Trial Title:
A Clinical Study of Tislelizumab Combined With TACE and Lenvatinib in the Neoadjuvant Treatment of Resectable HCC
NCT ID:
NCT06003673
Condition:
Hepatocellular Carcinoma Resectable
Conditions: Official terms:
Carcinoma
Carcinoma, Hepatocellular
Conditions: Keywords:
hepatocellular carcinoma
resectable
CNLC stage IIa-IIb
neoadjuvant therapy
Tislelizumab
Lenvatinib
Transarterial Chemoembolization (TACE)
Study type:
Interventional
Study phase:
Phase 4
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Combination Product
Intervention name:
neoadjuvant therapy
Description:
The enrolled patients undergo 2 cycles of neoadjuvant therapy, with each cycle consisting
of treatment every 3 weeks. On the first day of the first treatment cycle, conventional
transarterial chemoembolization (TACE) is performed, and concomitant intravenous infusion
of tislelizumab at a dose of 200mg is given, followed by oral administration of
lenvatinib at a dose of 8/12mg once daily. On the first day of the second cycle,
tislelizumab is again administered intravenously at a dose of 200mg, TACE is not
repeated, and lenvatinib treatment is continued. Within 2-4 weeks after the completion of
neoadjuvant therapy, the investigator evaluates the tumor's suitability for surgical
resection based on a comprehensive assessment of imaging results. Subsequently, eligible
patients undergo tumor resection surgery, followed by follow-up for survival and safety
monitoring.
Arm group label:
Neoadjuvant therapy group
Summary:
In order to improve the R0 resection rate, reduce distant metastasis, and lower
postoperative recurrence, there is a growing exploration of surgical treatments for
hepatocellular carcinoma (HCC), including preoperative neoadjuvant therapy and
postoperative adjuvant therapy. This study is a single-arm, prospective, exploratory
clinical trial aimed at evaluating the effectiveness and safety of combining tislelizumab
with transarterial chemoembolization (TACE) and lenvatinib as neoadjuvant therapy for
resectable CNLC stage IIa-IIb HCC patients. The primary research endpoint of this study
is recurrence-free survival (RFS). A total of 20 Chinese HCC patients with stage IIa-IIb
and tumors deemed resectable by the investigator are enrolled in this study. For stage
IIa patients, the inclusion criteria require meeting any of the following: unclear tumor
boundaries, proximity to blood vessels, or suspicious residual margins. The enrolled
patients undergo 2 cycles of neoadjuvant therapy, with each cycle consisting of treatment
every 3 weeks. On the first day of the first treatment cycle, conventional transarterial
chemoembolization (TACE) is performed, and concomitant intravenous infusion of
tislelizumab at a dose of 200mg is given, followed by oral administration of lenvatinib
at a dose of 8/12mg once daily. On the first day of the second cycle, tislelizumab is
again administered intravenously at a dose of 200mg, TACE is not repeated, and lenvatinib
treatment is continued. Within 2-4 weeks after the completion of neoadjuvant therapy, the
investigator evaluates the tumor's suitability for surgical resection based on
comprehensive assessment of imaging results. Subsequently, tumor resection surgery is
performed on eligible patients, followed by survival and safety follow-up for the
patients.
Detailed description:
1. Background
Primary liver cancer is one of the most common malignancies worldwide, ranking sixth
in terms of incidence and third in terms of cancer-related mortality. Hepatocellular
carcinoma (HCC) is the predominant type of primary liver cancer, accounting for
85%-90% of cases. Treatment options for HCC include hepatectomy, transplantation,
local ablation therapy, transarterial chemoembolization (TACE), radiation therapy,
and systemic therapy. Hepatectomy is currently the preferred treatment for HCC, but
the five-year recurrence rate after surgery is high, and the overall survival rate
for early-stage HCC is relatively low. Therefore, improving the prognosis of HCC is
of utmost importance.
In recent years, there has been increasing exploration of surgical treatments for
HCC, including neoadjuvant therapy and adjuvant therapy, to increase the R0
resection rate, reduce distant metastasis, and lower the risk of postoperative
recurrence. Neoadjuvant therapy for HCC refers to interventions such as preoperative
radiotherapy, interventional therapy, targeted therapy, immunotherapy, and portal
vein embolization (PVE) administered to patients with resectable HCC who have a high
risk of recurrence. These interventions aim to reduce liver inflammation, shrink
tumors, and eliminate early-stage microlesions, thereby improving the curative
resection rate and overall survival rate.
