Combined HAIC, TKI/Anti-VEGF and ICIs as Conversion Therapy for Unresectable Hepatocellular Carcinoma

NCT ID: NCT05713994

Last Updated: 2025-03-25

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Total Enrollment

300 participants

Study Classification

OBSERVATIONAL

Study Start Date

2020-05-19

Study Completion Date

2025-12-30

Brief Summary

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This study is conducted to evaluate the efficacy, prognosis, adverse effects, and factors for predicting therapeutic effects and clinical prognosis of combined therapy of hepatic artery infusion chemotherapy (HAIC), tyrosine kinase inhibitor/ anti-VEGF antibody, and anti-PD-1/ PD-L1 antibody for advanced hepatocellular carcinoma which initially unsuitable for the radical therapy, including resection, transplantation, or ablation. Factors are collected in preoperative routine blood examination, preoperative radiological imaging and pathological examination.

Detailed Description

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As a local interventional treatment, hepatic arterial infusion chemotherapy (HAIC) has shown better efficacy and safety than traditional transcatheter arterial chemoembolization (TACE) in the treatment of unresectable HCC. In addition, HAIC has been widely used as an alternative to sorafenib in advanced HCC in the eastern Asia. Systemic therapies such as tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), as well as the combined use of anti-VEGF antibody and ICIs have shown promising results in the treatment of advanced HCC. Numerous studies have shown that combination therapy has a trend toward better tumor response rates, survival outcomes, and downstaging rate to monotherapy.

This study is conducted by the by Chinese Collaborative Group of Liver Cancer (CCGLC), the Chinese Chapter of the International Hepato-Pancreato-Biliary Association (CC-IHPBA). It is estimated that 300 patients with advanced hepatocellular carcinoma will be enrolled in about 4 research centers. And it is planned to complete the enrollment within 1 year and it is expected that all enrolled subjects will reach the observation end point in 3 years.

Conditions

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Hepatocellular Carcinoma Non-resectable

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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HAIC-A-T cohort

Patients with advanced hepatocellular carcinoma who was initially evaluated unsuitable for the radical therapy and received combined HAIC plus bevacizumab (A) and atezolizumab (T) as conversion therapy for downstaging.

HAIC

Intervention Type PROCEDURE

administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.

Bevacizumab plus Atezolizumab

Intervention Type DRUG

Bevacizumab (15mg/kg, q3w) plus Atezolizumab (1200 mg, q3w)

HAIC-Len-ICI cohort

Patients with advanced hepatocellular carcinoma who was initially evaluated unsuitable for the radical therapy and received combined HAIC plus lenvatinib (Len) and anti-PD-1 antibody as conversion therapy for downstaging.

HAIC

Intervention Type PROCEDURE

administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.

Lenvatinib

Intervention Type DRUG

8mg; p.o.; q.d.

Anti-PD-1 monoclonal antibody

Intervention Type DRUG

HCC Patients treated with TKI plus anti-PD-1 monoclonal antibody as systemic therapy were recruited. Anti-PD-1 monoclonal antibodies include pembrolizumab (200 mg, q3w), nivolumab (3mg/kg, q2w), camrelizumab (200mg, q2w), tislelizumab (200mg, q3w), sintilimab (200 mg, q3w), or toripalimab (240mg, q3w).

HAIC-B-S cohort

Patients with advanced hepatocellular carcinoma who was initially evaluated unsuitable for the radical therapy and received combined HAIC plus bevacizumab biosimilar (Byvasda, B) and Sintilimab (Tyvyt, S) antibody as conversion therapy for downstaging.

HAIC

Intervention Type PROCEDURE

administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.

Bevacizumab Biosimilar IBI305 plus sintilimab

Intervention Type DRUG

Bevacizumab Biosimilar IBI305 (15mg/kg, q3w), and sintilimab (200 mg, q3w)

HAIC-Apa-C cohort

Patients with advanced hepatocellular carcinoma who was initially evaluated unsuitable for the radical therapy and received combined HAIC plus Apatinib (Apa) and Camrelizumab (C) antibody as conversion therapy for downstaging.

