Safety and Toxicity of CAR-T Cell Immunotherapy in Patients With Advanced Lung Cancer After Standard Treatment Failure: A Single-Arm and Single-Center Phase I Clinical Study
Phase: PHASE1
Conditions: Advanced Lung Cancer
Sponsor: Sun Yat-sen University

Plan date: 2017-08-12; version number: v2.0 
Study of the safety and efficacy of CAR-T cell 
therapy after standard treatment of advanced 
lung cancer: a single-arm, single-center phase 
I clinical study 
 
 
 
Study plan 
 
 
Date: August 12, 2017 
Version: Version 2.0 
 
 
SUN YAT-SEN UNIVERSITY CANCER CENTER 
Internal Medicine / Biotherapy Center 
Zhang Li, Xia Jianchuan 
GUANG ZHOU YIYANG BIOLOGICAL TECHNOLOGY Co., Ltd. 
Liu Heping 
 

Plan date: 2017-08-12; version number: v2.0 
目录 
Contents 
 
1. Background ........................................................................................... 1 
1.1 Introduction ..................................................................................... 1 
2. Significance ............................................................................................ 1 
2.1 Main objective ................................................................................ 1 
2.2 Secondary objectives ...................................................................... 1 
3. Subjects .................................................................................................. 2 
3.1 Inclusion criteria: ............................................................................ 2 
3.2 Exclusion criteria: ........................................................................... 3 
4. Study design and test methods ............................................................. 5 
4.1 Study design .................................................................................... 5 
4.2 Genomic analyses ........................................................................... 6 
5. Study plan .............................................................................................. 6 
5. 1. Pre-examination and evaluation of patients before treatment ...... 6 
5.2. Production of PD-L1 CAR lentivirus ............................................ 6 
5.3. Transduction of autologous T cells................................................ 7 
5.4. Quality control before CAR-T cell insfusion ................................ 7 
5.5. Infusion of PD-L1 CAR-T cells .................................................... 7 
5.6. Clinical safety monitoring and evaluation ..................................... 8 
6. Subject withdrawal criteria ............................................................... 10 
7. Criteria and evaluation methods for efficacy................................... 11 

Plan date: 2017-08-12; version number: v2.0 
8. Set up of the sample size ..................................................................... 12 
8.1 Data set.......................................................................................... 12 
8.2 Missing data .................................................................................. 13 
8.3 Statistical analysis methods .......................................................... 13 
9. Ethics .................................................................................................... 13 
9.1 Regulatory and ethical compliance ............................................... 13 
9.2 Responsibilities of researchers and ethic committees .................. 14 
9.3 Informed consent process ............................................................. 14 
10. Implementation plan......................................................................... 14 
11. References .......................................................................................... 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Plan date: 2017-08-12; version number: v2.0 
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Study of the safety and efficicay of CAR-T cell 
therapy after standard treatment of advanced 
lung cancer: a single-arm, single-center phase 
I clinical study 
 
1. Background 
1.1 Introduction 
Chimeric antigen receptor modified T lymphocyte therapy (CAR-T) is a 
combination of high affinity of chimeric antigen receptor for tumor antigen and T cell 
killing mechanism, through gene transduction of T Cells, to obtain the ability to 
specifically kill tumor cells, without MHC restriction . CAR-T cell therapy has shown 
high specificity, lethality and durability in clinical trials, providing new avenues for 
immune cell therapy and showing huge development potential and application 
prospects. 
2. Significance 
2.1 Main objective 
To study the safety and effectiveness of PD-L1 CAR-T cells in the treatment of 
patients with advanced non-small cell lung cancer (NSCLC). 
2.2 Secondary objectives 
1) Perform baseline WGS / WES on the biopsy tissues, TCR library analysis on the 
baseline and post-treatment plasma / blood cells, and perform intestinal flora 
metagene analysis on the fecal specimens at baseline and after treatment. ORR, 
disease control rate (DCR) correlation analysis, preliminary study of predictive factors 
for efficacy. 
2) Perform baseline WGS / WES on biopsy tissues, TCR analysis on plasma and 
blood cells at baseline and after treatment, and perform metabolic analysis of gut 
microbiota on fecal specimens at baseline and after treatment. Period PFS, overall 
survival (OS) association analysis, preliminary study of survival predictors. 

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3. Subjects 
3.1 Inclusion criteria: 
The number of cases to be enrolled in clinical trial was 20. Considering the 10% 
dropout rate during the study period, the number of lung cancer patients that met 
the inclusion criteria and were not included in the exclusion criteria should be 22 in 
this study. 
1) Pathological or cytological diagnosis of NSCLC, with stage IIIB / stage IV tumors 
(according to UICC / AJCC staging system version 8). 
2) Relapsed NSCLC or progression after standard treatment (surgery, radiotherapy, 
chemotherapy and targeted therapy, excluding PD-1 / PD-L1 immune checkpoint 
inhibitor treatment), or the patient refuse to receive chemotherapy. 
3) Before enrollment in the study, the patient needs to perform a second biopsy, 
retaining at least one biopsy, or at least 10 unstained sections. 
4) TKI and chemotherapy drugs must be discontinued before> = 21 days of the first 
day of infusion. Pulmonary radiotherapy must be discontinued> = 6 months before 
the first day of infusion. After discontinuing previous treatment, a baseline imaging 
scan must be obtained. 
5) According to the RECIST 1.1 standard, subjects must have measurable lesions that 
are examined by CT or MRI. Tumor imaging evaluation was performed within 28 days 
before CAR T cell therapy. 
6) Age> = 18 years old, weight> = 40kg. 
7) IHC detection of lung cancer biopsy tissue after standard treatment is positive for 
PD-L1 (> 10%). 
Roche Ventana rabbit monoclonal antibody SP142 approved by the FDA was used to 
detect the expression level of PD-L1 in lung cancer sections of patients enrolled in 
this project. 
8) Estimated survival time> = 12 weeks; 
9) ECOG score ≤ 2 points 

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10) Women of childbearing age must have a negative pregnancy test within 14 days 
before starting treatment and agree to take contraceptive measures with a failure 
rate of <1% per year during the study until the last follow-up. 
Contraceptive measures with a failure rate of <1% per year include bilateral fallopian 
tube ligation, male sterilization, correct use of hormonal contraceptives that 
suppress ovulation, intrauterine hormone release systems, and intrauterine copper 
birth control devices. 
11) The subject must have sufficient hematology and end-organ function and meet 
the laboratory values in the table below. These test results must be completed within 
7 days before the first cell application. 
System 
Laboratory value 
Hematology 
Leukocyte（WBC） 
>=3.5*109/L 
Neutrophil（ANC） 
>=1.5*109/L 
Hemoglobin（HGB） 
>=90g/L 
Platelets（PLT） 
>=80*109/L 
Coagulation 
Prothrombin time, Partial thromboplastin time,  
Plasma fibrinogen, Thrombin time 
Within normal range 
Liver 
Aspartate aminotransferase（AST） 
<2.5 * normal upper limit (ULN) 
ECOG score of 0-1 points for liver 
metastasis <5 * ULN 
Alanine aminotransferase（ALT） 
<2.5 * ULN 
ECOG score of 0-1 points for liver 
metastasis <5 * ULN 
Total bilirubin（TIBC） 
<1.5*ULN 
Kidney 
Serum creatinine（CR） 
<1.0*ULN 
12) Participate voluntarily in this experiment and sign the informed consent. 
3.2 Exclusion criteria: 
1) Subjects receiving systemic steroid therapy within <= 3 days before the first cell 

