Hepatic Artery Infusion Chemotherapy for Unresectable Hepatocelluar Carcinoma Who Failed to Systemic Therapy

Efficacy and Safety of Hepatic Artery Infusion Chemotherapy in Patients With Advanced or Unresectable Hepatocellular Carcinoma Who Have Progressed or Are Intolerant to Systemic Therapy

There are limited treatment options for patients with unresectable hepatocellular carcinoma (HCC) who failed to the combination therapy with targeted agents plus anti-PD-1/PD-L1. Hepatic artery infusion chemotherapy (HAIC) had shown potent antitumor effects in single-centered studies when was used as first-line therapy. However, HAIC was not used as second or third-line therapy.

Study Overview

• Status: Recruiting
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Hepatic artery infusion chemotherapy with FOLFOX regimens (oxaliplatin, fluorouracil, and leucovorin)

Detailed Description

The combination therapy of anti-angiogenic agents and anti-PD-1/PD-L1 antibodies had shown potent anti-tumor efficacy for unresectable or advanced hepatocellular carcinoma. However, the treatment options were limited when patients were failed the combination therapies. Hepatic artery infusion chemotherapy (HAIC) had shown potent anti-tumor efficacy with an acceptable safety profile as a first-line treatment for patients with intermediated-stage or advanced-stage hepatocellular carcinoma. In this study, the investigators aimed to evaluate the efficacy and safety of HAIC were used in the late-line setting, i.e., after the failure of combination therapy with anti-angiogenic agents and anti-PD-1/PD-L1 antibodies.

• Study Type: Interventional
• Enrollment (Anticipated): 49
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hui-Chuan Sun, MD&PhD; Phone Number: +86-21-64037181; Email: sun.huichuan@zs-hospital.sh.cn

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Zhongshan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Hepatocellular carcinoma diagnosed histologically/cytologically, or meeting the clinical diagnostic criteria of the "Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition)."
• Unresectable or advanced hepatocellular carcinoma that was assessed by the investigator. Advanced hepatocellular carcinoma was defined as BCLC C stage or Chinese Liver Cancer stage (CNLC) IIIa or IIIb stage.
• Had at least one measurable lesion in the liver.
• Liver function Child-Pugh classification of A or B7.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Patients who have received combination therapy with targeted agents combined with immune checkpoint inhibitors and have developed intolerable adverse effects or imaging confirmed intrahepatic tumor progression and have signed an informed consent form. Targeted agents include sorafenib, lenvatinib, donafenib, regorafenib, apatinib, bevacizumab (or biosimilar), and anlotinib; immune checkpoint inhibitors (mainly PD-1/PD-L1 antibodies) include pembrolizumab, nivolumab, camrelizumab, sintilimab, toripalimab, atezolizumab, and tislelizumab. Additional eligible subjects: subjects who have received at least one HAIC treatment were entered into safety evaluation (SAS); subjects who have received at least one imaging evaluation after treatment were entered into effectiveness evaluation (ITT).

• Adequate bone marrow and organ function. Reassessment of bone marrow and organ function as described above is required prior to each HAIC treatment.

  • Leukocytes ≥ 3 x 10^9/L within the last 14 days.
  • Platelets ≥ 50×10^9/L in the last 14 days without transfusion.
  • hemoglobin ≥ 90 g/L in the last 14 days without blood transfusion or erythropoietin administration.
  • total bilirubin ≤ 2 x the upper limit of normal (ULN)
  • albumin ≥ 30 g/L in the absence of human albumin or plasma transfusion within the last 14 days
  • AST and ALT ≤ 3 x ULN.
  • serum creatinine at ≤1.5×ULN.
  • International Normalized Ratio (INR) of prothrombin time ≤ 1.5×ULN.
  • Serum HBV DNA < 2 x 10^3 IU/mL; for HBV DNA > 2 x 10^3 IU/mL, treatment with nucleoside analogs for at least 1 week.
• Without grade 3 or higher adverse events (NCI CTCAE 4.0 criteria) induced by previous systemic therapy, or grade 3 or higher events reactions have recovered to grade 2 or lower.

