Combined TACE, TKI/Anti-VEGF and ICIs as Conversion Therapy for Advanced Hepatocellular Carcinoma (CCGLC-008)

Combined Transarterial Chemoembolization, Tyrosine Kinase Inhibitor/ Anti-VEGF Antibody, and Anti-PD-1/ PD-L1 Antibody as Conversion Therapy for Advanced Hepatocellular Carcinoma: a Multicenters, Real-world, Ambispective Cohort Study

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.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma Non-resectable
• Intervention / Treatment: Drug: Bevacizumab plus Atezolizumab; Drug: Lenvatinib; Drug: Bevacizumab Biosimilar IBI305 plus sintilimab; Drug: apatinib plus camrelizumab; Drug: Sorafenib; Drug: Donafenib; Drug: Regorafenib; Procedure: TACE; Drug: Anti-PD-1 monoclonal antibody

Detailed Description

The multicenter, non-random, open and ambispective real-world cohort study is conducted at 4 research centers, including 3 centers (Hankou, Sino-French New District, and Optical Valley) of Tongji hospital (Wuhan, China) and one in the second affiliated hospital of Fujian Medical University (Quanzhou, China). It is estimated that 300 patients with advanced HCC will be enrolled in these 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. Radiological assessments are performed every two cycles over the course of treatment, then every 3 months within the first two years following the completion of treatment and every 6 months thereafter, until PD were recorded. All subjects are followed until death or lost to follow up.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Ze-yang Ding, M.D.; Phone Number: +86-13407156200; Email: zyding@tjh.tjmu.edu.cn

Study Locations

• China
  • Fujian
    • Quanzhou, Fujian, China
      • Recruiting
      • The Second Affiliated Hospital of Fujian Medical University
      • Contact: Yan-jun Wang, M.D.; Phone Number: +86-15872415556; Email: wangyanjun@fjmu.edu.cn
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Recruiting
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Contact: Ze-yang Ding, M.D.
    • Wuhan, Hubei, China, 430073
      • Recruiting
      • Optical Valley branch of Tongji hospital
      • Contact: Zhanguo Zhang, M.D.
    • Wuhan, Hubei, China
      • Recruiting
      • Sino-French branch of Tongji hospital
      • Contact: Ganxun Li, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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

Description

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 or BCLC stage C.
6. 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.
7. hepatic vein invasion (VV1 to VV2) were allowed.
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 ×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.

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: main trunk of portal vein and superior mesenteric vein (Cheng's type III and IV) or inferior vena cava (IVC) (VV3).

Study Plan

How is the study designed?

