and assumptions
2.1 Research purposes
2.1.1 Main purpose
•To observe the curative effect of toripalimab, etoposide, cisplatin/carboplatin in
the treatment of small cell carcinoma of urinary system
2.1.2 Secondary Purpose
•To
observe
the
safety
and
tolerability
of
toripalimab,
etoposide,
and
cisplatin/carboplatin in the treatment of small cell carcinoma of the urinary system
2.2 Research Hypotheses
Test hypothesis: P0: the single-arm test group is invalid; P1: the single-arm test group
is effective.
3 Design
3.1 Design outline
3.1.1 Subject Population/Treatment Assignment
This study is a prospective, multicenter, open-label, single-arm phase II clinical
trial.
A
single-arm
experimental
group
of
toripalimab,
etoposide,
and
cisplatin/carboplatin was designed to evaluate its efficacy and safety in small cell
carcinoma of the urinary system.
After meeting the enrollment conditions, they received combination therapy:
toripalimab 240 mg, administered on the first day of each cycle, and a cycle of
administration every 3 weeks. Etoposide 100mg/m2, d1-3, cisplatin 25mg/m2, d1-3 or
carboplatin AUC=5 d1, administered on the first day of each cycle, a cycle of
administration
every
3
weeks.
Toripalimab
combined
with
etoposide
and
cisplatin/carboplatin was used for 4 to 6 courses of treatment. Evaluate the curative
effect with imaging every 2 courses. If there is an opportunity for local treatment after
chemotherapy, participate in multidisciplinary discussions to decide the next step of
treatment. For patients who can be treated with local treatment (surgery, radiotherapy)

7
after treatment, the investigator will receive maintenance treatment with toripalimab
240 mg/time, every 21 days, until the disease progresses or unacceptable toxicity
occurs. If the curative effect evaluation of the patient is complete remission (CR),
partial remission (PR) or stable disease (SD) after 4 to 6 courses of treatment,
maintenance therapy with toripalimab 240mg/time, every 21 days, until the disease
progression or intolerable toxicity. The maximum duration of maintenance treatment
is 2 years. Subjects who finished treatment entered the follow-up period and received
safety follow-up and survival follow-up.
3.1.2 Efficacy variables
3.1.2.1 Main Efficacy Parameters
• Progression-free survival (PFS)
3.1.2.2 Secondary Efficacy Parameters
• Complete Response Rate (CRR)
• Duration of Response (DOR)
• Objective Response Rate (ORR)
• Overall Survival (OS)
3.1.3 Security variable
• Adverse events and serious adverse events
• Symptoms and signs
• laboratory tests
• Treatment-emergent adverse events leading to dose adjustments, dosing
interruptions, delays, non-dosing, and/or study drug discontinuation
3.1.4 Assessment of Quality of Life
EQ-5D (Euro QoL five-dimensions questionnaire) and EORTC QLQ-C30
(European Organization for Research and Treatment of Cancer Quality of Life
Questionnaire
C30)
scale
and
Functional
Assessment
of
Cancer
Therapy
questionnaire were used to evaluate the quality of life.
3.2 Trial period
The trial is planned to be enrolled for 24 months and followed up for 12 months.

8
From the enrollment of the first subject to data analysis, the trial is expected to last for
36 months. During the trial, if the subjects do not stop treatment (see 11 for details),
they will receive 4-6 cycles of complete combined treatment and maintenance
treatment. Except for the occurrence of progression or death, the subjects should
complete the visit plan specified in the protocol.
3.2 Study endpoint
3.2.1 Efficacy Evaluation Criteria
Evaluation was performed according to Response Evaluation Criteria in Solid
Tumors (RECIST) version 1.1, see Appendix 1 for details.
3.2.2 Primary Endpoint
• Progression-free survival (PFS)
3.2.3 Secondary Endpoints
• Complete Response Rate (CRR)
• Duration of Response (DOR)
• Objective Response Rate (ORR)
• Overall Survival (OS)
• Safety and tolerability (type, frequency, severity, relationship of adverse events
to
study
treatment,
physical
examination,
vital
signs,
laboratory
tests,
concomitant medications/treatments, and dose adjustments)
• Patient's quality of life assessment
3.2.4 Exploratory Molecular Marker Research
The collected and preserved tumor samples (primary tumor and/or metastatic
tumor), blood, urine, and stool samples will be used for future exploratory research on
factors that may affect or predict efficacy (including efficacy and safety). The main
measurement contents are as follows (but not limited to):
Immune-related indicators: PD-L1 expression, etc.
Serological tumor markers (NSE, CEA, CA199, etc.)
Other biomarkers (SPARC, ERCC1, etc.), gene detection, homologous
recombination repair defect (HRD) detection, etc.

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3.3 Efficacy evaluation
3.3.1 Time for efficacy evaluation
Before drug administration in this study, after the 2nd, 4th, and 6th courses of
chemotherapy, and every 2 courses of maintenance, the curative effect evaluation was
performed, and all patients were required to undergo curative effect evaluation when
completing or withdrawing.
3.3.2 The means of evaluating the curative effect
Efficacy evaluation before administration, after the 2nd, 4th, and 6th cycles of
chemotherapy, and during maintenance therapy. Visceral lesions should be evaluated
by CT, MRI or PET-CT, and surface lesions should be evaluated by a physician's
physical examination and recorded in the original medical records as objective
evidence. Chest X-ray or B-ultrasound can be used to screen the suspected invasion
site, but CT, MRI or PET-CT must be used for evaluation after the lesion is
confirmed.
Because toripalimab is an immune checkpoint inhibitor, according to the
experience of similar drugs, some subjects will experience delayed or early tumor
pseudo-progression after receiving immunotherapy drugs. Therefore, this study
allowed subjects whose response assessment was indeterminate response (IR) to
continue treatment until PD was confirmed by the next imaging evaluation.
4
Experimental population
4.1 Clinical Trial Center
Sun Yat-sen University Cancer Center
4.2
Number of cases
Based on the characteristics of the population of patients with small cell
carcinoma of the urinary system and the statistical needs of the centers participating in
the trial, this trial is expected to enroll 33 subjects with small cell carcinoma of the
urinary system within 24 months.

10
4.3 Inclusion criteria
Patients should meet the following criteria to be enrolled in the trial:
1) Participate voluntarily and sign the informed consent;
2) Age ≥18 years old;
3) Life expectancy ≥3 months;
4) Physical condition score ECOG 0-2;
5) Pathologically diagnosed as genitourinary small cell carcinoma (recommended
central consultation for difficult pathology), including small cell carcinoma
primary in the kidney, ureter, bladder, urethra, and prostate. The stage is locally
advanced or advanced (stage IIIA or above, that is, cT3 or above N0 M0, or
cT1-4a N1-3 M0, or cT4b any N M0, or any T any N M1), or the investigator
judges that local treatment is not suitable for the time being (surgery, radiotherapy)
patients.
6) Patients whose pathology is mixed small cell carcinoma can be included, and
the small cell carcinoma component is ≥50%.
7) Have not received systemic treatment before, or the time interval from the last
adjuvant treatment is more than 6 months;
8) There are measurable or/and evaluable lesions (non-radiotherapy target areas)
(lesion evaluation according to Recist1.1 standard);
9) No serious organ (main organs: heart, lung, liver, kidney) dysfunction (refer to
the respective standards);
10) Blood routine indicators: white blood cell (WBC) ≥3 × 109/L; absolute
neutrophil count (ANC) ≥1.5 × 109/L; platelet (PLT) ≥100 × 109/L;
hemoglobin (Hgb) ≥8g /dL;
11) Blood biochemical indicators: AST (SGOT), ALT (SGPT) ≤2.5 × upper
limit of normal value (ULN) (in the case of no liver invasion) or ≤5 × upper
limit of normal value (ULN) (in the case of liver invasion ); total bilirubin (TBIL)
≤ULN; serum creatinine clearance calculated according to the CG formula > 30
mL/min

11
12) Coagulation function: prothrombin time (PT), international normalized ratio
(INR) ≤1.5 × ULN (unless warfarin is being used for anticoagulation);
13) Able to comply with the research visit plan and other program requirements;
14) All patients of childbearing age must agree to take effective contraceptive
measures during the study period and within 6 months of stopping treatment, and
the urine pregnancy test of female patients of childbearing age must be negative
before treatment.
4.4
Exclusion Criteria
Patients will be excluded from this study if they meet any of the following
criteria:
1) Received treatment for small cell carcinoma of the urinary system within 2 weeks
before enrollment;
2) Once diagnosed with prostate adenocarcinoma, received endocrine therapy (such as
enzalutamide, apalutamide, abiraterone, etc.) and chemotherapy (docetaxel) for
prostate adenocarcinoma, and is currently considering neuroendocrine differentiation
of prostate cancer ;
3) Mixed small cell carcinoma, in which the small cell carcinoma component is less
than 50%.
4) Medical history and comorbidities:
[1] Anti-tumor vaccine or cellular immunotherapy has been used before the first dose
of the study drug;
[2] Previously received systemic therapy for metastatic lesions;
[3] The patient is participating in other interventional clinical studies or less than 4
weeks before the end of the previous clinical study;
[4] Those who have been less than 4 weeks away from the last anti-tumor treatment
(radiotherapy, chemotherapy, targeted therapy, immunotherapy or local-regional
treatment). The adverse reactions related to anti-tumor treatment (except hair loss)
after the previous systemic anti-tumor treatment have not recovered to NCI-CTC AE

