Hepatic Arterial Infusion Chemotherapy with Serplulimab and the Bevacizumab Biosimilar HLX04 for Advanced Hepatocellular Carcinoma: A Prospective, Observational Phase II Clinical Trial
Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Patients
2.3. Treatment
2.4. Study Endpoints and Assessments
2.5. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Efficacy
3.3. Safety
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A. Main Inclusion and Exclusion Criteria
- Willing to participate in the clinical study; fully understands the study, has signed the informed consent form (ICF), and is willing and able to complete all trial procedures.
- Age ≥ 18 years at the time of signing the ICF.
- Diagnosed with hepatocellular carcinoma (HCC) via histopathology or cytology, or clinically diagnosed based on the American Association for the Study of Liver Diseases (AASLD) criteria.
- Barcelona Clinic Liver Cancer (BCLC) stage C, with or without portal vein tumor thrombus (VP3–4 or Cheng’s classification II–IV) confirmed by imaging.
- No prior systemic therapy for HCC, including chemotherapy, sorafenib, regorafenib, lenvatinib, or other small-molecule anti-angiogenic agents.
- At least one measurable target lesion per RECIST v1.1, which has not previously undergone surgery, radiotherapy, or other local therapies (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryotherapy, high-intensity focused ultrasound, transarterial chemoembolization, or transarterial embolization). Previously treated lesions may be selected as target lesions if they show clear progression per RECIST v1.1. Local treatments must have been completed at least 4 weeks before baseline screening, with treatment-related adverse events (AEs) recovered to NCI-CTCAE Grade ≤1.
- Child-Pugh liver function classification: Grade A or well-compensated Grade B (≤7 points) within 7 days prior to screening.
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 within 7 days prior to screening.
- Expected survival ≥12 weeks.
- For patients with HBsAg (+) or HBcAb (+), HBV-DNA must be <2000 IU/mL to be eligible. Patients negative for HCV antibodies or HCV-RNA are eligible. If HCV-RNA is positive, the patient must agree to receive standard antiviral therapy per local guidelines and have ALT/AST ≤ 3 × ULN.
- Normal major organ function as assessed within 14 days prior to randomization, without prior transfusion, albumin, recombinant human thrombopoietin, or colony-stimulating factor treatment.
System | Parameter | Criteria |
---|---|---|
Hematology | White Blood Cells (WBC) | ≥3.0 × 109/L |
Neutrophils (ANC) | ≥1.5 × 109/L | |
Platelets (PLT) | ≥75 × 109/L | |
Hemoglobin (Hb) | ≥90 g/L | |
Liver Function | Total Bilirubin (TBIL) | ≤1.5 × Upper Limit of Normal (ULN) |
Alanine Aminotransferase (ALT) | ≤5 × ULN (except for patients with HCV-RNA positivity) | |
Aspartate Aminotransferase (AST) | ≤5 × ULN (except for patients with HCV-RNA positivity) | |
Albumin | ≥28 g/L | |
Renal Function/Urinalysis | Creatinine (Cr) | ≤1.5 × ULN; if >1.5 × ULN, creatinine clearance rate should be ≥50 mL/min (calculated according to the Cockcroft-Gault formula) |
Proteinuria | Routine urine protein test ≤1+ or quantitative <1.0 g/24 h | |
Coagulation Function | Prothrombin Time (PT) | ≤1.5 × ULN |
Activated Partial Thromboplastin Time (APTT) | ≤1.5 × ULN | |
International Normalized Ratio (INR) | ≤1.5 × ULN |
- 12.
- Female patients must meet one of the following criteria:
- (1)
- Postmenopausal (no menstruation for ≥1 year without another known cause)
- (2)
- Surgically sterile (bilateral oophorectomy and/or hysterectomy)
- (3)
- If of childbearing potential:
- Negative serum pregnancy test within 7 days before randomization.
- Agreement to use highly effective contraception (failure rate <1% per year) or remain abstinent from the time of consent to at least 150 days after the last dose. Highly effective contraception includes bilateral tubal ligation, vasectomy of male partner, hormonal contraceptives that inhibit ovulation, or intrauterine devices (IUDs). Breastfeeding is not allowed.
- 13.
- Male patients must agree to abstain or use contraception as follows: If the partner is of childbearing potential or pregnant, the patient must use a condom or remain abstinent from the time of consent to at least 150 days after the last dose. The reliability of abstinence should be assessed based on trial duration, patient preference, and lifestyle. Periodic abstinence (calendar, ovulation, basal body temperature, or post-ovulation methods) and withdrawal are not considered reliable contraceptive methods.
- Known intrahepatic cholangiocarcinoma, mixed-cell carcinoma, or fibrolamellar carcinoma.
