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

Study Overview
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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.

Official Title
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Combined Hepatic Arterial Infusion Chemotherapy, Tyrosine Kinase Inhibitor/ Anti-VEGF Antibody, and Anti-PD-1/ PD-L1 Antibody as Conversion Therapy for Unresectable Hepatocellular Carcinoma

Conditions
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Hepatocellular Carcinoma Non-resectable

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


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 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. Exclusion Criteria: 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. 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.

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 |
| --- | --- |
| HAIC-A-T cohort<br>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<br>* administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.<br>* Other names: hepatic arterial infusion chemotherapy of FOLFOX;Drug: Bevacizumab plus Atezolizumab<br>* Bevacizumab (15mg/kg, q3w) plus Atezolizumab (1200 mg, q3w)<br>* Other names: Avastin plus Tecentriq;|
| HAIC-Len-ICI cohort<br>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<br>* administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.<br>* Other names: hepatic arterial infusion chemotherapy of FOLFOX;Drug: Lenvatinib<br>* 8mg; p.o.; q.d.<br>* Other names: Lenvima;Drug: Anti-PD-1 monoclonal antibody<br>* 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;|
| HAIC-B-S cohort<br>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<br>* administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.<br>* Other names: hepatic arterial infusion chemotherapy of FOLFOX;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;|
| HAIC-Apa-C cohort<br>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<br>* administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.<br>* Other names: hepatic arterial infusion chemotherapy of FOLFOX;Drug: apatinib plus camrelizumab<br>* Apatinib(250 mg; p.o.; q. d.); camrelizumab (200 mg; iv drip; q2w)<br>* Other names: Apa plus C;|
| HAIC-Sor-ICI cohort<br>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<br>* administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.<br>* Other names: hepatic arterial infusion chemotherapy of FOLFOX;Drug: Sorafenib<br>* 400mg; p.o. bid<br>* Other names: Nexavar;Drug: Anti-PD-1 monoclonal antibody<br>* 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;|
| HAIC-Don-ICI cohort<br>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<br>* administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.<br>* Other names: hepatic arterial infusion chemotherapy of FOLFOX;Drug: Donafenib<br>* 200mg; p.o. bid<br>* Other names: Zepsun;Drug: Anti-PD-1 monoclonal antibody<br>* 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;|
| HAIC-Reg-ICI cohort<br>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<br>* administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.<br>* Other names: hepatic arterial infusion chemotherapy of FOLFOX;Drug: Regorafenib<br>* 160 mg; p.o.; q.d.<br>* Other names: stivarga;Drug: Anti-PD-1 monoclonal antibody<br>* 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;|

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 |
| --- | --- | --- |
| overall response rate (ORR) 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; Stable disease (SD): Any cases that do not qualify for either partial response or progressive disease; Progressive disease (PD): An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started. ORR=CR+PR. | rom the date of first treatment to radiographically documented progression according to mRECIST, 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 mRECIST, 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, 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) | 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. | from the date of first study 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 (DCR) | Percentage of patients that had a CR, PR, or SD ≥ 6 months per mRECIST | from the date of first treatment to radiographically documented response according to mRECIST, 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. | assessed form the date of first followup to radiographically documented progression or or death from any cause, up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Neoplasms, Hepatocellular Carcinoma