12
≤level 1;
[5] Live vaccines have been vaccinated within 4 weeks before administration of the
study drug. Inactivated virus vaccines for seasonal influenza and injection are allowed,
but attenuated live influenza vaccines for intranasal administration are not allowed;
[6] The subject has any active, known or suspected autoimmune disease. Subjects
who are in a stable state and do not require systemic immunosuppressant therapy are
allowed to be enrolled;
[7] Subjects who required systemic treatment with corticosteroids (>10 mg/day of
prednisone or equivalent doses of other glucocorticoids) or other immunosuppressants
within 14 days before the first dose of study drug. Steroid replacement with inhaled or
topical steroids and curative doses of prednisone at doses > 10 mg/day is permitted in
the absence of active autoimmune disease;
[8] Patients with a known history of interstitial pneumonia or highly suspected
interstitial pneumonia; or patients who may interfere with the detection or treatment
of suspected drug-related pulmonary toxicity;
[9] Other active malignant tumors that require simultaneous treatment;
[10] Has a history of malignant tumors. Patients with basal cell carcinoma of the skin,
superficial bladder cancer, squamous cell carcinoma of the skin, or cervical carcinoma
in situ who underwent potentially curative therapy and had no disease recurrence
within 5 years from the end of treatment were excluded.
[11] Known history of organ transplantation and allogeneic hematopoietic stem cell
transplantation;
[12] Subjects who have undergone major surgery or severe trauma have less than 14
days before enrollment;
[13] Patients with active pulmonary tuberculosis should be excluded. Patients
suspected of having active pulmonary tuberculosis should be checked for chest X-ray,
sputum, and ruled out by clinical symptoms and signs. Patients with a history of
active tuberculosis infection within the previous 1 year, even if treated, should be
excluded; patients with a history of active tuberculosis infection more than 1 year ago

13
should also be excluded. Unless it is proven that the duration and type of
antituberculosis treatment previously used was appropriate;
[14] Severe acute or chronic infection requiring systemic therapy
[15] Heart failure (New York Heart Association Class III or IV) despite appropriate
medical therapy. Patients with poorly controlled coronary artery disease or poorly
controlled arrhythmia, or a history of myocardial infarction within 6 months prior to
screening.
5) Neutrophil count <1.0× 109/L, or hemoglobin <80g/L, or platelet count <90×
109/L. Hepatic insufficiency not related to tumor (transaminase more than 3 times the
upper limit of normal value and/or blood bilirubin greater than 2.0mg/dl). Renal
insufficiency not related to tumor (serum creatinine clearance <30 mL/min calculated
according to the CG formula).
6) Known history of positive human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS);
7) Untreated active hepatitis (hepatitis B: HBsAg positive and HBV DNA ≥
500IU/mL; hepatitis C: HCV RNA positive and abnormal liver function); co-infected
with hepatitis B and C;
8) Allergy to any study drug;
9) Pregnant and breastfeeding women;
4.5 Rejection criteria
For those who have been selected into this clinical study and fall into one of the
following situations, they will be counted as excluded cases:
1) After the subjects are selected, it is found that there are cases that do not meet the
case selection criteria;
2) Those who have taken less than 2 consecutive medications after being selected, and
cannot evaluate the objective curative effect (but can evaluate adverse reactions);
3) Patients who violate the requirements of the trial protocol.

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4.6 Exit Criterion
Patients can withdraw from clinical trials at any time and for any reason. When
the researchers think that it is not appropriate to continue the drug, they can also ask
the patient to withdraw from the interest of the patient.
If one of the following situations occurs to the subject during the trial, the investigator
should arrange for the subject to discontinue treatment and withdraw from the trial:
1) The subject's compliance is poor, and the medication cannot be taken on time and
in the right amount;
2) The use of other anti-tumor treatments affects the judgment of the results;
3) Adverse reactions occur, and the investigator judges that it is not appropriate to
continue this clinical study;
4) The subject is unwilling to continue the clinical study and withdraws voluntarily.
Before withdrawing from the trial, the latest follow-up and evaluation of various
indicators of efficacy and adverse reactions must be completed, and the reason and
date of withdrawal of the withdrawn patient must be recorded in detail.

15
5 Research Flow Chart
project
Baseline assessment
before enrollment
(within 2 weeks
before enrollment)
Toripalimab combined with etoposide,
cisplatin/carboplatin therapy
(1-6 courses of treatment)
Inspection at the end of 2, 4, 6
courses of combined treatment
Toripalimab
maintenance therapy
Imaging examination
X
X
X
Pathological
examination/consultation
X
eligibility criteria
X
Sign the informed consent
X
Demographics
X
Detailed
medical
history
and
complete physical examination
X
X
X
X
Clinical biochemistry, urine, and
stool laboratory tests
X
X
X
X
routine blood test
X
X
X
X
serum tumor markers
X
X
X
X
urine pregnancy test
X
electrocardiogram
X
X
X
X
tumor specimen
X
Blood
samples,
urine
samples,
stool samples
X
X
X
ECOG score
X
X
X
X
Abdomen, pelvis, chest CT/MRI
or PET-CT
X
X
X
Etoposide,
cisplatin/carboplatin
administration
X

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Administration of toripalimab
X
X
Adverse event
X
X
X
Accompanying treatment records
X
X
X
quality of life assessment
X
X
X
Confirmation
of
tumor
progression and survival status
X
X
X

17
6 Research Steps
6.1 Screening
The researchers gave informed consent to the subjects who met the enrollment
conditions, and only when the subjects signed the latest version of the informed
consent form could the next step of the research be carried out.
According to the inclusion/exclusion criteria of the protocol, the researchers
conducted or approved imaging data (tumor histopathology, abdominal and pelvic
CT/MRI plain scan + enhancement, endoscopic ultrasonography can be used as a
supplementary method of CT, PET/ CT scan is not used as a routine method) to
evaluate the tumor characteristics of the subjects. The evaluation content includes
tumor location, number, size, degree of invasion of large blood vessels, tumor
thrombus, extent of invasion of surrounding tissues, etc., and needs to be recorded in
the medical record. If the imaging examination cannot be obtained or is not
recognized by the researcher within two weeks before the subject's enrollment, it is
recommended that he undergo another CT in our hospital, and the researcher will
re-evaluate and record according to this examination.
6.2 Baseline
Prior to enrollment, the following will be reviewed to ensure inclusion/exclusion
criteria are met and baseline data obtained:
• Chest + abdomen + pelvic CT (plain scan + enhanced)
• Blood tumor markers
• Tumor histopathology or cytology
•
If the subject has relevant abnormal clinical symptoms or signs, and the
investigator suspects that it is caused by distant metastasis of the tumor, relevant
imaging examinations and/or laboratory examinations may be performed:
○Suspect brain and nervous system metastases, MRI examination
○Skeletal invasion is suspected, and ECT examination is performed
•
Blood
routine,
urine
routine,
stool
routine
+
occult
blood
test,
electrocardiogram

18
•
Liver function (AST, ALT,
γ -glutamyl transpeptidase, total bilirubin,
albumin, prealbumin), renal function (creatinine), electrolytes, blood glucose, blood
amylase
• Clotting function (prothrombin time)
• Urine pregnancy test (female subjects of childbearing potential)
• Vital signs, height, weight, physical examination
• ECOG score
• Collect the subject's past diabetes, treatment history, and allergy history, and
record them in the medical record
According to the imaging report, combined with other laboratory tests and
symptoms and signs, the researcher judges whether the subject has disease
progression, and records it in the medical record.
6.3 Enter the group
According to the inclusion/exclusion criteria, the investigators will judge
whether the subjects meet the enrollment conditions based on the results of the
baseline examination, third-party imaging and pathological results(test code). For
successfully enrolled subjects, the researchers need to obtain a copy of their ID card
for archiving.
6.4 Treatment
6.4.1 Treatment execution
After successful screening of subjects, the dosing plan is shown in Table 1. The
first dose of study drug will be administered within 72 hours of enrollment. All
patients will be continuously monitored for adverse events. Treatment revisions (eg,
dose withholding, reduction, interruption, or discontinuation) will be based on
specific laboratory and AE criteria. In each cycle, toripalimab will be given before
chemotherapy drugs.
Patients should receive antiemetics according to local standard treatment and
manufacturer's instructions. Because of the immunomodulatory effects of steroids,
their use as prechemotherapy should be limited when clinically feasible. It is

