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Hepatocellular Carcinoma (HCC)Phase 2NCT07331883

Sintilimab Combined With Bevacizumab Biosimilar as Adjuvant Treatment After Resection of Ruptured Hepatocellular Carcinoma (CLEAR-2)

A Phase 2 study testing Sintilimab plus bevacizumab biosimilar in people with Hepatocellular Carcinoma (HCC), run by Ruijin Hospital at 4 sites in China.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
Search all trials

Trial summary

Primary liver cancer-particularly hepatocellular carcinoma (HCC)-remains a major health burden in China, characterized by high incidence and mortality rates and poor 5-year survival. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Hepatocellular Carcinoma (HCC)
What is being tested?
Sintilimab plus bevacizumab biosimilar
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
35 participants
Where
4 sitesChina
Study dates
17 Nov 2025to 31 Mar 2029
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients voluntarily provide written informed consent, with authorization obtained from the patient or legal representative prior to any protocol-related procedures.
  • Age ≥ 18 years and ≤ 75 years; both female and male
  • Spontaneous tumor rupture with hemorrhage confirmed by imaging prior to or during surgery, with a postoperative pathological diagnosis of hepatocellular carcinoma (HCC).
  • For cases where tumor rupture is an incidental finding during surgery, a clinical history of abdominal pain within the two weeks preceding surgery is required.
  • CNLC Stage I-II.
  • Having undergone curative surgical resection, with intraoperative irrigation using ≥5000 mL of distilled water or normal saline, confirmed negative surgical margins on postoperative pathology, and achieving a complete response (CR) confirmed by imaging within 4-8 weeks after surgery.
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  • ECOG PS 0-1
  • Child-Pugh A (score ≤6).
  • Life expectancy ≥12 months
  • Laboratory test results obtained within 3 days prior to the first dose must meet the following criteria:
  • Hematological:(Except for hemoglobin, the patient must not have received a blood transfusion, granulocyte colony-stimulating factor [G-CSF], or hematopoietic agents within 2 weeks prior to screening.) i. Absolute neutrophil count ≥1.5 × 10⁹/L; ii. Platelet count ≥75 × 10⁹/L; iii. Hemoglobin ≥90 g/L.
  • Serum biochemistry:
  • Serum albumin ≥30 g/L; ii. Total bilirubin ≤1.5 × ULN; iii. ALT and AST ≤3 × ULN; iv. Serum creatinine ≤1.5 × ULN, or creatinine clearance >50 mL/min.
  • International normalized ratio (INR) ≤1.2 or prothrombin time (PT) ≤2 seconds above the upper limit of normal.
  • Urinalysis:Urine protein <2+.(If urine protein is ≥2+, a 24-hour urine protein test may be performed; patients may be enrolled if 24-hour urine protein <1.0 g.)
  • For patients with HBV infection (i.e., HBsAg-positive), HBV DNA must be tested. HBV DNA levels must be <2000 IU/mL (or <10⁴ copies/mL if the study site reports results in copies/mL). Patients with HBV DNA ≥2000 IU/mL must receive at least 1 week of antiviral therapy prior to the first dose, using only nucleos(t)ide analogues such as entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide. HBV DNA levels must show a ≥1-log (10-fold) reduction before initiation of study treatment. All HBV-infected patients must continue antiviral therapy throughout the entire study period. Patients who are HCV RNA-positive must receive antiviral treatment according to current clinical guidelines.
  • Female patients of childbearing potential must have a negative β-hCG pregnancy test prior to the first dose. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to use effective contraception during treatment and for 6 months after the last dose of study medication.

