Combined TACE, TKI/Anti-VEGF and ICIs as Conversion Therapy for Advanced Hepatocellular Carcinoma

NCT05717738 | Recruiting DMC FDA Drug

• 1 other identifier: TJ-IRB-20221202
• Study Type: observational
• Target: 300
• Locations: 1 country
• Sites: 4

Brief Summary

The aim of this study is to the efficacy, prognosis, adverse effects, and factors for predicting therapeutic effects and clinical prognosis of combined therapy of transarterial chemoembolization (TACE), Anti-VEGF antibodies or pan-target anti-angiogenic drugs, and anti-PD-1/ PD-L1 antibody for advanced hepatocellular carcinoma which initially unsuitable for the radical therapy, including resection, transplantation, or ablation.

Conditions

Hepatocellular Carcinoma Non-resectable

Keywords

Hepatocellular Carcinoma; Downstaging conversion therapy

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)

• Response Rate measured by mRECIST criteria

  from the date of first treatment to radiographically documented progression according to mRECIST v1.1, assessed up to 3 years

• Time to progression (TTP)

  from the date of first treatment to radiographically documented progression according to mRECIST1.1, 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 1.1, 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)

TACE-Len-ICI cohort

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

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

TACE-A-T cohort

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

Procedure: TACE; Drug: Bevacizumab plus Atezolizumab

TACE-B-S cohort

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

Procedure: TACE; Drug: Bevacizumab Biosimilar IBI305 plus sintilimab

TACE-Apa-C cohort

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

Procedure: TACE; Drug: apatinib plus camrelizumab

TACE-Sor-ICI cohort

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

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

TACE-Don-ICI cohort

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

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

TACE-Reg-ICI cohort

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

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

Interventions

TACE PROCEDURE

Procedure of TACE is standardized.

Also known as: transarterial chemoembolization

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

Lenvatinib DRUG

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

Also known as: levima

TACE-Len-ICI cohort

Anti-PD-1 monoclonal antibody DRUG

Advanced 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

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

TACE-B-S cohort

Bevacizumab plus Atezolizumab DRUG

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

Also known as: Avastin plus Tecentriq

TACE-A-T cohort

apatinib plus camrelizumab DRUG

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

Also known as: Apa plus C

TACE-Apa-C cohort

Sorafenib DRUG

400mg; p.o. bid

Also known as: Nexavar

TACE-Sor-ICI cohort

Donafenib DRUG

200mg; p.o. bid

Also known as: Zepsun

TACE-Don-ICI cohort

Regorafenib DRUG

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

Also known as: stivarga

TACE-Reg-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 or BCLC stage C.
• portal vein involvement (Chen's groups A, or Cheng's type I-II) 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.
• hepatic vein invasion (VV1 to VV2) were allowed.
• 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 ×109/L (3) Platelet count ≥50 ×109/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 12. Time interval between TACE and systemic therapy within 7 days.

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 2. Severe, active and uncontrolled co-morbidity including but not limited to:
• Persistent or activity (except the HBV and HCV) infection;
• symptoms of congestive heart failure and uncontrolled diabetes;
• uncontrolled hypertension, systolic pressure ≥ 160 mmHg or diastolic pressure ≥ 100 mmHg despite anti-hypertension medications ≤ 28 days before randomization or first dose of drug.
• unstable angina,
• uncontrolled arrhythmias,
• active ILD,
• severe chronic GI disease accompanied by diarrhea,
• 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.
• 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.
• \. 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) 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.
• \. Extrahepatic vascular involvement or thrombosis: main trunk of portal vein and superior mesenteric vein (Cheng's type III and IV) or inferior vena cava (IVC) (VV3).

Sponsors & Collaborators

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

Study Sites (4)

The Second Affiliated Hospital of Fujian Medical University

Quanzhou, Fujian, China

RECRUITING

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, 430030, China

RECRUITING

Optical Valley branch of Tongji hospital

Wuhan, Hubei, 430073, China

RECRUITING

Sino-French branch of Tongji hospital

Wuhan, Hubei, China

RECRUITING

Related Publications (3)

• Chiang CL, Chiu KWH, Chan KSK, Lee FAS, Li JCB, Wan CWS, Dai WC, Lam TC, Chen W, Wong NSM, Cheung ALY, Lee VWY, Lau VWH, El Helali A, Man K, Kong FMS, Lo CM, Chan AC. Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial. Lancet Gastroenterol Hepatol. 2023 Feb;8(2):169-178. doi: 10.1016/S2468-1253(22)00339-9. Epub 2022 Dec 15.

  PMID: 36529152 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

• Luo L, He Y, Zhu G, Xiao Y, Song S, Ge X, Wang T, Xie J, Deng W, Hu Z, Shan R. Hepatectomy After Conversion Therapy for Initially Unresectable HCC: What is the Difference? J Hepatocell Carcinoma. 2022 Dec 22;9:1353-1368. doi: 10.2147/JHC.S388965. eCollection 2022.

  PMID: 36578526 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

Carcinoma, Hepatocellular

Interventions

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

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Antineoplastic Agents, Immunological; Antineoplastic Agents; Therapeutic Uses; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aminopeptidases; Exopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Metalloexopeptidases; Metalloproteases; 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

Study Officials

• Ze-yang Ding, M.D.

  Tongji Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ze-yang Ding, M.D.

CONTACT

+86-13407156200; zyding@tjh.tjmu.edu.cn

Study Design

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

Study Record Dates

• First Submitted: January 29, 2023
• First Posted: February 8, 2023
• Study Start: January 20, 2022
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2024
• Last Updated: June 13, 2024

Record last verified: 2024-06

Locations

CN (4)