19
recommended to use the standard antiemetic regimen, and the optional antiemetic
drugs include 5-HT3 receptor antagonists alone or in combination with NK-1 receptor
antagonists (fosaprepitant, aprepitant, etc.), determined by the investigator .
In exceptional circumstances (e.g., dosing is withheld due to the need to manage
an AE or infusion-related reaction), dosing of subsequent study drug may be delayed
until the second day of each cycle.
Table 1 Dose selection and administration time for each patient
Table 1A Doses of cisplatin if tolerated
Study Drug
dosage
frequency of dosing
Route
of
administration
Toripalimab
240mg
Day 1 of each 21-day cycle
IV drip
Etoposide
100mg/m2
Day 1 to Day 3 of each 21-day cycle
IV drip
Cisplatin
25mg/m2
Day 1 to Day 3 of each 21-day cycle
IV drip
Table 1B Doses when cisplatin is not tolerated
Study Drug
dosage
frequency of dosing
Route
of
administration
Toripalimab
240mg
Day 1 of each 21-day cycle
IV drip
Etoposide
100mg/m2
Day 1 to Day 3 of each 21-day cycle
IV drip
Carboplatin
AUC 5
Day 1 of each 21-day cycle
IV drip
6.4.2 Cycle Time Settings
In this experiment, 4-6 courses of chemotherapy were used. Relevant inspections
were required before and after each course of treatment to evaluate safety events, and
imaging review was performed every 2 courses of treatment during the course of
treatment. After 4-6 courses of treatment, if there is no disease progression or
unacceptable
toxicity,
maintenance
treatment
will
be
initiated,
and
imaging
reexamination will be performed every 2 courses during the maintenance treatment to
evaluate the disease progression. For patients who are evaluated by the investigator

20
for local treatment (surgery, radiotherapy) after treatment, maintenance treatment can
be started after the end of local treatment.
6.4.3 Pre-treatment operation
The following operations need to be completed within one week before
medication:
• Chest, abdomen, pelvic CT (plain scan + enhanced)
• Blood tumor markers
•
Blood
routine,
urine
routine,
stool
routine
+
occult
blood
test,
electrocardiogram
•
Liver function (AST, ALT,
γ -glutamyl transpeptidase, total bilirubin,
albumin, prealbumin), renal function (creatinine), electrolytes, blood glucose, blood
amylase
• Clotting function (prothrombin time)
• Urine pregnancy test (female subjects of childbearing potential)
• Vital signs, height, weight, physical examination
• ECOG score
•
Collect subjects' previous diabetes history, treatment history, and allergy
history, and record them in medical records
6.4.4 Treatment administration
The subjects were administered according to the prescribed cycle. The
researchers decided whether to administer chemotherapeutic drugs and to adjust the
dosage according to the subjects' previous treatment and pre-medication laboratory
test results. When the subject has intolerable chemotherapy toxicity, the investigator
can reduce or stop the administration of chemotherapy (refer to the dose adjustment
regulations), but the investigator needs to record the reason for the reduction or
withdrawal in the medical record.
Common toxicities of chemotherapy drugs include nausea, vomiting, abdominal
pain, diarrhea, decreased blood cells (WBC, RBC, PLT, ANC, etc.), abnormal liver

21
and kidney function. If leakage occurs during the administration of chemotherapy
drugs, it may cause skin damage or even necrosis. Any adverse event that occurs
during the study, regardless of whether it is related to the study drug or not, should be
monitored and treated accordingly and recorded truthfully in the medical record.
6.4.5 Post-treatment inspection
Relevant laboratory tests need to be completed after the end of the study drug
(can overlap with the next pre-treatment test):
•
Blood
routine,
urine
routine,
stool
routine
+
occult
blood
test,
electrocardiogram
•
Liver function (AST, ALT,
γ -glutamyl transpeptidase, total bilirubin,
albumin, prealbumin), renal function (creatinine), electrolytes, blood glucose, blood
amylase
• Clotting function (prothrombin time)
• Blood tumor markers
6.5 Follow up
After the subject received the study drug treatment (the end of the course of
treatment or early termination due to any reason, except for death), CT was
re-examined every 2 courses of treatment (6 weeks) during the medication period; CT
was re-examined every 3 months after drug withdrawal until the disease relapsed ,
progression or metastasis, and then changed to telephone visits for survival follow-up,
every 3 months until the death of the patient or the second study analysis of the trial
(whichever occurs earlier). Tumor progression and death events need to be recorded,
as well as concomitant related treatments. All anti-cancer treatments received by the
subjects before death shall be recorded in the follow-up records.
6.6 Clinical Trial Completion
Before the second study analysis condition is met, the subject has a
progression/death event, and the trial is considered to be completed. When the

22
conditions for the second analysis are met, no recurrence/transfer/death occurs, and
the trial is also considered to be completed. The test completion time is stipulated as
follows:
•
If a progressive condition has occurred but study drug was not stopped
immediately, the last time study drug was given is the completion date of the study
• If the experiment was terminated because the second analysis was reached, fill
in the date of completion of the experiment, which is the time when the second
analysis was reached
• In case of death, the date of completion of the trial is the time of death of the
subject
6.7 Discontinuation of the trial visit
Once a trial-terminating event occurs, the following assessments should be
completed at the same time as withdrawal, if possible. If the subject terminates the
trial due to an adverse event, the subject needs to be followed up as much as possible
until the investigator determines that the adverse event has recovered, stabilized, or
cannot be changed.
The following procedures will be performed at the termination trial visit:
• The investigator must inform the subjects that they need to withdraw from the
trial and the reasons for withdrawal
• Record in detail the reason for the subject's early withdrawal from the trial and
the date of withdrawal in the scientific medical record and case report form (CRF)
• A safety assessment is required, including:
○Physical examination
○Weight and vital signs
○
Blood routine, urine routine, stool routine + occult blood test,
electrocardiogram
○Blood tumor markers
○Liver and kidney function, prothrombin time

23
○ECOG score
○Concomitant medication and adverse event report
• Regular follow-up of subjects by investigators or authorized persons
How to record when the trial was terminated:
• Terminate test on date of positive urine pregnancy test if pregnancy occurs
•
If the combined treatment violates the protocol, the trial date will be
terminated with the start date of the combined treatment
•
If
due
to
adverse
events
or
non-compliance,
the
subject's
last
imaging/laboratory evaluation date in the study will be the termination time of the
trial
• If the subject is lost to follow-up, the trial will be terminated on the date of the
last follow-up with clear survival information
• If the subject or his legal representative requests or should withdraw from the
study at the specific request of the research party, the date when the subject or his
legal representative or the research party makes the request shall be the termination
time of the trial
6.8 Plan deviation
Researchers should conduct research in accordance with the protocol and
corresponding laws and regulations. Prior to implementing protocol deviation
operations, written approval from the principal investigator is required.
The protocol deviation should be documented and explained by the investigator
or authorized personnel. If the subject is not eligible for enrollment or receives the
wrong dose of trial treatment, and has used the study drug at least once, for the sake
of safety, it is necessary to collect relevant data and notify the ethics committee of the
deviation according to relevant procedures.
6.9 Lab test
During the test, blood, urine, and feces samples were collected multiple times
before each cycle of medication. The following specific parameters need to be

24
determined:
• WBC/ANC/RBC/PLT/Hb
•
Aspartate
aminotransferase/alanine
aminotransferase/gamma-glutamyl
transpeptidase/total bilirubin/albumin/prealbumin/electrolytes/creatinine
• Prothrombin time
• CA19-9 and other tumor markers
• Blood tumor markers
• Routine urine/stool + occult blood test
• Glucose/amylase
• urine pregnancy test
All laboratory examinations are carried out in the Laboratory Department of the
hospital, and the relevant procedures of the hospital are followed, and the inspection
reference values of the hospital are used as the reference for examination indicators.
The investigator must review the results and sign off. For laboratory results to be
clinically significant, they must be reported as medical history or adverse events.
6.10 Imaging examination
Re-examination of imaging examination is required before every 2 cycles of
treatment, and re-examination every 3 months after the end of medication. include:
• Chest + abdomen + pelvic CT (plain scan + enhanced)
7 Experimental drug
7.1 Experimental Drugs and Preparations
7.1.1.
Toripalimab
Toripalimab is a monoclonal antibody in the form of intravenous injection in a
single-use vial containing 6mL of solution containing a total of 240mg of antibody.
7.1.2
Etoposide
Etoposide is a cytotoxic drug, which is in the form of intravenous injection and
packed in single-use vials, each bottle contains 5mL solution and 100mg drug.
7.1.3
Cisplatin

25
Cisplatin is a cytotoxic drug, it is in the form of intravenous injection, and it is
packed in a single-use medicine bottle, each bottle contains 6mL solution and 30mg
drug.
7.1.4 Carboplatin
Carboplatin is a cytotoxic drug, which is in the form of intravenous injection,
packed in single-use vials, each bottle contains 10mL solution and 100mg drug.
7.2 Labeling and Packaging
Etoposide, cisplatin, carboplatin, and toripalimab are already on the market, and
the labels and packaging are the same as the product specifications. The label is
printed with the following marks: [drug name], [drug number], [serial number],
[product batch number], [expiration date].
7.3 Storage conditions
Investigators are responsible for the drug counts in clinical trials. All test drugs
must be stored according to relevant standards and meet temperature control
requirements.
8 Treatment and Restraint
8.1 Treatment
8.1.1 Treatment rules and duration
Before the progress of the subject, the subjects must take the medication
according to the protocol until the completion of the course of treatment, and
follow-up as required after the course of treatment until the end of the second research
analysis.
After the progress of the subject, the investigator will decide whether to continue
the experimental drug treatment according to the condition of the subject, and if
continue to use the experimental drug. Can be stopped at any time before the end of
the trial at the investigator's discretion. After the course of treatment is over, the
subjects do not need to continue to use the study drugs as required.

