Concurrently vs Sequentially Combined HAIC With Targeted and Immunotherapy in Potentially Resectable HCC

NCT06041477 | Recruiting Phase 3

• 2 other identifiers: SL-B2022-793-012023001
• Study Type: interventional
• Target: 540
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to compare HAIC concurrently with sequentially combined with targeted and immunotherapies in terms of efficacy and safety in patients with potentially resectable intermediate and advanced HCC (CNLC stage IIa\~IIIa). The main questions it aims to answer are:

• Does a "strong combination" regimen of three simultaneous treatments (HAIC, targeted agents and immunotherapy) definitely result in a higher surgical conversion rate and better survival benefit?
• Can the combination of targeted and immunotherapies based on patients' response to HAIC therapy avoid over-treatment of some patients without affecting the surgical conversion rate and overall survival? Participants will be randomly assigned to receive either HAIC concurrently or sequentially combined with targeted and immunotherapies. Researchers will compare concurrent treatment group with sequential treatment group to see if there are different in terms of the conversion resection rate, long-term survival, and safety.

Conditions

Hepatocellular Carcinoma; Chemotherapy Effect; Chemotherapeutic Toxicity

Keywords

Hepatic artery infusion chemotherapy; Tyrosine kinase inhibitors; Immune checkpoint inhibitors; Intermediate and advanced stage hepatocellular carcinoma; combined therapy; conversion resection

Outcome Measures

Primary Outcomes (1)

• OS

  Overall survival of the participants

  From date of randomization until the date of death from any cause, assessed at least 36 months

Secondary Outcomes (5)

• PFS

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed at least 36 months

• ORR

  Assessed at the end of Cycle 2 and Cycle 4 (each cycle is 28 days)

• DCR

  Assessed at the end of Cycle 2 and Cycle 4 (each cycle is 28 days)

• CRR

  This outcome measure will be assessed at the end of Cycle 4 (each cycle is 28 days)

• Safety profiles of all participants

  This outcome measure will be assessed at the end of Cycle 1 to 4(each cycle is 28 days), and every 3 months through study completion, an average of 3 years

Study Arms (2)

concurrent treatment group

EXPERIMENTAL

Participants receive two cycles of HAIC (the drugs are oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2 over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks) in combination with targeted drug (lenvatinib 8mg/day) and immunotherapy (PD-1 antibody, dosage and frequency according to instructions), then evaluate the response of tumor, those who achieve complete response (CR) will receive surgical resection or follow-up, those with partial response (PR) or stable disease (SD) continue two cycles of combined therapy, and those with progress disease (PD) will be withdrawn and receive other treatments. After four cycles of combined therapy, second evaluation of efficacy will be performed, those who achieve CR will receive surgical resection or follow-up observation, and the other patients will be evaluated for the possibility of surgical resection or the subsequent treatment.

Drug: Oxaliplatin,calcium folinic acid, levofolinic acid, 5-FU; Drug: Concurrent Lenvatinib; Drug: Concurrent PD-1 antibody

sequential treatment group

ACTIVE COMPARATOR

Participants receive two cycles of HAIC (drugs of oxaliplatin 135 mg/m2 over 3 hours; calcium folinic acid 400 mg/m2 or levofolinic acid 200 mg/m2 over 1. 5 hours, 5-FU 400 mg/m2 over 2 hours, and 5-FU 2400 mg/m2 over 46 hours,every 4 weeks), then evaluate the response of tumor, and those who achieve complete response (CR ) will receive surgical resection or follow-up, while other patients continue to receive two cycles of combination therapy, i.e. HAIC combined with targeted drug (levatinib 8mg/day) and immunotherapy (PD-1 antibody, dose and frequency according to instructions). After four cycles, a second efficacy assessment will be performed, and patients who achieve CR will undergo surgical resection or follow-up observation, and the other patients will be evaluated for the possibility of surgical resection or the subsequent treatment.

Drug: Oxaliplatin,calcium folinic acid, levofolinic acid, 5-FU; Drug: Sequential Lenvatinib; Drug: Sequential PD-1 antibody

Interventions

Oxaliplatin,calcium folinic acid, levofolinic acid, 5-FU DRUG

Hepatic arterial infusion chemotherapy with (oxaliplatin 135mg/m2 over 3hrs, calcium folinic acid 400mg/m2 or levofolinic acid 200mg/ m2 over 1.5hrs, 5-FU 400mg/m2 over 2hrs, 5-FU 2400mg/m2 over 46hrs,every 4 weeks)

Also known as: Hepatic arterial infusion chemotherapy (HAIC)

concurrent treatment group; sequential treatment group

Concurrent Lenvatinib DRUG

Lenvatinib 8mg/day combined with the HAIC from the first cycle

Also known as: Concurrent targeted therapy

concurrent treatment group

Concurrent PD-1 antibody DRUG

PD-1 antibody which is approved by authorities for HCC treatment combined with the HAIC from the first cycle (dosage and frequency according to instructions)

Also known as: Concurrent immunotherapy

concurrent treatment group

Sequential Lenvatinib DRUG

Lenvatinib 8mg/day combined with the HAIC from the third cycle for those patients who do not achieve complete response (CR)

Also known as: Sequential targeted therapy

sequential treatment group

Sequential PD-1 antibody DRUG

PD-1 antibody which is approved by authorities for HCC treatment combined with the HAIC from the third cycle for those patients who do not achieve complete response (CR) (dosage and frequency according to instructions)

Also known as: Sequential immunotherapy

sequential treatment group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 and ≤75 years;
• ECOG PS score of 0\~1;
• Clinical or pathological diagnosis of hepatocellular carcinoma and meeting the stage IIa-IIIa of CNLC staging according to the relevant definitions in the 2015 edition of the Guidelines for Standardized Pathological Diagnosis of Primary Liver Cancer;
• Not having received previous treatment against hepatocellular carcinoma;
• Those who cannot be surgically resected after discussion by the multidisciplinary team of the participating centers , but have a potential chance of resection after conversion therapy, including: multiple tumors located in one lobe of the liver; portal vein cancer thrombus not reaching the main trunk, which can be resected together with the primary focus;
• Laboratory tests meet the following conditions, or the following conditions can be achieved with short-term treatment:
• Neutrophil count ≥2.0×109/L; Hemoglobin ≥ 100 g/L; Platelet count ≥ 75 × 109/L; Plasma albumin level ≥ 35 g/L; Plasma total bilirubin less than 2 times the upper limit of normal; Plasma alanine aminotransferase (ALT) less than 3 times the upper limit of normal; Plasma aspartate aminotransferase (AST) less than 3 times the upper limit of normal; Plasma creatinine less than 1.5 times the upper limit of normal; Plasma prothrombin time is normal or exceeds the upper limit of normal value by ≤ 4 seconds; Prothrombinogen international normalized ratio (INR) ≤ 2.2;
• Patients were fully informed about the study and signed an informed consent form.

You may not qualify if:

• Those with severe comorbidity including cardiac, cerebral, pulmonary, renal, and other vital organ function damage, combined with severe infections or other serious concomitant diseases (\> grade 2 CTCAE Version 5.0 adverse events), who cannot tolerate the treatment;
• Those with a history of other malignant tumors;
• Those with a history of related drug allergy;
• Those with known hypersensitivity to any component of the targeted and immunologic drugs to be applied;
• Those with a history of organ transplantation;
• Those who have received previous treatment targeting hepatocellular carcinoma (including interferon);
• Those with co-infection with HIV;
• Those with drugs abuse;
• Those who have had gastrointestinal bleeding or cardiovascular events within the last 30 days;
• Pregnant or breastfeeding women, or women of childbearing age who do not wish to use contraception;
• Persons with concomitant psychiatric disorders that preclude informed consent or affect acceptance of treatment;
• Other factors that may affect patient enrollment and assessment results.

Sponsors & Collaborators

• Sun Yat-sen University: lead
• The First Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine: collaborator
• Affiliated Hospital of Guangdong Medical University: collaborator
• First People's Hospital of Foshan: collaborator

Study Sites (1)

SUN Yat-sen University Cancer Center

Guangzhou, Guangdong, 510060, China

RECRUITING

Related Publications (10)

• 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.

  PMID: 33538338 RESULT

• Park JW, Chen M, Colombo M, Roberts LR, Schwartz M, Chen PJ, Kudo M, Johnson P, Wagner S, Orsini LS, Sherman M. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 2015 Sep;35(9):2155-66. doi: 10.1111/liv.12818. Epub 2015 Mar 25.

