EFFECT-neo: A Prospective, Open-label, Multicenter Phase III Study to Evaluate Efficacy and Safety of Pembrolizumab Combined With Standard Chemotherapy in the Neoadjuvant Treatment of Local Advanced (LA) HNSCC
Phase: PHASE3
Conditions: Head and Neck Squamous Cell Carcinoma, Neoadjuvant Therapy, Pembrolizumab
Sponsor: Beijing Tongren Hospital

 
 
 
EFFECT-neo: A Prospective, Open-label, Multicenter 
Phase III Study to Evaluate Efficacy and Safety of 
Pembrolizumab Combined With Standard Chemotherapy 
vs. Standard Chemotherapy Given Prior to Surgery for 
stage IIIA- IVB Locally Advanced Head and Neck 
Squamous Cell Carcinoma 
 
Version：       TRH-202301V1.0                      
Date：          2023/03/15                          
Department： Otorhinolaryngology Head and Neck Surgery            
Project manager：  Zhigang Huang                              
 
 
 
 
 
 
 
 

1、Background 
Head and neck squamous cell carcinoma (HNSCC) refers to a series of tumors 
in the head and neck region, including the oral cavity, pharynx, larynx, nasal 
cavity, paranasal sinuses, thyroid and salivary glands. Malignant tumors of the 
head and neck account for about 19.9% to 30.2% of all tumors in the body, 
and the incidence rate ranks sixth among all malignant tumors. More than 90% 
of the pathological types are squamous cell carcinomas [1-2]. The treatment of 
squamous cell carcinoma of the head and neck is mainly based on surgery. 
Early cases can be cured by simple surgical resection or radiotherapy, and 
advanced cases can be cured by surgery combined with radiotherapy or 
chemotherapy, which can achieve better curative effect. However, most 
patients with head and neck tumors are already in locally advanced (stage III-
IVB) or advanced stage when they see a doctor, and may have lost the 
opportunity for surgery, so they can only choose comprehensive treatment 
based on radiotherapy and chemotherapy. 
Neoadjuvant chemotherapy, also known as induction chemotherapy, refers to 
chemotherapy used before surgery or radiotherapy. It has good patient 
compliance, can reduce tumor burden, improve the rate of organ function 
preservation in surgical patients, eliminate potential metastatic lesions, and 
reduce distant metastasis. risks and other advantages [3]. Clinical research on 
induction chemotherapy began in the mid-1970s, and the most commonly 
used induction chemotherapy regimen was PF regimen (cisplatin (cisplatin, P) 

+ 5-fluorouracil (5-fluorouracil, 5-FU). Along with paclitaxel (docetaxel, T ), and 
is also exploring whether paclitaxel can be added to the induction 
chemotherapy regimen. For resectable HNSCC, the European GORTEC study 
showed that the addition of paclitaxel (T) on the basis of the PF regimen can 
improve the efficacy of induction chemotherapy, and its pCR rate The rate 
reached 13.4%, and the ORR was as high as 80%. A number of Phase II and 
Phase III clinical studies concluded that induction chemotherapy can reduce 
the rate of distant metastasis[4-6]. 
PD-L1 is a key negative regulator of autoreactive T cells, and plays a role in 
maintaining peripheral immune tolerance and suppressing autoimmunity in 
multiple ways, promoting T cell exhaustion and dysfunction, and tumor cells 
evading immune surveillance. PD-1/PD-L1 monoclonal antibody restores the 
function of tumor-specific T cells by blocking the combination of PD-1 and 
PD-L1, and achieves the effect of enhancing anti-tumor immunity. It has been 
used to treat a variety of tumors. Pembrolizumab is a fully humanized IgG4-
kappa anti-PD-1 monoclonal antibody. The FDA approved pembrolizumab in 
2016 for the treatment of platinum-resistant recurrent or metastatic head and 
neck squamous cell carcinoma. Currently, pembrolizumab combined with 
chemotherapy can be used as the first-line treatment for recurrent/metastatic 
head and neck squamous cell carcinoma. At the same time, pembrolizumab 
can also be used as a second-line treatment for recurrent/metastatic head 
and neck squamous cell carcinoma that is resistant to beneficiation. 

The efficacy of PD-1 monoclonal antibody as a neoadjuvant therapy in head 
and neck squamous cell carcinoma is not yet clear, but in view of the good 
effect of immunotherapy in head and neck squamous cell carcinoma, 
induction therapy with PD-1 monoclonal antibody is considered to have a 
good clinical effect Application prospects [7]. At present, relevant clinical trials 
are underway, such as a phase III clinical trial KEYNOTE-689 (NCT03765918) 
for cancers of the oral cavity, oropharynx, hypopharynx, and larynx, using 
pembrolizumab as neoadjuvant therapy, compared with traditional surgery 
combined with adjuvant therapy program, and the results of the study are yet 
to be published. The 2020 ASCO meeting reported the study of neoadjuvant 
therapy nivolumab combined with carboplatin and paclitaxel for resectable 
locally advanced head and neck cancer. The surgery rate was 100%, CT 
showed no tumor progression, and the margin negative rate was 100%. , The 
pathological complete response rate (pCR) was 42%. Grade 3 toxicity 
occurred in 37% of patients, and grade 3-4 neutropenia occurred in 4 patients. 
It suggested that the neoadjuvant therapy of nivolumab combined with 
carboplatin and paclitaxel was well tolerated and the efficacy was 
satisfactory[7]. 
In summary, we speculate that, compared with the traditional induction 
chemotherapy 
regimen, 
the 
induction 
chemotherapy 
regimen 
of 
pembrolizumab combined with chemotherapy may be safer and more 
effective, and easier for clinical application. At present, there are no research 

reports on the induction chemotherapy of pembrolizumab combined with 
cisplatin and nab-paclitaxel for patients with locally advanced operable head 
and neck squamous cell carcinoma. We intend to conduct a randomized 
controlled study on the efficacy and safety of pembrolizumab combined with 
chemotherapy as neoadjuvant therapy in Chinese patients with operable head 
and neck squamous cell carcinoma, and provide a basis for the neoadjuvant 
therapy of pembrolizumab combined with chemotherapy. 
Keyword ：Head and Neck Squamous Cell Carcinoma ，immunotherapy ，
chemotherapy 
 