Exclusion Criteria:

• Pathologic diagnosed with mixed liver cancer, fibrous lamellar cell carcinoma or other non-hepatocellular malignancy component.
• Previous or concurrent other malignancies, except adequately treated non-melanotic skin cancer, carcinoma in situ of the cervix, and papillary thyroid cancer
• History of organ transplantation or hepatic encephalopathy.
• Hypersensitivity to iodine-containing contrast agents, oxaliplatin, calcium folinic acid, and fluorouracil.
• History of gastrointestinal perforation and/or fistula within 6 months, history of intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection complicated by chronic diarrhea), Crohn's disease, ulcerative colitis, or long-term chronic diarrhea.
• Uncontrollable hypertension, systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg after optimal medical therapy, history of hypertensive crisis or hypertensive encephalopathy.
• Gastrointestinal bleeding due to portal hypertension within 6 months; G3 varices by gastrointestinal endoscopy within 3 months.
• Subjects requesting withdrawal of informed consent.
• Other circumstances that the investigator deems inappropriate for participation in the clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Hepatic Artery Infusion Chemotherapy; Subjects assigned to this arm will receive chemotherapy via catheterizations placed into the hepatic artery.

Drug: Hepatic artery infusion chemotherapy with FOLFOX regimens (oxaliplatin, fluorouracil, and leucovorin); The FOLFOX regiments were given via hepatic artery catheterization, including oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2, followed by fluorouracil infusion 2400 mg/m2 for 46 hours. If no severe adverse events occurred, the treatment will be repeated every 3 weeks.; Other Names: HAIC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response of intrahepatic lesions	Subjects with complete response or partial response assessed by RECIST v1.1 criteria.	up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
duration of response of intrahepatic lesions	the interval between the time of partial or complete response to the time of progressive disease in intrahepatic lesions.	up to 1 year
Progression free survival	the interval between the time of first HAIC treatment to the time of progressive disease or patient death	up to 1 year
Overall survival	the interval between the time of first HAIC treatment initiation to the time of patient death	up to 2 year
Treatment cycles of HAIC	the total cycles of HAIC treatments, when the subjects could not tolerate HAIC or lose the benefit from HAIC treatment, HAIC will be discontinued.	up to 1 year
Ratio of R0 resection	The ratio of subjects who underwent R0 resection to subjects received who received at least 1 cycle of HAIC.	up to 1 year
The rate of adverse events	Nature, incidence, severity and seriousness of the adverse events. Adverse events are graded according to the NCI-CTCAE (Version 5.0)	up to 1 year

Collaborators and Investigators

• Sponsor: Hui-Chuan Sun

Publications and helpful links

General Publications

• Zhou J, Sun H, Wang Z, Cong W, Wang J, Zeng M, Zhou W, Bie P, Liu L, Wen T, Han G, Wang M, Liu R, Lu L, Ren Z, Chen M, Zeng Z, Liang P, Liang C, Chen M, Yan F, Wang W, Ji Y, Yun J, Cai D, Chen Y, Cheng W, Cheng S, Dai C, Guo W, Hua B, Huang X, Jia W, Li Y, Li Y, Liang J, Liu T, Lv G, Mao Y, Peng T, Ren W, Shi H, Shi G, Tao K, Wang W, Wang X, Wang Z, Xiang B, Xing B, Xu J, Yang J, Yang J, Yang Y, Yang Y, Ye S, Yin Z, Zhang B, Zhang B, Zhang L, Zhang S, Zhang T, Zhao Y, Zheng H, Zhu J, Zhu K, Liu R, Shi Y, Xiao Y, Dai Z, Teng G, Cai J, Wang W, Cai X, Li Q, Shen F, Qin S, Dong J, Fan J. Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition). Liver Cancer. 2020 Dec;9(6):682-720. doi: 10.1159/000509424. Epub 2020 Nov 11.
• Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, Okusaka T, Kobayashi M, Kumada H, Kaneko S, Pracht M, Mamontov K, Meyer T, Kubota T, Dutcus CE, Saito K, Siegel AB, Dubrovsky L, Mody K, Llovet JM. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J Clin Oncol. 2020 Sep 10;38(26):2960-2970. doi: 10.1200/JCO.20.00808. Epub 2020 Jul 27.
• He MK, Liang RB, Zhao Y, Xu YJ, Chen HW, Zhou YM, Lai ZC, Xu L, Wei W, Zhang YJ, Chen MS, Guo RP, Li QJ, Shi M. Lenvatinib, toripalimab, plus hepatic arterial infusion chemotherapy versus lenvatinib alone for advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2021 Mar 25;13:17588359211002720. doi: 10.1177/17588359211002720. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2021
• Primary Completion (Anticipated): August 31, 2022
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: July 29, 2021
• First Submitted That Met QC Criteria: July 29, 2021
• First Posted (Actual): August 6, 2021

Study Record Updates

• Last Update Posted (Actual): August 13, 2021
• Last Update Submitted That Met QC Criteria: August 7, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Hepatic artery infusion chemotherapy
• 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; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin
• Other Study ID Numbers: 2LHAIC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No