26
8.1.2 Dosage adjustment
Dose withholding was defined as an interruption of the treatment regimen (i.e.,
delaying drug administration beyond the visit window). Dose interruption was defined
as infusion interruption.
Every effort should be made to administer study drug according to the planned
dose and schedule. In the event of severe toxicity, dosing may be delayed and/or
reduced according to the guidelines outlined below. Reasons for dose adjustments or
delays, supportive measures taken, and outcomes will be documented in the patient's
medical record.
The dose adjustment guidelines in this section are not a substitute for clinical
judgment. The investigator may temporarily suspend or adjust the dose due to other
reasons (such as adverse events, weight loss, laboratory findings).
Dosing interruptions were permitted if due to medical/surgical events or
logistical reasons unrelated to study treatment (eg, unrelated medical events, patient
leave, and/or vacation). However, patients are advised to continue study treatment
within 3 weeks of planned discontinuation.
8.1.2.1
General Guidance Regarding Dose Adjustments
Dosage adjustments for toripalimab and etoposide, cisplatin, and carboplatin
should be made according to the prescribing information and local practice, based on
the clinical judgment of the treating physician (Table 2).
• For AEs that have occurred at baseline, dose adjustments will be made based
on changes in toxicity grade, at the investigator's discretion. For example, if
a patient had Grade 1 asthenia at baseline and it rose to Grade 2 during
treatment, it would be considered a change from Grade 1, and the dose
adjustment would be aimed at downgrading to Grade 1 toxicity.
• When several toxicities of varying severity occur concurrently, dose
adjustments should be based on the highest level observed.
−If the investigator believes that the toxicity is due to only one part of the
study treatment, and the dose of this part has been suspended or adjusted

27
according to the following guidelines, the other part can continue to be
administered if there are no contraindications.
−If chemotherapy-related toxicity occurs, chemotherapy will be withheld
until the toxicity reaches baseline or ≤Grade 1 (whichever is more severe)
before the next dose of chemotherapy. Except for hair loss, grade 2 fatigue,
or other adverse events that the investigator believes will not affect the
safety assessment of the study drug. Toripalimab should continue to be
administered as planned. If the AE resolves within 10 days, chemotherapy
will be administered. Dosing of chemotherapy and toripalimab will be
resynchronized in the next cycle, which will be scheduled according to the
chemotherapy dose administration dates. If the AE does not resolve within
10 days, no chemotherapy will be given for this cycle. If the AE resolves
within 21 days, chemotherapy and toripalimab will be administered as
originally scheduled on Day 1 of the next treatment cycle.
−If toripalimab-related toxicity occurs, toripalimab dosing will be withheld.
The next dose of toripalimab could not be continued until the toxicity
reached baseline level or ≤grade 1 (whichever was more severe). Except
for hair loss, grade 2 fatigue, or other adverse events that the investigator
believes will not affect the safety assessment of the study drug.
Chemotherapy should be carried out as scheduled. If the AE resolves within
10 days, toripalimab will be administered. Dosing of chemotherapy and
toripalimab will be resynchronized in the next cycle, which will be
scheduled according to the chemotherapy dose administration dates. If the
AE did not resolve within 10 days, toripalimab should not be administered
during the current cycle. If the AE resolves within 21 days, toripalimab and
chemotherapy will be continued as originally planned on the first day of the
next treatment cycle.
8.1.2.2
Suspension or dose adjustment of toripalimab

28
The dose of toripalimab was not reduced in this study.
If the patient develops toxic side effects that are considered to be related to
toripalimab, and the drug needs to be suspended, the study treatment can be
temporarily suspended. If the dosing delay is ≤10 days, toripalimab will be
administered. If the hold-off is longer than 10 days, toripalimab will be omitted for
this cycle and the next cycle will be administered as planned as long as the AE
resolves within 21 days.
Patients should resume toripalimab treatment as soon as possible after the
adverse event resolves to baseline levels or grade 1, whichever is more severe, and
within 12 weeks of the last dose of toripalimab . If a patient cannot resume
toripalimab within 12 weeks of the last dose of toripalimab, the patient should
discontinue treatment.
If the patient meets the discontinuation criteria, but is still able to benefit from
the study treatment, the study treatment can be resumed.
Dose adjustments for irAEs and infusion-related reactions are described in
Appendix 3 and Section 10.3.6, respectively.
8.1.2.3
Dose suspension, interruption, or modification of etoposide, cisplatin,
and carboplatin
Dose adjustment guidelines for etoposide, cisplatin, and carboplatin, as described
below, depend on the severity of the toxicity and the risk-benefit assessment for the
patient, with the goal of maximizing patient compliance and access to supportive care.
The required etoposide, cisplatin, and carboplatin doses were calculated using
baseline body weight. If a patient's weight changes ≥10% from baseline (the newly
recorded weight will be the new baseline weight), a dose adjustment will be required.
If the weight change is <10%, no chemotherapy dose adjustment is necessary.
Study drug-related toxicity must subside to baseline levels or ≤Grade 1
(whichever is more severe) before the next dose, except for hair loss or Grade 2
fatigue or other adverse events that the investigator believes will not affect the safety
evaluation of the study drug .

29
During the treatment, if the patient develops severe neutropenia (ANC<0.5x
109/L for 1 week or more), the treatment dose of the subsequent course of treatment
should be reduced by 20%. If the above-mentioned severe neutropenia occurs again,
then reduce the subsequent treatment dose by 20%-25%. If the chemotherapy drug
has been suspended for more than 2 cycles (6 weeks) from the expected treatment
date, or if 2 doses are reduced into intolerance, the chemotherapy regimen should be
permanently stopped (as shown in Table 3).
Table 2 Guidelines for Dose Adjustment Levels
Starting dose
Dose level-1
Dose level-2
Dose level-3
Toripalimab
240mg
not allowed
not allowed
not allowed
Etoposide
100mg/m2
Decrease
20%-25%
Decrease
20%-25%
stop drug
Cisplatin
25mg/m2
Decrease
20%-25%
Decrease
20%-25%
stop drug
Carboplatin
AUC 5
Decrease
20%-25%
Decrease
20%-25%
stop drug
Table 3 Chemotherapy dose adjustments for cytotoxicity of etoposide, cisplatin, and
carboplatin
adverse events
treatment
neutropenia
grade 3
(0.5-0.99×109/L)
Chemotherapy withheld until recovery to ≤Grade 1 (≥1.5 x
109/L); restart at full dose
grade 4
1. Chemotherapy withheld until recovery to ≤grade 1; all

30
(＜0.5×109/L)
(for 1 week or more)
subsequent doses reduced by 1 dose level
2. If it occurs for the second time after the dose reduction, the
subsequent doses are all reduced by 1 dose level
3. If the third time occurs, stop chemotherapy.
Thrombocytopenia
grade 2
1. Chemotherapy withheld until back to normal; restart at full
dose
≥grade 3
1. Chemotherapy withheld until recovery to ≤grade 1; all
subsequent doses reduced by 1 dose level
2. If it occurs for the second time after the dose reduction, the
subsequent doses are all reduced by 1 dose level
3. If the third time occurs, stop chemotherapy.
Renal insufficiency
≥grade 3
1. Chemotherapy withheld until recovery to ≤grade 2; all
subsequent doses reduced by 1 dose level
2. If it occurs for the second time after the dose reduction, the
subsequent doses are all reduced by 1 dose level
3. If the third time occurs, stop chemotherapy.
Note: The investigator may decide to use supportive measures/treatment and/or secondary
prevention in the next cycle instead of lowering the dose if the patient's best interest is considered
and consistent with local practice. Dose adjustment recommendations are provided for
informational purposes only.
8.1.3 Treatment Allocation and Blinding
8.1.3.1 ID code
After the subjects sign the informed consent form, the researcher will assign an

