HLPDTLT: HAIC Combined With Targeted Therapy and Immunotherapy as Down-stage Therapy of LT

Sponsor

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05475613

Collaborator

(none)

Enrollment

Location

Arm

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a prospective single center, open-label, non-randomized, single arm exploratory study. The objective of this study is to evaluate the efficacy and safety of HAIC combined with targeted therapy and immunotherapy as down-stage therapy for hepatocellular carcinoma before liver transplantation.

Condition or Disease	Intervention/Treatment	Phase
Liver Transplantation Hepatocellular Carcinoma	Procedure: FOLFOX-HAIC Drug: Lenvatinib Drug: PD-1 inhibitor Procedure: Liver transplantation	Phase 2

Detailed Description

Due to the shortage of donor organs and the risk of tumor recurrence after transplantation, Milan criteria have become the standard guidelines for liver transplantation in patients with hepatocellular carcinoma and liver cirrhosis. But actually, a large number of patients with hepatocellular carcinoma beyond Milan criteria are in urgent need of liver transplantation. In recent years, remarkable progress has been made in the systemic therapies of hepatocellular carcinoma, such as hepatic arterial infusion chemotherapy (HAIC) combined with targeted therapy and immune checkpoint therapy, which can achieve an objective response rate (ORR) of more than 40% for advanced hepatocellular carcinoma. Therefore, can HAIC combined with targeted therapy and immunotherapy be used as down-stage therapy before liver transplantation of hepatocellular carcinoma patients beyond Milan criteria? 29 patients exceeding Milan criteria received down-stage therapy with HAIC+ targeted therapy + immunotherapy in our hospital in the past three years, and the retrospective analysis showed the 2-year recurrence free survival rate reached 83% after liver transplantation. Three of them experienced acute rejection after liver transplantation, which was cured by anti-rejection treatment. Therefore, this prospective single center, open-label, non-randomized, single arm exploratory study aims to evaluate the efficacy and safety of HAIC combined with targeted therapy and immunotherapy as down-stage therapy for hepatocellular carcinoma beyond Milan criteria before liver transplantation.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

75 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Prospective, Single-arm Study of HAIC Combined With Targeted Therapy and Immunotherapy Before Liver Transplantation for HCC Beyond the Milan Criteria

Anticipated Study Start Date :

Aug 1, 2022

Anticipated Primary Completion Date :

Jul 30, 2025

Anticipated Study Completion Date :

Jul 30, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: HAIC combined with targeted therapy and immunotherapy as down-stage therapy of LT HAIC combined with targeted therapy and immunotherapy as down-stage therapy before liver transplantation of hepatocellular carcinoma patients beyond Milan criteria	Procedure: FOLFOX-HAIC FOLFOX-HAIC regimen: oxaliplatin 130 mg/m2 on day 1 from hour 0 to 3; leucovorin 200 mg/m2 from hour 3 to 5, fluorouracil 400 mg/m2 bolus at hour 5, and then fluorouracil 2,400 mg/m2 over 46 hours, via hepatic artery, once every 4 weeks. Drug: Lenvatinib Lenvatinib 4mg Tab, 8 mg once per day orally. Treatment was given in 4-week cycles. Other Names: Targeted therapy Drug: PD-1 inhibitor PD-1 inhibitor 200mg Powder for Injection, 200 mg once via an intravenous drip. Treatment was given in 4-week cycles. Other Names: Immune checkpoint therapy Procedure: Liver transplantation Liver transplantation is routinely performed in patients who achieve complete response or partial response or stable disease after systemic therapy. Other Names: LT

Arm

Intervention/Treatment

Experimental: HAIC combined with targeted therapy and immunotherapy as down-stage therapy of LT

HAIC combined with targeted therapy and immunotherapy as down-stage therapy before liver transplantation of hepatocellular carcinoma patients beyond Milan criteria

Procedure: FOLFOX-HAIC

FOLFOX-HAIC regimen: oxaliplatin 130 mg/m2 on day 1 from hour 0 to 3; leucovorin 200 mg/m2 from hour 3 to 5, fluorouracil 400 mg/m2 bolus at hour 5, and then fluorouracil 2,400 mg/m2 over 46 hours, via hepatic artery, once every 4 weeks.

Drug: Lenvatinib

Lenvatinib 4mg Tab, 8 mg once per day orally. Treatment was given in 4-week cycles.

