Conditions: Carcinoma, Hepatocellular
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 400
Healthy volunteers: no

Brief summary:
This was a multicenter, randomized, double-blind, phase III trial. This clinical study evaluates the efficacy and safety of Apatinib in patients with advanced liver cancer who have progressed on Systemic Therapy (Chemotherapy and/or Targeted Therapy).

Approximately 400 patients who meet the entry criteria will be randomly assigned in a 2:1 ratio to Apatinib or placebo (1/3 chance to receive placebo).

Primary endpoint of the study is overall survival.

Detailed description:

Arms:
arm 1: 750 mg orally (p.o.) every day (qd), 28 days as one cycle arm 2: orally (p.o.) every day (qd), 28 days as one cycle

Interventions: intervention 1: Apatinib intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III 
Clinical Trial of Apatinib Mesylate Tablets as Second-Line Treatment in Patients with 
Advanced Hepatocellular Carcinoma   
Clinical trial registration number: NCT02329860  
Version Date: 10 Mar., 2017 


Translated from Original Document 
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 1 of 126 
 
A Randomized, Double-Blind, Parallel-Controlled, Multi-Center, 
Phase III Clinical Study Evaluating Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular 
Carcinoma 
Study Protocol 
 
Protocol No.: APTN-III-HCC 
Version No.: 1.4 
Version Date: 10 Mar., 2017 
 
 
 
 
 
Principal Investigator: 
 
Clinical Study Site: 
 
 
 
 
Sponsors: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Shanghai Hengrui Pharmaceutical Co., Ltd. 
 
 
 
All rights reserved by Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Confidential 
The information is not allowed to be used, disclosed, published or otherwise made 
public without permission. 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
 
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 2 of 126 
 
A Randomized, Double-Blind, Parallel-Controlled, Multi-Center, 
Phase III Clinical Study Evaluating Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular 
Carcinoma 
Study Protocol 
 
Clinical Study Site: 
 
 
 
Principal 
Investigator: 
 
Telephone: 
 
Fax: 
 
Address: 
 
Sponsor: 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Shanghai Hengrui Pharmaceutical Co., Ltd. 
Medical Director: 
 
Telephone: 
 
Fax: 
 
Address: 
 
Statistical Unit: 
Department of Epidemiology and Health Statistics, Nanjing 
Medical University 
Source Data 
Retention: 
 
 
 
Version No.: 
1.4 
Version Date: 
10 Mar., 2017 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 3 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator (signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 4 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 5 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 6 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 7 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 8 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 9 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 10 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 11 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 12 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 13 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 14 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 15 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 16 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study site: 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 17 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 18 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 19 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 20 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 21 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 22 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 23 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 24 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 25 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 26 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 27 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 28 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 29 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 30 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
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Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 31 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 32 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 33 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 34 of 126 
 
Protocol Signature Page 
Investigator Signature 
I will carefully execute the duties as an investigator in accordance with the Chinese GCP, and 
personally participate in or directly lead this clinical study. We have read and confirmed this 
protocol (protocol number: APTN-III-HCC, version number: 1.4, version date: 10 Mar., 
2017). I agree to fulfill my duties in accordance with Chinese laws, the Declaration of 
Helsinki, the Chinese GCP, and this study protocol. Any modification to the protocol must be 
reviewed and approved by the sponsor, and can only be implemented upon approval by the 
Ethics Committee, unless measures must be taken to protect the safety, rights, and interests of 
the subjects. 
 
 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 35 of 126 
 
Protocol Signature Page 
Signature of Statistical Unit 
I have read and confirmed this protocol (protocol number: APTN-III-HCC, version number: 
1.4, version date: 10 Mar., 2017). I agree to fulfill my duties in accordance with Chinese 
laws, the Declaration of Helsinki, the Chinese GCP, and this study protocol. Any 
modification to the protocol must be reviewed and approved by the sponsor, and can only be 
implemented upon approval by the Ethics Committee, unless measures must be taken to 
protect the safety, rights, and interests of the subjects. 
 
 
 
Study Site: 
 
 
 
 
 
 
Principal Investigator (print) 
 
 
Principal Investigator 
(signature) 
Signature Date 
(DD/MM/YYYY) 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
             
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 36 of 126 
 
Protocol Signature Page 
Sponsor Signature 
We have read and confirmed this protocol (protocol number: APTN-III-HCC, version 
number: 1.4, version date: 10 Mar., 2017). I agree to fulfill my duties in accordance with 
Chinese laws, the Declaration of Helsinki, the Chinese GCP, and this study protocol. 
 
 
 
 
 
Sponsor: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Shanghai Hengrui Pharmaceutical Co., Ltd. 
 
 
 
 
 
 
Manager in Charge (print) 
 
 
Manager in Charge (signature) 
Signature Date 
(DD/MM/YYYY) 
 
 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ......................................................................................................... 40 
SCHEDULE OF ACTIVITIES ................................................................................................ 45 
REGULATIONS FOR DOSE MODIFICATION .................................................................... 48 
ABBREVIATIONS AND DEFINITIONS .............................................................................. 50 
1 BACKGROUND .................................................................................................................. 52 
1.1 Epidemiology and Current Treatment of Hepatocellular Carcinoma ......................... 52 
1.2 Developments in Targeted Therapies for HCC ........................................................... 53 
1.3 Development Background of Apatinib ....................................................................... 55 
1.4 Results of Preclinical Studies of Apatinib .................................................................. 55 
1.5 Results of Clinical Studies of Apatinib ....................................................................... 59 
2 STUDY OBJECTIVES AND ENDPOINTS ........................................................................ 67 
2.1 Study Objectives ......................................................................................................... 67 
2.2 Primary Endpoints ...................................................................................................... 67 
2.3 Secondary Endpoints .................................................................................................. 67 
3 SELECTION AND WITHDRAWAL OF SUBJECTS ......................................................... 68 
3.1 Clinical Diagnostic Criteria ........................................................................................ 68 
3.2 Inclusion Criteria ........................................................................................................ 68 
3.3 Exclusion Criteria: ...................................................................................................... 70 
3.4 Termination Criteria .................................................................................................... 71 
3.5 Randomization Criteria ............................................................................................... 71 
4 STUDY DESIGN .................................................................................................................. 72 
4.1 Overall Design ............................................................................................................ 72 
4.2 Type of Comparison .................................................................................................... 73 
4.3 Sample Size Estimation .............................................................................................. 73 
4.4 Randomization and Stratification Factors ................................................................... 74 
4.5 Dosing Regimen.......................................................................................................... 74 
4.6 Efficacy Evaluation and Analysis ............................................................................... 76 
4.7 Follow-up within 28 Days after Treatment Discontinuation ...................................... 76 
4.8 Follow-Up of AEs ....................................................................................................... 76 
4.9 Survival Follow-Up .................................................................................................... 76 
5 INFORMED CONSENT ...................................................................................................... 77 
6 STUDY DRUGS ................................................................................................................... 77 
6.1 Information ................................................................................................................. 77 


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6.2 Labeling/Packaging..................................................................................................... 77 
6.3 Drug Dispensation ...................................................................................................... 78 
6.4 Drug Storage and Management .................................................................................. 78 
6.5 Disposal of Remaining Drugs ..................................................................................... 78 
7 CRITERIA FOR DOSE INTERRUPTION AND MODIFICATION ................................... 78 
7.1 Dose Level and Use of Drugs ..................................................................................... 78 
7.2 Dose Modification ...................................................................................................... 79 
8 CONCOMITANT MEDICATION ....................................................................................... 82 
8.1 Medications Prohibited or Used with Caution during the Study ................................ 82 
8.2 Medications and Treatments that May be Used Concomitantly during the Trial ....... 82 
8.3 Recommended Symptomatic Treatment for Common Adverse Drug Reactions ....... 83 
9 STUDY PROCEDURES ...................................................................................................... 86 
9.1 Screening Period (from signing informed consent form to  
obtaining random numbers) ........................................................................................ 86 
9.2 Treatment Period ......................................................................................................... 87 
9.3 Follow-Ups ................................................................................................................. 88 
10 EFFICACY EVALUATION ............................................................................................... 88 
10.1 Primary Endpoint and Observation Method ............................................................. 88 
10.2 Secondary Endpoints and Observation Methods ...................................................... 88 
11 SAFETY EVALUATION .................................................................................................... 90 
11.1 Definitions ................................................................................................................. 90 
11.2 Recording and Evaluation of Adverse Events ........................................................... 92 
11.3 SAE Reporting Procedures ....................................................................................... 93 
11.4 Emergency Unblinding ............................................................................................. 94 
11.5 Safety Monitoring Committee .................................................................................. 94 
12 DATA MANAGEMENT AND STATISTICAL ANALYSIS.............................................. 94 
12.1 Data Collection and Management ............................................................................. 94 
12.2 Statistical Analysis of Trial Data............................................................................... 96 
12.3 Statistical Analysis Plan ............................................................................................ 96 
13 DROPOUTS ....................................................................................................................... 98 
14 QUALITY CONTROL AND ASSURANCE ..................................................................... 99 
15 DISCUSSION, APPROVAL, AND AMENDMENT OF TRIAL PROTOCOL ................. 99 
16 LAWS, REGULATIONS AND ETHICS.......................................................................... 100 
17 TRIAL PROGRESS .......................................................................................................... 100 


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18 TRIAL PROTOCOL COMPLIANCE .............................................................................. 101 
Appendix 1. Response Evaluation Criteria in Solid Tumors RECIST Version 1.1 ............... 102 
Appendix 2 Child-Pugh Score ............................................................................................... 112 
Appendix 3 BCLC Staging (Barcelona Clinic Liver Cancer Staging System, 2010) ........... 113 
Appendix 4 ECOG Performance Status Scoring Criteria ...................................................... 114 
Appendix 5 New York Heart Association (NYHA) Functional Classification ...................... 115 
Appendix 6 List of Participating Study Centers .................................................................... 116 
Appendix 7 Labels of Apatinib Mesylate Tablets as a Second-Line  
Treatment for Advanced HCC............................................................................ 117 
Appendix 8 Percent Bone Marrow Content in Human Skeleton ........................................... 119 
Appendix 9 Quality of Life Score (EORTC QLQ-C30 V3.0 及HCC and HCC-18)............ 120 
Appendix 10 Flow Chart of Randomization and Enrollment for the Clinical  
Trial of Apatinib Mesylate Tablets as a Second-Line Treatment  
for Advanced Hepatic Carcinoma .................................................................... 125 
REFERENCES ..................................................................................................................... 126 
LIST OF TABLES 
Table 1. Effects of apatinib on KTRs ....................................................................................... 56 
Table 2. Efficacy of apatinib in the treatment of different solid tumors .................................. 61 
Table 3. Changes in plasma VEGF at different time points in 10 subjects .............................. 62 
Table 4. Inter-group comparison of efficacy results (FAS)...................................................... 65 
Table 5. Comparison of the incidences of AEs and ADRs between the two groups (SS) ....... 65 
Table 6. Common AEs (incidence ≥ 10%) in both groups....................................................... 66 
Table 7. Results of sample size estimation .............................................................................. 74 
Table 8. Doses and dose level modification of each group ...................................................... 79 
Table 11. Suggested treatments for proteinuria........................................................................ 85 
Table 12. Criteria for the causality between AEs and investigational drug ............................. 93 
Table 13. Contact information of each institution ................................................................... 94 
 


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PROTOCOL SYNOPSIS 
Study Title 
A Multicenter, Double-Blind, Randomized, Parallel-Controlled Phase III 
Clinical Study Evaluating Apatinib Mesylate Tablet as Second-Line Treatment 
in Patients with Advanced Hepatocellular Carcinoma (HCC) 
Protocol No. 
APTN-III-HCC 
Sponsors 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Shanghai Hengrui Pharmaceutical Co., Ltd. 
Nature 
Phase III clinical trial for IND application 
Study Population 
Patients with advanced HCC refractory to systemic treatment 
Study Objective 
To observe and evaluate the efficacy and safety of apatinib mesylate tablet as 
second-line treatment in patients with advanced HCC 
Study 
Endpoints 
Primary endpoint 
Overall survival (OS) 
Secondary 
endpoints 
Efficacy endpoints: 
Progression free survival (PFS); 
3-, 6-, and 12-month PFS rates; 
Time to progression (TTP); 
Objective response rate (ORR); 
Disease control rate (DCR); 
The percentage of evaluable patients with stable disease (SD) of ≥ 4 weeks 
(confirmed SD); 
6- and 12-month mortalities; 
Quality of life score; 
Safety endpoints: 
Vital signs, laboratory measurements, adverse events (AEs), serious 
adverse events (SAEs), treatment-related AEs and SAEs, and AEs of 
special interest (e.g., hypertension, proteinuria, and hand-and-foot 
syndrome [palmar-plantar erythrodysesthesia syndrome]); 
Judged as per NCI-CTCAE V4.0 criteria 
Study Design 
A randomized, double-blind, placebo-controlled, multi-center phase III clinical 
trial; 
Subjects will be stratified and randomized based on the ECOG PS (0 or 1), the 
past medication of sorafenib, and the presence of vascular invasion and/or 
extrahepatic metastasis 
Planned Enrollment 
A total of 360 subjects are planned to be enrolled, including 240 subjects in the 
apatinib group and 120 subjects in the placebo group. According to the 
resolution of scientific committee, additional subjects will be enrolled, i.e., 390 
subjects in total. 
Screening Criteria 
Clinical Diagnostic Criteria: 
"Guideline on Diagnosis and Treatment for Primary Liver Cancer" (2011 
Edition) states: 
The clinical diagnosis of HCC can be confirmed when the following conditions 
(1) + (2)a or conditions (1) + (2)b + (3) are met: 
(1) With evidence of cirrhosis and HBV and/or HCV infection (positive HBV 
and/or HCV antigen);  


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(2) Typical imaging features of HCC: Multidetector CT scan and/or dynamic 
contrast-enhanced MRI showing hepatic space-occupying lesions with 
arterial hypervascularity and venous or delayed phase washout; 
a One of the two imaging examinations (CT and MRI) showing the above 
features of liver cancer for those with lesions ≥ 2 cm in diameter;  
b Both CT and MRI imaging examinations showing the above features of liver 
cancer for those with lesions of 1-2 cm in diameter, so as to enhance the 
specificity of the diagnosis; 
(3) Serum AFP ≥ 400 μg/L for 1 month or ≥ 200 μg/L for 2 months, and when 
the increase in AFP level due to other reasons can be excluded, including 
pregnancy, germline embryogenic tumor, active liver disease and secondary 
liver cancer. 
Inclusion Criteria: 
1. Age: ≥ 18 years old; 
2. Patients strictly meeting the clinical diagnostic criteria in "Guideline on 
Diagnosis and Treatment for Primary Liver Cancer" (2011 Edition) or with 
histologically or cytologically confirmed recurrent/metastatic HCC, 
unsuitable for palliative surgery or radiation therapy, with at least one 
measurable lesion (must be ≥ 10 mm in longest diameter by spiral CT or ≥ 
15mm in shortest diameter for enlarged lymph nodes, as per RECIST 1.1, as 
shown in Annex 1); 
3. Patients with HCC refractory or intolerant to systematic chemotherapy (with 
oxaliplatin, alone or in a therapeutic combination) and/or molecular targeted 
therapy with sorafenib; 
Note: Definition of treatment failure: disease progression during treatment or 
relapse after treatment is completed (must have received ≥ 1 cycle of systemic 
chemotherapy with oxaliplatin (or plus other drugs) or ≥ 14 days of molecular 
targeted therapy with sorafenib); 
Definition of intolerability: Grade ≥ IV hematological toxicity or Grade ≥ III 
non-hematological toxicity or Grade ≥ II major organ injury such as the heart, 
liver, or kidneys during treatment. 
4. The interval between the last systemic treatment failure (with treatment 
discontinued) and the enrollment (time of signing the informed consent 
form) was ≥ 2 weeks, and the adverse event(s) had basically returned to 
normal (NCI-CTCAE ≤ Grade I); 
5. Child-Pugh score: Class A or Class B (≤ 7); the Child-Pugh scoring system 
is shown in Appendix 2; 
6. BCLC staging: B-C ("Barcelona Clinic Liver Cancer (BCLC) Staging 
System, 2010" is shown in Appendix 3); 
7. ECOG PS of 0–1 within 1 week before enrollment, as shown in Appendix 4; 
8. Expected survival ≥ 12 weeks; 
9. HBV DNA < 2000 IU/mL (104 copies/mL); 
10. Major organs must function normally, meeting the following criteria: 
(1) Hematology: (without blood transfusion, G-CSF, or medication within 14 
days prior to screening) 
a. HB ≥ 90 g/L;  
b. ANC ≥ 1.5 × 109/L; 
c. PLT ≥ 80 × 109/L; 
(2) Biochemistry: (no ALB transfusion within 14 days) 
a. ALB ≥ 29 g/L;  


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b. ALT and AST < 5  ULN; 
c. TBIL ≤ 1.5  ULN; 
d. Creatinine ≤ 1.5  ULN; 
(Only one of the two items, albumin or bilirubin, has a Child-Pugh score of 2) 
11. Women of childbearing potential must have a negative pregnancy test 
(serum or urine) within 7 days prior to enrollment, and be willing to take 
appropriate contraceptive measures during the trial and within 8 weeks 
after the last dose of the investigational drug. Male subjects should either 
undergo surgical sterilization, or agree to take appropriate contraceptive 
measures during the trial and within 8 weeks after the last dose of the 
investigational drug; 
12. Subjects must participate voluntarily, sign the informed consent form, have 
good compliance and corporate with follow-up visits. 
Exclusion Criteria: 
1. Patients who have received any local treatment within 4 weeks prior to 
participating in this study (including but not limited to surgery, radiation, 
hepatic artery embolization, TACE, hepatic arterial infusion, 
radiofrequency ablation, cryoablation, or percutaneous ethanol injection); 
2. Patients with known intrahepatic cholangiocarcinoma, mixed 
hepatocellular carcinoma and fibrolamellar hepatocellular carcinoma; other 
uncured malignancies currently or within the past 5 years, except for cured 
skin basal cell carcinoma or cervical carcinoma in situ; 
3. Patients planning to receive liver transplant (except for patients who have 
undergone liver transplant); 
4. Patients with symptomatic ascites requiring therapeutic paracentesis or 
drainage, or with a Child-Pugh score > 2; 
5. Patients with hypertension which cannot be controlled to the normal range 
by antihypertensives (systolic pressure > 140 mmHg, diastolic pressure > 
90 mmHg); 
6. Patients with Grade II or greater myocardial ischemia or myocardial 
infarction, uncontrolled arrhythmias (QTc interval ≥ 450 ms in males and ≥ 
470 ms in females); 
7. Patients with NYHA (see Appendix 5) Class III-IV cardiac insufficiency or 
LVEF (left ventricular ejection fraction) < 50% by echocardiography; 
8. Presence of multiple factors affecting oral medications (such as inability to 
swallow, chronic diarrhea, and intestinal obstruction, which significantly 
affect drug administration and absorption); 
9. Patients with a history of gastrointestinal bleeding within the past 6 months 
or a high risk of bleeding such as esophageal varices with bleeding risk, 
active ulcers, and fecal occult blood ≥ (++); in the case of fecal occult 
blood (+), a gastroscopy is required; 
10. Abdominal fistula, gastrointestinal perforation or abdominal abscess within 
28 days prior to the study; 
11. Abnormal coagulation function (INR > 1.5 or prothrombin time (PT) > 
ULN + 4 s), bleeding tendency or receiving thrombolytics or anticoagulant 
therapy; 
12. Patients with central nervous system metastases or known brain metastases; 
13. Patients with previous or current objective evidence of pulmonary fibrosis, 
interstitial pneumonia, pneumoconiosis, radiation pneumonitis, 
drug-induced pneumonitis, and severe lung function impairment; 
14. Urine protein ≥ ++ or 24-h urine protein > 1.0 g as indicated by urinalysis; 


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15. Had received treatment with a potent CYP3A4 inhibitor within 7 days prior 
to study participation, or had received treatment with a potent CYP3A4 
inducer within 12 days prior to study participation; 
16. Pregnant or lactating women; patients of child-bearing potential unwilling 
or unable to take effective contraceptive measures; 
17. Patients with a known history of mental illness or psychotropic substance 
abuse; 
18. Patients with bone metastasis who had received a palliative radiotherapy in 
an area of > 5% of bone marrow area within 4 weeks prior to the 
participation in this study. 
Termination Criteria: 
1. Subject withdraws informed consent and requests to withdraw from the 
study; 
2. Medical imaging examinations show disease progression; 
3. Subjects showing unacceptable toxicity after dose modification; 
4. Other reasons for which the investigator considers a withdrawal necessary; 
5. Study termination by the sponsor for the sake of safety. 
Investigational Drugs and 
Method of Administration 
Treatment group: Apatinib is given via oral administration after meals (the 
dosing time on each day should remain the same whenever possible) at an 
initial dose of 750 mg/day, once a day, 3 tablets per dose, in 28-day cycles. The 
dose can be adjusted based on the toxic reactions of the subjects as per protocol 
(first dose reduction: 500 mg/day, q.d.; second dose reduction: 250 mg/day, 
q.d.). If the toxic side effects are completely resolved after dose reduction, the 
dose can be resumed to the previous dose level; however, if the dose is reduced 
again, it should not be resumed again according to the protocol. 
Placebo group: Placebo is given via oral administration after meals (the dosing 
time on each day should remain the same whenever possible) at an initial dose 
of 750 mg/day, once a day, 3 tablets per dose, in 28-day cycles. The dose can 
be adjusted based on the toxic reactions of the subjects as per protocol (first 
dose reduction: 500 mg/day, q.d.; second dose reduction: 250 mg/day, q.d.); 
Study Period 
November 2013-March 2018  
Statistical Methods 
In this trial, placebo is used as a control and a superiority test is performed 
between the two groups. 
All statistical analyses will be performed using SAS. All statistical analyses are 
performed using two-tailed tests. P ≤ 0.05 is considered statistically significant, 
and 95% confidence is used for confidence intervals. 
Pre-set subgroup analysis: Subgroups will be pre-defined based on the 
following factors for a confirmatory subgroup analysis in this study: age ≤ 65 
years or > 65 years; ECOG PS 0 or 1; with or without vascular invasion; with 
or without extrahepatic metastases; with or without vascular invasion and 
extrahepatic metastases; positive or negative HBV; and with or without past 
history of sorafenib treatment. 
The baseline data is analyzed based on the full analysis set (FAS). All efficacy 
endpoints are analyzed based on the FAS and the per protocol set (PPS). The 
analysis of primary efficacy endpoint OS is carried out mainly in the FAS, but 
the PPS is used for the final analysis. The safety analysis is carried out based 
on the safety analysis set (SS). 
The measurement data obtained from various treatment groups during various 
visits will be statistically described by mean ± standard deviation or median 
(minimum, maximum). For comparison with baseline values of the screening 
period, paired t-tests are used to compare pre and post intra-group differences. 
Changes occurring in each group before and after treatment should be 


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compared by the analysis of variance (ANOVA) or rank sum test. The 
frequency data obtained from various treatment groups during various visits 
will be statistically described by frequency (proportions). Changes occurring in 
each group before and after treatment should be compared by χ2 test (exact 
test) or nonparametric test. 
● Dropout analysis: Descriptive analysis is mainly used. If necessary, the total 
dropout rate of each group and the comparison of dropout due to AEs will be 
tested by χ2 test or Fisher's exact test. 
● Balance analysis of baseline values: ANOVA or χ2 test is used to compare 
demographic data and other baseline values to evaluate the balance of 
various groups. 
● Efficacy analysis: 
For the comparison of 3-, 6-, and 12-month PFS rates, objective response rate 
(ORR), disease control rate (DCR), the percentage of patients with stable 
disease (SD) of ≥ 4 weeks (confirmed SD in particular), and 6- and 12-month 
mortalities, CMH-χ2 tests with and without central stratification are used to 
compare the efficacy between the two groups. In addition, the 95% confidence 
interval of the difference between the two groups is also calculated. Based on 
the product limit method and the actual condition of the data, 25%, 50% 
(median) and 75% of PFS and TTP, as well as PFS and OS at different time 
points after the start of treatment, are calculated and the endpoints are 
compared between the two groups using the Log-Rank test. 
● Safety analysis: Descriptive statistical analysis will be mainly used. The AEs 
and SAEs, treatment-related AEs and SAEs, and AEs and SAEs of special 
interest (e.g., hypertension, proteinuria, and hand-and-foot syndrome) are 
listed and summarized. If necessary, the incidence and severity of AEs and 
SAEs between different groups are compared using Fisher's exact test. 
Pre-Set Point for Efficacy 
Analysis 
Date of the 312th death (≥ 80% of the subjects have died) based on the full 
analysis set 
Version No. 
1.4 


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SCHEDULE OF ACTIVITIES 
    Treatment Cycle 
Visit 
 
Test Items        
Screening 
Period 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
Withdrawal 
28 Days 
after 
Withdrawal 
 
Follow-
up 1 
Follow-
up 2 
V1 (-3W) 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Vn 
Vn+1 
V100 
V101 
V201 
Date of Visit 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
√ 
Demographics 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor History 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgical History of 
Primary Lesions 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of Local Ablation 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of Intervention 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of Radiotherapy 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of Systemic 
Treatment 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past Medical History 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of Drug Allergy 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-Raya 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/Hepatitis C 
Markers and HBV-DNA 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum AFPb 
√ 
 
 
 
√ 
 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
√ 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Physical Examination 
√ 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
ECOG Performance 
Status Score 
√ 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Hematology 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
 
 
 
Blood Biochemistry 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
√ 
 
 
 
Urinalysisc 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
 
 


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    Treatment Cycle 
Visit 
 
Test Items        
Screening 
Period 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
Withdrawal 
28 Days 
after 
Withdrawal 
 
Follow-
up 1 
Follow-
up 2 
V1 (-3W) 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Vn 
Vn+1 
V100 
V101 
V201 
Coagulation Function 
√ 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
 
 
Pregnancy Testd 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stool Routinee 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiographyf 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECGg 
√ 
 
√ 
 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
 
 
 
Quality of Life Scoreh 
√ 
 
 
 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
 
 
 
 
Child-Pugh Score 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging 
Evaluation-Target Lesioni 
√ 
 
 
 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
 
 
√ 
 
Imaging 
Evaluation-Non-target 
Lesioni 
√ 
 
 
 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
 
 
√ 
 
Imaging Evaluation-New 
Lesioni 
 
 
 
 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
 
 
√ 
 
Inclusion and Exclusion 
Criteria 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment Assessment 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Return and 
Dispensing 
 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
 
Blood Pressure Record 
 
 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
 
Drug Interruption Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
 
Dose Modification Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
 
Additional Examinations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
 
Concomitant Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
 
Adverse Event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
 
Serious Adverse Event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as Second-Line Treatment for Advanced 
Hepatocellular Carcinoma 
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Protocol No.: 
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    Treatment Cycle 
Visit 
 
Test Items        
Screening 
Period 
C1 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
C9 
C10 
C11 
Withdrawal 
28 Days 
after 
Withdrawal 
 
Follow-
up 1 
Follow-
up 2 
V1 (-3W) 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Vn 
Vn+1 
V100 
V101 
V201 
Summary of Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
 