HAIC

Intervention Type PROCEDURE

administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.

apatinib plus camrelizumab

Intervention Type DRUG

Apatinib(250 mg; p.o.; q. d.); camrelizumab (200 mg; iv drip; q2w)

HAIC-Sor-ICI cohort

Patients with advanced hepatocellular carcinoma who was initially evaluated unsuitable for the radical therapy and received combined HAIC plus sorafenib (Sor) and anti-PD-1 antibody as conversion therapy for downstaging.

HAIC

Intervention Type PROCEDURE

administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.

Sorafenib

Intervention Type DRUG

400mg; p.o. bid

Anti-PD-1 monoclonal antibody

Intervention Type DRUG

HCC Patients treated with TKI plus anti-PD-1 monoclonal antibody as systemic therapy were recruited. Anti-PD-1 monoclonal antibodies include pembrolizumab (200 mg, q3w), nivolumab (3mg/kg, q2w), camrelizumab (200mg, q2w), tislelizumab (200mg, q3w), sintilimab (200 mg, q3w), or toripalimab (240mg, q3w).

HAIC-Don-ICI cohort

Patients with advanced hepatocellular carcinoma who was initially evaluated unsuitable for the radical therapy and received combined HAIC plus donafenib (Don) and anti-PD-1 antibody as conversion therapy for downstaging.

HAIC

Intervention Type PROCEDURE

administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.

Donafenib

Intervention Type DRUG

200mg; p.o. bid

Anti-PD-1 monoclonal antibody

Intervention Type DRUG

HCC Patients treated with TKI plus anti-PD-1 monoclonal antibody as systemic therapy were recruited. Anti-PD-1 monoclonal antibodies include pembrolizumab (200 mg, q3w), nivolumab (3mg/kg, q2w), camrelizumab (200mg, q2w), tislelizumab (200mg, q3w), sintilimab (200 mg, q3w), or toripalimab (240mg, q3w).

HAIC-Reg-ICI cohort

Patients with advanced hepatocellular carcinoma who was initially evaluated unsuitable for the radical therapy and received combined HAIC plus regorafenib (Reg) and anti-PD-1 antibody as conversion therapy for downstaging.

HAIC

Intervention Type PROCEDURE

administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.

Regorafenib

Intervention Type DRUG

160 mg; p.o.; q.d.

Anti-PD-1 monoclonal antibody

Intervention Type DRUG

HCC Patients treated with TKI plus anti-PD-1 monoclonal antibody as systemic therapy were recruited. Anti-PD-1 monoclonal antibodies include pembrolizumab (200 mg, q3w), nivolumab (3mg/kg, q2w), camrelizumab (200mg, q2w), tislelizumab (200mg, q3w), sintilimab (200 mg, q3w), or toripalimab (240mg, q3w).

Interventions

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HAIC

administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.

Intervention Type PROCEDURE

Bevacizumab plus Atezolizumab

Bevacizumab (15mg/kg, q3w) plus Atezolizumab (1200 mg, q3w)

Intervention Type DRUG

Bevacizumab Biosimilar IBI305 plus sintilimab

Bevacizumab Biosimilar IBI305 (15mg/kg, q3w), and sintilimab (200 mg, q3w)

Intervention Type DRUG

Lenvatinib

8mg; p.o.; q.d.

Intervention Type DRUG

Sorafenib

400mg; p.o. bid

Intervention Type DRUG

Donafenib

200mg; p.o. bid

Intervention Type DRUG

Regorafenib

160 mg; p.o.; q.d.