However, there is limited research supporting neoadjuvant therapy for HCC, and its
role in HCC treatment remains unclear. Neoadjuvant therapy has shown preliminary
efficacy in various cancers, such as increasing resection rates and preserving
sphincter function in colorectal cancer, demonstrating significant effects in
early-stage non-small cell lung cancer and advanced malignant melanoma, and showing
promise in resectable pancreatic cancer with high-risk factors. Previous
explorations of neoadjuvant therapy for HCC have included hepatic artery
chemotherapy, radiation therapy, and systemic therapy.
With the emergence of immunotherapy and its promising efficacy in advanced liver
cancer, research on immunotherapy as a neoadjuvant treatment has been conducted.
Studies have shown that neoadjuvant treatment with immunotherapy in resectable liver
cancer has achieved significant tumor necrosis and complete pathological responses.
However, current clinical trials have not reached definitive conclusions, and the
role of neoadjuvant therapy in patients with resectable HCC remains controversial.
Therefore, this study aims to evaluate the efficacy and safety of Tislelizumab in
combination with Transarterial Chemoembolization (TACE) and Lenvatinib as
neoadjuvant therapy for patients with resectable CNLC stage IIa-IIb hepatocellular
carcinoma (HCC), with the goal of providing a better treatment strategy to improve
the survival outcomes of these patients.
2. Study Objectives
2.1 Primary Objective:
- To evaluate the recurrence-free survival (RFS) of patients with resectable CNLC
stage IIa-IIb hepatocellular carcinoma (HCC) treated with Tislelizumab in
combination with Transarterial Chemoembolization (TACE) and Lenvatinib as
neoadjuvant therapy.
2.2 Secondary Objectives:
- To evaluate the objective response rate (ORR) of patients with resectable CNLC
stage IIa-IIb HCC treated with Tislelizumab in combination with TACE and
Lenvatinib as neoadjuvant therapy.
- To evaluate the pathological complete response (pCR) rate of patients with
resectable CNLC stage IIa-IIb HCC treated with Tislelizumab in combination with
TACE and Lenvatinib as neoadjuvant therapy.
- To evaluate the major pathological response (MPR) rate of patients with
resectable CNLC stage IIa-IIb HCC treated with Tislelizumab in combination with
TACE and Lenvatinib as neoadjuvant therapy.
- To evaluate the R0 resection rates of patients with resectable CNLC stage
IIa-IIb HCC treated with Tislelizumab in combination with TACE and Lenvatinib
as neoadjuvant therapy.
- To evaluate the overall survival (OS) of patients with resectable CNLC stage
IIa-IIb HCC treated with Tislelizumab in combination with TACE and Lenvatinib
as neoadjuvant therapy.
- To assess the safety (according to NCI-CTCAE v5.0) of patients with resectable
CNLC stage IIa-IIb HCC treated with Tislelizumab in combination with TACE and
Lenvatinib as neoadjuvant therapy.
3. Study Design
This is a single-arm, prospective, exploratory clinical trial aimed at investigating
the effectiveness and safety of Tislelizumab combined with Transarterial
Chemoembolization (TACE) and Lenvatinib as neoadjuvant therapy in approximately 20
patients with resectable CNLC stage IIa-IIb hepatocellular carcinoma (HCC) who have
not received any prior treatment. Patients in CNLC stage IIa must meet one of the
following criteria: unclear tumor margins, proximity to blood vessels, or suspicious
residual margins. The primary endpoint of this study is recurrence-free survival
(RFS), which will be assessed by the investigators based on the intention-to-treat
(ITT) population assessment.
Every effort will be made to ensure that the required tests and procedures outlined
in the protocol are conducted according to plan. However, unforeseen circumstances
may arise that are beyond the control of the investigators, making it difficult to
perform the required assessments. In such cases, the investigators will take all
necessary measures to ensure the safety and well-being of the participants. If a
required assessment cannot be performed as specified in the protocol, the
investigators will document the reasons for this occurrence. Additionally, any
unexpected situations that occur will be promptly reported to the research team.