Survival Follow-Up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: (1) The results of ECOG PS, hematology, urinalysis, blood biochemistry, coagulation function, quality of life score, and ECG must be collected within 1 week before 
randomization. 
(2) a: Chest X-ray: If the chest CT has been performed during the screening period, chest X-ray is not required. 
(3) b: Serum AFP: Only detected at the end of Cycle 2 and Cycle 5; not strictly required after Cycle 5. 
(4) c: Urinalysis: Not required for female subjects during their menstrual period. 
(5) d: Pregnancy test: Additional pregnancy tests can be carried out during the treatment period if necessary. 
(6) e: Stool routine (occult blood): In the case of fecal occult blood (+) during the screening period, a gastroscopy is required; and additional fecal occult blood tests 
can be carried out during the treatment period if necessary. 
(7) f: Echocardiography: Must be performed during the screening period. For clinically significant ECG abnormalities observed during the study period, an additional 
echocardiography examination is required. 
(8) g: ECG: The QTc interval must be indicated for 3 times, with about 5 min apart. ECG examination shall be carried out before drug administration during the 
screening period and then always after drug administration in each visit. For clinically significant ECG abnormalities, an additional echocardiography 
examination is required; if there are symptoms such as precordial pain and palpitations, the myocardial zymogram (creatine kinase, lactate dehydrogenase) 
should be tested immediately. The examination should be carried out every two cycles after Cycle 3. 
(9) h: Quality of life score: Must be measured before the efficacy evaluation; and measured every two cycles after Cycle 3. 
(10) i: Imaging examination: Screening period: including CT or MRI of the chest and abdomen. Brain CT/MRI is required for clinically suspected metastases to the 
central nervous system. A bone scan is required for clinically suspected bone metastasis. Treatment period: The examination should be carried out in Cycles 2 
and 3, and then every two cycles after Cycle 3. 
(11) i: Efficacy evaluation: The first efficacy evaluation is carried out at the end of Cycle 2; efficacy confirmation is carried out at 4 weeks after the first efficacy 
evaluation (i.e., at the end of Cycle 3), Afterwards, the efficacy evaluation is carried out every two cycles; 
For subjects who withdraw from the study due to unacceptable toxicity, the efficacy evaluation should be conducted upon withdrawal if the efficacy evaluation is 
not carried out within 4 weeks before withdrawal. Thereafter, the imaging examination is performed every 2 cycles until progressive disease. 
(12) Follow-up 1 (can be repeated for V101): The subjects who withdraw from the study due to unacceptable toxicity should be followed-up for tumor progression 
until the tumor progression is confirmed by imaging or the start of new anti-tumor treatment. 
(13) Follow-up 2 (can be repeated for V201): Survival follow-up, visit number from 201, 202, 203… 


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REGULATIONS FOR DOSE MODIFICATION 
NCI Toxicity Grade 
Regulations for Dose Modification 
Regulations for Toxicity 
Recovery upon 
Re-Administration after 
Treatment 
Discontinuation 
Regulations for 
Toxicity Recovery at 
the Beginning of Next 
Cycle 
Grade I Hematological 
Toxicity 
Maintain original dose 
After treatment 
discontinuation during 
treatment cycle, 
hematological toxicity 
must recover to Grade ≤ 
II before treatment can be 
resumed 
At the beginning of the 
next cycle of 
administration, 
hematological toxicity 
must recover to Grade 
≤ II before treatment 
can be started 
Grade II Hematological 
Toxicity 
Maintain original dose 
Grade III Hematological 
Toxicity 
Interrupt treatment and give symptomatic treatment until toxicity returns to Grade ≤ 
II, and then resume treatment at the original dose level 
Grade IV Hematological 
Toxicity 
Interrupt treatment and give symptomatic treatment until toxicity returns to Grade ≤ 
II, and then resume treatment at the next lower dose level; upon complete recovery of 
toxicity, dose may be re-adjusted to the previous level to continue treatment; if 
a Grade IV hematological toxicity occurs again after such re-adjustment, dose should 
be reduced accordingly and no further adjustments shall be allowed 
Grade I Non-Hematological 
Toxicity 
Maintain original dose 
After treatment 
discontinuation during 
treatment cycle, 
non-hematological toxicity 
must recover to Grade ≤ 
I before treatment can be 
resumed 
At the beginning of 
next cycle, 
non-hematological 
toxicity must recover 
to Grade ≤ I before 
treatment can be 
started 
Grade II Non-Hematological 
Toxicity 
Give symptomatic treatment and continue study administration at the same time, if 
toxicity returns to Grade ≤ I after one week, continue dosing; if the toxicity does not 
recover or even worsens, interrupt treatment until toxicity returns to Grade ≤ I, and 
then resume treatment at the original dose level 
Grade III 
Non-Hematological Toxicity 
Interrupt treatment and give symptomatic treatment until toxicity returns to Grade ≤ I, 
and then resume treatment at the original dose level, and reduce by 1 dose level for 
the next cycle; investigator may decide accordingly for certain patients based on the 
specific conditions without waiting for the next cycle; upon complete recovery of 
toxicity, dose may be re-adjusted to the previous level to continue treatment; if 
a Grade III non-hematological toxicity occurs again after such re-adjustment, dose 
should be reduced accordingly and no further adjustments shall be allowed 


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Hepatocellular Carcinoma 
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Version Date: 10 Mar., 2017 
Page 49 of 126 
 
NCI Toxicity Grade 
Regulations for Dose Modification 
Regulations for Toxicity 
Recovery upon 
Re-Administration after 
Treatment 
Discontinuation 
Regulations for 
Toxicity Recovery at 
the Beginning of Next 
Cycle 
Grade IV 
Non-Hematological Toxicity 
Interrupt treatment and give symptomatic treatment until toxicity returns to Grade ≤ I, 
and then resume treatment at the next lower dose level for at least 1 cycle; upon 
complete recovery of toxicity, dose may be re-adjusted to the previous level to 
continue treatment; if a Grade IV non-hematological toxicity occurs again after such 
re-adjustment, dose should be reduced accordingly and no further adjustments shall 
be allowed (if a life-threatening adverse reaction, such as Grade IV renal impairment, 
neurotoxicity, cardiotoxicity, or hepatotoxicity occurs, discontinue the treatment and 
withdraw) 


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Second-Line Treatment for Advanced Hepatocellular Carcinoma 
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ABBREVIATIONS AND DEFINITIONS 
The following abbreviations and special terms are used in this study protocol 
Abbreviations and Special Terms 
Definitions 
ACEI 
Angiotensin converting enzyme inhibitor 
AE 
Adverse event 
AFP 
Alpha-Fetoprotein 
AKP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
APTT 
Activated partial thromboplastin time 
ARB 
Angiotensin II receptor blocker 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
B-Scan 
B-mode ultrasound 
Ca 
Calcium 
Cl 
Chlorine 
Cr 
Creatinine 
CR 
Complete response 
CT 
Computed tomography 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DRQ 
Data ready queue 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic case report form 
EGFR 
Epidermal growth factor receptor 
Fbg 
Fibrinogen 
GCP 
Good Clinical Practice 
FAS 
Full analysis set 
Glu 
Glucose 
Hb 
HCC 
Hemoglobin 
Hepatocellular carcinoma 
HFS 
Hand-foot-skin reaction 
HMG-CoA 
β-Hydroxy β-methylglutaryl-coenzyme A 
ITT 
Intention to treat 
K 
Potassium 
LD50 
Median lethal dose 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
Na 
Sodium 
NCI-CTC 
National Cancer Institute Common Toxicity Criteria 
OB 
Occult blood 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PDGFR 
Platelet derived growth factor receptor 
PFS 
Progression free survival 


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Abbreviations and Special Terms 
Definitions 
PI 
Principal investigator 
PLT 
Platelet 
PR 
Partial response 
PRO 
Protein 
PPS 
Per-protocol set 
PT 
Prothrombin time 
q.d. 
Quaque die 
QoL 
Quality of life 
RBC 
Red blood cell 
RC 
Red color sign 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
RTKs 
Receptor tyrosine kinase 
γ-GT 
γ-glutamyltransferase 
SAE 
Serious adverse event 
SAS 
Safety analysis set 
SD 
Stable disease 
TT 
Thrombin time 
TTP 
Time to progression 
ULN 
Upper limit of normal 
URIC 
Uric acid 
VEGF 
Vascular endothelial growth factor 
VEGFR 
Vascular endothelial growth factor receptor 
WBC 
White blood cell 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
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Apatinib mesylate tablet is a novel drug developed and filed by Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. and Shanghai Hengrui Pharmaceutical Co., Ltd. The product 
(strength of 0.2 g) has been approved for phase I clinical trial by National Medical Products 
Administration (NMPA) in Apr. 2007 (approval no. 2007L00837), and for phase II/III clinical 
trials in May 2009 (approval no. 2009L03464). Having completed the technical review of the 
means of production at dosage strength of 0.25 g in Feb. 2014, the Center for Drug Evaluation 
(CDE) reissued clinical trial approval for strength of 0.25 g in Jun. 2014 (approval no. 
2014L00877). 
At present, the National Clinical Research Center in the 81st Hospital of the Chinese People's 
Liberation Army (Nanjing) is leading the nationwide multi-center phase III clinical trial of 
apatinib mesylate tablets as second-line treatment in patients with advanced hepatocellular 
carcinoma, in accordance with the "Provisions for Drug Registration" and "Good Clinical 
Practice" (GCP). To this end, this study protocol has been formulated. 
1 BACKGROUND 
1.1 Epidemiology and Current Treatment of Hepatocellular Carcinoma 
Primary hepatocellular carcinoma ranked fifth among common malignant tumors in the world 
in 2008, with about 748,300 new cases, accounting for 6% of all new cancer cases. Due to the 
poor prognosis of this disease, it is responsible for up to 695,900 deaths per year, hence 
making it the third leading cause of cancer deaths[1]. China is a high-risk area for liver cancer, 
accounting for about 55% of the world's liver cancer incidences, and about 50% of deaths[2], 
which is second only to lung cancer in cancer-related deaths. Liver cancer is more prevalent 
in men than in women, with male-to-female ratio of 2-5:1, and is most common in the age 
group of 35-45 years. A higher proportion of male patients has been observed in areas with 
higher incidence. 
Hepatocellular carcinoma (HCC) is the most common type of primary hepatocellular 
carcinoma, accounting for 90% of all primary hepatocellular carcinomas[3]. The most 
important risk factors for HCC are hepatitis B virus (HBV) infection, hepatitis C virus (HCV) 
infection, water contamination (blue-green algae toxins), alcoholism, and aflatoxin. HCC 
occurs mostly in patients with hepatitis and liver cirrhosis, at approximately 10-20 years after 
primary hepatic damage. 
Most early-stage liver cancers are asymptomatic, and majority of the patients have reached 
a locally advanced stage or distant metastasis at the time of diagnosis. Currently, there are no 
standard treatments for advanced HCC, and mounting challenges stand in the way of clinical 
therapies. The survival times of patients with advanced HCC in China fall within the range of 
3–6 months, and the longest survival time among patients worldwide is not more than 1 year[2]. 
This is largely attributed to the lack of effective systemic treatment for HCC patients. Due to 
its resistance to conventional chemotherapy, HCC is usually treated through surgical 


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operations (hepatectomy, liver transplantation, and palliative treatment), non-surgical 
approaches (locoregional treatment, arterial chemoembolization, chemotherapy, radiotherapy, 
biological therapy, and molecular targeted therapy), and other therapies (including 
participation in clinical studies). 
1.2 Developments in Targeted Therapies for HCC 
1.2.1 VEGF/VEGFR signaling pathway and angiogenesis of hepatocellular carcinoma 
Therapies targeting receptor tyrosine kinases (RTKs) are currently the focus of research in the 
treatment of malignant tumors. Today, it is well known that angiogenesis represents a crucial 
step in the development and progression of malignant tumors. Tumor angiogenesis is thought 
to provide nourishment for the tumor and eliminate metabolites, thus allowing tumor cells to 
be transferred to other parts of the body through the new blood vessels. Therefore, tumor cell 
growth can be suppressed and the occurrence of metastasis can be reduced through the 
effective inhibition of angiogenesis. As such, this has become a promising new strategy for 
cancer treatment. Tumor angiogenesis is mainly dependent on the regulation of vascular 
growth factors and vascular growth inhibitors. Growth factor receptors include: epidermal 
growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and 
platelet-derived growth factor receptor (PDGFR), etc., which play important roles in tumor 
angiogenesis, tumor nourishment, elimination of metabolites, distant metastasis, signaling in 
tumor cells, as well as the transmission of signals regulating cell growth, cell differentiation, 
cell adhesion, cell migration, and apoptosis. Among which, the most important growth factor 
is vascular endothelial growth factor (VEGF). The binding of VEGF to VEGF receptor 
(VEGFR) can induce VEGFR-mediated downstream signaling, ultimately leading to tumor 
angiogenesis. 
HCC is a typical hypervascular tumor. Its occurrence, development, metastasis, and invasion 
are all closely related to angiogenesis. In the pathogenesis of HCC, several of the 
aforementioned RTKs are up-regulated, causing disease progression and providing a key 
target for pharmacological treatment. At present, there are 3 known members of the VEGFR 
family, namely VEGFR-1 (flt-1), VEGFR-2 (KDR/flk-1), and VEGFR-3 (flt-4), all of which 
belong to the family of RTKs. Among them, VEGFR-1 has the highest binding affinity to 
VEGF, 10 times that of VEGFR-2, while VEGFR-2 plays a major role in VEGF-regulated 
angiogenesis. In HCC patients, VEGF binds to two major receptors, VEGFR-1 (flt-1) and 
VEGFR-2 (KDR/flk-1)[4]. VEGFR-1 and VEGFR-2 have distributions of 87% and 53% on 
human hepatocellular carcinoma tumor-derived endothelial cells, respectively[5], and are also 
expressed on hepatocellular carcinoma cells. Both VEGFR-1 and VEGFR-2 consist of 
7 immunoglobulin-like extracellular domains, a transmembrane domain, and an intracellular 
domain with a tyrosine kinase insert, with VEGFR-2 being the most crucial one. Expression 
of VEGFR-1 and VEGFR-2 is closely related to the formation of hepatic precancerous 
lesions, i.e., liver cirrhosis, and VEGFR-2 is closely related to the differentiation and 
prognosis of liver cancer. Both VEGFR-1 and VEGFR-2 antibodies cause dose-dependent 


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inhibition of angiogenesis in HCC models, which verifies the relationship between VEGFR 
and HCC, as well as provides a theoretical basis for the development of VEGFR as a target 
for HCC treatment. 
1.2.2 Research developments in targeted therapies for HCC 
In Dec. 2007, sorafenib became the first FDA-approved drug for the treatment of HCC, based 
on its remarkable benefits in terms of survival as demonstrated in the SHARP trial[6], in 
which PFS was increased by 73% (5.5 vs. 2.8 months), and OS was increased by 44% (10.7 
vs. 7.9 months) when compared with placebo. This kicked off the new era of targeted therapy 
for patients with HCC. In 2008, sorafenib was approved for the treatment of HCC in China, 
hence offering a new treatment option to numerous liver cancer patients in China. However, 
the application of sorafenib treatment remains limited due to its high cost (approx. RMB 
50,000 per patient per month). 
Furthermore, several multi-kinase inhibitors that are being developed have suffered setbacks 
in head-to-head comparisons with sorafenib: 
The phase III clinical trial of sunitinib (Pfizer) in patients with advanced liver cancer was 
terminated prematurely in Apr. 2010 due to the failure of sunitinib to improve survival in 
comparison to sorafenib, and the incidence of serious adverse events was higher in the 
sunitinib group than in the sorafenib group [7]. 
The multi-kinase inhibitor ABT-869 (Linifanib) developed by Abbott had also failed to 
demonstrate any advantages over sorafenib. As such, the phase III clinical trial of ABT-869 
was terminated based on the recommendation of the independent data monitoring committee 
(IDMC). 
A study involving 731 patients showed that Roche's Tarceva (erlotinib), an epidermal growth 
factor receptor tyrosine kinase inhibitor, had also failed to provide additional benefits, as 
compared with sorafenib. 
Brivanib is a tyrosine kinase inhibitor targeting VEGF receptor and basic fibroblast growth 
factor (bFGF, FGF-2) receptor. The phase II trial of brivanib in patients with unresectable, 
locally advanced or distant metastatic liver cancer[8] showed that 6-month PFS reached 
18.2%, median PFS was 2.7 months, and median survival was 10 months, with relatively 
mild side effects, mainly including weariness, hypertension, and diarrhea. However, brivanib 
failed in the comparison with sorafenib in the phase III non-inferiority clinical trial, because 
the overall survival for brivanib treatment was deemed unsatisfactory. 
In summary, sorafenib remains the most superior targeted drug in terms of overall efficacy 
and safety in the treatment of HCC. In addition, the studies on Eli Lilly's ramucirumab 
(IMC-1121B) and bevacizumab in combination with chemotherapy are ongoing. 


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Eli Lilly's ramucirumab (IMC-1121B) is a human monoclonal antibody (IgG1) against 
VEGFR2, which can bind to expressed VEGFR and block the VEGF/VEGFR signaling 
pathway, thereby inhibiting vascular endothelial cell mitosis and producing anti-angiogenic 
effects [9]. A randomized, double-blind, multi-center phase III clinical study of ramucirumab 
is currently ongoing. 
Anti-VEGF antibody: With its high affinity to VEGFR, anti-VEGF monoclonal antibody 
(mAb) can block VEGFR, thereby preventing the binding of VEGF to its receptor to inhibit 
VEGF activity. Bevacizumab is a recombinant humanized monoclonal antibody targeting 
VEGF-A. A phase II clinical trial of bevacizumab in combination with capecitabine and 
oxaliplatin in patients with unresectable and untransplantable HCC showed an efficacy of up 
to 20%, indicating that bevacizumab in combination with chemotherapy is a safe treatment 
regimen. Further research is required for the understanding of the therapeutic value of 
bevacizumab in HCC patients [10]. 
Dovitinib is an oral small molecule tyrosine kinase inhibitor targeting FGFR, VEGFR, and 
PDGFR. Huynh et al. [11] found that dovetinib is able to inhibit the proliferation and 
migration of HCC cells in mouse xenograft HCC model. The phase II clinical study of 
dovitinib in HCC patients is currently undergoing. 
1.3 Development Background of Apatinib 
Apatinib is a small molecule VEGFR tyrosine kinase inhibitor developed by Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. with independent intellectual property rights. The chemical name 
of apatinib is N-[4-(cyanocyclopentyl)phenyl][2-[(4-pyridylmethyl)amino](3-pyridyl)] 
formamide mesylate. Apatinib has a molecular formula of C25H27N5O3S, and molecular 
weight of 493.58 (mesylate). Apatinib exerts its anti-angiogenic effect mainly by inhibiting 
VEGFR. Preclinical studies have shown that it's superior to PTK787 in anti-tumor effect. 
Phase II studies in HCC patients have preliminarily validated the efficacy and safety of 
apatinib in treatment of advanced HCC. The objective of this phase III study is to confirm the 
efficacy and safety of apatinib in treatment of advanced HCC. 
1.4 Results of Preclinical Studies of Apatinib 
1.4.1 Metabolism study of apatinib in animals 
Results of PK studies in beagle dogs showed that: After a single intravenous dose of apatinib 
mesylate (i.v.bolus) at 5 mg/kg, maximum plasma concentrations (Cmax) of apatinib were 
6058 ng/mL (male) and 3523 ng/mL (female), areas under plasma concentration-time curve 
(AUC0→24h) were 12599 ng/mL·h (male) and 9106 ng/mL·h (female), elimination half-lives 
(T1/2) were 2.15 h (male) and 3.22 h (female), elimination rate constants (Kel) were 0.328 h-1 
(male) and 0.216 h-1 (female), mean residence times (MRT) were 3.08 h (male) and 3.81 h 
(female), plasma clearance rates (CL) were 0.385 L/h/kg (male) and 0.515 L/h/kg (female), 
apparent volumes of distribution (Vd) were 1.19 L/kg (male) and 1.94 L/kg (female). 


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After a single oral dose of apatinib mesylate at 5, 15, and 30 mg/kg, linear correlation was not 
observed in Cmax and AUC0→24h in male beagle dogs; however female beagle dogs exhibited 
linear correlation in Cmax (formula: y = 65.217x + 38.411, R2 = 0.9894) and AUC0→24h (formula: 
y = 451.29x - 547.16, R2 = 0.9939). Mean residence times (MRT) were 4.132 h (male) and 
4.327 h (female), and oral bioavailabilities (F) were 9.24% (male) and 15.42% (female). 
1.4.2 Preclinical efficacy studies of apatinib 
In vitro: The inhibitory effects of apatinib on the growth of various in vitro tumor cells such 
as colon cancer, lung cancer, gastric cancer, renal cell carcinoma, and leukemia were 
evaluated using SRB or MTT assays. Results showed that IC50 was greater than 20 M in all 
tumor cell lines above, far higher than the concentration required to inhibit the activity of 
tyrosine kinase receptors such as VEGFR, suggesting that apatinib has no cytotoxic effect. 
In vivo: Apatinib has significant anti-tumor effects on a variety of human tumors such as 
colon cancer, lung cancer, and gastric cancer xenografts in nude mice. Efficacy: Apatinib 
exerts obvious synergistic effects on traditional cytotoxic drugs such as oxaliplatin, 5-Fu, 
docetaxel, and doxorubicin, with a comparable efficacy to ZD6474 and AMG706, but more 
effective than PTK787. 
Anti-tumor mechanism: Apatinib effectively inhibits VEGFR2 at very low concentrations, 
and is able to inhibit kinases such as PDGFR, c-Kit, and c-Src at higher concentrations. Refer 
to Table 1 for details. The effect of apatinib on VEGFR2 is 13.7-fold higher than PTK787; 
apatinib also inhibits KDR-mediated downstream signaling. Apatinib also inhibits the growth 
of KDR/NIH3T3 cell lines with high-expression of VEGF, inhibits VEGF-induced 
proliferation, migration, and lumen formation of HUVEC cells, and inhibits the germination 
of microvessels on rat arterial rings. The anti-angiogenic effect of apatinib in vitro is stronger 
or equivalent to that of the control compound PTK787. 
Table 1. Effects of apatinib on KTRs 
Kinase 
Apatinib (IC50 ± SD nM) 
PTK787 (IC50 ± SD nM) 
VEGFR2 
2.43 ± 1.30 
33.30 ± 14.45 
Flt1 
70.08 ± 29.36 
84.69 ± 20.74 
PDGFRβ 
537.31 ± 190.46 
416.51 ± 143.73 
c-Kit 
420.31 ± 40.37 
606.11 ± 77.93 
EGFR 
> 1000 
> 1000 
ErbB2 
> 1000 
> 1000 
PGRFR1 
> 1000 
> 1000 
c-Src 
348.53 ± 194.42 
> 1000 


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1.4.3 Toxicity studies of apatinib in animals 
1.4.3.1 Acute toxicity study in animals 
(1) Mice: Forty ICR mice were randomly assigned to 2 groups, 20 per group (half females 
and half males), including a 5 g/kg treatment group and a solvent control group. After a single 
dose by oral gavage, the immediate reactions of mice were observed for 14 days, during 
which the toxicities and deaths were recorded. Apart from slow increase in body weight in the 
treatment group, no significant clinical toxicity and death occurred during the observation 
period. Gross anatomical examination was carried out in all mice on D15, and no drug-related 
changes were observed. 
(2) Rats: Eighty SD rats were randomly assigned to 4 groups, 20 per group (half females and 
half males), including two treatment groups (2 and 5 g/kg) and two corresponding solvent 
control groups. After a single dose by oral gavage, the immediate reactions of mice were 
observed for 14 days, during which the toxicities and deaths were recorded. During the 
observation period, the mortalities in female rats and male rats in the 5 g/kg group were 50% 
and 20%, respectively; in the 2 g/kg group, death was found in 1 female rat (mortality of 
10%), but no death was observed in male rats. Symptoms of toxicity, such as loose hair, 
reduced activity, listlessness, and slow weight gain, were observed in rats in the treatment 
groups post-administration; weight loss was observed in dead and moribund rats. The 
following observations were noted in 1 moribund female rat in the 5 g/kg group: Bilateral 
adrenal enlargement, yellow plaques in the right kidney, abnormal blood biochemical 
indicators, as well as abnormal hepatic and renal functions (> 3-fold elevation in ALT, AST, 
and BUN levels); histopathological examination showed scattered spotty necrosis of 
hepatocytes, adrenal hemorrhage, thymic atrophy, and reduced lymphocyte levels in the 
germinal center in the white pulp of spleen. No significant abnormalities were observed 
during gross anatomical examination in other deaths and rats dissected on D14. 
(3) Beagle dogs: Six beagle dogs around the age of 6 months (three per gender), weighing 
about 7 kg each, were included in the acute toxicity study to determine the approximate lethal 
dose in beagle dogs after oral administration. Single oral doses were administered in 50% 
escalation. Females received doses at 1050, 1575, and 2363 mg/kg, while males received 
doses at 1575, 2363, and 3545 mg/kg (1 dog per dose level). Decreased activity, limb 
weakness, gait instability, and slight weight loss were observed in female beagle dogs 
post-administration. Five-fold increase in BUN levels (17.3 mmol/L) was observed in dogs 
which received 2363 mg/kg. Male dogs started to vomit (2 times and drug in vomit) at 
approx. 2–4 h. Decreased activity, weakness in hind or all limbs, and reduced food intake 
were also observed in male dogs.The severity of toxicity increased with increasing dose. 
Significant toxicities were observed but no deaths occurred. 


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1.4.3.2 Long-term toxicity study in animals 
(1) Rats: SD rats received apatinib by oral gavage for 13 weeks, followed by a 4-week 
recovery period for observation. Rats were assigned to four groups: 3 treatment groups (5, 15, 
and 50 mg/(kg·d)), and 1 solvent control group, with each group consisting of 14 per gender. 
Results showed that: 5 mg/(kg·d) group: No drug-related changes were observed throughout 
the course of the study. 15 mg/(kg·d) group: Male rats showed mild increase in ALT levels 
during the dosing period, which resolved after discontinuation. 50 mg/(kg·d) group: During 
the dosing period, both male and female rats showed slow weight gain, decreased food 
intake, weight loss, as well as mild increases in hepatic function indicators (ALT, AST, ALP); 
no abnormalities in relevant ions, relevant enzymes, and estrogen in serum were observed; no 
drug-related changes were observed in histopathological examination of the liver and other 
organs; in addition, 3 female rats in this group died during the fasting period prior to 
anatomical examination, which may be related to weight loss, marasmus, malnutrition, and 
fasting post-dose; female rats in this group also showed broken incisors (11/14, 78.6%), slight 
decrease in tibia bone density (mainly caused by decrease in trabecular bone density), which 
were resolved after discontinuation apart from partial changes in bones; histopathological 
results showed that through gross observation of each organ, statistical analysis of organ 
weights and coefficients, and histological examination, incisor changes were observed in 
treatment groups compared with control group, mainly manifested as broken incisor, and in 
severe cases, a complete loss, partially of which were resolved after 4 weeks of recovery. 
Apart from some commonly seen spontaneous lesions, no drug-related pathological changes 
were observed in all treatment groups. 
(2) Beagle dogs: Twenty-four beagle dogs around the age of 6 months (12 per gender), 
weighing about 7 kg each, were randomized into 4 groups, with 6 dogs per group (3 male 
dogs and 3 female dogs) and were given oral doses of apatinib for 13 weeks. This study 
included 4 groups, i.e., 3 treatment groups (3, 10, and 30 mg/(kg·d)), and 1 control group. 
Results showed that the behavioral responses, body weight, and food intake of dogs in each 
dose group were similar to those in the control group. Hematology, blood biochemistry, 
electrocardiogram (ECG), and bone density test results showed that various indicators were 
similar between the treatment and control groups, and all results were within the normal 
range, indicating generally normal hepatic and renal functions. During the dosing period, the 
skin around the noses and mouths of dogs in the 30 mg/(kg·d) group appeared pale, and 
histopathological examination revealed thinner epidermis on the nose; while no abnormality 
was noted in the control group. 


