Clinical trial NCT05233358: HAIC Combined With Second-line "Target Immunity" for HCC With TACE Standard Treatment Low Response or Failure
Official title: HAIC Combined With Second-line "Target Immunity" for Advanced Hepatocellular Carcinoma With Low Response or Failure of TACE Combined With First-line "Target Immunity": A Prospective, Randomized- Control, Multicenter Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Hepatocellular Carcinoma
Keywords: Hepatocellular Carcinoma
Hepatic Artery Infusion Chemotherapy
Transarterial Chemoembolization
Target Immunity
Advanced
Lead sponsor: The Central Hospital of Lishui City
Sponsor class: OTHER
First posted: 2022-02-10
Enrollment: 176
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a prospective, randomized controlled, multicenter clinical study. The purpose of this study is to explore the efficacy and safety of hepatic artery infusion chemotherapy (HAIC) combined with second-line regorafenib and immune checkpoint inhibitors in the treatment of transarterial chemoembolization (TACE) combined with first-line molecular targeted drugs and immune checkpoint inhibitors with low response or failure in advanced hepatocellular carcinoma.

Detailed description: This is a randomized, open, parallel-controlled, multi-center clinical trial with a type of comparison using a merit test. This study will recruit 176 patients with advanced liver cancer who have received TACE combined with first-line "target immune" therapy and were rated as low response or treatment failure according to mRECIST criteria in multiple research centers across the country. Subjects randomly assigned to the experimental group will receive HAIC in combination with regorafenib and immune checkpoint inhibitors, and subjects randomly assigned to the control group will receive TACE in combination with regorafenib and immune checkpoint inhibitors.

Eligibility criteria: Inclusion Criteria:

* Voluntarily participate in this study and sign the informed consent;
* Age ≥18 years old to 70 years old;
* Patients diagnosed with primary liver cancer by histopathology, cytology or imaging;
* The China liver cancer staging is IIb-IIIa;
* Patients with intermediate and advanced liver cancer who must receive at least one cycle of TACE combined with first-line "target immune" therapy and are assessed as partial remission (PR), stable disease (SD）(low response), and progressive disease (PD) (failure) according to mRECIST criteria;
* At least one measurable (based on RECIST 1.1 criteria and mRECIST criteria) lesions, tumor lesions located at the local treatment site, if progressed, considered measurable;
* Local treatment (surgery, radiotherapy, radiofrequency/microwave ablation, cryoablation, percutaneous ethanol injection) can be used in the past, but it must be completed before 3 months;
* ECOG PS score ≤ 2;
* Child-Pugh liver function classification: grade A/B (≤9 points);
* Expected survival \> 3 months;
* Patients with active hepatitis B virus (HBV) infection: HBV DNA ≤2000 IU/mL (104 cps/ml) obtained within 28 days prior to initiation of study treatment, and receiving anti-HBV treatment for at least 14 days prior to study entry (based on local standard treatment) and willing to continue to receive treatment during the study;

Exclusion Criteria:

* Have received HAIC treatment in the past;
* Known allergy to possible therapeutic drugs;
* Previously received regorafenib treatment;
* According to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0), the toxicity grade caused by TACE combined with first-line "target immunity" treatment is \> grade 3;
* Patients with liver decompensation, including esophageal or gastric variceal bleeding or hepatic encephalopathy, pregnancy or breastfeeding and other aggressive malignant diseases;
* Use immunosuppressive drugs and high-dose hormone therapy within 2 weeks before randomization to achieve the purpose of immunosuppression (dose\>10mg/day prednisone or other hormones with equivalent efficacy);
* CART treatment within 3 months before randomization;
* Laboratory test values 1 week before randomization: blood routine: ① leukocyte \<3.0×109/L; ② absolute neutrophil count \<1.5×109/L; ③ platelets \<75×109/L; ④ hemoglobin \< 90g/L; liver function: ①serum albumin\<30g/L; ②ALT and AST\>5×ULN; renal function: ①serum creatinine\>1.5×ULN; ②Cr clearance rate\<50ml/min; ③estimated renal small Globular filtration rate (eGFR) \<30 mL/min/1.73 m2; coagulation function: ① international normalized ratio (INR)\> 2; ② prothrombin time (PT) exceeding the range of normal control\> 6 seconds;
* Uncontrolled hypertension (systolic blood pressure \> 180 mmHg, diastolic blood pressure \> 110 mmHg);
* Uncontrollable diabetes;
* Active heart disease, including myocardial infarction, unstable angina pectoris, NYHA class II and above heart failure, and poorly controlled arrhythmias (including QTcF interval \>450 ms in men and \>470 ms in women);
* Women are pregnant or breastfeeding;
* History of any active autoimmune disease or autoimmune disease, including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, vasculitis, glomerulonephritis, hyperthyroidism, or hypothyroidism, asthma requiring bronchodilator treatment, etc;
* Uncontrolled clinically significant ascites (uncontrolled with diuretics or paracentesis);
* Combined with active infection, except HBV and HCV;
* Arterial or venous thrombosis or embolic events, such as cerebrovascular accident (including transient ischemic attack), deep venous thrombosis or pulmonary embolism, occurred 6 months before starting drug treatment;
* Known central nervous system (CNS) metastasis or meningeal metastasis;
* The patient cannot receive follow-up or is participating in other clinical trials;
* The investigator believes that the patient has other conditions that make it inappropriate to participate in this study.

