Sintilimab Plus Bevacizumab Biosimilar as Neoadjuvant Therapy for Resectable Hepatocellular Carcinoma

Sintilimab Combined With Bevacizumab as Neoadjuvant Therapy for Resectable Hepatocellular Carcinoma Beyond the Milan Criteria: A Single-Arm, Prospective Phase II Study

Surgical resection is the preferred therapeutic modality for patients with resectable hepatocellular carcinoma (HCC). However, the recurrence rate of HCC remains up to 70%. Neoadjuvant therapy for HCC could potentially reduce the risk of postoperative recurrence and prolong overall survival. Nevertheless, there is no standard neoadjuvant treatment regimen for HCC to date. In recent years, targeted therapy and immunotherapy are proved to improve the prognosis of advanced HCC patients. Previous study (ORIENT-32) has confirmed that, compared with sorafenib, sintilimab combined with bevacizumab biosimilar can delay tumor progression, reduce the risk of death, and exhibit a favorable safety profile in patients with advanced HCC. Therefore, we conducted a prospective, single-arm phase II study to investigate the efficacy of sintilimab combined with a bevacizumab biosimilar as neoadjuvant therapy in patients with resectable HCC beyond the Milan criteria.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma; Neoadjuvant Therapy; Sintilimab; Bevacizimab
• Intervention / Treatment: Drug: sintilimab combined with bevacizumab biosimilar

• Study Type: Interventional
• Enrollment (Estimated): 37
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Sun yat-sen University Cancer Center
      • Contact: Zhongguo Zhou; Phone Number: +8602087343115; Email: zhouzhg@sysucc.org.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Able to provide informed consent and willing to sign an approved consent form;
2. Aged ≥ 18 years;
3. Clinically diagnosed or pathologically confirmed resectable hepatocellular carcinoma beyond the Milan criteria (CNLC Ib-IIa);
4. No prior anti-HCC treatment;
5. Child-Pugh class A.
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
7. Expected survival time of > 6 months.
8. Sufficient organ and bone marrow function.

Exclusion Criteria:

