Anlotinib + Benmelstobart + HAIC in Unresectable HCC: A Phase II Study

A single-arm, multicenter, phase II investigator-initiated exploratory clinical study will be adopted to evaluate the efficacy and safety of anlotinib combined with benmelstobart and hepatic arterial infusion chemotherapy (HAIC) as first-line treatment for patients with unresectable advanced hepatocellular carcinoma (uHCC) meeting CNLC and AASLD diagnostic criteria and with no prior systemic therapy. Patients received HAIC with the FOLFOX regimen (oxaliplatin 85 mg/m², leucovorin 400 mg/m², 5-fluorouracil 400 mg/m² bolus plus 2400 mg/m² continuous infusion over 23 h) every 3 weeks for a maximum of 6 cycles, plus oral anlotinib 10 mg on days 1-14 (with permitted dose reduction to 8 mg for toxicity) and intravenous benmelstobart 1200 mg over 60 min on day 1 of each 21-day cycle. Combination therapy continued for up to 2 years or until disease progression, intolerable toxicity, successful surgical conversion, or other discontinuation criteria. The primary endpoint is objective response rate (ORR) per RECIST v1.1. Secondary endpoints include ORR per mRECIST, progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), and safety. Exploratory endpoints are surgical conversion rate and changes in AFP and PIVKA-II. A total of 30 patients will be enrolled using a Simon two-stage design (stage 1: 9 patients; stage 2: 24 patients), accounting for a 20% dropout rate.

Inclusion criteria

• Age between 18 and 75 years, regardless of gender.
• Confirmed diagnosis of unresectable hepatocellular carcinoma (HCC) according to both the China Liver Cancer (CNLC) staging criteria and the American Association for the Study of Liver Diseases (AASLD) clinical diagnostic criteria.
• At least one measurable lesion as defined by the following criteria: the longest diameter ≥ 10 mm for non-nodal lesions, or the short-axis diameter ≥ 15 mm for nodal lesions; confirmed unresectable HCC; Child-Pugh liver function score ≤ 7.
• Naive to any local (ablation, hepatic arterial embolization/infusion therapy, liver transplantation) or systemic therapy (chemotherapy and/or molecular targeted therapy, immunotherapy; antiviral therapy excluded) for HCC at initial diagnosis, or patients with intrahepatic recurrence after previous radical resection.
• Expected survival time ≥ 12 weeks.
• No anti-HCC drugs (including modern traditional Chinese medicine preparations indicated for HCC: Lentinan Injection, Kanglaite Injection or Soft Capsules, Aidi or Kangsaidi Injection, Propaneed Oil, Huai'er Granules, and Ganfule Tablets) administered within 2 weeks prior to the first dose.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1.
• HBV DNA < 10^4 copies/ml (2000 IU/ml). If HBV DNA ≥ 10^4 copies/ml, antiviral therapy must be initiated first and continued until HBV DNA drops below 10^4 copies/ml before entering the study, along with ongoing antiviral medication and monitoring of liver function and HBV viral load.
• Normal function of major organs, meeting the following criteria:

a) Hematology (no blood transfusion or G-CSF administered within 14 days prior to screening): i. Hemoglobin (Hb) ≥ 90 g/L; ii. Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; iii. Platelet count (PLT) ≥ 75 × 10^9/L; b) Biochemistry (no albumin (ALB) administration within 14 days prior to testing): i. Albumin (ALB) ≥ 28 g/L; ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5.0 × upper limit of normal (ULN); iii. Total bilirubin (TBIL) ≤ 4.0 × ULN (patients with obstructive jaundice may be enrolled after percutaneous transhepatic cholangial drainage (PTCD)); iv. Creatinine ≤ 1.5 × ULN; v. Electrolytes essentially normal or normalized after treatment. c) Urinalysis: i. Urine protein ≤ 1+.

• The patient voluntarily consents to enrollment, signs the written informed consent form (ICF), and is able to comply with the required treatment and follow-up visits according to the protocol.

Exclusion criteria

• Histologically confirmed fibrolamellar HCC, sarcomatoid HCC, or combined hepatocellular-cholangiocarcinoma (HCC-ICC).
• Symptomatic moderate to massive pleural effusion/ascites.
• Obstructive jaundice, liver failure, or hepatic encephalopathy.
• Patients with a second primary cancer or multiple malignancies, except for HCC, carcinoma in situ of the cervix, and non-melanoma skin cancer, or a history of other malignancies previously diagnosed and explicitly cured for at least 5 years with no evidence of subsequent recurrence.
• Active bleeding or coagulation abnormalities (Prothrombin Time, PT > 16 s; Activated Partial Thromboplastin Time, APTT > 43 s; International Normalized Ratio, INR ≥ 2), bleeding tendency, or currently receiving thrombolytic, anticoagulant, or antiplatelet therapy.
• Concomitant use of medications that may prolong the QTc interval and/or induce Torsades de Pointes (TdP), or affect the metabolism of chemotherapeutic agents.
• Pregnant or lactating women; sexually active men or women of childbearing potential who are unwilling or unable to use effective contraception.
• Any significant clinical or laboratory abnormalities that, in the opinion of the investigator, would affect the safety evaluation, such as: uncontrolled active infection (> NCI-CTCAE v5.0 Grade 2), uncontrolled diabetes (> NCI-CTCAE v5.0 Grade 2), hypertension not controlled to below the specified range (systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg) despite treatment with two or more antihypertensive drugs, peripheral neuropathy ≥ Grade 2 (NCI-CTCAE v5.0), congestive heart failure ≥ Grade 2 (NCI-CTCAE v5.0), myocardial infarction within 6 months, or thyroid dysfunction (> NCI-CTCAE v5.0 Grade 2), etc.
• History of brain metastases, subdural metastasis, or severe mental illness; patients suspected of central nervous system (CNS) metastases must be excluded by cranial MRI.
• History of gastrointestinal bleeding or definite predisposition to gastrointestinal bleeding within the past 3 months, such as known active ulcer lesions, or fecal occult blood ≥ ++ (not eligible for enrollment); if persistent fecal occult blood is positive, a gastroscopy examination is required.
• Severe gastric fundus/esophageal wall varices requiring interventional treatment.
• Occurrence of abdominal or gastrointestinal perforation or intra-abdominal abscess within 4 weeks prior to the first dose.
• Significant abnormality in glomerular filtration rate (estimated creatinine clearance < 60 ml/min or serum creatinine > 1.5 × ULN).
• Active hepatitis C (i.e., anti-HCV positive or HCV-RNA positive with abnormal liver function); known history of HIV infection.
• Receipt of other investigational drugs or medical devices within 4 weeks prior to the first dose; or prior use of anti-tumor indicated drugs where less than 2 weeks or 5 drug half-lives (whichever is longer) have elapsed between the completion of previous treatment and the administration of the study drug, and adverse events caused by prior treatment have not recovered to ≤ CTCAE Grade 1.