Evaluate the Safety and Efficacy of Toripalimab Combined With Bevacizumab Versus Sorafenib Therapy for HCC

Advanced Hepatocellular Carcinoma (HCC) Clinical Trial

Official title:

A Randomized, Open-label, Multi-center Phase III Clinical Study to Evaluate the Safety and Efficacy of Toripalimab (JS001) Combined With Bevacizumab Versus Sorafenib as First-line Therapy for Advanced Hepatocellular Carcinoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04723004
• Other study ID #: JS001-035-III-HCC
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 15, 2020
• Est. completion date: December 31, 2024

Study information

• Verified date: August 2023
• Source: Shanghai Junshi Bioscience Co., Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a prospective, randomized, open-label, parallel-group, active controlled, multi-center phase III registration clinical study to observe, compare and evaluate the efficacy and safety of Toripalimab (hereafter referred to as JS001) combined with Bevacizumab versus Sorafenib as the first-line therapy for advanced HCC This study will enroll the patients with locally advanced or metastatic hepatocellular carcinoma who could not be radically cured and not receive any prior systemic therapy. The study will use PFS and OS as the co-primary endpoints, with approximately 280 patients planned to be enrolled.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 326
• Est. completion date: December 31, 2024
• Est. primary completion date: October 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Age of 18-75 years (inclusive), male or female.

2. Histological or cytological diagnosis of HCC or clinical diagnosis of HCC in cirrhotic patients per the American Association for the Study of Liver Diseases (AASLD) guideline.

3. Unresectable BCLC B/C

4. No previous systemic therapy for HCC, patients with prior adjuvant therapy alone who relapsed at 6 months or above after the last adjuvant therapy may be enrolled.

5. = 1 measurable lesion per RECISTv1.1.

6. Child-Pugh class A, with no history of hepatic encephalopathy.

7. ECOG PS 0 or 1.

8. Predicted life expectancy =12 weeks.

9. adequate main organ functions

10. In case of HBsAg (+) and/or HBcAb (+), HBV DNA is required to be < 2000 IU/mL. Patients with anti-HCV antibody positive and HCV- RNA>1000 copies/mL will be excluded; HBV/HCV co-infected patients will be excluded. patients with a prior history of HCV infection who tested negative for HCV-RNA can be considered HCV uninfected.

11. Female subjects of childbearing potential must receive serum pregnancy test within 7 days before randomization and the result should be negative, and should be willing to adopt reliable and effective contraceptive methods during the trial and within 60 days after the last dose of study drug. The male patients whose partners are women of childbearing potential must agree to use reliable and effective contraceptive methods during the trial and within 60 days after the last dose of study drug.

12. Being voluntary to participate in the study, sufficiently informed consent and signature of written informed consent form, with good compliance.

Exclusion Criteria:

1. Known ICC or mixed cell carcinoma, sarcomatoid HCC and hepatic fibrolamellar carcinoma.

2. History of malignancy other than HCC within 5 years prior to screening.

3. Hepatic surgery and/or local therapy or investigational treatment with for HCC within 4 weeks prior to randomization, or palliative radiotherapy for bone metastatic lesion within 2 weeks prior to randomization, or Chinese medicine preparation with anti-liver cancer effect within 2 weeks prior to randomization, and non-recovery (not recovered to = NCI-CTCAE v5.0 grade 1) from side effects of any such treatment (except alopecia).

4. Prior other anti-PD-1 antibody therapy or other immunotherapy against PD- 1 / PD-L1.

5. Uncontrolled pericardial effusion, uncontrolled pleural effusion or clinically obvious moderate/severe pleural effusion at screening.

6. History of gastrointestinal hemorrhage within 6 months prior to randomization; the patients with portal hypertension need to receive gastroscopy to exclude the patients with "red sign", if they are considered by investigators to have high risk for hemorrhage (including moderate-to-severe esophageal and/or gastric varices with hemorrhagic risk, locally active peptic ulcer and persistent fecal occult blood (+)). The patient needs to be excluded if there is a history of "red sign" in gastroscopy.

7. Having = grade 3 (NCI-CTC AE v5.0) gastrointestinal or non- gastrointestinal fistula at present.

8. Cancer thrombus in the main trunk of portal vein involving contralateral portal vein branch, or involving superior mesenteric vein. Cancer thrombus in inferior vena cava should be excluded.

9. Serious cardiovascular and cerebrovascular diseases

10. Having major bleeding and coagulation disorders or other obvious evidence on hemorrhagic tendency:

11. Medium to large surgical treatment within 4 weeks prior to randomization (except diagnostic biopsy).

12. Central nervous system metastases.

13. Serious, non-healing or dehiscing wound, active ulcer or untreated bone fracture.

14. Vaccination of live vaccine within 30 days prior to randomization.

15. Active autoimmune diseases requiring systemic treatment (i.e., immunomodulatory drug, corticosteroid or immunosuppressant) in the past 2 years; however, replacement therapy (e.g., thyroxine, insulin or physiological corticosteroid replacement therapy for renal or pituitary insufficiency), inhaled or topical corticosteroids will not be excluded.

16. History of clear interstitial lung disease or non-infectious pneumonia, unless induced by local radiotherapy; Presence of active tuberculosis during screening period or previous anti-tuberculosis treatment within one year prior to randomization.

17. Any serious acute and chronic infection requiring systemic antibacterial, antifungal or antiviral therapy at screening, not including viral hepatitis.

18. Known history of human immunodeficiency virus (HIV) infection.

19. Previously receiving allogeneic stem cell or solid organ transplantation.

20. Inability to swallow tablets, malabsorption syndrome or any condition that affects gastrointestinal absorption.

21. Known history of serious allergy to any monoclonal antibody, targeted anti- angiogenic drug.

22. Other unsuitable subjects as per the investigators.

Related Conditions & MeSH terms

• Advanced Hepatocellular Carcinoma (HCC)
• Carcinoma
• Carcinoma, Hepatocellular

Intervention

Combination Product:
• Toripalimab combined with Bevacizumab
Experimental group: Toripalimab, 240mg, IV infusion, every 3 weeks (q3w). combined with Bevacizumab 15mg/kg, IV infusion, every 3 weeks (q3w), Continuous infusion, in a cycle of 3 weeks (21 days), until occurrence of termination event specified in the protocol.

Drug:
• Sorafenib
Control group: Sorafenib 400mg, po, Bid, continuous administration, until occurrence of termination event specified in the protocol.

Locations

Country	Name	City	State
China	Beijing Cancer Hospital	Beijing	Beijing
China	China PLA General Hospital	Beijing	Beijing
China	Peking Union Medical College Hospital	Beijing	Beijing
China	The First Affiliated Hospital of Bengbu Medical college	Bengbu	Anhui
China	Jilin Cancer Hospital	Changchun	Jilin
China	Jilin Guowen Hospital	Changchun	Jilin
China	Hunan Cancer Hospital	Changsha	Hunan
China	Xiangya Hospital of Central South University	Changsha	Hunan
China	Sichuan Cancer Hospital	Chengdu	Sichuan
China	West China Hospital,Sichuan University	Chengdu	Sichuan
China	Army Medical Center of PLA	Chongqing	Chongqing
China	The First Affiliated Hospital of Chongqing Medical University	Chongqing	Chongqing
China	The Southwest Hospital Of AMU	Chongqing	Chongqing
China	The First Peoples Hospital of Foshan	Foshan	Guangdong
China	The First Affiliated Hospital of Gannan Medical University	Ganzhou	Jiangxi
China	Kaohsiung Medical University Chung-Ho Memorial Hospital	Gaoxiong	Taiwan
China	Nanfang Hospital of Southern Medical University	Guangzhou	Guangdong
China	SSun Yat-sen Memorial Hospital, Sun Yat-sen University	Guangzhou	Guangdong
China	Sun Yat-sen Memorial Hospital, Sun Yat-sen University	Guangzhou	Guangdong
China	The First Affiliated Hospital, Sun Yat-sen University	Guangzhou	Guangdong
China	Hainan General Hospital	Haikou	Hainan
China	ShuLan(HangZhou) Hospital	Hangzhou	Zhejiang
China	The First Affiliated Hospital,Zhejiang University School of Medicine	Hangzhou	Zhejiang
China	ZheJiang Cancer Hospital	Hangzhou	Zhejiang
China	ZheJiang Provincial People's Hospital	Hangzhou	Zhejiang
China	Harbin Medical University Cancer Hospital	Harbin	Heilongjiang
China	Anhui Cancer Hospital	Hefei	Anhui
China	Anhui Provincial Hospital	Hefei	Anhui
China	The Second Hospital of Anhui Medical University	Hefei	Anhui
China	Shandong Cancer Hospital	Jinan	Shandong
China	Yunnan Cancer Hospital	Kunming	Yunnan
China	The Frist Hospital of Lanzhou University	Lanzhou	Gansu
China	The first Affiliated hospital of Nanchang University	Nanchang	Jiangxi
China	The Second Affiliated hospital of Nanchang University	Nanchang	Jiangxi
China	NanJing Drum Tower Hospital	Nanjing	Jiangsu
China	Nantong Tumor Hospital	Nantong	Jiangsu
China	The Affiliated Hospital of Qingdao University	Qingdao	Shandong
China	Jia Fan	Shanghai
China	Yuebei People's Hospital	Shaoguan	Guangdong
China	Liaoning cancer hospital	Shenyang	Liaoning
China	MacKay Memorial Hospital	Taibei	Taiwan
China	Tianjin Medical University Cancer Institute & Hospital	Tianjin	Tianjin
China	The First Affiliated Hospital of Wenzhou Medical University	Wenzhou	Zhejiang
China	Hubei Cancer Hospital	Wuhan	Hubei
China	Tongji Hospital Tongji Medical College Of HUST	Wuhan	Zhejiang
China	Xiehe Hospital Tongji Medical College Of HUST	Wuhan	Zhejiang
China	Zhongnan Hospital of Wuhan University	Wuhan	Zhejiang
China	Gansu Wuwei Tumor Hospital	Wuwei	Gansu
China	First Affiliated Hospital of Xian Jiaotong University	Xi'an	Shanxi
China	Xi'an International Medical Center Hospital	Xi'an	Shanxi
China	The Affiliated Hospital of Xuzhou Medical University	Xuzhou	Jiangsu
China	Changhua Christian Hospital	Zhanghua	Taiwan
China	he First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan
China	Henan Provincial Cancer Hospital	Zhengzhou	Henan
Singapore	Curie Oncology	Singapore
Singapore	Tan Tock Seng Hospital	Singapore

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Junshi Bioscience Co., Ltd.

Countries where clinical trial is conducted

China,  Singapore, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS)	A duration from the date of initial treatment with Toripalimab Plus Bevacizumab or Sorafenib to disease progression (defined by RECIST 1.1) or death of any cause, whichever comes first.	Up to 2 years
Primary	Overall survival (OS)	Duration from the date of initial treatment with Toripalimab Plus Bevacizumab or Sorafenib monotherapy to the date of death due to any cause.	Up to 2 years
Secondary	ORR	The rate of participants that achieve either a complete response (CR) or a partial response (PR).	Up to 2 years
Secondary	DoR	Duration from the first time reported partial response or complete response to the first time of disease progression or death.	Up to 2 years
Secondary	Disease Control Rate (DCR)	Proportion of patients with reduction and non-change in tumor burden of a predefined amount, including complete remission, partial remission and stable disease	Up to 2 years
Secondary	TTP	Define as the time from randomization to the first documented disease progression	Up to 2 years
Secondary	Incidence of AEs/SAEs as Assessed by CTCAE v5.0	Analysis of adverse events (AEs) are based on treatment-related AEs (trAEs) and immune-related AEs (irAEs), and all-grade AEs and grade 3-4 AEs. AEs are evaluated by investigators according to the Common Terminology Criteria for Adverse Events, version 5.0	From date of consent informed until 60 days after the last investigational product administration. Up to 2 approximately years.
Secondary	TMB	Correlation between tumor mutation burden (TMB) and the efficacy of Toripalimab combined with Bevacizumab	Up to 12 years
Secondary	ADA	Serum levels and incidence of Anti-drug antibody of Toripalimab combined with Bevacizumab treatment group	Up to 12 years