PEARL Trial: Partial TACE Enhancing Anti-tumor Response With Lenvatinib in Unresectable HCC

Primary objective:

-1-year progression-free survival (PFS) by mRECIST

Secondary objectives:

* 1-year overall survival (OS)
* Objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1 and mRECIST
* Incidence of hepatic decompensation within 30 days after treatment (defined as: bilirubin > 3 mg/dL, new or worsened ascites, or hepatic encephalopathy)
* Duration of response (DOR)

Exploratory Endpoints:

* Depth of response (DpR)
* Immune profile changes from baseline (assessed by multiparametric flow cytometry and single-cell RNA sequencing)

• Lenvatinib (Drug): Oral lenvatinib 12 mg once daily for body weight 60 kg or greater, or 8 mg once daily for body weight less than 60 kg. Treatment continues until disease progression, unacceptable toxicity, or patient withdrawal.
• Partial transarterial chemoembolization (TACE) (Procedure), also known as Partial TACE: Transarterial chemoembolization targeting up to two liver segments containing the largest tumor volume or lesions at risk of rupture, performed within 4 weeks after starting lenvatinib. This liver-function-sparing approach limits the ischemic territory in order to preserve hepatic reserve.

Primary outcomes

• 1-year progression-free survival (PFS) by mRECIST [1 year after start of study treatment]: Percentage of participants alive and free of disease progression at 1 year. Progression-free survival is measured from the start date of study treatment to the date of first documented disease progression according to modified RECIST (mRECIST) or death from any cause, whichever occurs first.

Secondary outcomes

• 1-year overall survival (OS) [1 year after start of study treatment]: Percentage of participants alive at 1 year. Overall survival is measured from the start date of study treatment to the date of death from any cause.
• Objective response rate (ORR) by mRECIST [Up to 12 months after start of study treatment]: Percentage of participants with a best overall response of confirmed complete response or partial response, as assessed by modified RECIST (mRECIST). Tumor response is assessed by CT or MRI every 12 weeks from the start of study treatment; a first objective response is confirmed by a second imaging assessment 4 weeks later.
• Objective response rate (ORR) by RECIST v1.1 [Up to 12 months after start of study treatment]: Percentage of participants with a best overall response of confirmed complete response or partial response, as assessed by RECIST version 1.1. Tumor response is assessed by CT or MRI every 12 weeks from the start of study treatment; a first objective response is confirmed by a second imaging assessment 4 weeks later.
• Disease control rate (DCR) by mRECIST [Up to 12 months after start of study treatment]: Percentage of participants with a best overall response of confirmed complete response, partial response, or stable disease, as assessed by modified RECIST (mRECIST). Tumor response is assessed by CT or MRI every 12 weeks from the start of study treatment.
• Disease control rate (DCR) by RECIST v1.1 [Up to 12 months after start of study treatment]: Percentage of participants with a best overall response of confirmed complete response, partial response, or stable disease, as assessed by RECIST version 1.1. Tumor response is assessed by CT or MRI every 12 weeks from the start of study treatment.
• Duration of response (DOR) by mRECIST [Up to 12 months after start of study treatment]: Time from the date of first documented objective response (complete or partial response) to the date of first documented disease progression, as assessed by modified RECIST (mRECIST). Reported in months.
• Incidence of hepatic decompensation [Within 30 days after treatment]: Percentage of participants with hepatic decompensation within 30 days after treatment. Hepatic decompensation is defined as any of the following: total bilirubin greater than 3 mg/dL, new or worsened ascites, or hepatic encephalopathy.
• Incidence of treatment-emergent adverse events [From first dose of study treatment up to 30 days after the last dose]: Number of participants with treatment-emergent adverse events and serious adverse events, graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Other outcomes

• Depth of response (maximum percentage reduction from baseline in the sum of viable target lesion diameters) [Up to 12 months after start of study treatment]: Maximum percentage reduction from baseline in the sum of viable target lesion diameters, as assessed by modified RECIST (mRECIST). Reported as percentage change from baseline.
• Change from baseline in immune cell subset frequencies assessed by multiparametric flow cytometry [Baseline, within 24 hours before TACE, within 48 hours after TACE, Week 12, and Week 24]: Change from baseline in the frequencies of peripheral blood immune cell subsets measured by multiparametric flow cytometry, including CD4+ and CD8+ T cells, regulatory T cells, natural killer cells, mucosal-associated invariant T cells, and myeloid populations, together with the activation and exhaustion markers PD-1, TIM-3, HLA-DR, and CD38. Reported as percentage of live cells.
• Change from baseline in immune cell composition assessed by single-cell RNA sequencing [Baseline, within 24 hours before TACE, within 48 hours after TACE, Week 12, and Week 24]: Change from baseline in immune cell composition measured by single-cell RNA sequencing of peripheral blood mononuclear cells and tissue samples, reported as percentage of sequenced cells assigned to each annotated immune cell cluster.

Sex: All, ages: 20 Years to any

Inclusion Criteria:

Diagnosis of HCC confirmed by histology/cytology or typical imaging features, unsuitable for surgical resection or liver transplantation

* Age ≥ 20 years at the time of signing informed consent
* ECOG performance status 0-1
* BCLC stage B or C (without main portal vein thrombosis)
* Child-Pugh score 5-7 (Class A or B7) within 28 days of registration
* Adequate bone marrow, liver, and renal function
* Blood pressure adequately controlled
* Ability to understand and sign written informed consent

Exclusion Criteria:

Prior systemic therapy for HCC

* Main portal vein thrombosis
* Prior locoregional therapy within 4 weeks
* Uncontrolled hypertension
* Clinically significant cardiovascular disease within 6 months
* Pregnancy or breastfeeding