Who cannot join

  • Pathological diagnosis other than hepatocellular carcinoma, including cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma.
  • Intraoperative intraperitoneal lavage with chemotherapeutic agents
  • Child-Pugh class B or C
  • ECOG PS > 1
  • Postoperative imaging confirming the presence of extrahepatic metastasis, residual disease, or recurrence.
  • Prior systemic antitumor therapy, including targeted therapy, immunotherapy, investigational drugs, or local therapies such as TACE (preoperative TAE for hemostasis is allowed). Patients who received adjuvant TACE after resection are also excluded.
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  • Clinically symptomatic moderate or severe ascites requiring therapeutic paracentesis or drainage, or a Child-Pugh ascites score >2 (the presence of minimal ascites on imaging only, without associated symptoms, is excluded). Uncontrolled or moderate-to-large pleural effusion or pericardial effusion.
  • Current interstitial lung disease (ILD), or a history of ILD requiring glucocorticoid treatment, or other conditions that might interfere with the diagnosis or management of immune-related pulmonary toxicity, including pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), pneumoconiosis, drug-induced pneumonia, or idiopathic pneumonia. Patients with evidence of active pneumonia on screening chest computed tomography (CT) scans or severely impaired pulmonary function are excluded. History of radiation pneumonitis within the radiation field is permitted. Active tuberculosis.
  • Presence of an active autoimmune disease, or a history of autoimmune disease with potential for recurrence [including, but not limited to, autoimmune hepatitis, pneumonitis, uveitis, colitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism (patients with hypothyroidism controlled only with hormone replacement therapy are eligible)]. Patients with vitiligo, psoriasis, or alopecia not requiring systemic treatment, or well-controlled type I diabetes on insulin, or childhood asthma that has completely resolved in adulthood without any intervention are eligible. Asthmatic patients requiring bronchodilators for medical intervention are excluded.
  • Use of immunosuppressive agents or systemic corticosteroids for immunosuppressive purposes (at doses >10 mg/day prednisone or equivalent) within 2 weeks prior to initiation of study treatment. Inhaled or topical corticosteroids, and adrenal replacement steroid doses ≤10 mg/day prednisone equivalent, are permitted in the absence of active autoimmune disease.
  • History of gastrointestinal bleeding within 6 months prior to treatment, or definite predisposition to gastrointestinal bleeding, such as high-risk or severe esophageal/gastric varices, active peptic ulcer disease, or persistently positive fecal occult blood test (unless follow-up endoscopy rules out high-risk varices). Patients with esophageal/gastric varices identified on baseline CT/MRI may be eligible if assessed by the investigator as mild to moderate. Presence of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization.
  • Known hereditary or acquired bleeding (e.g., coagulation disorders) or thrombotic tendency, such as hemophilia, coagulopathy, thrombocytopenia, etc. Current therapeutic use of full-dose oral or injectable anticoagulants or thrombolytic agents (prophylactic use of low-dose aspirin, etc., is permitted).
  • History of thrombotic or embolic events within 6 months prior to treatment, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), pulmonary embolism, etc.
  • Poorly controlled or significant cardiac disease, including: (1) Cardiac dysfunction ≥ Grade II per New York Heart Association (NYHA) classification, or left ventricular ejection fraction (LVEF) <50% on echocardiography; (2) Unstable angina; (3) Myocardial infarction within 1 year prior to initiation of study treatment; (4) Clinically significant supraventricular or ventricular arrhythmia requiring treatment or intervention; (5) QTc interval >450 ms (males) or >470 ms (females).
  • Hypertension that is not adequately controlled with antihypertensive medication (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg, based on the average of ≥2 readings). History of hypertensive crisis or hypertensive encephalopathy.
  • Major vascular disease within 6 months prior to treatment (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis).
  • Severe, non-healing, or dehisced wounds, active ulcers, or unhealed bone fractures.
  • Inability to swallow tablets, malabsorption syndrome, or any condition compromising gastrointestinal absorption.
  • Severe infection within 4 weeks prior to treatment, including, but not limited to, hospitalization for infection, bacteremia, or severe pneumonic complications. Therapeutic antibiotics (oral or intravenous) within 14 days prior to randomization (prophylactic antibiotic use is permitted). Unexplained fever ≥38.5°C within 7 days prior to randomization, or baseline white blood cell count >15×10⁹/L.
  • Known congenital or acquired immunodeficiency (e.g., HIV infection).
  • Administration of live attenuated vaccines within 28 days prior to treatment, or anticipation of need for such vaccines during the study period.
  • Any other condition that, in the investigator's judgment, may affect the interpretation of results, compromise patient safety, or lead to premature study termination. This includes alcohol or substance abuse, other severe concurrent illnesses (including psychiatric disorders) requiring treatment, severe laboratory abnormalities, or significant social/familial circumstances.

Trial locations and contacts

4 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Yongjun Chen contact

+86 21 64370045

swakchenyj@hotmail.com

Feng Ye contact

+86 18917762950

China4 sites, 4 recruiting

  • The Third Bethune Hospital of Jilin University

    Changchun, Jilin, 130033

    Lianyue Guan, +86 13504310464, guanly@jlu.edu.cn

    Lianyue Guan

    Recruiting

  • Sanming First Hospital

    Sanming, Fujian, 365000

    Xiaokang Fu, +86 15859812105, vip_fuxiaokang@sina.com

    Xiaokang Fu

    Not yet recruiting

  • Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

    Shanghai, Shanghai Municipality, 200025

    Yongjun Chen, +86 21 64370045, swakchenyj@hotmail.com

    Yongjun Chen

    Recruiting

  • Huashan Hospital, Fudan University

    Shanghai, Shanghai Municipality, 200031

    Jinhong Chen, +86 13801977742, jinhongch@hotmail.com

    Jinhong Chen

    Recruiting

Other trials in China

About this study

Official title: Sintilimab Combined With Bevacizumab Biosimilar as Adjuvant Treatment After Resection of Ruptured Hepatocellular Carcinoma: A Prospective, Exploratory, Single-Arm Study (CLEAR-2)