31
identification code to them according to the order of enrollment. The code consists of
3 digits and represents the serial number of the subject. The researcher will fill in the
identification code in the "Subject Identification Code Table" and save. This test is an
open study without blinding.
8.1.3.2 Enrollment randomization
All subjects in this trial were included in the single-arm trial group, and no
randomization control was required.
8.1.4 Compliance Control
In this trial, all subjects were required to return to the hospital as scheduled to
complete all medication cycles and related inspections in accordance with the
requirements of the protocol. The number of drug cycles, the amount and duration of
the test drug actually received by the subject in each cycle, and the reasons for
violating the treatment plan should be recorded in the original medical records and
CRF to judge the compliance of the subject. The researchers need to maintain close
contact and communication with the subjects, and try to explain the subjects' doubts
about any medical operation and medical event during the research process. At the
same time, inform that low compliance may be required to withdraw from the trial to
improve the compliance of the subjects.
8.2 Experimental constraints
8.2.1 Permitted concomitant medications and treatments
• Can receive usual standard supportive care
• Acceptable treatment for any underlying medical condition (including diabetes)
8.2.2 Prohibited concomitant medications and treatments
• No other clinical investigational drugs are allowed during the study
• Chemotherapy drugs other than those specified in this protocol are not allowed to
be used during the study
• Other systemic anti-tumor treatments are not allowed before progression, including
chemotherapy, radiotherapy, radiofrequency ablation, molecular targeted therapy, etc.
8.2.3 Necessary concomitant medications and treatments

32
• Correspondingly sensitive antibiotics must be used in case of infection
• For information on other drugs that may interact with the study drug and affect its
metabolism, pharmacokinetics, or excretion, refer to the relevant drug leaflet
• Any concomitant medication or treatment during the study should be accurately
documented in the medical record and CRF
8.2.4 Subject constraints
• Must return to the hospital on time to complete all inspections and laboratory tests
required by the plan
• Cannot leave the hospital during inpatient treatment
• Need to promptly report any discomfort to the investigator
• Women of childbearing age are required to take appropriate contraceptive measures
throughout the treatment period of the trial and for 6 months after the end of the trial.
9 Treatment Evaluation
9.1 Screening Period Evaluation
Enrollment assessments must be completed within 14 days prior to study drug
administration. After obtaining informed consent, the investigator will conduct a
corresponding clinical assessment of the subject (see 6.1 and 6.2).
9.2 Evaluation during treatment
Corresponding clinical assessments (see 6.4.4 and 6.4.6) are required for the
subjects before the start of each treatment cycle and within 3 days after the
completion of the treatment cycle, so as to make a correct efficacy assessment (see
below).
9.3 Efficacy Evaluation
9.3.1 Efficacy variables
• see 3.4.3
9.3.2 Procedure description
• see 3.2.2
9.4 End of Study Treatment (EOT) Assessment

33
An EOT assessment should be performed on all patients who complete study
treatment, and the following procedures will be completed:
• Physical examination, weight, vital signs, ECOG score
• Concomitant medications and concomitant therapy evaluation
• Serum EBV DNA copy number
• Blood routine, liver and kidney function, blood sugar
• Imaging studies based on follow-up time
• Evaluation for peripheral neuropathy
• Assessment of adverse events (see 10.3)
9.5 Follow-up of disease recurrence and metastasis
See 6.5, 6.6, 6.7
9.6 Follow-up of overall survival
See 6.5, 6.6, 6.7
10 Safe variables
10.1 Variables and Procedure Descriptions
• Symptoms and signs
• laboratory tests
• Adverse Events (AEs) and Serious Adverse Events (SAEs)
Any abnormal symptoms, signs (including laboratory test results with clinical
significance) or medical diagnosis recorded by the medical staff from the enrollment
to the trial drug treatment of the subjects must be recorded in the medical records and
CRF.
After enrollment, the researchers need to conduct corresponding laboratory tests
according to the protocol, and record the results in the medical records and CRF.
Abnormal results with clinical significance should be recorded as adverse events.
10.2 Symptoms and signs
10.2.1 Medical History and Concomitant Medications

34
A complete medical history of the subject needs to be recorded. All concomitant
medications from the first day of cycle 1 to 30 days after the last use of the test drug
need to be recorded, including changes in dosage and reasons for use, etc.
10.2.2 Physical examination and weight
A complete physical examination should include, but is not limited to, evaluation
of the vital organs of the body:
• Head, ears, eyes, nose, throat
• Lungs and respiratory system
• Cardiovascular System
• Gastrointestinal system
• Central Nervous System
• skin
• lymphatic system
• musculoskeletal system
• Endocrine and metabolic system
All discrepancies from the baseline examination should be documented in the
medical record and CRF.
10.2.3 ECG
ECGs were performed before and after each treatment cycle, including a
baseline ECG assessment prior to the first treatment cycle. Any clinically significant
change from baseline should be reported as an adverse event and recorded in the
subject's medical record and CRF.
10.2.4 Imaging examination
Imaging evaluations, including CT scans, should be performed according to
protocol requirements, including baseline CT examinations before the first treatment
cycle. Any clinically significant change from baseline should be reported as an
adverse event and recorded in the subject's medical record and CRF. If additional
imaging evaluations are performed as part of the subject's routine examination, they
will also need to be evaluated and determined to be an adverse event.
10.3 Adverse Events

35
10.3.1 Definition
Any undesired treatment-related or unrelated medical event after the use of a
drug by a subject in a clinical trial is an adverse event. It can be any unfavorable and
unexpected signs, symptoms, abnormal results of laboratory tests, whether related to
drugs or not. All adverse events should be recorded in the CRF form. The intensity of
adverse events was graded according to the grading method recommended by the NCI
Common Toxicity Criteria Grading System.
During site visits, clinical monitors must systematically collect and verify
information on adverse events when reviewing patients' clinical records (raw data
check). Unresolved adverse events at the time of assessment require continued
follow-up until resolution. For adverse events that cannot be resolved during the
clinical possible observation period (such as blindness, neurotoxicity, loss of limbs,
etc.), the investigators will rate them as permanent unresolved events, and the
resolution time of the event in the CRF table will be left blank.
10.3.2
Adverse Event Correlation
Investigators should evaluate the possible association between adverse events,
study drugs and combined drugs, and evaluate according to the following 5-level
classification criteria:
(1) Definitely related: the reaction appears in a reasonable time sequence after
administration, and the reaction conforms to the known reaction type of the suspected
drug; it improves after stopping the drug, and the reaction reappears after repeated
administration.
(2) Possibly related: the reaction appears in a reasonable time sequence after
administration, and the reaction is consistent with the known reaction type of the
suspected drug; the patient's clinical status or other treatment methods may also
produce the reaction.
(3) Possibly irrelevant: the reaction does not conform to the reasonable time sequence
after the drug, and the reaction does not conform to the known reaction type of the
suspected drug; the patient's clinical status or other treatment methods may produce
the reaction.

36
⑷Irrelevant: The reaction does not conform to the reasonable time sequence after
drug administration, and the reaction is consistent with the known reaction type of the
non-test drug; the patient's clinical state or other treatment methods may produce the
reaction, and the disease state improves or other treatment methods are discontinued. ,
repeated use of other treatment methods to respond.
(5) Unable to assess: The occurrence of the reaction has no clear relationship with the
time sequence after the drug, and is similar to the known reaction type of the drug,
and other drugs used at the same time may also cause the same reaction.
The above items (1), (2) and (5) were recorded as the adverse reactions of the drugs in
this study.
Incidence rate of adverse reactions = number of adverse reactions/total number of
cases × 100%.
10.3.3 Serious Adverse Events
A serious adverse event was defined as an unexpected adverse event at any drug
dose that met any of the following criteria: 1) resulting in death; 2) life-threatening
due to the trial drug; 3) resulting in hospitalization or Prolonged hospital stay; 4)
permanent or significant loss of function/disability; 5) teratogenic or carcinogenic.
Some events requiring hospitalization or prolonged hospitalization may not be
reported as serious adverse events, including: 1) hospitalization due to social reasons
rather than adverse events; 2) hospitalization for elective surgery, examination or
other treatment that has been booked before entering the study. 3) Tumor progression
and related events.
10.3.4 Report Form
Reporting of serious adverse events requires the use of the SAE reporting form.
10.3.5 Serious Adverse Event Reporting – Investigator Procedures
Reporting of serious adverse events requires the use of the SAE reporting form.
When a serious adverse event occurs (drug-related or not), the investigator should
send the completed initial report to the team leader unit, Sun Yat-sen University
Cancer Center Ethics Committee (Tel: 020-87343363) within 24 hours (Guangzhou
Sun Yat-Sen University Cancer Prevention and Control Center, Tel: 020-87343363),

37
and report the final report (including the outcome of serious adverse events, etc., if the
serious adverse event is death, there is no need to post the final report) as soon as
possible and report to the above department again .
10.3.6 Assessment and recording of immune-related adverse events
Because of the potential for autoimmune disease with anti-PD-1 therapy, the
investigators considered immune-related AEs to be classified as immune-related AEs
(irAEs) and identified as irAEs on the CRF AE page until day 90 after treatment
discontinuation .
Investigators should refer to Appendix 3 for guidelines on the diagnostic
evaluation and management of irAEs, which are commonly seen with the use of
immune checkpoint inhibitors.
An exhaustive list of potential irAEs is presented in Table 5. Individual
conditions similar to the listed irAEs should be evaluated to determine whether these
are irAEs according to a diagnostic process similar to the reactions described in more
detail in Appendix 3.
10.3.6.1 Management of Adverse Events of Special Attention
As a routine precaution, patients must be monitored for at least 1 hour in an area
equipped with resuscitation equipment and rescue medication after the toripalimab
infusion on Day 1 of Cycle 1 and Cycle 2. Beginning with cycle 3, monitoring is
required for at least 30 minutes in an area equipped with resuscitation equipment and
first aid medication.
According to the NCI-CTCAE, the management of infusion-related reactions,
severe hypersensitivity reactions, and irAEs is outlined below.