3.1 Screening Period
The investigators will enroll participants according to the following steps:
3.1.1 Obtain informed consent with the participant's signature before conducting any
study-related procedures.
3.1.2 The principal investigator or designated personnel, who have undergone
appropriate training, will review the inclusion/exclusion criteria to formally
determine the eligibility of participants.
3.2 Treatment Period
During the treatment period, relevant physical examinations, laboratory tests, and
collection of adverse events (AEs) and concomitant medication information will be
conducted. The dispensing, retrieval, and inventory of medications will also be
recorded.
3.2.1 Neoadjuvant Stage
- Tislelizumab: 200 mg, administered intravenously on the first day of each
treatment cycle. Each cycle lasts for 3 weeks, with a total of 2 treatment
cycles. The initial infusion (first day of the first cycle) should be completed
within 60 minutes. If the infusion is well tolerated, subsequent infusions can
be administered within 30 minutes, followed by an additional 2-hour patient
monitoring period.
- Lenvatinib: 8 mg per dose (for weight <60 kg) or 12 mg per dose (for weight ≥60
kg), taken orally once daily until one week before surgery. The medication
should be taken at the same fixed time each day, with or without food. The
tablets should be swallowed whole. Alternatively, the tablet (without opening
or crushing it) can be mixed with one tablespoon of water or apple juice in a
glass to form a suspension. If a dose is missed and cannot be taken within 12
hours, it should be skipped, and the next dose should be taken at the regular
scheduled time.
- TACE: One session of TACE will be performed on the first day of the neoadjuvant
treatment, within the first cycle. The conventional TACE (cTACE) technique will
be used in this study.
3.2.2 Surgical Stage
After completing the neoadjuvant treatment, the feasibility of surgery will be
assessed by the investigator. Surgery will be performed for tumor resection within
2-4 weeks after the neoadjuvant treatment. The investigator and pathology department
will conduct an assessment of neoadjuvant treatment response (MPR and pCR).
3.2.3 Postoperative Stage
After the final treatment, patients will enter the treatment follow-up and safety
monitoring period. Patients who discontinue treatment due to disease progression
should continue to be followed up for their survival. Patients who discontinue
treatment or exit the study for reasons other than disease progression will undergo
tumor assessment every 12 weeks until disease progression, death, study completion,
or intolerable toxicity. The investigator may collect information on the patient's
survival (date of death and cause of death) and other anti-tumor treatments after
the completion of the study by conducting telephone interviews with the patient,
their family members, or local physicians. The details of each survival follow-up
should be accurately recorded in the original medical records. Safety follow-up is
required for all patients within 90 days after the last treatment.
4. Efficacy and Safety Assessment
The ITT population includes all enrolled patients and serves as the primary analysis
population for efficacy. The safety population includes all patients who received at
least one dose of the investigational drugs and will be used for safety analysis.
4.1 Efficacy Assessment
- Recurrence-Free Survival (RFS): The time from the first day of curative surgery to
tumor recurrence or death from any cause.
- Objective Response Rate (ORR): The proportion of participants with the best overall
response (BOR) of complete response (CR) or partial response (PR) assessed by the
investigator according to RECIST v1.1 during the neoadjuvant stage.
- Pathological Complete Response Rate (pCR): The proportion of patients assessed by
the investigator, after completion of neoadjuvant treatment, with no residual tumor
cells in the resected tumor.
- Major Pathological Response Rate (MPR): The proportion of patients assessed by the
investigator, after completion of neoadjuvant treatment, with ≤10% residual viable
tumor cells in the resected tumor.
- R0 Resection Rate: The proportion of patients achieving R0 resection among all
surgical patients.
- Overall Survival (OS): The time from the start of treatment to death from any cause.
4.2 Safety Assessment
Safety will be evaluated by monitoring and recording all adverse events (AEs) and serious
adverse events (SAEs) in terms of their incidence and severity, graded according to
NCI-CTCAE v5.0. Laboratory test results (such as hematology, clinical chemistry, urine
analysis), vital signs, ECOG performance status, and physical examinations will also be
used to assess safety. Descriptive statistics will be used to analyze all safety data in
the safety population.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Participants must voluntarily enroll in this study and provide signed informed
consent.
2. Male or female patients between the ages of 18 and 75 years old.
3. Patients diagnosed with hepatocellular carcinoma (HCC) confirmed by histopathology
or imaging.
4. Chinese liver cancer staging of IIa-IIb with hepatocellular carcinoma considered
resectable by the investigator. For IIa-stage patients, they must meet at least one
of the following criteria: unclear tumor margins, proximity to blood vessels, or
suspicious residual margins.
5. At least one measurable lesion according to the Response Evaluation Criteria in
Solid Tumors (RECIST v1.1) guidelines (measurable lesions with CT scan long diameter
≥ 10 mm or lymph node lesions with CT scan short diameter ≥ 15 mm, and no prior
local treatment such as radiation or cryotherapy).
6. Child-Pugh liver function class A.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
8. No prior systemic treatment for HCC.
9. For HBsAg-positive patients, HBV-DNA < 200,000 IU/ml (106 copies/ml), and receiving
routine antiviral therapy.
10. Expected survival of at least 3 months.
11. Normal major organ function, meeting the following criteria:
- Hematology criteria:
- Hemoglobin (HB) ≥ 90 g/L;
- Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1500/m3);
- Platelet count (PLT) ≥ 75 × 109/L.
- Biochemistry criteria:
- Total bilirubin (TBIL) ≤ 2 × ULN;
- ALT, ALP, and AST ≤ 5 × ULN;
- Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 50 ml/min
(calculated using the Cockcroft-Gault formula: CrCL (mL/min) = [(140 - age) ×
body weight (kg) × F] / (SCr(mg/dL) × 72). Where F=1 for males and F=0.85 for
females; SCr=serum creatinine).
- Coagulation function: International Normalized Ratio (INR) ≤ 2.3.
12. Blood pressure (BP) controlled with a maximum of 3 antihypertensive medications,
defined as BP ≤ 150/90 mmHg at screening, and no changes in antihypertensive
treatment within one week before Cycle 1/Day 1.
13. Doppler echocardiography: Left Ventricular Ejection Fraction (LVEF) ≥ lower limit of
normal (50%).
14. Women of childbearing potential must use reliable contraceptive methods or undergo
pregnancy testing (serum or urine) within 7 days before enrollment, with negative
results, and agree to use appropriate contraceptive methods during the trial and for
8 weeks after the last dose of investigational drugs. For males, they must agree to
use appropriate contraceptive methods during the trial and for 8 weeks after the
last dose of investigational drugs or have undergone surgical sterilization.
Exclusion Criteria:
1. Extrahepatic metastasis of primary liver cancer.
2. Diffuse liver cancer with tumor burden ≥ 50% of liver volume; and/or macrovascular
invasion of the portal vein classified as Type IV; and/or inferior vena cava tumor
thrombosis.
3. Prior treatment with targeted immunotherapy agents, including but not limited to
anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated antigen 4
(anti-CTLA-4) antibodies.
4. Contraindications for Transarterial Chemoembolization (TACE) treatment.
5. Participation in other investigational drug trials within the past 4 weeks.
6. Medical history and comorbidities:1)Active, known, or suspected autoimmune diseases,
including a history of allogeneic organ transplantation, allogeneic hematopoietic
stem cell transplantation, HIV positive history, or acquired immunodeficiency
syndrome (AIDS) history. 2)Severe cardiovascular diseases: Grade II or higher
myocardial ischemia or myocardial infarction, poorly controlled arrhythmia; NYHA
Class III-IV heart failure, or left ventricular ejection fraction (LVEF) < 50% based
on echocardiography. 3)Active infections. 4)Known allergies to components of
Tislelizumab or Lenvatinib. 5)History of substance abuse, alcoholism, or drug
addiction.
7. Ineligibility as determined by the investigator.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
The First Affiliated Hospital of Fujian Medical University
Address:
City:
Fuzhou
Zip:
350000
Country:
China
Status:
Recruiting
Contact:
Last name:
Zhang Zhibo, PhD
Phone:
008618559853003
Email:
wql0211@gmail.com
Start date:
July 1, 2023
Completion date:
July 1, 2025
Lead sponsor:
Agency:
First Affiliated Hospital of Fujian Medical University
Agency class:
Other
Source:
First Affiliated Hospital of Fujian Medical University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06003673
