The Efficacy and Safety of TACE, Lenvatinib and Camrelizumab in the Treatment of BCLC Stage B/C Hepatocellular Carcinoma: a Single-arm, Single-center, Open-label Study
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

1 
 
Prospective research project scheme of Union 
Hospital affiliated to Tongji 
Medical College of Huazhong 
University of Science and 
Technology  
  Version number: 
01 
  Version date: 
20201007 
 Project name: 
The Efficacy and Safety of TACE, Lenvatinib and 
Camrelizumab in the Treatment of BCLC Stage B/C 
Hepatocellular Carcinoma: a Single-arm, Single-center, 
Open-label Study 
20201007 
   
Scheme number: 
 
Main researcher: 
Xiongbin 

2 
  
radiology department 
Affiliated department: 
 
Start and end years: 
2021.1.1-2022.12.1 
 
Union medical college affiliated to Tongji medical college, Huazhong 
university of science and technology 
 
October 6, 2020 

3 
1. research summary
1.1 summary 
Research name: 
 Introduction to 
research: 
 Research 
purposes: 
The Efficacy and Safety of TACE, Lenvatinib and Camrelizumab in 
the Treatment of BCLC Stage B/C Hepatocellular Carcinoma: a 
Single-arm, Single-center, Open-label Study 
This study is a single-center, single-arm, open-label prospective clinical 
trial. By recording the time to disease progression (PFS), overall survival 
time (OS) and tumor treatment response of the patients included in the 
trial, we intend to evaluate the survival benefit of patients with BCLC B/C 
stage hepatocellular carcinoma treated with TACE, Levatinib and 
Camrelizumab. Meanwhile, the immune indexes before and after treatment were 
detected,Optimize the dosage, explore the mechanism of combined treatment 
in liver cancer, and lay the foundation for screening more suitable 
treatment groups; Observe and evaluate the safety of combined therapy 
through laboratory detection indicators and adverse event records; 
Immunohistochemistry, pathology and cell were used.Biological, proteomic 
and imaging methods were used to comprehensively evaluate the changes after 
combined treatment. 
To evaluate the safety and clinical efficacy of TACE, lamivudine combined 
with Camrelizumab in the treatment of BCLC B/C hepatocellular 
carcinoma, focusing on the application value of anti-angiogenesis 
therapy combined with immunotherapy in the treatment of hepatocellular 
carcinoma.  

4 
 Research 
object: 
 Research unit/
place: 
Research intervention: 
 Duration of study: 
 
Participants' 
participation time: 
A total of 40 patients with BCLC B/C stage hepatocellular carcinoma were 
enrolled in this experiment. The patients were treated with TACE, 
Levatinib and Camrelizumab, and the maximum out-of-group rate was 
estimated to be 20%. Men and women, aged from 18 to 75.  
 
Union hospital affiliated to Tongji medical college, Huazhong university of 
science and technology. 
  
Patients included in the trial were treated with TACE, lamivudine combined 
with Camrelizumab. 
2021.1.1-2022.12.1 
Subjects from the initial visit to the end of follow-up or experiment. 

5 
2. Research background
2.1 research significance 
 
At present, the treatment methods for advanced liver cancer mainly include local 
interventional therapy, targeted therapy and immunotherapy. This study focuses on patients with 
primary liver cancer diagnosed by clinical and imaging, histology or cytology, and liver cancer 
patients with B/C stage according to BCLC. To study the medium-and long-term efficacy of TACE, 
lenvartinib combined with carilizumab in the treatment of BCLC B/C stage liver cancer,And evaluate 
it effectively; To evaluate the safety and effectiveness of lamivudine combined with carilizumab in 
the treatment of liver cancer, and clarify the application value of combined treatment, so as to lay 
a foundation for evaluating the clinical efficacy of patients with advanced liver cancer. 

6 
2.2 research background 
 
Immunocheckpoint inhibitors and cell-based cancer immunotherapy are widely used in a variety of 
advanced malignant tumors by regulating tumor immune response [1-3]. Studies have shown that 
programmed death receptor 1(PD-1) is an immune checkpoint molecule, which negatively regulates the 
immune function of T cells by interacting with its ligand PD-L1 [4, 5]. More and more evidence shows 
that,PD-1/PD-L1 interaction is one of the main cancer escape mechanisms of human beings [6, 7]. 
Tumor cells overexpress PD-L1 or PD-L2, and interact with PD-1 molecules expressed in activated T 
cells, which inhibits T cell receptor (TCR) signal transduction, and finally leads to inactivation 
and loss of proliferative ability of effector T cells, which leads to tumor immune escape. Based on 
this mechanism of tumor,The new immunotherapy that blocks the interaction between PD-1 and PD-L1 has 
changed the treatment strategies of many malignant tumors [8, 9]. By inhibiting the negative 
regulatory effect of PD-1/PD-L1 pathway on T cells, the anti-tumor immune response of the body is 
enhanced, the T cell reaction activity against tumors of patients is improved, and the proliferation 
of effective T lymphocytes is promoted.Finally, it provides patients with an important and lasting 
immune response to their malignant tumors.  
Camrelizumab is a humanized anti-PD-1 monoclonal antibody with high affinity IgG4 independently 
developed by Suzhou Hengrui Pharmaceutical Co., Ltd., which can selectively prevent the activation 
of PD-1 and its downstream signal pathway, and restore immune function by activating effector T 
lymphocytes and cell-mediated immune response [10]. Some studies show that,The application of 
Camrelizumab in patients with advanced solid tumors has shown some clinical value [11-14], 
and predictive biomarkers such as PD-L1 expression level and tumor mutation load can screen out 
patients with high response to PD-1/PD-L1 monoclonal antibody [15, 16]. Even so, PD- 1/PD-L1 
blocking therapy only brings clinical benefits to less than 20% of cancer patients [17].It 
indicated that patients who used these drugs only depended on their insufficient pre-existing 
endogenous anti-tumor specific T cells.  

7 
 
Anti-angiogenic drugs can specifically bind to vascular endothelial growth factor (VEGF) and 
its receptor 2(VEGFR2), achieving the dual effects of enhancing cytotoxic chemotherapy and realizing 
molecular targeted therapy [18]. Some recent studies have shown that angiogenesis inhibitors can 
regulate tumor microenvironment and relieve hypoxia of tumor cells, which may promote tumor immune 
recovery [19, 20].Levatinib mesylate is a multi-target receptor tyrosine kinase inhibitor, which 
can block a series of regulatory factors such as VEGFR1-3, KIT and RET in tumor cells, and 
significantly inhibit angiogenesis in tumor tissues. At present, FDA approves its first-line 
treatment for unresectable hepatocellular carcinoma patients. In a phase III clinical study,The 
overall survival rate of lamivudine in the first-line treatment of unresectable hepatocellular 
carcinoma is no less than that of sorafenib (13.6 months vs 12.3 months) [21]. Another basic study 
shows that lenvartinib regulates cancer immunity in tumor microenvironment by reducing tumor-
associated macrophages (TAM), and can enhance anti-tumor activity through IFN signaling pathway when 
combined with PD-1 inhibitor [22]. In addition, previous studies found that,Compared with TACE 
alone, transcatheter arterial chemoembolization (TACE) combined with anti-angiogenic agents showed a 
good response to tumor treatment, but the incidence of treatment-related adverse events was 
high, and the survival time of patients was not significantly improved [24]. Therefore,In this 
study, TACE, a powerful anti-angiogenic drug, and Camrelizumab, a new PD-1 inhibitor, were combined 
to treat patients with liver cancer, so as to improve their quality of life and improve their 
survival benefits.  
The purpose of this study is to explore the clinical outcome of TACE, Lenvatinib combined with 
carilizumab in patients with BCLC B/C stage liver cancer, to monitor the complications and tumor 
treatment response of patients, to study the suitable population for combined treatment, and to 
evaluate the hepatorenal and cardiotoxicity of drugs to human body. Focus on exploring the mechanism 
and application value of anti-angiogenesis therapy combined with immunotherapy in the treatment of 
liver cancer. 

8 
References 
[1]. Pennock GK, Chow LQ. The Evolving Role of Immune Checkpoint Inhibitors in Cancer Treatment. 
Oncologist. 2015,20(7):812-822. 
[2]. Khalil DN, Smith EL, Brentjens RJ, Wolchok JD. The future of cancer treatment: immunomodulation, 
CARs and combination immunotherapy. Nat Rev Clin Oncol. 2016,13(5):273-290. 
[3]. Balar AV, Weber JS. PD-1 and PD-L1 antibodies in cancer: current status and future directions. Cancer 
Immunol Immunother. 2017,66(5):551-564. 
[4]. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, 
Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. 
Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation 
of lymphocyte activation. J Exp Med. 2000,192(7):1027-1034. 
[5]. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the 
escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA. 
2002,99(19):12293-12297. 
[6]. Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, Wu X, Ma J, Zhou M, Li X, Li Y, Li G, Xiong W, Guo 
C, Zeng Z. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 
2019,18(1):10. 
[7]. Juneja VR, McGuire KA, Manguso RT, LaFleur MW, Collins N, Haining WN, Freeman GJ, Sharpe AH. 
PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell 
cytotoxicity. J Exp Med. 2017,214(4):895-904. 
[8]. Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of Resistance to PD-1 and PD-L1 Blockade. Cancer J. 
2018,24(1):47-53. 
[9]. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 
2018,359(6382):1350-1355. 
[10]. Markham A, Keam SJ. Camrelizumab: First Global Approval. Drugs. 2019,79(12):1355-1361. 
[11]. Mo H, Huang J, Xu J, Chen X, Wu D, Qu D, Wang X, Lan B, Wang X, Xu J, Zhang H, Chi Y, Yang Q, Xu 
B. Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in 
advanced solid tumours: a dose-escalation, phase 1 study. Br J Cancer. 2018,119(5):538-545. 
[12]. Lv JW, Li JY, Luo LN, Wang ZX, Chen YP. Comparative safety and efficacy of anti-PD-1 monotherapy, 
chemotherapy alone, and their combination therapy in advanced nasopharyngeal carcinoma: findings from 
recent advances in landmark trials. J Immunother Cancer. 2019,7(1):159. 
[13]. Song Y, Wu J, Chen X, Lin T, Cao J, Liu Y, Zhao Y, Jin J, Huang H, Hu J, Luo J, Zhang L, Xue H, Zhang 
Q, Wang W, Chen C, Feng J, Zhu J. A Single-Arm, Multicenter, Phase II Study of Camrelizumab in Relapsed or 
Refractory Classical Hodgkin Lymphoma. Clin Cancer Res. 2019. 
[14]. Fang W, Yang Y, Ma Y, Hong S, Lin L, He X, Xiong J, Li P, Zhao H, Huang Y, Zhang Y, Chen L, Zhou N, 
Zhao Y, Hou X, Yang Q, Zhang L. Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus 
cisplatin for nasopharyngeal carcinoma: results from two single-arm, phase 1 trials. Lancet Oncol. 
2018,19(10):1338-1350. 
[15]. Shekarian T, Valsesia-Wittmann S, Brody J, Michallet MC, Depil S, Caux C, Marabelle A. Pattern 
recognition receptors: immune targets to enhance cancer immunotherapy. Ann Oncol. 2017,28(8):1756- 1766. 
[16]. Villaruz LC, Ancevski Hunter K, Kurland BF, Abberbock S, Herbst C, Dacic S. Comparison of PD- L1 
immunohistochemistry assays and response to PD-1/L1 inhibitors in advanced non-small-cell lung cancer 

9 
in clinical practice. Histopathology. 2019,74(2):269-275. 
[17]. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol. 2016,27(8):1492-1504. 
[18]. Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet. 
2016,388(10043):518-529. 
[19]. Hato T, Zhu AX, Duda DG. Rationally combining anti-VEGF therapy with checkpoint inhibitors in hepatocellular carcinoma. 
Immunotherapy. 2016,8(3):299-313. 
[20]. Manegold C, Dingemans AC, Gray JE, Nakagawa K, Nicolson M, Peters S, Reck M, Wu YL, Brustugun OT, Crinò L, Felip E, Fennell 
D, Garrido P, Huber RM, Marabelle A, Moniuszko M, Mornex F, Novello S, Papotti M, Pérol M, Smit EF, Syrigos K, van Meerbeeck JP, 
van Zandwijk N, Chih-Hsin Yang J, Zhou C, Vokes E. The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic 
Treatment of Advanced NSCLC. J Thorac Oncol. 2017,12(2):194-207. 
[21]. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular 
carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018,391(10126):1163-1173. 
[22]. Kato Y, Tabata K, Kimura T, Yachie-Kinoshita A, Ozawa Y, Yamada K, Ito J, Tachino S, Hori Y, Matsuki M, Matsuoka Y, Ghosh S, 
Kitano H, Nomoto K, Matsui J, Funahashi Y. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through 
reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS One. 2019,14(2):e0212513. 
[23]. Wang Z, Zhou W, Zhang H, Qiao L. Combination of anti-angiogenesis agents and transarterial embolization: Is it a promising 
approach for the treatment of liver cancer?. Discov Med. 2015,20(108):51- 55. 
[24]. Fan W, Yuan G, Fan H, Li F, Wu Y, Zhao Y, Yao W, Wang Y, Xue M, Yang J, Li J. Apatinib Combined With Transarterial 
Chemoembolization in Patients With Hepatocellular Carcinoma and Portal Vein Tumor Thrombus: A Multicenter Retrospective Study. Clin 
Ther. 2019,41(8):1463-1476. 
2.3 Expected results of research 
① with enough sample size, explore the beneficiaries of TACE, Lenvatinib combined with Camrelizumab 
in the treatment of BCLC B/C stage liver cancer; 
 ② To evaluate the efficacy and safety of TACE, Levatinib and Camrelizumab combined therapy, and 
provide theoretical and practical support for further research;  
  
③ To study the incidence of adverse events of TACE, Levatinib and Camrelizumab, and provide 
practical support for further explaining the safety of drugs. 
2.4 Risk/benefit assessment 
2.4.1  Known potential risks 
① Adverse drug reactions: including but not limited to (1) side effects of Camrelizumab zumab: Reactive
Cutaneous Capillary Endothelial Proliferation, anemia, fever, fatigue, hypothyroidism, proteinuria, 
cough and loss of appetite. ⑵ Side effects of lamivudine:Fatigue, loss of appetite, joint and 
muscle soreness, weight loss, stomatitis, nausea and vomiting, abdominal pain and diarrhea, headache, 
hypertension, proteinuria, plantar erythema syndrome .
② Post-②TACE embolism syndrome: fever, abdominal pain, digestive tract reaction (nausea, vomiting), etc.

10 
2.4.2  Known potential benefits 
 
(1) relatively complete disease assessment; 2 Longer survival time and better quality of life; (3)
Pay special attention to the illness and observe it closely; ④ Appropriate economic subsidies. 
2.4.2 assessment of potential risks/benefits 
At present, the treatment of advanced liver cancer is lacking, and the curative effect needs to 
be improved. Patients included in this study will receive advanced and perfect treatment programs, 
which will make it possible to get longer survival time and higher quality of life. The potential 
risks of this study are mainly adverse drug reactions. The research team includes chief physicians and 
attending physicians.With rich clinical experience and professional knowledge, once adverse events 
(including drug reactions and important adverse events) occur, researchers will fully 
evaluate whether the adverse events are related to drugs, actively take symptomatic measures, and keep 
follow-up observation in order to eliminate or reduce the impact of adverse events. At the same 
time, record it in detail on the case report form.In case of serious adverse events, fill in the 
serious adverse events form and report it to the applicant, ethics committee, CFDA safety 
supervision department and health administrative department within 24 hours.  
3. Data of main researchers
3.1  Name, qualification and contact information of the main researcher 
 
(full) name 
 
Xiong
bin 
 
gender 
 
man 
 
present 
incumbency 
 
Deputy director 
of radiology 
 
place of work 
Department of radiology, union hospital affiliated to Tongji medical 
college, Huazhong university of science and technology 
 
Address and 
zip code 
Radiology Department, Union Hospital, No.1277 Jiefang Avenue, 
Wuhan City, Hubei Province 430022 

11 
 
specialized 
subject 
 Radiointervention
al 
radiology 
 
academic 
degree 
 
docto
r 
 
graduated 
institutions 
 
Tongji Medical College, Huazhong 
University of Science and 
Technology 
 
Graduation 
time 
 
June, 2008 
 
contact 
number 
18627081029 
 
mailbox 
herr_xiong@126.com 
Educational experience 
(university, other) 
 
School name 
From (time) 
To (time) 
 
specialized 
subject 
 
degree 
 Wuhan Tongji 
Medical 
University 
1993.9 
1998.6 
 
Clinical 
Medicine 
 
bachelor 
 
Tongji Medical College, 
Huazhong University of Science 
and Technology  
2001.9 
2004.6 
 
Imaging medicine 
and nuclear science 
 Medicine 
(intervention) 
 
master 
 
Tongji Medical College, 
Huazhong University of Science 
and Technology  
2005.9 
2008.6 
 
Imaging medicine 
and nuclear science 
 Medicine 
(intervention) 
 
doctor 
working situation 
 
Work unit name 
 
post 
 
From (time) 
 
To (time) 

12 
 
Wuhan union hospital radiology 
 
Resident 
assistance 
 
teach 
1998.7 
2003.6 
Radiology Hospital of Freiburg 
University, 
Germany 
 visiting 
scholar 
2007.1 
2008.9 
Wuhan union hospital radiology 
 