- History of hepatic encephalopathy.
- Portal hypertension with upper gastrointestinal bleeding within 6 months, or esophageal/gastric varices with red signs (gastroscopy required within 6 months before randomization), or high bleeding risk per investigator assessment.
- Known central nervous system (CNS) or leptomeningeal metastases.
- Presence of distant metastases (hepatic portal lymph node metastases are permitted).
- Co-infection with HBV and HCV (detectable HBV-DNA or HBsAg-positive with anti-HCV antibody-positive or detectable HCV-RNA).
- Other active malignancies within the past 5 years (except cured localized cancers such as basal cell carcinoma, squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the prostate, cervix, or breast).
- Prior or planned organ or bone marrow transplantation.
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring frequent drainage (≥ once per month).
- Stroke, myocardial infarction, unstable angina, or uncontrolled arrhythmia within the past 6 months (including QTc interval ≥450 ms in males or ≥470 ms in females, calculated using the Fridericia formula).
- Heart failure NYHA > II or LVEF < 50% on echocardiogram.
- Uncontrolled hypertension despite optimal medical management (systolic BP ≥ 150 mmHg or diastolic BP ≥ 100 mmHg).
- History of hypertensive crisis or hypertensive encephalopathy.
- Active HIV infection, tuberculosis, or other active infections.
- History or current evidence of pulmonary fibrosis, interstitial lung disease, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severely impaired lung function that may interfere with drug safety evaluation.
- Active or suspected autoimmune disease, except controlled hypothyroidism on replacement therapy or controlled Type 1 diabetes on insulin therapy.
- Receipt of a live vaccine within 28 days.
- Systemic corticosteroid (>10 mg/day prednisone or equivalent) or immunosuppressive therapy within 14 days before screening, unless for acute, short-term use (e.g., contrast allergy prophylaxis). Inhaled or topical steroids are permitted.
- Major surgery within 28 days (defined as requiring ≥3 weeks for recovery before study treatment initiation).
- Prior treatment with T-cell co-stimulation or immune checkpoint inhibitors, including but not limited to CTLA-4, PD-1, or PD-L1/2 inhibitors.
- Prior treatment with bevacizumab or its biosimilars.
- Participation in another clinical trial within 14 days before randomization.
- Known allergy to monoclonal antibodies, study drug excipients, platinum, or fluoropyrimidine-based chemotherapy agents.
- Pregnant or breastfeeding women.
- Evidence of non-gastrointestinal bleeding (e.g., hemoptysis, abnormal vaginal bleeding) at screening or Grade 2 bleeding within 3 months, or Grade ≥3 bleeding within 6 months before consent.
- Full-dose anticoagulation or thrombolytic therapy within 7 days prior to randomization (except prophylactic anticoagulation for an open intravenous line, provided INR ≤ 1.5 × ULN and APTT ≤ 1.5 × ULN within 14 days before randomization). Prophylactic low-molecular-weight heparin (e.g., enoxaparin 40 mg/day) is allowed.
- Chronic daily NSAID use. Occasional NSAID use for symptom relief (e.g., headache, fever) is allowed.
- The following conditions within 6 months:
- (1)
- Esophagotracheal fistula, gastrointestinal perforation, intra-abdominal fistula, or intra-abdominal abscess.
- (2)
- Intestinal obstruction or symptoms requiring parenteral hydration/nutrition or enteral feeding.
- (3)
- Intra-abdominal inflammatory processes, including peptic ulcer, diverticulitis, or colitis.
- (4)
- Major vascular diseases (e.g., aortic aneurysm requiring repair or recent peripheral arterial thrombosis).
- Unhealed wounds, active ulcers, or untreated fractures.
- History of substance abuse or drug dependence.
- Any other condition deemed unsuitable by the investigator.
