Ivarmacitinib Combined With Camrelizumab and Apatinib for Unresectable Advanced Hepatocellular Carcinoma With Acquired Resistance to Immune Checkpoint Therapy: A Single-Arm Exploratory Clinical Study

Inclusion Criteria

• •1. Patients with a diagnosis of hepatocellular carcinoma, confirmed either by clinical diagnosis (per the Chinese Guidelines for the Diagnosis and Treatment of Primary Liver Cancer \[2022 Edition\]) or by pathological diagnosis.
• •2. Patients classified as Barcelona Clinic Liver Cancer (BCLC) stage B and assessed by the responsible hepatobiliary surgeon as unsuitable for radical resection, or patients with BCLC stage C disease.
• •3. Patients with unresectable hepatocellular carcinoma who have developed secondary (acquired) drug resistance. This is defined as having received at least 4 cycles of a first-line targeted therapy combined with immunotherapy regimen recommended by guidelines . Eligible prior regimens include specified combinations (e.g., Camrelizumab + Apatinib; Atezolizumab + Bevacizumab; Sintilimab + Bevacizumab) or other guideline-recommended first-line targeted agents (Donafenib, Lenvatinib, Sorafenib, Cabozantinib, Regorafenib) combined with first-line immunotherapy (Tislelizumab, Durvalumab, Pembrolizumab). Furthermore, patients must have achieved a partial response in the primary lesion but subsequently experienced disease progression after the 4th immunotherapy cycle, as confirmed per RECIST 1.1 criteria (including increase in size of primary lesion, or emergence of new lesions/metastases).
• •4. At least one measurable lesion according to RECIST 1.1 criteria (target lesion with longest diameter ≥ 10 mm, or lymph node with short axis ≥ 15 mm).
• •5. Anticipated life expectancy \> 3 months.
• •6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.
• •7. Adequate organ and bone marrow function, as evidenced by the following laboratory values within 7 days prior ： (1)Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L in the absence of granulocyte colony-stimulating factor support within the last 14 days; (2)Platelets ≥ 60 × 10⁹/L without transfusion within the last 14 days; (3)Hemoglobin \> 9 g/dL without transfusion or erythropoietin use within the last 14 days; (4)Total bilirubin ≤ 2 × upper limit of normal (ULN); (5)Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN; (6)Serum creatinine ≤ 1.5 × ULN and creatinine clearance (calculated using the Cockcroft-Gault formula) ≥ 60 mL/min; (7)Adequate coagulation function, defined as an International Normalized Ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN; (8)Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within the normal range. If baseline TSH is outside the normal range, study participants may still be enrolled if total T3 (or free T3) and free T4 are within the normal range; (9)Myocardial enzyme profile within normal limits (isolated laboratory abnormalities judged by the investigator as clinically insignificant are also permitted);
• •8. For female study participants of childbearing potential, a negative urine or serum pregnancy test must be obtained within 3 days prior to the first dose of study drug (Cycle 1, Day 1). If the urine pregnancy test result is not confirmatory, a serum pregnancy test is required. A female not of childbearing potential is defined as being postmenopausal for at least 1 year, or surgically sterilized, or having undergone a hysterectomy.