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This study aims to evaluate the effectiveness and safety of a combination therapy with Fuxinqibai monoclonal antibody, Tislelizumab, and Lenvatinib in patients with advanced, unresectable TP53-mutated hepatocellular carcinoma (HCC) who have previously failed systemic immunotherapy.
Eligible patients will receive:
Fuxinqibai 200 mg IV every 3 weeks Tislelizumab 200 mg IV every 3 weeks Lenvatinib 8 mg (≤60 kg) or 12 mg (>60 kg) orally once daily Treatment will continue until disease progression, unacceptable toxicity, start of a new anticancer therapy, withdrawal of consent, or other protocol-defined reasons. Tumor response will be evaluated by RECIST v1.1 every 6 weeks, and confirmed after 4 weeks if response is observed.
Safety will be monitored through adverse events and laboratory tests, graded according to NCI CTCAE v5.0. After treatment ends, patients will be followed every 6 weeks for tumor assessment and every 12 weeks for survival, until death, loss to follow-up, or withdrawal of consent.
Primary Objective: To assess the objective response rate (ORR) of the combination therapy.
Secondary Objectives: To evaluate overall efficacy, safety, and explore potential biomarkers predicting treatment response.
Full description
Study Title
Evaluation of Firsekibart Combined with Tirelizumab and Lenvatinib in Patients with Unresectable, Advanced TP53-Mutant Hepatocellular Carcinoma After Progression on Prior Systemic Immunotherapy: An Open-Label, Single-Arm Clinical Study
Brief Summary
This open-label, single-arm study investigates the efficacy and safety of Firsekibart in combination with Tirelizumab and Lenvatinib in adult patients with unresectable, advanced TP53-mutant hepatocellular carcinoma (HCC) who have progressed after prior PD-1/PD-L1-based systemic immunotherapy. The primary objective is to determine the objective response rate (ORR). Secondary objectives include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety and tolerability, quality of life (QoL), pathological response, patterns of disease progression, and exploration of predictive biomarkers in tumor tissue and blood.
Study Design
This study consists of three phases: screening, treatment, and follow-up. Eligible patients will receive treatment in 3-week cycles.
Treatment Regimen
Firsekibart: 200 mg IV on Day 1 of each 3-week cycle
Tirelizumab: 200 mg IV on Day 1 of each 3-week cycle, administered 1 hour after Firsekibart
Lenvatinib: 8 mg/day orally if ≤60 kg or 12 mg/day if >60 kg
Treatment continues until disease progression, unacceptable toxicity, initiation of new anticancer therapy, withdrawal of consent, death, or investigator decision. Dose adjustments follow protocol-defined criteria.
Efficacy Assessments
Primary Endpoint: ORR per RECIST v1.1
Secondary Endpoints:
DCR per mRECIST
DOR
PFS
OS
Safety and tolerability (AEs, SAEs, lab abnormalities, ECG changes)
QoL
Pathological response
Disease progression patterns (intrahepatic, vascular invasion, extrahepatic spread)
Predictive biomarkers in tumor tissue and blood
Imaging (enhanced CT or MRI) is performed at baseline and every 6 weeks (±7 days) during treatment. Confirmatory scans are required for any partial or complete response after 4 weeks.
Safety Assessments
AEs are graded per NCI CTCAE v5.0. Safety monitoring includes laboratory evaluations, ECG, vital signs, and physical exams. SAEs and treatment-related AEs are recorded. Additional evaluations may be performed based on clinical judgment.
Eligibility Criteria Inclusion Criteria
Age ≥18 years; able to provide informed consent
Histologically or cytologically confirmed advanced or unresectable HCC
TP53 mutation confirmed by central laboratory testing from fresh liver tumor biopsy
Progression after at least one prior PD-1/PD-L1 therapy
Disease assessed by MDT as unresectable (R0 resection not feasible, insufficient functional liver volume, or multifocal disease)
BCLC stage B or C
At least one measurable lesion per RECIST v1.1
ECOG performance status 0-1
Child-Pugh A liver function
Adequate hematologic, hepatic, renal, and coagulation function
Life expectancy ≥12 weeks
Effective contraception for women of childbearing potential and male partners
Ability to comply with study procedures and visit schedule
Exclusion Criteria
Eligible for curative local therapy
Mixed or sarcomatoid HCC or other malignancies
Hematologic malignancy
Hepatic encephalopathy or liver transplant history
Symptomatic effusions requiring intervention
Active viral hepatitis exceeding protocol thresholds (HBV DNA >2000 IU/mL, HCV RNA >10³ copies/mL)
HIV infection
CNS metastases
Recent major bleeding or thromboembolic events
Uncontrolled cardiovascular or pulmonary disease
Active autoimmune disease requiring systemic therapy within 2 years
Prior immunosuppressive therapy within 4 weeks (with exceptions)
Major surgery within 4 weeks
Pregnancy or breastfeeding
Extensive metastatic disease (≥5 lesions, major vascular involvement)
Participation in other clinical trials within 4 weeks
Any condition increasing risk or interfering with study participation per investigator judgment
Study Procedures
Screening Phase: Informed consent, baseline labs, imaging, and TP53 testing
Treatment Phase: 3-week cycles of Firsekibart + Tirelizumab + Lenvatinib; tumor response assessed every 6 weeks
Dose Modifications: Based on toxicity and body weight changes
Safety Monitoring: Labs, ECG, physical exam, AE reporting; additional checks per clinical indication
Follow-Up Phase: Survival assessments every 12 weeks until death, loss to follow-up, or withdrawal of consent
Statistical Analysis
Analysis Sets: Full analysis set (FAS), per-protocol set (PPS), safety set (SS)
Descriptive Statistics: Mean, SD, median, min, max for continuous variables; frequency and proportion for categorical variables
Efficacy Analysis: ORR and DCR as proportions; PFS and OS estimated using Kaplan-Meier method with 95% CI
Safety Analysis: Incidence of AEs, SAEs, lab abnormalities, and ECG changes; coded per MedDRA
Interim Analysis: After first 10 patients complete ≥3 cycles, evaluate early efficacy to determine continuation
Sample Size and Duration
Phase 1: 10 patients; proceed to Phase 2 if ≥3 responders observed
Phase 2: Enroll additional patients to reach ≥25 total
Total enrollment expected within 12 months
Observation period: 24 months
Treatment continues until progression, unacceptable toxicity, or discontinuation criteria met
Withdrawal and Study Termination
Patients may withdraw for:
Requesting discontinuation of study treatment
Clinically significant AEs or lab abnormalities
Investigator judgment for safety or compliance reasons
Loss to follow-up or death
Study may be terminated by investigator if continuation is deemed unsafe or unfeasible.