Infusion-related reactions
Symptoms of infusion-related reactions include fever, chills/rigidity, nausea, pruritus,
angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia,

38
dizziness, or hypertension. Severe reactions can include acute respiratory distress
syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock.
Patients should be monitored closely for such reactions. If an infusion-related reaction
occurs, immediate admission to an intensive care unit or equivalent setting and
appropriate medical therapy (including epinephrine, corticosteroids, intravenous
antihistamines, bronchodilators, and oxygen) must be administered.
Table 4 Treatment Modifications for Study Drug-Induced Infusion Reaction Symptoms
NCI-CTCAE level
Treatment adjustments for toripalimab
Grade 1 - Mild
Mild transient reaction; does not indicate interruption of
infusion; does not indicate intervention
Infusion speed decreased by 50%. All deterioration should
be closely monitored. Medical management as needed.
Subsequent
infusions
should
be
performed
after
the
administration of the prechemotherapy drug, and the
infusion should be completed at a reduced infusion rate.
Grade 2 - Moderate
Indicates interruption of therapy or infusions, but responds
rapidly
to
symptomatic
therapy
(eg,
antihistamines,
NSAIDs, narcotics, IV fluids); suggests prophylaxis for ≤
24 hours
Stop the infusion. If the infusion-related reaction has
resolved or the severity has been reduced to Grade 1, the
infusion can be resumed at 50% of the previous rate. All
deterioration should be closely monitored. Proper medical
management should be planned as described below.
Subsequent
infusions
should
be
performed
after
the
administration of the prechemotherapy drug, and the
infusion should be completed at a reduced infusion rate.
Grade 3 - Severe
Prolonged (eg, lack of rapid response to symptomatic
medication and/or brief interruption of infusion); recurrence
of symptoms after initial improvement; clinical sequelae
suggestive of hospitalization.
Stop the infusion immediately. Proper medical management
should be planned as described below.
Patients should suspend study medication.
Grade 4 - life-threatening
Stop the infusion immediately. Proper medical management

39
Life-threatening consequences; prompt urgent medical
attention.
should be planned as described below.
Patients should suspend study medication.
Hospitalization is recommended.
If the toripalimab infusion rate is reduced by 50% or suspended due to an
infusion-related reaction, the reduced rate must be maintained and chemotherapy
premedication administered for all subsequent infusions. If the patient experiences a
second infusion-related reaction (≥Grade 2) with a slower infusion rate, the infusion
should be discontinued and toripalimab therapy should be discontinued in the patient.
NCI-CTCAE Grade 1 or 2 Infusion Reactions: Appropriate medical
management should be instituted based on the type of reaction. These include, but are
not limited to, antihistamines (eg, diphenhydramine or equivalent), antipyretics (eg,
paracetamol or equivalent), and if consideration suggests oral or intravenous use,
corticosteroids, epinephrine , bronchodilators and oxygen. In the next cycle, patients
should receive an oral antihistamine (eg, diphenhydramine or equivalent) and an
antipyretic (eg, paracetamol or equivalent) as prechemotherapy and should be closely
monitored for clinical signs and symptom.
NCI-CTCAE Grade 3 or 4 Infusion Reactions: Immediately institute
appropriate medical management measures based on the type and severity of the
reaction. These include, but are not limited to, oral or intravenous antihistamines,
antipyretics, corticosteroids, epinephrine, bronchodilators, and oxygen.

Severe allergic reactions and flu-like symptoms
If hypersensitivity reactions occur, patients must be treated according to best
available medical practice as described in the Complete Guidelines for the Emergency
Management of Anaphylaxis developed by the Resuscitation Council (UK) Working
Group. Patients should be instructed to report any delayed reactions to the investigator
immediately.
If systemic / rapid anaphylaxis occurs (typically within minutes of drug / antigen
administration, it is characterized by respiratory distress; laryngeal edema; and / or

40
intense bronchospasm; and is usually followed by vascular collapse or shock, and
previous dyspnea disappears; skin manifestations, such as itching and urticaria with /
without edema. And gastrointestinal manifestations, such as nausea, vomiting,
spasmodic abdominal pain and diarrhea), infusion must be stopped immediately and
the patient must be arranged to withdraw from the study.
If anaphylaxis is observed, the patient will receive an injection of epinephrine
and an infusion of dexamethasone, followed by immediate monitoring of the patient
and notification to the intensive care unit, which may require transfer if necessary.
To prevent flu-like symptoms, 25 mg of indomethacin or an equivalent dose of
NSAIDs (i.e., 600 mg ibuprofen, 500 mg naphthalene Proprietary Sodium).
Alternative treatment for fever (ie, paracetamol) may be given to the patient at the
investigator's discretion.

Immune-related adverse events
Immune-related AEs deserve special attention in this study. If the following
events or similar events occur, the investigator should rule out other explanations
(such as co-medication, infectious disease, metabolic, toxin, PD, or other neoplastic
causes) and perform appropriate diagnostic tests, including but not limited to serology,
immunology and histological (biopsy) data. If other causes have been ruled out, the
AE requires the use of systemic steroids, other immunosuppressants, or endocrine
therapy; and the AE is consistent with an immune-mediated mechanism of action, the
irAE index in the AE CRF should be checked.
A list of potential irAEs is presented in Table 5 below. In patients receiving
toripalimab, all conditions similar to those listed should be evaluated to determine
whether they are immune-related.
Based on the guidelines of the European Society of Medical Oncology and the
American Society of Clinical Oncology, recommendations on diagnostic evaluation
and management of irAEs are given. Common immune-related toxicities are listed in
Appendix 3. For all adverse events not included in Appendix 3, please refer to the
American Society of Clinical Oncology Clinical Practice Guidelines for further

41
guidance on the diagnostic evaluation and management of immune-related toxicities.
Table 5 Immune-related adverse events
body organ system
affected
event
Skin (mild-common)
Pruritus or maculopapular rash; Vitiligo
skin (moderate)
Folliculitis or urticarial dermatitis; erythematous/lichenoid rash; acute febrile
neutropenic dermatosis
Skin (severe-rare)
Full Thickness Necrolysis/Stevens-Johnson Syndrome
gastrointestinal tract
Colitis (including diarrhea with abdominal pain or endoscopic/radiological evidence of
inflammation); pancreatitis; hepatitis; elevated transaminases (ALT/AST); bowel
perforation
endocrine
Thyroiditis, hypothyroidism, hyperthyroidism, hypophysitis with features of
hypopituitarism such as fatigue, weakness, weight gain, insulin-dependent diabetes
mellitus, diabetic ketoacidosis, adrenal insufficiency
breathe
Noninfectious pneumonia/diffuse alveolitis
eyes
Episcleritis; Conjunctivitis; Conjunctivitis/Uveitis
neuromuscular
Arthritis, arthralgia, myalgia, neuropathy, Guillain-Barre syndrome, aseptic meningitis,
myasthenic syndrome/myasthenia gravis, meningoencephalitis, myositis
blood
Anemia, leukopenia, thrombocytopenia
kidney
Interstitial nephritis, glomerulonephritis, acute renal failure
heart
Pericarditis, myocarditis, heart failure
Recommendations for the management of irAEs are detailed in Appendix 3.
Study drug was discontinued if toxicity did not decrease to Grade ≤1 within 12
weeks. Treatment should be permanently discontinued in patients who recur with an
event of the same or greater severity.
10.4 Pregnancy Events in Clinical Trials
Any subject participating in the trial should notify the organizer if a pregnancy

42
event occurs. Although pregnancy is strictly speaking not an AE, all pregnancy
situations need to be followed up to the end for results to be judged. This information
is of great relevance to drug safety and public health. It is the investigator's
responsibility to report all pregnancies in the trial using the pregnancy event reporting
form.
If a pregnancy event occurs within 30 days of using the test drug or stopping the
test drug, the investigator or his partner should contact the superior competent
authority to discuss the management of the subject. The content of the report of the
pregnancy event includes the expected date of delivery, and the report form of the
pregnancy event shall be submitted within 24 hours after the occurrence of the
pregnancy event according to the procedure for reporting the SAE. If the pregnancy
needs to be terminated, the estimated time of termination is required.
If the spouse of the subject has a pregnancy event instead of the subject himself,
the completion of the pregnancy event report form needs to include the subject's
screening number, initials, and date of birth. Details about the spouse need to be
recorded
in
the
Narrative
section
of
the
Pregnancy
Event
Report
form.
Subjects/spouses should be followed up until the end of the trial. If the pregnancy is
terminated before the expected date of delivery, the investigator needs to truthfully
record this situation. After the pregnancy is over, the investigator needs to record and
determine the pregnancy results.
11
Withdrawal and Discontinuation of Research Regulations
11.1 patient withdrawal
Patients can withdraw from clinical trials at any time and for any reason, and it
will not affect the rights of researchers to treat their diseases. From the perspective of
the interests of the subjects, the researchers have the right to ask the subjects to
withdraw for any reason, including concomitant diseases, adverse events or treatment
failure. The Clinical Research Core Group reserves the right to ask subjects to
withdraw due to protocol violations, administrative reasons, or other valid and ethical
reasons.

