Hepatocellular CarcinomaPhase 2NCT05171335
Neoadjuvant Combination Therapy of Lenvatinib and TACE for Transplant-Eligible Large Hepatocellular Carcinoma Patients
A Phase 2 study testing Lenvatinib and Transcatheter Arterial Chemoembolization in people with Hepatocellular Carcinoma, run by The Methodist Hospital Research Institute at 1 site in United States.
Trial summary
This study will examine the effects of a six-month regimen of neoadjuvant lenvatinib in combination with transcatheter arterial chemoembolization (TACE) prior to liver transplantation in patients with hepatocellular carcinoma (HCC) beyond Milan Criteria. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hepatocellular Carcinoma
- What is being tested?
- Lenvatinib and Transcatheter Arterial Chemoembolization
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteUnited States
- Study dates
- 20 Aug 2022to 30 Sep 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adults (≥18 years old) with histologically or cytologically confirmed HCC beyond Milan Criteria
- Must be treatment naïve and eligible for TACE procedure
- Must be on the liver transplant waiting list and not require any other solid organ transplant
- Eastern Cooperative Oncology Group performance status of 0 or 1
- Patients with hepatitis B virus (HBV) infection (as characterized by positive HBV surface antigen and/or anti-hepatitis B core antibodies (HBcAbs) with detectable HBV DNA (≥10 IU/mL or above the limit of detection per local laboratory) must receive antiviral therapy at least after study enrollment per institutional practice to ensure adequate viral suppression (HBV DNA ≤2000 IU/mL). Patients must be managed for 6 months after the last dose of study treatment. Antiviral therapy will be concurrent with lenvatinib.
- Patients with hepatitis C virus (HCV) infection (as characterized by the presence of detectable HCV RNA or anti-HCV antibody) must be managed per local institutional practice and for 6 months after the last dose of study treatment. Antiviral therapy will be concurrent with lenvatinib.
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- For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation
- For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner while undergoing active treatment up to 1 week after
- Adequate organ and marrow function, as defined below:
- Hemoglobin ≥9 g/dL
- Platelet count ≥50,000/μL
- Total bilirubin ≤3.0
- Albumin ≥2 g/dL
- International normalized ratio ≤2
- Cardiac ejection fraction ≥45%
- Able to swallow orally administered medication
- Capable of signing informed consent form (ICF) and complying with the study protocol, in the investigator's judgement
Who cannot join
- Mixed hepatocellular-cholangiocarcinoma or HCC within Milan criteria
- Previously received chemotherapy or immunotherapy for HCC
- Child Pugh assessment score greater than or equal to B8
- Uncontrolled blood pressure (BP; Systolic BP>140 mmHg or diastolic BP >90 mmHg) despite an optimized regimen of antihypertensive medication
- Electrolyte abnormalities that have not been corrected
- Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening
Show all 18Show fewer
- Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy
- Participants having > 1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is <1 g/24 hours
- Evidence of portal vein thrombosis that precludes the TACE procedure
- History of another primary malignancy except for the following:
- Prostate cancer of pathologic stage less than or equal to T2cN0M0 determined from a prior prostatectomy without biochemical recurrence and who, in the opinion of the investigator, are not deemed to require active intervention, or patients with incidental histologic findings of prostate cancer that has not been treated prior to the study and who do not require specific therapy for prostate cancer beyond surgery and also are considered to be at low risk for recurrence per the investigator
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
- Active infection, including tuberculosis or human immunodeficiency virus
- Known intolerance to lenvatinib or any of the excipients
- Females who are breastfeeding or pregnant
- Females of childbearing potential who do not agree to use highly effective contraception during the active treatment phase of the study and for 30 days after the last dose of the study treatment
- Males who do not agree to use highly effective contraception during the active treatment phase of the study and for 30 days after the last dose of the study treatment
Trial locations and contacts
1 site in 1 country.