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therapy. 
Note: a. Corticosteroids can be used to treat AE, SAE, and ECI after the study of cell 
therapy. 
 b. Not including subjects who are receiving steroid replacement therapy every day. A 
daily dose of 5-7.5 mg of prednisone is an alternative therapy. 
c. An equivalent dose of hydrocortisone therapy may also be admitted into the trial 
as an alternative therapy. 
2) Subjects who have received previous systemic cytotoxic chemotherapy, biological 
therapy or major surgery within 3 weeks before the application of the first dose of 
test cells, and received lung radiotherapy> 30Gy within 6 months before the 
application of the first cell infusion. 
3) Subjects who have received CAR-T, CIK and other cell therapies, anti-PD-1, 
anti-PD-L1 antibody therapy. 
4) Subjects with known central nervous system metastases and / or cancerous 
meningitis. 
Note: Subjects who have previously received brain metastasis treatment can also 
participate in this study, as long as the patient is stable (no neurological symptoms) 
and no new brain metastases are found at least 4 weeks after brain metastasis 
treatment (such as surgery, RT); Imaging evidence of no metastasis and 
discontinuation of hormone therapy at least 3 days before the first application of the  
cells. 
5) In the past 2 years, have active autoimmune diseases that require systemic 
treatment (such as the use of disease-modifying drugs, corticosteroids or 
immunosuppressants). 
Note: Alternative therapy (i.e., thyroxine, insulin, or physiological corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
systemic treatment. Subjects requiring inhaled glucocorticoid therapy need not be 
excluded from this study. Subjects with vitiligo or cured childhood asthma / allergic 
disease can participate in the study. Subjects who need local steroid injections can 
participate in the study. 
6) Subjects with interstitial pneumonia or a history of pneumonia requiring oral or 
intravenous steroid therapy. 

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7) Difficulties in transduction of the patient's lymphocyte with lentiviral vectors 
(<20%) or inability to effectively expand (<5 times) during evaluation. 
8) Subjects who have received allogeneic tissue / solid organ transplantation. 
9) Subjects who have been vaccinated or will be vaccinated with live vaccines within 
30 days before the application of the first cells. Seasonal influenza vaccines that do 
not contain live vaccines are allowed. 
10) Subjects with active infections requiring intravenous systemic treatment. 
11) Subjects with a history of human immunodeficiency virus (HIV) (HIV1 / 2 
antibody) infection. 
12) Active hepatitis B or hepatitis C is known. Subjects with positive HBsAg need to 
be excluded. Active hepatitis C is defined as positive for hepatitis C antibodies, and it 
is known that quantitative HCV RNA results exceed the detection limit of analysis. 
13) The history of mental illness or drug abuse that can’t comply with the 
requirements of the experiment. 
14) Pregnant or breastfeeding, or male subjects whose spouses are expected to 
become pregnant during the study period (from screening visit to 60 days after the 
last application of the cells). 
 
4. Study design and test methods 
4.1 Study design 
1) For patients with non-small cell lung cancer that progressed after standard 
treatment and meet the recruitment criteria for the protocol, they must provide 
tumor biopsy tissue specimens and unstained paraffin tissue sections during the 
screening period. 
2) Intravenously infuse the cells according to the protocol. Before the infusion, take 
10 ml of the peripheral blood of the patient for baseline laboratory tests; take the 
fecal specimen of the patient for baseline flora metagene analysis. During the 
patient's follow up the efficacy evaluation (CT / MRI re-examination) was performed, 
each time 10 ml of peripheral blood and stool samples were collected. If the patient 
meets the withdrawal criteria (such as disease progression PD, DLT out of the group, 