The attending 
physician said 
 
teacher 
2003.7 
2012.10 
Wuhan union hospital radiology 
 
associate chief 
physician 
2012.11 
2017.10 
Wuhan union hospital radiology 
 
Master tutor 
2013.12 
 
hitherto 
Wuhan union hospital radiology 
 
associate 
professor 
2016.11 
 
hitherto 
Wuhan union hospital radiology 
 
archiater 
2017.11 
 
hitherto 
Wuhan union hospital radiology 
 
Deputy director 
of teaching and 
research section 
2018.12 
 
hitherto 
wuhan union hospital 
 
doctoral 
supervisor 
2018.12 
 
hitherto 
GCP and related training and participation in 
clinical trials 
Clinical research projects hosted or participated in 
（1） Multi-center randomized controlled study of portal vein irradiation stent implantation combined with 
hepatic 
arterial chemoembolization in the treatment of primary liver cancer complicated with portal vein tumor 
thrombus 
（2）Intravascular brachytherapy combined with stent and transcatheter arterial chemoembolization in 
the treatment of hepatocellular carcinoma with portal vein tumor thrombus: a multicenter, randomized 
controlled study 
（3） 
A multicenter, randomized controlled study of transcatheter arterial chemoembolization combined with
sorafenib in the treatment of advanced liver cancer
 
 

13 
（4） Scheme validation study of traditional Chinese medicine to reduce recurrence rate of stage I hepatitis B 
related liver cancer after comprehensive minimally invasive surgery, 2018ZX10303502- 001, under study, 
participating 
（5） 
Scheme validation study on improving clinical benefit rate of stage II hepatitis b-related liver
cancer after comprehensive minimally invasive surgery with traditional Chinese medicine,
2018ZX10303502-002, under research, participating 
（6） 
A multicenter randomized controlled study on the effect of shunt left/right branch of portal vein on
hepatic encephalopathy after TIPS operation.
3.2  Information on main participants 
序
号 
ser
ial 
num
ber 
姓名 
(full) 
name 
性别 
gende
r 
职称 
professiona
l title
专业 
specialize
d subject 
是否 GCP 培训 
GCP training 
or not 
研究中承担的角色 
Role assumed in research 
（eg.PI、sub-I、 
CRC） 
1 
宋松林 
Songsong
lin 
男 
man 
主治医师 
attending 
physician 
影像医学与 
Imaging 
medicine and 
核医学 
nuclear 
medicine 
否 
no 
sub-I 
2 
钱坤 
Qian Kun 
男 
man 
主治医师 
attending 
physician 
影像医学与 
Imaging 
medicine and 
核医学 
nuclear 
medicine 
否 
no 
sub-I 
3 
刘一鸣 
Liu 
Yiming 
男 
man 
主治医师 
attending 
physician 
影像医学与 
Imaging 
medicine and 
核医学 
nuclear 
medicine 
否 
no 
sub-I 

14 
4 
袁峰 
Yuanfeng 
男 
man 
主治医师 
attending 
physician 
影像医学与 
Imaging 
medicine and 
核医学 
nuclear 
medicine 
否 
no 
sub-I 
5 
周晨 
Chen 
Zhou 
男 
man 
住院医师 
resident 
影像医学与 
Imaging 
medicine and 
核医学 
nuclear 
medicine 
否 
no 
sub-I 
6 
任衍乔 
Ren 
Yanqiao 
男 
man 
博士生 
Doctor 
影像医学与 
Imaging 
medicine and 
核医学 
nuclear 
medicine 
否 
no 
CRC 
7 
刘家成 
Liu 
Jiacheng 
男 
man 
博士生 
Doctor 
影像医学与 
Imaging 
medicine and 
核医学 
nuclear 
medicine 
否 
no 
CRC 
8 
石钦 
Shi Qin 
男 
man 
硕士生 
Postgraduat
es 
影像医学与 
Imaging 
medicine and 
核医学 
nuclear 
medicine 
否 
no 
CRC 
9 
杨崇图 
Yang 
chongtu 
男 
man 
硕士生 
Postgraduat
es 
影像医学与 
Imaging 
medicine and 
核医学 
nuclear 
medicine 
否 
no 
CRC 
1 
0 
黄松江 
Huang 
Songjian
g 
男 
man 
硕士生 
Postgraduat
es 
影像医学与 
Imaging 
medicine and 
核医学 
nuclear 
medicine 
否 
no 
CRC 
4. 
research objective

15 
In this study, the time to progression free (PFS), overall survival (OS) and response to tumor 
therapy were recorded in the included patients to evaluate the survival benefit of TACE combined 
with rivarotinib and carrerizumab;To detect the immune indexes before and after the combined 
treatment, optimize the dosage, and explore the application mechanism of combined therapy in liver 
cancer,To lay a foundation for screening more suitable treatment population;The safety of combined 
treatment was evaluated by laboratory test indexes and adverse event records;Immunohistochemistry, 
pathology, cell biology, proteomics and imaging were used to evaluate the changes after combined 
therapy.  
5. 
research design
5.1  
overall design 
5.1.1  
Research staging 
 January 2021 to June 2021  
10-15 patients were enrolled, and the basic characteristics of the study population and relevant research
information were recorded. 
2021 年 6 月～2021 年 12 月  
入 
10-15 patients were enrolled, and the basic characteristics and related research information 
of the study population were recorded, and the previous study population was followed up 
regularly.  
December 2021 to June 2022  
 
10-15 patients were enrolled, and the basic characteristics and related research information 
of the study population were recorded, and the previous study population was followed up 
regularly.  

16 
 June 2022 to December 2022  
Regular follow-up of the previous study population, collation of research data, data analysis, 
statistics and summary, write research 
  
Research Report and published papers. 
5.1.2 。 
This study is a single center clinical trial. 
5.1.3  
Research intervention settings 
1. TACE treatment: the patients were selected according to the inclusion criteria. The HBV-DNA
titer of the patients with positive detection of HBV-DNA was 10 ^ 4. Antiviral treatment was 
required for 1-2 weeks. TACE could be performed after the HBV-DNA titer decreased.  
(1)  Hepatic arteriography: Seldinger's method was used, femoral artery cannula was punctured 
through skin, and catheter was placed in celiac trunk or common hepatic artery for angiography;We 
should pay attention to find the collateral artery of tumor;Indirect portal venography should be 
done through splenic artery to understand the blood flow of portal vein.  
(2) 
Hepatic arterial chemoembolization (TACE):
① Chemotherapeutic drug used: epirubicin (≤60mg);
  