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1.5 Results of Clinical Studies of Apatinib 
1.5.1 Phase I tolerance test of apatinib 
According to the modified Fibonacci method, the designed doses of apatinib were 250 mg, 
500 mg, 750 mg, 850 mg, and 1000 mg. According to the experimental design, the Grade IV 
hematological toxicity and/or Grade ≥ III non-hematological toxicity occurring in the first 
course of treatment (28 days) were determined as dose limiting toxicities (DLTs). A total of 
18 subjects could be used for tolerability evaluation, with 3 subjects in each dose group 
(6 subjects in the 850 mg dose group). 
DLT was observed in the 1000 mg dose group of apatinib, characterized by Grade III 
hypertension (2 out of 3 patients) and Grade III hand-foot-skin reaction (1 patient). All had 
recovered following dose discontinuation and were controlled through dose reduction. In the 
additional 850 mg dose group, none of the 6 patients showed DLT. For further safety 
considerations, the observation time of the 850 mg group was extended to 2 cycles and DLT 
was still not present, so the 850 mg dose was identified as the maximum tolerated dose 
(MTD). 
The main adverse events in the first cycle of the tolerability study included: hand-foot-skin 
reactions (2 cases of Grade I in the 500 mg/day group; 2 cases of Grade I and 1 case of Grade 
II in the 750 mg/day group; 1 case of Grade I and 2 cases of Grade II in the 850 mg/day 
group; 1 case of Grade III in the 1000 mg/day group; 9 cases in total, 47.4%); hypertension 
(1 case of Grade I in the 250 mg/day group; 1 case of Grade II in the 850 mg/day group; 1 case of 
Grade II in the 1000 mg/day group; 9 cases in total, 47.4%); white blood cell decreased 
(1 case of Grade II in the 500 mg/day group; 2 cases of Grade II and 1 case of Grade I in the 
750 mg/day group; 3 cases of Grade I and 1 case of Grade II in the 850 mg/day group; 1 case 
of Grade II in the 1000 mg/day group; 6 cases in total, 31.6%); oral mucositis (1 case in 
Grade I in the 250 mg/day group; 1 case of Grade I and 1 case of Grade II in the 750 mg/day 
group; 1 case of Grade I and 1 case of Grade II in the 1000 mg/day group; 5 cases in total, 
26.3%); pyrexia (2 cases of Grade II in the 250 mg/day group; 1 case of Grade II in the 
500 mg/day group; 1 case of Grade I in the 850 mg/day group; 4 cases in total, 21.1%); 
platelet count decreased (1 case of Grade II in the 500 mg/day group; 1 case of Grade II in 
the 750 mg/day group; 1 case of Grade II in the 750 mg/day group; 1 case of Grade II in the 
1000 mg/day group; 3 cases in total, 15.8%); asthenia (2 cases of Grade II in the 850 mg/day 
group; 1 case of Grade II in the 1000 mg/day group; 3 cases in total, 15.8%); bilirubin 
increased (1 case of Grade I in the 750 mg/day group; 1 case of Grade I in the 850 mg/day 
group; 2 cases in total, 10.5%); headache (1 case of Grade I in the 1000 mg/day group, 1 case 
of Grade II in the 850 mg/day group; 2 cases in total, 10.5%); abdominal pain (1 case of 
Grade II in the 500 mg/day group, 1 case of Grade I in the 750 mg/day group; 2 cases in total, 
10.5%); low back pain (1 case of Grade II in the 750 mg/day group, 1 case of Grade I in the 
1000 mg/day group; 2 cases in total, 10.5%); esophagitis (1 case of Grade II in the 


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500 mg/day group; 1 case of Grade I in the 750 mg/day group; 2 cases in total, 10.5%); 
nausea (1 case of Grade II in the 750 mg/day group; 1 case in total, 5.3%); tongue pain 
(1 case of Grade I in the 1000 mg/day group; 1 case in total, 5.3%); anterior chest pain 
(1 case of Grade II in the 500 mg/day group; 1 case in total, 5.3%); chest pain (1 case of 
Grade II in the 500 mg/day; 1 case in total, 5.3%); transaminases increased (1 case of Grade 
II in the 850 mg/day group; 1 case in total, 5.3%); pruritus (1 case of Grade I in the 
500 mg/day group, 5.3%); epigastric discomfort (1 case of Grade I in the 850 mg/day group, 
5.3%); hoarseness (1 case of Grade I in the 850 mg/day group; 1 case in total, 5.3%); stomach 
discomfort (1 case of Grade II in the 850 mg/day group, 5.3%); chest tightness, cough (1 case 
of Grade I in the 850 mg/day group; 1 case in total, 5.3%); proteinuria (1 case of Grade I in 
the 850 mg/day group, 5.3%); sinus bradycardia (1 case of Grade I in the 500 mg/day group, 
5.3%); lung abscess (1 case of Grade I in the 850 mg/day group; 1 case in total, 5.3%); 
constipation (1 case of Grade I in the 250 mg/day group, 5.3%); intestinal obstruction (1 case 
of Grade I in the 250 mg/day group I, 5.3%). 
Adverse events mentioned above that were definitely unrelated or unlikely related to apatinib 
included pruritus, esophagitis, lung abscess, abdominal pain, constipation, and intestinal 
obstruction. Primary treatment-related adverse drug reactions included hand-foot-skin 
reactions, white blood cell count decreased, hypertension, fever, bilirubin increased, 
oesophagitis, dermal toxicity, thrombocytopenia, nausea, asthenia, headache, transaminases 
increased, oral mucositis, epigastric discomfort, tongue pain, hoarseness, stomach discomfort, 
chest tightness and cough, proteinuria, and sinus bradycardia. In 850 mg and lower dose 
groups, hematological toxicities were of Grade I–III, including white blood cell count 
decreased and thrombocytopenia, while other non-hematological toxicities were of Grade I–
II, which could recover to normal after symptomatic treatment. 
1.5.2 Phase I clinical pharmacodynamic (PD) observation of apatinib 
From May 2007 to December 2008, a phase I clinical study of apatinib was conducted at 
Fudan University Shanghai Cancer Center, including 3 studies, i.e., a tolerability study, 
a pharmacokinetic study, and a phase I supplement clinical study. This study enrolled a total 
of 81 subjects with advanced solid tumors who were refractory to standard treatment or had 
no effective standard treatment. Nine of the subjects were not evaluated, and 3 others were 
only administered with a low dose of 250 mg/day. A total of 69 subjects received apatinib 
treatment at doses of 500–1000 mg/day (only 3 subjects received 1000 mg/day), and a total of 
56 patients were evaluated. Refer to Table 2 for a summary of tumor types of the 69 subjects 
and efficacy in the 56 evaluable subjects: 


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Table 2. Efficacy of apatinib in the treatment of different solid tumors 
 
Gastric 
Cancer 
Colorectal 
Cancer 
Lung 
Cancer 
Breast 
Cancer 
Nasopharyngeal 
Cancer 
Renal 
Carcinoma 
Esophageal 
Cancer 
Hepatocellular 
Carcinoma 
Small 
Intestinal 
Stromal 
Tumor 
Neurilemmoma 
Malignant of 
Left Iliac Fossa 
Not 
Evaluable 
1 
7 
1 
1 
1 
0 
1 
1 
0 
0 
CR 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
PR 
2 
2 
0 
0 
0 
1 
0 
0 
1 
0 
SD 
5 
15 
3 
4 
1 
0 
4 
1 
0 
0 
PD 
1 
7 
1 
2 
0 
0 
0 
0 
0 
1 
Death 
Without 
Evaluation 
3 
1 
0 
0 
0 
0 
0 
0 
0 
0 
Objective 
Response 
Rate 
18.1% 
8% 
0 
0 
0 
100% 
0 
0 
100% 
0 
Disease 
Control Rate 
63.6% 
68% 
75% 
66.7% 
100% 
100% 
100% 
100% 
100% 
0 
Total 
12 
32 
5 
7 
2 
1 
5 
2 
1 
1 
Result analysis: 
A total of 69 subjects with various types of solid tumors were included in statistical analysis, 
and 13 were deemed unevaluable for efficacy. Of the 69 subjects included in the statistics, 
16 subjects were given 500 mg, 37 subjects were given 750 mg, 13 subjects were given 
850 mg, and 3 subjects were given 1000 mg.  
Analysis of ORR showed that 1 evaluable case was found for each of renal carcinoma and 
small intestinal stromal tumor, with both achieving PR. 11 and 25 evaluable patients were 
included for the gastric cancer and colorectal cancer respectively, and higher response rates of 
18.1% and 8%, respectively, were achieved.  
Based on the analysis of DCR, 1 each of evaluable patient for nasopharyngeal cancer, HCC, 
and GIST were observed, and all had achieved SD. Due to the small sample size, the efficacy 
should be assessed with caution. There were 4, 4, and 6 evaluable patients for esophageal 
cancer, lung cancer, and breast cancer, respectively, with DCRs of 100%, 75%, and 66.7%. 
1.5.3 Phase I clinical pharmacokinetic study of apatinib 
The single-dose study involved oral administration at 3 dose levels of 500, 750 and 850 mg to 
subjects with cancer, including 7 male subjects and 5 female subjects in low-dose group, 6 male 
subjects and 3 female subjects in medium-dose group, and 6 male subjects and 6 female 
subjects in high-dose group. In this study, drugs were administered within 0.5 h after meals, 
and blood and urine samples were collected at multiple time points within 48 h. Results 
showed that M1 was a major metabolite of apatinib in humans, with AUCM1/AUCapatinib of 
1.15-5.06, as well as 48-h cumulative excretion in urine, Cum.AeM1/Cum.Aeapatinib of 
24.5-353. T1/2 values of apatinib and M1 were 8.93 ± 0.81 h and 12.5 ± 1.666 h, respectively. 
At the same dose level, large inter-individual variability was seen in apatinib and M1 
exposure (AUC and Cmax); significant gender difference was observed in the high-dose group 
(P < 0.05), in which, AUC in females was 1.96 times higher than that in males, and Cmax was 


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3.57 times higher than that in males. The levels of apatinib and M1 exposure in male and 
female subjects were non-linearly but positively correlated to oral doses. 
The food-effect study mainly compared the differences in absorption of a single oral dose of 
apatinib given at 1 h before meals and 0.5 h after meals. The concentrations of M1 were also 
examined. Blood and urine samples were collected at multiple time points within 48 h. 
Results showed that there was no significant difference in Tmax and Cmax of apatinib in the 
blood of male and female subjects with respect to the order of eating and drug administration 
(P > 0.05). In addition, the AUC, T1/2 and Cum.Ae of apatinib, as well as relevant 
pharmacokinetic parameters of M1 were not affected by the order of eating and drug 
administration (P > 0.05). 
Due to the relatively long half-life of M1 (T1/2: 12.9 ± 1.85 h), the repeated-dose trial mainly 
focused on M1 accumulation in vivo, and changes in apatinib (T1/2: 9.24 ± 1.40 h) 
concentrations were observed concurrently during the trial. The drugs were administered 
once a day for 4 weeks during the trial, and blood and urine samples were collected at 
multiple time points within 24 h on Days 1, 14, and 28 after the start of the trial. Results 
showed that: Although M1 and apatinib had relatively long half-lives, no significant 
accumulations of M1 and apatinib were observed in subjects on D14 vs. D1 (P > 0.05). 
However, a significant increase in M1 exposure was noted in male subjects on D28 vs. D1 
(P < 0.05). Apatinib: AUC (1d), AUC (14d), and AUC (28d) were 9260 ± 4308, 7256 ± 4709, 
and 21930 ± 20098 ng·h/mL, respectively; Cmax (1d), Cmax (14d), and Cmax (28d) were 1285 ± 
776, 693 ± 430, and 1602 ± 1755 ng/mL, respectively. M1: AUC (1d), AUC (14d), and AUC 
(28d) were 13846 ± 7061, 10899 ± 6702, and 39784 ± 21900 ng·h/mL, respectively; Cmax 
(1d), Cmax (D14d), and Cmax (28d) were 1193 ± 673, 908 ± 597, and 1728 ± 1233 ng/mL, 
respectively. There was no significant accumulation of apatinib and M1 based on the 
cumulative levels of urinary and renal excretion (P > 0.05). Cum.Ae (1d), Cum.Ae (14d), and 
Cum.Ae (28d) of M1 were 30281 ± 8141, 34537 ± 15867, and 33466 ± 17737 µg, 
respectively. 
1.5.4 Study on the effect of apatinib on serum VEGF 
The phase I clinical PK/PD study of apatinib enrolled 10 subjects who completed 0-28 days 
of VEGF testing. The results are shown in Table 3: 
Table 3. Changes in plasma VEGF at different time points in 10 subjects 
Subject 
Day 0 
Day 14 
Day 28 
1 
1627 
323 
3962 
2 
822 
1144 
497 
3 
244 
524 
312 
4 
240 
419 
475 
5 
280 
797 
920 


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Subject 
Day 0 
Day 14 
Day 28 
6 
518 
2000 
1841 
7 
1105 
1728 
1630 
8 
162 
467 
761 
9 
417 
761 
826 
10 
266 
477 
512 
Mean 
568 
864 
1174 
Standard Deviation 
477 
581 
1101 
As shown in Table 3, significant increase in VEGF levels was observed in 8 patients due to 
apatinib; 1 patient experienced an increase on D14, followed by a decline on D28; in 
addition, 1 patient reported abnormally elevated VEGF levels pre-dose, which decreased first 
and then increased post-dose. In general, progressive increases in serum VEGF levels were 
observed in 10 patients with various advanced solid tumors post-dose. Serum concentration 
was 568 ± 477 ng/mL on D1 pre-dose, 864 ± 581 ng/mL on D14 post-dose, and 1174 ± 
1101 ng/mL on D28 post-dose. No statistically significant difference in serum VEGF levels 
was observed pre- and post-dose. This may be related to the small sample size. 
1.5.5 Results of phase II clinical trial of apatinib in patients with gastric cancer 
This is a randomized, double-blind, double-dummy, parallel controlled, multi-center phase II 
clinical trial. 
A total of 141 subjects completed the trial, including 48 in the placebo group, 47 in the 
850 mg q.d. group, and 46 in the 425 mg b.i.d. group. 
Primary endpoint: PFS; secondary endpoints: ORR, DCR, OS, and safety. 
mPFS values of the 850 mg q.d. group, 425 mg b.i.d. group, and placebo group were 110, 96, 
and 42 days, respectively. mOS values of the 850 mg q.d. group, 425 mg b.i.d. group, and 
placebo group were 145, 128, and 75 days, respectively. DCR values of the 850 mg q.d. 
group, 425 mg b.i.d. group, and placebo group were 51.06%, 34.78%, and 10.42%, 
respectively. ORR values of the 850 mg q.d. group, 425 mg b.i.d. group, and placebo group 
were 6.38%, 13.04%, and 0%, respectively. 
AEs in the placebo, 850 mg q.d., and 425 mg b.i.d. groups were reported by 36, 42, and 
44 subjects, with incidences of 75%, 89.36%, and 95.65%, respectively; severe AEs (NCI 
CTC Grade III–IV) occurred in 18, 30, and 48 subjects, with incidences of 37.5%, 48.94%, 
and 73.91%, respectively. The incidence of AE was higher in both 850 mg q.d. and 425 mg 
b.i.d. groups as compared with the placebo group, and the incidence in the 425 mg b.i.d. 
group was higher than that in the 850 mg q.d. group. 


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1.5.6 Results of phase III clinical trial of apatinib in patients with gastric cancer 
This is a randomized, double-blind, parallel-controlled, nation-wide multi-center phase III 
clinical trial to validate the efficacy and safety of apatinib in patients with advanced gastric 
cancer. 
In this trial, 267 randomized patients who received at least one dose were included in FAS 
analysis, including 176 patients in the treatment group and 91 patients in the control group. 
In the FAS, endpoint events were observed in 146 (82.95%) subjects in the treatment group 
and 78 (85.71%) subjects in the control group, with an incidence > 80% in both groups, 
indicating that the statistical model is reliable. 
Analysis showed that as of 23 May, 2013, without taking the influence of crossover design 
into consideration, median OS (mOS) values were 6.5 and 4.7 months in the treatment and 
control groups, respectively. The mOS in the treatment group was 1.8 months longer than the 
control group, P = 0.0149. The HR of treatment group to control group was 0.709 and the 
95% CI was (0.537, 0.937), with P = 0.0156. The above results demonstrated that apatinib 
provided significant survival benefits when compared with placebo. 
All the 267 subjects in this trial were included in the SS for analysis. Results showed that: 
The incidences of AEs in the treatment and control groups were 98.30% v.s 90.11%, P = 
0.0038; the incidences of Grade ≥ II AEs were 88.07% v.s 67.03%, P = 0.0001; the 
incidences of Grade III–IV AEs were 60.23% v.s 41.76%, P = 0.0045. 
The incidence of ADRs in the treatment and control groups were 92.05% v.s 71.43%, P = 
0.0000; the incidence of Grade ≥ II ADRs were 80.68% v.s 45.05%; the incidences of Grade 
III–IV ADRs were 51.70% v.s 24.18%, P = 0.0000. 
The incidence of SAEs in the treatment and control groups were 15.34% v.s 16.48%, P = 
0.8598; the incidence of serious ADRs were 6.25% v.s 6.59%, P = 1.0000. 
1.5.7 Results of phase II clinical trial of apatinib in patients with HCC 
A randomized, open-label, multi-center phase II clinical trial evaluating apatinib mesylate 
tablets in advanced HCC was initiated in Jul. 2010 by the 81st Hospital of the Chinese 
People's Liberation Army and other sites. 
The trial involved two treatment groups: 850 mg and 750 mg groups. Primary endpoint: TTP; 
secondary endpoints: OS, ORR, DCR, AFP, QoL, and safety. 
Simon's two-stage design for the clinical study of anti-tumor drugs is used. Sample size is 
determined based on disease control rate (DCR). It was assumed that patients receiving the 
best supportive care for this indication could achieve DCR of 30%. Patients in the apatinib 
group achieved DCR of 50%, indicating that apatinib is superior to the best supportive care in 
terms of DCR. Based on the optimal design criteria, with  = 0.05 and  = 0.2, and using 


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NCSS & PASS, 15 patients were enrolled in each group in the first stage. If 5 patients reach 
DCR, the sample size would be expanded to 46 patients. If 15 of the 46 patients reach DCR, 
subsequent studies could be carried out at this dose. Taking dropout factors into 
consideration, a total of 36 subjects were enrolled in the first stage, and sample size was 
expanded to 117 in the second stage, i.e., 81 subjects were enrolled (including 51 in the 
850 mg group and 30 in the 750 mg group). 
As of Jun. 2013, the results are as follows: 
The phase II clinical trial of apatinib mesylate tablet in patients with advanced HCC had an 
actual enrollment of 121 subjects, including 70 in the 850 mg group and 51 in the 750 mg 
group. 
Efficacy results showed that in the FAS (ITT population), mTTP values in the 850 mg and 
750 mg groups were 4.2 and 3.3 months, and mOS values were 9.7 and 9.8 months, 
respectively. ORRs were 8.6% and 0.0%, and DCRs were 48.6% and 37.3%, respectively. 
Table 4. Inter-group comparison of efficacy results (FAS) 
Group 
mTTP (month) 
mOS (month) 
ORR (%) 
DCR (%) 
850 mg 
4.2 
9.7 
8.6 
48.6 
750 mg 
3.3 
9.8 
0.0 
37.3 
Safety results showed that the incidences of AEs in the 850 mg and 750 mg groups were 
98.6% and 94.1%, respectively; the incidences of severe AEs (NCI CTCAE Grade III–V) 
were 67.1% and 72.6%, respectively. The incidences of ADRs in the 850 mg and 750 mg 
groups were 95.7% and 90.2%, respectively; the incidences of severe ADRs (NCI CTCAE 
Grade III–V) were 58.6% and 58.8%, respectively. The incidences of SAEs were 18.6% and 
23.5%, respectively; and the incidences of serious ADRs were 4.3% and 5.9%, respectively. 
Table 5. Comparison of the incidences of AEs and ADRs between the two groups (SS) 
 
Group 
Yes 
No 
Total 
Incidence 
(%) 
Inter-Group 
Comparison P 
Adverse Events 
(n) 
850 mg group 
69 
1 
70 
98.57 
0.3090 
750 mg group 
48 
3 
51 
94.12 
 
Grade III–V Adverse 
Events 
(n) 
850 mg group 
47 
23 
70 
67.14 
0.5551 
750 mg group 
37 
14 
51 
72.55 
 
Adverse Drug 
Reactions 
(n) 
850 mg group 
67 
3 
70 
95.71 
0.2790 
750 mg group 
46 
5 
51 
90.20 
 
Grade III–V Adverse 
Drug Reactions 
(n) 
850 mg group 
41 
29 
70 
58.57 
1.0000 
750 mg group 
30 
21 
51 
58.82 
 


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Group 
Yes 
No 
Total 
Incidence 
(%) 
Inter-Group 
Comparison P 
Serious Adverse 
Events 
850 mg group 
13 
57 
70 
18.57 
0.5060 
(n) 
750 mg group 
12 
39 
51 
23.53 
 
Serious Adverse Drug 
Reactions 
850 mg group 
3 
67 
70 
4.29 
0.6960 
(n) 
750 mg group 
3 
48 
51 
5.88 
 
Common adverse events (incidence ≥ 10%) mainly included: transaminases increased, 
hypertension, proteinuria, hand-and-foot syndrome, etc., most of which were mild to 
moderate, and all were controllable. Refer to Table 6 for details: 
Table 6. Common AEs (incidence ≥ 10%) in both groups 
Adverse Events 
Group 
Total 
Adverse Events 
n (%) 
Grade III–V Adverse Events 
n (%) 
Transaminases Increased 
850 mg 
70 
44 (62.9) 
8 (11.4) 
 
750 mg 
51 
25 (49.0) 
7 (13.7) 
Bilirubin Increased 
850 mg 
70 
44 (62.9) 
8 (11.4) 
 
750 mg 
51 
24 (47.1) 
8 (15.7) 
Hypertension 
850 mg 
70 
36 (51.4) 
3 (4.3) 
 
750 mg 
51 
25 (49.0) 
7 (13.7) 
Proteinuria 
850 mg 
70 
33 (47.1) 
1 (1.4) 
 
750 mg 
51 
24 (47.1) 
2 (3.9) 
Gamma-Glutamyltransferase Increased 
850 mg 
70 
30 (42.9) 
13 (18.6) 
 
750 mg 
51 
6 (31.4) 
5 (9.8) 
Hand-and-Foot Syndrome 
850 mg 
70 
29 (41.4) 
4 (5.7) 
 
750 mg 
51 
15 (29.4) 
4 (7.8) 
Platelet Count Decreased 
850 mg 
70 
27 (38.6) 
6 (8.6) 
 
750 mg 
51 
23 (45.1) 
7 (13.7) 
White Blood Cell Count Decreased 
850 mg 
70 
21 (30.0) 
3 (4.3) 
 
750 mg 
51 
17 (33.3) 
2 (3.9) 
Lactate Dehydrogenase Increased 
850 mg 
70 
19 (27.1) 
2 (2.9) 
 
750 mg 
51 
6 (11.8) 
2 (3.9) 
Neutrophil Count Decreased 
850 mg 
70 
18 (25.7) 
4 (5.7) 
 
750 mg 
51 
16 (31.4) 
3 (5.9) 
Abdominal Pain 
850 mg 
70 
18 (25.7) 
4 (5.7) 
 
750 mg 
51 
7 (13.7) 
0 (0.0) 
Asthenia 
850 mg 
70 
17 (24.3) 
3 (4.3) 
 
750 mg 
51 
9 (17.7) 
2 (3.9) 


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The 850 mg and 750 mg groups had comparable efficacy. In terms of safety, the types and 
incidence of AEs and ADRs observed in both groups were also similar. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 Study Objectives 
To observe and evaluate the efficacy and safety of apatinib mesylate tablet as second-line 
treatment in patients with advanced HCC. 
2.2 Primary Endpoints 
● 
Overall survival (OS) 
Defined as the time from randomization to death from any cause. 
2.3 Secondary Endpoints 
● 
Progression free survival (PFS) 
Defined as the time from randomization to the occurrence of progressive disease (PD) or 
death, whichever occurs first. 
● 
3-, 6-, and 12-month PFS rates 
Defined as the proportions of evaluable patients without disease progression from the 
start of the trial to 3, 6, and 12 months. 
● 
Time to progression (TTP) 
Defined as the time from randomization to radiographic disease progression. 
● 
Objective response rate (ORR) 
Defined as the proportion of evaluable subjects who have a tumor response assessed by 
RESIST 1.1, including complete response (CR) and partial response (PR). 
● 
Disease control rate (DCR) 
Defined as the proportion of evaluable subjects who have disease control assessed by 
RESIST 1.1, including CR, PR and stable disease (SD) (≥4 weeks）. 
Evaluable subjects are defined as all subjects who have received at least 2 cycles (8 weeks) of 
apatinib treatment and have received a tumor evaluation after 2 treatment cycles (8 weeks). If 
the efficacy reaches CR, PR or SD, the subject must be reexamined 4 weeks after the first 
evaluation. 
● 
The percentage of evaluable patients with stable disease (SD) of ≥ 4 weeks (confirmed 
SD in particular) 
● 
6- and 12-month mortalities 
● 
Quality of life score (EORTC QLQ-C30 and HCC-18); 


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● 
Drug safety: Vital signs, laboratory measurements, AEs, SAEs, treatment-related AEs 
and SAEs, and AEs of special interest (e.g., hypertension, proteinuria, and hand-and-foot 
syndrome [palmar-plantar erythrodysesthesia syndrome]); judged as per NCI-CTCAE 
V4.0. 
3 SELECTION AND WITHDRAWAL OF SUBJECTS 
3.1 Clinical Diagnostic Criteria 
"Guideline on Diagnosis and Treatment for Primary Liver Cancer" (2011 Edition) states: 
The clinical diagnosis of HCC can be confirmed when the following conditions (1) + (2)a or 
conditions (1) + (2)b + (3) are met: 
(1) With evidence of cirrhosis and HBV and/or HCV infection (positive HBV and/or HCV 
antigen);  
(2) Typical imaging features of HCC: Multidetector CT scan and/or dynamic 
contrast-enhanced MRI showing hepatic space-occupying lesions with arterial 
hypervascularity and venous or delayed phase washout; 
a One of the two imaging examinations (CT and MRI) showing the above features of liver 
cancer for those with lesions ≥ 2 cm in diameter;  
b Both CT and MRI imaging examinations showing the above features of liver cancer for 
those with lesions of 1-2 cm in diameter, so as to enhance the specificity of the diagnosis; 
(3) Serum AFP ≥ 400 μg/L for 1 month or ≥ 200 μg/L for 2 months, and when the increase in 
AFP level due to other reasons can be excluded, including pregnancy, germline 
embryogenic tumor, active liver disease and secondary liver cancer. 
3.2 Inclusion Criteria 
Inclusion criteria: 
1. Age: ≥ 18 years old; 
2. Patients strictly meeting the clinical diagnostic criteria in "Guideline on Diagnosis and 
Treatment for Primary Liver Cancer" (2011 Edition) or with histologically or cytologically 
confirmed recurrent/metastatic HCC, unsuitable for palliative surgery or radiation therapy, 
with at least one measurable lesion (must be ≥ 10 mm in longest diameter by spiral CT or 
≥ 15 mm in shortest diameter for enlarged lymph nodes, as per RECIST 1.1, as shown in 
Annex 1);  
3. Patients with HCC refractory or intolerant to systematic chemotherapy (with oxaliplatin, 
alone or in a therapeutic combination) and/or molecular targeted therapy with sorafenib; 


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Note: Definition of treatment failure: disease progression during treatment or relapse after 
treatment is completed (must have received ≥ 1 cycle of systemic chemotherapy with 
oxaliplatin (or plus other drugs) or ≥ 14 days of molecular targeted therapy with sorafenib); 
Definition of intolerability: Grade ≥ IV hematological toxicity or Grade ≥ III 
non-hematological toxicity or Grade ≥ II major organ injury such as the heart, liver, or 
kidneys during treatment. 
4. The interval between the last systemic treatment failure (with treatment discontinued) and 
the enrollment (time of signing the informed consent form) was ≥ 2 weeks, and the adverse 
event(s) had basically returned to normal (NCI-CTCAE ≤ Grade I); 
5. Child-Pugh score: Class A or Class B (≤ 7); the Child-Pugh scoring system is shown in 
Appendix 2; 
6. BCLC staging: B-C (the "Barcelona Clinic Liver Cancer (BCLC) Staging System, 2010" is 
shown in Appendix 3); 
7. ECOG PS of 0–1 within 1 week before enrollment, as shown in Appendix 4; 
8. Expected survival ≥ 12 weeks; 
9. HBV DNA < 2000 IU/mL (104 copies/mL); 
10. Major organs must function normally, meeting the following criteria: 
(1) Hematology: (without blood transfusion, G-CSF, or medication within 14 days prior to 
screening) 
d. HB ≥ 90 g/L; 
e. 
ANC ≥ 1.5 × 109/L; 
f. 
PLT ≥ 80 × 109/L; 
(2) Biochemistry: (no ALB transfusion within 14 days) 
e. ALB ≥ 29 g/L; 
f. 
ALT and AST < 5  ULN; 
g. TBIL ≤ 1.5  ULN; 
h. Creatinine ≤ 1.5  ULN; 
(Only one of the two items, albumin or bilirubin, has a Child-Pugh score of 2) 
11. Women of childbearing potential must have a negative pregnancy test (serum or urine) 
within 7 days prior to enrollment, and be willing to take appropriate contraceptive 
measures during the trial and within 8 weeks after the last dose of the investigational 
drug. Male subjects should either undergo surgical sterilization, or agree to take 


