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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hepatocellular Carcinoma Non-resectable

Intervention / Treatment
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* Procedure: TACE
* Drug: Lenvatinib
* Drug: Anti-PD-1 monoclonal antibody
* Drug: Bevacizumab Biosimilar IBI305 plus sintilimab
* Drug: Bevacizumab plus Atezolizumab
* Drug: apatinib plus camrelizumab
* Drug: Sorafenib
* Drug: Donafenib
* Drug: Regorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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: 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. 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| TACE-Len-ICI cohort<br>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<br>* Procedure of TACE is standardized.<br>* Other names: transarterial chemoembolization;Drug: Lenvatinib<br>* 8mg; p.o.; q.d.<br>* Other names: levima;Drug: Anti-PD-1 monoclonal antibody<br>* 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).<br>* Other names: PD-1 inhibitor;|
| TACE-A-T cohort<br>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<br>* Procedure of TACE is standardized.<br>* Other names: transarterial chemoembolization;Drug: Bevacizumab plus Atezolizumab<br>* Bevacizumab (15mg/kg, q3w) plus Atezolizumab (1200 mg, q3w)<br>* Other names: Avastin plus Tecentriq;|
| TACE-B-S cohort<br>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<br>* Procedure of TACE is standardized.<br>* Other names: transarterial chemoembolization;Drug: Bevacizumab Biosimilar IBI305 plus sintilimab<br>* Bevacizumab Biosimilar IBI305 (15mg/kg, q3w), and sintilimab (200 mg, q3w)<br>* Other names: Byvasda (B) plus S;|
| TACE-Apa-C cohort<br>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<br>* Procedure of TACE is standardized.<br>* Other names: transarterial chemoembolization;Drug: apatinib plus camrelizumab<br>* Apatinib(250 mg; p.o.; q. d.); camrelizumab (200 mg; iv drip; q2w)<br>* Other names: Apa plus C;|
| TACE-Sor-ICI cohort<br>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<br>* Procedure of TACE is standardized.<br>* Other names: transarterial chemoembolization;Drug: Anti-PD-1 monoclonal antibody<br>* 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).<br>* Other names: PD-1 inhibitor;Drug: Sorafenib<br>* 400mg; p.o. bid<br>* Other names: Nexavar;|
| TACE-Don-ICI cohort<br>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<br>* Procedure of TACE is standardized.<br>* Other names: transarterial chemoembolization;Drug: Anti-PD-1 monoclonal antibody<br>* 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).<br>* Other names: PD-1 inhibitor;Drug: Donafenib<br>* 200mg; p.o. bid<br>* Other names: Zepsun;|
| TACE-Reg-ICI cohort<br>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<br>* Procedure of TACE is standardized.<br>* Other names: transarterial chemoembolization;Drug: Anti-PD-1 monoclonal antibody<br>* 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).<br>* Other names: PD-1 inhibitor;Drug: Regorafenib<br>* 160 mg; p.o.; q.d.<br>* Other names: stivarga;|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatocellular Carcinoma, Downstaging conversion therapy