Local Consolidation After Sintilimab Plus Lenvatinib for Metastatic Liver Cancer

Official title

Comprehensive Local Consolidative Therapy Versus Continued Sintilimab Plus Lenvatinib Alone After Induction Sintilimab Plus Lenvatinib in Patients With Oligo-Extrahepatic Metastatic Hepatocellular Carcinoma: A Multicenter Prospective Randomized Trial

Overview

This study evaluates whether comprehensive local consolidative therapy added to continued sintilimab plus lenvatinib improves survival compared with continued sintilimab plus lenvatinib alone in patients with oligo-extrahepatic metastatic hepatocellular carcinoma. All enrolled participants receive induction treatment with sintilimab plus lenvatinib for 4 cycles. Participants who achieve disease control and are confirmed by central multidisciplinary review to be feasible for complete consolidation are randomized in a 1:1 ratio to receive either comprehensive local consolidative therapy followed by continued systemic therapy or continued systemic therapy alone. The primary outcome is overall survival.

Detailed description

This is a multicenter, prospective, open-label, randomized, event-driven phase 3 strategy trial in patients with oligo-extrahepatic metastatic hepatocellular carcinoma (HCC). All enrolled participants receive induction therapy with sintilimab 200 mg intravenously every 3 weeks plus lenvatinib orally once daily for 4 cycles. The recommended lenvatinib dose is 12 mg once daily for participants with body weight greater than or equal to 60 kg and 8 mg once daily for participants with body weight less than 60 kg. Approximately 620 participants are expected to enter induction, and approximately 400 participants are expected to undergo 1:1 randomization after induction.

After 4 induction cycles, participants undergo imaging reassessment and central multidisciplinary team review. Only participants with disease control by blinded independent central review and central confirmation that all residual active lesions can be safely covered by comprehensive local consolidative therapy are eligible for randomization. Randomized participants are assigned to either comprehensive local consolidative therapy plus continued sintilimab and lenvatinib or continued sintilimab and lenvatinib alone.

Comprehensive local consolidative therapy is intended to treat all residual active lesions, including intrahepatic and extrahepatic disease, using protocol-specified stereotactic body radiotherapy, thermal ablation, surgery, or a combination thereof. Consolidative treatment should begin within 4 to 8 weeks after randomization. In the control arm, planned full-lesion consolidative local treatment is not permitted before RECIST-defined progression, although urgent palliative local treatment may be allowed when medically necessary and will be recorded.

The primary endpoint is overall survival from randomization. Key secondary endpoints include progression-free survival, time to strategy failure, time to widespread progression, no-evidence-of-disease rate at 12 weeks after randomization, local control rate, time to next-line systemic therapy, quality of life, and safety. Imaging is performed during induction at Week 6 and Week 12, then every 6 weeks through Week 54 after randomization and every 9 weeks thereafter until progression, treatment discontinuation, death, or study end. Safety monitoring includes treatment-related adverse events, immune-related adverse events, anti-VEGF-related adverse events, and local treatment-related complications.

Interventions

• Drug Sintilimab
  Sintilimab 200 mg administered as an intravenous infusion every 3 weeks during induction and continued after randomization until disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, or a maximum duration of 24 months, according to protocol.
• Drug Lenvatinib
  Lenvatinib administered orally once daily during induction and continued after randomization until disease progression or unacceptable toxicity. The recommended dose is 12 mg once daily for participants with body weight greater than or equal to 60 kg and 8 mg once daily for participants with body weight less than 60 kg. Dose interruption, reduction, and discontinuation are managed according to protocol and product labeling.
• Procedure Comprehensive Local Consolidative Therapy
  Protocol-specified comprehensive local consolidative therapy directed at all residual active lesions after induction treatment, including stereotactic body radiotherapy, thermal ablation, surgery, or a combination thereof, performed within 4 to 8 weeks after randomization.

Primary outcome measures

• Overall Survival [Time frame: From randomization until death from any cause, assessed up to 60 months]

Secondary outcome measures (2)

• Time to Strategy Failure [Time frame: From randomization through 60 months]
• Time to Widespread Progression [Time frame: From randomization through 60 months]

Eligibility criteria

Inclusion criteria

• Age 18 to 75 years
• Hepatocellular carcinoma confirmed by imaging and/or histology according to institutional diagnostic standards
• Advanced or unresectable disease with extrahepatic metastases meeting protocol-defined oligo-extrahepatic metastatic disease criteria: 1 to 5 extrahepatic metastatic lesions and no more than 2 involved extrahepatic organs
• At least 1 measurable lesion according to RECIST version 1.1
• No prior systemic therapy for advanced or metastatic hepatocellular carcinoma
• ECOG performance status 0 to 1
• Child-Pugh class A or stable Child-Pugh B7
• Adequate hematologic, hepatic, renal, and coagulation function according to protocol
• Baseline center multidisciplinary team assessment indicating potential feasibility for complete consolidative intent if disease control is achieved after induction
• Written informed consent and willingness to comply with treatment, follow-up, and protocol-required assessments

Exclusion criteria

• More than 5 extrahepatic metastatic lesions or more than 2 involved extrahepatic organs
• Diffuse peritoneal seeding, leptomeningeal disease, or uncontrolled brain metastases
• Main portal vein trunk invasion, extensive inferior vena cava or right atrial tumor thrombus, or disease considered unlikely to become fully consolidable after induction
• Diffuse intrahepatic disease or liver tumor burden considered unlikely to be controllable with protocol-specified local treatment
• Prior PD-1, PD-L1, CTLA-4, anti-VEGF monoclonal antibody, tyrosine kinase inhibitor, or other systemic antitumor therapy for advanced HCC
• Active autoimmune disease requiring systemic immunosuppression
• Active severe infection, including uncontrolled bacterial or fungal infection, active tuberculosis, or uncontrolled hepatitis B without appropriate antiviral therapy
• Gastrointestinal bleeding within the previous 6 months, or untreated or uncontrolled high-risk gastroesophageal varices
• Uncontrolled hypertension, recent major thrombotic event, myocardial infarction, unstable angina, or stroke
• Active interstitial lung disease or noninfectious pneumonitis requiring systemic treatment
• Severe proteinuria or renal dysfunction considered unsuitable for lenvatinib treatment
• Pregnancy or breastfeeding
• Any condition that, in the investigator's judgment, would make participation unsafe or compromise protocol compliance

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 1 center

• Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology — Wuhan

Identifiers

NCT: NCT07537946 · EXACT-EMH-HCC-011

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