Efficacy and Safety Comparison Between Intensified Therapy and Conversion Therapy For Advanced HCC After Failure of First-line

Efficacy and Safety Comparison Between Intensified Therapy (Plus Lenvatinib) and Conversion Therapy (Regorafenib Combined With PD-(L)1 Inhibitor) For Advanced Hepatocellular Carcinoma After Failure of First-line Bevacizumab Plus Sintilimab: A Prospective, Randomized, Two-Cohort, Phase II Study

Although immunotherapy-based therapies (including targeted-immunotherapy or dual-immunotherapy protocols) have become the first-line standard treatment for advanced hepatocellular carcinoma (HCC), there remains a lack of high-level evidence to guide the selection of second-line therapies following progression in immune checkpoint inhibitors (ICIs). Additionally, direct comparative data are scarce for combination treatment modalities such as "continuation of the original first-line regimen with added agents" or "switching to agents with different mechanisms".

To address this clinical need and explore novel second-line treatment strategies for advanced HCC, we plan to conduct an exploratory clinical trial to investigate the efficacy and safety comparison between intensified therapy (plus lenvatinib) and conversion therapy (regorafenib combined with PD-1 inhibitor) for advanced hepatocellular carcinoma after failure of fFirst-line bevacizumab plus sintilimab.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellulcar Carcinoma
• Intervention / Treatment: Drug: Intensified Therapy; Drug: Conversion Therapy

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Recruiting
      • Sun yat-sen University Cancer Center
      • Contact: Ming Shi, MD; Phone Number: 8620-87343115; Email: shiming@mail.sysu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosed with hepatocellular carcinoma (HCC) based on histological or clinical diagnostic criteria;
2. Classified as unresectable HCC following multidisciplinary assessment;
3. Presence of at least one tumor lesion measurable according to EASL criteria;
4. Child-Pugh liver function class A/B, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score 0-2;
5. Disease progression confirmed by CT/MRI and evaluated according to modified RECIST (mRECIST)/RECIST v1.1 criteria after ≥2 cycles of first-line therapy with bevacizumab (15 mg/kg intravenous infusion, once every 3 weeks) combined with sintilimab (200 mg intravenous infusion, once every 3 weeks);
6. Received ≥2 cycles of post-progression treatment with bevacizumab plus sintilimab, lenvatinib, or regorafenib combined with PD-1 inhibitors;
7. Age ≥18 and ≤75 years;
8. Capability to comprehend the study protocol and provide written informed consent;
9. Laboratory parameters: hemoglobin(Hb) ≥8.5 g/dL, white blood cell (WBC) count >2000/mm³, platelet (PLT) count ≥75,000/mm³, absolute neutrophil count (ANC) >1500/mm³, total bilirubin ≤30 μmol/L, serum albumin ≥30 g/L, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤5 times the upper limit of normal (ULN), serum creatinine ≤1.5 times ULN, international normalized ratio (INR) ≤1.5, prothrombin time (PT) ≤18 seconds;
10. Availability of complete baseline data, treatment records, and follow-up data (including imaging assessments, laboratory tests, and clinical documentation).

Exclusion Criteria:

1. Life expectancy ≤2 months;
2. Presence of intrahepatic cholangiocarcinoma, mixed hepatocellular-cholangiocarcinoma, or other non-HCC malignancies;
3. Active concurrent malignancy or severe comorbid conditions;
4. First-line treatment with other anticancer therapies (chemotherapy, radiotherapy, surgery, or other interventions) concurrently;
5. Pregnancy or lactation;
6. Known hypersensitivity to study drugs;
7. Clinically significant gastrointestinal bleeding within 30 days prior to enrollment;
8. Refusal to comply with study and/or follow-up procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intensified Therapy Group; Bevacizumab, Sintilimab, Lenvatinib.	Drug: Intensified Therapy; Bevacizumab, 15mg/kg, iv drip, q3w; Sintilimab, 200mg/dose, iv drip, q3w; Lenvatinib, for weight ≤60 kg, 8 mg/d, po, qd; for weight >60 kg, 12 mg/d, po, qd.
Experimental: Conversion Therapy Group; Regorafenib, PD-1 inhibitor.	Drug: Conversion Therapy; Regorafenib, 160mg/d, po, qd; PD-1 inhibitor (Sintilimab, Camrelizumab, Tislelizumab, Toripalimab, Pembrolizumab), 200mg/dose, iv drip, q3w.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is the length of time from the date of randomization until death from any cause.	6 months
Progression Free Survival (PFS)	PFS is defined as the time from the date of randomization to the date of the first objectively documented tumor progression or death due to any cause.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR, as determined based on tumor response according to RECIST 1.1, is defined as the proportion of all randomized subjects whose best overall response (BOR) is either a CR or PR.	6 months
Adverse Events	ORR, as determined based on tumor response according to RECIST 1.1, is defined as the proportion of all randomized subjects whose best overall response (BOR) is either a CR or PR.	30 days

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): January 5, 2026
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: March 24, 2026
• First Submitted That Met QC Criteria: March 24, 2026
• First Posted (Actual): March 30, 2026

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 24, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Bevacizumab; Lenvatinib; PD-1; Regorafenib; Sintilimab; second-line treatment
• Other Study ID Numbers: SinBev+Len

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No