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

Sponsor
The Methodist Hospital Research Institute (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05171335
Collaborator
Eisai Inc. (Industry)
50
Enrollment
1
Location
2
Arms
62.9
Anticipated Duration (Months)
0.8
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

We propose a regimen of six months 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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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

Study Type:
Interventional
Anticipated Enrollment :
50 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Neoadjuvant Combination Therapy of Lenvima Plus Transcatheter Arterial Chemoembolization (TACE) for Transplant-Eligible Patients With Large Hepatocellular Carcinoma
Anticipated Study Start Date :
Dec 30, 2021
Anticipated Primary Completion Date :
Sep 30, 2026
Anticipated Study Completion Date :
Mar 30, 2027

Arms and Interventions

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

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Percent Tumor Necrosis [At time of transplant surgery]

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

    Secondary Outcome Measures

    1. Adverse Event Occurrence [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

    2. Response Rate to Lenvatiib [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. Tumor Staging [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.

    4. 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]

      Concentration of VEGF, VEGF receptor-2, antiopoietin-2, FGF19, and FGF23 in serum.

    5. Microvessel Density [At time of transplant surgery]

      Microvessel density of explanted tumor tissue evidenced by CD31 immunohistochemistry.

    6. Explant Biomarkers [At time of transplant surgery]

      Concentration of VEGF, VEGF receptor-2, antiopoietin-2, FGF19, and FGF23 on explant tissue.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Houston Methodist Research Institute Houston Texas United States 77030

    Sponsors and Collaborators

    • The Methodist Hospital Research Institute
    • Eisai Inc.

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Maen Abdelrahim, MD, PhD, Pharm.B, Associate Professor of Medicine in Oncology, Houston Methodist Academic Institute, The Methodist Hospital Research Institute
    ClinicalTrials.gov Identifier:
    NCT05171335
    Other Study ID Numbers:
    • PRO00028690
    First Posted:
    Dec 28, 2021
    Last Update Posted:
    Dec 28, 2021
    Last Verified:
    Dec 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    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
    Keywords provided by Maen Abdelrahim, MD, PhD, Pharm.B, Associate Professor of Medicine in Oncology, Houston Methodist Academic Institute, The Methodist Hospital Research Institute
    lenvatinib
    Liver Transplantation
    Neoadjuvant Therapy
    Liver Neoplasms
    liver cancer
    liver cancer, adult
    transplantation
    Chemoembolization, Therapeutic
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Hepatocellular
    Lenvatinib

    Study Results

    No Results Posted as of Dec 28, 2021