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.

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.

Inclusion Criteria:

• Ability to understand and sign written informed consent prior to any study-related procedures.

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:

• Candidates suitable for local curative therapy.

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.

This is an open-label study; no participants, care providers, investigators, or outcomes assessors are masked