Reference 
[1]. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: 
GLOBOCAN estimates of incidence and mortality worldwide for 36 
cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6):394-424. 
[2]. Argiris A, Harrington K, Tahara M, et al. Evidence-Based Treatment 
Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the 
Head and Neck. 2017;7:72 
[3]. Pointreau Y, Garaud P, Chapet S, et al. Randomized trial of induction 
chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel 
for larynx preservation[J]. J Natl Cancer Inst, 2009, 101(7): 498-506. DOI: 
10.1093/jnci/djp007 
[4]. Paccagnella A, Ghi MG, Loreggian L, et al. Concomitant 

chemoradiotherapy versus induction docetaxel, cisplatin and 5 
fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally 
advanced head and neck cancer: a phase II randomized study[J]. Ann 
Oncol, 2010, 21(7): 1515-1522. DOI: 10.1093/ annonc/mdp573. 
[5]. Licitra L, Vermorken JB. Is there still a role for neoadjuvant chemotherapy 
in head and neck cancer[J]? Ann Oncol, 2004, 15(1): 7-11. 
[6]. Hitt R, Grau JJ, López-Pousa A, et al. A randomized phase III trial 
comparing induction chemotherapy followed by chemoradiotherapy 
versus chemoradiotherapy alone as treatment of unresectable head and 
neck cancer[J]. Ann Oncol, 2014, 25(1): 216-225. DOI: 
10.1093/annonc/mdt461. 
[7]. Borch TH, Donia M, Andersen MH, et al. Reorienting the immune system 
in the treatment of cancer by using anti-PD-1 and anti-PD-L1 
antibodies[J]. Drug Discov Today, 2015, 20(9):1127-1134. 
 
2、Research purpose and research content 
(1) Purpose  
A randomized controlled study was conducted to investigate the efficacy and 
safety of adjuvant pembrolizumab combined with standard chemotherapy in 
Chinese patients with operable head and neck squamous cell carcinoma. 
(2) Research content 
The trial is a prospective, randomized, multicenter study aimed at evaluating 

the effectiveness and safety of pembrolizumab combined with standard 
chemotherapy versus standard chemotherapy in the neoadjuvant treatment 
of resectable locally advanced head and neck squamous cell carcinoma. The 
study consisted of 3 phases: screening period, treatment period and follow-
up period. After all patients signed the informed consent form, they entered a 
screening period of up to 28 days, during which the subjects will complete the 
screening assessment according to the visit plan. 
For 
patients 
who 
meet 
the 
inclusion 
criteria, 
1:1 
randomization, 
pembrolizumab 200mg d1 + chemotherapy (see 3.1 for detailed 
chemotherapy regimen) 2 cycles (experimental group), 2 cycles of 
chemotherapy (control group), and then stratified according to the patient's 
condition . If the imaging evaluation after neoadjuvant treatment is CR, 
adjuvant radiotherapy (60-66Gy) will be given; if the imaging evaluation is PR 
or SD, surgery (within 2 weeks) will be performed, followed by standard 
treatment. If the imaging evaluation is PD, the patients will be removed from 
the group and given standard treatment. The enrolled patients must closely 
monitor the adverse reactions of chemotherapy, and record the time, grading, 
treatment measures, outcome, etc. All patients were reviewed every 3 months 
for 1 year; after 1 year, they were reviewed every 6 months for 3 years; 
recurrence and survival data were recorded. 
(3) Study Outcome Measures  
Primary Outcome Measure:  

1. Pathological complete response rate (pCR) of pembrolizumab combined 
with standard chemotherapy neoadjuvant therapy in patients with locally 
advanced head and neck squamous cell carcinoma 
pCR was defined as the absence of residual invasive squamous cell 
carcinoma within the primary tumor specimen on resection/needle 
biopsy [Time Frame: 12 week] 
2. Pathological complete response rate (pCR) of standard chemotherapy 
neoadjuvant chemotherapy in patients with locally advanced head and 
neck squamous cell carcinoma 
Secondary Outcome Measures: 
1. The objective response rate (ORR) of neoadjuvant therapy with 
pembrolizumab combined with standard chemotherapy 
ORR was defined as the percentage of participants in the analysis 
population who have a Complete Response (CR: disappearance of all 
target lesions) or a Partial Response (PR: ≥30% decrease in the sum of 
diameters of target lesions) per RECIST 1.1 [Time Frame: 12 week] 
2. The objective response rate (ORR) of neoadjuvant chemotherapy with 
standard chemotherapy 
3. The 1-year and 2-year event-free survival rates (1y-EFS, 2y-EFS) after 
pembrolizumab combined with standard chemotherapy neoadjuvant 

therapy 
EFS is defined as the time from randomization to any event, including 
disease progression, discontinuation of treatment for any reason, or 
death [Time Frame: 2 year] 
4. The 1-year and 2-year event-free survival rate (1y-EFS, 2y-EFS) after 
neoadjuvant chemotherapy with standard chemotherapy 
5. The functional preservation rate of pembrolizumab combined with 
standard chemotherapy 
Functional preservation is defined as preserving and repairing the 
anatomical structure of the larynx, and reconstructing the breathing and 
pronunciation functions of the larynx, or protecting the appearance of 
the tongue and physiological functions such as speech, chewing and 
swallowing [Time Frame: 3 year] 
6. The functional preservation rate of standard chemotherapy 
7. The 2-year overall survival rate (2y-OS) after Neoadjuvant 
pembrolizumab combined with standard chemotherapy 
OS was defined as the time from randomization to death due to any 
cause. Participants without documented death at the time of the final 
analysis were censored at the date of the last follow-up [Time Frame: 2 
year] 
8. The 2-year overall survival rate (2y-OS) after Neoadjuvant Therapy with 
standard chemotherapy 

9. Pathological complete response rate (pCR) of pembrolizumab combined 
with standard chemotherapy as neoadjuvant therapy in patients of 
locally advanced head and neck squamous cell carcinoma with CPS 
(combined positive score) ≥1 
10. Pathological complete response rate (pCR) of pembrolizumab combined 
with standard chemotherapy as neoadjuvant therapy in patients of 
locally advanced head and neck squamous cell carcinoma with CPS 
(combined positive score) ＜1 
11. The 2-year event-free survival rates (2y-EFS) after pembrolizumab 
combined with standard chemotherapy neoadjuvant therapy with CPS 
(combined positive score) ≥1 
12. The 2-year event-free survival rates (2y-EFS) after pembrolizumab 
combined with standard chemotherapy neoadjuvant therapy with CPS 
(combined positive score) ＜1 
13. The 2-year overall survival rate (2y-OS) after Neoadjuvant 
pembrolizumab combined with standard chemotherapy with 
CPS(combined positive score) ≥1 
14. The 2-year overall survival rate (2y-OS) after Neoadjuvant 
pembrolizumab combined with standard chemotherapy with 
CPS(combined positive score) ＜1 
15. Incidence of Treatment-Emergent Adverse Events (TRAEs) of 
pembrolizumab combined with standard chemotherapy in neoadjuvant 

therapy 
TRAEs include 5 levels, base on Common Terminology Criteria for 
Adverse Events (CTCAE) is widely accepted as the standard 
classification and severity grading scale for adverse events in cancer 
therapy, clinical trials and other oncology settings.[Time Frame: 3 year] 
16. Incidence of Treatment-Emergent Adverse Events (TRAEs) of 
neoadjuvant chemotherapy with standard chemotherapy 
17. The quality of life of pembrolizumab combined with standard 
chemotherapy neoadjuvant therapy measured by KPS scores 
A standard way of measuring the ability of cancer patients to perform 
ordinary tasks. The KPS scores range from 0 to 100. A higher score 
means the patient is better able to carry out daily activities [Time Frame: 
3 year] 
18. The quality of life of standard chemotherapy neoadjuvant therapy 
measured by KPS scores 
 
3、Study design 
(1) Overall Study Design  
 
A prospective, unblinded randomized, multicenter phase III study; 
 
Patients who met the inclusion criteria were randomized in a 1:1 ratio and 
given 2 cycles of pembrolizumab 200 mg d1 + chemotherapy (see the 
table below for detailed chemotherapy regimens) (experimental group) 

and 2 cycles of chemotherapy (control group), and were divided 
according to the patient's condition. layer. If the imaging evaluation is CR 
after neoadjuvant treatment, radiotherapy (60-70Gy) ± chemotherapy 
(investigator's choice) will be given as adjuvant treatment; if the imaging 
evaluation is PR or SD, surgery (within 2 weeks) will be performed, and then 
standard treatment will be given. treat. 
 
If the imaging evaluation is PD, standard treatment will be given. 
 
Enrolled patients must closely monitor the adverse reactions of 
chemotherapy and record the time, grade, treatment measures, 
outcomes, etc. All patients were reviewed every 3 months for 1 year; after 
1 year, they were reviewed every 6 months for 3 years; patient recurrence 
and survival data were recorded. 
The chemotherapy regimen is as follows: 
Drug 
Dose/Potency Administration 
route 
Dosing interval 
Pembrolizumab
200mg 
IV 
Day 1 of each 3-week cycle 
Cisplatin 
75mg/m2 
IV 
Day 1 of each 3-week cycle 
Carboplatin 
AUC 2 
IV 
Day 1-3 of each 3-week 
cycle 
nab-Paclitaxel 
260mg/m2 
IV 
Day 1 of each 3-week cycle 
Docetaxel 
75mg/m2 
IV 
Day 1 of each 3-week cycle 

Fluorouracil 
750mg/m2 
IV 
Day 1-5 of each 3-week cycle 
Nedaplatin 
80-100mg/m2 
IV 
Day 2-4 of each 3-week 
cycle 
Liposomal 
paclitaxel 
135-175mg/m2 
IV 
Day 1 of each 3-week cycle 
(2) Study duration 
Based on the calculation that all 10 centers enroll 7-8 patients per month, 
272 patients are planned to enroll, and the enrollment time will take about 4 
years. The adverse reactions of chemotherapy must be closely monitored, 
and the time, grading, treatment measures, and outcome should be 
recorded. and so on.  
(3) Study flow chart 
 
(4) Study object 
1. Inclusion criteria  
The following conditions must be met at the same time: 
1) Patients with stage IIIA-IVB head and neck squamous cell carcinoma 

confirmed by histology and/or cytology; 
2) Have not received immunotherapy in the past; 
3) The researchers believe that he can safely receive pembrolizumab 
combined with chemotherapy or neoadjuvant chemotherapy; 
4) Age ≥18 years; 
5) ECOG 0-2; 
6) Measurable disease as defined by RECIST v1.1; 
7) Organs function normally; 
8) Female and male participants of reproductive potential must agree to 
use appropriate contraception throughout the study period and for 180 
days after the last study treatment; 
9) Male participants must not donate sperm throughout the study and for 
180 days after the last study treatment. 
 
2.Exclusion Criteria: 
1) Presence of distant metastasis; 
2) Female subjects with a positive urine pregnancy test within 72 hours 
before the start of the study or within 24 hours after starting radiation 
therapy (with or without cisplatin); 
3) received a live vaccine within 30 days before enrollment; 

4) Diagnosed with immunodeficiency or receiving systemic steroid 
treatment or any other form of immunosuppressive treatment within 7 
days before enrollment; 
5) Have imaging detectable (even if asymptomatic and/or previously 
treated) central nervous system metastases and/or cancerous 
meningitis; 
6) Have undergone surgery before commencing the study or have failed 
to recover adequately from toxicity or complications resulting from the 
intervention; 
7) Previous allogeneic tissue/solid organ transplant; 
8) Severe hypersensitivity reaction (≥Grade 3) to pembrolizumab or any 
of its excipients, radiotherapy, platinum, paclitaxel, 5-FU or their 
analogs; 
9) Have an active autoimmune disease requiring systemic therapy in the 
past 2 years; 
10) History of (non-infectious) pneumonia requiring steroid treatment; 
11) Have a history of human immunodeficiency virus (HIV) infection; 
12) Have a history of hepatitis B or be positive for hepatitis B virus (defined 
as a positive reaction to hepatitis B surface antigen [HBsAg]) or active 
hepatitis C (defined as detection of hepatitis C virus [HCV] ribonucleic 
acid). 

13) Have any medical history, treatment, or laboratory abnormalities that 
could confound the study results, interfere with participant 
participation throughout the study, or be detrimental to the best 
interests of the participant (e.g., Hashimoto's thyroiditis, etc.); 
14) Have a known history of mental illness or substance abuse disorder 
 
3. Exit criteria  
Subject withdrawal refers to the interruption of a clinical trial by a subject 
for any reason. Subjects must withdraw from this trial for the following 
reasons: 
1) Discussed by MDT before operation, the imaging assessment was 
progressive disease (PD) 
2) Serious noncompliance with the requirements of this trial 
3) Clinical signs or laboratory test results suggestive of pregnancy 
4) Taking illegal drugs, or using other substances that the researchers 
believe are likely to cause toxicity or otherwise affect the research 
results 
5) Diseases or conditions that occurred during the trial, which, in the 
judgment of the investigator, significantly affected the evaluation of 
clinical status and study endpoints 
6) another cancer 
7) Subject lost to follow-up 

8) Those who interrupted taking the study drug for more than 28 days 
9) Subject died 
10) In all cases, the reason for withdrawal must be documented on the 
case report form and in the subject's medical record. 
11) The subject himself or his legal representative requests to withdraw 
12) In the opinion of the investigator, continued participation in the trial 
would be detrimental to the subject's health 
13) Subjects were blinded for any reason 
14) Specific requirements for trial sponsors 
The studies did not accept healthy volunteers and did not involve 
vulnerable groups. 
(5) Definitions of Treatment/Intervention Groups and Controls  
Experimental Arm：Pembrolizumab+ standard chemotherapy 
Active Comparator Arm：Standard chemotherapy 
(6) Randomization, allocation concealment, and blinding  
1. Methods for generating random sequence assignments 
Simple random method  
2. Method of random assignment  
Take random number table and random remainder grouping. 
3. Blinding and unblinding  
The trial was an open-label, non-blinded study. 
（7）Study program 

1. Study treatment/Intervention Period 
The experimental group received pembrolizumab 200 mg d1 + 
chemotherapy regimen, q21d*2 cycles (experimental group), and the 
control group received chemotherapy regimen, q21d*2 cycles (control 
group), and were later stratified according to the patient's condition. If the 
imaging evaluation is CR after neoadjuvant treatment, radiotherapy (60-
70Gy) ± chemotherapy (investigator's choice) will be given as adjuvant 
treatment; if the imaging evaluation is PR or SD, surgery (within 2 weeks) 
will be performed, and then standard treatment will be given. treat. If 
progressive disease (PD) occurs, treatment is carried out according to 
routine diagnosis and treatment. 
1.1 Evaluation stage 
Treatment cycle: A treatment cycle (course of treatment) refers to every 
3 weeks from the start of the first study drug application. 
1.2 Screening stage 
Before taking study drug, the following information should be collected  
during the screening phase: 
1) An informed consent form must be signed before starting any trial-
related procedures; recruitment into this trial means signing an 
informed consent form. 
2) Use RECIST and iRECIST standards for tumor radioactivity 
assessment. 

3) All suspicious lesions require imaging scanning. If bone metastases 
are suspected, a bone scan should be performed. 
4) Conduct a complete physical examination on the subject and collect 
relevant medical history. Note: Relevant symptoms and signs that 
have existed before recruitment (signing of informed consent) and 
have not progressed at the time of signing of informed consent 
should be recorded on the medical history page. 
5) Symptoms and signs that existed before recruitment (signing the 
informed consent form) and were progressing when signing the 
informed consent form, as well as symptoms and signs that appeared 
or worsened after recruitment (even before starting to take the study 
drug), According to NCI-CTCAE version 5.0 guidelines, adverse 
events should be recorded on the adverse events page. 
6) 12-lead electrocardiogram (ECG). 
7) Vital signs: After the subject rested for 5 minutes, measure and 
record his blood pressure (mmHg), heart rate (beats/min), respiratory 
rate (beats/min) and body temperature (°C). 
8) Virus testing: anti-HIV, syphilis antibodies, anti-HCV, five hepatitis B 
tests, and HBV-DNA. 
9) Laboratory tests: Routine blood tests, blood biochemistry, routine 
urine tests, thyroid function, cortisol, pancreatic amylase and lipase 
tests are required, and other tests such as lymphocyte 

subpopulation, CPS test and oropharyngeal cancer p16 test (non- 
must). 
10) Demographic information: age, gender, weight, height, race. 
11) Concomitant combined medications and treatments. 
1.3 Observation period 
During treatment, a blood routine (required), urine routine, stool routine + 
occult blood, liver and kidney function and electrolytes, thyroid function, 
and pancreatic function tests (if necessary, the researcher can add the 
above based on the actual situation of the subject) examine). AEs were 
observed and recorded at any time during the research process. An 
electrocardiogram is performed once every cycle. If symptoms such as 
precordial pain and palpitations occur, the myocardial enzyme spectrum 
should be detected immediately, the electrocardiogram should be 
checked at any time, and cardiac color ultrasound should be performed; 
vital signs, PS score, physical examination, and fasting should be 
performed once every cycle. Blood glucose monitoring and 
comprehensive coagulation examination. Note: After 2 cycles of 
neoadjuvant therapy, imaging evaluation is required. 
1.4 Follow-up period 
Eligible patients will undergo an imaging evaluation after completion of 
radiotherapy (including receiving CCRT or postoperative RT). Imaging 
evaluations will be performed every 3 months within the next 1 year 

(brain MRI or brain CT and bone scan examinations will be determined by 
the researcher whether and when the patient needs them); after 1 year, 
reexamination will be performed every 6 months for 3 years. . If the 
subject received any subsequent anti-cancer treatment after completion 
of treatment, treatment details (at least for the first treatment) will be 
collected. Post-trial follow-up will end at the time of the final overall 
survival (OS) analysis. If a subject discontinues medication due to an 
adverse event or abnormal clinical laboratory test values, the subject 
should be followed up until the adverse event resolves, the subject's 
condition becomes stable, or 30 days (whichever occurs first). 
2. Supply of Investigational Drug/Treatment/Intervention 
Cisplatin, carboplatin, nedaplatin, liposome paclitaxel, albumin-paclitaxel, 
docetaxel, fluorouracil and other drugs are provided by this research 
center, and patients routinely pay for treatment. Pembrolizumab is 
purchased at the patient's own expense during the entire treatment 
process. The policy of charitable drug donation is: purchase 2 cycles and 
add 2 cycles, and purchase 2 more cycles and then donate the drug to 
15 cycles. 
3. Chemotherapy dose adjustment  
Pretreatment before chemotherapy: 

Adequate hydration therapy must be performed prior to cisplatin 
administration. Standard chemotherapy can only be given after the 
infusion of pembrolizumab injection is completed. 
Dose adjustment 
For the dose adjustment of cisplatin, carboplatin, nedaplatin, paclitaxel 
liposome, nab-paclitaxel, fluorouracil and docetaxel in the regimen, 
please refer to the approved product instructions. During the study, if 
the researcher judges that the toxicity of chemotherapy drugs is 
intolerable (such as grade 4 hematological toxicity, ≥ grade 3 febrile 
neutropenia and ≥ grade 3 non-hematological toxicity (except nausea 
and vomiting) etc.), the dose of chemotherapy drugs can be adjusted 
upon the judgment of the researcher. In principle, 2 dose adjustments 
are allowed, and it is recommended that the first dose adjustment be 75% 
of the original dose, and the second adjustment be 50% of the original 
dose 
Treatment adjustments for pembrolizumab-related immune-related 
AEs 
Dosing suspension or discontinuation may be required based on 
individual patient safety and tolerability. Dosage increases or decreases 
are not recommended. 
Table 1 Treatment Modifications for irAEs Associated with Pembrolizumab 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
Other allowed pembrolizumab dose interruptions 
Treatment with pembrolizumab may be discontinued for conditions other 
than treatment-related AEs such as medical/surgical events or logistical 
reasons not related to study treatment. Unless otherwise discussed with 
the investigator, subjects should resume study treatment within 3 weeks 
of planned discontinuation. The reason for the discontinuation should be 
documented in the subject's study record. 
Pembrolizumab AE management 
Immune-Related Pneumonia: 
Among patients receiving pembrolizumab, a total of 278 (4.4%) patients 
developed pneumonia, 122 (1.9%), 70 (1.1%), and 15 grade 2, 3, 4, and 5 
cases, respectively. (0.2%) and 12 cases (0.2%), the median time to the 
onset of pneumonia was 3.2 months (range 2 days to 26.8 months), and 
the median duration was 2.0 months (range 1 day to 25.34 months) . 
Patients with a history of previous chest radiation had a higher incidence 
of pneumonia (8.1%) than those without prior chest radiation (3.3%). 

