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

Hepatocellular Carcinoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04994236
• Other study ID #: 2LHAIC
• Status: Recruiting
• Phase: Phase 2
• Start date: July 1, 2021
• Est. completion date: December 31, 2022

Study information

• Verified date: August 2021
• Source: Shanghai Zhongshan Hospital
• Contact: Hui-Chuan Sun, MD&PhD
• Phone: +86-21-64037181
• Email: sun.huichuan[@]zs-hospital.sh.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 49
• Est. completion date: December 31, 2022
• Est. primary completion date: August 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Hepatocellular Carcinoma

Intervention

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.

Locations

Country	Name	City	State
China	Zhongshan Hospital	Shanghai	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Hui-Chuan Sun

Country where clinical trial is conducted

China, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective response of intrahepatic lesions	Subjects with complete response or partial response assessed by RECIST v1.1 criteria.	up to 1 year
Secondary	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
Secondary	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
Secondary	Overall survival	the interval between the time of first HAIC treatment initiation to the time of patient death	up to 2 year
Secondary	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
Secondary	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
Secondary	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