Conclusion
This study evaluates Firsekibart combined with Tirelizumab and Lenvatinib in TP53-mutant, unresectable HCC post-immunotherapy. The protocol includes comprehensive eligibility criteria, standardized dosing, rigorous safety and efficacy monitoring, and biomarker exploration. The results aim to provide critical evidence for the clinical utility of this combination in a well-defined high-risk population.
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Inclusion criteria
Age ≥18 years at the time of signing informed consent.
Histologically or cytologically confirmed advanced or unresectable hepatocellular carcinoma (HCC).
Documented disease progression after prior systemic immunotherapy, including at least one PD-(L)1 inhibitor.
Confirmed TP53 mutation in fresh liver tumor tissue by central laboratory testing.
Determined by liver tumor MDT to be unsuitable for curative surgery (R0 resection not feasible, insufficient normal liver volume, or other criteria).
BCLC stage B or C.
At least one measurable lesion per RECIST v1.1 confirmed by BICR.
ECOG performance status 0-1.
Child-Pugh class A within 7 days prior to randomization.
Adequate organ and bone marrow function within 7 days prior to enrollment:
ANC ≥1.5×10^9/L, Platelets ≥75×10^9/L, HGB ≥9 g/dL
TBIL ≤2×ULN, ALT/AST ≤5×ULN, Albumin ≥28 g/L, ALP ≤5×ULN
Creatinine ≤1.5×ULN or CCr ≥50 mL/min, urine protein <2+ (or 24-h urine protein <1 g if baseline ≥2+)
INR ≤2.3 or PT prolongation ≤6 sec
Expected survival ≥12 weeks.
Women of childbearing potential and male participants with partners of childbearing potential must use effective contraception during treatment and for 6 months after last dose.
Ability and willingness to comply with study procedures and visits.
Exclusion criteria
Mixed liver tumors containing sarcomatoid or intrahepatic cholangiocarcinoma components.
Hematologic malignancies.
History of hepatic encephalopathy or prior liver transplantation.
Symptomatic pleural effusion, ascites, or pericardial effusion requiring drainage; asymptomatic small effusions allowed.
Active HBV (HBV DNA >2000 IU/mL) or HCV (HCV RNA >10^3 copies/mL) infection; co-infection HBsAg+/HCV Ab+ excluded.
CNS metastases.
Significant recent variceal bleeding (within 6 months).
Life-threatening hemorrhagic events within 3 months.
Significant thromboembolic events within 6 months.
Use of high-dose aspirin (>325 mg/day) or other platelet inhibitors within 2 weeks prior to first dose.
Unresolved grade ≥2 toxicities from prior therapies (excluding hair loss or asymptomatic lab abnormalities).
Symptomatic heart failure NYHA II-IV or LVEF <50%.
Uncontrolled arrhythmias or congenital long QT syndrome, QTc >500 ms.
Active bleeding disorders or on thrombolytic therapy.
Recent history of gastrointestinal perforation, fistula, obstruction, or significant bowel disease.
Radiotherapy within 3-7 weeks prior to first dose with residual toxicity.
History of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-induced lung injury, or severe impaired lung function.
Active tuberculosis or treatment for TB within 1 year.
HIV infection or active, untreated syphilis.
Active or uncontrolled severe infection within 4 weeks prior to first dose.
Active autoimmune disease requiring systemic treatment within 2 years. Known primary immunodeficiency.
Use of systemic immunosuppressants within 4 weeks prior to first dose (nasal/inhaled steroids at physiologic dose allowed).
Receipt of live attenuated vaccines within 4 weeks prior to first dose.
Major surgery within 4 weeks prior to first dose, or unhealed wounds. Minor procedures like IV lines excluded.
Uncontrolled metabolic disorders or organ/systemic disease posing excess risk.
History of other malignancy within 5 years, except curatively treated basal cell carcinoma, squamous cell carcinoma, or in situ carcinoma.
Known hypersensitivity to study drugs or formulation components.
History of aortic dissection or visceral artery aneurysm.
Participation in another clinical trial within 4 weeks prior to first dose.
Pregnant or breastfeeding women.
Extensive metastatic disease (≥5 lesions) or major vascular invasion.
Other acute or chronic diseases, psychiatric conditions, or lab abnormalities deemed by investigator to increase risk or interfere with study.
Primary purpose
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Interventional model
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25 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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