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.
