Infusion of PD1/PDL1/CTLA4 Inhibitors Via Hepatic Arterial for Immunotherapy of Hepatocellular Carcinoma

Phase 3

Recruiting

• Conditions: Liver Cancer
• Interventions: Drug: PD1/PDL1 inhibitor

• Registration Number: NCT03949231
• Lead Sponsor: Second Affiliated Hospital of Guangzhou Medical University

Brief Summary

This trial was designed to investigate the survival outcomes, response rates, and safety of patients with Barcelona-Clinical Hepatocellular Carcinoma (BCLC)-C-stage liver cancer by hepatic artery versus vein infusion of PD1/PDL1/CTLA4 inhibitor or their combinations.

Detailed Description

Liver cancer is the fifth most common malignancy worldwide, but the mortality rate ranks third. China has a large population base, with more than 400,000 new cases each year, and more than half of the world's new liver cancer and deaths. More than 70% of liver cancer patients in China are diagnosed at mid-to-late stage and have lost the chance of surgery. Only 10%-15% of newly diagnosed patients can undergo radical resection, and the recurrence rate after 5 years is as high as 50%-80%. So far, sorafenib is still the only standard treatment that can prolong the overall survival of advanced hepatocellular carcinoma. SHARP's latest research shows that sorafenib can only extend patients with advanced liver cancer for 2.8 months, and many adverse reactions; regofenib can be used in patients with advanced liver cancer after taking sorafenib resistance, but the overall efficiency is still low. It is difficult to be widely used in patients with advanced liver cancer, and more alternative therapies are urgently needed.

PD1/PDL1 inhibitor is widely used in treatment of various cancers in China now. The hepatic arterial chemotherapy infusion for advanced liver cancer, through the "first pass effect" of drug treatment, can significantly increase the local drug concentration of the tumor, improve the efficacy, reduce systemic adverse reactions, meanwhile Folfox regimen has been confirmed by the hepatic arterial chemotherapy infusion program. To the investigator's knowledge, no studies have been developed on the survival benefit of hepatic arterial infusion of immunotherapeutic agents in patients with advanced liver cancer. This phase III clinical trial was designed to compare the effects of PD1/PDL1/CTLA4 inhibitor or their combinations via IA and IV on the survival benefit of patients with advanced liver cancer, including ORR, DCR, median survival time, and safety.

Study Timeline

• Study Start: 2019-01-01
• Study First Submitted: 2019-05-13
• Study First Submitted QC: 2019-05-13
• Study First Posted: 2019-05-14
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-22
• Last Update Posted: 2024-06-26
• Primary Completion: 2029-01-01
• Study Completion: 2038-01-02

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

1. Cytohistological confirmation is required for diagnosis of HCC.、
2. Signed informed consent before recruiting
3. Age between 18 to 80 years with estimated survival over 3 months.
4. Child-Pugh class A or B/Child score > 7; ECOG score < 2
5. Tolerable coagulation function or reversible coagulation disorders
6. Laboratory examination test within 7 days prior to procedure: WBC≥3.0×10E9/L; Hb≥90g/L； PLT ≥50×10E9/L；INR < 2.3 or PT < 6 seconds above control；Cr ≤ 145.5 umul/L；Albumin > 28 g/L；Total bilirubin < 51 μmol/L
7. At least one tumor lesion meeting measurable disease criteria as determined by RECIST v1.1.
8. Patients with advanced (unresectable and/or metastatic, stage C based on Barcelona-Clinic Liver Cancer [BCLC] staging classification) hepatocellular carcinoma which would not be suitable for treatment with loco-regional therapies or have progressed following locoregional therapy such as surgical resection, percutaneous hepatic arterial embolization, radiofrequency ablation, and percutaneous interventional therapy.
9. Birth control.
10. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.

Exclusion Criteria

1. Patients participated in clinical trials of equipment or drugs (signed informed consent) within 4 weeks;

2. Patients accompany by ascites, hepatic encephalopathy and esophageal and gastric varices bleeding;

3. Any serious accompanying disease, which is expected to have an unknown, impact on the prognosis, include heart disease, inadequately controlled diabetes and psychiatric disorders;

4. Patients accompanied with other tumors or past medical history of malignancy;

5. Pregnant or lactating patients, all patients participating in this trial must adopt appropriate birth control measures during treatment;

6. Patients have poor compliance.

   Any contraindications for hepatic arterial infusion procedure:

   A.Impaired clotting test (platelet count < 60000/mm3, prothrombin activity < 50%).

   B.Renal failure / insufficiency requiring hemo-or peritoneal dialysis. C.Known severe atheromatosis. D.Known uncontrolled blood hypertension (> 160/100 mm/Hg).

7. Patients have the past history of liver cancer treatment, such as transplantation, resection, radiotherapy, chemotherapy and so on;

8. Allergic to adriamycin chemotherapy drugs，contrast agent and lipiodol;

9. Any agents which could affect the absorption or pharmacokinetics of the study drugs

10. Subjects unable to suffer the discomfort of the HAI procedure

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PD1/PDL1/CTLA4 inhibitor or their combinations vein infusion	PD1/PDL1 inhibitor	Regular IV infusion of PD1/PDL1/CTLA4 inhibitor or their combinations in 30 minutes.
PD1/PDL1/CTLA4 inhibitor or their combinations hepatic artery infusion	PD1/PDL1 inhibitor	Interventional technique to place microcatheter in hepatic artery to infuse PD1/PDL1/CTLA4 inhibitor or their combinations in 30 minutes.

Primary Outcome Measures

Name	Time	Method
Overall survival	2 years	Overall survival (OS) will be defined as the elapsed time from the enrollment to death from any cause. For surviving patients, follow-up will be censored at the date of last contact (or last date known to be alive). Follow-up for OS will occur every 12 weeks (±1 month) until death or withdrawal of consent from the study.

Secondary Outcome Measures

Name	Time	Method
Adverse event rate	2 years	Adverse event rate will be defined as the rate of patients who developed adverse event.
Progression-free survival	2 years	Progression-free survival (PFS) will be defined as the elapsed time from the first date of study treatment until documented disease progression (as per mRECIST) or death from any cause, whichever is earlier. For patients who remain alive without progression, follow-up time will be censored at the date of last disease assessment.

Trial Locations

Locations (1)

The Second Affiliated Hospital of Guangzhou Medical University; 🇨🇳 Guanzhou, Guangdong, China