Clinical trial NCT04723004: Evaluate the Safety and Efficacy of Toripalimab Combined With Bevacizumab Versus Sorafenib Therapy for HCC
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Advanced Hepatocellular Carcinoma (HCC)
Lead sponsor: Shanghai Junshi Bioscience Co., Ltd.
Sponsor class: OTHER
First posted: 2021-01-25
Enrollment: 326
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: Up to 2 years
measure: Overall survival (OS)
timeFrame: Up to 2 years
Secondary outcomes:
measure: ORR
timeFrame: Up to 2 years
measure: DoR
timeFrame: Up to 2 years
measure: Disease Control Rate (DCR)
timeFrame: Up to 2 years
measure: TTP
timeFrame: Up to 2 years
measure: Incidence of AEs/SAEs as Assessed by CTCAE v5.0
timeFrame: From date of consent informed until 60 days after the last investigational product administration. Up to 2 approximately years.
measure: TMB
timeFrame: Up to 12 years
measure: ADA
timeFrame: Up to 12 years
Other outcomes:
Locations:
city: Bengbu
country: China
facility: The First Affiliated Hospital of Bengbu Medical college
state: Anhui
city: Hefei
country: China
facility: Anhui Cancer Hospital
state: Anhui
city: Hefei
country: China
facility: Anhui Provincial Hospital
state: Anhui
city: Hefei
country: China
facility: The Second Hospital of Anhui Medical University
state: Anhui
city: Beijing
country: China
facility: Beijing Cancer Hospital
state: Beijing
city: Beijing
country: China
facility: China PLA General Hospital
state: Beijing
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Chongqing
country: China
facility: Army Medical Center of PLA
state: Chongqing
city: Chongqing
country: China
facility: The First Affiliated Hospital of Chongqing Medical University
state: Chongqing
city: Chongqing
country: China
facility: The Southwest Hospital Of AMU
state: Chongqing
city: Lanzhou
country: China
facility: The Frist Hospital of Lanzhou University
state: Gansu
city: Wuwei
country: China
facility: Gansu Wuwei Tumor Hospital
state: Gansu
city: Foshan
country: China
facility: The First Peoples Hospital of Foshan
state: Guangdong
city: Guangzhou
country: China
facility: Nanfang Hospital of Southern Medical University
state: Guangdong
city: Guangzhou
country: China
facility: SSun Yat-sen Memorial Hospital, Sun Yat-sen University
state: Guangdong
city: Guangzhou
country: China
facility: Sun Yat-sen Memorial Hospital, Sun Yat-sen University
state: Guangdong
city: Guangzhou
country: China
facility: The First Affiliated Hospital, Sun Yat-sen University
state: Guangdong
city: Shaoguan
country: China
facility: Yuebei People's Hospital
state: Guangdong
city: Haikou
country: China
facility: Hainan General Hospital
state: Hainan
city: Harbin
country: China
facility: Harbin Medical University Cancer Hospital
state: Heilongjiang
city: Zhengzhou
country: China
facility: he First Affiliated Hospital of Zhengzhou University
state: Henan
city: Zhengzhou
country: China
facility: Henan Provincial Cancer Hospital
state: Henan
city: Wuhan
country: China
facility: Hubei Cancer Hospital
state: Hubei
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Changsha
country: China
facility: Xiangya Hospital of Central South University
state: Hunan
city: Nanjing
country: China
facility: NanJing Drum Tower Hospital
state: Jiangsu
city: Nantong
country: China
facility: Nantong Tumor Hospital
state: Jiangsu
city: Xuzhou
country: China
facility: The Affiliated Hospital of Xuzhou Medical University
state: Jiangsu
city: Ganzhou
country: China
facility: The First Affiliated Hospital of Gannan Medical University
state: Jiangxi
city: Nanchang
country: China
facility: The first Affiliated hospital of Nanchang University
state: Jiangxi
city: Nanchang
country: China
facility: The Second Affiliated hospital of Nanchang University
state: Jiangxi
city: Changchun
country: China
facility: Jilin Cancer Hospital
state: Jilin
city: Changchun
country: China
facility: Jilin Guowen Hospital
state: Jilin
city: Shenyang
country: China
facility: Liaoning cancer hospital
state: Liaoning
city: Jinan
country: China
facility: Shandong Cancer Hospital
state: Shandong
city: Qingdao
country: China
facility: The Affiliated Hospital of Qingdao University
state: Shandong
city: Xi'an
country: China
facility: First Affiliated Hospital of Xian Jiaotong University
state: Shanxi
city: Xi'an
country: China
facility: Xi'an International Medical Center Hospital
state: Shanxi
city: Chengdu
country: China
facility: Sichuan Cancer Hospital
state: Sichuan
city: Chengdu
country: China
facility: West China Hospital，Sichuan University
state: Sichuan
city: Gaoxiong
country: China
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
state: Taiwan
city: Taibei
country: China
facility: MacKay Memorial Hospital
state: Taiwan
city: Zhanghua
country: China
facility: Changhua Christian Hospital
state: Taiwan
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute & Hospital
state: Tianjin
city: Kunming
country: China
facility: Yunnan Cancer Hospital
state: Yunnan
city: Hangzhou
country: China
facility: ShuLan（HangZhou) Hospital
state: Zhejiang
city: Hangzhou
country: China
facility: The First Affiliated Hospital,Zhejiang University School of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: ZheJiang Cancer Hospital
state: Zhejiang
city: Hangzhou
country: China
facility: ZheJiang Provincial People's Hospital
state: Zhejiang
city: Wenzhou
country: China
facility: The First Affiliated Hospital of Wenzhou Medical University
state: Zhejiang
city: Wuhan
country: China
facility: Tongji Hospital Tongji Medical College Of HUST
state: Zhejiang
city: Wuhan
country: China
facility: Xiehe Hospital Tongji Medical College Of HUST
state: Zhejiang
city: Wuhan
country: China
facility: Zhongnan Hospital of Wuhan University
state: Zhejiang
city: Shanghai
country: China
facility: Jia Fan
city: Singapore
country: Singapore
facility: Curie Oncology
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
Study officials:
References: