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

NCT ID: NCT06041477

Last Updated: 2024-08-27

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

540 participants

Study Classification

INTERVENTIONAL

Study Start Date

2023-10-31

Study Completion Date

2030-07-31

Brief Summary

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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.

Detailed Description

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Participants in the concurrent treatment group will 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(PR) or stable disease (SD) continue two cycles of combined therapy, and those with progress disease (PD) will be withdrawn and receive other treatments.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.

Participants in the sequential treatment group will 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.

Conditions

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Hepatocellular Carcinoma Chemotherapy Effect Chemotherapeutic Toxicity

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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concurrent treatment group

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.

Group Type EXPERIMENTAL

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

Intervention Type 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)

Concurrent Lenvatinib

Intervention Type DRUG

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

Concurrent PD-1 antibody

Intervention Type 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)

sequential treatment group

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.

Group Type ACTIVE_COMPARATOR

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

Intervention Type 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)

Sequential Lenvatinib

Intervention Type DRUG

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

Sequential PD-1 antibody

Intervention Type 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)

Interventions

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

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)

Intervention Type DRUG

Concurrent Lenvatinib

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

Intervention Type DRUG

Concurrent PD-1 antibody

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)

Intervention Type DRUG

Sequential Lenvatinib

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

Intervention Type DRUG

Sequential PD-1 antibody

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)

Intervention Type DRUG

Other Intervention Names

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Hepatic arterial infusion chemotherapy (HAIC) Concurrent targeted therapy Concurrent immunotherapy Sequential targeted therapy Sequential immunotherapy

Eligibility Criteria

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Inclusion Criteria

1. Age ≥18 and ≤75 years;
2. ECOG PS score of 0\~1;
3. 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;
4. Not having received previous treatment against hepatocellular carcinoma;
5. 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;
6. 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;
7. Patients were fully informed about the study and signed an informed consent form.

Exclusion Criteria

1. 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;
2. Those with a history of other malignant tumors;
3. Those with a history of related drug allergy;
4. Those with known hypersensitivity to any component of the targeted and immunologic drugs to be applied;
5. Those with a history of organ transplantation;
6. Those who have received previous treatment targeting hepatocellular carcinoma (including interferon);
7. Those with co-infection with HIV;
8. Those with drugs abuse;
9. Those who have had gastrointestinal bleeding or cardiovascular events within the last 30 days;
10. Pregnant or breastfeeding women, or women of childbearing age who do not wish to use contraception;
11. Persons with concomitant psychiatric disorders that preclude informed consent or affect acceptance of treatment;
12. Other factors that may affect patient enrollment and assessment results.
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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The First Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine

OTHER

Sponsor Role collaborator

Affiliated Hospital of Guangdong Medical University

OTHER

Sponsor Role collaborator

First People's Hospital of Foshan

OTHER

Sponsor Role collaborator

Sun Yat-sen University

OTHER

Sponsor Role lead

Responsible Party

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Wei Wei

Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Wei Wei, Ph.D, M,D

Role: PRINCIPAL_INVESTIGATOR

Sun Yat-sen University

Locations

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SUN Yat-sen University Cancer Center

Guangzhou, Guangdong, China

Site Status RECRUITING

Countries

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China

Central Contacts

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Shao Hua Li, Ph.D, M,D

Role: CONTACT

008615088064187

Rong Ping Guo, M,D

Role: CONTACT

008618819809988

Facility Contacts

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Shao Hua Li, Ph.D, M.D

Role: primary

008615088064187

Wei Wei, Ph.D, M.D

Role: backup

008613725208259

References

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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.

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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.

Reference Type RESULT
PMID: 25752327 (View on PubMed)

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.

Reference Type RESULT
PMID: 29307467 (View on PubMed)

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.

Reference Type RESULT
PMID: 12372721 (View on PubMed)

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.

Reference Type RESULT
PMID: 24293372 (View on PubMed)

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.

Reference Type RESULT
PMID: 31070690 (View on PubMed)

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.

Reference Type RESULT
PMID: 29471013 (View on PubMed)

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.

Reference Type RESULT
PMID: 29061175 (View on PubMed)

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.

Reference Type RESULT
PMID: 32418078 (View on PubMed)

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.

Reference Type RESULT
PMID: 36525610 (View on PubMed)

Other Identifiers

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2023001

Identifier Type: OTHER

Identifier Source: secondary_id

SL-B2022-793-01

Identifier Type: -

Identifier Source: org_study_id

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