United States1 site
Houston Methodist Research Institute
Houston, Texas, 77030
About this study
Official title: Neoadjuvant Combination Therapy of Lenvima Plus Transcatheter Arterial Chemoembolization (TACE) for Transplant-Eligible Patients With Large Hepatocellular Carcinoma
This study will examine the effects of a six-month regimen of neoadjuvant lenvatinib in combination with transcatheter arterial chemoembolization (TACE) prior to liver transplantation in patients with hepatocellular carcinoma (HCC) beyond Milan Criteria. Clinical, outcomes, and exploratory data will be compared to a matched, retrospective cohort.
Read the detailed description
HCC is the third leading cause of cancer death worldwide with more than 230,000 cases of HCC since 2000 and an estimated 42,000 new cases next year. The purpose of this trial is to examine if combination therapy of lenvatinib (LENVIMA®, Eisai Inc., Woodcliff Lake, NJ) plus transcatheter arterial chemoembolization (TACE) will promote tumor necrosis evidenced by explant pathology in patients with large HCC (>5 cm). TACE blocks blood supply to the tumor and induces tumor necrosis, but this causes hypoxia and subsequent angiogenesis.
In 2015, HCC was the leading diagnosis among liver transplant recipients (27.2%). Transplantation of patients diagnosed with HCC is largely based on tumor size, since this is thought to correlate with posttransplant outcomes. However, emerging evidence shows that tumor stability or response to locoregional therapy (LRT) can be surrogate markers of favorable biology and improved outcomes following transplantation. LRT, including TACE or radiofrequency ablation, that promote tumor stability (defined as no tumor progression in 6 months) serve as bridging therapies to liver transplantation. In tumors that respond to ablation, LRT further augments the success of liver transplantation and reduces the risk of HCC recurrence post-transplant.
Liver transplantation provides the ultimate curative option for patients with HCC with improved overall survival (OS) and recurrence-free survival (RFS) of 85% and 92% at 4 years, respectively, compared to 18.4% without transplantation. To limit disease progression and promote tumor stability while on the transplant waitlist, patients with unresectable HCC typically undergo neoadjuvant treatment. Although the National Comprehensive Cancer Network (NCCN) guidelines recommend the use of neoadjuvant therapy for the management of HCC, no clear-cut guidelines are given regarding the type of LRT or other therapeutic agents. LRT effectively improves 2-yr OS between 20-60% and TACE can achieve complete response in 65.2% of patients. LRT is utilized for preventing tumor growth while on the waitlist and to downstage large tumors to standard Milan Criteria (reduce tumor size to ≤ 5cm). Based on the United Network of Organ Sharing (UNOS) criteria, down-staging of tumors to Milan allows the addition of artificial Model for End-stage Liver Disease (MELD) points to patients while waiting for transplantation to decrease their waiting time. Such additional points afford patients with HCC a timely transplantation since they do not exhibit manifestations of liver failure that drives the MELD score toward transplantation.
Large tumors (>5 cm) commonly require multiple TACE procedures and response failure results in dropout/removal from the transplant waiting list. Despite the partial success of TACE, incomplete tumor necrosis following TACE increases the risk of disease progression and drop-out while waiting for transplantation. Thus, robust neoadjuvant therapies that yield superior tumor necrosis are needed to thwart disease progression and reduce dropout from the transplant waitlist. Additionally, achieving superior tumor necrosis may be accompanied by improved OS and RFS post-transplantation.
Lenvatinib is an inhibitor of the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF receptor substrate 2α (FRS2α) phosphorylation.
Multitargeted tyrosine kinase inhibitors (TKI) restrict tumor angiogenesis and have been successfully utilized as rescue therapy in patients with HCC following failed TACE. TACE blocks blood supply to the tumor and induces tumor necrosis, but this causes hypoxia and subsequent angiogenesis. The antiangiogenesis mechanisms of TKI/VEGF inhibitors may therefore complement the mechanisms of TACE to provide superior tumor necrosis. Investigations of lenvatinib (Lenvima) demonstrate its mechanism of action as an inhibitor of not only VEGF-driven but also fibroblast growth factor (FGF)-driven proliferation and angiogenesis, resulting in anti-tumor activity across diverse HCC models. In clinical trials of patients with unresectable HCC, the REFLECT study demonstrated non-inferiority in OS and significant improvement in time to progress, overall response rate, and progression-free survival with lenvatinib compared to sorafenib. Altogether, these findings suggest that lenvatinib is potentially a potent and successful therapeutic agent that may synergize with TACE to: i) enhance tumor necrosis while on the wait list, ii) reduce the possibility of patient drop-out while awaiting transplantation, and iii) improve OS and RFS of patients after liver transplant.
- Conditions
- Hepatocellular Carcinoma
- Being tested
- Lenvatinib, Transcatheter Arterial Chemoembolization
- Keywords
- lenvatinib, Liver Transplantation, Neoadjuvant Therapy, Liver Neoplasms, liver cancer, liver cancer, adult, transplantation, Chemoembolization, Therapeutic
- Medical subject headings
- Carcinoma, Hepatocellular, Liver Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LenvatinibDrug
Also called LENVIMA®
Participants will receive approximately six, 28-day cycles of lenvatinib (LENVIMA®, Eisai Inc., Woodcliff Lake, NJ). Lenvatinib will be administered at 12 mg orally once daily for patients with a body weight ≥60 kg and at 8 mg orally once daily for patients with a body weight of <60 kg.
Administration of lenvatinib will occur at least 2 weeks before the first standard of care TACE procedure and study drug treatment will continue for 6 months. Lenvatinib will be held for 7 days before and 7 days after each TACE. Participants can receive up to 3 TACE procedures per protocol depending on their response and transplantation time.
Transcatheter Arterial ChemoembolizationProcedure or surgery
Also called TACE
Traditional standard of care: Transcatheter Arterial Chemoembolization (TACE) treatment for hepatocellular carcinoma. Chemotherapeutic drug-coated particles are inserted via a catheter into an artery that supplies blood to a tumor where the drug works to cut off blood supply to the tumor.
| Study group | Role | What they receive |
|---|---|---|
| Lenvatinib in Combination with TACE Prior to Liver Transplantation | Experimental | Regimen of six months neoadjuvant lenvatinib in combination with TACE prior to liver transplantation in patients with hepatocellular carcinoma (HCC) beyond Milan Criteria. Receives: Drug: Lenvatinib; Procedure: Transcatheter Arterial Chemoembolization |
| Matched Historical Control Patients | Other | Historical controls will be liver transplant recipients matched on age, etiology of liver disease (viral vs. non-viral), listing tumor size, and number of TACE procedures to cases in the intervention group who receive a transplant. Receives: Procedure: Transcatheter Arterial Chemoembolization |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent Tumor Necrosis
Percent tumor necrosis measured via pathology of explanted liver at time of transplant
Measured: At time of transplant surgery
Secondary outcomes (6)
Adverse Event Occurrence
Proportion of adverse events with grade 3 or higher score based on the Common Terminology Criteria for Adverse Events (CTCAE) v.5
Measured: At time of first dose of lenvatinib; 1, 2, 3, 4, 5, 6, 7, 8 months after first dose
Response Rate to Lenvatiib
Response rate (RR) of lenvatinib following TACE by assessing radiologic images (relative to baseline scans) using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria
Measured: 3, 6, 9, and 12 months after enrollment
Tumor Staging
Proportion of tumors that are down-staged to standard Milan criteria (tumors < 5cm) based on CT/MRI imaging, relative to baseline CT/MRI imaging of abdomen and pelvis.
Measured: 3, 6, 9, and 12 months after enrollment
Serum Biomarkers
Concentration of VEGF, VEGF receptor-2, antiopoietin-2, FGF19, and FGF23 in serum.
Measured: At eligibility screening; within 14 days prior to the administration of the first dose of lenvatinib; at time of administration of first dose of lenvatinib; 1, 2, 3, 4, 5, 6, 7, 8 months after first dose
Microvessel Density
Microvessel density of explanted tumor tissue evidenced by CD31 immunohistochemistry.