Other Names:

Targeted therapy

Drug: PD-1 inhibitor

PD-1 inhibitor 200mg Powder for Injection, 200 mg once via an intravenous drip. Treatment was given in 4-week cycles.

Other Names:

Immune checkpoint therapy

Procedure: Liver transplantation

Liver transplantation is routinely performed in patients who achieve complete response or partial response or stable disease after systemic therapy.

Other Names:

Outcome Measures

Primary Outcome Measures

The 2-year relapse-free survival rate [2-year]
From the beginning of treatment to tumor recurrence or death from any cause.

Secondary Outcome Measures

The 2-year overall survival [2-year]
The time elapsed from the beginning of treatment to death during the 2-year follow-up period.
1-year and 2-year survival rate [2-year]
The probability of survival from the beginning of treatment to the end of 1-year and 2-year follow-up.
The 1-year relapse-free survival rate [1-year]
From the beginning of treatment to tumor recurrence or death from any cause.
Disease Control Rate [1-year]
The proportion of CR, PR and SD.
Tumor R0 resection rate [2-year]
Pathological indicators
tumor necrosis rate [2-year]
Pathological indicators
ECOG score [2-year]
Health-related quality
KPS score [2-year]
Health-related quality
AFP level before and after treatment [2-year]
AFP

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

1. Written informed consent must be obtained prior to any screening procedures, and the patient is willing and able to comply with scheduled visits, treatment plan and laboratory tests.

The diagnosis of HCC is confirmed by at least two types of imaging examination (ultrasound, CT, MRI) with contrast enhanced.
The patient with HCC beyond Milan criteria is scheduled for liver transplantation, and has no extrahepatic metastases, lymph node metastases and main portal vein or hepatic vein invasion.
The Child-Pugh score of the patient is ≤7, and the patient has no encephalopathy, or controllable ascites.
Eastern Cooperative Oncology Group (ECOG) scale for assessment of patient Performance Status (PS score) is≤ 2, and KPS score is ≥60.
The patient has not received any systemic treatment within 6 months after the diagnosis of HCC.
Adequate bone marrow, liver and renal function are assessed by central lab by means of the following laboratory requirements: (1)Neutrophils≥1.5109/L; platelets≥50109/L; (2)Bilirubin ≤2 times the upper limit of normal; Albumin > 28 g/L; Alanine transaminase (ALT) and aminotransferase (AST) ≤ 5 times the upper limit of normal; (4)Prothrombin time (PT)-international normalized ratio (INR) < 1.5, or PT ≥18 seconds; (5)Serum creatinine ≤ 1.5 times the upper limit of normal, and creatinine clearance ≥ 60ml/min(calculated by Cockcroft-Gault formula).
Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and 6 months after the completion of trial.

Exclusion Criteria:

1. The patient has suffered from other malignant tumors, except for fully treated non-melanoma skin cancer, cervical carcinoma in situ, and thyroid papillary carcinoma.

The patient has organic disease of heart, lung and brain, uncontrollable mental illness, serious mental illness, alcoholism or drug abuse, uncontrollable systemic infection, including HIV infection、active tuberculosis and etc.
The patient with severe portal hypertension is at higher risk of bleeding as assessed by the investigators.
The patient has any life-threatening event in the past 6 months, including but not limited to acute myocardial infarction, unstable angina pectoris, congestive heart failure, cerebrovascular accident, pulmonary embolism, massive haemorrhage, etc.
The patient has uncontrolled hypertension, or a history of hypertensive crisis or hypertensive encephalopathy.
The patient has severe pulmonary hypertension that cannot be controlled by drugs.
The patient has severe coagulation dysfunction, have bleeding tendency or is receiving thrombolysis, or anticoagulation therapy, or antiplatelet therapy.
The patient has history of autoimmune diseases such as rheumatism, lupus, psoriasis, crohn's disease and ulcerative colitis.

9.The patient has received any prior systemic chemotherapy or molecular-targeted therapy or immunotherapy for HCC such as Sorafenib, Lenvatinib, PD-1/PD-L1 inhibitor, CAR-T, TCR-T, etc.

The Patient has underwent major surgical procedure, or significant traumatic injury within 4 weeks of the start of protocol treatment.
The patient is known to have a history of severe allergies to any monoclonal antibodies, targeted therapy drugs, or chemotherapeutic agents.
Other factors judged by the investigator may affect the safety of the subjects or the compliance of the trial, such as serious laboratory abnormalities, or other family or social factors.