Intervention Type DRUG

apatinib plus camrelizumab

Apatinib(250 mg; p.o.; q. d.); camrelizumab (200 mg; iv drip; q2w)

Intervention Type DRUG

Anti-PD-1 monoclonal antibody

HCC Patients treated with TKI plus anti-PD-1 monoclonal antibody as systemic therapy were recruited. Anti-PD-1 monoclonal antibodies include pembrolizumab (200 mg, q3w), nivolumab (3mg/kg, q2w), camrelizumab (200mg, q2w), tislelizumab (200mg, q3w), sintilimab (200 mg, q3w), or toripalimab (240mg, q3w).

Intervention Type DRUG

Other Intervention Names

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hepatic arterial infusion chemotherapy of FOLFOX Avastin plus Tecentriq Byvasda (B) plus S Lenvima Nexavar Zepsun stivarga Apa plus C PD-1 inhibitor

Eligibility Criteria

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Inclusion Criteria

1. Age ≥ 18 years old;
2. Diagnosis of HCC is according to the American Association for the Study of Liver Diseases or European Association for the Study of the Liver guidelines of HCC management;
3. at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or mRESIST criteria;
4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
5. Hepatocellular carcinoma (HCC) was assessed as not suitable for radical resection, liver transplant, or ablation treatment after the assessment of a multidisciplinary team because either: (1) R0 resection was not feasible; (2) remnant liver volume was less than 30% in patients who did not have cirrhosis or 40% in patients with cirrhosis, or the results of an indocyanine green test were higher than 15%; (3) patients had Barcelona Clinic Liver Cancer (BCLC) stage B and beyond Up-to-seven criteria; or (4) patients had BCLC stage C.
6. Portal vein involvement (Chen's groups A and B, or Cheng's type I-III) is allowed: Chen's group A1 or Cheng's type I, tumor thrombus is involved in segmental or sectoral branches of the portal vein or above; Chen's group A2 or Cheng's type II, involvement of the first branch of portal vein; Chen's group B or Cheng's type III, involvement of the main portal vein.
7. Hepatic vein invasion (VV1 to VV2) were allowed. Patients with tumor thrombus in inferior vena cava (VV3 type, Sakamoto type 1) can be included; However, patients with inferior vena cava tumor thrombus exceeding the diaphragmatic plane (Sakamoto type II) and reaching the right atrium (Sakamoto type III) cannot be included in the study;
8. Patients with extrahepatic oligometastasis is allowed: extrahepatic oligometastasis was defined as up to three metastatic lesions in up to two organs with the largest diameter of 3 cm
9. Child-Pugh liver function class A-B7
10. No prior transplantation, TACE, or radioembolization to the liver was allowed. Prior locoregional therapies, such as surgical resection, radiotherapy, radiofrequency ablation, percutaneous ethanol injection or cryoablation, are allowed if the disease have progressed since prior treatment. Local therapy must have been completed at least 4 weeks prior to the baseline scan.
11. Adequate organ and marrow function, as defined below:

(1) Hemoglobin≥80 g/L; (2) Absolute neutrophil count ≥1.5 ×10\^9/L; (3) Platelet count ≥50 ×10\^9/L; (4) Total bilirubin \< 51 μmol/L; (5) Alanine transaminase (ALT) and aminotransferase (AST)≤5×ULN; (6) Albumin ≥28 g/L; (7) INR ≤1.6; (8) Serum creatinine \< 110 μmol/L.

Exclusion Criteria

1. Prior invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured
2. Severe, active and uncontrolled co-morbidity including but not limited to:

(1) Persistent or activity (except the HBV and HCV) infection; (2) symptoms of congestive heart failure and uncontrolled diabetes; (3) uncontrolled hypertension, systolic pressure≥160 mmHg or diastolic pressure≥100 mmHg despite anti-hypertension medications≤28 days before randomization or first dose of drug; (4) unstable angina; (5) uncontrolled arrhythmias; (6) active ILD; (7) severe chronic GI disease accompanied by diarrhea; (8) compliance with requirements may limit the research, resulted in significant increase risk of AE or influence Subjects provided psychiatric/social problem status on their ability to provide written informed consent; (9) A history of active primary immunodeficiency or human immunodeficiency virus; (10) Active or previous records of autoimmune disease or inflammatory diseases, including inflammatory bowel disease (e.g., colitis or Crohn's disease\], diverticulitis, except \[diverticulosis\], systemic lupus erythematosus (SLE), sarcoidosis syndrome or Wegener syndrome (e.g., granulomatous vasculitis, gray's disease, rheumatoid arthritis, the pituitary gland inflammation and uveitis\]); (11) A history of hepatic decompensation, including refractory ascites, gastrointestinal bleeding, or hepatic encephalopathy.