43
Although the withdrawal of subjects should be avoided as much as possible, it
is necessary to know that withdrawals of subjects will occur in clinical research.
Regardless of when the subject withdraws from the study for any reason, the subject's
final study assessment must be completed and the reason for withdrawal must be
indicated. All documentation on the subject must be as complete as possible. As long
as the patient did not withdraw his consent, these withdrawn patients were followed
up and the disease was recorded as if they had not withdrawn.
Investigators must follow up those who drop out due to poor compliance to
obtain reasons for non-attendance. When a patient withdraws, the study will do its
best to complete and report observations as comprehensively as possible. As long as
the patient does not withdraw his consent, these patients will continue to be followed
if possible and their disease recorded as if they had not withdrawn.
Withdrawals due to concomitant diseases or adverse events must be documented
in detail on the observation form, along with all other appropriate and valuable
information.
11.2 Early Termination of Study
Reasons for early termination may include external events, recurrence of serious
adverse events, increased treatment-related mortality, or insufficient enrollment in
clinical trials. All investigators will be notified in writing when the clinical study is
terminated early. Any researcher who wants to stop participating in this clinical study
must immediately inform the principal investigator of his/her decision.
11.2.1
Study follow-up
11.2.2
follow-up time
Subjects were followed up after the end of treatment or withdrawal from the
study for other reasons, and the follow-up was once every three months, and changed
to once every six months after two years, until the end of the whole study.
11.2.3
Follow-up content
Subject
follow-up
includes
collection
of
subject
complaints,
physical
examination, blood and urine routine, biochemical routine and tumor evaluation. The
above-mentioned follow-up visits were recorded in the original medical records. The

44
content of tumor evaluation should be filled in the CRF form.
12 Statistical analysis
12.1 Statistical analysis population
•
Full
analysis
population
(FAS):
includes
all
subjects
who
entered
randomization and received at least one study drug (experimental drug or control
drug). The FAS is the primary data set for the evaluation of the primary and secondary
efficacy measures.
• Population according to the protocol (PPS): including all those in the analysis
set who did not have major protocol deviations, completed the study according to the
protocol or observed the second analysis endpoint of the trial, did not receive other
combined treatments that may affect the efficacy of the study drug during the period,
and maintained Subjects with good compliance. The division standard is determined
by the research party and the statistical party before data analysis.
• Safety Analysis Population (SS): Include all subjects who have received the
study drug once and have safety records after administration.
12.2 Statistical method
After the test plan is determined, professional statisticians and the main
researchers will negotiate to formulate a statistical analysis plan. SPSS 18.0 statistical
software was used. All statistical tests used one-sided or two-sided tests as needed,
and a P value less than 0.05 was considered statistically significant. The description of
quantitative indicators will calculate the mean, standard deviation, median, minimum
value, maximum value, lower quartile, upper quartile, and classification indicators
describe the number of cases and percentages of each category. The comparison of the
general conditions of the two groups will use corresponding analysis methods
according to the type of indicators, and the comparison of quantitative data between
groups will use paired sample t test or Wilcoxon rank sum test. Chi-square test or
Fisher's exact probability method was used for categorical data, and Wilcoxon rank
sum test or CMH test for hierarchical data.
12.2.1Enrollment and completion

45
In principle, all patients who meet the inclusion/exclusion criteria can be enrolled,
and the number of enrollment and completion is summarized, and a list of dropped
cases is listed. Different data set size, case distribution, total dropout rate comparison,
and detailed list of termination reasons for each group. Describe the patient's
demographic characteristics (age, height, vital signs, etc.), medical history, and
medication history, and compare the age, height, and weight of the two groups to
measure the comparability of the data.
12.2.2 Adherence analysis
• Medication compliance analysis: Follow up whether the patient is using the test
drug on time and in the right amount, and whether the drug and food prohibited in the
protocol are not used
• Combined drug analysis: It is necessary to count the number of combined drugs
and make a detailed list to statistically analyze the potential impact of combined drugs
on the efficacy of experimental drugs
12.2.3 Baseline Data Analysis
According to the baseline check indicators listed in 6.2, the n value, mean,
standard deviation, median, minimum value, and maximum value will be described
for continuous data, and the frequency and percentage of each group will be described
for categorical data.
12.2.4 Efficacy analysis
The analysis objects are FAS and PPS
12.2.4.1 Primary efficacy analysis
Progression-free survival (PFS) will be analyzed using Kaplan-Meier curves
depicting the change in the experimental group during the analysis. Subjects who
withdraw from the trial early before the study analysis will be censored at the time of
the last tumor imaging assessment or the last follow-up visit (whichever is later).
12.2.4.2 Secondary efficacy analysis
The objective response rate (ORR) is the proportion of subjects with complete
remission and partial remission according to the efficacy evaluation to the total
number of subjects. Overall survival (OS) will be analyzed using Kaplan-Meier

46
curves depicting the changes in the experimental groups during the analysis. Subjects
who withdraw from the trial early before the study analysis will be censored at the
time of the last tumor imaging assessment or the last follow-up visit (whichever is
later).
12.2.5 Safety Analysis
Including monitoring and recording all AEs and SAEs (including the
number of events and the incidence of subjects), routine blood and biochemical
indicators, body weight, vital signs, physical examination, and all treatments and
concomitant medications. Safety indicators include: body weight, vital signs, clinical
laboratory parameters, AE, etc. For laboratory parameters, actual values at each
assessment, values changed from baseline, and abnormal classification (below, normal,
or above reference range) will be tabulated by treatment group, over time. For body
weight and vital signs, the actual value and baseline change value at each evaluation
will be tabulated according to the treatment group and the change over time.
The ratio of the number of subjects with AEs during treatment to the number of
subjects eligible for safety evaluation was used
To represent the incidence of AE. AE rates will be summarized using the Study
Data Coding System (MedDRA) organ class and standard terminology. AEs that
occurred during treatment were defined as AEs that occurred on or after the day of the
first dose to the day of or before the last dose + 30 days or the day when the treatment
was terminated. The severity of toxic reactions was graded according to NCI-CTCAE
version 5.0. When analyzing by subject, subjects with the same event occurring more
than once are only counted once, and the worst CTCAE grade event is selected.
All AEs are listed and described in detail in terms of type, grade, frequency of
occurrence, severity, duration, relationship with trial drugs, treatment measures and
outcomes, etc.
12.3
Sample size calculation
This study is a single-arm design. According to the existing clinical data, the

47
parameters for calculating the sample size are as follows:
1. Enrollment time = 24 months, follow-up time = 12 months (the overall time is 36
months), referring to the previous research results and the historical comparison of
our center, the PFS of chemotherapy alone = 5 months, assuming that the PFS of
chemotherapy combined with immunotherapy increased to 10 months.
2. α=0.05 (two-sided).
3. The test has a power of 90%.
Based on the above parameter considerations, according to the logrank test of
single-arm PFS, 30 subjects are required. Considering the dropout rate of 10% during
the study, 33 subjects were finally required to be enrolled.
13 Regulatory matters
13.1 Ethics and compliance with GCP
All researchers must comply with the requirements of the International
Conference on Harmonization (ICH) Guideline E6 in terms of Good Clinical Practice
(GCP) on drug clinical research management practices, ethical regulations, and
research protocols to implement research.
•
Institutional
Review
Board/Ethics
Committee
(IRB/EC)
Approval:
Investigators should obtain IRB approval of the study protocol, revisions to the study
protocol, informed consent, investigator brochure, and any File approval is required.
•
Ethical considerations for research implementation: research protocols and
SOPs must comply with the GCP requirements and the Declaration of Helsinki on
human medical research ethics.
• Subject Information and Informed Consent: The Principal Investigator or his
authorized person will be responsible for obtaining informed consent. The context of
the study and the benefits and risks of participating in the study should be clearly
explained. The subjects will obtain a copy of the signed and dated informed consent
form, and the researcher will keep the original. Confirmation of informed consent
should be recorded in the subject's medical records before any testing or intervention
(including screening and evaluation) is performed according to the research protocol.

