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 (DRIVE-II)
Status and phase
Conditions
Treatments
Details and patient eligibility
About
The goal of this prospective Phase II clinical trial is to evaluate the efficacy and safety of QL1706-based combination therapy in patients with hepatocellular carcinoma (HCC) who have failed prior targeted-immunotherapy (e.g., anti-PD-1/PD-L1 + antiangiogenic therapy).
The main question is:
Can the combination of localized-regional therapy (e.g., HAIC/TACE) and systemic dual immunotherapy (QL1706) overcome resistance and improve outcomes in second-line HCC treatment?
Participants will:
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Receive QL1706 (a dual immune checkpoint inhibitor) combined with either:
Hepatic arterial infusion chemotherapy (HAIC)/transarterial chemoembolization (TACE), or Antiangiogenic targeted therapy.
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Undergo regular imaging (e.g., MRI/CT) and biomarker assessments for efficacy monitoring.
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Be evaluated for adverse events (AEs) and quality of life.
This study seeks to establish a novel therapeutic paradigm for HCC patients after targeted-immunotherapy failure, addressing the unmet need for evidence-based second-line strategies.
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
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Voluntary Participation, Willingly signs the written informed consent form.
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Aged 18-65 years (inclusive), any gender.
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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.
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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.
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Liver Function: Child-Pugh class A or class B (score ≤7), with no history of hepatic encephalopathy.
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Performance Status: ECOG PS score 0 or 1.
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Life Expectancy ≥12 weeks.
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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).
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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).
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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.
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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.
Exclusion criteria
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Histologically/cytologically confirmed fibrolamellar HCC, sarcomatoid HCC, cholangiocarcinoma, or mixed hepatocellular-cholangiocarcinoma.
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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).
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History of or planned liver transplantation.
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Clinically significant ascites requiring therapeutic paracentesis, uncontrolled pleural/pericardial effusion (asymptomatic minimal ascites on imaging allowed).
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Known CNS metastases or leptomeningeal disease.
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Tumor thrombus involving both main portal vein and superior mesenteric vein, or portal vein and inferior vena cava.
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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").
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Life-threatening hemorrhage within 3 months requiring transfusion/surgery/medical intervention.
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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.
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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).
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Abdominal fistula/GI perforation/abscess within 6 months.
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Bowel obstruction/clinical signs of GI obstruction within 6 months.
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Non-healing wounds, active ulcers, or untreated fractures.
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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.
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Immunosuppressants (>10 mg/day prednisone equivalent) within 2 weeks.
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Severe hypersensitivity to monoclonal antibodies.
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Hepatic encephalopathy or CNS metastases.
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Organ transplant history.
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Symptomatic ascites requiring drainage within 3 months.
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Uncontrolled hypertension (≥140/90 mmHg despite treatment).
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Arterial/venous thrombosis within 6 months (stroke, DVT, PE).
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Bleeding/thrombotic disorders (hemophilia, coagulopathy, thrombocytopenia).
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Proteinuria ≥++ with 24-h urine protein >1.0 g.
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Active infection (fever ≥38.5°C within 7 days or WBC >15×10⁹/L).
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Interstitial lung disease (current or steroid-requiring history).
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Active tuberculosis (confirmed by imaging/sputum/clinical assessment).
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Immunodeficiency (HIV/syphilis).
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Severe infection within 4 weeks (hospitalization required) or antibiotics within 2 weeks (prophylaxis allowed).
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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).
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Immunomodulators (interferons, interleukins) within 2 weeks.
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Other investigational drugs within 4 weeks.
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Allogeneic stem cell/organ transplant.
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HBV-HCV coinfection.
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Hypersensitivity to trial drug components/monoclonal antibodies/antiangiogenic agents.
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Live vaccines within 4 weeks or planned during study.
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Major surgery within 4 weeks or planned during study (biopsies/IV catheterization allowed).
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Other exclusionary factors per investigator judgment (substance abuse, severe comorbidities, psychosocial risks).
Trial design
Primary purpose
Allocation
Interventional model
Masking
62 participants in 2 patient groups
Trial contacts and locations
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Data sourced from clinicaltrials.gov
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