SHR-1701 Plus Apatinib for Second-Line Treatment in Targeted-Immune Pretreated Advanced Hepatocellular Carcinoma

This is a prospective, open-label, multicenter phase II clinical study. Eligible patients will receive combination therapy of SHR-1701 and apatinib with detailed administration regimens as follows:

SHR-1701: 30 mg/kg via intravenous infusion once every 3 weeks (Q3W); Apatinib: 250 mg taken orally once daily (QD). TACE intervention is permitted during treatment, which can only be conducted after the first efficacy assessment.Treatment will be continued until disease progression, intolerable toxicity, or other treatment discontinuation criteria are met.

A safety lead-in phase is designed for this study: the first 6 subjects will be enrolled initially. Enrollment can proceed to recruit subsequent participants until a total of 80 eligible patients are enrolled if no more than 2 cases of dose-limiting toxicity (DLT) are observed within the lead-in phase. If 3 or more DLT events occur, subject enrollment will be suspended immediately, followed by a comprehensive safety assessment. The research team will decide to terminate the current dose cohort or adjust the dosage of study drugs for enrollment restart based on the assessment results.The whole study is expected to be completed within 3 years. Statistical analyses including interim and final analyses will be performed with SPSS or R software.

Inclusion criteria

• Aged 18-75 years, male or female; signed informed consent form with good compliance;
• Patients with histologically confirmed hepatocellular carcinoma or meeting clinical diagnostic criteria, currently unresectable or metastatic;
• Prior receipt of first-line combined targeted and immunotherapy with subsequent disease progression or intolerance;
• At least one measurable lesion meeting the criteria of RECIST v1.1;
• ECOG performance status of 0 or 1;
• Expected survival ≥ 12 weeks;
• Child-Pugh Class A (score 5-6);
• Adequate organ and bone marrow function as defined below (tested within 14 days prior to initiation of study treatment):

1)Hematology laboratory values (no blood transfusion, granulocyte colony-stimulating factor [G-CSF], or corrective hematologic agents administered within 14 days before screening): A. Hemoglobin (Hb) ≥ 90 g/L; B. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; C. Platelet count (PLT) ≥ 75 × 10⁹/L; 2)Serum chemistry laboratory values (no albumin transfusion within 14 days before screening): A. Total serum bilirubin (BIL) ≤ 2 × ULN (≤ 3 × ULN for patients with Gilbert syndrome); B. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN;

C. For patients with liver metastases, ALT and AST ≤ 5 × ULN; serum creatinine (Cr) ≤ 1.5 × ULN OR endogenous creatinine clearance ≥ 50 mL/min (calculated via the Cockcroft-Gault formula):

Male: Creatinine clearance = [(140 - age) × body weight] / (72 × serum Cr); Female: Creatinine clearance = [(140 - age) × body weight] / (72 × serum Cr) × 0.85(Body weight in kg; serum Cr in mg/dL) 9.Controllable proteinuria and blood pressure: urine protein <2+ (or 24-hour urinary protein <1.0 g, or urine protein/creatinine ratio [UPC] <1.0); systolic blood pressure ≤140 mmHg and diastolic blood pressure ≤90 mmHg (achievable with antihypertensive medications); 10.Evaluation of portal hypertension and varices: esophagogastroduodenoscopy (EGD) performed within 6 months prior to enrollment; patients with medium-to-high risk esophageal and gastric varices must have completed prophylactic treatment per guidelines (e.g., endoscopic variceal ligation [EVL]/non-selective beta-blockers [NSBB]), and study treatment shall be initiated no earlier than 14 days after EVL; 11.Hepatitis B and C criteria: For subjects with positive HBsAg or HBcAb, HBV-DNA shall be below the lower limit of quantification, and nucleos(t)ide antiviral therapy shall be initiated and administered throughout the study period. Subjects with HCV infection shall have stable virological status (either receiving DAA therapy or previously cured); 12.Fertility requirements: Fertile subjects agree to use reliable contraception from enrollment until 6 months after the last study drug administration, with a negative pregnancy test prior to enrollment; 13.Recovery from prior therapies: All toxicities related to previous anti-tumor therapies have recovered to Grade 1 or baseline levels (except acceptable alopecia, stable hypoendocrine function, etc.). At least 3 weeks have elapsed since the last systemic anti-tumor therapy, at least 4 weeks since major surgery, and at least 4 weeks since local therapy (TACE, RFA, etc.) with stable recovery.

Exclusion criteria

• History of severe hypersensitivity or irreversible toxic reactions to similar PD-L1 agents or VEGFR-2 TKIs;
• Child-Pugh Class B or C, refractory ascites requiring paracentesis at least weekly, Grade ≥2 hepatic encephalopathy, or MELD score >12 (optional, subject to institutional SOPs);
• High bleeding risk: Grade ≥3 gastrointestinal hemorrhage, perforation, active ulcer or uncontrolled bleeding diathesis within the past 6 months; untreated medium-to-large varices or high-risk signs identified on EGD without completed prophylactic intervention; clinical indication for potent anticoagulants or dual antiplatelet therapy that cannot be discontinued or substituted (aspirin ≤100 mg daily may be permitted at the Investigator's discretion);
• Prior treatment with apatinib or PD-L1 monoclonal antibody immune checkpoint inhibitors;
• Uncontrolled hypertension (persistent blood pressure ≥140/90 mmHg despite medical treatment), persistent proteinuria ≥2+ or uncorrected 24-hour urinary protein ≥1.0 g;
• Severe cardiovascular diseases: myocardial infarction (MI), unstable angina, NYHA Class III-IV heart failure, clinically significant arrhythmia, QTcF interval ≥470 ms within the preceding 6 months, or recent arterial/venous thromboembolic events;
• Recent surgical procedures or unhealed wounds: major surgery performed within 4 weeks prior to enrollment with unhealed incision; gastrointestinal perforation or fistula occurring within 6 months prior to enrollment;
• Active infections: bacterial or fungal infections requiring intravenous antibiotics, active tuberculosis; high HBV-DNA replication without antiviral therapy initiated; uncontrolled HIV infection (e.g., CD4 count <200/μL or detectable viral load) or history of opportunistic infections;
• Active autoimmune disease or immunodeficiency requiring systemic immunosuppressive therapy (prednisone equivalent >10 mg daily). The following subjects may be eligible: stable hypothyroidism on replacement therapy, type 1 diabetes mellitus, localized cutaneous vitiligo/psoriasis, and inflammatory bowel disease in remission without need for systemic immunosuppression (at the Investigator's discretion);
• Prior severe immune-related adverse events (irAEs ≥ Grade 3, such as severe pneumonitis, colitis, hepatitis, neuromuscular disorders, myocarditis, etc.) or recurrent irAEs requiring long-term immunosuppression.
• Symptomatic central nervous system metastases or metastases requiring glucocorticoid control; asymptomatic lesions stable for ≥4 weeks may be considered for enrollment (per institutional policy).
• History of other malignant tumors within the past 3 years, excluding cured basal/squamous cell skin carcinoma, cervical carcinoma in situ, or other cured low-risk malignancies.
• Pregnancy or breastfeeding; hypersensitivity to any component of the study drugs.