Neoadjuvant Intra-tumor Double Immunotherapy for Hepatocellular Carcinoma.

Phase II Study of Neoadjuvant CT-Guided Intra-tumor Double Checkpoint Blockades for Untreated Hepatocellular Carcinoma (HCC) Amenable for Surgical Resection

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

Study Overview

• Status: Recruiting
• Conditions: Surgery; Hepatic Cancer
• Intervention / Treatment: Drug: ipilimumab, pembrolizumab, durvalumab, idarubicin, bevacizumab

Detailed Description

Antibodies against CTLA4, PD1 or 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 neoadjuvant therapy 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 neoadjuvant treatment 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 neoaduvant therapy on patients with HCC, including safety, pCR, mPR, 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
  • Guangdong
    • Guanzhou, Guangdong, China, 51260
      • Recruiting
      • The second Affiliated Hospital of Guangzhou Medical University
      • Contact: Zhenfeng Zhang, MD,PhD; Phone Number: 02034153532; Email: zhangzhf@gzhmu.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed previously untreated hepatocellular carcinoma (HCC). If a diagnostic biopsy is available, a pre-treatment biopsy is not required. Patients with a suspected HCC are eligible, but pathology must be confirmed prior to initiating treatment on study.
2. The patient must be a suitable candidate for surgery, in the opinion of the treating physician.
3. Signed and dated written informed consent must be provided by the patient prior to admission to the study in accordance with International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines and to the local legislation.
4. Eastern Cooperative Oncology Group (ECOG) performance status score 0-1
5. Absolute neutrophil count (ANC) >= 1.5 x 10^9/L; Hemoglobin >= 8.0 g/dL; Platelets >= 100 x 10^9/L; Total bilirubin =< 1.5 x upper limit of normal (ULN) (except subjects with Gilbert syndrome who can have total bilirubin < 3.0 mg/dL); Creatinine =< 1.5 x ULN or calculated creatinine clearance >= 50 mL/min using Cockcroft-Gault formula for creatinine clearance calculation OR 24-hour urine creatinine clearance >= 50 mL/min.
6. Birth control.
7. 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. 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: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: IT injection of double ICIs; Neoadjuvant therapy: intra-tumor injection of double ICIs only.	Drug: ipilimumab, pembrolizumab, 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, total 3-4 times. Arm 2. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab combined with idarubicin is administrated via intra-tumor fine needle injection in 15 min, every 3 weeks, total 3-4 times. 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, total 3-4 times.; Other Names: Other ICIs
Experimental: Group 2: IT injection of double ICIs and chemodrug; Neoadjuvant therapy: intra-tumor injection of double ICIs and chemodrug.	Drug: ipilimumab, pembrolizumab, 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, total 3-4 times. Arm 2. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab combined with idarubicin is administrated via intra-tumor fine needle injection in 15 min, every 3 weeks, total 3-4 times. 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, total 3-4 times.; Other Names: Other ICIs
Experimental: Group 3: IT injection of double ICIs and chemodrug plus bevacizumab; Neoadjuvant therapy: intra-tumor injection of double ICIs and chemodrug plus bevacizumab.	Drug: ipilimumab, pembrolizumab, 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, total 3-4 times. Arm 2. Ipilimumab +pembrolizumab or Ipilimumab +durvalumab combined with idarubicin is administrated via intra-tumor fine needle injection in 15 min, every 3 weeks, total 3-4 times. 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, total 3-4 times.; Other Names: Other ICIs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pCR rate for the study groups	Pathologic complete response (pCR) is defined as after neoadjuvant therapy, the surgical specimen can not find any residual cancer cells.	Six months
mPR rate for the study groups	Major pathologic response (MPR) is defined as pathological less than 10% survival cancer cells after tumor resection.	Six months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity of the study groups	Toxicity is assessed by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4.	Six months
Overall survival	To correlate major pathologic response with recurrence-free and overall survival.	Six years
Response rates to neoadjuvant treatment	Response rates are assessed by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1.	Six years
Recurrence-free survival	Recurrence-free survival is measured as routine.	Six 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): July 1, 2024
• Primary Completion (Estimated): December 30, 2028
• Study Completion (Estimated): December 30, 2033

Study Registration Dates

• First Submitted: July 2, 2024
• First Submitted That Met QC Criteria: July 2, 2024
• First Posted (Actual): July 9, 2024

Study Record Updates

• Last Update Posted (Actual): July 9, 2024
• Last Update Submitted That Met QC Criteria: July 2, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Surgery; Immunotherapy; Neoadjuvant therapy; Intra-tumor injection; PD1 antibody; PDL1 antibody; CTLA4 antibody; Hepatocellular Carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Carcinoma; Carcinoma, Hepatocellular; 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-ICIs-HCC-Neoadjuvant-027

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