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Characteristics | Patients (N = 32) |
---|---|
Age (year), median (IQR) | 62.0 (53.0~66.8) |
Sex n (%) | |
Male | 26 (81.2) |
Female | 6 (18.8) |
Drinking history n (%) | |
No | 18 (56.2) |
Yes | 14 (43.8) |
Smoking history n (%) | |
No | 15 (46.9) |
Yes | 17 (53.1) |
Family history of liver cancer n (%) | |
No | 29 (90.6) |
Yes | 3 (9.4) |
HBV infection n (%) | |
No | 10 (31.2) |
Yes | 22 (68.8) |
HCV infection n (%) | |
No | 30 (93.8) |
Yes | 2 (6.2) |
Hypertension n (%) | |
No | 22 (68.8) |
Yes | 10 (31.2) |
Diabetes n (%) | |
No | 25 (78.1) |
Yes | 7 (21.9) |
Cardiovascular and cerebrovascular diseases n (%) | |
No | 29 (90.6) |
Yes | 3 (9.4) |
Cirrhosis n (%) | |
No | 12 (37.5) |
Yes | 20 (62.5) |
Portal vein cancer thrombus n (%) | |
No | 16 (50.0) |
Yes | 16 (50.0) |
Number of lesions n (%) | |
Single lesion | 5 (15.6) |
Multiple lesions | 27 (84.4) |
Lymph node metastasis n (%) | |
No | 29 (90.6) |
Yes | 3 (9.4) |
Extrahepatic metastasis n (%) | |
No | 27 (84.4) |
Yes | 5 (15.6) |
CNLC stage n (%) | |
Ib | 2 (6.3) |
IIa | 2 (6.3) |
IIb | 5 (15.6) |
IIIa | 14 (43.8) |
IIIb | 9 (28.1) |
AJCC stage n (%) | |
II | 1 (3.1) |
IIIA | 8 (25.0) |
IIIB | 16 (50.0) |
IVA | 2 (6.3) |
IVB | 5 (15.6) |
Serplulimab/Bevacizumab + TACE/HAIC cycles n (%) | |
≥3 cycles | 28 (87.5) |
<3 cycles | 4 (12.5) |
Indicator | N = 32 |
---|---|
Number of assessable cases n (%) | 32 (100) |
CR n (%) | 0 (0.0) |
PR n (%) | 17(53.1) 1 |
SD n (%) | 12 (37.5) |
PD n (%) | 3 (9.4) 2 |
ORR | 17 (53.1, 95%CI: 34.7–70.9) |
DCR | 29 (90.6, 95%CI: 75.0–97.5) |
No. | Age | Gender | HBV Infection | Portal Vein Tumor Thrombus | CNLC Stage | Treatment Cycles (Preoperative) | Preoperative Tumor Assessment | Surgical Method |
---|---|---|---|---|---|---|---|---|
1 | 57 | Male | Yes | No | Ib | 4 | SD | Hepatic segments IV, V, VII resection + Cholecystectomy |
2 | 72 | Female | Yes | No | IIb | 3 | PR | Left hepatectomy + Cholecystectomy |
3 | 66 | Male | No | Yes | IIIa | 3 | PR | Right hepatectomy + Right caudate lobectomy + Cholecystectomy |
4 | 50 | Male | No | Yes | IIIa | 3 | PR | Hepatectomy |
5 | 54 | Male | Yes | Yes | IIIa | 4 | PR | Right hepatectomy + Cholecystectomy + Lymph node dissection |
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Share and Cite
Li, H.; Si, T.; Li, R.; Xie, X.; Liu, Y.; Fu, L.; Bai, Y.; Yao, J.; Zhang, X.; Yang, M.; et al. Hepatic Arterial Infusion Chemotherapy with Serplulimab and the Bevacizumab Biosimilar HLX04 for Advanced Hepatocellular Carcinoma: A Prospective, Observational Phase II Clinical Trial. Cancers 2025, 17, 3235. https://doi.org/10.3390/cancers17193235
Li H, Si T, Li R, Xie X, Liu Y, Fu L, Bai Y, Yao J, Zhang X, Yang M, et al. Hepatic Arterial Infusion Chemotherapy with Serplulimab and the Bevacizumab Biosimilar HLX04 for Advanced Hepatocellular Carcinoma: A Prospective, Observational Phase II Clinical Trial. Cancers. 2025; 17(19):3235. https://doi.org/10.3390/cancers17193235
Chicago/Turabian StyleLi, Huikai, Tongguo Si, Rentao Li, Xiaojing Xie, Yang Liu, Linlin Fu, Yu Bai, Junchao Yao, Xihao Zhang, Mao Yang, and et al. 2025. "Hepatic Arterial Infusion Chemotherapy with Serplulimab and the Bevacizumab Biosimilar HLX04 for Advanced Hepatocellular Carcinoma: A Prospective, Observational Phase II Clinical Trial" Cancers 17, no. 19: 3235. https://doi.org/10.3390/cancers17193235
APA StyleLi, H., Si, T., Li, R., Xie, X., Liu, Y., Fu, L., Bai, Y., Yao, J., Zhang, X., Yang, M., & Mu, X. (2025). Hepatic Arterial Infusion Chemotherapy with Serplulimab and the Bevacizumab Biosimilar HLX04 for Advanced Hepatocellular Carcinoma: A Prospective, Observational Phase II Clinical Trial. Cancers, 17(19), 3235. https://doi.org/10.3390/cancers17193235