Pneumonia led to discontinuation of pembrolizumab in 105 (1.7%) patients. 
151 patients recovered from pneumonia, and 2 patients recovered with 
sequelae. Among patients with non-small cell lung cancer, a total of 160 
patients (5.7%) developed pneumonia, 62 cases (2.2%), 47 cases (1.7%), 
and 14 cases (0.5%) of grade 2, 3, 4, and 5 pneumonia respectively and 10 
cases (0.4%) in NSCLC patients with previous thoracic radiotherapy, the 
incidence of pneumonia was 8.9%. 
Immune-related colitis: 
Among patients receiving pembrolizumab, colitis occurred in 115 patients 
(1.8%), with 33 (0.5%), 66 (1.0%), and 4 (1.0%) grade 2, 3, and 4 cases, 
respectively. 0.1%), the median time to onset of colitis was 4.3 months 
(range 7 days to 24.3 months), the median duration was 0.9 months (range 
1 day to 10.5+ months), and colitis resulted in 31 cases (0.5%) patients 
discontinued pembrolizumab treatment. Eighty-nine patients recovered 
from colitis, and 2 patients had sequelae after recovery. 
Immune-Related Hepatitis: 
Hepatitis occurred in 57 (0.9%) patients receiving pembrolizumab, with 9 
(0.1%), 36 (0.6%), and 9 (0.1%) grade 2, 3, and 4 cases, respectively. %), 
the median time to hepatitis onset was 2.8 months (range 8 days to 21.4 
months), the median duration was 1.1 months (range 1 day to 20.9+ 
months), and hepatitis resulted in 24 cases (0.4% ) patients discontinued 
pembrolizumab treatment. 39 cases of hepatitis were cured. 

Immune-related nephritis: 
Among patients receiving pembrolizumab monotherapy, a total of 25 
patients (0.3%) developed nephritis, 8 patients (0.1%), 14 patients (0.2%) 
and 1 patient ( <0.1%). The median time to onset of nephritis was 3.5 
months (range 12 days to 21.4 months). Median duration was 1.9 months 
(range 6 days to >12 months). Nephritis led to discontinuation of 
pembrolizumab in 10 (0.2%) patients. 15 patients recovered from nephritis, 
and 3 patients recovered with sequelae. In patients with non-squamous 
NSCLC treated with pembrolizumab plus pemetrexed lead chemotherapy 
(Cn=488), the incidence of nephritis (all grades) was 1.4%, and the 
incidence of grade 3 nephritis was 0.8%, The incidence of grade 4 
nephritis was 0.4%. 
Immune-Related Endocrine Diseases: 
A total of 47 (0.7%) patients receiving pembrolizumab developed adrenal 
insufficiency, including 20 (0.3%), 20 (0.3%), and 3 patients with grade 2, 3, 
or 4 (<0.1%). The median time to onset of adrenal insufficiency was 5.4 
months (1 day to 17.7 months). Median duration was not reached (3 days 
to over 26.2 months). Four patients (0.1%) discontinued the drug due to 
adrenal insufficiency. Sixteen patients with adrenal insufficiency were 
cured, and 4 patients were cured with sequelae. 
Among the patients treated with pembrolizumab, a total of 39 patients 
(0.6%) developed hypophysis , with 14 (0.2%), 21 (0.3%), and 1 (0.3%) 

grade 2, 3, and 4 cases ( <0.1%). The median time to onset of hypophysis 
was 5.6 months (range 1 day to 17.7 months). Median duration was 3.3 
months (range 3 days to 20+ months). Hypophysis led to discontinuation 
of pembrolizumab in 8 (0.1%) patients. Eighteen patients recovered from 
hypophysis, and 9 patients recovered with sequelae. 
Hyperthyroidism occurred in a total of 263 (4.1%) patients receiving 
pembrolizumab, with 68 (1.1%) and 7 (0.1%) grade 2 or 3 cases, 
respectively. The median time to onset of hyperthyroidism was 1.4 months 
(range 1 day to 23.2 months). Median duration was 1.9 months (range 4 
days to 29.2+ months). Hyperthyroidism led to discontinuation of 
pembrolizumab in 3 (<0.1%) patients. 207 patients (78.7%) were cured of 
hyperthyroidism, and 5 patients were cured with sequelae. 
Hypothyroidism occurred in a total of 696 (11.0%) patients receiving 
pembrolizumab, with 513 (8.1%) and 8 (0.1%) grade 2 or 3 cases, 
respectively. The median time to onset of hypothyroidism was 3.4 months 
(range 1 day to 20.5 months). Median duration was not reached (range 2 
days to 32.6+ months). Two patients (<0.1%) discontinued pembrolizumab 
due to hypothyroidism. Hypothyroidism was cured in 159 patients (22.8%), 
and 10 patients were cured with sequelae. Among 909 HNSCC patients 
treated with pembrolizumab monotherapy, hypothyroidism occurred in 
16.1% (all grades) and grade 3 in 0.3%. Among 276 HNSCC patients 
treated with pembrolizumab combined with platinum and 5-FU 

chemotherapy, the incidence of hypothyroidism was 15.2%, all grade 1 or 
2. 
Immune-Related and Skin Adverse Reactions: 
Among patients receiving pembrolizumab, a total of 93 (1.5%) patients 
experienced immune-related severe skin reactions, with 12 (0.2%) and 67 
(1.1%) grade 2, 3, or 5 cases, respectively. %) and 1 case (<0.1%). The 
median time to onset of severe skin reactions was 3.2 months (range 3 
days to 19.4 months). Median duration was 1.8 months (range 1 day to 
27.3+ months). Severe skin reactions led to discontinuation of 
pembrolizumab in 9 (0.1%) patients. 67 cases of severe skin reactions 
were cured. 
4. Concomitant treatment and follow-up 
If a certain drug treatment is considered necessary for the subject's health 
and is not expected to interfere with the evaluation of pembrolizumab or 
interact with it, it can continue to be used during the study. 
All concomitant medications must be reported on a Case Report Form 
(CRF). In addition, any diagnoses, treatments, or procedures performed 
during the trial should be documented, including dates, indications, 
interventions, and a description of any clinical findings. 
Patients were not allowed to receive any other anti-cancer treatment 
during the trial. 
Any other medications necessary for the patient may be used at the 

