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
Overview
- Phase
- Not Applicable
- Status
- Recruiting
- Sponsor
- Ze-yang Ding, MD
- Enrollment
- 300
- Locations
- 2
- Primary Endpoint
- Number of Patients Amendable to Curative Surgical Interventions
Overview
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.
Detailed Description
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.
Study Design
- Study Type
- Observational
- Observational Model
- Cohort
- Time Perspective
- Prospective
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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.
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.
- •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.
- •Pregnant women or breast-feeding patients.
- •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.
Arms & Interventions
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.
Intervention: HAIC (Procedure)
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.
Intervention: Bevacizumab plus Atezolizumab (Drug)
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.
Intervention: HAIC (Procedure)
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.
Intervention: Lenvatinib (Drug)
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.
Intervention: Anti-PD-1 monoclonal antibody (Drug)
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.
Intervention: HAIC (Procedure)
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.
Intervention: Bevacizumab Biosimilar IBI305 plus sintilimab (Drug)
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.
Intervention: HAIC (Procedure)
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.
Intervention: apatinib plus camrelizumab (Drug)
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.
Intervention: HAIC (Procedure)
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.
Intervention: Sorafenib (Drug)
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.
Intervention: Anti-PD-1 monoclonal antibody (Drug)
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.
Intervention: HAIC (Procedure)
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.
Intervention: Donafenib (Drug)
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.
Intervention: Anti-PD-1 monoclonal antibody (Drug)
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.
Intervention: HAIC (Procedure)
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.
Intervention: Regorafenib (Drug)
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.
Intervention: Anti-PD-1 monoclonal antibody (Drug)
Outcomes
Primary Outcomes
Number of Patients Amendable to Curative Surgical Interventions
Time Frame: from the date of first treatment to the date of last treatment, an average of 3 years
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.
Secondary Outcomes
- 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)
- Time to progression (TTP)(from the date of first treatment to radiographically documented progression according to mRECIST, assessed up to 3 years)
- Incidence of Study-Related Adverse Events(from the date of first treatment to 90 days after last treatment, around 3 years and 90 days)
- Duration of response(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)
- 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)
- Disease control rate (DCR)(from the date of first treatment to radiographically documented response according to mRECIST, 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)
- Pathological response(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)
- Quality of Life (QoL) after treatment(assessed form the date of first followup to radiographically documented progression or or death from any cause, up to 3 years)
Investigators
Ze-yang Ding, MD
Professor
Tongji Hospital