Measured: At time of transplant surgery
Explant Biomarkers
Concentration of VEGF, VEGF receptor-2, antiopoietin-2, FGF19, and FGF23 on explant tissue.
Measured: At time of transplant surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Dec 2021
- Study start20 Aug 2022
- Primary completion30 Sep 2025
- Study completion30 Sep 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (20)Papers the sponsor has linked to this study.
- Other trials for Hepatocellular CarcinomaStudies of the same condition, open and under way.
- More trials run by The Methodist Hospital Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Methodist Hospital Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Eisai Inc.
- Responsible party
- Principal investigator, Maen Abdelrahim, MD, PhD, Pharm.B, The Methodist Hospital Research Institute
- Investigators
- Maen Abdelrahim, MD, Principal investigator, The Methodist Hospital Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05171335
- Sponsor's protocol ID
- PRO00028690
- Status last verified
- Oct 2026
- First submitted
- 10 Dec 2021
- Last updated
- 7 Oct 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Hsiao P, Hsieh KC, Chen YS, Hsu CC, Lo GH, Li YC, Hsieh PM, Lin HY, Wu TC, Yeh JH, Lin CW. Sorafenib with concurrent multiple-line therapies improves overall survival in advanced stage hepatocellular carcinoma. Medicine (Baltimore). 2019 Jun;98(25):e16074. doi: 10.1097/MD.0000000000016074.
PubMed 31232945Wu FX, Chen J, Bai T, Zhu SL, Yang TB, Qi LN, Zou L, Li ZH, Ye JZ, Li LQ. The safety and efficacy of transarterial chemoembolization combined with sorafenib and sorafenib mono-therapy in patients with BCLC stage B/C hepatocellular carcinoma. BMC Cancer. 2017 Sep 12;17(1):645. doi: 10.1186/s12885-017-3545-5.
PubMed 28899349Zhang W, Jin K, Wang F, Zhangyuan G, Yu W, Liu Y, Zhang H, Zhang P, Sun B. Differences in the prognostic value of tumor size on hepatocellular cancer-specific survival stratified by gender in a SEER population-based study. United European Gastroenterol J. 2019 Aug;7(7):933-941. doi: 10.1177/2050640619845602. Epub 2019 Apr 24.
PubMed 31428418White DL, Thrift AP, Kanwal F, Davila J, El-Serag HB. Incidence of Hepatocellular Carcinoma in All 50 United States, From 2000 Through 2012. Gastroenterology. 2017 Mar;152(4):812-820.e5. doi: 10.1053/j.gastro.2016.11.020. Epub 2016 Nov 23.
PubMed 27889576Lenvima [Package Insert]. Eisai R&D Management Co., Ltd. http://www.lenvima.com/pdfs/prescribinginformation. pdf. Published 2020. Accessed June 12, 2020.
Yang JD, Larson JJ, Watt KD, Allen AM, Wiesner RH, Gores GJ, Roberts LR, Heimbach JA, Leise MD. Hepatocellular Carcinoma Is the Most Common Indication for Liver Transplantation and Placement on the Waitlist in the United States. Clin Gastroenterol Hepatol. 2017 May;15(5):767-775.e3. doi: 10.1016/j.cgh.2016.11.034. Epub 2016 Dec 21.
PubMed 28013117Daoud A, Teeter L, Ghobrial RM, Graviss EA, Mogawer S, Sholkamy A, El-Shazli M, Gaber AO. Transplantation for Hepatocellular Carcinoma: Is There a Tumor Size Limit? Transplant Proc. 2018 Dec;50(10):3577-3581. doi: 10.1016/j.transproceed.2018.04.038. Epub 2018 Apr 18.
PubMed 30577241Bharat A, Brown DB, Crippin JS, Gould JE, Lowell JA, Shenoy S, Desai NM, Chapman WC. Pre-liver transplantation locoregional adjuvant therapy for hepatocellular carcinoma as a strategy to improve longterm survival. J Am Coll Surg. 2006 Oct;203(4):411-20. doi: 10.1016/j.jamcollsurg.2006.06.016. Epub 2006 Aug 17.