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etc.), the investigator decides that the patient needs to withdraw from the clinical 
trial and needs to retain 10 ml of peripheral blood and feces before exiting the 
clinical trial. 
3) After the patient receives the infusions, the doctor decides if the treatment is 
effective during the follow-up, the patient won ’t receive other treatments; if the 
treatment is ineffective, the patient will be observed for one month according to the 
patient ’s wishes. No other drugs can be used for treatment, and the patient will be 
out of the group after the treatment is evaluated again within 1 month; if the third 
(5th month) follow up evaluation is still effective, that is, all three evaluations are PR 
or SD. The patient can be receive one more free treatment; regardless of whether it 
is effective, patients can decide to withdraw at any time during the study according 
to their own wishes. If the treatment is effective (stable SD, partial or complete 
remission PR / CR), the follow-up will continue for up to 2 years. 
4.2 Genomic analyses 
1) Next generation sequencing (NGS) 
       Whole genome sequencing (WGS) 
       Whole Exons Sequencing (WES) 
2) Dynamic detection of TCR library 
3) Dynamic analysis of intestinal flora metagenes 
5. Study plan 
5. 1. Pre-examination and evaluation of patients before treatment 
Within 48 hours after the patient signed the informed consent form, the patient’s 
blood samples were drawn and  was tested for hepatitis B, hepatitis C and HIV. It 
takes about 4 days to assess whether the subject's PBMCs are suitable for producing 
PD-L1 CAR-T cells. 
5.2. Production of PD-L1 CAR vector lentivirus 
PD-L1 CAR lentiviruses were packaged in 293T cells, and the collected viruses were 
concentrated and purified, their titers were determination, and frozen at -80°C and 
used for the transduction of autologous T cells. 

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5.3. Transduction of autologous T cells 
According to the following table, collect a certain amount of blood from the patient, 
isolate PBMC cells by Ficoll density gradient centrifugation. The T cells were further 
purified and activated by CD3/CD28 beads. Then PD-L1 CAR lentiviruses were added 
with the predetermined MOI ratio. Culture and expand and the transduced cells. The 
blood collection volume corresponding to the absolute counts of lymphocytes is 
shown in the table below: 
Body Weight
（kg） 
Lymphocyte Count
（×109/L） 
Blood volume required 
（ml） 
Remarks 
40-50kg 
1-2×109/L 
200 
 
 
2-3×109/L 
100 
 
 
3-4×109/L 
66 
 
50-60kg 
1-2×109/L 
240 
 
 
2-3×109/L 
120 
 
 
3-4×109/L 
80 
 
60-70kg 
1-2×109/L 
280 
 
 
2-3×109/L 
140 
 
 
3-4×109/L 
94 
 
70-80kg 
1-2×109/L 
320 
 
 
2-3×109/L 
160 
 
 
3-4×109/L 
107 
 
80-90kg 
1-2×109/L 
360 
 
 
2-3×109/L 
180 
 
 
3-4×109/L 
120 
 
5.4. Quality control before CAR-T cell transfusion 
The live cell count, transduction efficiency, T cell phenotype, endotoxin, bacteria, and 
mycoplasma of PD-L1 CAR-T cells are vigorous tested, and the replication-competent 
lentiviruses are also tested by PCR. All of these tests will determine whether they 
meet the clinical application standards. The batches that do not meet the standard, 
will be discarded and recorded. 
5.5. Infusion of PD-L1 CAR-T cells 
The cells will be infused into the patient if the cells are not contaminated with any 
pathogenic microorganisms, and the patients are treated with chemotherapy 
(cyclophosphamide: 250mg / m2 × 3days; fludarabine: 25mg / m2 × 3days) to 
remove Treg cells and reduce lymphocytes. It is beneficial for the expansion of PD-L1 

