RecruitingNCT05713994

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

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

Sponsor

Ze-yang Ding, MD

Enrollment

300 participants

Start Date

May 19, 2020

Study Type

OBSERVATIONAL

Conditions

Hepatocellular Carcinoma Non-resectable

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.

Eligibility

Min Age: 18 Years

Inclusion Criteria12

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 Criteria9

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. 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).
\. 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: 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.

Interventions

PROCEDUREHAIC

administration of oxaliplatin , fluorouracil, and leucovorin via the tumor feeding arteries every 3 weeks.

DRUGBevacizumab plus Atezolizumab

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

DRUGBevacizumab Biosimilar IBI305 plus sintilimab

Bevacizumab Biosimilar IBI305 (15mg/kg, q3w), and sintilimab (200 mg, q3w)

DRUGLenvatinib

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

DRUGSorafenib

400mg; p.o. bid

DRUGDonafenib

200mg; p.o. bid

DRUGRegorafenib

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

DRUGapatinib plus camrelizumab

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

DRUGAnti-PD-1 monoclonal antibody

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).