Checkpoint Inhibitor Combinations Therapy as First Line for HCC Via IT

Intra-tumor Delivery of Double Checkpoint Inhibitors, Chemodrug, and/or Bevacizumab Therapy as First Line for Hepatocellular Carcinoma

This trial is designed to investigate the safety, response rates and survival outcomes of patients with hepatocellular carcinoma by infusion of CTLA4, PD1 and PDL1 antibodies combination with chemodrug or/and bevacizumab through intra-tumor (IT).

Study Overview

• Status: Recruiting
• Conditions: Antibody; Liver Cancer
• Intervention / Treatment: Drug: ipilimumab+pembrolizumab or ipilimumab+durvalumab, idarubicin, bevacizumab

Detailed Description

Antibodies against CTLA4, PD1 and PDL1 are representative drugs for the check-points inhibitory agents, and their clinical indications have been approved in various types of tumors, including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, and classical Hodgkin's lymphoma and late recurrent head and neck squamous cell carcinoma patients, et al. Those drugs are regularly systemically administrated by vein infusion, however, local delivery of those drugs via interventional radiology technique including trans-artery or intra-tumor injection may increase the local drug concentration of the tumor, improve the efficacy, and reduce systemic adverse reactions. CTLA4 antibody ipilimumab has been widely effectively using to combine with PD1 or PDL1 antibody and this study is to combine ipilimumab and PD1 antibody or PDL1 antibody, so called double checkpoint inhibitors combination therapy, as first line for hepatocellular carcinoma (HCC) via intra-tumor admistration. To the investigator's knowledge, no studies have been developed on the safety, efficacy and survival benefit of the double checkpoint inhibitors combination therapy for cancer patients as first line via intra-tumor delivery. This phase II clinical trial is designed to assess the safety and survival benefit of ipilimumab and pembrolizumab or durvalumab combination with or without chemodrug or bevacizumab as first line therapy on patients with HCC, including PFS, ORR, DCR, and median survival time.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bingjia He, MD; Phone Number: +862039195965; Email: 464677938@qq.com
• Study Contact Backup: Name: Zhenfeng Zhang, MD, PhD; Phone Number: +862039195966; Email: zhangzhf@gzhmu.edu.cn

Study Locations

• China
  • Guangzhou, China, 510260
    • Recruiting
    • Second Affiliated Hospital of Guangzhou Medical University
    • Contact: Bingjia He; Phone Number: +862039195965; Email: 464677938@qq.com
    • Contact: Zhenfeng Zhang, MD, PhD; Phone Number: +862039195966; Email: zhangzhf@gzhmu.edu.cn
    • Principal Investigator: Zhenfeng Zhang, MD, PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Cytohistological confirmation is required for diagnosis of cancer.
2. Signed informed consent before recruiting.
3. Age above 18 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. Birth control.
9. 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. Allergic to contrast agent;
8. Any agents which could affect the absorption or pharmacokinetics of the study drugs
9. Other conditions that investigator decides not suitable for the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IT injection of double ICI; Arm 1: intra-tumor injection of double ICIs only.	Drug: ipilimumab+pembrolizumab or ipilimumab+durvalumab, idarubicin, bevacizumab; This study has 3 subgroups: Arm 1. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab is administrated with a total dose of 1-2mg/kg via intra-tumor fine needle injection in 10 min, every 3 weeks. Arm 2. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab combined with idarubicin is administrated via intra-tumor fine needle injection in 15 min, every 3 weeks. Arm 3. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab combined with idarubicin plus bevacizumab is administrated via intra-tumor fine needle injection in 20 min, every 3 weeks.; Other Names: Local ICIs.
Experimental: IT injection of double ICI and chemodrug; Arm 2: intra-tumor injection of double ICIs and a chemodrug.	Drug: ipilimumab+pembrolizumab or ipilimumab+durvalumab, idarubicin, bevacizumab; This study has 3 subgroups: Arm 1. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab is administrated with a total dose of 1-2mg/kg via intra-tumor fine needle injection in 10 min, every 3 weeks. Arm 2. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab combined with idarubicin is administrated via intra-tumor fine needle injection in 15 min, every 3 weeks. Arm 3. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab combined with idarubicin plus bevacizumab is administrated via intra-tumor fine needle injection in 20 min, every 3 weeks.; Other Names: Local ICIs.
Experimental: IT injection of double ICI and chemodrug plus bevacizumab; Arm 3: intra-tumor injection of double ICIs, a chemodrug, and bevacizumab.	Drug: ipilimumab+pembrolizumab or ipilimumab+durvalumab, idarubicin, bevacizumab; This study has 3 subgroups: Arm 1. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab is administrated with a total dose of 1-2mg/kg via intra-tumor fine needle injection in 10 min, every 3 weeks. Arm 2. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab combined with idarubicin is administrated via intra-tumor fine needle injection in 15 min, every 3 weeks. Arm 3. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab combined with idarubicin plus bevacizumab is administrated via intra-tumor fine needle injection in 20 min, every 3 weeks.; Other Names: Local ICIs.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease control rate	Disease control rate will be defined as objective response rate + steady disease rate.	5 years
Progression-free survival	Progression-free survival (PFS) will be defined as the elapsed time from the first date of study treatment until documented disease progression (as per RECIST 1.1) 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.	5 years
Duration of remission (DOR)	DOR will be defined as the duration of the cancer remission.	5 years
Safety of IT delivery of drugs combination treatment	Safety will be assessed by recording all types of advise effects upon and after the treatment.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	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.	5 years

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital of Guangzhou Medical University
• Investigators: Principal Investigator: Zhenfeng Zhang, MD, PhD, Second Affiliated Hospital of Guangzhou Medical University

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2024
• Primary Completion (Estimated): December 30, 2030
• Study Completion (Estimated): December 30, 2035

Study Registration Dates

• First Submitted: June 22, 2024
• First Submitted That Met QC Criteria: June 27, 2024
• First Posted (Actual): July 1, 2024

Study Record Updates

• Last Update Posted (Actual): July 1, 2024
• Last Update Submitted That Met QC Criteria: June 27, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Hepatocellular Carcinoma; Intra-tumor injection; First line; anti-angiogenesis; PD1 antibody; PDL1 antibody; CTLA4 antibody; chemodrug
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antibiotics, Antineoplastic; Immune Checkpoint Inhibitors; Durvalumab; Bevacizumab; Pembrolizumab; Idarubicin; Ipilimumab
• Other Study ID Numbers: ZZ-IT-ICI-HCC 1line-023

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes