Clinical Trials Logo

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


Clinical Trial 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


Related Conditions & MeSH terms


NCT number NCT05171335
Study type Interventional
Source The Methodist Hospital Research Institute
Contact
Status Enrolling by invitation
Phase Phase 2
Start date June 20, 2022
Completion date December 30, 2027

See also
  Status Clinical Trial Phase
Recruiting NCT04209491 - Interest of the Intervention of a Nurse Coordinator in Complex Care Pathway
Completed NCT03963206 - Cabozantinib toLERANCE Study in HepatoCellular Carcinoma (CLERANCE) Phase 4
Completed NCT03268499 - TACE Emulsion Versus Suspension Phase 2
Recruiting NCT05044676 - Immune Cells as a New Biomarker of Response in Patients Treated by Immunotherapy for Advanced Hepatocellular Carcinoma
Recruiting NCT05263830 - Glypican-3 as a Prognostic Factor in Patients With Hepatocellular Carcinoma Treated by Immunotherapy
Recruiting NCT05095519 - Hepatocellular Carcinoma Imaging Using PSMA PET/CT Phase 2
Recruiting NCT05497531 - Pilot Comparing ctDNA IDV vs. SPV Sample in Pts Undergoing Biopsies for Hepatobiliary and Pancreatic Cancers N/A
Completed NCT05068193 - A Clinical Trial to Compare the Pharmacokinetics and Bioequivalence of "BR2008" With "BR2008-1" in Healthy Volunteers Phase 1
Active, not recruiting NCT03781934 - A Study to Evaluate MIV-818 in Patients With Liver Cancer Manifestations Phase 1/Phase 2
Terminated NCT03655613 - APL-501 or Nivolumab in Combination With APL-101 in Locally Advanced or Metastatic HCC and RCC Phase 1/Phase 2
Active, not recruiting NCT03170960 - Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors Phase 1/Phase 2
Active, not recruiting NCT04242199 - Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INCB099280 in Participants With Advanced Solid Tumors Phase 1
Completed NCT04401800 - Preliminary Antitumor Activity, Safety and Tolerability of Tislelizumab in Combination With Lenvatinib for Hepatocellular Carcinoma Phase 2
Withdrawn NCT05418387 - A Social Support Intervention to Improve Treatment Among Hispanic Kidney and Liver Cancer Patients in Arizona N/A
Active, not recruiting NCT04039607 - A Study of Nivolumab in Combination With Ipilimumab in Participants With Advanced Hepatocellular Carcinoma Phase 3
Terminated NCT03970616 - A Study of Tivozanib in Combination With Durvalumab in Subjects With Advanced Hepatocellular Carcinoma Phase 1/Phase 2
Recruiting NCT04118114 - Phase II Study of PRL3-ZUMAB in Advanced Solid Tumors Phase 2
Recruiting NCT06239155 - A Phase I/II Study of AST-3424 in Subjects With Advanced Solid Tumors Phase 1/Phase 2
Recruiting NCT03642561 - Evaluation the Treatment Outcome for RFA in Patients With BCLC Stage B HCC in Comparison With TACE Phase 2/Phase 3
Completed NCT03222076 - Nivolumab With or Without Ipilimumab in Treating Patients With Resectable Liver Cancer Phase 2