investigator's discretion. Prophylactic use of drugs for the treatment of 
nausea, vomiting, antiallergic, acute cholinergic reactions, and diarrhea is 
permitted. Including a small amount of oral steroids for a short period of 
time to resist vomiting and stimulate appetite. 
All subjects should spare loperamide (imodium); hematopoietic growth 
factors (such as G-CSF or GM-CSF) should be used in the treatment of 
febrile neutropenia and Level 3 and above have decreased white blood 
cells and neutrophils, but they cannot be used as preventive drugs. 
Growth factors should be discontinued at least 48 hours before the start 
of the next cycle of chemotherapy. Palliative surgery was allowed during 
treatment. Palliative radiotherapy is permitted for non-target lesions 
during treatment, but should be carefully evaluated for disease 
progression. Whether study treatment should be interrupted during 
radiotherapy may be at the discretion of the investigator or delayed until 
the patient recovers from acute reversible adverse reactions. 
The following concomitant treatments are permitted: 
In accordance with the guidelines of the American Society of Clinical 
Oncology (ASCO) and relevant domestic clinical guidelines, the use of 
recombinant human granulocyte colony-stimulating factor, 
erythropoietin, interleukin 11, and recombinant human thrombopoietin is 
allowed. 
Supportive treatment: including antiemetic, antidiarrheal, acid 

suppression, antipyretic, antiallergic, diabetes treatment, hypertension 
treatment, use of antihypertensive drugs, use of analgesics, use of 
antibiotics and others (including but not limited to blood products usage 
of). 
Each subject will have a treatment visit and a safety assessment visit 
every 3 weeks (± 3 days) during postoperative treatment, and the 
planned follow-up time is 3 years; tumor imaging will be performed every 
12 weeks after surgery or starting concurrent chemoradiotherapy 
Medical examination and efficacy evaluation. If the subject has 
terminated the study treatment and his imaging evaluation did not reach 
PD, tumor imaging examination and efficacy evaluation should still be 
performed every 6 weeks (±7 days) until the disease progresses and new 
anti-tumor treatment is started , died or lost to follow-up. After the 
subject terminates the study treatment, a safety follow-up should be 
conducted 30 days (±7 days) after the last dose, and AEs related to the 
study drug should be collected within 90 days after the last dose (or 
before starting new anti-tumor treatment) with all SAE. All subjects who 
have received pembrolizumab injection at least once will be followed up 
every 3 months (±14 days) after the end of treatment until the end of the 
study, death or loss of follow-up. 
（8）Evaluation  
During the observation period of treatment, a blood routine (mandatory), 

urine routine, stool routine + occult blood, liver and kidney function and 
electrolytes, thyroid function, and pancreatic function tests (if necessary, 
the researcher can test the subject based on the actual situation) In 
addition to the above inspection). AEs were observed and recorded at any 
time during the research process. An electrocardiogram is performed 
every cycle. If symptoms such as precordial pain and palpitations occur, 
the myocardial enzyme spectrum should be detected immediately, the 
electrocardiogram should be checked at any time, and a cardiac color 
ultrasound should be performed; vital signs, PS score, physical 
examination, and fasting should be performed once every cycle. Blood 
glucose monitoring and comprehensive coagulation examination. During 
the follow-up period, an imaging evaluation will be performed after the 
completion of radiotherapy (including CCRT or postoperative RT). Imaging 
evaluations will be performed every 3 months within the next 1 year (brain 
MRI or brain CT and bone scan examinations will be determined by the 
researcher whether and when the patient needs them); after 1 year, 
reexamination will be performed every 6 months for 3 years. . If the subject 
received any subsequent anti-cancer treatment after completion of 
treatment, treatment details (at least for the first treatment) will be 
collected. Post-trial follow-up will end at the time of the final overall survival 
(OS) analysis. If a subject discontinues medication due to an adverse event 
or abnormal clinical laboratory test values, the subject should be followed 

up until the adverse event resolves, the subject's condition becomes 
stable, or 30 days (whichever occurs first). After subjects terminate study 
treatment, safety follow-up should be conducted 30 days (±7 days) after 
the last dose, and AEs related to the study drug should be collected within 
90 days after the last dose (or before starting new anti-tumor treatment) 
With all SAE. All subjects who have received at least one pembrolizumab 
injection treatment will undergo survival follow-up every 3 months (±14 
days) after the end of treatment until the end of the study, subject death or 
loss to follow-up. 
1. Imaging Evaluation 
Evaluate the curative effect according to the standard of RECIST version 
1.1. 
According to RECIST version 1.1, if there is more than one measurable 
lesion at baseline assessment, all lesions should be recorded and 
measured, and the total number of lesions should not exceed 5 (not more 
than 2 per organ), e.g., only one or two cumulative For patients with organs, 
a maximum of 2 or 4 target lesions were selected as the baseline 
measurement lesions. 
Measurable lymph nodes must meet the following criteria: short axis ≥ 15 
mm measured by CT. The baseline only needs to detect the short diameter, 
and usually the short diameter of the nodule is used to judge whether the 
nodule has metastasized. Choose a plane from sagittal plane or coronal 

plane), take the minimum value as the short diameter. 
The calculated sum of the diameters of all target lesions (including the 
longest diameter of non-nodular lesions and the shortest diameter of 
nodular lesions) will be reported as the sum of baseline diameters. If lymph 
node diameters are included, only the short diameter is counted as 
mentioned above. The sum of the baseline diameters will serve as a 
reference value for the baseline level of disease. 
All other lesions, including pathological lymph nodes, can be considered as 
non-target lesions and do not need to be measured, but should be 
recorded at baseline assessment, such as "present", "absent" or "clear 
progress" in rare cases. Extensive target lesions can be documented with 
target organs (eg, extensive liver metastases). The best type of CT scan is a 
diagnostic-quality helical or multislice CT with oral and intravenous 
contrast enhancement. If there is a contraindication to intravenous 
contrast enhancement, conventional CT should be used for evaluation of 
thoracic tumors. Abdominal and pelvic scans should be performed with 
MRI with intravenous contrast or CT with oral contrast. Brain scans should 
be performed with MRI or CT with intravenous contrast, if necessary. For 
suspicious new lesions, imaging examinations can be performed in 
combination with clinical indications. Patients who achieved a CR or PR 
were confirmed at a time point of ≥ 4 weeks. 
Neoadjuvant treatment specimen selection method: 