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CAR-T cells in vivo to enhance the anti-tumor effect of CAR-T cells. After the 
chemotherapy, the peripheral blood will be collected the day before the CAR-T 
infusion and the blood routine tests will be carried out. The effect of chemotherapy 
was evaluated according to the number of lymphocytes and T cell subsets. 
To ensure safety, PD-L1 CAR-T cells were infused at three different times, 10%, 30%, 
and 60% of the total infusion on Day 0, Day 3, and Day 7, respectively. The total 
amount of cell infusion is (1-2) × 106 PD-L1 CAR-T cells / kg. The cells are suspended 
in 100ml of normal saline and infused into the body at a rate of about 50 drops / 
minute. After being infused to patients, the remaining cells are kept frozen (-80 
℃) 
for later tests if severe adverse reactions happen. 
5.6. Clinical safety monitoring and evaluation 
(1) All adverse events were recorded according to nci-ctcae (v4.02): 
Adverse events are defined as any unexpected medical events that occur after  
medication, regardless of whether there is a causal relationship between the event 
and the treatment. The lack of efficacy in clinical trials cannot be regarded as an 
adverse event, because the purpose of clinical trials is to evaluate the efficacy of 
treatment: 
1) Fever: including agranulocytosis fever. It is necessary to take imaging examination 
and determine etiology, find the source of infection, and empirically treat with 
broad-spectrum antibiotics. 
2) Abnormal liver and kidney functions: administer liver protection treatment; 
determine the causes of renal function abnormality (prerenal, renal, postrenal), and 
corresponding support treatment. 
3) Muscle pain and bone pain: except for mechanical injury, analgesic treatment 
(NSAIDs, weak opioids or strong opioids) can be given. 
4) Respiratory insufficiency (hypoxemia): Patients with mild symptoms should be 
given oxygen inhalation by nasal catheter, while patients with severe symptoms 
should contact ICU for mechanical ventilation and assisted respiration. Except for 
pulmonary infection (imaging and etiology), it can be treated with hormone 
anti-inflammatory therapy. 
5) Hypotension: in addition to infection, it is considered to be related to the vascular 
leakage reaction caused by cytokine. Fluids should be supplemented adequately, and 

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vasopressors (dopamine, adrenaline) should be used properly for severe cases . If 
necessary, anti-IL-6 antibody (tocilizumab for IL-6 receptor or siltuximab for IL-6) will 
be applied [47]. 
6)Other adverse events are evaluated accordance with nci-ctcae4.
（http://ctep.cancer.gov/protocolDevelopment/electronic_ applications/ ctc.htm 
(2013)) to be graded and actively treated. 
(2) Monitoring and evaluation of cytokine release syndrome (CRS) 
 1) Definition of cytokine release syndrome (CRS) 
According to the NCI-CTCAE (v4.02) evaluation criteria for common adverse events, 
CRS is defined as a group of clinical disorders with characteristics of fever, nausea, 
headache, tachycardia, hypotension, rash and dyspnea. 
  2) Clinical manifestations / evaluation criteria of cytokine release syndrome (CRS) 
a) Fever for three consecutive days; 
b) The maximum value of two cytokines is 75 times higher than the standard or the 
maximum value of one cytokine is 250 times higher than the standard; 
c) At least one toxicity-related clinical symptom occurs, such as hypotension that 
(requires at least one vasopressor), hypoxia (PO2 <90%), neurological symptoms. 
d) CRP level ≥20mg / dl. 
3) The grading standards for cytokine release syndrome are set forth according to the 
revised version of NCI-CTCAE (v4.02) 
a) Level 1: Mild reaction, treatment can be continued without special intervention 
treatment; 
b) Level 2: Intervention or interruption of treatment is required, the treatment needs 
to be given quickly (such as the use of antihistamines, NSAIDs, narcotic drugs, 
intravenous administration), and preventive medical measures should be taken ≤24h; 
c) Grade 3: Any one or more of the following severe symptom signs: the patient's 
baseline blood pressure level drops by ≥20% (systolic, diastolic, or average arterial 
pressure), and the person cannot quickly improve after treatment and / or infusion 
intervention within 24 hours ; Grade 3 respiratory dysfunction; Grade 3 renal 
dysfunction; Grade 3 neurological dysfunction; 
d) Level 4: requires positive pressure breathing or mechanical ventilation. 