3\. Known to produce allergic or hypersensitive reactions to any study drug or any excipient thereof.

4\. Significant clinical gastrointestinal bleeding or a potential risk of bleeding was identified by the investigator during the 30 days prior to study entry.

5\. Tumors of the central nervous system, including metastatic brain tumors. 6. Pregnant women or breast-feeding patients. 7. Has received anti-tumor system therapy for HCC. Non-anti-tumor purpose combined hormone therapy (e.g., hormone replacement therapy) is excluded.

8\. Is currently using, or has used an immunosuppressive drug within 14 days prior to the first dose of the investigational drug. This standard has the following exceptions: (1) intranasal, inhaled, topical or topical steroids. (e.g., intraarticular); (2) Systemic corticosteroid therapy not exceeding 10 mg/ day of prednisone; (3) prophylactic use of steroids for hypersensitivity. (e.g., CT scan pretherapy medication).

9\. A live attenuated vaccine was administered within 30 days prior to the first administration of the study drug. Note: If enrolled, patients shall not receive live attenuated vaccine within 30 days of receiving study drug therapy and after the last administration of study drug.

10\. Extrahepatic vascular involvement or thrombosis: superior mesenteric vein (Cheng's type IV), or with inferior vena cava tumor thrombus exceeding the diaphragmatic plane (Sakamoto type II) or reaching the right atrium (Sakamoto type III) cannot be included in the study.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Chinese Cooperative Group of Liver Cancer

OTHER

Sponsor Role collaborator

Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province

OTHER

Sponsor Role collaborator

Haplox Biotechnology Co., Ltd.

INDUSTRY

Sponsor Role collaborator

Geneplus-Beijing Co. Ltd.

INDUSTRY

Sponsor Role collaborator

The Second Affiliated Hospital of Fujian Medical University

OTHER

Sponsor Role collaborator

Ze-yang Ding, MD

OTHER

Sponsor Role lead

Responsible Party

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Ze-yang Ding, MD

Professor

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Wanguang Zhang, M.D.

Role: STUDY_CHAIR

Tongji Hospital

Locations

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The Second Affiliated Hospital of Fujian Medical University

Quanzhou, Fujian, China

Site Status RECRUITING

TongjiHospital

Wuhan, Hubei, China

Site Status RECRUITING

Countries

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China

Central Contacts

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ZeYang Ding, M.D.

Role: CONTACT

+86-13407156200

Facility Contacts

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Yan-jun Wang, M.D.

Role: primary

+15872415556

Ze-yang Ding, M.D.

Role: primary

13407156200

References

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Mazzaferro V, Citterio D, Bhoori S, Bongini M, Miceli R, De Carlis L, Colledan M, Salizzoni M, Romagnoli R, Antonelli B, Vivarelli M, Tisone G, Rossi M, Gruttadauria S, Di Sandro S, De Carlis R, Luca MG, De Giorgio M, Mirabella S, Belli L, Fagiuoli S, Martini S, Iavarone M, Svegliati Baroni G, Angelico M, Ginanni Corradini S, Volpes R, Mariani L, Regalia E, Flores M, Droz Dit Busset M, Sposito C. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020 Jul;21(7):947-956. doi: 10.1016/S1470-2045(20)30224-2.

Reference Type BACKGROUND
PMID: 32615109 (View on PubMed)

Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.

Reference Type BACKGROUND
PMID: 32402160 (View on PubMed)

Other Identifiers

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2020-S205

Identifier Type: -

Identifier Source: org_study_id

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