② embolic materials used: lipiodol (≤20ml), gelatin sponge particles or microspheres. (3)
Technical operation requirements: use microcatheter to superselective intubate the blood supply 
artery branch of tumor, and inject embolic materials containing chemotherapy drugs, and the dosage 
should be controlled according to the size of tumor, blood supply and the number of blood supply 
arteries of tumor.After treatment, common hepatic arteriography was performed again to understand 
the immediate effect of transcatheter arterial chemoembolization. If liver cancer is complicated 
with arterioportal fistula, the fistula should be blocked with granular embolic agent with 
appropriate diameter, and then embolic materials should be added for embolization chemotherapy.  
The treatment method of levatinib: taking levatinib from the fourth day after TACE; Oral

17 
lamivudine dose: 8mg/d for patients below 60Kg; Patients over 60Kg were taken at 12mg/d .. For 
patients with adverse reactions related to lamivudine, symptomatic treatment and treatment can be 
given to alleviate the adverse reactions of patients. If the patient has gastrointestinal bleeding, 
stop taking the medicine.Take it after the bleeding has improved.  
The usage of Camrelizumab: Intravenous infusion was started on the fourth day after TACE, and the
dose was 200mg once every three weeks. Provisions on dose suspension: If the patient has 
intolerable adverse reactions during taking Lenvatinib and Camrelizumab, they can temporarily 
suspend Lenvatinib or Camrelizumab to alleviate the adverse reactions, but the continuous 
suspension time shall not exceed one month.If the dose suspension is not carried out as required 
during the research process, it will be rejected.  
  
5.2 Define the study endpoint 
  
Patient death, tumor progression, tumor progression beyond TACE treatment, and the trial was closed on 
December 1, 2022. 
5.3 Determine the sample size 
。  
A total of 40 patients with BCLC B/C stage liver cancer were enrolled in this experiment, 
and were treated with TACE, Levatinib and Camrelizumab. It is estimated that the maximum out-
of-group rate is 20%.  
6. Research objects
6.1 Entry criteria 

18 
1.18 -75 years old, male or female, with a pre-survival period of more than 12 weeks; 
2.
Primary liver cancer confirmed by clinical and imaging, histology or cytology;
3. 
Patients with liver cancer in B/C stage according to BCLC;
4. 
Never used molecular targeted therapy drugs or immune checkpoint inhibitors before;

19 
5. The behavioral state score of the American Eastern Cancer Cooperative Group (ECOG) is 0 or 1;
6. The main organs function normally, and there are no serious abnormalities of blood, heart, lung, 
liver and kidney function and immunodeficiency diseases. Laboratory examination
 
Meet the following requirements: a. hemoglobin (HGB)≥90g/L; B. neutrophil count (ANC)≥1.5×109/L; 
C. platelet count (PLT)≥100×109/L; D.ALT and AST≤2.5×ULN; Liver metastasis, ALT and AST≤5×
ULN; E. total bilirubin (TBIL)≤1.5 times the upper limit of normal value (ULN); F. serum Cr ≤ 
1 ′ uln, endogenous creatinine clearance rate > 50ml/min(Cockcroft-Gault formula); G. urine 
routine is normal, or urine protein < (++), or 24-hour urine protein amount < 1.0 g;  
7.Coagulation function is normal, there is no active bleeding and thrombotic disease: a.
international standardized ratio INR≤1.5×ULN; B. partial thromboplastin time APTT≤1.5×ULN; C. 
prothrombin time PT≤1.5×ULN;  
8. 
The subjects voluntarily joined the study and signed the informed consent form.
6.2 Exclusion criteria 

20 
1 within five years or at the same time suffering from other active malignant tumors except liver
cancer. Cured localized tumors, such as skin basal cell carcinoma, skin squamous cell carcinoma, 
superficial bladder cancer, prostate cancer in situ, cervical cancer in situ, breast cancer in 
situ, etc., can be grouped; 
2. The tumor size of liver cancer is ≥ 70% of liver parenchyma or 
there is extrahepatic metastasis;  
3. 
Pregnant or lactating women;
4. 
It is known to be allergic to carilizumab, lenvartinib or pharmaceutical excipients;
5. 
After other anti-tumor treatments, including surgical treatment, local treatment and systemic 
treatment, within 4 weeks before entering the group;
6. 
Having received organ or allogeneic bone marrow transplantation;
7. ；
Suffering from any active autoimmune disease or history of autoimmune disease (including but not
limited to interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, 
myocarditis, nephritis, hyperthyroidism and hypothyroidism (which can be included after hormone 
replacement therapy));  
8. 
Use immunosuppressive drugs within 14 days before the first use of the study drug, excluding nasal 
spray and inhaled corticosteroids or systemic steroid hormones with physiological dose (i.e., 
prednisolone or other corticosteroids with the same physiological dose);  
9. 
Vaccinate live attenuated vaccine within 4 weeks before the first administration or during the 
study period;
10.
 
Severe infection (such as intravenous drip of antibiotics, antifungal or antiviral drugs) occurred
within 4 weeks before the first administration, or fever of unknown origin > 38.5°C occurred 
during the screening period/before the first administration;  
11.
Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell 
transplantation;
12.
There is objective evidence to show that there have been or are currently suffering from pulmonary
fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, and 
severe impairment of lung function;  

21 
13. Patients with hypertension, but still unable to drop to normal range after 3 months of 
antihypertensive drug treatment (systolic blood pressure ≤140 mmHg/diastolic blood pressure ≤ 
90 mmHg);  
14. 
Suffering from uncontrollable clinical symptoms or diseases of the heart, including but not
limited to congestive heart failure (NYHA grade > II grade); Unstable or severe angina pectoris; 
Acute myocardial infarction occurred within 6 months; Patients with clinically significant 
supraventricular or ventricular arrhythmia who need clinical intervention; Left ventricular 
ejection fraction (LVEF)<50%;  
15. 
Patients with active bleeding or patients with severe bleeding risk caused by various reasons,
including but not limited to severe bleeding (bleeding within 3 months > 30 ml), hemoptysis 
(bleeding within 4 weeks > 5 ml) and thromboembolic events (including stroke events and/or 
transient ischemic attacks) within 12 months;  
16. 
Participate in other clinical trials or participate in any other drug clinical research within 4
weeks, or take no more than 5 drugs from the last study
 