  PMID: 25752327 RESULT

• Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018 Mar 31;391(10127):1301-1314. doi: 10.1016/S0140-6736(18)30010-2. Epub 2018 Jan 5.

  PMID: 29307467 RESULT

• Schwartz JD, Schwartz M, Mandeli J, Sung M. Neoadjuvant and adjuvant therapy for resectable hepatocellular carcinoma: review of the randomised clinical trials. Lancet Oncol. 2002 Oct;3(10):593-603. doi: 10.1016/s1470-2045(02)00873-2.

  PMID: 12372721 RESULT

• Shi HY, Wang SN, Wang SC, Chuang SC, Chen CM, Lee KT. Preoperative transarterial chemoembolization and resection for hepatocellular carcinoma: a nationwide Taiwan database analysis of long-term outcome predictors. J Surg Oncol. 2014 Apr;109(5):487-93. doi: 10.1002/jso.23521. Epub 2013 Nov 30.

  PMID: 24293372 RESULT

• He M, Li Q, Zou R, Shen J, Fang W, Tan G, Zhou Y, Wu X, Xu L, Wei W, Le Y, Zhou Z, Zhao M, Guo Y, Guo R, Chen M, Shi M. Sorafenib Plus Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin vs Sorafenib Alone for Hepatocellular Carcinoma With Portal Vein Invasion: A Randomized Clinical Trial. JAMA Oncol. 2019 Jul 1;5(7):953-960. doi: 10.1001/jamaoncol.2019.0250.

  PMID: 31070690 RESULT

• Lyu N, Kong Y, Mu L, Lin Y, Li J, Liu Y, Zhang Z, Zheng L, Deng H, Li S, Xie Q, Guo R, Shi M, Xu L, Cai X, Wu P, Zhao M. Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):60-69. doi: 10.1016/j.jhep.2018.02.008. Epub 2018 Feb 20.

  PMID: 29471013 RESULT

• He MK, Le Y, Li QJ, Yu ZS, Li SH, Wei W, Guo RP, Shi M. Hepatic artery infusion chemotherapy using mFOLFOX versus transarterial chemoembolization for massive unresectable hepatocellular carcinoma: a prospective non-randomized study. Chin J Cancer. 2017 Oct 23;36(1):83. doi: 10.1186/s40880-017-0251-2.

  PMID: 29061175 RESULT

• Li S, Mei J, Wang Q, Guo Z, Lu L, Ling Y, Xu L, Chen M, Zheng L, Lin W, Zou J, Wen Y, Wei W, Guo R. Postoperative Adjuvant Transarterial Infusion Chemotherapy with FOLFOX Could Improve Outcomes of Hepatocellular Carcinoma Patients with Microvascular Invasion: A Preliminary Report of a Phase III, Randomized Controlled Clinical Trial. Ann Surg Oncol. 2020 Dec;27(13):5183-5190. doi: 10.1245/s10434-020-08601-8. Epub 2020 May 16.

  PMID: 32418078 RESULT

• Li SH, Mei J, Cheng Y, Li Q, Wang QX, Fang CK, Lei QC, Huang HK, Cao MR, Luo R, Deng JD, Jiang YC, Zhao RC, Lu LH, Zou JW, Deng M, Lin WP, Guan RG, Wen YH, Li JB, Zheng L, Guo ZX, Ling YH, Chen HW, Zhong C, Wei W, Guo RP. Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study. J Clin Oncol. 2023 Apr 1;41(10):1898-1908. doi: 10.1200/JCO.22.01142. Epub 2022 Dec 16.

  PMID: 36525610 RESULT

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Oxaliplatin; Leucovorin; Fluorouracil

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Wei Wei, Ph.D, M,D

  Sun Yat-sen University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Shao Hua Li, Ph.D, M,D

CONTACT

008615088064187; lishaoh@sysucc.org.cn

Rong Ping Guo, M,D

CONTACT

008618819809988; guorp@sysucc.org.cn

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: July 23, 2023
• First Posted: September 18, 2023
• Study Start: October 31, 2023
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2030
• Last Updated: August 27, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)