Efficacy and Safety of Camrelizumab Plus Rivoceranib and Local Therapy for Hepatocellular Carcinoma With Lung Metastases (CAPLocal) : A Multicentre, Single-Arm,Prospective Cohort Study

Overview

1.1. Main Objectives The objective response rate (ORR) determined by the researchers based on RECIST v1.1 was used to evaluate the efficacy of systemic therapy (carrycept combined with apatinib) in combination with or without local treatment (surgery, radiotherapy, or ablation therapy) for patients with advanced hepatocellular carcinoma with pulmonary metastases. 1.2. Secondary objectives Through efficacy indicators such as progression-free survival (PFS) and objective response rate (ORR) determined by researchers based on RECIST v1.1 and mRECIST, evaluate the efficacy of systemic therapy (carrietumab combined with apatinib) combined or not with local treatment (surgery, radiotherapy, or ablation therapy) for patients with advanced hepatocellular carcinoma with pulmonary metastases. Evaluate the safety of combining systemic therapy (caretuximab-rbsm in combination with apatinib) with or without local treatment (surgery, radiotherapy, or ablation therapy) for patients with advanced hepatocellular carcinoma with pulmonary metastases. 1.3. Exploratory Purpose Evaluate the cumulative duration (the sum of the time spent in a NED state) and the safety of local treatments for patients who have undergone comprehensive treatment and have no detectable active lesions on imaging studies (NED). Explore the correlation between biomarkers and the efficacy of combined treatment regimens. Explore the relationship between the number, diameter, and treatment outcomes of pulmonary metastases in hepatocellular carcinoma.

Primary outcome measures

• Objective response rate [Time frame: From enrollment to the end of treatment at Week 12]

Eligibility criteria

Inclusion criteria

Patients must meet all of the following inclusion criteria in order to be eligible for participation in this study:

• The patient voluntarily participates in this study and signs an informed consent form.
• Age: 18 to 85 years old, both male and female are eligible.
• Patients with hepatocellular carcinoma (HCC) confirmed through histopathological examination of tumor tissue or imaging assessments \[refer to the Guidelines for the Diagnosis and Treatment of Primary Hepatocellular Carcinoma (2024 Edition)\].
• There are extrahepatic pulmonary metastases that have not been treated locally, and the number of these metastases is ≤5.
• Has not received any form of systematic treatment for HCC.
• There must be at least one measurable lesion (according to the RECIST v1.1 criteria, this measurable lesion must have a longitudinal diameter ≥ 10 mm on spiral CT scans or a short diameter ≥ 15 mm for enlarged lymph nodes; lesions that have previously received local treatment and have clearly progressed according to the RECIST v1.1 standards can be considered target lesions).
• Neutrophil-to-lymphocyte ratio (NLR) of less than or equal to 3.
• The Child Pugh liver function classification is Grade A or B (≤7).
• The Eastern Cooperative Oncology Group (ECOG) behavioral status is 0 or 1 for patients in the eastern United States.
• Good lung function, expected to be able to tolerate surgery or localized treatment.
• Other major organ functions are generally normal (the blood system, kidneys, etc., function well).

Muscular marrow function is adequate: white blood cell count ≥ 4.0 × 10\^9/L, absolute neutrophil count (ANC) ≥ 2.0 × 10\^9 / L, platelet count ≥ 100 × 10 \^ 9 / L, hemoglobin concentration ≥ 90 g/L (no blood transfusions, no use of hematopoietic factors, and no medication correction within 2 weeks prior to the first administration).

For patients not receiving anticoagulant therapy, the INR (International Normalized Ratio) and APTI (Activated Partial Thromboplastin Time) values are ≤ 1.5 times the upper limit of normal.

Sufficient renal function: creatinine clearance ≥ 60 mL/min.

• Patients with active hepatitis B virus (HBV) infection must receive anti-HBV treatment prior to the initiation of the study treatment and must be willing to undergo antiviral therapy throughout the study period. Patients with hepatitis C virus (HCV) RNA-positive status must receive antiviral treatment according to local standard treatment guidelines and have liver function levels within the range of CTCAE Grade 1 elevation.
• Women of childbearing age should have a negative serum or urine pregnancy test within 7 days prior to enrollment in the study, and must be non-lactating patients who have given their consent to use contraceptive measures during the study period and for 6 months after its completion. Men must agree to use contraceptive measures both during the study period and within 6 months after its conclusion.
• The participant voluntarily consents to receive treatment related to this clinical study and agrees to participate in follow-up assessments.