PubMed 17000383SEER stats. Liver and intrahepatic bile duct cancer. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Cancer Stat Facts Web site. https://seer.cancer.gov/statfacts/html/livibd.html. Published 2019. Accessed December 8, 2019.
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996 Mar 14;334(11):693-9. doi: 10.1056/NEJM199603143341104.
PubMed 8594428Young S, Sanghvi T, Lake JJ, Rubin N, Golzarian J. Predicting post-transarterial chemoembolization outcomes: A comparison of direct and total bilirubin serums levels. Diagn Interv Imaging. 2020 Jun;101(6):355-364. doi: 10.1016/j.diii.2019.12.006. Epub 2020 Jan 13.
PubMed 31948887Lee S, Kang JH, Kim DY, Ahn SH, Park JY, Kim BK, Kim SU, Han KH. Prognostic factors of sorafenib therapy in hepatocellular carcinoma patients with failure of transarterial chemoembolization. Hepatol Int. 2017 May;11(3):292-299. doi: 10.1007/s12072-017-9792-3. Epub 2017 Mar 21.
PubMed 28324324Matsuki M, Hoshi T, Yamamoto Y, Ikemori-Kawada M, Minoshima Y, Funahashi Y, Matsui J. Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models. Cancer Med. 2018 Jun;7(6):2641-2653. doi: 10.1002/cam4.1517. Epub 2018 May 7.
PubMed 29733511Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
PubMed 29433850Victor DW 3rd, Monsour HP Jr, Boktour M, Lunsford K, Balogh J, Graviss EA, Nguyen DT, McFadden R, Divatia MK, Heyne K, Ankoma-Sey V, Egwim C, Galati J, Duchini A, Saharia A, Mobley C, Gaber AO, Ghobrial RM. Outcomes of Liver Transplantation for Hepatocellular Carcinoma Beyond the University of California San Francisco Criteria: A Single-center Experience. Transplantation. 2020 Jan;104(1):113-121. doi: 10.1097/TP.0000000000002835.
PubMed 31233480
Study at a glance
From the registry record, last updated by the sponsor on 7 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neoadjuvant Combination Therapy of Lenvima Plus Transcatheter Arterial Chemoembolization (TACE) for Transplant-Eligible Patients With Large Hepatocellular Carcinoma
- ClinicalTrials.gov ID
- NCT05171335
- Acronym / sponsor ID
- PRO00028690
- Conditions
- Hepatocellular Carcinoma
- Keywords
- lenvatinib, Liver Transplantation, Neoadjuvant Therapy, Liver Neoplasms, liver cancer, liver cancer, adult, transplantation, Chemoembolization, Therapeutic
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 5 participants (actual)
- Lead sponsor
- The Methodist Hospital Research InstituteUniversity, hospital or other
- Collaborators
- Eisai Inc.
- Study start
- 20 Aug 2022 (actual)
- Primary completion
- 30 Sep 2025 (actual)
- Study completion
- 30 Sep 2025 (actual)
- First posted
- 28 Dec 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will examine the effects of a six-month regimen of neoadjuvant lenvatinib in combination with transcatheter arterial chemoembolization (TACE) prior to liver transplantation in patients with hepatocellular carcinoma (HCC) beyond Milan Criteria. Clinical, outcomes, and exploratory data will be compared to a matched, retrospective cohort.
Detailed description
HCC is the third leading cause of cancer death worldwide with more than 230,000 cases of HCC since 2000 and an estimated 42,000 new cases next year. The purpose of this trial is to examine if combination therapy of lenvatinib (LENVIMA®, Eisai Inc., Woodcliff Lake, NJ) plus transcatheter arterial chemoembolization (TACE) will promote tumor necrosis evidenced by explant pathology in patients with large HCC (>5 cm). TACE blocks blood supply to the tumor and induces tumor necrosis, but this causes hypoxia and subsequent angiogenesis.