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4) Treatment of cytokine release syndrome (CRS) 
a) In view of the potential clinical risks of CART treatment, we will closely monitor the 
patient's vital signs after CART infusion; if fever occurs, blood is drawn for C-reactive 
protein, serum ferritin, serum IL-6 and sIL. Early detection of potential cytokine 
release syndrome, and active supportive treatment. 
b) If necessary, use IL-6R blocking monoclonal antibody (tocilizumab) as early as 
possible in the treatment of suspected severe patients. The dose is 4 mg / kg, which 
can be repeated once. The use of tocilizumab alone can relieve fever and CRS 
symptoms without inhibiting the proliferation of CAR-T cells. IL-6R blocking 
monoclonal antibody (Yamero tocilizumab) is a prescription drug produced by Roche 
can be provided adequately by the hospital. 
c) The use of high-dose steroid hormones equivalent to or above the doses of 100 
mg prednisone per day can quickly reverse the clinical symptoms of CRS. However, 
corticosteroid drugs can also inhibit the proliferation of CAR-T in vivo, so that 
patients with CRS treated with steroid drugs have a higher recurrence rate and affect 
the efficacy of CAR-T treatment. 
(3) Treatment of unspecific tissue damage 
Lung cancer cells and myeloid-derived immunosuppressive cells (MDSCs) in cancer 
tissues, although specifically express PD-L1, can be killed by PD-L1 CAR-T cells, but 
normal cells in the inflammatory site are also expressed under IFNγ induction, and 
there exists the possibility that normal tissues can be damaged by PD-L1 CAR-T cells 
(on-target, off-tumor toxicities). After receiving PD-L1 CAR-T cell infusion, patients 
need to be observed closely, especially the functions of brain, heart, lung, liver, 
kidney and other important organs. 
 (4) If the patient has serious side effects after treatment, high-dose corticosteroid 
therapy is required; the incidence of adverse events in clinical studies> 1/3; the 
progress of the disease, etc., can be regarded as a criterion for the termination of 
study. 
6. Subject withdrawal criteria 
Patients can withdraw from treatment and evaluation at any stage of the study, but 
as long as the patients treated with CAR-T they will participate in safety and efficacy 
evaluation. The reasons for withdrawal are as follows: 

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1. Voluntary withdrawal, patients can freely withdraw from the trial at any time, and 
will not affect future treatment; 
2. The investigator believes that the patient's compliance with the study is poor; 
3. Missing follow-up; 
4. Those who have disease progression or intolerable adverse reactions, and the 
doctor determines that it is not appropriate to continue the study. 
7. Criteria and evaluation methods 
for efficacy 
1) Use flow cytometry or quantitative PCR to monitor the proliferation and survival of 
PD-L1 CAR-T cells in vivo. CAR-T cell proliferation and survival in vivo will be 
monitored regularly by flow cytometry or quantitative PCR after the last (day 7) 
infusion of CAR-T cells. Observe and test every 2 months for 1 year, and then every 
quarter for 2 years after infusion. 
2) Record the anti-tumor effect every follow up after infusion of PD-L1 CAR-T. 
We will adopt RECIST (Response Evaluation Criteria in Solid Tumors version 1.1) [48] 
and Immune-Related Response Criteria [49] to evaluate the anti-tumor efficacy of 
PD-L1CAR-T cells . 
a. If effective, determine whether they are partial response (PR) or complete 
response (CR). Due to the small number of subjects, the response should be 
recorded in detail. 
b. At the same time, record their progression-free survival (PFS). 
3) Record the secondary tumors. 
4) Record the overall survival and cause of death. 
5) For patients with preserved tumor cells, determine the correlation between the 
activity of CAR-T cells to kill tumor cells in vitro and clinical response. 
6) Check whether the host produces cellular and humoral immunity against PD-L1 
CAR T cells, determine the host's production of antibodies against PD-L1 CAR or 
other transgenic genes. 
7) Determine the cell subsets of PD-L1 CAR-T cells (CD3, CD4, CD8, Tcm, Tem, and 

