Evaluation of Lenvatinib Efficacy in Hepatocellular Carcinoma Patients on Liver Transplantation Waiting List Post-TACE Failure

Trial ID: 2024-516408-40-00
Protocol: APHP220267
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Hepatocellular carcinoma

Objectives

The primary objective of this study is to estimate the proportion of **liver transplantation (LT)** among patients with non-resectable **hepatocellular carcinoma (HCC)** who are treated with **lenvatinib** after failing to achieve a complete response following two transarterial chemoembolization (TACE) procedures. This objective is clinically relevant as it aims to determine the potential of lenvatinib to facilitate liver transplantation in patients who have limited treatment options due to the failure of TACE, thereby potentially improving survival outcomes.

Secondary objectives include:

Estimating the time to progression under lenvatinib and until LT.
Comparing the progression rate under lenvatinib and until LT with a theoretical proportion of 20%.
Estimating the response rate by imaging before LT.
Estimating the response rate by liver specimen pathology after LT.
Estimating the recurrence rate after LT.
Demonstrating the safety of this sequential strategy.
Characterizing the immune cell population changes in peripheral blood under treatment.

Participants

The clinical trial involves participants diagnosed with **non-resectable hepatocellular carcinoma (HCC)**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have adequate bone marrow, liver, and renal function, as well as a QT/QTc interval of less than 480 ms. The trial includes individuals who have undergone transarterial chemoembolization (TACE) as a bridge to liver transplantation (LT) and have not achieved a complete response after two TACE procedures. Participants must be registered on a national waiting list for LT and have an initial French AFP score of 2 or less. The trial population is selected based on specific inclusion criteria, including the requirement for informed, written consent and having rights to French social insurance. The sponsor has not provided information regarding the total number of participants. The study considers lifestyle factors such as the use of effective contraception for women of childbearing potential and sexually active participants with WOCBP partners. The trial includes a vulnerable population, ensuring comprehensive ethical considerations are in place.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **lenvatinib** in patients with non-resectable hepatocellular carcinoma (HCC) who are on the waiting list for liver transplantation following transarterial chemoembolization (TACE) failure. This is a Phase Ib/II trial, characterized by a randomized, double-blind, controlled design. The trial is expected to commence recruitment on July 10, 2024, and conclude by August 10, 2028. The primary objective is to estimate the proportion of liver transplants (LT) among patients treated with lenvatinib who do not achieve a complete response after two TACE procedures.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as adequate bone marrow, liver, and renal function, and registration on the national waiting list for LT. Following the screening, participants will be randomized to receive lenvatinib in the form of 4 mg hard capsules, administered orally. The trial will include regular follow-up visits to monitor the progression of the disease using imaging techniques based on RECIST and mRECIST criteria, as well as to assess safety through adverse event (AE) and serious adverse event (SAE) reporting according to the current CTCAE guidelines.

The expected duration of participant involvement will vary depending on individual response to treatment and progression status, with regular assessments to determine eligibility for continued participation. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, or withdrawal of consent. The end-of-study visit will involve a comprehensive evaluation of treatment outcomes, including response rates by imaging and liver specimen pathology post-transplantation, as well as recurrence rates and immunophenotyping analyses. The trial aims to provide valuable insights into the potential benefits of lenvatinib for patients with HCC awaiting liver transplantation.

Treatment

The clinical trial involves the administration of **Lenvatinib**, marketed under the name **LENVIMA 4 mg hard capsules**. This experimental medication is presented in the form of hard capsules, which are administered orally. The capsules are contained in a high-density polyethylene (HDPE) bottle and are distinct from the commercial formulation as they lack any markings. The active substance, **Lenvatinib**, is of chemical origin and is classified under the ATC code L01EX08. The medication is not a pediatric formulation and is intended for use in adult patients. The trial aims to evaluate the efficacy of Lenvatinib in patients with hepatocellular carcinoma (HCC) who are on the waiting list for liver transplantation following the failure of transarterial chemoembolization (TACE).

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of Lenvatinib. The dosing schedule and frequency of administration are not detailed in the provided data. Participant compliance with the medication regimen will be monitored throughout the trial to ensure adherence to the prescribed treatment protocol. The trial's main objective is to estimate the proportion of liver transplantation among patients treated with Lenvatinib who do not achieve a complete response after two TACE procedures.