Exclusion criteria

Patients who meet any of the following criteria will not be eligible to participate in this study:

• Known cases of cholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma, and fibrolamellar cell carcinoma; having had an active malignant tumor other than HCC within 5 years or concurrently. Limited-stage tumors that have been cured, such as basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial carcinoma, cervical intraepithelial carcinoma, and breast intraepithelial carcinoma, can be included.
• Has previously received anti-cancer treatments targeting metastatic lesions.
• The site of extrahepatic metastasis is not the lungs, or there are more than 2 distant metastasized organs (including 2).
• Suffering from any severe infection, serious mental or physical illness, or laboratory test abnormalities that are uncontrollable, which may pose an unacceptable risk, negatively impact trial compliance, or affect the administration, distribution, metabolism, and excretion of the investigational drug. Examples include unstable heart disease, chronic kidney disease, poorly controlled diabetes, mood disorders, mental disorders, central nervous system abnormalities, chronic diarrhea, ascites, and pleural effusions requiring treatment.
• Suffers from hypertension and cannot achieve adequate control with antihypertensive medication (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg). It is permissible to use antihypertensive treatment to achieve these parameters. Has previously experienced a hypertensive crisis or hypertensive encephalopathy.
• Infection with human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) (or active viral hepatitis).
• Received experimental treatments from other clinical studies concurrently during the course of this trial.
• Long-term use of immunosuppressive agents following organ transplantation.
• According to the researchers' assessment, the subject may have other factors that could lead to the forced discontinuation of this study. These include non-compliance with the protocol, the presence of other serious conditions (including mental illnesses) requiring concurrent treatment, significant laboratory abnormalities, a history of substance abuse or drug use, combined with psychological, social, familial, or geographic factors, which could impact the subject's safety or the collection of data and samples.

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

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Wu C, Ren X, Zhang Q. Incidence, risk factors, and prognosis in patients with primary hepatocellular carcinoma and lung metastasis: a population-based study. Cancer Manag Res. 2019 Apr 8;11:2759-2768. doi: 10.2147/CMAR.S192896. eCollection 2019. PMID 31040715
• Reig M, Sanduzzi-Zamparelli M, Forner A, Rimola J, Ferrer-Fabrega J, Burrel M, Garcia-Criado A, Diaz A, Llarch N, Iserte G, Molla M, Kelley RK, Galle PR, Mazzaferro V, Salem R, Sangro B, Singal AG, Vogel A, Yanagihara TK, Ayuso C, Torres F, Bruix J. BCLC strategy for prognosis prediction and treatment recommendations: The 2026 update. J Hepatol. 2026 Mar;84(3):631-654. doi: 10.1016/j.jhep.2025.10. PMID 41151697
• Vogel A, Chan SL, Dawson LA, Kelley RK, Llovet JM, Meyer T, Ricke J, Rimassa L, Sapisochin G, Vilgrain V, Zucman-Rossi J, Ducreux M; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2025 May;36(5):491-506. doi: 10.1016/j.annonc.2025.02.006. Epub 2025 Feb 20. No a PMID 39986353
• Xu J, Shen J, Gu S, Zhang Y, Wu L, Wu J, Shao G, Zhang Y, Xu L, Yin T, Liu J, Ren Z, Xiong J, Mao X, Zhang L, Yang J, Li L, Chen X, Wang Z, Gu K, Chen X, Pan Z, Ma K, Zhou X, Yu Z, Li E, Yin G, Zhang X, Wang S, Wang Q. Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial. Clin Cancer Res. 2021 Feb 15;27(4 PMID 33087333
• Zhao S, Ren S, Jiang T, Zhu B, Li X, Zhao C, Jia Y, Shi J, Zhang L, Liu X, Qiao M, Chen X, Su C, Yu H, Zhou C, Zhang J, Camidge DR, Hirsch FR. Low-Dose Apatinib Optimizes Tumor Microenvironment and Potentiates Antitumor Effect of PD-1/PD-L1 Blockade in Lung Cancer. Cancer Immunol Res. 2019 Apr;7(4):630-643. doi: 10.1158/2326-6066.CIR-17-0640. Epub 2019 Feb 12. PMID 30755403
• Llovet JM, Kudo M, Merle P, Meyer T, Qin S, Ikeda M, Xu R, Edeline J, Ryoo BY, Ren Z, Masi G, Kwiatkowski M, Lim HY, Kim JH, Breder V, Kumada H, Cheng AL, Galle PR, Kaneko S, Wang A, Mody K, Dutcus C, Dubrovsky L, Siegel AB, Finn RS; LEAP-002 Investigators. Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): a randomised, double-blind, pha PMID 38039993
• Qin S, Chan SL, Gu S, Bai Y, Ren Z, Lin X, Chen Z, Jia W, Jin Y, Guo Y, Hu X, Meng Z, Liang J, Cheng Y, Xiong J, Ren H, Yang F, Li W, Chen Y, Zeng Y, Sultanbaev A, Pazgan-Simon M, Pisetska M, Melisi D, Ponomarenko D, Osypchuk Y, Sinielnikov I, Yang TS, Liang X, Chen C, Wang L, Cheng AL, Kaseb A, Vogel A; CARES-310 Study Group. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy fo PMID 37499670
• Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX, Chan SL, Melkadze T, Sukeepaisarnjaroen W, Breder V, Verset G, Gane E, Borbath I, Rangel JDG, Ryoo BY, Makharadze T, Merle P, Benzaghou F, Banerjee K, Hazra S, Fawcett J, Yau T. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol PMID 35798016

Identifiers

NCT: NCT07482670 · 202602023

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