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appropriate contraceptive measures during the trial and within 8 weeks after the last dose 
of the investigational drug; 
12. Subjects must participate voluntarily, sign the informed consent form, have good 
compliance and corporate with follow-up visits. 
3.3 Exclusion Criteria: 
1. Patients who have received any local treatment within 4 weeks prior to participating in this 
study (including but not limited to surgery, radiation, hepatic artery embolization, TACE, 
hepatic arterial infusion, radiofrequency ablation, cryoablation, or percutaneous ethanol 
injection); 
2. Patients with known intrahepatic cholangiocarcinoma, mixed hepatocellular carcinoma and 
fibrolamellar hepatocellular carcinoma; other uncured malignancies currently or within the 
past 5 years, except for cured skin basal cell carcinoma or cervical carcinoma in situ; 
3. Patients planning to receive liver transplant (except for patients who have undergone liver 
transplant); 
4. Patients with symptomatic ascites requiring therapeutic paracentesis or drainage, or with 
a Child-Pugh score > 2; 
5. Patients with hypertension which cannot be controlled to the normal range by 
antihypertensives (systolic pressure > 140 mmHg, diastolic pressure > 90 mmHg); 
6. Patients with Grade II or greater myocardial ischemia or myocardial infarction, 
uncontrolled arrhythmias (QTc interval ≥ 450 ms in males and ≥ 470 ms in females); 
7. Patients with NYHA (see Appendix 5) Class III-IV cardiac insufficiency or LVEF (left 
ventricular ejection fraction) < 50% by echocardiography; 
8. Presence of multiple factors affecting oral medications (such as inability to swallow, 
chronic diarrhea, and intestinal obstruction, which significantly affect drug administration 
and absorption); 
9. Patients with a history of gastrointestinal bleeding within the past 6 months or a high risk 
of bleeding such as esophageal varices with bleeding risk, active ulcers, and fecal occult 
blood ≥ (++); in the case of fecal occult blood (+), a gastroscopy is required; 
10. Abdominal fistula, gastrointestinal perforation or abdominal abscess within 28 days prior 
to the study; 
11. Abnormal coagulation function (INR > 1.5 or prothrombin time (PT) > ULN + 4 s), 
bleeding tendency or receiving thrombolytics or anticoagulant therapy; 
12. Patients with central nervous system metastases or known brain metastases; 


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13. Patients with previous or current objective evidence of pulmonary fibrosis, interstitial 
pneumonia, pneumoconiosis, radiation pneumonitis, drug-induced pneumonitis, and 
severe lung function impairment; 
14. Urine protein ≥ ++ or 24 h urine protein > 1.0 g as indicated by urinalysis; 
15. Had received treatment with a potent CYP3A4 inhibitor within 7 days prior to study 
participation, or had received treatment with a potent CYP3A4 inducer within 12 days 
prior to study participation; 
16. Pregnant or lactating women; patients of child-bearing potential unwilling or unable to 
take effective contraceptive measures; 
17. Patients with a known history of mental illness or psychotropic substance abuse; 
18. Patients with bone metastasis who had received a palliative radiotherapy in an area of > 
5% of bone marrow area within 4 weeks prior to the participation in this study. 
3.4 Termination Criteria 
1. Subject withdraws informed consent and requests to withdraw from the study; 
2. Medical imaging examinations show disease progression; 
3. Subjects showing unacceptable toxicity even after dose modification; 
4. Other reasons for which the investigator considers a withdrawal necessary; 
5. Study termination by the sponsor for the sake of safety. 
3.5 Randomization Criteria 
Randomization should only be performed after the patients have successfully completed the 
baseline evaluation and been confirmed as compliant with the inclusion criteria. The 
randomization system will assign a unique number to each subject and assign the 
investigational drug to the subject based on this number, and the administration of the 
investigational drug must be started within 48 h after randomization. Each site must complete 
the baseline eCRF of all subjects participating in randomization, even if the patients have not 
been treated by the investigational drug. 
Stratification factors for randomization are as follows: 
ECOG PS: 0 or 1 
Received prior treatment with sorafenib: yes or no 
Presence of vascular invasion and/or extrahepatic metastasis: yes or no 


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4 STUDY DESIGN 
4.1 Overall Design 
This is a randomized, double-blind, placebo-controlled, nation-wide multi-center phase III 
clinical trial comparing the efficacy and safety of apatinib and placebo in the treatment of 
patients with advanced HCC. The overall design is shown in Figure 4.1 below. 
This trial plans to be carried out at multiple sites in China. The list of participating study 
centers is shown in Appendix 6. It is planned to enroll a total of 360 patients with advanced 
HCC. According to the resolution of scientific committee, additional subjects will be 
enrolled, i.e., 390 subjects in total, who will be randomly assigned to the treatment group and 
the placebo group in a 2:1 ratio. 
If none of the following conditions occur, such as withdrawal of informed consent from by 
subject, unacceptable toxicity, or conditions rendering the subject not suitable for further trial 
participation based on the opinion of the investigator, the study treatment of each subject will 
be continued until confirmed radiographic progression. The efficacy and safety index should 
be monitored during the trial. 
The 28-day follow-up is necessary after treatment discontinuation, and then the subjects will 
continue to be followed to gather information on their survival. 
 
 


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Figure 4.1. Overall design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2 Type of Comparison 
This is a placebo-controlled trial, so a superiority test is used for comparison. 
The primary efficacy endpoint of this trial is OS. If the HR is statistically significant and the 
difference reaches a clinically recognized level (HR ≤ 0.84 in the comparison between the 
treatment group and the placebo group), the investigational drug is considered to be superior 
to the placebo. 
4.3 Sample Size Estimation 
In this trial, placebo is used as a control and a superiority test is performed between the two 
groups. 
For OS, according to the results of the FAS analysis for the phase II clinical trial and relevant 
literature reports: The median OS in the placebo group is set to 6 months, and the median OS 
in the apatinib mesylate group is set to 8.5 months. Based on α2 = 0.05, a 80% power of the 
Randomization (2:1): Treatment group:placebo group 
● 
The investigator at the study site should confirm the medical 
history data of subjects 
● 
Login into the randomization system and enter information 
● 
Subjects are stratified and randomized based on the ECOG PS (0 or 
1), the prior treatment of sorafenib (yes or no), and the presence of 
vascular invasion and/or extrahepatic metastasis (yes or no) 
● 
Obtain the random number and drug number 
Screening: Carried out within 3 weeks before 
Follow-up: Starts immediately after withdrawing from study treatment 
● 
The subjects will be reexamined on D28 after the last dose 
● 
Follow-up of AEs 
● 
The survival follow-up is conducted once per month by telephone  
Treatment and efficacy evaluation: 
● 
Until confirmed radiographic disease progression or other situations resulting in 
discontinuation 
● 
Efficacy evaluation: The efficacy evaluation should be performed every two cycles 
(± 7 days); in case of unacceptable toxicity even after dose modification or treatment 
withdrawal requested by the subject, the final tumor imaging evaluation should be 
performed at the time of withdrawal 
● 
Evaluation of other endpoints: Quality of life score, safety, etc. 


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test, a 15% lost to follow-up rate in each group, an enrollment period of 12 months, and the 
duration of the entire study of 36 months, the 2:1 treatment group:placebo group design, and 
the formula for the sample size of the Log-rank test of OS comparison between two groups 
(calculated by PASS software), 222 patients are required in the treatment group and 
109 patients are required in the placebo group, i.e., a total of 331 patients, as shown in the 
table below. Considering dropout and other factors, this trial plans to enroll 360 patients, 
including 240 for the treatment group and 120 for the placebo group. According to the 
resolution of scientific committee, the enrollment shall be expanded to 390 subjects (see the 
Resolution of Scientific Committee on 31 Oct., 2016). 
Table 7. Results of sample size estimation 
Parameter Type I 
Error 
Median Survival 
Sample Size 
Ratio 
Treatment:
Control 
Results 
Treatment 
Group 
Placebo 
Group 
Treatment 
Group 
Placebo 
Group 
Total Number 
of Subjects 
OS 
0.05 
8.5 
6 
2:1 
222 
109 
331 
4.4 Randomization and Stratification Factors 
The randomization method used in this trial is as follows: Subjects are randomized to two 
groups in a 2:1 ratio to receive apatinib or placebo treatment. 
The subjects are allocated by central randomization and enrolled competitively at all sites. 
The central randomization system provided by Department of Epidemiology and Health 
Statistics of Nanjing Medical University will be used for central randomization. After all 
eligible subjects are screened by study personnel at each study site participating in this trial 
and confirmed by the investigator of each site, their screening information will be entered 
into the randomization system to generate the random numbers and drug numbers. 
Corresponding study drugs will be dispensed based on the drug numbers. Subjects must begin 
the assigned study treatment within 48 h after randomization. 
Stratification factors for randomization include: 
ECOG PS: 0 or 1 
Received prior treatment with sorafenib: yes or no 
Presence of vascular invasion and/or extrahepatic metastasis: yes or no 
4.5 Dosing Regimen 
4.5.1 Investigational drug 
Apatinib mesylate tablets 


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4.5.2 Dose 
Treatment group: Apatinib, 750 mg, q.d.; The dose can be reduced according to toxicity, with 
the first reduction to 500 mg, q.d., and the second reduction to 250 mg, q.d.; each treatment 
cycle contains 28 days. 
Placebo group: Placebo, q.d. Each treatment cycle contains 28 days. 
Considerations for the use of 750 mg in the treatment group: 
1. According to the phase I PK data, the Cmax and AUC of the 850 mg group were both higher 
than those of the 750 mg group, and it was speculated that the toxicity of the 850 mg group 
might be higher than that of the 750 mg group; 
2. According to the phase II study of apatinib in HCC, the efficacy of the 850 mg group was 
comparable to that of the 750 mg group (TTP, OS; the DCR in the 850 mg group was 
slightly higher than that in the 750 mg group); 9 patients in the 850 mg group withdrew 
from the study due to adverse events with the duration of treatment less than 1 cycle 
(including 4 cases of gastrointestinal hemorrhage), while 3 patients in the 750 mg group 
withdrew from the study due to adverse events with the duration of treatment less than 
1 cycle (no hemorrhage). Considering that the primary endpoint of phase III trial is OS, 
the dose of 750 mg, which showed better tolerability in HCC patients, is selected for the 
study. 
4.5.3 Method of administration 
Apatinib or placebo is administered orally in a double-blind manner at the dose specified for 
each group, once a day after meals (the time of administration should be as close as possible 
on each day). 
4.5.4 Treatment cycle 
Subjects who achieve complete response (CR), partial response (PR), and stable disease (SD) 
should continue treatment until PD, unacceptable toxicity, or subjects request to discontinue 
treatment. 
Notes: For subjects with PD, treatment should be discontinued in principle. However, in view 
of the treatment characteristics of molecular targeted drugs, there are certain defects to adopt 
the evaluation method of cytotoxic chemotherapy. After receiving molecular targeted therapy, 
although the tumor of some subjects was enlarged, remarkable necrosis or denaturation was 
observed inside the tumor, and CT showed that the internal density of the tumor lesion 
decreased. It is generally considered to be beneficial to subjects under this circumstance. 
Therefore, it is specified in the study protocol that: if obvious necrosis or denaturation is 
observed in the tumor tissue, tumor-related symptoms are significantly improved or remained 
stable, the subject voluntarily continues the treatment, and continuing treatment may achieve 


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survival benefits as judged by the principal investigator, the subject can continue to receive 
the treatment until intolerance of toxicity or PD again, with strict observation. 
4.6 Efficacy Evaluation and Analysis 
Efficacy evaluation should be performed every two cycles (this is based on calendar days and 
is not affected by treatment interruption), and the evaluation time is ± 7 days at the end of the 
cycle (except for statutory holidays). CT or MRI examinations are required for evaluation. 
The radiographic technique should be consistent for all the tests of a subject, and all the 
images should be retained. If the efficacy reaches CR, PR or SD by imaging, the subject must 
be reexamined 4 weeks to confirm the evaluation. 
In the case of imaging-confirmed PD, the subject should discontinue the treatment and then 
enter the follow-up period. Other anti-tumor treatments are prohibited before PD. 
For subjects who withdraw from the trial due to unacceptable toxicity, the efficacy evaluation 
by imaging should be conducted upon withdrawal if the efficacy evaluation is not carried out 
within 4 weeks before withdrawal. Thereafter, the imaging examination is performed with the 
same frequency, i.e., every 2 cycles until PD or initiating other anti-tumor treatments to get 
the result of their radiographic PD. 
4.7 Follow-up within 28 Days after Treatment Discontinuation 
All subjects should continue safety evaluation within 28 days after the last dose. During the 
follow-up visit on D28 (± 3 days, except for statutory holidays) after the treatment 
discontinuation, physical examination, ECOG PS, hematology and blood biochemistry tests 
should be carried out, and adverse events, concomitant medication and the new anti-cancer 
therapy treatment should be recorded. 
4.8 Follow-Up of AEs 
Adverse events that have not resolved after discontinuing apatinib treatment should be 
followed and a final evaluation should be made. The follow-up of adverse events ends on 
D28 after treatment discontinuation. 
4.9 Survival Follow-Up 
After the 28-day safety follow-up, the subject, his/her family members, or local physicians 
should be interviewed by telephone once a month to collect survival (date and cause of death) 
and post-treatment information (including received treatments) until death, lost to follow-up, 
or study termination by Hengrui. Each survival follow-up should be documented in the 
follow-up form in detail. 
 
 


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5 INFORMED CONSENT 
The clinical investigator must fully inform the subjects that participation in the clinical trial is 
voluntary, and subjects have the right to withdraw from the trial at any stage without being 
discriminated against with their medical treatment and rights unaffected, and they can 
continue to receive other therapies. All subjects should be informed that the participation of 
the trial and their personal information will be kept confidential. The subjects should also be 
informed of the nature, objectives, expected potential benefits, and possible risks and 
inconvenience of the clinical trial, other alternative treatment options, and rights and 
obligations of the subjects in accordance with the "Declaration of Helsinki". Subjects are 
given sufficient time to consider whether to participate in the trial and sign the informed 
consent form. 
6 STUDY DRUGS 
6.1 Information 
Investigational drug: apatinib mesylate tablets 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: Tablet 
Strength: 250 mg/tablet, batch number: ××××, date of manufacture: ××××; 
Administration: oral administration after meals (best to take at the same time on each day); 
Shelf life: 2 years (tentative); 
Storage conditions: kept in a sealed container away from light at room temperature. 
Control: Apatinib dummy tablets; 
Manufacturer: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Dosage form: tablet; 
Strength: 250 mg/dummy tablet, batch number: ××××, date of manufacture: ××××; 
Administration: oral administration after meals (best to take at the same time on each day); 
Shelf life: 2 years (tentative); 
Storage conditions: kept in a sealed container away from light at room temperature. 
6.2 Labeling/Packaging 
The label is shown in Appendix 7. The drug is packaged in aluminum-plastic blister packs 
with 10 tablets per pack and 11 packs in each small box, and 6 small boxes in each medium 
box. 


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6.3 Drug Dispensation 
The stratified randomization method is used in this trial. The randomization table will be 
generated by the statisticians from Nanjing Medical University using the statistical software 
SAS. The drug number will be randomly assigned to each site. After eligible patients are 
enrolled to each site, drug administrators dispense corresponding drugs to each subject 
according to the order of the enrollment time. 
Drug dispensation should be managed strictly. The designated staff in participating study 
center should keep and fill in the Request and Use Record. Remaining drugs and packages 
should be timely retrieved during the trial and delivered to the sponsor after the end of trial. 
In the event of treatment discontinuation, the participating study center should retrieve the 
remaining drugs at the end of each cycle and dispense study drugs of the next cycle. The 
monitor should regularly inspect the use and recording of drugs, monitor and handle the 
retrieval condition at any time. 
6.4 Drug Storage and Management 
In accordance with GCP, study drugs should be stored, dispensed and retrieved by the 
participating study center. The study drugs should be kept in a sealed container away from 
light at room temperature. 
Apatinib is not permitted to be used except for this trial. 
6.5 Disposal of Remaining Drugs 
The investigator should record the date and dose of administration of each subject. The total 
dose of study drug assigned to each patient is 110% of his/her designed dose. Remaining 
investigational drugs should be returned to the sponsor after the end of each cycle. 
7 CRITERIA FOR DOSE INTERRUPTION AND MODIFICATION 
7.1 Dose Level and Use of Drugs 
The dose levels in the treatment and placebo groups are: 1) starting dose: 750 mg, q.d.; 2) 
second dose level: 500 mg, q.d.; 3) third dose level: 250 mg, q.d. The initial dose of each 
group can be reduced by two levels. After dose reduction, the dose can be resumed to the 
previous dose level if the toxicity is completely recovered; if the dose is reduced again, no 
further modification is allowed. The administered doses and dose modification of each group 
are shown in the table below, and the dose can be modified according to the "Dose 
Modification" column shown below. 
 
 


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Table 8. Doses and dose level modification of each group 
 
Treatment Group 
Placebo Group 
Starting dose 
■■■ 
□□□ 
First dose reduction 
■■ 
□□ 
Dose re-modification 
Toxicity recoverya 
■■■ 
□□□ 
Second dose reductionb 
■■ 
□□ 
Third dose reduction 
■ 
□ 
Dose re-modification 
Toxicity recoverya 
■■ 
□□ 
Fourth dose reductionb 
■ 
□ 
Note: ■ = Apatinib mesylate tablets 250 mg/tablet, □ = Apatinib mesylate dummy tablets 
a After dose reduction, the dose can be resumed to the previous dose level if the toxicity is completely 
recovered; 
b If the dose is reduced again, it should not be resumed again. 
7.2 Dose Modification 
According to the results of the phase I clinical trial of apatinib, considering that the exposure 
levels in men and women are different after apatinib administration, and that the drug shows 
certain individual differences, the dose of apatinib should be modified appropriately in the 
trial (assuming continuous administration). The treatment can be interrupted in terms of drug 
toxicity and be resumed after the toxicity is alleviated; the dose can also be reduced and be 
resumed to the previous dose level after the toxicity has been completely recovered; if the 
dose is reduced again due to toxicity, it should not be resumed again. The final study report 
should include statistics of the dose intensity and time of treatment interruption. Specific 
rules are as follows: 
7.2.1 Criteria for dose interruption or dose reduction 
The dose is only allowed to be interrupted and reduced in the case of Grade ≥ III 
hematological toxicity or Grade ≥ II non-hematological toxicity. Among the events of 
non-hematological toxicity, controllable nausea and vomiting as well as fever (under 38°C) 
with a clear cause can be handled with active symptomatic treatments without the need for 
dose interruption and dose reduction. 
7.2.2 Dose interruption 
The total duration of drug interruption during each treatment cycle should not be more than 
2 weeks, so as to maintain the intensity of the study treatment received by the subjects. 
7.2.3 Dose reduction 
In each dosing cycle, only one dose reduction is allowed (i.e., the reduction of one dose 
level); after dose reduction, the dose can be resumed to the previous dose level after the 
toxicity has completely recovered; however, if the dose is reduced again, it should not be 


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resumed again. Each subject is only allowed up to two dose reductions, i.e., after the dose is 
reduced to the third dose level, the dose is not allowed to be resumed, but the dose can be 
interrupted. 
7.2.4 Discontinuation criteria based on LVEF 
For asymptomatic subjects, if their LVEF is decreased by ≥ 20% from baseline but not 
decreased to < 50% of baseline, they can still be treated with apatinib, but their LVEF should 
be reevaluated after 2 weeks at most. If LVEF is still decreased after reevaluation, apatinib 
should be interrupted. LVEF is evaluated every 2 weeks thereafter, and the subject can reduce 
one dose level to restart apatinib treatment after LVEF recovery. For such subjects, LVEF 
monitoring is still required in Week 2 ( 3 days) and Week 4 ( 3 days) after the 
administration is restarted, and LVEF monitoring should be performed every 4 weeks 
( 3 days) thereafter. 
If the LVEF value is below the lower limit of normal specified by the study site or drops to < 
50%, the subject should withdraw from the study. The LVEF should be continuously 
monitored every 4 weeks ( 3 days) thereafter until resolved or after at least 16 weeks of 
continuous monitoring. 
7.2.5 Discontinuation criteria based on prolonged QT interval 
1) If the patient's ECG shows QTcF > 480 ms, the use of apatinib should be interrupted, and 
the following measures should be immediately taken: 
 (1) Immediately notify the sponsor, safety monitoring committee or scientific committee; 
 (2) Analyze serum potassium and magnesium, and if it is lower than the lower limit of 
normal, use supplements to correct serum potassium and magnesium to within the normal 
range; 
 (3) The concomitant medication must be reviewed; 
 (4) The use of apatinib and the compliance with the dose must be verified; 
 (5) Perform an ECG examination within 1 h after the first episode of QTcF > 480 ms; 
 (6) If QTcF is still > 480 ms, repeat the ECG examinations at least once a day when 
clinically needed, until QTcF is < 480 ms; 
 (7) If QTcF is still > 480 ms in repeated measurements and lasts for more than 2 weeks, 
apatinib treatment must be discontinued. 
2) Guidelines for resuming drug administration: 
 (1) If the cause of QTcF prolongation (except apatinib) is determined, and if QTcF returns to 
< 450 ms within 2 weeks after correction and is within 20 ms of the baseline value, apatinib 
treatment can be resumed at the same dose; 


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 (2) If the cause of QTcF prolongation cannot be determined, and if QTcF returns to < 450 ms 
within 2 weeks and is within 20 ms of the baseline value, apatinib treatment can be resumed 
at the same dose; 
 (3) If QTcF exceeds 480 ms again after the subject is exposed to the investigational drug 
again, the use of the investigational drug should be discontinued; 
 (4) After the subject is exposed to the investigational drug again, if QTcF is prolonged by 
more than 20 ms from baseline or is between 450 and 480 ms and lasts for more than 
2 weeks, the dose of the investigational drug should be modified as follows: 
• Reduced from apatinib, 750 mg, q.d. to apatinib, 500 mg, q.d.; 
• Reduced from apatinib, 500 mg, q.d. to apatinib, 250 mg, q.d.; 
• Withdrawal. 
7.2.6 Discontinuation criteria based on liver function 
1) If the subject has ALT > 5  ULN and total bilirubin > 2  ULN, the following measures 
must be taken: 
(1) Immediately discontinue the use of the investigational drug and give active symptomatic 
treatments; 
(2) Complete the SAE form and handle it in accordance with the requirements for SAE in 
Section 11 of this protocol; 
(3) Follow-up the event according to the requirements for "Follow-up of Adverse Events" in 
Section 4 of this protocol, and check liver function every week until it returns to the baseline 
level; 
7.3 If the subject experiences any of the following conditions: 
ALT > 8  ULN or ALT > 5  ULN for more than 2 weeks: The patient must be reexamined 
within 3 days after the first occurrence of the event, and then reexamined weekly to monitor 
whether the ALT value continues to increase. If the ALT value continues to increase, the use 
of the apatinib should be interrupted. The liver function should be reexamined within 
2 weeks. If the treatment is effective and the subject is willing to continue to receive the 
apatinib treatment after obtaining the results of the liver function test, the subject can resume 
the apatinib treatment at the next lower dose level after obtaining the permission of the 
investigator and the medical director of the sponsor, and the liver function of the patient 
should be monitored every 2 weeks until it returns to the baseline level. 
Other rules 
To ensure the consistency of dose modifications throughout the study, treatment should be 
first discontinued before undergoing a dose modification for each dose cycle. The dose can 
only be reduced if the subject still cannot tolerate the dose after dose interruption. 


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8 CONCOMITANT MEDICATION 
8.1 Medications Prohibited or Used with Caution during the Study 
8.1.1 Drugs that interfere with liver P450 enzymes 
Apatinib has a strong inhibitory effect on CYP3A4, YP2C9 and CYP2C19 (IC50 < 0.5 µM). 
Omeprazole should be used with caution during the treatment. CYP3A4 inducers 
(carbamazepine, rifampicin and phenobarbital) and inhibitors (ketoconazole, itraconazole, 
erythromycin and clarithromycin), CYP3A4 substrates (simvastatin, cyclosporine and 
pimozide), and other drugs metabolized via CYP3A4 (such as benzodiazepines, 
dihydropyridine, calcium ion antagonist and HMG-COA reductase inhibitors) should be used 
with caution. CYP2C9 substrates (diclofenac, phenytoin, piroxicam, S-warfarin, and 
tolbutamide) and CYP2C19 substrates (diazepam, imipramine, lansoprazole, and 
S-mephenytoin) should be used with caution. 
8.1.2 Drugs that prolong the QT interval of the heart 
As tinib drugs may cause toxicities of prolonged QT interval in clinical applications, drugs 
that may prolong the QT interval should be used with caution during the trial, including 
antibiotics, antiarrhythmics, antipsychotics, antifungal drugs, antimalarial drugs, and 
antidepressants (such as clarithromycin, quinidine, risperidone, fluconazole, mefloquine, 
amitriptyline, azithromycin, sotalol, fluphenazine, ketoconazole, chloroquine, imipramine, 
erythromycin, amiodarone, droperidol, clomipramine, roxithromycin, disopyramide, 
haloperidol, dosulepin, metronidazole, procainamide, thioridazine, doxepin, moxifloxacin, 
pimozide, olanzapine, and clozapine). 
8.1.3 Traditional Chinese medicine and immunological agents with anticancer effects 
NMPA-approved Chinese medicine preparations for liver cancer (including Delisheng 
injection, Kanglaite injection, Aidi injection, Huaier granule, GFL tablets) and 
immunomodulators (interferon and interleukin-2) are prohibited during the trial. 
8.2 Medications and Treatments that May be Used Concomitantly during the Trial 
The patient could receive the best supportive care. Bisphosphonates for bone metastasis is 
permitted while the subject is receiving study medication. If systemic or local analgesia is not 
effective in controlling painful lesions of bone metastases, a small area of palliative 
radiotherapy (the area of the radiotherapy must be <5% of the bone marrow region, and the 
percent bone marrow in human skeleton is shown in the figure of Appendix 8) is allowed. 
Comorbidities and various AEs should be actively treated. All concomitant medications 
should be documented in the eCRF in strict accordance with the GCP regulations. 


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8.3 Recommended Symptomatic Treatment for Common Adverse Drug Reactions 
8.3.1 Hand-foot-skin reaction 
Hand-foot-skin reaction (HFSR) is s skin toxicity with palmar-plantar dysesthesia or acral 
erythema and manifests especially in areas under pressure or force. It may occur in patients 
with tumor during chemotherapy or molecular targeted therapy. HFSR is characterized by 
numbness, dysesthesia, paraesthesia, tingling, no pain or pain, skin swelling, or erythema, 
desquamation, chapping, scleroma-like blisters, and severe pain. 
Grading of HFSR: 
Grade 1: numbness/dysesthesia/paraesthesia, painless swelling or erythema of the hands 
and/or feet and/or discomforts that does not affect normal activities. 
Grade 2: painful erythema and swelling of the hands and/or feet and/or discomforts affecting 
patients' activities of daily living. 
Grade 3: wet desquamation, ulcers, blisters or severe pain of hands and/or feet and/or severe 
discomfort that causes the patients to be unable to work or perform activities of daily living. 
Intense pain and loss of skin function, relatively rare. 
Symptomatic treatment and management of HFSR: 
Some necessary symptomatic and supportive treatments must be taken, including: strengthen 
skin care, keep skin clean, and avoid secondary infections; avoid pressure or friction; use 
moisturizers or lubricants, topically use lotions or lubricants containing urea and 
corticosteroids; topically use antifungal or antibiotic treatment if necessary. 
8.3.2 Hypertension 
Management of treatment-related hypertension 
● 
Monitoring and handling of hypertension: Blood pressure should be monitored once 
a week during the first 6 cycles of the targeted pharmacological treatment. Once 
hypertension occurs, the following standard treatments can be given: Angiotensin II 
receptor blocker (ARB), angiotensin converting enzyme inhibitor (ACEI), beta blocker, 
diuretics, etc., or the combined application of above drugs. 
● 
Preferably selected medications (drugs not metabolized through the liver): 
1) Valsartan (Diovan), 80–320 mg q.d.; 
2) Atenolol (Tenormin), 50–100 mg q.d.; 
3) HCTZ (Hyzaar), 12.5–100 mg q.d.; 
4) Telmisartan (Micardis), 20–80 mg q.d.; 
5) For those with difficulty controlling blood pressure: Amlodipine (Norvasc), 2.5– 
10 mg q.d. 


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Clinical staging of hypertension and routine treatment at each stage 
● 
Pre-hypertension: (120–139/80–89 mmHg, or a systolic blood pressure of 120–139 mmHg) 
There is no indication for the use of antihypertensive drugs, and only blood pressure 
monitoring is needed; 
● 
Grade 1 hypertension: (140–159/90–99 mmHg, or a systolic blood pressure of 140–
159 mmHg) 
Use of antihypertensive drugs and monitoring of blood pressure; most patients use 
thiazide-type diuretics, while ARB, ACEI, β blockers and calcium channel blockers can 
also be considered; 
The administration of apatinib can be continued, and a combination of two 
antihypertensive drugs can be considered if the antihypertensive effect is not ideal. 
● 
Grade 2 hypertension: (160–179/100–109 mmHg, or a systolic blood pressure of 160–
179 mmHg) 
Combination use of two drugs (usually a combination of thiazide-type diuretics with 
ARB, ACEI, β blockers, or calcium channel blockers); monitoring of blood pressure; 
● 
Grade 3 hypertension: (≥ 180/110 mmHg, or a systolic blood pressure of ≥ 180 mmHg) 
Combination use of two drugs (usually a combination of thiazide-type diuretics with 
ARB, ACEI, β blockers, or calcium channel blockers); the blood pressure is closely 
monitored; other risk factors (such as target organ damage, diabetes and other 
accompanying clinical symptoms) are evaluated, and appropriate measures are taken; 
● 
Hypertensive crisis: Refers to a serious clinical condition featured by an excessively 
elevated blood pressure and a diastolic blood pressure exceeding 16.0–17.3 kPa (120–
130 mmHg). At present, there is no unified classification of hypertensive crisis in China 
and abroad. Recently, hypertensive crisis is usually divided into two types from the 
perspective of clinical treatment: (1) Hypertension emergencies: A diastolic blood 
pressure of > 16.0 kPa (120 mmHg), accompanied with acute or progressive target organ 
damage, such as cerebral infarction, intracranial or subarachnoid hemorrhage, and 
hypertensive encephalopathy, etc. Among them, progressive or acute hypertension based 
on chronic essential hypertension is the most common (about 40%–50% of all cases). 
(2) Hypertension urgencies: A diastolic blood pressure of > 16.0 kPa (120 mmHg) 
without or with only slight organ damage; in such patients, sodium nitroprusside or 
nifedipine is used to rapidly reduce the blood pressure, diazepam and phenobarbital are 
used to prevent seizures, and furosemide and mannitol are used to induce dehydration 
and reduce intracranial pressure, etc.; 
Note: For those with hypertensive crisis, the application of apatinib should be discontinued 
immediately and the subjects should withdraw from this clinical trial. 


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8.3.3 Management of gastrointestinal hemorrhage 
Gastrointestinal hemorrhage, including fecal occult blood (++) and above, hematemesis or 
bloody stool, should be given active symptomatic treatment. Patients with upper 
gastrointestinal hemorrhage should be fasted and given acid suppression, gastric mucosal 
protection, hemostasis (transamin, reptilase, etc.), as well as octreotide if necessary; patients 
with lower gastrointestinal hemorrhage should be given hemostasis, blood transfusion and 
supportive care, etc.; for those whose bleeding cannot be controlled, assistance from the 
surgery department should be requested. 
8.3.4 Suggestions for the treatment of proteinuria 
For those with two consecutive episodes of urine protein (++), a 24 h urine protein test is 
required. 
Table 11. Suggested treatments for proteinuria 
UPC < 3 g 
Treatment is continued at the same dose level and the patient is monitored as 
clinically indicated 
UPC ≥ 3 g 
Step 1: Obtain 24-h urine protein 
Step 2: If the 24-h urine protein is < 3 g, the subject can continue the treatment at 
the same dose level; 
If the 24-h urine protein is ≥ 3 g, interrupt the treatment until UPC returns to < 3 g, 
and then resume the treatment at a lower dose, and monitor the UPC throughout 
the entire subsequent treatment. If UPC is ≥ 3 g, obtain 24-h urine protein. 
Step 3: If the 24-h urine protein is still ≥ 3 g after repeated dose reductions, 
discontinue the trial and follow up the subject according to the protocol. 
Note: In case of nephrotic syndrome, the treatment with the investigational drug should be discontinued and the 
subject should withdraw from the clinical trial. 
8.3.5 Interstitial pulmonary fibrosis 
The clinical physicians should fully understand the conditions of subjects and be familiar 
with the drugs that may lead to pulmonary toxicity. The clinical symptoms of the patients and 
their changes in chest X-ray or CT should be monitored closely. Once a patient shows acute 
lung symptoms of cough, chest tightness, labored breathing, dyspnea, and hemoptysis of 
unknown causes, the investigational drug should be interrupted immediately to promptly 
identify the cause of the symptoms and exclude other causes (such as infection and heart 
failure). It is recommended to add a chest CT imaging examination, etc. Alveolar lavage fluid 
analysis and surgical lung biopsy are important means to diagnose interstitial lung disease. 
Currently, no therapy yields a satisfactory result against pulmonary fibrosis, and correction of 
hypoxemia and timely administration of corticosteroids are recommended following 
"Guidelines for Diagnosis and Treatment of Idiopathic Pulmonary (Interstitial) Fibrosis 
(draft)" issued by the Chinese Medical Association Respiratory Diseases Branch. 
Note: The suggestions for the symptomatic treatments of above adverse events are for 
reference only. For specific countermeasures, please consult a specialist. 


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9 STUDY PROCEDURES 
9.1 Screening Period (from signing informed consent form to obtaining random 
numbers) 
Subjects must sign the informed consent form before undergoing any screening procedures. 
Unless otherwise stated, the following screening procedures should be completed within 
21 days prior to randomization. 
● 
Patients sign the informed consent form. 
● 
Collection of medical history, including past treatment history, current medical history, 
drug allergies, and concurrent diseases. 
● Physical examination, height, weight, and vital signs (body temperature, blood pressure, 
heart rate, and respiratory rate). 
● 
Chest x-ray, not required if the subject have undergone chest CT. 
● 
CT or MRI of the chest, abdomen, pelvis and other relevant lesions. 
● 
Brain CT/MRI, required for clinically suspected metastases to the central nervous system 
only. 
● 
Bone scan, required for clinically suspected bone metastasis only. 
● Test of hepatitis B and hepatitis C markers, and HBV DNA. 
● Test of serum AFP. 
The following information should be collected within 7 days before randomization: 
● ECOG PS. 
● Hematology, urinalysis, and routine stool test. 
● Hepatic and renal function (total bilirubin, direct bilirubin, indirect bilirubin, ALT, AST, 
AKP, r-GT, LDH, total protein, albumin, blood urea nitrogen, creatinine, uric acid). 
● Electrolytes (potassium, sodium, chlorine, calcium, phosphorus). 
● Coagulation function (PT or INR). 
● Pregnancy test (serum or urine, only for women of childbearing potential). 
● Echocardiography (mainly to observe LVEF). 
● 12-Lead ECG (the QTc interval must be indicated), for 3 times with about 5 minutes apart. 
● Quality of life score (EORTC QLQ-C30 and HCC18). 
● Randomization should be carried out after all screening evaluations are completed. 


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9.2 Treatment Period 
● 
Check the blood pressure once a week post-administration. If the blood pressure is 
abnormal, follow up with the blood pressure every day, and check the blood pressure 
three times a week for two cycles after the blood pressure returns to normal, and once 
a week thereafter. 
● 
Within the first two cycles of administration, carry out the following examinations every 
two weeks ( 3 days, except for statutory holidays): hematology, urinalysis (not required 
for female subjects during their menstrual period), hepatic and renal function, and 
electrolytes. From Cycle 3, the examination is carried out once only at the end of each 
cycle ( 3 days, except for statutory holidays). 
● 
Within the first three cycles of administration, a 12-Lead ECG is carried out at the end of 
each cycle ( 3 days, except for statutory holidays), and then carried out at the end of 
every two cycles ( 7 days, except for statutory holidays). Each examination is carried 
out after administration for 3 times with about 5 min apart and QTc interval indicated. 
If there are symptoms such as precordial pain and palpitations, the myocardial zymogram 
(creatine kinase, lactate dehydrogenase) should be tested immediately, and ECG should 
be performed at any time. For clinically significant ECG abnormalities, 
echocardiography (LVEF) should be performed. 
● 
Physical examination, vital signs, PS score, and coagulation function tests are performed 
every cycle ( 3 days, except for statutory holidays). 
● 
CT or MRI examination and objective efficacy evaluation of tumor are performed once at 
the end of every two cycles ( 7 days, except for statutory holidays). If the efficacy 
reaches CR, PR or SD, the subject must be reexamined 4 weeks after the first evaluation. 
Note: For subjects who withdraw from the trial due to unacceptable toxicity, the efficacy 
evaluation should be conducted upon withdrawal if the efficacy evaluation is not carried out 
within 4 weeks before withdrawal. Thereafter, the imaging examination is performed at the 
same frequency, i.e., every 2 cycles until PD or use of other anti-tumor treatments. The 
radiographic evidence of PD of these subjects must be obtained. 
● 
The quality of life score must be evaluated before each objective efficacy evaluation of tumor. 
● 
Serum AFP is tested once at the end of Cycle 2 ( 7 days, except for statutory holidays) 
and at the end of Cycle 5 ( 7 days, except for statutory holidays). There is no strict 
requirement after Cycle 5. 
● 
If patients have abnormal stools such as hematochezia or melena, the fecal occult blood 
examination should be performed. 
● 
AEs should be observed and recorded frequently. 


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9.3 Follow-Ups 
9.3.1 28-day follow-up after the end of treatment 
All subjects should continue safety evaluation within 28 days after the last dose. During the 
follow-up visit on D28 ( 3 days, except for statutory holidays) after the end of treatment, 
physical examination, vital signs, ECOG PS, hematology, and hepatic and renal function tests 
should be carried out, and adverse events, concomitant medication and concomitant treatment 
should be evaluated. 
9.3.2 Follow-up of AEs 
Adverse events that have not resolved after discontinuing apatinib treatment should be 
followed and a final evaluation should be made. The follow-up of adverse events ends on 
D28 after treatment discontinuation. 
9.3.3 Survival follow-up 
After the 28-day safety follow-up, the subject, his/her family members or local physicians 
should be interviewed by telephone once a month to collect survival (date and cause of death) 
and post-treatment information (including received treatments) until the death endpoint, lost 
to follow-up, or study termination by Hengrui. Each survival follow-up should be 
documented in the follow-up form in detail. 
10 EFFICACY EVALUATION 
10.1 Primary Endpoint and Observation Method 
Overall survival (OS): 
Defined as the time from the date of randomization to death from any cause. 
10.2 Secondary Endpoints and Observation Methods 
● 
PFS 
PFS is defined as the time from randomization until the date of documented progression 
or death from any cause, whichever occurs first. 
 
The PFS is assessed as per RECIST 1.1. The analysis of this endpoint includes all tumor 
assessments during the treatment period and the follow-up period. If the patient has 
several endpoints that can all be evaluated as PD, then use the first documented PD when 
analyzing PFS. The study endpoint also includes relapse, the occurrence of new lesions, 
and death. The initiation of other systemic or targeted anti-tumor treatment is also 
considered disease progression. 


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● 
3-, 6-, and 12-month PFS rates 
Refer to the proportions of evaluable patients without disease progression from the start 
of the trial to 3, 6, and 12 months. 
● 
Time to progression (TTP) 
Refers to the time from randomization to any documentation of radiologic progression. 
The PFS is assessed as per RECIST 1.1. The analysis of this endpoint includes all tumor 
assessments during the treatment period and the follow-up period. 
● 
Objective response rate (ORR) 
Refers to the proportion of patients who achieve tumor shrinkage to a certain volume and 
maintain for a certain period of time, including CR and PR. Objective response is 
evaluated based on RECIST 1.1. Subjects must have measurable lesions at baseline. The 
tumor can be accessed as complete response (CR), partial response (PR), stable disease 
(SD), and disease progression (PD) according to RECIST 1.1 criteria. 
● 
Disease control rate (DCR); 
Refers to the proportion of evaluable patients with confirmed CR, PR, or SD (≥ 4 weeks). 
● 
The percentage of evaluable patients with stable disease (SD) of ≥ 4 weeks (confirmed 
SD in particular) 
● 
6- and 12-month mortalities 
● 
Quality of life score (QoL); 
In reference with EORTC QLQ-C30 (version 3, Chinese version) and HCC-18. See Appendix 
9 for details. 
Evaluation method: Observe and score the changes in the clinical symptoms and objective 
test results of tumor patients before and after treatment. Timing of evaluation: Pre-treatment 
and at the end of Cycles 2 and 3 of treatment. At the end of every two cycles, the quality of 
life scale should be recorded and evaluated, and the scores of the various areas of the scale 
should be recorded in the eCRF according to the requirements in the Appendix. 
 
 


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11 SAFETY EVALUATION 
11.1 Definitions 
11.1.1 Adverse event (AE) 
An adverse event (AE) refers to any untoward medical occurrence in a clinical investigation 
subject and which does not necessarily have a causal relationship with the treatment. AEs 
include but are not limited to: Abnormal laboratory findings; clinically significant symptoms 
and signs; allergies; 
According to the needs of management, safety monitoring (reporting of AEs or SAEs) should 
be performed from the signing of the informed consent form by the subject to 28 days after 
the last dose. 
11.1.2 Adverse drug reaction (ADR) 
All toxicities and unintentional reactions to a drug associated with any dose should be 
considered as adverse drug reactions (ADRs). A drug reaction means that a potential causal 
relationship between the drug and AE is at least reasonable, which means that the relationship 
cannot be excluded. 
11.1.3 Serious adverse event (SAE) 
An SAE refers to a medical occurrence during the clinical trial that results in hospitalization, 
prolonged hospitalization, disability, incapacity, life threatening events or death, or congenital 
malformation. The following unexpected medical events are included: 
 
Events resulting in death; 
 
Life-threatening events (defined as events where the subject is at immediate risk of death 
at the time of the onset); 
 
Events resulting in hospitalization or prolonged hospitalization; 
 
Events resulting in permanent or serious disability/incapacity; 
 
Congenital anomalies or birth defects. 
 
Overdose. 
 
Pregnancy during the clinical trial. 
Criteria for other SAEs specified in the protocol: 
 
Cardiac insufficiency - defined as any symptom or sign of reduced LVEF (NCI CTCAE 
Grade 3), or LVEF reduced by ≥ 20% from baseline and below the lower limit of normal 
(or reduced to < 50%). 


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 
ALT > 5  ULN and total bilirubin > 2  ULN (such as direct bilirubin > 35%; the 
bilirubin ratio should be measured). 
Note: If possible, the bilirubin ratio assay should be completed. If the test cannot be 
performed due to limited capacity and the subject has reached the criteria of total bilirubin 
of > 2  ULN, the event should be reported as an SAE. 
Progressive disease 
Progressive disease (including progressive signs and symptoms) should not be reported as an 
SAE. However, death due to progressive disease during the trial or safety reporting period 
should be reported as an SAE. Hospitalizations due to signs and symptoms of progressive 
disease should not be reported as an SAE. During the trial or safety reporting period, if the 
final outcome of the cancer is death, then the event leading to death should be reported as an 
SAE. 
Other anti-tumor treatments 
If a subject is to start another anti-tumor treatment, AEs except death will be reported until 
the start of the new anti-tumor treatment. Death that occurs within the SAE reporting period 
after study treatment is completed should be reported regardless of whether the patient 
received other treatment. 
Hospitalization 
During the trial, AEs resulting in hospitalization or prolonged hospitalization should be 
considered serious AEs. Any initial hospital admission by a medical facility meets this 
criterion (even if less than 24 hours). 
Hospitalization does not include the following: 
 
Hospitalization at a rehabilitation institution 
 
Hospitalization at a sanatorium 
 
General emergency admission 
 
Day surgery (e.g., outpatient/same-day/ambulatory surgery) 
Hospitalization or prolonged hospitalization not related to the worsening of adverse events is 
not considered an SAE. For example: 
 
Hospitalization due to pre-existing disease without occurrence of new AEs or worsening 
of the pre-existing disease (e.g., for testing persistent laboratory abnormalities that 
started before the study); 
 
Hospitalization for management reasons (e.g., annual routine physical examination); 


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 
Hospitalization during the study as specified in the study protocol (e.g., as required by 
the protocol); 
 
Elective hospitalization unrelated to the deterioration of an AE (e.g., elective cosmetic 
surgery); 
 
Scheduled treatment or surgery that should be documented in the entire study protocol 
and/or in subject's individual baseline information; 
 
Hospitalization merely for use of blood products. 
Diagnostic or therapeutic invasive (e.g., surgery) or non-invasive procedures should not be 
reported as adverse events. However, the disease condition leading to such procedures should 
be reported if it meets the definition of an adverse event. For example, acute appendicitis 
during the adverse event reporting period should be reported as an adverse event and the 
appendectomy should be documented as the treatment method for the event. 
11.2 Recording and Evaluation of Adverse Events 
All AEs should be described by terms in NCI-CTCAE 4.0 and recorded in eCRF accordingly. 
In addition, SAE Report Form (including initial or follow-up reports) should be completed. 
All subjects participating in the trial must be summarized. Reasons for withdrawal or 
rejection should be explained. A detailed individual report should be prepared if there is any 
death or serious toxic reaction in the trial. The cause of death, especially the relationship with 
the investigational drug, should be investigated. All AEs in the follow-up should be closely 
monitored until such events are properly resolved or the subject's condition is stable. 
The following aspects of each AE should be recorded in the eCRF: 
(1) Onset time (start time) and recovery time (end time) 
(2) Assessment and classification of AE by investigator in accordance with NCI-CTCAE 
version 4.0. If the severity of several AEs is not classified in NCI-CTCAE, the 
investigator can evaluate the grade in accordance with NCI-CTCAE. 
(3) The potential relationship between the AE and the investigational drug can be assessed 
with 5 grades of causality: Definitely related, probably related, possibly related, unlikely 
related, and not related. Events that are assessed to be "definitely related", "probably 
related", and "possibly related" are considered related to the investigational drug. When 
calculating the incidence of adverse drug reactions, the total number of these three 
categories is used as the numerator and the total number of subjects in safety set is used as 
the denominator. 
 
 


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Table 12. Criteria for the causality between AEs and investigational drug 
Criteria 
Definitel
y Related 
Probably 
Related 
Possibly 
Related 
Unlikely 
Related 
Not 
Related 
Reasonable temporal relationship 
Yes 
Yes 
Yes 
Yes 
No 
Is the adverse reactions for this drug known? 
Yes 
Yes 
Yes 
No 
No 
Can the reasons for removal be improved? 
Yes 
Yes 
Yes or No 
Yes or No 
No 
Does the same event recur after re‑challenging? 
Yes 
No 
No 
No 
No 
Can the event be explained by other reasons? 
No 
No 
No 
No 
No 
(4) Measures taken for the investigational drug (such as continued medication, dose 
reduction, continued medication after interruption, discontinuation, and other conditions, 
please explain in details). 
(5) Outcome defined as follows: resolved, improved, not improved, and aggravated. 
Note: If a patient experiences the same AE several times, it must be recorded and 
re-evaluated each time. 
11.3 SAE Reporting Procedures 
Serious adverse events that occur starting from the signing of the informed consent form until 
28 days (inclusive) after the last dose should be reported. Any SAE occurring during the trial 
must be immediately reported to the clinical research associate (CRA), the principal 
investigator, the PLA Tumor Center of the 81st Hospital of the Chinese People's Liberation 
Army and the Medical Director of Jiangsu Hengrui Pharmaceuticals Co., Ltd. via fax or 
phone. Meanwhile, the "New Drug Clinical Trial Serious Adverse Event (SAE) Report Form" 
should be completed, signed, dated, and submitted to NMPA within 24 hours. 
During the continued treatment period, SAE should be reported to the sponsor within 24 
hours. All information regarding the SAE should be documented in the SAE form. SAEs that 
occur during the continued treatment period until 28 days after the last dose should also be 
reported. SAEs that occur 28 days after the last dose are generally not reported unless 
suspected to be related to the investigational drug. 
SAEs should be documented in detail, including symptoms, severity, date of onset, time of 
treatment, measures taken, time and method of follow-up, as well as outcome. If the 
investigator believes that an SAE is unrelated to the investigational drug but potentially 
related to study conditions (e.g., termination of the original treatment, or complications 
during the trial), then this relationship should be detailed in the SAE page of the case report 
form. If the severity of an ongoing SAE or its relationship to the investigational drug 
changes, a follow-up report of the SAE should be submitted to Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. immediately. All SAEs should be followed until resolved or 
stabilized. 


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Table 13. Contact information of each institution 
Institution 
Contact 
Telephone 
Fax 
National Medical Products 
Administration 
Safety Supervision 
Department 
010-68313344-1003 
010-88363228 
PLA Tumor Center of the 81st Hospital 
of the Chinese People's Liberation Army 
Shukui Qin 
Xiufeng Liu 
025-84453667 
025-84453906 
Jiangsu Hengrui Pharmaceuticals Co., 
Ltd. 
Shunjiang Yu 
 021-68868768 
021-50819731 
11.4 Emergency Unblinding 
The emergency unblinding table is a sealed document provided by the sponsor that contains 
the treatment allocation for each subject. Unless there is a mandatory medical reason, the 
investigator should not unblind the subjects at will. Only when a subject experiences an 
emergency situation such as an SAE, the responsible investigator at the study site and the 
principal investigator can jointly decide whether to unblind. The blind code should be kept by 
dedicated technicians from the Department of Epidemiology and Health Statistics of Nanjing 
Medical University. If unblinding is necessary, the medical director of the sponsor should be 
notified and the dedicated technicians should be contacted to obtain the blind code within 24 h. 
Once unblinded, the subject should immediately withdraw from the trial. 
11.5 Safety Monitoring Committee 
During the trial, a drug safety monitoring committee composed of the principal investigator, 
the medical director of Hengrui and the person in charge of drug safety will be established to 
review the safety data generated during the trial. If a significant safety signal is found, such as 
the occurrence of an SAE or the need to interrupt the treatment, the drug safety monitoring 
committee can also host meetings to review and discuss the corresponding relationship 
between the safety data and the drug along with major changes to the protocol. 
12 DATA MANAGEMENT AND STATISTICAL ANALYSIS 
12.1 Data Collection and Management 
Data will be collected and managed using the electronic case report form (eCRF). 
12.1.1 Data collection 
Data will be collected using the eCRF. Jiangsu Hengrui Pharmaceuticals Co., Ltd. will 
provide an electronic data capture (EDC) system. Company staff will deliver EDC system 
training to the designated staff of study site. Access to EDC system will only be granted to 
the study site staff who have completed the training. The PI or dedicated data entry person 
(CRC) should input data into the EDC system in accordance with the requirements of the 
visit procedures and the eCRF completion guide. The logic verification program in the 
system will verify the integrity and logic of the clinical trial data entered into the EDC system 


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and generate an error message prompt for questionable data. The PI or CRC is permitted to 
modify or explain the problematic data. After the database is locked, the investigator will 
receive a CD-ROM or copy of subject data to archive at the study site. 
12.1.2 Data management and quality control 
To ensure authenticity and reliability and improve the quality of the clinical data, the CRA 
will monitor the integrity, consistency, and accuracy of the trial data in the database, and 
guide the study site staff to add or correct the data whenever necessary. The CRA or data 
manager will send electronic query form to the PI or CRC for problematic data. The PI or 
CRC must respond and provide correction or explanation of the problematic data. Multiple 
queries may be raised when necessary until the problem is solved. The medical director and 
data manager should perform consistency comparison of SAEs periodically. 
At the end of the study, the data manager and medical personnel will conduct a final quality 
control on all data in the database, summarize all protocol deviations and violations during 
the trial, and hold a data verification meeting. Database locking and unblinding will be 
carried out after the quality requirements have been met. The data manager will export the 
data to the statistics department for data analysis. 
12.1.3 Data review and study site monitoring 
Before the initiation of the study, a representative from Jiangsu Hengrui Pharmaceuticals Co., 
Ltd. will introduce study protocol and eCRF (Part 2) to the investigator and staff at the initial 
visit to the study site. During the study, the CRA will visit the study site regularly to monitor 
the completeness of the subject's records and the accuracy of the eCRF, compliance with the 
study protocol and GCP, and enrollment progress, and to ensure that the investigational drugs 
are stored, dispensed, and counted as required. During these visits, the major research 
personnel are required to assist the work of CRA. 
The investigator must keep the source documents of each subject, including all medical 
records and visit records (outpatient or inpatient record), such as demographic indicators, 
medical information, lab results, ECGs, and result of other examinations and evaluations. All 
information on the eCRF must come from the source documents of the subject. The 
investigator must also keep the informed consent forms signed by the subjects. 
The investigator must ensure all source documents are available for monitoring to verify the 
consistency with the eCRF. Jiangsu Hengrui Pharmaceuticals Co., Ltd. requires to completely 
monitor the signed informed consent forms, compliance with inclusion/exclusion criteria, 
SAEs records, and all data required for evaluation of primary endpoints and safety endpoints. 
Additional monitoring will be performed on consistency of source data and eCRF according 
to monitoring plan specified by the trial. No information related to subjects' identity in the 
source document will be disclosed. 


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12.2 Statistical Analysis of Trial Data 
● 
Full analysis set (FAS): According to the intention-to-treat (ITT) principle, all 
randomized subjects who have received 1 dose of study medication are included for 
efficacy analysis. For subjects whose entire course of treatment cannot be observed, the 
last observation data can be transferred to the final study results (LOCF). 
● 
Per-protocol set (PPS): All subjects who are in compliance with the protocol, have good 
compliance, have received at least 1 cycle of treatment (except for those with clear 
medical evidence of PD), and have completed the eCRF according to protocol 
requirements, and have not taken any prohibited medications during the trial. No 
imputation is made for missing data. The statistical analysis will be performed for the 
drug efficacy based on the FAS and PPS. Before database locking, the principal 
investigator, statistician, and sponsor should determine the final PPS during the data 
review meeting. 
● 
Safety analysis set (SAS): All enrolled subjects who have received at least one dose of 
the investigational drug and have safety data after the dose are included in the safety set. 
This dataset is used for safety analysis. 
12.3 Statistical Analysis Plan 
Time for efficacy analysis and safety assessment: Based on the full analysis set, when 
312 deaths (≥ 80% of patients died) occur, a final verification of the data in eCRF shall be 
performed. After the data integrity is verified and all quality assurance (QA) and quality 
control (QC) procedures on the data management are performed, the randomization protocol 
must be disclosed, and the data from the clinical database will be retrieved to record and 
statistically analyze the efficacy and safety data. In the efficacy analysis, the data cutoff date 
is the date when the 312th death occurs. In the analysis of overall survival (OS), if the subject 
does not die at or before the cutoff date, and if there are data (study visits, survival 
follow-ups, etc.) confirming that the subject has died or is still alive after the cutoff date, the 
subject data will be reviewed on the cutoff date. If the last date of known survival of a subject 
is before or at the cutoff date, the data of the subject will be reviewed on the day of last 
known survival. In the analyses of progression-free survival (PFS) and time to disease 
progression (TTP), if the subject has neither disease progression events (for TTP and PFS) 
nor death (for PFS only) at or before the cutoff date, then the data of the subject will be 
reviewed on the subject’s last day of radiographic tumor assessment on or before the cutoff 
date, except for the following case: For any radiographic tumor assessment as per the 
RECIST v1.1 criteria that indicates no evidence of progression, the review date will be set as 
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Pre-set subgroup analysis: Subgroups will be pre-defined based on the following factors for 
a confirmatory subgroup analysis in this study: age ≤ 65 years or > 65 years; ECOG score 
0 or 1; with or without vascular invasion; with or without extrahepatic metastases; with or 
without vascular invasion and extrahepatic metastases; positive or negative HBV; and with or 
without past history of sorafenib treatment. 
All statistical analyses will be performed using SAS. All statistical analyses are performed 
using two-tailed tests. P ≤ 0.05 is considered statistically significant, and 95% confidence is 
used for confidence intervals. 
Analyses were performed as per groups based on the initial dose and the dose at the end of 
treatment, respectively. 
The baseline data is analyzed based on the full analysis set (FAS). All efficacy endpoints are 
analyzed based on the FAS and the per protocol set (PPS). The analysis of primary efficacy 
endpoint OS is carried out mainly in the ITT, but the PPS is additionally used for verification 
in the final analysis. The safety analysis is carried out based on the safety analysis set (SS). 
The measurement data obtained from various treatment groups during various visits will be 
statistically described by mean ± standard deviation or median (minimum, maximum). For 
comparison with baseline values of the screening period, paired t-tests are used to compare 
pre and post intra-group differences. Changes occurring in each group before and after 
treatment should be compared by the analysis of variance (ANOVA) or rank sum test. The 
frequency data obtained from various treatment groups during various visits will be 
statistically described by frequency (proportions). Changes occurring in each group before 
and after treatment should be compared by χ2 test (exact test) or nonparametric test. 
● 
Dropout analysis: Descriptive analysis is mainly used. If necessary, the total dropout rate 
of each group and the comparison of dropout due to AEs will be tested by χ2 test or 
Fisher's exact test. 
● 
Balance analysis of baseline values: ANOVA or χ2 test is used to compare demographic 
data and other baseline values to evaluate the balance of various groups. 
The demographics include: age, gender, course of disease, ECOG PS, pathological grade, 
clinical stage, vascular invasion and/or extrahepatic metastasis (such as portal vein invasion, 
N1 (regional lymph node metastasis) or M1 (distant metastasis), yes or not), past treatment 
(surgical history of primary lesions, history of interventional procedures, history of 
radiotherapy, history of neoadjuvant chemotherapy), etiology of liver cancer (HBV infection, 
HCV infection, alcoholic cirrhosis or other), and α-fetoprotein (AFP) (low, normal, or high). 
All statistical parameters and analyses at baseline are determined based on characteristics 
obtained before first study medication (before randomization for subjects who have not 
received treatment). Unless otherwise stated, the baseline value of a specific variable is 
defined as the last value of the parameter obtained before the first study medication. 


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● 
Efficacy analysis: 
For the comparison of 3-, 6-, and 12-month PFS rates, objective response rate (ORR), disease 
control rate (DCR), the percentage of patients with stable disease (SD) of ≥ 4 weeks 
(confirmed SD in particular), and 6- and 12-month mortalities, CMH-χ2 tests with and 
without central stratification are used to compare the efficacy between the two groups. In 
addition, the 95% confidence interval of the difference between the two groups is also 
calculated. Based on the product limit method and the actual condition of the data, 25%, 50% 
(median) and 75% of PFS and TTP, as well as PFS and OS at different time points after the 
start of treatment, are calculated and the endpoints are compared between the two groups 
using the Log-Rank test. 
● 
Safety analysis: Descriptive statistical analysis will be mainly used. The AEs and SAEs, 
treatment-related AEs and SAEs, and AEs and SAEs of special interest (e.g., 
hypertension, proteinuria, and hand-and-foot syndrome) are listed and summarized. If 
necessary, the incidence and severity of AEs and SAEs between different groups are 
compared using Fisher's exact test. For laboratory results, the cases in which the 
pre-treatment values are normal but the post-treatment values are abnormal will be 
described, and the relationship between the abnormal changes and the investigational 
drug will be evaluated. 
13 DROPOUTS 
All eligible subjects who have signed the informed consent form have the right to withdraw 
from the clinical trial at any time. Subjects who have not received 1 cycle of treatment and 
undergone safety and efficacy assessments are considered drop-outs, regardless of the time 
and reason for withdrawal (withdrawals due to clear medical evidence of progression are not 
drop-outs). After a subject drops out, the investigator must document the reason for the 
drop-out in the eCRF, complete all the assessments possible, and document the last visit in 
the eCRF. Any drop-outs due to adverse drug reactions, which are determined to be related to 
the investigational drug during follow-up, must be documented in the eCRF and the 
investigator must be notified. Subjects who have undergone screening but withdrawn without 
obtaining a medication number are not considered dropouts. When conducting the safety 
assessment, a statistical analysis should also be performed for subjects who complete an 
entire treatment cycle and have detailed documents available. 
Subjects who withdraw are not permitted to be enrolled again, and the subjects' number may 
not be reused. 
 
 


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14 QUALITY CONTROL AND ASSURANCE 
● 
The clinical study sites must be NMPA-approved drug research sites with clinical 
research qualifications; 
● 
Study staff must be physicians trained for clinical trials, and must work under the 
supervision of senior professionals; 
● 
Before the trial is started, the clinical wards must be inspected to ensure that standard 
requirements are met and first-aid equipment are available; 
● 
Professional nursing staff are responsible for administering the drugs and they must be 
fully aware of the administration process to ensure subject compliance; 
● 
Study sites must carry out the study in strict accordance with the protocol, and the eCRF 
must be completed truthfully; 
● 
The scientific committee must be established. The scientific committee is chaired by 
Professor Jianming Xu, and is composed of Professor Shukui Qin, Professor Ying Cheng, 
Professor Jun Liang, Professor Xuenong Ouyang, Professor Hao Yu (statistician), and 
sponsor's representative. The scientific committee is responsible for providing general 
guidance on execution and implementation of the trial, including (but not limited to) 
safety and enrollment rate, as well as providing guidance on published data from 
perspective of science. 
● 
The CRA should follow the standard operating procedure and monitor the clinical trial to 
ensure that all data are documented and reported accurately and completely, all eCRFs 
are entered correctly and consistent with source data, and the trial is implemented as per 
protocol; 
● 
In the event of SAEs, the CRA must inform all study sites immediately and temporarily 
suspend the trial whenever necessary; 
● 
Participating sites must allow audits by the sponsor and regulatory authorities. It is 
especially important for the investigator and study staff to provide time and convenience 
for monitoring and auditing. 
15 DISCUSSION, APPROVAL, AND AMENDMENT OF TRIAL 
PROTOCOL 
The above "Clinical Study Protocol" and "Clinical Study Case Report Form" shall be 
formulated after discussion by the principal investigators of participating centers, approved 
by Jiangsu Hengrui Pharmaceuticals Co., Ltd., and implemented upon approval by the ethics 
committees of participating centers. During the clinical trial, any revisions to the protocol 
should be reported to the Ethics Committee for approval or filing. 


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16 LAWS, REGULATIONS AND ETHICS 
Laws and Regulations 
According to the requirements of relevant regulations in China, an application should be 
submitted to the NMPA to obtain a clinical trial approval number before starting a clinical 
trial of a new drug. The clinical trial approval number of this investigational drug, apatinib, is 
2014L00877. Before the start of this trial, it should be approved or archived by relevant 
regulatory authorities. The clinical trial should also be implemented in compliance with all 
applicable regulatory requirements. 
Ethical Standards 
This clinical trial must comply with the "Declaration of Helsinki" (1996), NMPA's "Good 
Clinical Practice" (GCP)[15], and related regulations. 
Ethics Committee 
This trial protocol must be reviewed and approved by the ethics committee of each site prior 
to implementation. During the review by the ethics committee, the sponsor and the 
investigator should provide the ethics committee with relevant clinical trial documents, 
including but not limited to: "Ethical Review Application", "Clinical Study Approval" from 
NMPA, "Clinical Study Letter of Authorization", "List of Clinical Trial Staff", "Certificate of 
Analysis of the Investigational Drug", "Sample Informed Consent Form", "Clinical Trial 
Protocol", "Case Report Form (CRF)", and "Investigator's Brochure" for clinicians. During 
the trial, revisions to this protocol must be reported to the ethics committee and put on record. 
Confidentiality of Subject Information 
In the course of this trial, a great effort will be made to protect the personal privacy of all 
subjects. The sponsor's forms, study reports, publications, and any other published materials 
must not include the name of subjects unless required by law. This trial will use highly 
confidential methods to transmit data in order to prevent the leakage of the personal data of 
the subjects. 
17 TRIAL PROGRESS 
The trial is expected to be carried out from November 2013 to March 2018. 


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18 TRIAL PROTOCOL COMPLIANCE 
The investigator shall try his/her best to avoid protocol violations. At any time, the 
investigator should not contact Jiangsu Hengrui Pharmaceuticals Co., Ltd. and ask for 
approval of protocol violations, because any authorized protocol violation should never be 
allowed. If the investigator believed that a certain protocol deviation could improve the 
implementation of the trial, the investigator must consider protocol revisions. However, the 
revised protocol can only be implemented after it is approved by Jiangsu Hengrui 
Pharmaceuticals Co., Ltd. and the medical ethics committee. All major protocol violations 
should be recorded and reported on the clinical trial report. 


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Appendix 1. Response Evaluation Criteria in Solid Tumors RECIST Version 1.1. 
1 MEASURABILITY OF TUMOR AT BASELINE 
1.1 Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
Measurable lesions 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter is to 
be recorded) with a minimum size of: 
● 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
● 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable); 
● 20 mm by chest X-ray 
● Malignant lymph nodule: pathologically enlarged and measurable, single lymph nodule 
must be ≥ 15 mm in short axis by CT scan (CT scan slice thickness no greater than 5 mm). 
At baseline and during follow-up, only the short axis will be measured and followed. 
Non-measurable lesions 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodule with ≥ 10 mm to < 15 mm short axis) as well as truly non-measurable lesions. 
Non-measurable lesions include: meningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast cancer, lymphangitis carcinomatosa of the skin or lung, abdominal 
masses unable to be diagnosed or followed by imaging techniques, and cystic lesions. 
Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions: 
● Bone scan, PET scan or plain films are not considered adequate to measure bone lesions. 
However, these techniques can be used to confirm the presence or disappearance of bone 
lesions; 
● Lytic lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by tomography techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability 
described above; 


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● Blastic lesions are non-measurable. 
Cystic lesions: 
● Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
● Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment; 
● Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
locoregional therapy, are usually considered non-measurable unless there has been 
demonstrated progression in the lesion. Study protocols should detail the conditions under 
which such lesions would be considered measurable. 
1.2 Specifications by Methods of Measurements 
Measurements of lesions 
All measurements should be recorded in metric notation if clinically assessed. All baseline 
evaluations should be performed as close as possible to the treatment start and never more 
than 28 days (4 weeks) before the beginning of the treatment. 
Method of evaluation 
The same method and technique should be used to assess lesions at baseline and during 
follow-up. Imaging based evaluation should always be done rather than clinical examination 
unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). For the case 
of cutaneous lesions, documentation by color photography including a ruler to estimate the 
size of the lesion is suggested. When lesions can be evaluated by both imaging and clinical 
examination, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, especially when tumor progression is an 
important clinical endpoint, since CT is more sensitive, particularly in identifying new 
lesions. Chest X-ray is only applicable when the measured lesion boundary is clear and the 
lungs are well ventilated. 
 
 


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CT, MRI: CT is currently the best available and reproducible method for efficacy evaluation. 
This guideline has defined measurability of lesions on CT scan based on the assumption that 
CT slice thickness is ≤ 5 mm. When CT scans have slice thickness greater than 5mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for whole body scans). 
Ultrasound: Ultrasound should not be used as a method to measure lesion size. Ultrasound 
examinations are operation-dependent, and cannot be reproduced at a later date. It cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be 
used instead. 
Endoscopy and laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm CR when biopsies are 
obtained, or to determine relapse in trials where recurrence following CR or surgical excision 
is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
However, if the marker levels exceed the upper normal limit at baseline, they must return to 
the normal levels for evaluation of complete response. Because tumor markers are disease 
specific, instructions for their measurement should be incorporated into protocols on 
a disease specific basis. Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer), have been published. In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line treatment in ovarian cancer. 
Cytology/histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual benign tumor tissue is commonly 
observed in lesions of germ cell neoplasm). When effusions are known to be a potential 
adverse effect of treatment (e.g., with certain taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumor has met the criteria for response 
or stable disease in order to differentiate between response (or stable disease) and progressive 
disease. 
2. TUMOR RESPONSE EVALUATION 
2.1 Evaluation of Target Lesion 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
compared to baseline. 


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Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition, the sum must also demonstrate an absolute increase of at least 
5mm (the appearance of one or more new lesions is also considered disease progression). 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
2.2 Special Notes on the Assessment of Target Lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10mm on study. This means that when 
lymph nodes are included as target lesions, the sum of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm. eCRFs or other data collection methods may therefore be designed to have 
target nodal lesions recorded in a separate section where, in order to qualify for CR, each 
node must achieve a short axis < 10 mm. For PR, SD and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become too small to measure: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or 
lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that 
the radiologist may not feel comfortable assigning an exact measure and may report them as 
being "too small to measure". When this occurs, it is important that a value be recorded on 
the eCRF. If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly 
seen but too small to measure, a default value of 5mm could be assigned. (Note: It is less 
likely that this rule will be used for lymph nodules since they usually have a definable size 
when normal and are frequently surrounded by adipose tissues as in the retroperitoneum; 
however, if a lymph nodule is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm could be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially 
non-reproducible, therefore providing this default value will prevent false evaluation based 
upon measurement error. To reiterate, however, if the radiologist is able to provide an actual 
measure, that should be recorded, even if it is below 5mm. 
Lesions that split or coalesce: When non-nodal lesions fragmented, the longest diameters of 
the fragmented portions should be added together to calculate the target lesion sum. Similarly, 
as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced 


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such that they are no longer separable, the vector of the longest diameter in this instance 
should be the maximal longest diameter for the coalesced lesion. 
2.3 Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions. While some non-target lesions may actually be measurable, 
they need not be measured and instead should be assessed only qualitatively at the time 
points specified in the protocol. 
Complete response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodules must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive disease (PD): Unequivocal progression of existing non-target lesions. Note: the 
appearance of one or more new lesions is also considered disease progression. 
2.4 Special Notes on the Assessment of Progression of Non-Target Lesions 
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease, to achieve unequivocal progression on the 
basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that the overall tumor load has increased sufficiently to the point 
where treatment must be discontinued. A modest increase in the size of one or more 
non-target lesions is usually not sufficient to quality for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in the 
face of SD or PR of target disease will therefore be extremely rare. 
When the patient has only non-measurable disease: This circumstance arises in some phase 
III trials when it is not a criterion of study inclusion to have measurable disease. The same 
general concepts apply here as noted above, however, in this instance there is no measurable 
disease assessment. Because worsening in non-target disease cannot be easily quantified (by 
definition: if all lesions are truly non-measurable), a useful test that can be applied when 
assessing patients for unequivocal progression is to consider if the increase in overall disease 
load based on the change in non-measurable disease is comparable in magnitude to the 
increase that would be required to declare PD for measurable disease. For example, an 
increase in tumor burden representing an additional 73% increase in volume (which is 
equivalent to a 20% increase diameter in a measurable lesion). Examples include an increase 
in a pleural effusion from "trace" to "large", an increase in lymphangitic disease from 
localized to widespread, or may be described in protocols as "sufficient to require a change in 
treatment". Examples include an increase in a pleural effusion from trace to large, an increase 
in lymphangitic disease from localized to widespread, or may be described in protocols as 


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"sufficient to require a change in therapy". If unequivocal progression is seen, the patient 
should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so, therefore the increase must be substantial. 
2.5 New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of radiographically detected lesions; however, the finding of a new lesion 
should be unequivocal. For example, it should not be attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumor (for example, some new bone lesions that may be simply healing, or re-occurrence of 
pre-existing lesions). This is particularly important when the patient's baseline lesions show 
partial or complete response. For example, necrosis of a liver lesion may be reported on a CT 
scan report as a new cystic lesion, which it is not. 
A lesion identified on a follow-up study that was not scanned at baseline is considered a new 
lesion and will indicate disease progression. An example of this is the patient who has 
visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals 
metastases. The patient's brain metastases are considered to be evidence of PD even if he/she 
did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued treatment and 
follow-up evaluation are required to clarify if it represents a truly new disease. If repeated 
scans confirm there is definitely a new lesion, then progression should be declared using the 
date of the initial identification. 
While FDG-PET response assessments generally need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible new disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following process: 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, 
PD is confirmed. 
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression occurring 
at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). 


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If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the imaging examination, this is not PD. 
2.6 Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements is made at an evaluation, 
usually the case is also considered not evaluable at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) has/have no 
effect on the assigned time point response. 
2.7 Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodules decrease to 
a normal size of < 10 mm, they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodules are normal in order not to overstate 
progression should it be based on increase in size of the nodes. As noted earlier, this means 
that patients with CR may not have a total sum of zero on the eCRF. 
In trials where confirmation of response is required, repeated "NE" time point evaluations 
may complicate best response determination. The analysis plan for the trial must address how 
missing data/evaluations will be addressed in determination of response and progression. For 
example, in most trials it is reasonable to consider a patient with time point responses of 
PR-NE-PR as a confirmed response. 
Patients with an overall deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
symptomatic deterioration. Efforts should be made to evaluate objective progression even 
after discontinuation of treatment. Symptomatic deterioration is not a description of an 
objective response: it is a reason for discontinuation of treatment. The objective response 
status of such subject is to be determined by evaluation of target and non-target lesions as 
shown in Attached Tables 1-3. 
Conditions that are defined as early progression, early death and not evaluable are study 
specific and should be clearly described in each protocol (depending on treatment duration 
and treatment cycle). 
In some circumstances it may be difficult to distinguish residual lesions from normal tissues. 
When the evaluation of complete response depends upon this definition, it is recommended 
that the local lesion be investigated via biopsy before assigning a status of complete response. 
FDG-PET may be used to confirm a response to a CR in a manner similar to a biopsy in cases 
where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use 
of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 


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Attached Table 1. Time point response-patients with target (+/– non-target) lesions 
Target Lesion 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluable 
No 
PR 
PR 
Non-PD or not all evaluable 
No 
PR 
SD 
Non-PD or not all evaluable 
No 
SD 
Not all evaluable 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Note: CR = complete response, PR = partial response, SD = stable disease, PD = progressive 
disease, and NE = non evaluable. 
 
Attached Table 2. Time point response-patients with non-target lesions only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/Non-PD 
Not all evaluable 
No 
Not evaluable 
Equivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Note: For non-target lesions, "Non-CR/non-PD" is preferred over SD. Since SD is 
increasingly used as an endpoint for efficacy evaluation, non-CR/non-PD response is 
developed to address the absence of lesion measurability.  
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
evaluation. If at the next scheduled evaluation, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
 
 
 


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Attached Table 3. Best overall response when confirmation of CR and PR required 
Overall 
Response at First 
Time Point 
Overall Response 
at Subsequent 
Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
CR 
PD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
CR 
NE 
SD (provided minimum criteria for SD duration met, otherwise, NE) 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD (provided minimum criteria for SD duration met, otherwise, PD) 
PR 
NE 
SD (provided minimum criteria for SD duration met, otherwise, NE) 
NE 
NE 
NE 
Note: CR is complete response, PR is partial response, SD is stable disease, PD is progressive disease, and NE 
is non-evaluable. a: If a CR is truly met at first time point, then any disease seen at a subsequent time point, even 
the disease meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD is met. However, 
sometimes CR may be claimed when subsequent scans suggest small lesions were likely still present and in fact 
the patient had PR, not CR at the first time point. Under these circumstances, the original CR should be changed 
to PR and the best response is PR. 
2.8 Confirmatory Measurement/Duration of Response 
Efficacy confirmation 
In non-randomized trials where tumor response is the primary endpoint, confirmation of PR 
and CR is required to ensure responses identified are not the result of measurement error. 
However, in studies where stable disease or progression are the primary endpoints, 
confirmation of response is not required since it will not add value to the interpretation of 
trial results. In the case of SD, measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general not less than 6–8 weeks) that is defined in the 
study protocol.  
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest 
measurements recorded on study). The duration of overall complete response is measured 
from the time criteria are first met for CR until the first date that recurrent or progressive 
disease is truly documented. 
 
 


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Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum 
in trial (if the baseline sum is the smallest, this is the reference for calculation of PD). The 
clinical relevance of the duration of stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease for a minimum period of time is an 
endpoint in a particular trial, the protocol should specify the minimal time interval required 
between two measurements for determination of SD. 
Note: The duration of response and stable disease as well as the progression-free survival are 
influenced by the frequency of follow-up after baseline evaluation. It is not in the scope of 
this guideline to define a standard follow-up frequency. The frequency should take into 
account many parameters including disease types and stages, treatment cycle and standard 
practice. However, these limitations of the precision of the measured endpoint should be 
taken into account if comparisons between trials are to be made. 
2.9 PFS/TTP 
Many trials of advanced tumors use PFS or TTP as the primary endpoint. If the protocol 
requires the presence of measurable lesions in all patients, the evaluation of progress will be 
relatively simple. An increasing number of trials allow the participation of patients with and 
without measurable lesions. In this case, the clinical findings of progressive disease in 
patients without measurable lesions must be described in detail. Because there is often 
a deviation in the determination of the date of progress, the observation time points for 
different treatment groups should be the same. 
 
 


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Appendix 2 Child-Pugh Score 
Parameter 
Score 
 
1 
2 
3 
Hepatic encephalopathy 
No 
Grade 1–2 
Grade 3-4 
Ascites 
No 
Mild 
Moderate and above 
Prothrombin time prolonged or INR 
1–3 s 
4-6 s 
> 6 s 
< 1.7 
1.7-2.3 
> 2.3 
Bilirubin total (μmol/L) 
< 34 
34-51 
> 51 
Serum albumin (g/L) 
> 35 
28-35 
< 28 
 
 
Note: Class A is 5 to 6 points; Class B is 7 to 9 points; Class C is 10 to 15 points;  
Subjects with Class A or good Class B (i.e., a score of 7) can be enrolled. 


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Appendix 3 BCLC Staging (Barcelona Clinic Liver Cancer Staging System, 2010) 
Stage 
PS Score 
Tumor Status 
Hepatic Function 
Status 
Number of Tumors 
Tumor Size 
Stage 0: very early 
stage 
0 
Single 
< 2 cm 
Portal hypertension 
absent 
Stage A: early stage 
0 
Single 
Within 3 
Any 
< 3 cm 
Child-Pugh A-B 
Stage B: 
intermediate stage 
0 
Multiple nodular 
tumors 
Any 
Child-Pugh A-B 
Stage C: advanced 
stage 
0 
Multiple nodular 
tumors 
Any 
Child-Pugh A-B 
Stage D: terminal 
stage 
0 
Any 
Any 
Child-Pugh C 
 
Note: PS score: ECOG Performance Status Score.  
 