1. Known as cholangiocarcinoma (ICC) or mixed hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, and hepatic fibrolamellar carcinoma;
2. History of organ transplantation or hepatic encephalopathy
3. Pleural fluid, ascites, and pericardial effusion with clinical symptoms requiring drainage
4. History of esophageal or gastric variceal bleeding caused by portal hypertension within the past 6 months; Documented severe (Grade 3) varices identified by endoscopy within 3 months prior to enrollment; Evidence of portal hypertension and assessed by the investigator as being at high risk of bleeding.
5. Arterial and venous thromboembolic events in the past 6 months, including myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis or any other serious thromboembolism history;
6. Any life-threatening bleeding event occurring within the past 3 months;
7. Severe bleeding tendency, coagulopathy, or ongoing thrombolytic therapy.
8. Chronic requirement for medications that inhibit platelet function, such as aspirin (>325 mg/day), dipyridamole, or clopidogrel.
9. Uncontrolled hypertension, defined as systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg despite optimal medical management; history of hypertensive crisis or hypertensive encephalopathy.
10. Symptomatic congestive heart failure (New York Heart Association [NYHA] Functional Class II-IV); symptomatic or poorly controlled arrhythmias; history of congenital long QT syndrome; or corrected QT interval (QTc) >500 ms at screening (calculated using Fridericia's formula).
11. History of gastrointestinal perforation and/or fistula, intestinal obstruction (including incomplete obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection complicated by chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic persistent diarrhea within the past 6 months.
12. Major surgical procedure (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to enrollment; presence of unhealed wounds, ulcers, or fractures; or tissue biopsy or other minor surgical procedure within 7 days prior to enrollment, excluding venous catheterization for intravenous infusion.
13. Past or current history of pulmonary diseases including pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-induced pneumonia, or severe impairment of lung function.
14. Active acute or chronic hepatitis B or C infection, defined as: hepatitis B virus (HBV) DNA >2000 IU/mL or 10⁴ copies/mL; hepatitis C virus (HCV) RNA >10³ copies/mL; or concurrent positivity for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies.
15. Active tuberculosis (TB); ongoing anti-TB treatment; or anti-TB treatment completed within 1 year prior to the initiation of study treatment.
16. Human immunodeficiency virus (HIV) infection (positive for HIV 1/2 antibodies); known syphilis infection.
17. Severe active infection or infection with poor clinical control.
18. Active autoimmune disease requiring systemic therapy (e.g., disease-modifying antirheumatic drugs, corticosteroids, or immunosuppressants) within 2 years prior to enrollment. Substitution therapy (e.g., thyroid hormone, insulin, or physiological doses of corticosteroids for adrenal or pituitary insufficiency) is permitted. A history of known primary immunodeficiency is excluded. Patients with isolated positive autoimmune antibodies must be evaluated by the investigator to confirm the absence of underlying autoimmune disease.
19. Use of immunosuppressive drugs within 4 weeks prior to enrollment, excluding intranasal, inhaled, or other topical corticosteroids, or systemic corticosteroids at physiological doses (i.e., ≤10 mg/day of prednisone or equivalent). Temporary use of corticosteroids for the management of dyspnea related to asthma, chronic obstructive pulmonary disease (COPD), or other conditions is permitted.
20. Administration of live-attenuated vaccines within 4 weeks prior to enrollment or planned administration of live-attenuated vaccines during the study period.
21. Use of immunomodulatory agents (including thymosin, interferons, or interleukins) within 2 weeks prior to enrollment, excluding local administration for the control of pleural effusion or ascites.
22. Uncontrolled/uncorrectable metabolic disorders, other non-malignant organ/systemic diseases, or cancer-related sequelae that pose a high medical risk and/or introduce uncertainty in survival assessment.
23. Diagnosis of other malignant tumors within 5 years prior to enrollment, excluding curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or curatively resected carcinoma in situ. For malignant tumors diagnosed more than 5 years prior to drug administration, pathological or cytological confirmation of recurrent or metastatic lesions is required.
24. Prior receipt of any anti-angiogenic agents, anti-PD-1 antibodies, anti-PD-L1/L2 antibodies, anti-CTLA-4 antibodies, or other immunotherapies.
25. Known hypersensitivity to sintilimab, bevacizumab formulations, or their excipients; or history of severe hypersensitivity reactions to other monoclonal antibodies.
26. Receipt of treatment in other clinical trials within 4 weeks prior to enrollment.
27. Pregnant or breastfeeding female patients.
28. Other acute or chronic diseases, psychiatric disorders, or abnormal laboratory findings that, in the investigator's judgment, would: increase the risk associated with study participation or study drug administration; interfere with the interpretation of study results; or render the patient ineligible for study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sintilimab combined with bevacizumab biosimilar	Drug: sintilimab combined with bevacizumab biosimilar; Drug: Sintilimab: 200mg IV Q3W D1 (3 cycles) Drug: Bevacizumab Biosimilar: 15mg/kg, IV, Q3W, D1 (2 cycles)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1-year recurrence free survival rate	Defined as the proportion of patients who remain free from any tumor recurrence or death within 1 year after liver resection.	Up to 2 years
Adverse Events (AEs)	Defined as the proportion of patients with AEs assessed by NCI CTCAE v5.0;	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0 resection rate	Defined as the proportion of patients received R0 resection	Up to 2 years
pathological complete response	Defined as the proportion of patients who had pathological complete response	Up to 2 years
major pathological response	Defined as the proportion of patients who had major pathological response	Up to 2 years
Overall survival	Defined as the interval from the date of enrollment to the date of death or to the date of last follow-up (whichever occurs first)	Up to 2 years
Recurrence free survival	Defined as the time from the date of liver resection to the date of recurrence or death (whichever occurs first)	Up to 2 years
Time to recurrence	Defined as the time from the date of liver resection to the date of tumor recurrence	Up to 2 years

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2026
• Primary Completion (Estimated): January 1, 2029
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: December 23, 2025
• First Submitted That Met QC Criteria: December 23, 2025
• First Posted (Estimated): January 8, 2026

Study Record Updates

• Last Update Posted (Estimated): January 16, 2026
• Last Update Submitted That Met QC Criteria: January 15, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: B2024-720-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No