48
• Subject data protection: Subjects shall not be identified by name in any study
report. Research reports are for research purposes only. Every effort will be made to
ensure the confidentiality of subjects' personal medical data.
13.2 Responsibilities of the researcher
•
Ensure that staff assisting with the study are fully aware of the protocol,
revisions, study treatments, and study-related responsibilities and functions. The
Investigator shall maintain a list of Assistant Investigators and other qualified
personnel who have been assigned significant research-related responsibilities.
• Responsible for maintaining records of all patients who have signed informed
consent and been screened for study entry. For patients who fail screening, the reason
must be documented in the patient's source file.
•
During monitoring visits, investigators or their authorized personnel must
review data, resolve queries, and allow direct access to patient records (medical
records, study-related charts, etc.) for primary data reconciliation. Investigators must
complete the CRF in a timely and accurate manner.
13.3 Informed consent
Before subjects are enrolled in the trial, the researchers must explain to them the
purpose, methods, possible benefits, potential risks and possible discomforts of the
trial. Inform the subjects that participation in the trial is voluntary, that they can
withdraw at any time, and that participation in the trial has no effect on the treatment
of their disease. The privacy of the subjects will be protected. The subjects or
guardians should have enough time to read the informed consent form and ask
questions. Before being selected, the subjects or their guardians must sign the
informed consent form, and the subjects keep a copy of the informed consent form.
13.4 Good Clinical Practice (GCP)
This clinical study will be conducted in accordance with the "Declaration of
Helsinki" and China's Good Clinical Practice (GCP). The research protocol must be
approved by the Ethics Committee of the clinical research unit before it can be

49
implemented. The researchers will ensure that the clinical research is carried out in
compliance with the laws, regulations, scientific and ethical standards of the People's
Republic of China on medical research. If it is found that the research protocol needs
to be revised during the research process, the revised research protocol must be
submitted to the ethics committee of the responsible unit for record/approval before
implementation. If important new information related to the research drug is found,
the informed consent must be revised in writing and sent to the ethics committee of
the responsible unit for approval, and the subject’s consent must be obtained again.
13.5 Confidentiality of Subject Personal Data
In this trial, only the information needed for research on the effectiveness and
safety of the drug was collected. When collecting and using these data, relevant laws
and regulations on the protection of privacy will be complied with.
13.6
Plan revision
If necessary during the research process, the research protocol can be revised to
guide the next step of the research. The revision of the protocol must comply with the
relevant regulations of GCP. The researchers and the organizers will formulate a
revised draft of the protocol according to the progress of the research, and it must be
reviewed and approved by the ethics committee before it can be implemented.
Protocol revisions approved by the ethics committee must be part of the revised
protocol.
13.7 Institutional Review Board/Independent Ethics Committee Review and
Approval
Before the study begins, the study protocol, informed consent form, and any
other corresponding documents will be submitted to the IRB/EC with a cover or form
listing the submitted documents, date of issue, and the research center to be approved.
Documentation will also be submitted to regulatory agencies as required by local law,
if applicable.

50
13.8 Research Progress Plan
• Trial start date: December 2022
• Trial end date: December 2024
14 Data Management and Record Keeping
14.1 Data handling
14.1.1 Data handling
The researcher needs to fill in the data of the enrolled subjects into the CRF, and
the patients who fail the screening do not need to fill in. Researchers should ensure
that the data filled in the CRF is accurate and complete, and at the same time keep the
original records intact. The CRF filling of each enrolled subject must be completed on
time. After the completed CRF was reviewed, it was handed over to the data
administrator of this trial for data entry and management.
14.1.2 Data input
The data entry and management are in the charge of the designated data
management unit. Data administrators use computer software to compile data entry
programs for data entry and management. In order to ensure the accuracy of the data,
it should be proofread by others after the input is completed.
14.1.3 Medical Information Coding
Coding of medical information will use the following tools:
• MedDRA 11.0 (Medical History and Adverse Events)
• WHO Drug 2008.03 (concomitant medication)
• NCI-CTCAE 5.0 (Toxic Reaction)
14.1.4 Data audit
The main researchers, data managers, and statistical analysts will review the
established database, and lock the database after confirming the research data set and
statistical analysis plan.
14.2 Record keeping
According to the GCP guidelines, the principal investigator must keep all data

51
related to the clinical trial, such as the subject's medical records, drug disposal records,
signed informed consent, and approval documents from the ethics committee, for 5
years after the termination of the clinical trial.
14.3 Privileges for raw data/documents
Any observations and inspection results in clinical trials should be recorded in the
medical records and correctly filled in the CRF by the researchers in a timely,
accurate, complete, standardized, and truthful manner. It is not allowed to be changed
arbitrarily. If it is really due to a mistake, the researcher should keep the original
record clear and legible when making any correction, and the corrector should sign
the name and time. Raw data/documents must be properly kept in the research center
in accordance with the requirements of ICH GCP and local regulations.
The higher-level competent department and the drug supervision and management
department can monitor, inspect, and inspect the clinical trial implementation process
and original data/source documents. Inspectors, inspectors, and regulatory authorities
have the right to check all original data/source documents related to the test, but have
no right to modify them. If a problem is found, the researcher must be notified to
make corrections and sign.
15 Specimen Collection and Storage
15.1 Specimen Collection Standard Operating Procedures
Subject specimens were collected according to the standard operating procedures
(SOP) for the collection of blood samples and tumor tissue specimens in the tissue
bank of our hospital.
15.2 Specimen storage
Subject specimens are stored by the principal investigator. After the patients
signed the informed consent to enroll in the group, their postoperative tumor tissue
will routinely retain paraffin and frozen specimens. After all subjects are enrolled, the
tumor specimens (paraffin) will be made into tissue chips. After the blood sample is
centrifuged, the serum and blood cells are stored separately.

52
16 Quality Control and Quality Assurance
16.1 Data Quality Assurance
In order to ensure the integrity, accuracy and reliability of the data, the following
measures were taken in this study: Qualified and experienced research units and
researchers were selected. Before the start of the study, use lectures and written
materials to introduce the content of the research plan to the researchers in detail, and
jointly formulate solutions to possible problems; the completeness and accuracy of the
data are regularly checked by the inspector; if the data is found to be in doubt , should
be communicated with the researchers in a timely manner and confirmed or corrected;
in the statistical stage, the data should be checked blindly. If there is a deviation, it
will be confirmed or corrected by the researcher.
16.2 Monitor
16.2.1
Purpose of inspection
Ensure that clinical trials are carried out in strict accordance with the protocol
and relevant regulations, ensure data integrity, reliability and consistency of
multi-center data, and coordinate the uniformity of trial progress.
16.2.2
The content of the audit
Supervisors regularly visit clinical research units to monitor and report on the
progress of the trial. Supervisors have the right to check the original data of all
patients related to this study. The monitoring content mainly includes: whether the
subjects meet the inclusion criteria; whether the filling of the case report form (CRF)
is timely, accurate, complete, and credible; whether the methods and doses of the
subjects' medication meet the requirements of the protocol. Whether all adverse
events are recorded in the CRF form; at the same time, ensure that all errors or
omissions are corrected, and are signed and dated by the researcher.
Inspectors are also responsible for transmitting various forms of data, including
normal value data of clinical tests, to ensure that there is a scientific and consistent
clinical testing system between the participating units and the team leader unit.
If there are serious adverse events or deaths (including chemotherapy-related
deaths) related or unrelated to this study during the clinical trial, the managing doctor

53
or the hospital shall take appropriate measures immediately.
17 Inspect
The sponsor may have representatives visit the research unit to check all the
research records of this trial, including original documents, and compare them with
the CRF form. Before the audit, the research unit will be notified to make appropriate
preparations. Drug regulatory agencies may conduct similar inspections. In this case,
the investigator should notify the sponsor immediately.
18 Post Policy
The results of this study can be published in medical journals, journals or used
for teaching purposes. In addition, this study and its results may be submitted for
inclusion in all appropriate health agency registries of research and published on
health agency research registry websites (eg, ClinicalTrials.gov), as required by local
health agency regulations. The first author is selected based on several considerations,
including but not limited to: research participation, contribution to protocol
development, and analysis and input in the research manuscript, relevant abstracts and
presentations.
19 Clinical Trial Management Information
19.1 Organizational Units
Unit: Sun Yat-sen University Cancer Center
Address: No. 651, Dongfeng East Road, Guangzhou
Tel: 020-87343088
Zip code: 510060

54
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Furtado, P., et al., Review of small cell carcinomas of the prostate. 2011. 2011: p. 543272.
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Farci, F., et al., Primary small cell carcinoma of the ureter: Case report and review of the
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Ismaili, N., et al., Outcome of recurrent and metastatic small cell carcinoma of the bladder.
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21 Declaration of investigator
I would like to sign my name and agree to the following:
I have read the protocol, I agree to the protocol and acknowledge all necessary
details to be carried out during the study described in the protocol. I will implement
the program design and specific regulations and try to complete the research within
the specified time. Under my management/supervision, I will give a copy of the
protocol and related information to the researchers involved in the trial. I discuss these
documents with them to make sure they fully understand the study protocol and study
steps. I will inform them that this information is confidential and belongs to the
research center and that it will not be disclosed to third parties. I understand that the
ethics committee, the higher authorities, or the drug regulatory department may
terminate or stop the recruitment at any time for any reason, or if I think it is
necessary to protect the best interests of the subjects. I agree to conduct this research
in full compliance with the requirements of the State Food and Drug Administration,
the Ethics Committee, and ICH GCP.
Investigator's signature
Date