 


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Appendix 4 ECOG Performance Status Scoring Criteria 
0 
Fully active, able to carry on all pre-disease performance without restriction; 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light house work, office work; 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours; 
3 
Capable of only limited selfcare, confined to bed or chair 50% or more of waking hours; 
4 
Completely disabled; cannot carry on any selfcare, totally confined to bed or chair; 
5 
Death  
 
 
 
 


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Appendix 5 New York Heart Association (NYHA) Functional Classification 
Heart Function 
Classification 
Manifestation 
Grade of Heart 
Failure 
Class I 
No limitation of physical activity; ordinary physical 
activity does not cause undue fatigue, palpitation, or 
dyspnea. i.e., cardiac functional compensatory period 
 
Class II 
Slight limitation of physical activity. Comfortable at 
rest, ordinary physical activity results in fatigue, 
palpitations, dyspnea, or angina. Also known as 
Grade I or mild heart failure. 
I 
Class III 
Marked limitation of physical activity, comfortable at 
rest, less than ordinary activity causes the above 
symptoms. Also known as Grade II or moderate heart 
failure. 
II 
Class IV 
Unable to carry on any physical activity. Symptoms 
of congestive heart failure or angina at rest; if any 
physical activity is undertaken, discomfort increases. 
Also known as Grade III or severe heart failure. 
III 
 
 
 


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Appendix 6 List of Participating Study Centers 
No. 
Name of Participating Study Center 
1 
The 81st Hospital of the Chinese People's Liberation Army 
2 
The First People's Hospital of Changzhou 
3 
Nantong Tumor Hospital 
4 
The First Affiliated Hospital of Bengbu Medical College 
5 
Sir Run Run Shaw Hospital, Zhejiang University School of Medicine 
6 
Zhongshan Hospital, Fudan University 
7 
Affiliated Hospital, Academy of Military Medical Sciences 
8 
302 Hospital of the Chinese People's Liberation Army 
9 
The Affiliated Hospital of Qingdao University 
10 
Cancer Hospital, Chinese Academy of Medical Sciences 
11 
Fuzhou General Hospital of Nanjing Military Region 
12 
Cancer Hospital of Shantou University Medical College 
13 
The First Affiliated Hospital of Guangzhou Medical University 
14 
Sun Yat-sen University Cancer Center  
15 
Guangdong Provincial People's Hospital 
16 
Zhongshan Hospital, Xiamen University 
17 
The First Affiliated Hospital of Guangzhou University of Chinese Medicine 
18 
Harbin Medical University Cancer Hospital 
19 
Jilin Cancer Hospital 
20 
The Sixth People's Hospital of Shenyang 
22 
The Second Hospital of Dalian Medical University 
23 
The First Hospital of China Medical University 
24 
The Third Affiliated Hospital of Army Medical University 
25 
West China Hospital of Sichuan University 
26 
Jiangxi Cancer Hospital 
27 
The Fourth Hospital of Hebei Medical University 
28 
Fujian Cancer Hospital 
29 
Beijing Cancer Hospital 
30 
The First Affiliated Hospital, College of Medicine, Zhejiang University 
31 
Chinese PLA General Hospital 
32 
Beijing Friendship Hospital, Capital Medical University 
33 
Hunan Cancer Hospital 
 


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Appendix 7 Labels of Apatinib Mesylate Tablets as a Second-Line Treatment 
for Advanced HCC 
Treatment group: 750 mg q.d. 
Label: 
Initiation of administration: Administration at the initial dose in Cycles 1–6 
Pack label 
 
 
 
Small box label 
Apatinib Mesylate Tablets for a Phase III Clinical Trial on HCC 
For clinical use only 
Clinical approval No.: 2014L00877 
Drug No.: 
Medication for Cycle X 
Quantity: 10 tablets per pack, 11 packs per box 
Strength: 250 mg/tablet 
Indication: For the treatment of advanced hepatocellular carcinoma 
Method of administration: 3 tablets daily (please follow the prescription 
when the dose is reduced or resumed to the 
previous dose) 
Once a day after meals (the dosing time on each 
day should remain the same whenever possible) 
Storage: Store in a sealed container away from light at room temperature. 
Batch No.: ×××× 
Shelf life: Tentatively 2 years, till XX Day XX Month 20XX 
Study Site: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Note: Please return the remaining products to the pharmacist 
 
 
 
 
Apatinib Mesylate Tablets for a Phase III Clinical Trial on HCC 
Strength: 250 mg/tablet 
Indication: For the treatment of advanced hepatocellular carcinoma 
Method of administration: 3 tablets daily (please follow the prescription when the dose 
is reduced or resumed to the previous dose) 
Once a day after meals (the dosing time on each day should 
remain the same whenever possible) 
Batch No.: ×××××× 
Shelf life: Tentatively 2 years, till XX Day XX Month 20XX 


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Medium box label 
Apatinib Mesylate Tablets for a Phase III Clinical Trial on HCC 
For clinical use only 
Clinical approval No.: 2014L00877 
Drug No.: 
Quantity: 6 small boxes per medium box 
Strength: 250 mg/tablet 
Indication: For the treatment of advanced hepatocellular carcinoma 
Method of administration: 3 tablets daily (please follow the prescription 
when the dose is reduced or resumed to the 
previous dose) 
Once a day after meals (the dosing time on each 
day should remain the same whenever possible) 
Storage: Store in a sealed container away from light at room temperature 
Batch No.: ×××× 
Shelf life: Tentatively 2 years, till XX Day XX Month 20XX 
Study Site: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
Note: Please return the remaining products to the pharmacist 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 8 Percent Bone Marrow Content in Human Skeleton 
 
 


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Appendix 9 Quality of Life Score (EORTC QLQ-C30 V3.0 and HCC-18) 
We would like to know about you and your health status. Please answer all the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" 
answers. The information you provide will be kept strictly confidential. 
Please fill in your code (No.): __________ 
Date of Birth (DD/MM/YYYY): _________ 
Today's Date (DD/MM/YYYY): _________ 
 
Not at all 
A little 
Quite a bit 
Very much 
1. Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase? 
1 
2 
3 
4 
2. Do you have any trouble taking a long walk? 
1 
2 
3 
4 
3. Do you have any trouble taking a short walk outside? 
1 
2 
3 
4 
4. Do you need to stay in bed or a chair during the day? 
1 
2 
3 
4 
5. Do you need help with eating, dressing, bathing or 
using the toilet? 
1 
2 
3 
4 
During the past week: 
Not at all 
A little 
Quite a bit 
Very much 
6. Were you limited in doing either your work or other 
daily activities? 
1 
2 
3 
4 
7. Were you limited in pursuing your hobbies or other 
leisure time activities? 
1 
2 
3 
4 
8. Were you short of breath? 
1 
2 
3 
4 
9. Have you had pain? 
1 
2 
3 
4 
10. Did you need to rest? 
1 
2 
3 
4 
11. Have you had trouble sleeping? 
1 
2 
3 
4 
12. Have you felt weak? 
1 
2 
3 
4 
13. Have you lacked appetite? 
1 
2 
3 
4 
14. Have you felt nauseated? 
1 
2 
3 
4 
15. Have you vomited? 
1 
2 
3 
4 
16. Have you been constipated? 
1 
2 
3 
4 


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During the past week: 
1 
2 
3 
4 
17. Have you had diarrhea? 
1 
2 
3 
4 
18. Were you tired? 
1 
2 
3 
4 
19. Did pain interfere with your daily activities? 
1 
2 
3 
4 
20. Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television? 
1 
2 
3 
4 
21. Did you feel tense? 
1 
2 
3 
4 
22. Did you worry? 
1 
2 
3 
4 
23. Did you feel irritable? 
1 
2 
3 
4 
24. Did you feel depressed? 
1 
2 
3 
4 
25. Have you had difficulty remembering things? 
1 
2 
3 
4 
26. Has your physical condition or medical treatment 
interfered with your family life? 
1 
2 
3 
4 
27. Has your physical condition or medical treatment 
interfered with your social activities? 
1 
2 
3 
4 
28. Has your physical condition or medical treatment 
caused you financial difficulties? 
1 
2 
3 
4 
 
 
 
 
 
For the following questions, please circle the number 
from 1 to 7 that best applies to you 
 
 
 
 
29. How would you rate your overall health during the 
past week? 
 
 
 
 
   1     2     3     4     5     6     7 
 
 
 
 
Very poor                          Excellent 
 
 
 
 
30. How would you rate your overall quality of life 
during the past week? 
 
 
 
 
   1     2     3     4     5     6     7 
 
 
 
 
Very poor                          Excellent 
 
 
 
 
 
 
 
 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
 
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 122 of 126 
 
During the past week: 
Not at all 
A little 
Quite a bit 
Very much 
31. Did you feel thirsty? 
1 
2 
3 
4 
32. Was there any problem with your taste? 
1 
2 
3 
4 
33. Was your arm or leg muscle reduced? 
1 
2 
3 
4 
34. Did you have bloating? 
1 
2 
3 
4 
35. Were you troubled by the appearance of your belly? 
1 
2 
3 
4 
36. Were you troubled by the yellowing of your skin or 
eyes (jaundice)? 
1 
2 
3 
4 
37. Did you feel itchiness? 
1 
2 
3 
4 
38. Did you have shoulder pain? 
1 
2 
3 
4 
39. Did you have abdominal pain? 
1 
2 
3 
4 
40. Did you have fever? 
1 
2 
3 
4 
41. Were you afraid of cold (rigors)? 
1 
2 
3 
4 
42. Were you worried that you would not get enough 
nutrition? 
1 
2 
3 
4 
43. Did you feel full soon after you started eating? 
1 
2 
3 
4 
44. Were you worried that you are underweight? 
1 
2 
3 
4 
45. Did you feel less energetic than expected? 
1 
2 
3 
4 
46. Did you find it difficult to get things done? 
1 
2 
3 
4 
47. Did you need to sleep during the day? 
1 
2 
3 
4 
 
 
 
 
 
In the past four weeks: 
 
 
 
 
48. Did the disease or treatment affect your sexual life? 
 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
 
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 123 of 126 
 
Note: 
1. Quality of life assessment instructions: 
EORTC's QLQ-C30 (V3.0) is the core questionnaire for all cancer patients, with a total of 
30 items. Items 29 and 30 have a 7-point scale, scoring 1-7 points depending on the answer. 
Other items have a 4-point scale: Not at all, A little, Quite a bit, and Very much, scoring 1-4 
points. 
2. Calculation of EORTC QLQ-C30 scale (dimension) score (coarse score) 
For the convenience of statistical analysis and application, the scale is often divided into 
scales. A scale is an aspect of a quality of life component, also known as a dimension, which 
is analyzed as an independent variable. The EORTC QLQ-C30 (V3.0) comprises 30 items 
divided into 15 scales, including 5 functioning scales (physical, role, cognitive, emotional and 
social), 3 symptom scales (fatigue, pain and nausea/vomiting), 1 global health status/quality 
of life scale, and 6 single-item scales (each one is a scale). Refer to the following for 
breakdown of these scales. 
To get the score of each scale, add up the scores of the items in each scale and divide by the 
number of items in each scale (Raw Score RS), that is, RS = (Q1+Q2+...+Qn)/n.  


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
 
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 124 of 126 
 
Classification of various scales in EORTC QLQ-C30 
 
Items 
Item Number 
Physical Functioning  
5 
1-5 
Role Functioning 
2 
6-7 
Emotional Functioning 
4 
21-24 
Cognitive Functioning 
2 
20-25 
Social Functioning 
2 
26-27 
Global Health Status 
2 
29-30 
Weariness 
3 
10, 12, and 18 
Nausea and Vomiting 
2 
14-15 
Pain 
2 
9, 19 
Dyspnoea 
1 
8 
Insomnia 
1 
11 
Appetite Loss 
1 
13 
Constipation 
1 
16 
Diarrhea 
1 
17 
Financial Difficulties 
1 
28 
 
3. Calculation of EORTC QLQ-C30 Standard Score 
To compare the scores between each scale, a linear transformation is further carried out to 
standardize the RS so that the standard score (SS) ranges from 0-100. In addition, another 
purpose of the transformation is to reverse the direction of the score. Except for items 29 and 
30 which are reversed items (the larger the score, the worse the quality of life), the scoring 
rules for QLQ-C30 clearly state that the higher the score for functional scale and global 
health status, the higher level of functioning and QoL, but a high score for symptom scale 
represents a high level of symptoms/problems (worse QoL). Therefore, the score of 
functional scale needs to be reversed when being standardized. Specifically, the following 
formula is used (where R is the full score range for each domain or item). 
Functional scale: SS = [1 - (RS - 1)/R] × 100 
Symptom scale and global health status: SS = [(RS - 1)/R] × 100 
 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as Second-Line Treatment for Advanced Hepatocellular 
Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
 
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 125 of 126 
 
Appendix 10 Flow Chart of Randomization and Enrollment for the Clinical Trial of Apatinib Mesylate Tablets as 
a Second-Line Treatment for Advanced Hepatic Carcinoma 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Contact: 
Professor Shukui Qin, the 81st Hospital of the Chinese People's Liberation Army 
Tel: 025-84453667 
Professor Hao Yu, Department of Epidemiology and Health Statistics of Nanjing Medical University 
Tel: 025-86662934/13814056262 
Medical Director: Shunjiang Yu, Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
Tel: 021-68868768 
 
Signing of 
Informed 
Consent 
Form 
Informed 
consent 
form 
Screening 
Qualified 
Log into the 
Interactive 
Web 
Response 
System 
Doctor visit 
of patients 
with 
advanced 
HCC 
Obtain the random 
number and drug 
number based on 
patient information 
Distribute drugs 
based on the 
drug number 
Start trial and drug 
administration 
 
The 
investigator 
at each site 
verifies the 
information 
of enrolled 
subjects 
Qualified 


Phase III Clinical Study Protocol of Apatinib Mesylate Tablet as 
Second-Line Treatment for Advanced Hepatocellular Carcinoma 
Confidential 
Protocol No.: 
APTN-III-HCC 
 
Version No.: 1.4 
Version Date: 10 Mar., 2017 
Page 126 of 126 
 
REFERENCES 
1. Jemal A, Bray F, Meliaas M, et al. Global cancer statistics 2008. CA Cancer J Clin, 2011, 
61:69-90. 
2. Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008, Cancer Incidence and Mortality 
Worldwide: IARC CancerBase No. 10. Lyon, France: International Agency for Research 
on Cancer; Year. Available at:http://globocan.iarc.fr. 2010, Last accessed 8/17/2010. 
3. Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in 
hepatocellular carcinoma. Dig Liver Dis, 2010, 42: S206-S214. 
4. Yoshiji H, Kuriyama S, Hicklin D J et al. The vascular endothelial growth factor receptor 
KDR/Flk-1 is a major regulator of malignant ascites formation in the mouse hepatocellular 
carcinoma model. Hepatology, 2001, 33:841-847. 
5. von Marschall Z, Cramer T, Hocker M et al. Dual mechanism of Vascular endothelial 
growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut, 2001, 
48(1):87-96. 
6. Josep ML, Sergio R, Vincenzo M, et al. Sorafenib in Advanced Hepatocellular Carcinoma. 
N Engl J Med, 2008, 359:378-90. 
7. Pfizer discontinues phase 3 trial of Sutent in advanced hepatocellular carcinoma [press 
release]. Business Wire Web site. 2010-10-13. Available from: URL: 
http://www.businesswire.com/news/home/20100422006892/en/Pfizer-Discontinues-Phase-
Ⅲ-Trial-Sutent-Advanced. 
8. Park J W, Finn R S, Kim J S et al. Phase II, open-label study of brivanib as first-line 
therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res, 2011, 17(7): 
1973-1983. 
9. Spratlin J. Ramucirumab (IMC-1121B): Monoclonal antibody inhibition of vascular 
endothelial growth factor receptor-2. Curr Oncol Rep, 2011, 13(2): 97-102. 
10. Sun W, Sohal D, Haller D G, et al. Phase II trial of bevacizumab, capecitabine, and 
oxaliplatin in treatment of advanced hepatocellular carcinoma. Cancer, 2011, 
117(14) :3187-3192. 
11. Huynh H, Chow P K, Tai W M, et al. Dovitinib demonstrates antitumor and antimetastatic 
activities in xenograft models of hepatocellular carcinoma. J Hepatol, 2012, 56(3): 
595-601. 
12. Eisenhauer, EA, Therasse P, Boqaerts J, et al., New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 2009, 45(2) : 228-247. 

SAP_001.pdf: 
Title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase III 
Clinical Trial of Apatinib Mesylate Tablets as Second-Line Treatment in Patients with 
Advanced Hepatocellular Carcinoma   
Clinical trial registration number: NCT02329860  
Version Date: 18 Jul. 2019 


Translated from Original Document 
 
 
 
 
A Randomized, Double-Blind, Placebo-Controlled, 
Multicenter Phase III Clinical Trial of 
Apatinib Mesylate Tablets as Second-Line Treatment in 
Patients with Advanced Hepatocellular Carcinoma 
Protocol No.: APTN-III-HCC   
 
 
 
Statistical Analysis Plan 
(V2.0) 
  
 
 
 
Sponsors: Jiangsu Hengrui Pharmaceuticals Co., Ltd. 
 
 
Statistical 
Institution: 
Shanghai Hengrui Pharmaceutical Co., Ltd. 
 
Department of Biostatistics, School of Public Health, 
Nanjing Medical University 
 
 
18 Jul. 2019 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
 
Statistical Analysis Plan 
(V2.0) 
 
 
 
Investigational Drug: 
Apatinib mesylate tablets 
Trial Title: 
A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced 
Hepatocellular Carcinoma 
Clinical Phase: 
Phase III 
Sponsor: 
Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai Hengrui 
Pharmaceutical Co., Ltd. 
Principal Investigator: 
 
 
 
Written by: 
 
 
 
 
 
 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
 
Signature Page of Statistical Analysis Plan 
 
Trial Title: A Phase III Clinical Trial of Apatinib Mesylate Tablets as Second-Line Treatment in 
Patients with Advanced Hepatocellular Carcinoma 
Principal Investigator: 
Signature                 
Date                  
 
Sponsors: Jiangsu Hengrui Pharmaceuticals Co., Ltd.   
Shanghai Hengrui Pharmaceutical Co., Ltd. 
Signature                 
Date                  
 
Statistical Institution: Department of Biostatistics, School of Public Health, Nanjing Medical 
University 
Written by                 
Date                  
Reviewed by                   Date                  
  


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
TABLE OF CONTENTS 
1 
ABBREVIATIONS ································
································
······················
 1 
2 
PROTOCOL SYNOPSIS ································
································
···············
 2 
2.1 Study Objectives ............................................................................................................... 2 
2.2 Study Population ............................................................................................................... 2 
2.3 Study Design ..................................................................................................................... 2 
2.4 Sample Size ....................................................................................................................... 2 
2.5 Randomization Method ..................................................................................................... 3 
2.6 Interim Analysis ................................................................................................................ 3 
3 
EFFICACY EVALUATION ENDPOINTS ································
·························
 3 
3.1 Primary Efficacy Endpoint ............................................................................................... 3 
3.2 Secondary Efficacy Endpoints .......................................................................................... 3 
4 
SAFETY ENDPOINTS ································
································
·················
 4 
4.1 Adverse Events ................................................................................................................. 4 
4.2 Vital Signs and Physical Examination .............................................................................. 5 
4.3 Laboratory Tests ............................................................................................................... 5 
5 
OTHER EVALUATION PARAMETERS ································
···························
 6 
6 
ANALYSIS SETS ································
································
·······················
 6 
6.1 Full Analysis Set (FAS) .................................................................................................... 6 
6.2 Per-Protocol Set (PPS) ...................................................................................................... 6 
6.3 Safe Set (SS) ..................................................................................................................... 6 
7 
STATISTICAL ANALYSIS ································
································
···········
 7 
7.1 General Principles ............................................................................................................. 7 
7.1.1 
Significance level ................................................................................................ 7 
7.1.2 
Hypothesis test .................................................................................................... 7 
7.1.3 
Data principles .................................................................................................... 7 
7.2 Study Population ............................................................................................................... 9 
7.2.1 
Case Distribution ................................................................................................ 9 
7.2.2 
Protocol violations and deviations ...................................................................... 9 
7.2.3 
Analysis of subject characteristics of two groups ............................................. 10 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
7.3 Efficacy Evaluation ......................................................................................................... 10 
7.3.1 
Analysis of primary efficacy endpoint .............................................................. 10 
7.3.2 
Analysis of secondary efficacy endpoints .......................................................... 11 
7.4 Safety Evaluation ............................................................................................................ 12 
7.4.1 
Adverse events .................................................................................................. 12 
7.4.2 
Drug exposure and dose modification .............................................................. 13 
7.4.3 
Vital signs ......................................................................................................... 13 
7.4.4 
Laboratory test parameters ................................................................................ 13 
7.4.5 
ECG................................................................................................................... 13 
7.4.6 
Physical examination ........................................................................................ 13 
7.4.7 
Concomitant medications.................................................................................. 13 
7.5 Interim Analysis .............................................................................................................. 14 
7.6 Other Analyses ................................................................................................................ 14 
7.6.1 
Subgroup analysis ............................................................................................. 14 
7.6.2 
Other Analyses .................................................................................................. 14 
8 
STATISTICAL ANALYSIS SOFTWARE ································
·························
 15 
9 
REFERENCES ································
································
··························
 16 
10 ATTACHED TABLES ································
································
················
 17 
Appendix 1. Classification table of protocol deviations ································
················
 17 
Appendix 2. Adverse events of special interest ································
··························
 19 
Appendix 3. Derivative variables for apatinib/placebo ································
·················
 20 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
1
1 
ABBREVIATIONS 
AE 
Adverse Event 
CI 
Confidence Interval 
CMH 
Cochran–Mantel–Haenszel 
NCI-CTCAE 4.0 
The National Cancer Institute-Common Terminology Criteria for Adverse Events 
V4.0 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
EORTC QLQ-C30 
Quality of Life Questionnaire 
FAS 
Full Analysis Set 
HCC 
Hepatocellular Carcinoma 
HR 
Hazard Ratio 
ITT 
Intention to Treat 
M  
Median 
Max 
Maximum 
Mean 
Mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PPS 
Per-Protocol Set 
Q1 
25th Percentile 
Q3 
75th Percentile 
SAE 
Serious Adverse Event 
Std 
Standard Deviation 
SS 
Safety Set 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal 
 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
2
2 PROTOCOL SYNOPSIS 
2.1  Study Objectives 
To observe and evaluate the efficacy and safety of apatinib mesylate tablets (hereinafter referred 
to as apatinib) as second-line treatment in patients with advanced hepatocellular carcinoma 
(HCC). 
2.2  Study Population 
Patients with relapsed or metastatic HCC refractory or intolerant to systemic chemotherapy 
(oxaliplatin alone or in a therapeutic combination) and/or molecular targeted therapy with 
sorafenib. 
2.3  Study Design 
A randomized, double-blind, placebo-controlled, and multicenter trial design. 
2.4  Sample Size 
In this trial, placebo is used as a control and a superiority test is performed between the two 
groups. 
Assuming the median OS for the placebo group and the apatinib group is 6 months and 8.5 months, 
respectively, according to FAS analysis results for a phase II clinical trial and relevant literature 
reports, assuming the two-sided α = 0.05 and 80% power, with 2:1 randomization (treatment vs 
placebo), the lost to follow-up rate for each group is 15%, and assuming the accrual period is 
12 months, and the duration of study period is 36 months, 331 subjects is required to be enrolled 
(222 subjects in the treatment group, 109 subjects in the placebo group) according to the 
calculation formula of the Log-rank test for the OS comparison between two groups (calculated 
by the PASS software), see Table 1 below. Considering dropout and other factors, this trial plans 
to enroll 360 patients, including 240 for the treatment group and 120 for the placebo group. 
According to the resolution of scientific committee on 31 Oct. 2016, 390 subjects are planned to 
be enrolled (see the Resolution of Scientific Committee on 31 Oct., 2016). 
Table 1. Results of sample size estimation 
Parameter
Type I 
Error 
Median Survival 
Sample Size Ratio 
Treatment:Control 
Results 
Treatment
Group 
Placebo 
Group 
Treatment
Group 
Placebo 
Group 
Total 
Number of 
Subjects 
OS 
0.05 
8.5 
6 
2:1 
222 
109 
331 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
3
2.5 Randomization Method 
The randomization method used in this trial is as follows: Subjects are randomized to two groups 
in a 2:1 ratio to receive apatinib or placebo treatment. 
The subjects are allocated by central randomization and enrolled competitively at all sites. The 
central randomization system provided by the Department of Biostatistics of Nanjing Medical 
University will be used for central randomization. After all eligible subjects are screened by 
study personnel at each study site participating in this trial and confirmed by the investigator of 
each site, their screening information will be entered into the randomization system to generate 
the randomization numbers and drug numbers. Corresponding study drugs will be dispensed 
based on the drug numbers. Subjects must begin the assigned study treatment within 48 h after 
randomization. 
Stratification factors for randomization include: 
 ECOG PS: 0 or 1 
 Treatment with sorafenib: yes or no 
 Presence of vascular invasion and/or extrahepatic metastasis: yes or no 
2.6  Interim Analysis 
None. 
3 EFFICACY EVALUATION ENDPOINTS 
3.1 Primary Efficacy Endpoint 
Overall survival (OS): the time from the date of randomization to death of any cause. 
3.2 Secondary Efficacy Endpoints 
 Progression free survival (PFS): the time from the date of randomization to onset of 
progressive disease (PD) (as per RECIST 1.1) or death, whichever occurs first; 
 3-, 6-, and 12-month PFS rates; 
 Time to progression (TTP): the time from the date of randomization to any documentation of 
radiologic progression (as per RECIST 1.1); 
 Duration of response (DOR): the time from the first recording of tumor response to the first 
recording of objective tumor progression or death of any cause; 
 Objective response rate (ORR): the proportion of subjects with confirmed complete response 
(CR) and partial response (PR) when the objective response is assessed as per RECIST 1.1; 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
4
 The proportion of subjects with stable disease (SD) for ≥ 6 weeks; 
 Disease control rate (DCR): the proportion of subjects with confirmed CR, PR, and SD 
(for ≥ 6 weeks); 
 6- and 12-month survival rates; 
 Quality of life score: EORTC QLQ-C30 and HCC18. 
4 SAFETY ENDPOINTS 
Safety evaluation parameters include vital signs, laboratory measurements, adverse events (AEs), 
serious adverse events (SAEs), treatment-related AEs and SAEs, and AEs specific to this type of 
drugs (e.g., hypertension, proteinuria, and hand-and-foot syndrome); judged per NCI-CTCAE 
V4.0. 
4.1 Adverse Events 
AEs, treatment-related adverse events (TRAEs), and SAEs that have occurred during the study 
period. 
An AE refers to any untoward medical occurrence in a clinical investigation subject and which 
does not necessarily have a causal relationship with the treatment. AEs include but are not 
limited to: laboratory abnormalities; clinically significant symptoms and signs; allergies; 
According to the needs of management, safety monitoring (reporting of AEs or SAEs) should be 
performed from the signing of the informed consent form by the subject to 28 days after the last dose. 
Treatment-related AEs (TRAEs): All toxicities and unintentional reactions to a drug associated 
with any dose should be considered as Treatment-related AEs (TRAEs). Treatment-related AE 
means that a potential causal relationship between the drug and AE is at least reasonable, which 
means that the relationship cannot be excluded. The potential relationship between an AE and 
the investigational drug is assessed with 5 grades of causality: definitely related, probably 
related, possibly related, unlikely related, and not related. Events that are assessed to be 
"definitely related", "probably related", and "possibly related" are considered related to the 
investigational drug. When calculating the incidence of Treatment-related AEs, the total number 
of these three categories is used as the numerator and the total number of subjects in safety set is 
used as the denominator. 
A SAE refers to a medical occurrence during the clinical trial that results in hospitalization, 
prolonged hospitalization, disability, incapacity, life threatening events or death, or congenital 
malformation. The following unexpected medical events are included: 
 Events resulting in death; 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
5
 Life-threatening events (defined as events where the subject is at immediate risk of death at 
the time of the onset); 
 Events resulting in hospitalization or prolonged hospitalization; 
 Events resulting in permanent or serious disability/incapacity; 
 Congenital anomalies or birth defects; 
 Overdose; 
 Pregnancy during the clinical trial. 
Criteria for other SAEs specified in the protocol: 
 Cardiac insufficiency — defined as any symptom or sign of reduced LVEF (NCI CTCAE 
Grade 3), or LVEF reduced by ≥ 20% from baseline and below the lower limit of normal 
(or reduced to < 50%). 
 ALT > 5  ULN and total bilirubin > 2  ULN (such as direct bilirubin > 35%; the bilirubin 
ratio should be measured). 
4.2  Vital Signs and Physical Examination 
 Vital signs: body temperature, heart rate, respiratory rate, and blood pressure; 
 Physical examination: including general conditions, head and face, skin, lymphatic system, 
eyes (sclera, pupil), respiratory system, cardiovascular system, abdomen (including liver and 
spleen), reproductive-urinary system, neuromuscular system, nervous system, mental status, 
and other conditions. 
4.3  Laboratory Tests 
 Hematology: including hemoglobin (HB), red blood cell count (RBC), white blood cell 
count (WBC), absolute neutrophil count (ANC), neutrophil ratio (N), lymphocyte ratio 
(Lym), monocyte ratio (Mon), and platelet count (PLT); 
 Urinalysis: including urine protein (PRO), urine red blood cells (RBC), and urine white 
blood cells (WBC); 
 Stool routine: occult blood; 
 Liver and kidney functions: including total bilirubin (Tbil), direct bilirubin (dBiL), indirect 
bilirubin (iBiL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), Gamma-glutamyltransferase (GGT), lactate dehydrogenase (LDH), total 
protein (TP), albumin (ALB), creatinine (Cr), urea nitrogen (BUN), and uric acid (UA); 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
6
 Electrolytes: potassium ion (K
＋), sodium ion (Na
＋), chloride ion (Cl-), calcium ion (Ga2＋), 
and blood phosphorus (P);Coagulation function: prothrombin time (PT), activated partial 
thromboplastin time (APTT), thrombin time (TT), plasma fibrinogen (Fbg), and international 
normalized ratio (INR); 
 
12-Lead ECG: QTc value, heart rate, QTcF, and ECG description. 
5 OTHER EVALUATION PARAMETERS 
 