In 2015, HCC was the leading diagnosis among liver transplant recipients (27.2%). Transplantation of patients diagnosed with HCC is largely based on tumor size, since this is thought to correlate with posttransplant outcomes. However, emerging evidence shows that tumor stability or response to locoregional therapy (LRT) can be surrogate markers of favorable biology and improved outcomes following transplantation. LRT, including TACE or radiofrequency ablation, that promote tumor stability (defined as no tumor progression in 6 months) serve as bridging therapies to liver transplantation. In tumors that respond to ablation, LRT further augments the success of liver transplantation and reduces the risk of HCC recurrence post-transplant.
Liver transplantation provides the ultimate curative option for patients with HCC with improved overall survival (OS) and recurrence-free survival (RFS) of 85% and 92% at 4 years, respectively, compared to 18.4% without transplantation. To limit disease progression and promote tumor stability while on the transplant waitlist, patients with unresectable HCC typically undergo neoadjuvant treatment. Although the National Comprehensive Cancer Network (NCCN) guidelines recommend the use of neoadjuvant therapy for the management of HCC, no clear-cut guidelines are given regarding the type of LRT or other therapeutic agents. LRT effectively improves 2-yr OS between 20-60% and TACE can achieve complete response in 65.2% of patients. LRT is utilized for preventing tumor growth while on the waitlist and to downstage large tumors to standard Milan Criteria (reduce tumor size to ≤ 5cm). Based on the United Network of Organ Sharing (UNOS) criteria, down-staging of tumors to Milan allows the addition of artificial Model for End-stage Liver Disease (MELD) points to patients while waiting for transplantation to decrease their waiting time. Such additional points afford patients with HCC a timely transplantation since they do not exhibit manifestations of liver failure that drives the MELD score toward transplantation.
Large tumors (>5 cm) commonly require multiple TACE procedures and response failure results in dropout/removal from the transplant waiting list. Despite the partial success of TACE, incomplete tumor necrosis following TACE increases the risk of disease progression and drop-out while waiting for transplantation. Thus, robust neoadjuvant therapies that yield superior tumor necrosis are needed to thwart disease progression and reduce dropout from the transplant waitlist. Additionally, achieving superior tumor necrosis may be accompanied by improved OS and RFS post-transplantation.
Lenvatinib is an inhibitor of the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib inhibits other kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF receptor substrate 2α (FRS2α) phosphorylation.
Multitargeted tyrosine kinase inhibitors (TKI) restrict tumor angiogenesis and have been successfully utilized as rescue therapy in patients with HCC following failed TACE. TACE blocks blood supply to the tumor and induces tumor necrosis, but this causes hypoxia and subsequent angiogenesis. The antiangiogenesis mechanisms of TKI/VEGF inhibitors may therefore complement the mechanisms of TACE to provide superior tumor necrosis. Investigations of lenvatinib (Lenvima) demonstrate its mechanism of action as an inhibitor of not only VEGF-driven but also fibroblast growth factor (FGF)-driven proliferation and angiogenesis, resulting in anti-tumor activity across diverse HCC models. In clinical trials of patients with unresectable HCC, the REFLECT study demonstrated non-inferiority in OS and significant improvement in time to progress, overall response rate, and progression-free survival with lenvatinib compared to sorafenib. Altogether, these findings suggest that lenvatinib is potentially a potent and successful therapeutic agent that may synergize with TACE to: i) enhance tumor necrosis while on the wait list, ii) reduce the possibility of patient drop-out while awaiting transplantation, and iii) improve OS and RFS of patients after liver transplant.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lenvatinib in Combination with TACE Prior to Liver Transplantation | Experimental | Drug: Lenvatinib, Procedure: Transcatheter Arterial ChemoembolizationRegimen of six months neoadjuvant lenvatinib in combination with TACE prior to liver transplantation in patients with hepatocellular carcinoma (HCC) beyond Milan Criteria. |
| Matched Historical Control Patients | Other | Procedure: Transcatheter Arterial ChemoembolizationHistorical controls will be liver transplant recipients matched on age, etiology of liver disease (viral vs. non-viral), listing tumor size, and number of TACE procedures to cases in the intervention group who receive a transplant. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Adults (≥18 years old) with histologically or cytologically confirmed HCC beyond Milan Criteria
- Must be treatment naïve and eligible for TACE procedure
- Must be on the liver transplant waiting list and not require any other solid organ transplant
- Eastern Cooperative Oncology Group performance status of 0 or 1
- Patients with hepatitis B virus (HBV) infection (as characterized by positive HBV surface antigen and/or anti-hepatitis B core antibodies (HBcAbs) with detectable HBV DNA (≥10 IU/mL or above the limit of detection per local laboratory) must receive antiviral therapy at least after study enrollment per institutional practice to ensure adequate viral suppression (HBV DNA ≤2000 IU/mL). Patients must be managed for 6 months after the last dose of study treatment. Antiviral therapy will be concurrent with lenvatinib.
