QL1706 and Lenvatinib Combined With FOLFOX Systemic Chemotherapy as Second-line Treatment in Advanced Hepatocellular Carcinoma Patients

Inclusion Criteria:

• Patient voluntarily agrees to participate in this study and provides written informed consent.
• Age ≥ 18 years; both male and female patients are eligible.
• Histologically or cytologically confirmed, or clinically diagnosed, hepatocellular carcinoma (HCC) prior to study treatment.
• Barcelona Clinic Liver Cancer (BCLC) stage B or C, and unsuitable for surgery or local-regional therapy, or disease progression after surgery and/or local-regional therapy.
• Local-regional therapy (including but not limited to surgery, radiotherapy, hepatic artery embolization, transarterial chemoembolization [TACE], hepatic arterial infusion, radiofrequency ablation, cryoablation, or percutaneous ethanol injection) completed at least 4 weeks prior to the baseline imaging scan (2 weeks for palliative radiotherapy), and all toxicities induced by local-regional therapy (excluding alopecia) must have recovered to ≤ Grade 1 per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI-CTCAE v5.0).
• Documented disease progression or intolerance after at least one prior standard first-line immunotherapy and/or targeted therapy for HCC.
• At least one measurable lesion per RECIST v1.1 (the measurable lesion must have a longest diameter ≥ 10 mm on spiral CT scan, or a short-axis diameter ≥ 15 mm on CT scan for lymph node lesions; lesions previously treated with local-regional therapy may be selected as target lesions if clearly progressive per RECIST v1.1).
• Child-Pugh liver function class A, or good class B (score ≤ 7).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Life expectancy ≥ 12 weeks.
• Adequate major organ function, meeting all of the following requirements (assessed within 7 days prior to initiation of study treatment):
• Hematology: absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L; platelet count (PLT) ≥ 75 × 10^9/L; hemoglobin ≥ 90 g/L;
• Serum biochemistry: albumin ≥ 25 g/L; total bilirubin ≤ 3.0 × upper limit of normal (ULN); alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 5 × ULN; creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (CrCl) > 50 mL/min calculated by the Cockcroft-Gault formula: Male: CrCl = ((140 - age) × weight) / (72 × serum Cr); Female: CrCl = ((140 - age) × weight) / (72 × serum Cr) × 0.85 (weight in kg; serum Cr in mg/mL);
• International normalized ratio (INR) ≤ 2.3, or prothrombin time (PT) prolonged by ≤ 6 seconds above the normal control;
• Urine protein < 2+ (if urine protein ≥ 2+, 24-hour urine protein quantification may be performed; patients with 24-hour urine protein < 1.0 g are eligible).
• Patients with active hepatitis B virus (HBV) infection must receive anti-HBV therapy prior to initiation of study treatment and be willing to continue antiviral therapy throughout the entire study period; patients positive for hepatitis C virus (HCV) ribonucleic acid (RNA) must receive antiviral therapy according to local standard treatment guidelines, with liver function test elevations within CTCAE Grade 1.
• Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to study enrollment, must not be breastfeeding, and must agree to use contraception during the study period and for 6 months after the end of the study; male patients must agree to use contraception during the study period and for 6 months after the end of the study.

Exclusion Criteria:

• Known cholangiocarcinoma, sarcomatoid HCC, mixed-cell carcinoma (combined hepatocellular-cholangiocarcinoma), or fibrolamellar carcinoma; other active malignancy(ies) other than HCC within the past 5 years or concurrently. Patients with adequately treated localized tumors, such as basal cell carcinoma or squamous cell carcinoma of the skin, superficial bladder cancer, carcinoma in situ of the prostate, cervix, or breast, are eligible.
• Patients who are planning to undergo, or have previously undergone, organ or allogeneic bone marrow transplantation.
• Clinically symptomatic moderate or severe ascites requiring therapeutic paracentesis or drainage; uncontrolled pleural effusion or pericardial effusion of moderate volume or greater.
• History of gastrointestinal (GI) bleeding within 6 months prior to initiation of study treatment, or a definite tendency toward GI bleeding, such as: esophageal or gastric fundal varices at risk of bleeding or with severe varices, locally active GI ulcerative lesions, or persistently positive fecal occult blood; such patients are not eligible.
• Abdominal fistula, GI perforation, or intra-abdominal abscess within 6 months prior to initiation of study treatment.
• Known hereditary or acquired hemorrhagic tendency (e.g., coagulation dysfunction) or thrombotic tendency.
• Currently receiving, or recently received (within 10 days prior to initiation of study treatment), aspirin > 325 mg/day (maximum antiplatelet dose), dipyridamole, ticlopidine, or cilostazol.
• Thrombotic or embolic events within 6 months prior to initiation of study treatment, such as cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), pulmonary embolism, etc.
• Uncontrolled cardiac symptoms or diseases, such as: (1) heart failure of New York Heart Association (NYHA) Class II or above; (2) unstable angina pectoris; (3) myocardial infarction within 1 year; (4) clinically significant supraventricular or ventricular arrhythmia requiring clinical intervention; (5) hypertension inadequately controlled by medication, with a high risk of apatinib treatment as assessed by the investigator.
• Prior hypertensive crisis or hypertensive encephalopathy.
• Major vascular disease within 6 months prior to initiation of study treatment (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis).
• Severe, unhealed, or dehiscent wounds, active ulcers, or untreated bone fractures.
• Major surgery (excluding diagnostic procedures) within 4 weeks prior to initiation of study treatment, or anticipated major surgery during the study period.
• Inability to swallow tablets, malabsorption syndrome, or any condition affecting GI absorption.
• Intestinal obstruction within 6 months prior to initiation of study treatment, and/or clinical signs or symptoms of GI obstruction.
• Evidence of intra-abdominal free air that cannot be explained by paracentesis or recent surgical procedures.
• Prior or current central nervous system (CNS) metastases.
• History of hepatic encephalopathy.
• Current interstitial pneumonia or interstitial lung disease, or a history of interstitial pneumonia or interstitial lung disease requiring corticosteroid therapy; or other pulmonary conditions that may interfere with the assessment and management of immune-related pulmonary toxicity, such as pulmonary fibrosis, organizing pneumonia, pneumoconiosis, drug-induced pneumonitis, idiopathic pneumonitis, or severely impaired pulmonary function; active tuberculosis.
• Active autoimmune disease or a history of autoimmune disease with a risk of recurrence (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism [patients whose condition can be controlled by hormone replacement therapy alone are eligible]); patients with asthma requiring bronchodilator medical intervention are not eligible.
• Use of immunosuppressive agents or systemic corticosteroids for the purpose of immunosuppression (prednisone > 10 mg/day or equivalent doses of other corticosteroids) within 14 days prior to initiation of study treatment.
• Severe infection within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia; oral or intravenous therapeutic antibiotics within 2 weeks prior to initiation of study treatment (patients receiving prophylactic antibiotics, e.g., for prevention of urinary tract infection or chronic obstructive pulmonary disease exacerbation, are eligible).
• Congenital or acquired immunodeficiency (e.g., patients with HIV infection).
• Receipt of live attenuated vaccines within 28 days prior to initiation of study treatment, or anticipated need for such vaccination during camrelizumab treatment or within 60 days after the last dose of camrelizumab.
• Receipt of other investigational drugs within 28 days prior to initiation of study treatment.
• In the judgment of the investigator, any other factors that may affect the study results or lead to premature termination of the study, such as alcohol abuse or drug abuse, other serious illnesses (including psychiatric disorders) requiring concomitant treatment, severe laboratory abnormalities, or family or social factors that may compromise patient safety.