Efficacy

Efficacy in this clinical trial will be assessed primarily by evaluating the proportion of patients with **transarterial chemoembolization (TACE)** failure who undergo liver transplantation (LT) after treatment with lenvatinib. This primary endpoint will provide insight into the effectiveness of lenvatinib in facilitating LT in patients with hepatocellular carcinoma (HCC) who have not achieved a complete response after two TACE procedures.

Secondary endpoints will include the time to progression under lenvatinib before LT, assessed through imaging techniques based on RECIST and mRECIST criteria. Additionally, the response rate before LT will be evaluated by imaging, and the response rate by liver specimen pathology will be assessed after LT. The recurrence rate after LT will also be monitored through imaging. Safety will be evaluated by recording adverse events (AEs) and serious adverse events (SAEs) using the current Common Terminology Criteria for Adverse Events (CTCAE). Ancillary analyses will include endpoints associated with the immunophenotyping of peripheral blood immune cell populations.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient presenting with non resectable HCC
Initial French AFP score < or = 2
Registered on national waiting list for LT
Who underwent TACE as a bridge to LT (i.e. persistent active disease, including stable disease or partial response or progression)
With no complete response after 2 TACE (i.e. persistent active disease, including stable disease or partial response or progression)
Non eligible for percutaneous ablation
Informed, written consent obtained from the patient
Having the rights to French social insurance
Aged of 18 years or older
Adequate bone marrow, liver and renal function as assessed by the following laboratory tests: - Hemoglobin > 8.5 g/dL - Absolute neutrophil count ≥ 1500/mm3 (≥ 1200/mm3 for black/African, American) - Platelet count ≥ 60,000/ mm3 - Total bilirubin ≤ 2 mg/dL or 34 mcmol/l - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN) - Serum creatinine ≤ 1.5 x ULN - Prothrombine time-international normalized ratio (PT-INR) < 2.3 and PTT < 50 % - Glomerular Filtration Rate (GFR) ≥ 30 mL/min/1.73 m2
Patient with QT/QTc < 480 ms
Women of childbearing potential (WOCBP) need to accept one effective method of contraception until 1 month after the last lenvatinib intake and avoid pregnancy
Patients who are sexually active with WOCBP partners need to accept one effective method of contraception until 1 month after lenvatinib intake and men must agree to use adequate contraception

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Exclusion Criteria

Contraindication of lenvatinib and excipient: 1) Cardiovascular: - Rhythmic or ischemic recent or uncontrolled cardiac disease: Pacemakers or patients who have a history of cardiac arrhythmias or irregular heartbeats (in case of electroporation procedure) - Congestive heart failure New York Heart Association (NYHA) ≥ class 2 - Unstable angina or myocardial infarction within the past 6 months before enrolment - Uncontrolled arterial hypertension (systolic ≥ 140 mmHg, diastolic ≥ 90 mmHg) 2) Ongoing ascites: Refractory ascites according to EASL guidelines definition (ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to sodium restriction and diuretic treatment) 3) Coagulopathy 4) Ongoing infection > Grade 2 according to NCI-current CTCAE . Hepatitis B is allowed if no active replication is present (below 100 IU/mL). Hepatitis C is allowed if no antiviral treatment is ongoing
Known hypersensitivity to the study drug or excipients in the formulation
Decompensated cirrhosis (Child-Pugh > A6)
Prior systemic therapy with oral TKI and/or immunotherapy
Past or concurrent history of neoplasm other than HCC, except for in situ carcinoma of the cervix uteri and/or non-melanoma skin cancer and superficial bladder tumours. Any cancer curatively treated > 3 years prior to study entry is permitted
Recent digestive bleeding associated with portal hypertension (whithin the 3 months prior to inclusion in the study)
Advanced or Metastatic HCC (BCLC C)
Persistent proteinuria of NCI-current CTCAE ≥ Grade ≥ Grade 3
Project of living donor
Pregnant or lactating woman
Curator or guardianship or patient placed under judicial protection
Participation in other interventional research during the study
History within the past 3 months before enrollment of haemorrhage, gastrointestinal perforation, gastrointestinal or non-gastrointestinal fistula
History of aneurism
Hypokalemia, hypomagnesemia and hypocalcemia