Imaging 
was PR or 
SD 
Gross specimen preparation is consistent with the initial 
resection specimen 
Regardless of the size of the tumor, at least 1-5 
representative regional tissues should be sent for 
examination 
Diagnosis of Pathological complete response requires careful 
sampling as with initial resection specimens 
The percentage of residual tumor should be reported (in 10% 
increments) based on evaluation of multiple specimen 
sections. 
Imaging 
was CR 
Select at least 2 points for pathology 
 
2. Safety assessment 
The trial will conduct a safety analysis of all subjects who received at least one 
dose of study drug. The physical examination, vital sign data (heart rate, blood 
pressure, respiration rate, and temperature), body weight, incidence of 
adverse events, and abnormal laboratory values will be summarized. In 
addition to this, a summary of the reasons for discontinuation of medication 
or dose change etc. will be made. The trial will use NCI-CTCAE version 5.0 to 
assess toxicity and reported serious adverse events. 
Biomarkers refer to indicators that can be used to objectively mark and 

evaluate the normal physiological process, pathological process and 
pharmacological response to treatment of the human body. Using an 
exploratory approach in this trial, the trial sponsor hopes to use tissue and 
plasma protein biomarkers to help better understand the impact of 
immunotherapy as first-line treatment of HNSCC on its prognosis. Assess PD-
L1 expression in tumor tissue at baseline, etc. These tests are of experimental 
nature, and need to obtain the approval of the ethics committee and the 
informed consent signed by the subjects to voluntarily participate in the 
additional gene pharmacology test of this study. 
 
(9) Adverse Event Report 
1. Adverse event 
Serious adverse events resulting from protocol-mandated interventions 
were reported only after informed consent was obtained but before 
study drug treatment was initiated. All adverse events will be reported 
after initiation of study drug treatment and up to 28 days after the last 
study drug dose. Any serious adverse events thought to be related to 
previous study drug treatment after 28 days after the last dose of study 
drug were also reported. All adverse events need to be recorded in the 
AE section of the CRF. 
2. Definition of Adverse Events  
An adverse event is any unfavorable medical condition that occurs in a 

subject or in a clinical trial subject taking a pharmaceutical product. 
Adverse events do not necessarily have a causal relationship with 
treatment. Thus, an adverse event may be any unfavorable and 
unexpected sign (including abnormal laboratory results), symptom, or 
disease temporally associated with the investigational product or device, 
whether or not considered to be related to the medicinal product or device. 
Whether considered to be related to the drug itself, adverse events related 
to the use of drugs in humans include the following: 
(1) Adverse events that occur during normal clinical use of the drug 
(2) Adverse events caused by accidental or intentional overdose 
(3) Adverse events caused by drug abuse 
(4) Adverse events caused by drug withdrawal 
Even if it is not related to the research product itself, if there are good 
reasons to believe that the adverse event is only caused by the subject's 
participation in this trial (such as adverse events or serious adverse events 
caused by interruption of antihypertensive drugs during the washout 
period), must be reported as an adverse event. 
Any clinical manifestation that did not achieve the expected efficacy, even 
if it had been recorded as a data point in the case report form (CRF), was 
not recorded as an adverse event. However, if the criteria for a "serious" 
adverse event are met, it must be faithfully recorded and reported. 
Within the extended scope of the above definition, the events that 

occurred before signing the informed consent and starting to take the 
study drugs will also be considered as adverse events, so their relevant 
data will be collected. 
3. Check result is abnormal  
The investigator is responsible for assessing the causal relationship 
between all adverse events and the study drug. The principal investigator 
can entrust a clinician related to this trial to be responsible for this work, 
but the responsibility is still borne by the principal investigator. 
Investigators must maintain a list of relevant qualified persons whom they 
have commissioned for this work 
4. Serious Adverse Event  
A serious adverse event is any adverse medical condition occurring at 
any dose if it: 
(1) cause death 
(2) life-threatening 
(3) Hospitalization or prolonged hospitalization is required 
(4) Causes persistent or permanent disability or incapacity 
(5) Causes congenital deformities or birth defects 
(6) Other important medical events (including abnormal laboratory test 
results and others that need to be discussed with the investigator or 
relevant personnel of the sponsor). The event may not be immediately 
life-threatening, result in death or hospitalization, but, based on 

appropriate medical judgment, may endanger the subject, or require 
intervention to prevent any of the consequences listed in the above 
definition to avoid the above-mentioned occurrence of any event. 
Life-threatening: "Life-threatening" in the definition of "serious adverse 
event" means that the subject has a risk of death when the adverse event 
occurs. However, it does not refer to adverse events that may cause 
death if they are more serious. 
Hospitalization: Any event resulting in hospitalization or prolonged 
hospitalization was considered a serious adverse event. 
However, it should be noted that invasive treatments during 
hospitalization may meet the criteria of 'medically significant' and thus 
may be reported as serious adverse events based on clinical judgment. In 
addition, local regulations take precedence if local health authorities 
have more strictly defined requirements. 
A disability is a severe impairment of a person's ability to perform daily 
living. 
Medically important event: Any adverse reaction is considered serious 
because it has the potential to harm the subject and may require invasive 
treatment to prevent other serious conditions from occurring. For the 
determination of medically important events, see the "WHO Adverse 
Event Terms - List of critical terms. These terms refer to or may describe 
a serious disease state. 

Because it may be associated with a serious disease state, events 
reported in this way ensure adequate attention and may trigger more 
decisive action than reporting under other terms. 
5. Severity Evaluation 
The following criteria shall be used for grading: 
The intensity or severity of adverse events should be documented using 
the National Cancer Institute-Common Toxicity Criteria Version 5.0 (NCI-
CTCAE v.5.0). 
6. Relevance judgment 
The evaluation of the relationship between adverse events and study 
drug treatment is the clinical judgment made by the investigator based 
on all available data when completing the case report form. 
A rating of "not relevant" should include: 
There is a clear alternative explanation, such as bleeding at the surgical 
site or irrationality, e.g., subject was involved in a car accident, but there is 
no indication that the drug caused disorientation in the subject that 
contributed to the accident; found several days after the first dose 
cancer. 
A rating of "Related" means that it is reasonable to suspect that the 
adverse event is related to treatment with the investigational drug. 
Factors considered in assessing adverse event and study drug 
relationship are: 

(1) Chronological sequence: Adverse events should occur after 
medication. The length of time between dosing and event should be 
assessed in the clinical record of adverse events. 
(2) Recovery after drug withdrawal, drug relapse: When considering the 
common clinical course of adverse events, the reaction of the subject 
after drug withdrawal or after drug re-administration should be 
considered at the same time. 
(3) Basic diseases, concomitant diseases, and concurrent diseases: Each 
report should evaluate the natural history and course of the disease 
being treated, as well as any other diseases that the subject may have. 
(4) Concomitant medication or treatment: Other drugs or treatments that 
the subject is receiving should also be considered together to determine 
whether there is any suspected possibility of causing adverse events. 
(5) Pharmacology and pharmacokinetics of the test drug: The 
pharmacokinetic properties (absorption, distribution, metabolism and 
excretion) of the study drug and the pharmacodynamics of individual 
subjects should be considered。 
 
(10) Data management and statistical analysis 
1. Quality management: the principle of double entry of data, quality 
control in the process of multi-center research data collection, data 
cleaning and verification 

To comply with GCP guidelines, monitoring and review procedures 
defined/agreed by the trial sponsor will be followed. Each test center will 
be inspected regularly by an inspector to ensure that the test is carried 
out in accordance with the requirements of the test protocol, GCP and 
legal affairs. The monitoring content includes going to the test center to 
check the completeness and clarity of the case report form (CRF) on the 
spot, checking the original records of the inspection, and clarifying 
management matters 
2. Statistical Analysis 
2.1 Sample size determination  
α=0.05; β=0.8; combined with the previous control group in the oral 
cancer phase III clinical study, the TPF pCR rate was 13.4%. Assuming 
that the experimental group is better than the control group (2 times 
superior effect, that is, the pCR reaches 26.8%), set pCR Reaching 30% 
is the superiority test. Calculate the sample size of the experimental 
group and the control group as 136 people, as follows: 
N1={z1−α/2∗√p¯∗q¯∗(1+1/k)+z1−β∗p1∗q1+√(p2∗q2/k)}2/Δ2 
q1=1−p1 
q2=1−p2 
p¯=(p1+kp2)/（1+K） 
q¯=1−p¯ 
N1={1.96∗√0.202∗0.798∗(1+1/1)+0.84∗√0.27∗0.73+((0.134∗

0.866)/1)}2/0.1362 
N1=136 
N2=K∗N1=136 
2.2 Analysis population 
The main population of effectiveness analysis: 
i. 
Intention-to-treat (ITT) population, defined as all subjects 
participating in the study. 
ii. 
People in different CPS states. 
iii. 
The population for safety analysis consists of all subjects who 
have received at least one dose of study drug 
2.3 Efficacy Analysis and Statistical Methods  
Short-term efficacy indicators: 
pCR determines the pCR ratio through time-to-time results. If you want 
to perform stratified analysis on CPS ≥ 1 and CPS < 1, you can apply 
Miettinen method to carry out weighted analysis under 95% two-sided 
confidence interval. 
Long-term efficacy indicators: 
The 2y-OS and 1y/2yEFS rates will be analyzed using the Kaplan-Meier 
method, plotted from the beginning of the pembrolizumab combined 
with chemotherapy group to the data censored (including distant 
metastasis, local treatment failure, Death) time Kaplan-Meier graph, 
while calculating mEFS, mOS difference (95% two-sided confidence 

interval). 
2.4 Safety Analysis and Statistical Methods  
All safety parameters will be summarized by treatment group in a 
descriptive summary table. NCI-CTCAE version 5.0 will be used to 
monitor the adverse reactions of the subjects. Treatment-induced 
adverse events, drug-related adverse reactions, trial procedure-
related adverse reactions, and safety experimental parameters will be 
summarized by treatment group and CTC class. 
2.5 Interim analysis 
The trial plans to conduct an interim efficacy analysis when enrollment 
reaches 70% (i.e. after enrollment of 190 patients) 
 
(11) Data Collection and Management 
1. Case Report Forms/Electronic Data Records  
Entries in the case report form (CRF) must be verifiable from the source 
file or entered directly into the CRF. In the latter case, what is recorded in 
the CRF will be considered the original source. Identification of verified 
source data parameters and source documents must be documented. 
Trial documents and all original data should be retained until notified by 
the trial sponsor for destruction. 
2. Data management 
Describe the scheme for entry, coding, confidentiality and storage, 

including any relevant measures to improve data quality (such as double 
entry, data range checking, etc.) 
To comply with GCP guidelines, monitoring and review procedures 
defined/agreed by the trial sponsor will be followed. Each test center will 
be inspected regularly by an inspector to ensure that the test is carried 
out in accordance with the requirements of the test protocol, GCP and 
legal affairs. The monitoring content includes going to the test center to 
check the completeness and clarity of the case report form (CRF) on the 
spot, checking the original records of the inspection, and clarifying 
management matters. 
3. Subject rights protection and informed consent 
Subjects will be given a core information and informed consent form. 
Before starting this trial, the investigator must have obtained the written 
permission/consent of the ethics committee/institutional review board 
for the written informed consent and any written information provided to 
the subjects. Written approval from the ethics committee/institutional 
review board and approved subject information/informed consent must 
be documented in the trial file. 
Written informed consent must be obtained from the subject before any 
trial-related procedure begins. The date that the subject participated in 
this trial and signed the informed consent form should be accurately 
recorded in the subject file. 

In accordance with relevant laws and/or regulations, all subjects 
participating in this trial will be able to enjoy the insurance provided by 
the trial sponsor. 
All records that personally identify subjects will be kept confidential and 
will not be made public to the extent permitted by relevant laws and/or 
regulations. The names of the subjects will also not be submitted to the 
trial sponsor. On the case report form, only the subject number is recorded. 
If the subject's name or initials appear in any other documentation (such 
as a pathology report), the subject's name or initials must be removed 
before a copy of the document is submitted to the trial sponsor. Research 
results stored on computers will be kept in accordance with local data 
protection laws. Subjects will be informed in writing that representatives 
of the trial sponsor, the ethics committee/institutional review board, or 
health authorities may inspect their medical records for verification of the 
information collected; all personal information for inspection will be kept 
under the strictest Confidentiality and compliance with local data 
protection laws. If the trial results are made public, the identities of the 
participants will remain confidential. The Investigator will maintain a list so 
that the subject's records can be identified. 
4. Use and publication of data 
All materials and test results of this trial, as well as all intellectual 
property rights thereof, belong to the sponsor of this trial. Trial sponsors 

may use the data for a variety of purposes, such as submitting it to 
government authorities or disclosing it to other investigators. The trial 
sponsor confirms that the investigator can disclose the trial results when 
the trial is completed. Manuscripts or abstracts submitted by 
researchers will be reviewed promptly and will not be rejected without 
reason. If there is a disagreement between the parties, the content to be 
published should be discussed in order to find a mutually satisfactory 
solution. 
 
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