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

NCT05713994 | Recruiting DMC

• 1 other identifier: 2020-S205
• Study Type: observational
• Target: 300
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Hepatocellular Carcinoma Non-resectable

Keywords

Liver Neoplasms; Hepatocellular Carcinoma

Outcome Measures

Primary Outcomes (1)

• Number of Patients Amendable to Curative Surgical Interventions

  Number of patients amendable to curative surgical interventions defined as number of patients receiving curative surgical resection, transplantation, or ablation after successful down-sizing of tumor(s) by intervention.

  from the date of first treatment to the date of last treatment, an average of 3 years

Secondary Outcomes (10)

• overall response rate (ORR) measured by mRECIST criteria

  rom the date of first treatment to radiographically documented progression according to mRECIST, assessed up to 3 years

• Time to progression (TTP)

  from the date of first treatment to radiographically documented progression according to mRECIST, assessed up to 3 years

• Time to intrahepatic tumor progression (TTITP)

  from the date of first treatment to radiographically documented intrahepatic tumor progression according to mRECIST, assessed up to 3 years

• Progression-free survival (PFS)

  from the date of first treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause, whichever occurs first, assessed up to 3 years

• Overall survival (OS)

  from the date of first treatment to the date of death from any cause, assessed up to 5 years

Study Arms (7)

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.

Procedure: HAIC; Drug: Bevacizumab plus Atezolizumab

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.

Procedure: HAIC; Drug: Lenvatinib; Drug: Anti-PD-1 monoclonal antibody

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.

Procedure: HAIC; Drug: Bevacizumab Biosimilar IBI305 plus sintilimab

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.

Procedure: HAIC; Drug: apatinib plus camrelizumab

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.

Procedure: HAIC; Drug: Sorafenib; Drug: Anti-PD-1 monoclonal antibody

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.

Procedure: HAIC; Drug: Donafenib; Drug: Anti-PD-1 monoclonal antibody

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.

Procedure: HAIC; Drug: Regorafenib; Drug: Anti-PD-1 monoclonal antibody

Interventions

HAIC PROCEDURE

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

Also known as: hepatic arterial infusion chemotherapy of FOLFOX

HAIC-A-T cohort; HAIC-Apa-C cohort; HAIC-B-S cohort; HAIC-Don-ICI cohort; HAIC-Len-ICI cohort; HAIC-Reg-ICI cohort; HAIC-Sor-ICI cohort

Bevacizumab plus Atezolizumab DRUG

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

Also known as: Avastin plus Tecentriq

HAIC-A-T cohort

Bevacizumab Biosimilar IBI305 plus sintilimab DRUG

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

Also known as: Byvasda (B) plus S

HAIC-B-S cohort

Lenvatinib DRUG

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

Also known as: Lenvima

HAIC-Len-ICI cohort

Sorafenib DRUG

400mg; p.o. bid

Also known as: Nexavar

HAIC-Sor-ICI cohort

Donafenib DRUG

200mg; p.o. bid

Also known as: Zepsun

HAIC-Don-ICI cohort

Regorafenib DRUG

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

Also known as: stivarga

HAIC-Reg-ICI cohort

apatinib plus camrelizumab DRUG

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

Also known as: Apa plus C

HAIC-Apa-C cohort

Anti-PD-1 monoclonal antibody 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).

Also known as: PD-1 inhibitor

HAIC-Don-ICI cohort; HAIC-Len-ICI cohort; HAIC-Reg-ICI cohort; HAIC-Sor-ICI cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients with advanced hepatocellular carcinoma which initially unsuitable for the radical therapy, including resection, transplantation, or ablation.

You may qualify if:

• Age ≥ 18 years old;
• 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;
• at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or mRESIST criteria;
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
• 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.
• 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.
• 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;
• 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
• Child-Pugh liver function class A-B7
• 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.
• 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.

You may not qualify if:

• 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
• 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.
• \. Known to produce allergic or hypersensitive reactions to any study drug or any excipient thereof.
• \. Significant clinical gastrointestinal bleeding or a potential risk of bleeding was identified by the investigator during the 30 days prior to study entry.
• \. 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.
• \. 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).
• \. 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.
• \. 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.

Sponsors & Collaborators

• Ze-yang Ding, MD: lead
• Chinese Cooperative Group of Liver Cancer: collaborator
• Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province: collaborator
• Haplox Biotechnology Co., Ltd.: collaborator
• Geneplus-Beijing Co. Ltd.: collaborator
• The Second Affiliated Hospital of Fujian Medical University: collaborator

Study Sites (2)

The Second Affiliated Hospital of Fujian Medical University

Quanzhou, Fujian, 362000, China

RECRUITING

TongjiHospital

Wuhan, Hubei, 430000, China

RECRUITING

Related Publications (2)

• 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.

  PMID: 32615109 BACKGROUND

• 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.

  PMID: 32402160 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Tissue, blood, urine, and feces. Part of cancer tissue and blood samples are utilized for high-throughput sequencing.

MeSH Terms

Conditions

Liver Neoplasms; Carcinoma, Hepatocellular

Interventions

Bevacizumab; atezolizumab; sintilimab; lenvatinib; Sorafenib; donafenib; regorafenib; apatinib; camrelizumab; Glutamyl Aminopeptidase; spartalizumab; Immune Checkpoint Inhibitors

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Liver Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Aminopeptidases; Exopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Metalloexopeptidases; Metalloproteases; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents, Immunological; Antineoplastic Agents; Therapeutic Uses

Study Officials

• Wanguang Zhang, M.D.

  Tongji Hospital

  STUDY CHAIR

Central Study Contacts

ZeYang Ding, M.D.

CONTACT

+86-13407156200; dingzyang@sina.com

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 16, 2023
• First Posted: February 6, 2023
• Study Start: May 19, 2020
• Primary Completion: June 30, 2025
• Study Completion: December 30, 2025
• Last Updated: March 25, 2025

Record last verified: 2025-03

Locations

CN (2)