Neoadjuvant Combination Therapy of Lenvatinib and TACE for Transplant-Eligible Large Hepatocellular Carcinoma Patients

NCT05171335 | Enrolling By Invitation Phase 2 FDA Drug

• 1 other identifier: PRO00028690
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief 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. Clinical, outcomes, and exploratory data will be compared to a matched, retrospective cohort.

Conditions

Hepatocellular Carcinoma

Keywords

lenvatinib; Liver Transplantation; Neoadjuvant Therapy; Liver Neoplasms; liver cancer; liver cancer, adult; transplantation; Chemoembolization, Therapeutic

Outcome Measures

Primary Outcomes (1)

• Percent Tumor Necrosis

  Percent tumor necrosis measured via pathology of explanted liver at time of transplant

  At time of transplant surgery

Secondary Outcomes (6)

• Adverse Event Occurrence

  At time of first dose of lenvatinib; 1, 2, 3, 4, 5, 6, 7, 8 months after first dose

• Response Rate to Lenvatiib

  3, 6, 9, and 12 months after enrollment

• Tumor Staging

  3, 6, 9, and 12 months after enrollment

• Serum Biomarkers

  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

  At time of transplant surgery

Study Arms (2)

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.

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.

Procedure: Transcatheter Arterial Chemoembolization

Interventions

Lenvatinib DRUG

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.

Also known as: LENVIMA®

Lenvatinib in Combination with TACE Prior to Liver Transplantation

Transcatheter Arterial Chemoembolization PROCEDURE

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.

Also known as: TACE

Lenvatinib in Combination with TACE Prior to Liver Transplantation; Matched Historical Control Patients

Eligibility Criteria

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

You may qualify if:

• 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.
• 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%

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• The Methodist Hospital Research Institute: lead
• Eisai Inc.: collaborator

Study Sites (1)

Houston Methodist Research Institute

Houston, Texas, 77030, United States

Location

Related Publications (20)

• 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.

  PMID: 31232945 BACKGROUND

• Wu 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.

  PMID: 28899349 BACKGROUND

• Zhang 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.

  PMID: 31428418 BACKGROUND

• White 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.

  PMID: 27889576 BACKGROUND

• Lenvima [Package Insert]. Eisai R&D Management Co., Ltd. http://www.lenvima.com/pdfs/prescribinginformation. pdf. Published 2020. Accessed June 12, 2020.

  BACKGROUND

• 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.

  PMID: 28013117 BACKGROUND

• Daoud 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.

  PMID: 30577241 BACKGROUND

• Bharat 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.

  PMID: 17000383 BACKGROUND

• SEER 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

• 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.

  PMID: 8594428 BACKGROUND

• Young 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.

  PMID: 31948887 BACKGROUND

• Lee 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.

  PMID: 28324324 BACKGROUND

• Matsuki 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.

  PMID: 29733511 BACKGROUND

• Kudo 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.

  PMID: 29433850 BACKGROUND

• Victor 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.

  PMID: 31233480 BACKGROUND

• Highlights of prescribing information: Lenvima. In:2020.

  BACKGROUND

• Oligane HC, Xing M, Kim HS. Effect of Bridging Local-Regional Therapy on Recurrence of Hepatocellular Carcinoma and Survival after Orthotopic Liver Transplantation. Radiology. 2017 Mar;282(3):869-879. doi: 10.1148/radiol.2016160288. Epub 2016 Sep 27.

  PMID: 27673508 BACKGROUND

• Kudo M. Proposal of Primary Endpoints for TACE Combination Trials with Systemic Therapy: Lessons Learned from 5 Negative Trials and the Positive TACTICS Trial. Liver Cancer. 2018 Sep;7(3):225-234. doi: 10.1159/000492535. Epub 2018 Aug 23. No abstract available.

  PMID: 30319982 BACKGROUND

• Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010 Feb;30(1):52-60. doi: 10.1055/s-0030-1247132. Epub 2010 Feb 19.

  PMID: 20175033 BACKGROUND

• Hastie T, Tibshirani R, Wainwright M. Statistical Learning with Sparsity: The Lasso and Generalizations. Boca Raton, FL: CRC Press; 2015.

  BACKGROUND

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Liver Neoplasms

Interventions

lenvatinib

Condition Hierarchy (Ancestors)

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

Study Officials

• Maen Abdelrahim, MD

  The Methodist Hospital Research Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine in Oncology, Houston Methodist Academic Institute

Study Record Dates

• First Submitted: December 10, 2021
• First Posted: December 28, 2021
• Study Start: June 20, 2022
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 30, 2027
• Last Updated: September 21, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)