Laboratory parameters of tumor markers: alpha-fetoprotein (AFP). 
6 
ANALYSIS SETS 
There are three analysis sets in this study: full analysis set (FAS), per-protocol set (PPS), and 
safety set (SS). 
6.1 Full Analysis Set (FAS) 
According to the intention-to-treat (ITT) principle, the FAS includes all the randomized subjects 
who have received at least one dose of the study drug. 
According to the ITT principle, all the subjects will be included in the analysis according to their 
randomized groups. The FAS is the primary analysis set for the efficacy analysis of this study. 
6.2 Per-Protocol Set (PPS) 
The PPS is a subset of the FAS and is defined as all subjects who are in compliance with the 
protocol, have good compliance, have received at least 1 cycle of the study drug (except for 
those with clear medical evidence of PD), and have completed the eCRF. 
The statistical analysis will be performed for the drug efficacy based on the FAS and PPS. 
Before database locking, the principal investigator, statistician, and sponsor determine the final 
PPS during the data review meeting. 
6.3 Safe Set (SS) 
The SS is defined as all randomized subjects who have received at least one dose of the 
investigational drug and have safety records after drug administration. 
For the safety analysis, all subjects should be analyzed based on the group of actually received 
study drug. 
In this trial, baseline data are analyzed based on the FAS; primary efficacy endpoints are 
analyzed based on FAS (primary) and PPS; data of laboratory tests and AEs/Treatment-related 
AEs are analyzed based on the SS. In addition, ORR, DCR, and the percentage of subjects with 
SD will also be analyzed among subjects with evaluable efficacy. 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
7
Subjects with evaluable efficacy are defined as all subjects who have received at least 2 cycles 
(8 weeks) of apatinib treatment and received a tumor evaluation after 2 treatment cycles 
(8 weeks). If the efficacy reaches CR or PR, it should be confirmed 4 weeks later. 
7 STATISTICAL ANALYSIS 
7.1 General Principles 
For continuous variables, the number of non-missing subjects, mean, standard deviation, median, 
minimum, and maximum should be listed. The decimal places of minimum and maximum are 
consistent with those of the records in the database. Mean and median retain one more decimal 
place than that of the source data recorded in the database; standard deviation retains two more 
decimal places than that of the source data recorded in the database. Unless otherwise stated, the 
"baseline" in this study is defined as the last non-missing measurement value obtained prior to 
the first use of the study drugs, including the measurements taken on the day of the first dose and 
prior to the administration of the first dose. 
For categorical variables, a frequency table (frequency and percentage) will be used. Percentages 
retain one decimal place. 
7.1.1 Significance level 
For group comparisons, all hypothesis tests are performed using two-sided tests with an α = 0.05. 
If P is ≤ 0.05, the difference of the test is considered to be statistically significant. A 95% 
confidence interval is used in this study. 
7.1.2 Hypothesis test 
The primary efficacy endpoint for this trial is OS. 
The log-rank test is used for the comparison between the investigational drug group and control 
group: 
Hypothesis: 
H0: The survival function of the apatinib group is the same as that of the placebo group; 
H1: The survival function of the apatinib group is different from that of the placebo group. 
α level: 0.05 (two-sided). 
7.1.3 Data principles 
Missing dates: If a previous date is incomplete, which affects the calculation of subsequent dates, 
the previous date is estimated as follows: 
If the date of first dose is missing, a randomization date will be replaced. 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
8
Apart from exceptional circumstances, the following filling rules apply to the missing dates of 
safety data events. 
If the date of an event is completely missing, the date is not imputed. If the day is missing but the 
year and month of the event onset are the same as those of study treatment, then the missing day 
is imputed with the day of first date of study treatment, otherwise it is imputed with the first day 
of that month; if the day of the end date is missing, then it is imputed with the last day of that 
month. 
If both month and day of an event onset date are missing but its year is the same as that of study 
treatment, then they are imputed with the month and day of starting study treatment, otherwise, 
they are imputed with 1 Jan. 
If the date of death is completely missing, the last known survival date + 1 day of the subject is 
used as the date of death. 
All imputed dates must be before the date of withdrawal of informed consent form, lost to 
follow-up, and death. 
Missing data of laboratory tests, ECG, and vital signs are not imputed.  
The laboratory test results are generally continuous numeric variables or character variables. If 
the continuous numeric variables contain special characters (such as < xx and > xx) in the eCRF, 
they are processed using the following rules: 
(1) If a measured value is < xx or ≤ xx, half of the xx value will be used for analysis; 
(2) If a measured value is > xx or ≥ xx, the value of xx will be used for analysis. 
Dates in the date listings are listed as per CRF. 
Descriptive statistics for summary include number of cases, number of missing cases, mean, 
standard deviation, median, minimum, and maximum. 
The change from the baseline is defined as measured value in post-treatment follow-up - 
measured value at baseline. 
The time (days) related to the efficacy endpoint: (post-treatment date - date of randomization) + 
1. The selection of the post-treatment date follows the definition of efficacy endpoint. 
The formula of OS calculation: 
Death case: (date of death - date of randomization) + 1; 
Surviving case: (date of the last survival - date of randomization) +1, as censored data. 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
9
The formula of PFS calculation: 
The start and end dates of PFS for events with outcomes: 
1: Date of radiographic PD (earliest date of progression of target lesions, non-target lesions, or 
new lesions) - date of randomization +1; 
2: Date of death - date of randomization + 1. 
If the above 1 and 2 are both met in the one case, the earliest time is taken. 
The start and end dates of PFS for events without outcomes:  
1: With imaging examination: date of the last adequate imaging examination - date of 
randomization + 1, as censored data; 
2: Without imaging examination: 1 day (i.e., the date of censorship is the date of randomization), 
as censored data. 
With a new anti-tumor treatment: date of the last imaging examination prior to or onset on 
starting the new anti-tumor treatment - date of randomization + 1, as censored data. 
The start and end dates of PFS for those with an endpoint event but missing 2 or more (at least 
18 weeks) imaging examinations: 
1: Date of the last imaging examination before event observed - date of randomization +1, as 
censored data. 
For the definition of new anti-tumor treatment, refer to Section 7.6.2. 
7.2 Study Population 
7.2.1 Subject Distribution 
Description of the subject enrollment, dropout cases, completion of scheduled treatment, and 
premature discontinuation: number of subjects and percentage; 
Distribution of subjects in each data set; 
Distribution of subjects with evaluable efficacy; 
Listing of dropout and premature discontinuation by subject: status of drug administration, 
reasons for trial termination, etc. 
7.2.2 Protocol violations and deviations 
Summarize and describe the protocol violations and deviations. See Appendix 1 for the 
classification of protocol violations. 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
10 
7.2.3 Analysis of subject characteristics of two groups 
Age: Describe using mean, standard deviation, maximum, minimum, and median. 
Gender: Calculate the percentage. 
Height and weight: Describe using mean, standard deviation, maximum, minimum, and median. 
Tumor history: The course of disease is described using mean, standard deviation, maximum, 
minimum, and median. The percentages for pathological grade, clinical stage, presence of 
extrahepatic metastasis, presence of vascular invasion, alpha-fetoprotein (AFP < 400 μg/L, ≥ 
400 μg/L; AFP < 200 μg/L, ≥ 200 μg/L), and cause of liver cancer (HBV infection: positive for 
either HbsAg or HbeAg; HCV infection: positive) are calculated. 
Target lesion and non-target lesion at baseline: The sum of diameters of target lesion is described 
using mean, standard deviation, maximum, minimum, and median. The percentages for target 
lesion, location of target lesion, non-target lesion, and location of non-target lesion are calculated. 
The percentages for history of primary lesion surgery, local ablation therapy, interventional 
procedure, radiotherapy, systemic treatment, past medical history, and drug allergy are 
calculated. Among them, the history of primary lesion surgery and past medical history are 
coded by the system organ class (SOC) and preferred term (PT) of the ICH Medical Dictionary 
for Regulatory Activities (MedDRA 21.0, Chinese version). The percentages for number of local 
ablation therapies and number of past interventional procedures are calculated. 
The percentages for baseline ECOG PS, Child-Pugh classification of liver function, Barcelona 
clinic liver cancer (BCLC) staging, and hepatitis B and hepatitis C markers (including HbsAg, 
HbsAb, HbeAg, HbeAb, HbcAb, and HCV) are calculated. 
Baseline vital signs (body temperature, heart rate, respiratory rate, and blood pressure): describe 
using mean, standard deviation, maximum, minimum, and median. The baseline is defined as the 
closest recent non-missing measured value to date of drug administration taken. 
Baseline physical examination of various systems: The percentages of normal, abnormal, and 
unchecked results are calculated. 
Baseline quality of life (QLQ-C30) scores and EORTC QLQ-HCC18 scores in various 
dimensions: describe using mean, standard deviation, maximum, minimum, and median. 
7.3 Efficacy Evaluation 
7.3.1 Analysis of primary efficacy endpoint 
The primary efficacy endpoint for this study is OS. The OS analysis is performed based on FAS 
and PPS when at least 312 deaths are collected in this study (≥ 80% of patients died), of which 
FAS is the primary analysis set. 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
11
The survival functions of the apatinib group and placebo group are estimated by the 
Kaplan-Meier method, and the survival curve is plotted. The survival functions of the two groups 
are compared using the log-rank test with and without considering the stratification factors for 
randomization. In this study, the stratified log-rank test considering the stratification factors in 
randomization system is the primary test. In addition, under the assumption of proportional 
hazards, the Cox proportional hazards models with and without stratification factors are used to 
estimate the hazard ratio (HR) and calculate the corresponding 95% CI. In addition, the Cox 
proportional hazard model including other baseline factors may also be considered to estimate 
the HR between the two groups and calculate its 95% CI. 
For the sensitivity analysis of OS, see Section 7.6.2. 
7.3.2 Analysis of secondary efficacy endpoints 
 Secondary efficacy endpoints of PFS and TTP are summarized using descriptive statistics 
based on FAS and PPS according to the above general principles and analyzed using similar 
methods as those for primary efficacy endpoint. 
 Based on FAS and PPS, the 3-, 6-, and 12-month PFS rates, the Kaplan-Meier method was 
used to estimate rates and corresponding 95% CIs of the two groups are calculated using the 
log-log transformation according to the normal approximation with back transformation to 
CIs on the untransformed scale. 
 The secondary efficacy endpoint DOR, including the investigator assessed results as per 
RECIST v1.1, is analyzed based on FAS and PPS. DoR will only be assessed in subjects 
whose BoR is PR or CR. The end date of tumor response must be consistent with the PD 
date of PFS or the date of death, and the Kaplan-Meier product-limit method will be used to 
calculate the median survival time of each treatment group and estimate the corresponding 
95% CIs. The analysis is carried out using methods similar to those for the primary efficacy 
endpoint. 
 Based on FAS, PPS, and evaluable patients, the ORR and DCR in the two groups are 
calculated and their 95% CIs are calculated using the Clopper-Pearson method. The 
difference of rates between groups are calculated and its 95% CIs are calculated using the 
Wald (normal approximation) method. The P values are calculated by the stratified 
Cochran–Mantel–Haenszel (CMH) (primary analysis) and the unstratified Pearson 
chi-square tests. Confirmed and unconfirmed CR/PR are analyzed, respectively. 
 Based on FAS, PPS, and evaluable patients, the percentage of patients with SD for ≥ 6 weeks 
are calculated, and their 95% CIs are calculated using the Clopper-Pearson method. The 
difference between groups and its 95% CI are calculated using the Wald (normal 
approximation) method. The P values are calculated by the stratified CMH and the 
unstratified Pearson chi-square tests. 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
12 
 Based on FAS and PPS, the 6- and 12-month OS rates, the Kaplan-Meier method is used to 
estimate rates and corresponding 95% CIs of the two groups are calculated using the log-log 
transformation according to the normal approximation with back transformation to CIs on 
the untransformed scale. 
 Based on the FAS, the changes of the total quality of life scores from baseline between the 
two groups for each time point are compared by analysis of variance model (ANOVA). The 
changes from baseline in global health status, total quality of life score, and score of EORTC 
QLQ-HCC18 at each scale for each time point are compared by Wilcoxon rank-sum test 
between groups. 
7.4 Safety Evaluation 
7.4.1 Adverse events 
AEs are encoded according to the current MedDRA 21.0 and then processed in statistical 
analysis. 
The incidences of AEs, treatment-related adverse events (TRAEs), AEs leading to drug 
interruption, dose reduction, and drug discontinuation, and SAEs are summarized. If multiple 
AEs occurred in the same subject, the number of subject is counted as one when calculating the 
incidence; if a subject experiences multiple times of a same AE, the number of subject is counted 
as one when calculating the incidence of the AE. 
AEs are summarized in the frequency table based on SOC and PT. The incidence is calculated 
based on SOC and symptom/sign (the number of cases is counted as number of subjects who 
have experienced at least one AE). 
Severity of AEs and treatment-related adverse events: If a subject experiences multiple times of 
the same AE, the most severe one will be used in the analysis of the severity of the AE. 
A list of cases of AEs and SAEs is provided. 
The median time to the onset of the first event is calculated for the adverse events of special 
interest (AESIs). AESIs include hypertension, proteinuria, hand-and-foot syndrome, hemorrhage, 
electrocardiogram QT prolonged, and white blood cell count decreased. The specific 
classification definitions are shown in Appendix 2. 
Time to the onset of first event (days) = onset date of first event − date of the first dose + 1 
In addition, for the comparisons of the incidences of AEs between the treatment group and the 
control group, the Fisher's exact method may be used to calculate the P value, which is only used 
for clinical reference, rather than the deduction of statistical significance. 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
13 
7.4.2 Drug exposure and dose modification 
The drug exposure in the two groups is described using mean, standard deviation, maximum, 
minimum, and median. 
The treatment interruption and dose modification during the trial are summarized. 
The duration of drug exposure, actual dose intensity, and relative dose intensity of apatinib and 
placebo are summarized using mean, standard deviation, median, maximum, and minimum. 
The specific definition rules of derived variables for the study drugs apatinib and placebo are 
shown in Appendix 3. 
7.4.3 Vital signs 
Measured values and their changes before and after treatment are described using mean ± 
standard deviation, maximum, minimum, and median. 
7.4.4 Laboratory test parameters 
Hematology, blood biochemistry, and AFP: Measured values and their changes before and after 
treatment are described using mean ± standard deviation, maximum, minimum, and median. 
Normal and abnormal changes after treatment are described in a shift table. 
Urinalysis: Normal and abnormal changes after treatment are described using a shift table. 
Stool routine: Normal and abnormal changes after treatment are described using a shift table. 
The proportion of subjects with "abnormalities with clinical significance" will be presented, 
where the clinical significance of the abnormality is judged by the investigator. 
7.4.5 ECG 
ECG: The normal and abnormal changes before and after the treatment based on the normality 
and abnormality judged by the investigator are described. 
7.4.6 Physical examination 
The normality and abnormality before and after the treatment are described. 
7.4.7 Concomitant medications 
The usage and frequency of use of each drug for concomitant medications during the study 
period (including WBC-elevating drugs and platelet-elevating drugs used within 14 days before 
screening, any changes in the concomitant medications during the screening period, new 
concomitant medications after screening, medications for AEs, and concomitant medications 
during the follow-up period) are summarized. 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
14 
7.5 Interim Analysis 
None 
7.6 Other Analyses 
7.6.1 Subgroup analysis 
Subgroup analyses are performed for the primary efficacy endpoint according to the following 
factors, and the forest plot on HR is produced: 
Age (≤ 65 years old, > 65 years old) 
ECOG PS (0, 1) 
Presence of vascular invasion (yes, no) 
Presence of extrahepatic metastasis (yes, no) 
Presence of vascular invasion and/or extrahepatic metastasis (yes, no) 
Treatment with sorafenib (yes, no) 
Previous systemic treatment line(s) (one line, ≥ two lines) 
HBV (positive, negative) 
Alpha-fetoprotein (AFP < 400g/L, ≥ 400g/L) 
Alpha-fetoprotein (AFP < 200 g/L, ≥ 200 g/L) 
Child-Pugh score (Grade A, Grade B) 
BCLC stage (B, C) 
Previous liver transplant (yes, no) 
7.6.2 Other Analyses 
To assess the balance of new anti-tumor treatments between groups during the study, new 
anti-tumor treatments (including systemic treatment and local treatment) are summarized. In 
addition, the new anti-tumor treatments are classified, and the subgroup analyses of OS are 
performed. New anti-tumor treatments are classified into chemotherapy, targeted therapy, 
immunotherapy, and local treatments (TACE, surgery, ablation therapy, and radiotherapy). New 
anti-tumor treatments do not include traditional Chinese medicine and immunomodulators. 
Before database locking, classification of new anti-tumor treatments is finally determined and 
archived. 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
15 
Other sensitivity analyses of OS include: 
1) The OS of two groups will be compared by the Wilcoxon test and Max-Combo[1] method. 
2) The survival time of subjects are censored at the start of new anti-tumor treatments. 
3) In the OS analysis, some subjects who have received some other types of anti-tumor 
treatments (which may have a major impact on survival) during the study are excluded, such 
as subjects with subsequent PD1/PD-L1 treatments will be excluded. 
4) Rank-preserving structural failure time model (RPSFTM) proposed by Robins and Tsiatis[2] : 
The OS of subjects who have received apatinib (or other targeted therapies) during the study 
anti-tumor treatment is adjusted using the RPSFTM method. This analysis will be based on 
the population defined by FAS and the sensitivity analysis method 2), respectively. 
5) IPCW method proposed by Robins and Finkelstein[3]: Using the IPCW method to analyze the 
HR between the treatment group and control group, with reference to relevant medical 
literature, the baseline variables and time-related variables are planned to be considered in the 
IPCW model including ECOG PS, age, gender, presence of extrahepatic metastasis, number 
of line(s) of past treatment, BCLC grade, etc. If necessary, the duration of study drug 
exposure, and liver function parameters (such as ALT, AST, and bilirubin) may also be 
included. The bootstrap method is used to sample from the treatment group and control group, 
and the 95% CI of the HR is estimated. 
6) The two-stage method proposed by Latimer et al.[4]: Use the two-stage method to adjust the 
OS of the subjects receiving the new anti-tumor treatment in the treatment group and control 
group, respectively. If necessary, relevant variables are included in the two-stage model (see 
the variables to be included in the IPCW method). 
In addition, the stratification factors for randomization in the OS analysis in Section 7.3 will be 
based on the stratification information in the subject randomization system unless otherwise 
specified. If the stratification factor information in the randomization system and EDC clinical 
database are inconsistent (the stratification information in the randomization system is incorrect) 
for some subjects, their stratification information in the EDC clinical database will be used for 
the sensitivity analysis. 
8 
STATISTICAL ANALYSIS SOFTWARE 
Jiangsu Hengrui Pharmaceuticals Co., Ltd. is responsible for the data management, and the 
Department of Biostatistics, School of Public Health, Nanjing Medical University undertakes the 
statistical analysis of this study. All statistical analyses will be performed using SAS 9.4. 
 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
16 
9 REFERENCES 
[1]. Public Workshop: Oncology Clinical Trials in the presence of non-proportional hazards. 
2018. 
https://healthpolicy.duke.edu/sites/default/files/atoms/files/oncology_trials_workshop_meeti
ng_summary_0.pdf. 
[2]. Robins, J. and Tsiatis, A. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Communications in Statistics – Theory and 
Methods 1991; 20(8):2609-2631. 
[3]. Robins, J. and Finkelstein, D. Correcting for noncompliance and dependent censoring in an 
AIDS clinical trial with Inverse Probability of Censoring Weighted (IPCW) Log-Rank Tests. 
Biometrics 2000; 56: 779-788. 
[4]. Latimer, N., Abrams, K., Lambert, P., Crowther, M., et al. Adjusting for treatment switching 
in randomised controlled trials – A simulation study and a simplified two-stage method. 
Statistical Methods in Medical Research 2017; 26(2): 724-751. 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
17 
10 ATTACHED TABLES 
Appendix 1. Classification table of protocol deviations 
Class 
Sub-Class 
Description of Protocol Deviation 
Grade 
1-Inclusion/Excl
usion Criteria 
Eligibility 
Not meet a certain inclusion criterion, and/or not meet 
a certain exclusion criterion 
Critical 
1-Inclusion/Excl
usion Criteria 
Eligibility 
Misunderstanding of the inclusion/exclusion criteria causes 
the subject enrollment not meeting the protocol 
requirements 
Critical 
2-Informed 
Consent 
Informed consent 
criteria 
The subject has been randomized or started treatment with 
the study drug before signing the informed consent form 
Critical 
2-Informed 
Consent 
Informed consent 
criteria 
The subject signs the informed consent form after starting 
any study-related procedures 
Critical 
2-Informed 
Consent 
Informed consent 
criteria 
The subject signs an incorrect version of the informed 
consent form (the latest version is not signed) 
Critical 
2-Informed 
Consent 
Informed consent 
criteria 
The contact information of the ethics committee or study 
site is not shown or recorded in the informed consent form 
Major 
2-Informed 
Consent 
Informed consent 
criteria 
The informed consent form is not dated (including by the 
subject and/or the investigator) 
Major 
2-Informed 
Consent 
Informed consent 
criteria 
The informed consent process is not recorded or the record 
is incomplete 
Major 
2-Informed 
Consent 
Informed consent 
criteria 
The informed consent procedure is not followed 
Critical 
2-Informed 
Consent 
Informed consent 
criteria 
The investigator who signs the informed consent form is 
not in the authorization form or is not authorized 
Major 
3-Visit Schedule 
Criteria for visit 
schedule 
Items scheduled for the visits of the treatment period are 
not carried out: physical examination, vital sign 
measurement, quality of life scoring, and ECOG scoring 
Minor 
3-Visit Schedule 
Criteria for visit 
schedule 
Items scheduled for the visits of the treatment period are 
not carried out: except for physical examination and/or 
vital sign measurement, quality of life scoring, and ECOG 
scoring 
Major 
3-Visit Schedule 
Criteria for visit 
schedule 
The first imaging examination after treatment and assessed 
as PD is carried out beyond the time window 
Major 
3-Visit Schedule 
Criteria for visit 
schedule 
The image examinations other than the ones described 
above are carried out beyond the time window, or the 
number of image examinations is more than required 
Minor 
3-Visit Schedule 
Criteria for visit 
schedule 
The imaging examination is not done, or the examination 
method or technique is inconsistent with that at baseline 
Critical 
3-Visit Schedule 
Criteria for visit 
schedule 
The end-of-treatment visit/safety visit is carried out beyond 
the time window 
Minor 
3-Visit Schedule 
Criteria for visit 
schedule 
The end-of-treatment visit/safety visit is not done, or there 
are missing examination items 
Major 
3-Visit Schedule 
Criteria for visit 
schedule 
The survival follow-up is carried out beyond the time 
window/is missing 
Minor 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
18 
Class 
Sub-Class 
Description of Protocol Deviation 
Grade 
3-Visit Schedule 
Criteria for visit 
schedule 
Other than those mentioned above, the subject has not 
conducted the visit as required by the protocol or has not 
completed the examination and other procedures required 
for the visit 
Depends on 
the situation 
(minor or 
major) 
4-Subject Diary 
Criteria for study 
procedures 
Less than 80% of the diary card is completed 
Minor 
4-Subject Diary 
Criteria for study 
procedures 
The subject has not brought the diary card to the study site 
Major 
5-Concomitant 
Medications 
Criteria for 
concomitant 
medications 
The subject has used a drug prohibited by the trial protocol 
Depends on 
the situation 
(major or 
critical) 
6-Subject 
Discontinuation 
Criteria for study 
procedures 
The subject meets the criteria for study withdrawal or 
discontinuation, but the subject has not discontinued the 
study 
Critical 
6-Subject 
Discontinuation 
Criteria for study 
procedures 
Discontinues the study drug but does not follow the 
protocol requirements 
Major 
7-Study Drugs 
Criteria for study 
procedures 
No drug is administered within 48 h after randomization 
Minor 
7-Study Drugs 
Criteria for study 
procedures 
Cases that the storage conditions of apatinib exceed the 
requirements for a short period of time that does not affect 
the quality of the drug according to the requirements on the 
instructions for the storage and use of apatinib 
Major 
7-Study Drugs 
Criteria for study 
procedures 
Cases that the sponsor shall be contacted immediately 
according to the requirements on the instructions for the 
storage and use of apatinib 
Critical 
7-Study Drugs 
Compliance to 
study drugs 
Missed dose or overdose of the study drug 
Depends on 
the situation 
(major or 
critical) 
7-Study Drugs 
Compliance to 
study drugs 
The total duration of drug interruption during each 
treatment cycle exceeds 2 weeks 
Critical 
7-Study Drugs 
Compliance to 
study drugs 
The subject is given a drug to be used by other group 
Critical 
7-Study Drugs 
Criteria for study 
procedures 
The study site or the subject has discarded the bottle of 
used drug Discrepancies in the inventory of the study drugs 
Minor 
7-Study Drugs 
Other criteria 
No continuous temperature records 
Major 
7-Study Drugs 
Compliance to 
study drugs 
In addition to the above, other non-compliance with the use 
of the study drugs 
Depends on 
the situation 
(minor or 
major) 
8-Safety 
Monitoring 
SAE 
The report of SAEs has not met the time limit required by 
GCP or related regulations 
Critical 
8-Safety 
Monitoring 
Review of safety 
reports 
The investigator has not reviewed and signed the safety 
reports of subjects in time 
Major 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
19 
Class 
Sub-Class 
Description of Protocol Deviation 
Grade 
8-Safety 
Monitoring 
AESIs 
Incorrect and inappropriate reporting time of AEs 
Critical 
9-Study 
Procedures 
Management 
criteria 
The responsibility authorization form has not been updated 
before the start of the study procedures 
Minor 
9-Study 
Procedures 
Criteria for study 
procedures 
The study operation of the investigator has exceeded the 
scope of authorization 
Major 
9-Study 
Procedures 
Management 
criteria 
Non-compliance with other study-related procedures in 
addition to the above-mentioned clinical trial protocol and 
drug manual. 
Depends on 
the situation 
9-Study 
Procedures 
Criteria of ethical 
approval 
Use study-related documents that are not ethically 
approved 
Critical 
9-Study 
Procedures 
Monitoring of 
entire study by 
principal 
investigator  
The motoring is insufficient, especially in terms of the lack 
of evidence for the monitoring by the principal investigator 
regarding the safety of subjects 
Major 
9-Study 
Procedures 
Criteria for source 
documents 
The study site has changed the placement location of the 
source records of subjects without notifying the clinical 
research associate (CRA) or providing the CRA with 
access rights; or the source records are stored at the study 
site without giving the CRA sufficient rights to access the 
source records (including HIS/LIS) (per ICH GCP R2 
4.1.4, the investigator/study site shall allow the sponsor's 
monitoring agency to conduct monitoring and verification.) 
Major 
9-Study 
Procedures 
Randomization 
procedures 
Error in information of randomized stratification 
Major 
 
Appendix 2. Adverse events of special interest 
Adverse Event of Special Interest 
Preferred Terms of AE 
Hypertension 
Blood pressure increased 
Hypertension 
Hypertension 
Proteinuria 
Protein urine present 
Proteinuria 
Urine protein 
Proteinuria 
Proteinuria 
Hand-and-Foot Syndrome 
Palmar-plantar erythrodysesthesia syndrome 
Hemorrhage 
Upper gastrointestinal hemorrhage 
Hemorrhage 
Gastrointestinal hemorrhage 
Hemorrhage 
Gingival bleeding 
Hemorrhage 
Anal hemorrhage 
Hemorrhage 
Hematochezia 
Hemorrhage 
Melena 
Hemorrhage 
Mouth hemorrhage 


Protocol No. 
APTN-HCC-III 
Statistical Analysis Plan for A Phase III Clinical Trial of Apatinib Mesylate Tablets as 
Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma V2.0 
 
Department of Biostatistics, School of Public Health, Nanjing Medical University 
20 
Adverse Event of Special Interest 
Preferred Terms of AE 
Hemorrhage 
Mucosal hemorrhage 
Hemorrhage 
Subcutaneous hemorrhage 
Hemorrhage 
Purpura 
Hemorrhage 
Cerebral hemorrhage 
Hemorrhage 
Brain stem hemorrhage 
Hemorrhage 
Pharyngeal hemorrhage 
Hemorrhage 
Bronchial hemorrhage 
Hemorrhage 
Hemoptysis 
Hemorrhage 
Epistaxis 
Hemorrhage 
Hepatic hemorrhage 
Hemorrhage 
Scleral hemorrhage 
Hemorrhage 
Vaginal hemorrhage 
Electrocardiogram QT prolonged 
QT interval prolonged 
White blood cell count decreased 
White blood cell count decreased 
White blood cell count decreased 
Leukopenia 
 
Appendix 3. Derivative variables for apatinib/placebo 
Variable 
Apatinib/Placebo 
Protocol-Specified Method of 
Administration 
Once a day, 750 mg each time, every 4 weeks in a treatment cycle 
Duration of Drug Exposure (days) 
Date of last administration - date of first administration + 1 
Planned Duration of Treatment 
(days) 
Date of last administration - date of first administration + 1 
Actual Cumulative Doses of All 
Cycles (mg) 
Summarize the actual dose (mg) in all treatment cycles: [duration of drug 
exposure (day) - (end date of dose modification - start date of dose 
modification) (day)] × 750 (mg) + (end date of dose modif ication - start date 
of dose modification) (day) × dose after modification (mg) - (end date of dose 
interruption - start date of drug interruption) (day) × interrupted dose (mg)  
Planned Dose Intensity (mg/day) 
750 (mg/day) 
Actual Dose Intensity (mg/day) 
Actual cumulative dose in all treatment cycles (mg) / [planned duration of 
treatment (day)] 
Relative Dose Intensity (%) 
100 × [actual dose intensity (mg/day)] / [planned dose intensity (mg/day)]