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

September 15, 2022 updated by: Maen Abdelrahim, MD, PhD, Pharm.B, The Methodist Hospital Research Institute

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.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

50

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Houston, Texas, United States, 77030
        • Houston Methodist Research Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 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:

    1. Hemoglobin ≥9 g/dL
    2. Platelet count ≥50,000/μL
    3. Total bilirubin ≤3.0
    4. Albumin ≥2 g/dL
    5. International normalized ratio ≤2
    6. 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

Exclusion Criteria:

  • 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:

    1. 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
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    3. 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Lenvatinib in Combination with TACE Prior to Liver Transplantation
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

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.

Other Names:
  • LENVIMA®
Procedure: Transcatheter Arterial Chemoembolization
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.
Other Names:
  • TACE
OTHER: Matched Historical Control Patients
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
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.
Other Names:
  • TACE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percent Tumor Necrosis
Time Frame: At time of transplant surgery
Percent tumor necrosis measured via pathology of explanted liver at time of transplant
At time of transplant surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse Event Occurrence
Time Frame: At time of first dose of lenvatinib; 1, 2, 3, 4, 5, 6, 7, 8 months after first dose
Proportion of adverse events with grade 3 or higher score based on the Common Terminology Criteria for Adverse Events (CTCAE) v.5
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
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
3, 6, 9, and 12 months after enrollment
Tumor Staging
Time Frame: 3, 6, 9, and 12 months after enrollment
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.
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
Concentration of VEGF, VEGF receptor-2, antiopoietin-2, FGF19, and FGF23 in serum.
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
Microvessel density of explanted tumor tissue evidenced by CD31 immunohistochemistry.
At time of transplant surgery
Explant Biomarkers
Time Frame: At time of transplant surgery
Concentration of VEGF, VEGF receptor-2, antiopoietin-2, FGF19, and FGF23 on explant tissue.
At time of transplant surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Methodist Hospital Research Institute

Collaborators

Eisai Inc.

Investigators

  • Principal Investigator: Maen Abdelrahim, MD, The Methodist Hospital Research Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 20, 2022

Primary Completion (ANTICIPATED)

June 30, 2026

Study Completion (ANTICIPATED)

December 30, 2027

Study Registration Dates

First Submitted

December 10, 2021

First Submitted That Met QC Criteria

December 10, 2021

First Posted (ACTUAL)

December 28, 2021

Study Record Updates

Last Update Posted (ACTUAL)

September 21, 2022

Last Update Submitted That Met QC Criteria

September 15, 2022

Last Verified

September 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PRO00028690

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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