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Treg). 
8. Set up of the sample size 
According to the number of cases of the phase I clinical trial, the number of the 
patients with advanced lung cancer receiving PD-L1 CAR-T cell therapy was 
determined as follows: 
The number of cases to enroll in this clinical trial was 20. Considering the 10% 
dropout rate during the study period, the number of cases of lung cancer that met 
the inclusion criteria and were not included in the exclusion criteria was 22 in this 
study: 
The study was of exploratory nature, so the sample size was set to include all 
available patients who received PD-L1 CAR-T treatment. 
8.1 Data set 
Intention-to-treat population (ITTP): Refers to all cases that express an intention to 
receive treatment and sign an informed consent. 
Adjusted intention-to-treat population (MITTP): refers to signing an informed 
consent form and having at least one effective data record on the main efficacy 
indicators after receiving treatment. Baseline data analysis is based on MITTP. The 
efficacy analysis is based on the results of MITTP analysis. 
People who meet the protocol (PPP): refer to the cases that meet the inclusion 
criteria, do not belong to the exclusion criteria, and complete the treatment plan, 
that is, analyze the cases that complete the trial plan, have good compliance, and 
complete the CRF regulations (PP analysis). PP analysis is mainly used for the main 
therapeutic indexes. PPP needs to meet a series of conditions: 
(1) Join the plan. Complete all evaluations without violating the selection and 
exclusion criteria specified in the plan; 
(2) Complete at least one course of autologous CAR T cell infusion; 
(3) No other drugs that affect the evaluation of efficacy are used. 
Safety Evaluation Population (SAP): Cases with safety index records. The incidence of 
adverse reactions took SAP as the denominator. 

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8.2 Missing data 
Use LOCF estimation (last observation carry forward) for missing data of important 
indicators. 
8.3 Statistical analysis methods 
Statisticians and main researchers formulate statistical analysis plans based on the 
research plan and complete the documentation before the data is locked. Statistical 
analysis was performed using SPSS 20.0 statistical analysis software. 
The curative effect evaluation used the solid tumor curative effect evaluation 
standard RECIST1.1 to evaluate the objective response rate ORR and disease control 
rate DCR. The dose data is expressed by x ± s, and the comparison of different time 
points is by repeated measurement analysis of variance. The description of 
classification indicators uses various types of cases and percentages. Descriptive 
statistics of the completion of the study and the efficacy indicators. The demographic 
data is grouped into other statistical descriptions. Patients who withdrew or died 
before treatment and patients who did not complete the required safety observation 
evaluation will be evaluated separately. 
The safety assessment will be descriptive, and safety indicators include adverse 
events, laboratory examination data, and vital signs. The type, severity, frequency 
and relationship with the test substance of all adverse events that occurred during 
the study will be listed. Specially note the cases where the study was terminated due 
to adverse events and serious adverse events occurred. For laboratory tests, list the 
completed items in the form of cross-tabs before and after treatment. Examination 
items with abnormal values and clinical significance should be listed. 
9. Ethics 
9.1 Regulatory and ethical compliance 
Design, execute, and report this clinical trial in accordance with Chinese GCP and 
other locally applicable regulations, and the ethical rules stipulated in the Declaration 
of Helsinki 

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9.2 Responsibilities of researchers and ethic committees 
Before the start of the study, the research protocol and the written informed consent 
must be reviewed and approved by the ethics committee of a formal research 
institution. The investigator agreed to conduct the study in accordance with these 
documents and all instructions and operations shown in this test protocol. 
9.3 Informed consent process 
Qualified patients can only be enrolled in this study after providing written 
EC-approved informed consent. 
10. Implementation plan 
Period 
Content and goals 
2017/9-2018/9 
Collection of tumor tissue and peripheral blood samples of all 
enrolled patients and corresponding clinical information 
collection Immediately carry out clinical trial treatment to 
evaluate safety and efficacy 
2018/10-2019/3 
The collected clinical samples are collected for sequencing and 
basic data analysis 
2019/4-2019/9 
Analyze data, draw conclusions, write papers, submit articles 
and publish articles 
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