A Phase II, Single-Arm, Prospective Trial on the Efficacy and Safety of QL1706 Combination Regimen as Second-Line Therapy for Targeted-Immunotherapy-Resistant Hepatocellular Carcinoma

Korábbi kezelés

• Other active malignancies within 5 years prior to enrollment, except cured localized tumors (e.g., basal cell carcinoma, squamous cell skin cancer, superficial bladder cancer, in situ prostate/cervical/breast cancer).
• Organ transplant history.
• Recent treatments:
  • Liver surgery/HCC locoregional therapy within 4 weeks
  • Palliative bone radiotherapy within 2 weeks
  • Anti-HCC herbal medicine within 2 weeks
  • Unresolved toxicities (>Grade 1 per CTCAE v5.0, except alopecia).
• Other investigational drugs within 4 weeks.
• Allogeneic stem cell/organ transplant.
• Live vaccines within 4 weeks or planned during study.
• Major surgery within 4 weeks or planned during study (biopsies/IV catheterization allowed).

Más betegség

• History of or planned liver transplantation.
• Known CNS metastases or leptomeningeal disease.
• High-risk variceal bleeding:
  • Esophageal/gastric variceal bleeding within 6 months
  • High-grade varices on endoscopy within 3 months
  • Portal hypertension with bleeding risk (splenomegaly, active ulcers, occult blood+, or endoscopic "red signs").
• Life-threatening hemorrhage within 3 months requiring transfusion/surgery/medical intervention.
• Significant bleeding risk:
  • Hemoptysis/tumor bleeding within 2 weeks
  • Thromboembolism within 6 months
  • Therapeutic anticoagulation (except prophylactic LMWH) within 2 weeks
  • Antiplatelet therapy (aspirin >325 mg/day, clopidogrel >75 mg/day) within 10 days
  • Tumor invasion of major vessels/airways/mediastinum.
• Abdominal fistula/GI perforation/abscess within 6 months.
• Active autoimmune diseases or history of autoimmune diseases with potential recurrence (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism [patients with hypothyroidism controlled by hormone replacement therapy alone are not excluded]). Note: Patients with non-systemic skin conditions (e.g., vitiligo, psoriasis, alopecia), well-controlled type 1 diabetes on insulin, or childhood asthma with complete remission in adulthood requiring no intervention may be enrolled. Asthma patients requiring bronchodilator therapy are excluded.
• Severe hypersensitivity to monoclonal antibodies.
• Uncontrolled hypertension (≥140/90 mmHg despite treatment).
• Arterial/venous thrombosis within 6 months (stroke, DVT, PE).
• Bleeding/thrombotic disorders (hemophilia, coagulopathy, thrombocytopenia).
• Interstitial lung disease (current or steroid-requiring history).
• Active tuberculosis (confirmed by imaging/sputum/clinical assessment).
• Immunodeficiency (HIV/syphilis).
• Severe infection within 4 weeks (hospitalization required) or antibiotics within 2 weeks (prophylaxis allowed).
• HBV-HCV coinfection.
• Hypersensitivity to trial drug components/monoclonal antibodies/antiangiogenic agents.

Laborértékek

• Severe cardiovascular disease:
  • Significant arrhythmias (requiring intervention), QTcF ≥450 ms (M)/470 ms (F)
  • ACS/heart failure/stroke/TIA within 6 months
  • NYHA class ≥II or LVEF <50%
  • Uncontrolled hypertension (≥160/100 mmHg despite ≥2 agents).
• Active infection (fever ≥38.5°C within 7 days or WBC >15×10⁹/L).

Egyéb

• Histologically/cytologically confirmed fibrolamellar HCC, sarcomatoid HCC, cholangiocarcinoma, or mixed hepatocellular-cholangiocarcinoma.
• Clinically significant ascites requiring therapeutic paracentesis, uncontrolled pleural/pericardial effusion (asymptomatic minimal ascites on imaging allowed).
• Tumor thrombus involving both main portal vein and superior mesenteric vein, or portal vein and inferior vena cava.
• Bowel obstruction/clinical signs of GI obstruction within 6 months.
• Non-healing wounds, active ulcers, or untreated fractures.
• Immunosuppressants (>10 mg/day prednisone equivalent) within 2 weeks.
• Hepatic encephalopathy or CNS metastases.
• Symptomatic ascites requiring drainage within 3 months.
• Proteinuria ≥++ with 24-h urine protein >1.0 g.
• Immunomodulators (interferons, interleukins) within 2 weeks.
• Other exclusionary factors per investigator judgment (substance abuse, severe comorbidities, psychosocial risks).

• Voluntary Participation, Willingly signs the written informed consent form.
• Aged 18-65 years (inclusive), any gender.
• Histologically, cytologically, or clinically confirmed hepatocellular carcinoma (HCC) with disease progression after first-line targeted therapy combined with immunotherapy, or intolerable to first-line targeted-immunotherapy combination treatment.
• No prior exposure to VEGF monoclonal antibodies, CTLA-4 inhibitors, or bispecific antibodies. For arm 1: No prior treatment with oxaliplatin or fluorouracil-based drugs.
• Liver Function: Child-Pugh class A or class B (score ≤7), with no history of hepatic encephalopathy.
• Performance Status: ECOG PS score 0 or 1.
• Life Expectancy ≥12 weeks.
• Measurable Lesion: ≥1 measurable target lesion per RECIST v1.1 (not previously irradiated/localized; lesions in prior treatment areas are acceptable if progression is confirmed).
• Preserved organ \& bone marrow function (within 7 days before treatment; no blood products/growth factors within 14 days prior):
  • Neutrophil count (ANC) ≥1.5×10⁹/L
  • Platelets ≥75×10⁹/L
  • Hemoglobin ≥90 g/L
  • Albumin ≥28 g/L
  • ALT/AST/Alkaline phosphatase (AKP) ≤3×ULN
  • Total bilirubin (TBIL) ≤2×ULN
  • INR ≤2 or PT prolongation ≤6 sec above ULN
  • Urine protein <2+ (if ≥2+, 24-hour urine protein must be <1.0 g).
• Viral Hepatitis Management
  • If HBsAg-positive: HBV DNA <2000 IU/mL or 10⁴ copies/mL, with ongoing antiviral therapy (entecavir/tenofovir disoproxil fumarate/tenofovir alafenamide/emtecavir).
  • HCV-infected patients with undetectable HCV RNA are considered HCV-negative.
• Contraception
  • Fertile participants (male/female) must use reliable contraception (hormonal/barrier/abstinence) during and for ≥180 days post-treatment.
  • Women of childbearing potential must have a negative serum pregnancy test within 7 days before enrollment.