Primary outcomes:
measure: Progression Free Survival
timeFrame: The time from enrollment to tumor progression or death from any cause, whichever came first, measured in "months", assessed up to 2 years.
Secondary outcomes:
measure: Overall Survival
timeFrame: Time from enrollment to death from any cause, in "months", assessed up to 2 years. For patients who are still alive at the time of data analysis, overall survival is calculated based on the date when the patient is last known to be alive.
measure: To Tumor Untreatable Progression
timeFrame: The time interval between receiving HAIC or TACE and the patient's inability to receive further intra-arterial treatment, assessed up to 12 months.
measure: Objective Response Rate
timeFrame: Proportion of patients who achieved complete remission (CR) or partial remission (PR) according to mRECIST criteria, assessed up to 12 months.
measure: Disease Control Rate
timeFrame: Proportion of patients with complete remission (CR), partial remission (PR), and stable disease (SD) according to mRECIST criteria, assessed up to 12 months.
measure: Duration of Overall Response
timeFrame: The time from the first assessment of the tumor as complete remission or partial remission to the first assessment as disease progression or death from any cause, assessed up to 12 months.
measure: The incidence of adverse events and serious adverse events
timeFrame: Every follow-up time, assessed up to 2 years.
Other outcomes:
Locations:
Study officials:
affiliation: The Central Hospital of Lishui City
name: Liyun Zheng, MD.
role: STUDY_DIRECTOR
References:
citation: Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.
citation: 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.
citation: Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018 Jul;19(7):940-952. doi: 10.1016/S1470-2045(18)30351-6. Epub 2018 Jun 3.
citation: Odagiri N, Hai H, Thuy LTT, Dong MP, Suoh M, Kotani K, Hagihara A, Uchida-Kobayashi S, Tamori A, Enomoto M, Kawada N. Early Change in the Plasma Levels of Circulating Soluble Immune Checkpoint Proteins in Patients with Unresectable Hepatocellular Carcinoma Treated by Lenvatinib or Transcatheter Arterial Chemoembolization. Cancers (Basel). 2020 Jul 24;12(8):2045. doi: 10.3390/cancers12082045.
citation: Wang Y, Zhou C, Liu J, Shi Q, Huang S, Yang C, Li T, Chen Y, Xiong B. Increased Liquefactive Necrosis Formation After Transarterial Chemoembolization Combined with Molecular Targeted Agents Plus Immune Checkpoint Inhibitors for Hepatocellular Carcinoma. Cancer Manag Res. 2021 Sep 7;13:6935-6941. doi: 10.2147/CMAR.S328812. eCollection 2021.
citation: Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. doi: 10.1016/S1470-2045(15)70156-7. Epub 2015 May 13.
citation: Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9. Epub 2016 Dec 6.
citation: Ikeda M, Shimizu S, Sato T, Morimoto M, Kojima Y, Inaba Y, Hagihara A, Kudo M, Nakamori S, Kaneko S, Sugimoto R, Tahara T, Ohmura T, Yasui K, Sato K, Ishii H, Furuse J, Okusaka T. Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial. Ann Oncol. 2016 Nov;27(11):2090-2096. doi: 10.1093/annonc/mdw323. Epub 2016 Aug 29.