Half-life; 
17.
Other circumstances that the researcher thinks are not suitable for inclusion.
6.3 Recruitment of subjects 

22 
Recruitment targets are outpatients and inpatients who come to our department for diagnosis 
and treatment, and patients who have been transferred to our department from other hospitals 
or departments, which must meet the inclusion and exclusion criteria of this study. 
Recruitment sites are outpatient and inpatient departments of our department. During the follow-
up visit, the subjects will be reimbursed for travelling expenses or given appropriate financial 
subsidies. 
7. Research intervention
7.1 give research intervention 
7.1.1 Description of research intervention 
 Patients included in the trial were treated with TACE, lamivudine combined with 
Camrelizumab. The specific operation is described in the above intervention measures. 
7.1.2 Dosage and Administration Method 
 
① treatment mode of levatinib: taking levatinib from the fourth day after TACE; Oral lamivudine
dose: 8mg/d for patients below 60Kg; Patients over 60Kg were taken at 12mg/d .. 
② Usage of Camrelizumab: Intravenous infusion was started on the fourth day after TACE, once 
every three weeks, with a dose of 200mg. 
7.1.3 Items and times of clinical and laboratory examinations to be conducted 
 Clinical treatment: the number of TACE is determined by the researcher according to the 
patient's condition. Lenvatinib and Camrelizumab were used until the patients reached the study 
endpoint.  
Laboratory examination: items include blood routine, urine routine, stool routine+occult blood, 
liver function, kidney function and tumor markers 
（ (AFP, CA19-9, CEA, CA125), immunological index examination, etc. 4-6 weeks after the first TACE 

23 
treatment, all subjects were reexamined for liver CT plain scan+enhancement or MRI plain 
scan+enhancement, tumor markers, blood routine, liver and kidney function, coagulation function, 
urine routine, stool routine+occult blood and other laboratory tests, whether there is hepatic 
encephalopathy and ECOG score; If the initial review is CR, it will be reviewed every 2- 3 
months;If the initial reexamination is not CR, reexamine every 4-6 weeks and perform TACE treatment 
in time  
7.2 Preparation/Disposal/Storage/Responsibility 
7.2.1 Responsibility 
Related drugs are purchased by patients from hospitals. 
7.2.2 Composition, appearance, packaging and labeling of drugs 
① Camrelizumab: General name: Camrelizumab for injection; Trade name: Erica; English name:
Camrelizumab for Injection. Drug composition: active ingredient: Camrelizumab zumab (humanized 
anti-PD-1 
monoclonal antibody); Adjuvant ingredients: α-trehalose dihydrate, polysorbate 20, glacial acetic 
acid, sodium hydroxide and water for injection. outside Appearance: white to off-white powder or 
block. Packaging: injection bottled with neutral 
borosilicate glass tube, 200 mg/ bottle x 1 bottle/ Box. 

24 
② Lenvatinib: General name: Lenvatinib mesylate capsule; Trade name: Leweima; English name:
Lenvatinib Mesilate Capsules. Composition of medicine: the active ingredient is lamivudine mesylate. 
Appearance: white to white granular. Packing: 4mg/ capsule *30 capsules/box.  
7.2.3 Storage and Stability of Products 
(1) Carrilizumab was stored and transported at 2-8℃ away from light.
② Lenvatinib was stored and transported in a ventilated place at room temperature.
7.2.4 preparation 
 
①Carrilizumab was administered by trained health professionals, and reconstituted and
diluted by aseptic technique. Infusion is completed within 30-60 minutes. Intravenous
injection or rapid intravenous injection should not be used. 
② Lenvatinib is a capsule preparation, which should be taken orally. It should be taken at a
fixed time every day, either on an empty stomach or with food. It should be swallowed as a
whole, or it can be mixed with one tablespoon of water or apple juice in a glass to form a 
suspension. The capsule must stay in the liquid for at least 10 minutes and stir for at 
least 3 minutes to dissolve the capsule shell.Then swallow the suspension. After drinking, 
you must add the same amount of water or apple juice (one tablespoon) to the glass 
中，搅拌数次，然后喝完玻璃杯中所有的液体。 
Stir several times, then drink all the liquid in the glass. 
7.3 Follow-up and Compliance 
  
4-6 weeks after the first TACE treatment, all subjects were reexamined for liver CT plain
scan+enhancement or MRI plain scan+enhancement, tumor markers, blood routine, liver and kidney 
function, coagulation function, urine routine, stool routine+occult blood and other laboratory 
tests, whether there is hepatic encephalopathy and ECOG score; If the initial review is CR, it 
will be reviewed every 2-3 months; If the initial reexamination is not CR, reexamine every 4-6 
weeks and timely perform TACE treatment.  

25 
7.5 research intervention commitment 
 
All treatment measures and means used for patients will be strictly registered on the case 
report form by special personnel and recorded in the hospital routine medical records. 
8.1 Suspension of research intervention 
(1)
Patients who have any serious adverse events during the trial need to stop treatment;
(2)
Patients or clients withdraw informed consent or request to stop treatment;
(3)
Patient lost follow-up;
(4)
Patient is pregnant;
(5)
Patients should also be followed up after termination of treatment or withdrawal of treatment, to 
understand the disease state until death or the end of research.
8.2 suspension/withdrawal of subjects 
(1)
Those who do not conform to the test plan are found during the test;
(2)
During the trial, other anti-tumor treatments, such as ablation, radiotherapy, chemotherapy and
traditional Chinese medicine treatment, were carried out besides TACE, Lenvatinib and 
Camrelizumab, so that the curative effect could not be evaluated. The reasons for the 
rejected cases should be explained in writing;  
（3） 
Those who stop treatment due to serious adverse reactions are not included in the curative effect
analysis, but should be included in the statistics of adverse reactions.

26 
 
8.3 Lost visits 
When the subject stops the scheduled study follow-up, fails to complete the prescribed 
procedure, or the researcher cannot contact the subject, it is regarded as lost follow-up. The 
researcher will record and describe the patient's lost follow-up, and the main researcher and 
relevant personnel will evaluate it to decide whether to include the experimental results.  
9. Evaluation of research outcome
Evaluation of primary and secondary outcomes 
9.1.1  
leading indicator 
Progression free survival, PFS). Definition of PFS: It refers to the period from the beginning 
of treatment to the progression of tumor or death for any reason. 
9.1.2  
Secondary indicators: 
（1） 
Total survival time (OS); OS definition: the time from the patient's enrollment to the last follow-up
or death. 
（2） 
Time-Time-to-tumor progression, TTP); TTP definition: It refers to the period from the beginning of
treatment to the observation of disease progression. 
（3） 
TACE-to-unaccessible progression ttup; TTUP definition: refers to the period from the time when
patients with tumor diseases receive treatment to the time when they are unsuitable for TACE treatment 
(unable to receive or benefit from TACE treatment).  
The patients who can't accept TACE further include: the liver function deteriorated to Child-Pugh C 
grade, extrahepatic diffusion including inferior vena cava invasion, complete embolism of portal vein 
trunk, tumor volume exceeding 70% of liver volume, ECOG score ≥2 points; The failure to benefit from 
TACE treatment include: 1-3 months aft full selective TACE, re-evaluating that response after tumor 
treatment with enhanced CT/MRI,There are still two or more consecutive poor responses (active 
lesions > 50%), or two or more consecutive intrahepatic tumor progression (compared with the number 

27 
of tumors before TACE treatment, the number of tumors after TACE treatment increases) 
(4)
The time of extrahepatic metastasis; That is, from the time of the first visit to the time of 
extrahepatic metastasis in the follow-up.
(5)
Objective reaction rate (ORR): (ratio of Cr+PR);
(6)
Disease control rate (DCR): (ratio of Cr+PR+SD);
According to the modified response evaluation criteria in solid tumors, 
M resistance), the curative effect is defined as CR (complete remission), PR (partial remission), SD 
(stable) and PD (progress); 
(7)
The times of TACE treatment in the two groups;
(8)
Incidence, category and severity of adverse events of advanced liver cancer in two groups.
9.2 Safety and other evaluations 
(1)
Blood routine, electrolyte, urine routine and stool routine;
(2)
Electrocardiogram, chest DR, liver function, kidney function and heart function;
(3)
Coagulation function test;
(4)
Incidence of clinical adverse events: record in detail at any time.
Patients with abnormal safety test indexes after medication must be followed up and recorded in detail. 
9.3 Adverse Events and serious adverse events 

28 
9.3.1  
Adverse event (AE) definition 
 
Adverse events: injuries caused by medical treatment, contrary to the natural outcome of 
diseases, prolong the hospital stay of patients, and all events leading to disability, including 
preventable and preventable adverse events. Unpreparable adverse events refer to preventable 
injuries caused by correct medical behavior;Preventable adverse events refer to injuries caused by 
errors or equipment failures that cannot be prevented in medical treatment. 
9.3.2  
Serious adverse events (SAE) definition 
。  
Serious adverse events (SAE) refers to events such as hospitalization, prolonged 
hospitalization, disability, affecting working ability, endangering life or death, and leading to 
congenital malformation.  
9.3.3 
Classification of adverse events 
9.3.3.1  
Event severity 
；  
Severity classification (NCI-CTCAE version 4.0, National Cancer Institute): Grade I: mild, 
asymptomatic or mild, only seen in clinic or diagnosis, without treatment; 
  
Grade 2: Moderate, requiring minor, local or non-invasive treatment, or limited instrumental 
activities of daily living of the same age; Grade III: serious or medically significant but not 
immediately life-threatening, or leading to hospitalization or prolonged hospitalization, or 
disability, or serious limitation of personal daily activities;  
  
Grade 4: life threatening, requiring 
emergency treatment. Grade 5: Death 
related to adverse events.  
9.3.3.2  
Correlation with research intervention 
 Relationship 
with 
research 
 
describe 

29 
intervention 
 
Definitely 
Clinical events (including laboratory test abnormalities) that have a 
reasonable time relationship with the use of the test drug and cannot be 
explained by basic diseases or other drugs.The adverse events disappeared 
after drug withdrawal;The AE must be a known reaction in pharmacology or 
Phenomenology: the result of provocation test is positive. 
 Probably 
relevant 
It has a reasonable time relationship with drug use and is unlikely to be 
attributed to the use of underlying diseases or other drugs  
Clinical events with reasonable withdrawal reaction (including abnormal 
laboratory tests).There is no need to confirm the excitation test results. 
May be relevant 
es) that have a reasonable time relationship with drug use but may also 
be explained by underlying diseases or other drugs.Information on 
withdrawal reactions may be "None" Or "unknown.". 
 
Probably not 
There is no reasonable time relationship with drug use and can be explained by 
basic diseases or other drugs 
Events (including laboratory test abnormalities). 
 
irrelevant 
Clinical events (including laboratory test abnormalities) unrelated to drug 
use. 
9.3.3.3  
Anticipation 

30 
The team of researchers includes clinicians with rich clinical experience and professional 
knowledge. Once an adverse event occurs, the researcher will confirm that the adverse event is 
expected or unexpected. If the nature, severity or frequency of the adverse event does not match the 
risk information described in previous studies, it will be considered as unexpected. 
9.3.4 time, frequency, follow-up and outcome of adverse event assessment 
 
All AE including local and systemic reactions were collected using case report form (CRF). The 
information collected included the description of the event, the time of occurrence, the doctor's 
assessment of the severity, the relationship with the research product, and the time from the event 
to resolution / stabilization.All AE will be fully resolved.At each study follow-up, the investigator 
will ask about the AE / SAE that has occurred since the last follow-up,AE / SAE will be followed up 
until it is resolved or stabilized.  
9.3.5 adverse event reporting 
  