Key exclusion criteria (18 listed)
- Mixed hepatocellular-cholangiocarcinoma or HCC within Milan criteria
- Previously received chemotherapy or immunotherapy for HCC
- Child Pugh assessment score greater than or equal to B8
- Uncontrolled blood pressure (BP; Systolic BP>140 mmHg or diastolic BP >90 mmHg) despite an optimized regimen of antihypertensive medication
- Electrolyte abnormalities that have not been corrected
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LenvatinibAlso: LENVIMA®Participants will receive approximately six, 28-day cycles of lenvatinib (LENVIMA®, Eisai Inc., Woodcliff Lake, NJ). Lenvatinib will be administered at 12 mg orally once daily for patients with a body weight ≥60 kg and at 8 mg orally once daily for patients with a body weight of <60 kg. Administration of lenvatinib will occur at least 2 weeks before the first standard of care TACE procedure and study drug treatment will continue for 6 months. Lenvatinib will be held for 7 days before and 7 days after each TACE. Participants can receive up to 3 TACE procedures per protocol depending on their response and transplantation time. | Drug | Lenvatinib in Combination with TACE Prior to Liver Transplantation |
| Transcatheter Arterial ChemoembolizationAlso: TACETraditional standard of care: Transcatheter Arterial Chemoembolization (TACE) treatment for hepatocellular carcinoma. Chemotherapeutic drug-coated particles are inserted via a catheter into an artery that supplies blood to a tumor where the drug works to cut off blood supply to the tumor. | Procedure or surgery | Lenvatinib in Combination with TACE Prior to Liver Transplantation, Matched Historical Control Patients |
Primary outcome
Percent Tumor Necrosis
Time frame: At time of transplant surgery
Percent tumor necrosis measured via pathology of explanted liver at time of transplant
6 secondary outcomes
Adverse Event Occurrence
Time frame: At time of first dose of lenvatinib; 1, 2, 3, 4, 5, 6, 7, 8 months after first dose
Response Rate to Lenvatiib
Time frame: 3, 6, 9, and 12 months after enrollment
Tumor Staging
Time frame: 3, 6, 9, and 12 months after enrollment
Serum Biomarkers
Time frame: At eligibility screening; within 14 days prior to the administration of the first dose of lenvatinib; at time of administration of first dose of lenvatinib; 1, 2, 3, 4, 5, 6, 7, 8 months after first dose
Microvessel Density
Time frame: At time of transplant surgery
Explant Biomarkers
Time frame: At time of transplant surgery
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Oct 2026.
- Background: PubMed 31232945Hsiao P, Hsieh KC, Chen YS, Hsu CC, Lo GH, Li YC, Hsieh PM, Lin HY, Wu TC, Yeh JH, Lin CW. Sorafenib with concurrent multiple-line therapies improves overall survival in advanced stage hepatocellular carcinoma. Medicine (Baltimore). 2019 Jun;98(25):e16074. doi: 10.1097/MD.0000000000016074.
- Background: PubMed 28899349Wu FX, Chen J, Bai T, Zhu SL, Yang TB, Qi LN, Zou L, Li ZH, Ye JZ, Li LQ. The safety and efficacy of transarterial chemoembolization combined with sorafenib and sorafenib mono-therapy in patients with BCLC stage B/C hepatocellular carcinoma. BMC Cancer. 2017 Sep 12;17(1):645. doi: 10.1186/s12885-017-3545-5.