Number of groups / cohorts

7

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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.	Drug: Lenvatinib; 8mg; p.o.; q.d.; Other Names: levima; Procedure: TACE; Procedure of TACE is standardized.; Other Names: transarterial chemoembolization; Drug: Anti-PD-1 monoclonal antibody; 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).; Other Names: PD-1 inhibitor
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.	Drug: Bevacizumab plus Atezolizumab; Bevacizumab (15mg/kg, q3w) plus Atezolizumab (1200 mg, q3w); Other Names: Avastin plus Tecentriq; Procedure: TACE; Procedure of TACE is standardized.; Other Names: transarterial chemoembolization
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.	Drug: Bevacizumab Biosimilar IBI305 plus sintilimab; Bevacizumab Biosimilar IBI305 (15mg/kg, q3w), and sintilimab (200 mg, q3w); Other Names: Byvasda (B) plus S; Procedure: TACE; Procedure of TACE is standardized.; Other Names: transarterial chemoembolization
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.	Drug: apatinib plus camrelizumab; Apatinib(250 mg; p.o.; q. d.); camrelizumab (200 mg; iv drip; q2w); Other Names: Apa plus C; Procedure: TACE; Procedure of TACE is standardized.; Other Names: transarterial chemoembolization
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.	Drug: Sorafenib; 400mg; p.o. bid; Other Names: Nexavar; Procedure: TACE; Procedure of TACE is standardized.; Other Names: transarterial chemoembolization; Drug: Anti-PD-1 monoclonal antibody; 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).; Other Names: PD-1 inhibitor
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.	Drug: Donafenib; 200mg; p.o. bid; Other Names: Zepsun; Procedure: TACE; Procedure of TACE is standardized.; Other Names: transarterial chemoembolization; Drug: Anti-PD-1 monoclonal antibody; 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).; Other Names: PD-1 inhibitor
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.	Drug: Regorafenib; 160 mg; p.o.; q.d.; Other Names: stivarga; Procedure: TACE; Procedure of TACE is standardized.; Other Names: transarterial chemoembolization; Drug: Anti-PD-1 monoclonal antibody; 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).; Other Names: PD-1 inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to intrahepatic tumor progression (TTITP)	Time to intrahepatic tumor progression (TTITP): measured from the date of first treatment to radiographically documented intrahepatic tumor progression according to mRECIST 1.1. This does not include death from any cause.	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)	measured from the date of first treatment to radiographically documented progression according to mRECIST 1.1 or death from any cause (whichever occurs first). Participants alive and without disease progression or lost to follow-up will be censored at the date of their last radiographic assessment.	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
Response Rate measured by mRECIST criteria	Complete response (CR): Disappearance of any intra-tumoral arterial enhancement in all target lesions; Partial response (PR): At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions. Response rate is the rate of CR plus PR.	from the date of first treatment to radiographically documented progression according to mRECIST v1.1, assessed up to 3 years
Time to progression (TTP)	Time to progression (TTP): measured from the date of first treatment to radiographically documented progression according to mRECIST 1.1. This does not include death from any cause.	from the date of first treatment to radiographically documented progression according to mRECIST1.1, assessed up to 3 years
Overall survival (OS)	measured from date of first treatment to the date of death from any cause. Participants alive or lost to follow-up will be censored at the date of their last visit.	from the date of first treatment to the date of death from any cause, assessed up to 5 years
Incidence of Study-Related Adverse Events	Incidence, nature, and severity of adverse events graded according to the United States National Cancer Institute The Common Terminology Criteria for Adverse Events (NCI-CTCAE 5.0).	from the date of first treatment to 90 days after last treatment, around 3 years and 90 days
Pathological response	Pathological response is assessed as the percentage of surface with non-viable cancer cells (represented by necrosis or fibrosis, the ultimate stage of necrosis) in relation to the total tumor area and will be equal to: 100% - viable cancer cells (%). If there are multiple tumors, the mean percentage will be used. Pathological complete response (pCR) is defined by the absence of viable tumor cells in any nodule.	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 5 years.
Disease control rate	Percentage of patients that had a CR, PR, or SD ≥ 6 months per mRECIST1.1.	from the date of first treatment to radiographically documented response according to mRECIST 1.1, assessed up to 3 years.
Duration of response	Defined as the time from first documented evidence of CR or PR until the first documented sign of disease progression (PD) or death from any cause.	from the date of first documented evidence of CR or PR to first documented sign of PD or death from any cause according to mRECIST 1.1, assessed up to 3 years
Quality of Life (QoL) after treatment	The life quality of every subject is assessed every 3 months during follow up according to the 45-item FACT-Hep questionnaire, which assesses generic HRQL concerns and disease-specific issues.	3 year

Collaborators and Investigators

• Sponsor: Tongji Hospital
• Collaborators: The Second Affiliated Hospital of Fujian Medical University; Geneplus-Beijing Co. Ltd.; Chen Xiao-ping Foundation for the Development of Science and Technology of Hubei Province; Haplox Biotechnology Co., Ltd.; Chinese Cooperative Group of Liver Cancer
• Investigators: Principal Investigator: Ze-yang Ding, M.D., Tongji Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 20, 2022
• Primary Completion (Actual): December 31, 2023
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: January 29, 2023
• First Submitted That Met QC Criteria: January 29, 2023
• First Posted (Actual): February 8, 2023

Study Record Updates

• Last Update Posted (Actual): June 13, 2024
• Last Update Submitted That Met QC Criteria: June 12, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Hepatocellular Carcinoma; Downstaging conversion therapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Antibodies; Sorafenib; Bevacizumab; Antibodies, Monoclonal; Lenvatinib; Apatinib; Immune Checkpoint Inhibitors; Atezolizumab
• Other Study ID Numbers: TJ-IRB-20221202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes