HAIC Combined with PD-1 Inhibitor in Potentially Resectable Locally Advanced HCC (HAICPD1-HCC)

November 27, 2024 updated by: XU li, Sun Yat-sen University

Hepatic Arterial Infusion Chemotherapy Combined with PD-1 Inhibitor in Treating Potentially Resectable Locally Advanced Hepatocellular Carcinoma: a Prospective, Phase II Clinical Study

Hepatocellular carcinoma patients are mostly diagnosed at locally advanced stage. Nowadays, hepatic artery interventional therapy and/or systemic therapy are the main treatments options for these patients. Our previous study showed that compared to than conventional transcatheter arterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC) has better objective response, better safety profile, and increased resection rates. The PD-1 inhibitors emerged in recent years have shown good momentum in the treatment of hepatocellular carcinoma. The single-drug treatment on advanced hepatocellular carcinoma has a tumor response rate of 17%, the disease control rate exceeds 60%, and the overall survival time exceeds 12 months. And it has good tolerance and less adverse events. In studies of other cancer, combined with traditional chemotherapy can further improve the efficacy of PD-1 inhibitors. Our study is a prospective phase II clinical study for patients with potentially resectable locally advanced hepatocellular carcinoma (tumor confined to the liver with invasion to branches of the portal vein or hepatic vein). Progressive survival (PFS) is the primary end point of study. The OS and overall survival rate, RFS, ORR, DCR, conversion rate, pathological response, and safety are the secondary endpoints. The efficacy and safety of HAIC combined with PD-1 inhibitor in the treatment of potentially resectable locally advanced hepatocellular carcinoma will be discussed.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Sintilimab (IBI308) is a recombinant human IgG4 PD-1 monoclonal antibody. It has been proved in many preclinical and in vitro trials that the effect of blocking PD-1 pathway with Sintilimab on. The results of preclinical pharmacodynamics, animal pharmacokinetics and toxicology all indicated that Sintilimab has clear targets, reliable cell lines and drug stability. It has considerable characteristics and has shown good activity in various preclinical studies.

Hepatocellular carcinoma patients are mostly diagnosed in locally advanced stage, and hepatic artery interventional therapy and/or systemic therapy are the main treatments options for these patients. In recent years, some researchers have reported that chemotherapy plays a critical role in transcatheter arterial intervention (Shi et al. JNCI, 2012, 105: 59). Compared with transcatheter arterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC) provides a more stable and long-lasting local control rate, which promised better outcomes. However, the effectiveness of HAIC varies greatly depending on the chemotherapy drug used, with an efficiency ranging from 7-81% and OS ranging from 6-15.9 months.

The single-drug treatment of PD-1 inhibitor in advanced hepatocellular carcinoma has a tumor response rate of 17%, the disease control rate exceeds 60%, and the overall survival time exceeds 12 months. And it has good tolerance and less adverse events. In studies in other cancers, combined with traditional chemotherapy can further improve the efficacy of PD-1 inhibitors.

Our study is a prospective phase II clinical study for patients with potentially resectable locally advanced hepatocellular carcinoma (tumor confined to the liver with invasion to branches of the portal vein or hepatic vein). Progressive survival (PFS) based on RECIST 1.1 is the primary end point of the present study. The OS and overall survival rate, RFS, ORR, DCR, conversion rate, pathological response, and safety are the secondary endpoints. The exploratory endpoints included the research on biomarkers. The efficacy and safety of HAIC combined with PD-1 inhibitor in the treatment of potentially resectable locally advanced hepatocellular carcinoma will be discussed.

Radiological assessments are performed every two cycles over the course of treatment, then every 3 months within the first two years following the completion of treatment and every 6 months thereafter, until PD were recorded. All subjects are followed until death or lost to follow up. The recurrence, metastasis sites, detection methods, adjuvant treatment and accurate survival time were recorded in detail.

Due to the lack of historical data and expected effect size for this population, the sample size of this pilot study is arbitrarily set at 40, including two intervention arms. Arm A will included 30 patients who receive HAIC combined with sintilimab. Arm B will included 10 patients who receive only HAIC. The patients are assigned to any group according to their willing.

The Kaplan-Meier method was used to estimate progression-free survival and overall survival; the Log-rank method was used for single factor analysis; the Cox model was analyzed by multivariate analysis. All the statistical tests were two-sided, and P < 0.05 was considered statistically significant.

Study Type

Interventional

Enrollment (Actual)

40

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Guangdong
      • Guangzhou, Guangdong, China, 510060
        • Sun Yat-sen University Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age between 18 years and 70 years.
  2. Hepatocellular carcinoma: patients need to be diagnosed as hepatocellular carcinoma (HCC) histologically before treatment.
  3. Never received any anti-cancer treatment in the past.
  4. potentially resectable Locally advanced HCC: with at least one measurable lesion (RECIST 1.1), and tumor(s) confined to the left or right hemi-liver, with macroscopic invasion to branch of the portal vein and/or hepatic vein.
  5. No extrahepatic metastases.
  6. No contraindications for the treatment of HAIC and PD-1 inhibitors.
  7. KPS≥90.
  8. Liver function: Child-Pugh class A.
  9. The expected survival of the patient is more than 6 months.
  10. Adequate hematological and organ function.

  11. The following conditions are met:

    Platelet≥75×10^9/L; White blood cell≥3.0×10^9/L; Hemoglobin≥90 g/L; Serum creatinine≤1.5 × upper limit of normal (ULN); PT≤3 second extension; total bilirubin ≤1.5 x ULN； AST and ALT ≤2.5 x ULN.

  12. Agree to accept postoperative follow-up required by the design of this study.
  13. Patients must have the ability to understand and voluntarily sign the informed consent, and must sign an informed consent before starting any specific procedure for the study.

Exclusion Criteria:

  1. In combined with severe heart, lung, kidney or other important organ dysfunction, or combined with serious infection or other serious associated diseases, that cannot tolerate treatment (> CTCAE Version 4.03 adverse events of grade 2).
  2. With uncontrolled hepatitis B (HBV-DNA>2000 IU/ml and elevated ALT).
  3. Multi-nodules hepatocellular carcinoma beyond hemi-hepatic range.
  4. Patients with tumor thrombus reaches or exceeds the portal vein.
  5. History of other malignancies.
  6. History of allergic reactions to related drugs.
  7. History of organ transplantation.
  8. Pregnant women, nursing mothers.
  9. Patients have other factors that may interfere with patient enrollment and assessment results.
  10. Refuse follow-up as required by this study protocol and refuse to sign informed consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A, Combination group (HAIC+PD-1)
HAIC+PD-1
Combination product: HAIC+PD1
Sintilimab ( 200mg Q3W iv D1)+FOLFOX-HAIC（oxaliplatin, 130 mg/m2 and leucovorin, 200 mg/m2, and fluorouracil, 400 mg/m2, bolus and 2400 mg/m2 over 46 hours Q3W D2 D3), maximally 8 cycles Multi-disciplinary consultation was organized to decide the chance of surgery and subsequent treatment per 2 treatment cycles. Patients who achieved partial response (PR) or minor response (MR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and were assessed as eligible for R0 resection go on to undergo surgical resection. After recovery from operation , sintilimab monotherapy was given per three weeks for maximally 16 doses. Patients who were ineligible for resection would continue to receive the combination therapy.
Other Names:
  • Sintilimab (IBI308)
  • FOLFOX-HAIC
Experimental: B, HAIC group (HAIC only)
HAIC
Drug: HAIC
FOLFOX-HAIC: oxaliplatin, 130 mg/m2 and leucovorin, 200 mg/m2, and fluorouracil, 400 mg/m2, bolus and 2400 mg/m2 over 46 hours Q3W D2 D3, for maximally 8 cycles, and the safety parameters are reviewed before the start of each course of HAIC treatment. Patients who achieve partial response (PR) or minor response (MR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and are assessed as eligible for R0 resection go on to undergo surgical resection. No other anti-tumor therapies are allowed before PD or postoperative relapse is confirmed.
Other Names:
  • FOLFOX-HAIC

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS) assessed by RECIST 1.1
Time Frame: From date of the first treatment until the date of progression or death from any cause, whichever occurs first, assessed up to 96 months
The duration from treatment initiation to disease progression or death from any cause in patients who did not undergo surgery, or to the date of postoperative relapse or death from any cause in patients who had received surgery, whichever occurs first. The baseline of the tumor before the initial treatment was used as a reference, and the assessments are performed according to the RECIST 1.1 criteria based on the imaging test (enhanced CT or MRI).
From date of the first treatment until the date of progression or death from any cause, whichever occurs first, assessed up to 96 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival (OS)
Time Frame: From date of the first treatment until the date of death from any cause, assessed up to 96 months
The time between the first HAIC +PD1 treatment and death from any cause.
From date of the first treatment until the date of death from any cause, assessed up to 96 months
1-, 2- and 3-year Overall Survival (OS) rate
Time Frame: From date of the first treatment until the date of death from any cause, assessed up to 96 months
The percentage of patients who were still alive at the 1-, 2-, and 3-year time point since the first cycle of treatment. The end point of observation is death due to tumor.
From date of the first treatment until the date of death from any cause, assessed up to 96 months
Safety: the percentage of participants with treatment-related adverse events as assessed by CTCAE v4.03
Time Frame: From date of the first treamtment until 100 days after the last treatment.
adverse events will be assessed and reported according to NCI CTC AE v4.03.
From date of the first treamtment until 100 days after the last treatment.
Pathological Response: pathological complete response (pCR) and major pathological response (MPR: >90% of tumor necrosis)
Time Frame: Through study completion, an average of 1 year.
According to post-operative pathology, the proportion of tumor necrosis, viable. tumor cells, and tumor infiltrating lymphocytes indicated by surgical resected specimens.
Through study completion, an average of 1 year.
Objective Response Rate (ORR) assessed by RECIST 1.1
Time Frame: Through study completion, an average of 3 year.
The proportion of complete response or partial response as optimal response among all treated patients.
Through study completion, an average of 3 year.
Disease Control Rate (DCR)
Time Frame: Through study completion, an average of 3 year.
The proportion of complete response, partial response or stable disease as optimal response assessed by RECIST 1.1 among all treated patients.
Through study completion, an average of 3 year.
Conversion rate
Time Frame: Through study completion, an average of 1 year.
The proportion of patients who received surgical resection among all treated patients.
Through study completion, an average of 1 year.
Recurrence-free survival (RFS)
Time Frame: From date of the surgery until the date of first recurrence/metastasis after resection or death from any cause, assessed up to 96 months
The time between surgery and first recurrence/metastasis after resection or death from any cause, whichever occurs first.
From date of the surgery until the date of first recurrence/metastasis after resection or death from any cause, assessed up to 96 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Biomarkers of treatment response by single-cell RNA sequencing
Time Frame: From date of first dose until the date of first documented progression, assessed up to 96 months
To find biomarkers of treatment response by investigating the variation of tumor and immune cells before and after treatment.
From date of first dose until the date of first documented progression, assessed up to 96 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sun Yat-sen University

Collaborators

Innovent Biologics, Inc.

Investigators

  • Principal Investigator: Min-shan Chen, MD, PhD, Sun Yat-sen University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 25, 2019

Primary Completion (Actual)

July 20, 2020

Study Completion (Estimated)

December 31, 2025

Study Registration Dates

First Submitted

March 2, 2019

First Submitted That Met QC Criteria

March 7, 2019

First Posted (Actual)

March 11, 2019

Study Record Updates

Last Update Posted (Actual)

December 3, 2024

Last Update Submitted That Met QC Criteria

November 27, 2024

Last Verified

November 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HAICPD1-HCC

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The data that support the findings of this study will be openly available in Research Data Deposit at https://www.researchdata.org.cn/default.aspx, after publication.

IPD Sharing Time Frame

since publication

IPD Sharing Access Criteria

open

IPD Sharing Supporting Information Type

  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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