- Background: PubMed 31428418Zhang W, Jin K, Wang F, Zhangyuan G, Yu W, Liu Y, Zhang H, Zhang P, Sun B. Differences in the prognostic value of tumor size on hepatocellular cancer-specific survival stratified by gender in a SEER population-based study. United European Gastroenterol J. 2019 Aug;7(7):933-941. doi: 10.1177/2050640619845602. Epub 2019 Apr 24.
- Background: PubMed 27889576White DL, Thrift AP, Kanwal F, Davila J, El-Serag HB. Incidence of Hepatocellular Carcinoma in All 50 United States, From 2000 Through 2012. Gastroenterology. 2017 Mar;152(4):812-820.e5. doi: 10.1053/j.gastro.2016.11.020. Epub 2016 Nov 23.
- BackgroundLenvima [Package Insert]. Eisai R&D Management Co., Ltd. http://www.lenvima.com/pdfs/prescribinginformation. pdf. Published 2020. Accessed June 12, 2020.
- Background: PubMed 28013117Yang JD, Larson JJ, Watt KD, Allen AM, Wiesner RH, Gores GJ, Roberts LR, Heimbach JA, Leise MD. Hepatocellular Carcinoma Is the Most Common Indication for Liver Transplantation and Placement on the Waitlist in the United States. Clin Gastroenterol Hepatol. 2017 May;15(5):767-775.e3. doi: 10.1016/j.cgh.2016.11.034. Epub 2016 Dec 21.
- Background: PubMed 30577241Daoud A, Teeter L, Ghobrial RM, Graviss EA, Mogawer S, Sholkamy A, El-Shazli M, Gaber AO. Transplantation for Hepatocellular Carcinoma: Is There a Tumor Size Limit? Transplant Proc. 2018 Dec;50(10):3577-3581. doi: 10.1016/j.transproceed.2018.04.038. Epub 2018 Apr 18.
- Background: PubMed 17000383Bharat A, Brown DB, Crippin JS, Gould JE, Lowell JA, Shenoy S, Desai NM, Chapman WC. Pre-liver transplantation locoregional adjuvant therapy for hepatocellular carcinoma as a strategy to improve longterm survival. J Am Coll Surg. 2006 Oct;203(4):411-20. doi: 10.1016/j.jamcollsurg.2006.06.016. Epub 2006 Aug 17.
- BackgroundSEER stats. Liver and intrahepatic bile duct cancer. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Cancer Stat Facts Web site. https://seer.cancer.gov/statfacts/html/livibd.html. Published 2019. Accessed December 8, 2019.
- Background: PubMed 8594428Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F, Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996 Mar 14;334(11):693-9. doi: 10.1056/NEJM199603143341104.
- Background: PubMed 31948887Young S, Sanghvi T, Lake JJ, Rubin N, Golzarian J. Predicting post-transarterial chemoembolization outcomes: A comparison of direct and total bilirubin serums levels. Diagn Interv Imaging. 2020 Jun;101(6):355-364. doi: 10.1016/j.diii.2019.12.006. Epub 2020 Jan 13.
- Background: PubMed 28324324Lee S, Kang JH, Kim DY, Ahn SH, Park JY, Kim BK, Kim SU, Han KH. Prognostic factors of sorafenib therapy in hepatocellular carcinoma patients with failure of transarterial chemoembolization. Hepatol Int. 2017 May;11(3):292-299. doi: 10.1007/s12072-017-9792-3. Epub 2017 Mar 21.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Maen Abdelrahim, MD principal investigator
The Methodist Hospital Research Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Lenvatinib and Transcatheter Arterial Chemoembolization in people with Hepatocellular Carcinoma, run by The Methodist Hospital Research Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent Tumor Necrosis (time frame: At time of transplant surgery). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05171335, which also lists 20 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Oct 2026.