The potential clinical adverse events during treatment were evaluated according to nci-ctcae 
4.0.Once adverse events (including major adverse events) occur, researchers will fully evaluate 
whether the adverse events are related to drugs, actively take symptomatic measures, and maintain 
follow-up observation,In order to eliminate or reduce the impact of adverse events.At the same time, 
record in detail on the case report form, fill in the serious adverse event form in case of serious 
adverse event, and report to the sponsor, ethics committee, CFDA safety supervision department and 
health administrative department within 24 hours.  
9.3.6 serious adverse event reporting 
 
The investigator will immediately report any SAE to the sponsor, whether or not related to the study 
intervention. 
10. Statistical analysis
10.1 一般方法
10.1 general methods 

31 
  
The target value of PFS was 9.2 months, and the difference was statistically significant 
(P<0.05). The secondary curative effect index OS was tested with the target value of 15 months, and 
the difference was statistically significant (P<0.05). The other secondary curative effect indexes 
TTP, TTUP, time of extrahepatic metastasis, objective response rate (ORR) and disease control rate 
(DCR) were mainly descriptive statistics.Paired T-test was performed on immunological indexes and 
biochemical indexes before and after treatment, and the difference was statistically significant 
(P<0.05).  
10.2  
Analysis of primary and secondary study endpoints 
10.2.1  
leading indicator 
  Definition of PFS: It refers to the period from the beginning of treatment to the progression 
of tumor or death for any reason.  
10.2.2 
Secondary indicators 
（1） 。
Total survival time (OS); OS definition: the time from the first visit to the last follow-up or death
after enrollment. 
（2） 
Time-Time-to-tumor progression, TTP);
  
TTP definition: It refers to the period from the beginning of treatment to the observation of disease 
progression. 
（3） 
TACE-to-unaccessible progression ttup;
  
TTUP definition: refers to patients with tumor diseases from the beginning of receiving treatment to 
unsuitable for TACE treatment (unable to receive further or from TACE) 
Benefit from treatment). 
The patients who can't accept TACE further include: the liver function deteriorated to Child-Pugh C 
grade, extrahepatic diffusion including inferior vena cava invasion, complete embolism of portal vein 
trunk, tumor volume exceeding 70% of liver volume, ECOG score ≥2 points;  

32 
Failure to benefit from TACE treatment includes: 1-3 months after full selective TACE, re-evaluating 
the response of tumor after treatment with enhanced CT/MRI, and still having two or more consecutive 
poor responses (active lesions > 50%), or still having two or more consecutive intrahepatic 
progression of tumor (compared with the number of tumors before TACE treatment, the number of tumors 
after TACE treatment increased)  
(4)
Time of extrahepatic metastasis
(5)
Objective reaction rate (ORR): (ratio of Cr+PR);
(6)
Disease control rate (DCR): (ratio of Cr+PR+SD);
According to the modified response evaluation criteria in solid tumors, 
m 
M resistance), the curative effect is defined as CR (complete remission), PR (partial remission), SD 
(stable) and PD (progress); 
(7)
The times of TACE treatment in the two groups;
(8)
Incidence, category and severity of adverse events of advanced liver cancer in two groups.
10.3 safety analysis 
The researcher will fully evaluate the patient's condition in the whole process, and once 
serious adverse events occur, such as hepatic encephalopathy, upper gastrointestinal bleeding, 
hepatorenal syndrome, hepatopulmonary syndrome and serious laboratory examination abnormality, they 
will be given treatment such as drug withdrawal and symptomatic treatment, and keep close follow-up 
until the patient's symptoms or laboratory examination abnormality are alleviated or disappeared. 
10.4 
10.4 baseline descriptive analysis 
  Descriptive statistics were used to compare the demographic characteristics, BCLC stages, 
Child-
Pugh grades and laboratory indicators at baseline among the groups. 
11. 
11. Supporting documents and precautions
11.1 
11.1 informed consent process 

33 
Informed consent will be completed before the subjects agree to participate in the research, 
and will continue throughout the whole research process. Informed consent is approved by the Ethics 
Committee, and the subjects should read the informed consent. The researcher will explain the 
research process and answer the questions raised by the research object; And inform the subjects of 
possible risks and their rights.Subjects can discuss with their families or guardians before 
agreeing to participate. The researcher must inform the research object that it is voluntary to 
participate in the research and can withdraw from the research at any time. Copies of informed 
consent can be provided to the subjects for preservation. The rights and welfare of research 
subjects will be protected,And stressed that the quality of their medical care will not be affected 
by refusing to participate in the research. 
11.2 隐私保护 
11.2 privacy protection 
 In this experiment, the personal information and condition of the subjects will be kept 
strictly confidential, and only open to the subjects and those whom the subjects are willing to make 
known. 
11.3 collection and use of specimens and data 
Specimens collected during normal diagnosis and treatment of patients and used for blood 
routine, urine routine, liver and kidney function in hospitals will not be recycled, but will be 
tested or kept by a third party. The testing unit and address will be indicated, and after testing, 
they will be taken back and stored in the refrigerator of the laboratory. These data will be kept 
until the end of the experiment. 
11.4 
11.4 quality control and quality assurance 
1)
The experimental scheme will be scrutinized repeatedly by the research team and the opinions of 
relevant personnel will be widely collected.
2)
Selected patients will be evaluated by blind method.
3)
The efficacy and safety analysis will be evaluated by blind method.
4)
The establishment and modification of each project of CRF can be traced back to the specific 
implementers.

34 
5) 
A corresponding mechanism will be established to regularly review and review the collected
information and data.

35 
11.5 data processing and record keeping 
1
11. 5.1 data collection and management
 
Paper materials include CRF and informed consent; PACS system data include 
medical records, imaging examinations, laboratory results, etc. These 
materials 
will be sorted and stored by the research team. All data should be clear to 
ensure its traceability.  
11. 5.2 研究数据保留
11. 5.2 research data retention
The collected data will be kept for 3 years after the end of the whole 
experiment, so as to facilitate retrospective analysis, and will be approved by 
the main researcher and relevant institutions before destruction. 
11.6 publishing and data sharing agreements are fair, just and open 
 
11.7 conflict of interest statement There is no potential conflict of interest.