Primary liver cancer-particularly hepatocellular carcinoma (HCC)-remains a major health burden in China, characterized by high incidence and mortality rates and poor 5-year survival. Spontaneous rupture of HCC (SRHCC), although a relatively uncommon complication, is associated with extremely high mortality and marked geographic variation, with disproportionately higher incidence and rupture-related deaths reported in Asian populations. For patients with preserved liver function and resectable tumors, hepatic resection can offer favorable long-term survival and even a potential cure. However, despite surgical removal, the risk of postoperative recurrence is substantially increased, and long-term outcomes remain unsatisfactory. Currently, there is no validated adjuvant therapy to reduce recurrence or improve survival after resection.

In recent years, immune checkpoint inhibitors (ICIs) in combination with anti-angiogenic agents have demonstrated synergistic antitumor activity and manageable safety in advanced HCC. Notably, studies of sintilimab plus a bevacizumab biosimilar have shown significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Moreover, emerging evidence in the adjuvant and perioperative settings suggests that PD-1 blockade may delay recurrence in high-risk patients, such as those with microvascular invasion.

Based on the high postoperative recurrence rate in SRHCC patients and the existing therapeutic gap, along with established evidence of the efficacy of immune checkpoint inhibitors combined with antiangiogenic therapy in advanced HCC, conducting a prospective Phase II single-arm study of adjuvant therapy with sintilimab plus the bevacizumab biosimilar holds significant clinical and scientific value. This study aims to evaluate the tolerability of this combination regimen in postoperative SRHCC patients at high risk of recurrence. It is expected to provide a more effective treatment option for patients diagnosed with spontaneously ruptured hepatocellular carcinoma, improve their prognosis, and offer scientific evidence for future treatment strategies.

Being tested
Sintilimab plus bevacizumab biosimilar
Medical subject headings
Carcinoma, Hepatocellular

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Sintilimab plus bevacizumab biosimilarDrug

    Sintilimab (200 mg, iv, d1, q3w) in combination with bevacizumab biosimilar (15mg/kg, iv, d1, q3w)

Study groups in NCT07331883
Study groupRoleWhat they receive
Experimental ArmExperimentalSintilimab (200 mg, iv, d1, q3w) in combination with bevacizumab biosimilar (15mg/kg, iv, d1, q3w)
Receives: Drug: Sintilimab plus bevacizumab biosimilar

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. DIsease-free Survival (DFS)

    The time from initial curative-intent treatment to the date of the first documented tumor progression as determined by the investigator (per RECIST 1.1), or death due to any cause.

    Measured: Through out the study (up to 3 years)

Secondary outcomes (5)

  1. Overall Survival (OS)

    the time from initial curative-intent treatment until death due to any cause.

    Measured: Through out the study (up to 3 years)

  2. Adverse Event description as assessed by CTCAE V5.0

    Number of Participants With Abnormal Laboratory Values and Adverse Events That Are Related to Treatment

    Measured: Through out the study (up to 3 years)

  3. the proportion and timing of intrahepatic recurrence

    documenting the proportion and timing of intrahepatic recurrence

    Measured: Through out the study (up to 3 years)

  4. the proportion and timing of extrahepatic metastasis

    the proportion and timing of extrahepatic metastasis

    Measured: Through out the study (up to 3 years)

  5. the proportion and timing of peritoneal metastasis

    the proportion and timing of peritoneal metastasis

    Measured: Through out the study (up to 3 years)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jan 2026
  2. Study start17 Nov 2025
  3. Primary completion1 Dec 2028 (estimated)
  4. Study completion31 Mar 2029 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
35 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07331883
Sponsor's protocol ID
CLEAR-2
Status last verified
Nov 2025
First submitted
26 Nov 2025
Last updated
27 Mar 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Cheng Y, Ye F, Sun HC, Chen Y. Adjuvant Sintilimab Plus Bevacizumab After Curative Resection of Spontaneously Ruptured Hepatocellular Carcinoma: Protocol for a Prospective, Exploratory, Single-Arm Study (CLEAR-2). J Hepatocell Carcinoma. 2026 Jul 16;13:614872. doi: 10.2147/JHC.S614872. eCollection 2026.

    PubMed 42519234

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Sintilimab plus bevacizumab biosimilar in people with Hepatocellular Carcinoma (HCC), run by Ruijin Hospital at 4 sites in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: looking for participants now, as of the sponsor's last update on 27 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Yongjun Chen (+86 21 64370045, swakchenyj@hotmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

DIsease-free Survival (DFS) (time frame: Through out the study (up to 3 years)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07331883, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2026; AzTrials last refreshed its copy on 8 Nov 2026.

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