Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT04997850 |
| Other study ID # |
311576 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2020 |
| Est. completion date |
December 1, 2024 |
Study information
| Verified date |
May 2022 |
| Source |
West China Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
We adopted the prospective cohort study to compare the safety and efficacy of Transarterial
Chemoembolization (TACE) + Lenvatinib + Programmed Cell Death Protein 1 (PD-1) Antibody in
the treatment of advanced unresectable liver cancer.The purposes of our study include：1.
Primary objective: To compare the safety and efficacy of TACE combined with Lenvatinib and
PD-1 antibody versus TACE alone in the conversion-resection of patients with advanced
unresectable hepatocellular carcinoma.2. Secondary objective: To compare the long-term
outcome of TACE combined with Lenvatinib and PD-1 antibody versus TACE alone for patients
with advanced unresectable hepatocellular carcinoma.
Description:
Hepatocellular carcinoma (hepatocellular carcinoma,HCC,) accounts for 85% to 90% of primary
liver cancer. Worldwide, there are more than 700000 new cases of liver cancer every year, 55%
of which are concentrated in China, which is the fourth most common malignant tumor and the
third leading cause of death in China. More importantly, the onset of liver cancer is hidden,
and 70% to 80% of patients with liver cancer are in the middle and advanced stage when they
are first diagnosed, so they lose the opportunity for surgical treatment. Therefore, liver
cancer seriously affects the life and health of the people. For these unresectable middle and
advanced liver cancer, that is, Barcelona stage (barcelona clinic liver cancer,BCLC) stage C,
BCLC and the European Association for the study of liver Diseases ((European Association for
the Study of Liver Diseases)) recommended transarterial chemoembolization (transarterial
chemoembolization,TACE) and systematic treatment, respectively. However, a number of clinical
studies have shown that the prognosis of patients with advanced liver cancer who underwent
surgical resection is significantly better than that of TACE or systemic therapy alone.
Therefore, how to convert unresectable liver cancer into resectable liver cancer has always
been a hot issue in clinical research.
Hepatectomy is to reduce the tumor load and tumor stage through some or several treatments,
so that unresectable liver cancer can become resectable liver cancer and tumor resection.
There are two purposes of translational therapy: one is that translational therapy can reduce
tumor size, reduce tumor stage and improve its biological characteristics; the other is that
translational therapy can select tumors with good biological characteristics. In 1977, Shafer
et al reported that a single unresectable hepatoblastoma was successfully resected after
radiotherapy and chemotherapy, and first mentioned the concept of liver cancer transformation
therapy. Subsequently, sitzmann, Tang and fan reported the use of 131I or 90Y labeled anti
ferritin antibody, TACE and TACE in the treatment of unresectable liver cancer. Finally, 8%
to 18% of HCC patients underwent transformation resection. To be sure, the combination of
multiple ways of transformation therapy can improve the success rate of transformation and
prolong the survival of patients. But these studies are retrospective, the sample size is
small, and the treatment plan is lack of unity. In addition, with the continuous emergence of
targeted drugs and immune checkpoint blocking therapy (such as programmed death receptor-1,
PD-1), the treatment mode of liver cancer has changed, and the success rate of transformation
and resection may also be improved. Therefore, a prospective clinical study is urgently
needed to explore the safety and effectiveness of hepatectomy in the new era of molecular
targeted drugs and immunotherapy.
The treatment of liver cancer transformation includes local treatment and systemic therapy.
The former includes TACE, transcatheter embolization, radiofrequency ablation, percutaneous
alcohol injection, etc., among which TACE is the most commonly used local treatment. Fan and
other scholars analyzed 65 patients with TACE after operation for liver cancer: the diameter
of median tumor decreased from 9.9cm to 3.7cm, 35.9% (14/39) patients recovered AFP level,
and the 1-year, 3-year and 5-year survival rate of patients were 80%, 65% and 56%,
respectively. However, the pathological findings showed that 83.1% (54/65) of the tumors
still failed to complete necrosis. Obviously, TACE is difficult to achieve complete necrosis
of tumor as a non radical treatment. Moreover, the lack of 4 blood damage caused by TACE can
induce the up regulation of related molecules (such as vascular endothelial growth factor
(VEGF) which can promote the growth, invasion and metastasis of tumor. Therefore, TACE
combined with antiangiogenic drugs can theoretically inhibit the angiogenesis and tumor
growth induced by TACE, and TACE can reduce tumor effect or permit sensitization of
antiangiogenic drugs. Solafeni and lumbotinib are first-line systemic therapy drugs for
advanced liver cancer patients approved by FDA and CFDA. As a multi-target receptor tyrosine
kinase inhibitor (TKI), they mainly inhibit VEGF receptor-1,2,3, FGF receptor-1,2,3,4, PDGFR
α, RET and kit, thus inhibiting the proliferation of tumor cells, inducing apoptosis and
playing an anti angiogenesis role. However, compared with solafeni, the binding of lumbotini
with target molecules has stronger affinity. Based on an open label, multicenter, phase III
non inferior effect clinical study, the results showed that the median survival time (13.6
months vs. 12.3 months) of the patients with liver cancer was the same as that of solafeni
group, but the progression time (9.2 months vs. 3.6 months) and objective remission rate
(24.1% vs. 9.2%) were better than those in the solafeni group. Therefore, TACE combined with
lumbotinib may have better clinical outcomes.
Immune checkpoint blocking therapy may enhance the immune response induced by local
treatment. TACE and other local treatment can make the body produce immune response. Local
treatment leads to tumor cell death, apoptosis (non-cell necrosis) induces specific immunity
of tumor, such as the release of calcium net protein and other endoplasmin on the cell
surface, ATP secretion during the apoptosis and foaming stage, and the release of high
mobility group box associated with cell death of non-histone chromatin group 1 1. HMGB1)
promotes the collection, activation and entry of dendritic cells into the tumor
microenvironment. The tumor antigen of tumor cells is phagocyted and the best antigen is
presented to T cells. This process is called immunogenic cell death (ICD). Adriamycin
(epirubicin, doxorubicin) as the most commonly used chemotherapeutic agent of TACE can
enhance the immunogenicity of ICD. Therefore, TACE has been shown to promote ICD and induce
tumor associated antigen-specific reactions. Ni Quanfa et al. Found that the levels of CD3 +,
CD4 +, CD4 + / CD8 + increased significantly at 3 and 4 weeks after TACE treatment. Liao Juan
and other researchers found that TACE can correct the low immune function of patients with
HCC and make them partially recover. Kazumasa hiroishi and others studied 20 patients with
HCC receiving TACE and RFA respectively. 80% of patients produced tumor specific antibody and
cd8+ immune response one month later. Lakshmana ayaru et al. Found that APF specific CD4 + T
cells increased after HCC embolization. Immune checkpoint blockade refers to blocking the
inhibitory receptors or ligands on the surface of T cells, such as PD-1 / PD-L1, CTLA4 and
Vista, to partially reverse T cell failure and improve tumor T cell response. This innovative
treatment has been verified in a variety of solid tumors. Sangro et al. Showed that local
treatment combined with immune checkpoint blocking therapy is safe and effective in patients
with liver cancer. Moreover, TACE combined with immune checkpoint blocking therapy can
further enhance the anti-tumor immunity without overlapping toxicity. Subsequently, a large
number of clinical trials, such as nct03572582, nct03383458, nct03397654, were carried out
worldwide to evaluate the efficacy of local treatment combined with immune checkpoint
blocking therapy in patients with liver cancer.
In conclusion, current studies have shown that transformation therapy can benefit patients
with unresectable HCC, but there are still some problems, such as low success rate of
transformation, limited treatment options and so on. However, the new first-line drug for
liver cancer is synergistic with TACE, and immune checkpoint blocking therapy may enhance the
immune response induced by TACE. Therefore, this study is to compare the success rate of TACE
combined with lenvastinib and sindilimab in the treatment of advanced unresectable liver
cancer, and to explore the feasibility of the combined regimen in the treatment of liver
cancer.
The clinical trial was monitored and audited by Ethics Committee on biological research, West
China Hospital of Sichuan University.We will arrange special personnel in charge to compare
the research data with the electronic medical records of West China hospital to ensure data
consistency.The indexes we included refer to World Health Organization drug dictionary,
MedDRA.The patients included in this clinical study were unresectable hepatocellular
carcinoma patients. According to the existing guidelines, local treatment (such as TACE) and
/ or systemic treatment (lenvastinib) were the preferred treatment. Other treatment options
include other targeted drugs (sorafenib), radiotherapy, chemotherapy and traditional Chinese
medicine.In addition to regular follow-up and recording of the above examination results,
patients undergoing transformation resection also need to be followed up and recorded in
detail the postoperative combined treatment (radiotherapy, chemotherapy, immunotherapy,
traditional Chinese medicine treatment) and combined medication (anti hepatitis B virus
drugs, interferon, thymosin, other immunity enhancing drugs, Chinese patent medicine) and so
on The starting and ending date, dosage and frequency of medication were analyzed. For the
patients with failure of transformation resection, whether in the experimental group or the
control group, they were still followed up every 3-4 months until the end of the event or the
end of the trial. During each follow-up, the subjects, their family members or local doctors
were asked by telephone or on-site visit. The window was opened for 10 days to collect the
relapse / death (relapse / death date and cause of death) and the combined treatment
information after the study treatment. Each survival follow-up should be recorded in the
follow-up table.71 people are expected to be included in the experimental group and the
control group, and the lost follow-up rate is less than 20%。Whether it is related to the
research measures or not, any adverse medical event that is related to any medical measure in
the study, unexpected, and adverse medical events are adverse events (AE). All observed or
actively provided AE, whether caused by any study group or research measure, shall be
recorded on AE page of pathological report. Serious adverse events shall be reported to
ethics and relevant health administrative departments within 24 hours, and timely diagnosis
and treatment shall be given.
The main researchers organize relevant training to ensure the research specifications are
carried out, the filling of case report form or research record form and other reports follow
GCP principles and research programs. TACE treatment for all patients is the responsibility
and implementation of Professor luwusheng, liver surgery. The patients purchased the drug by
themselves, and the patients actively recorded the drug taking cards during the drug
administration. The silimab is kept by GCP center and is provided to patients free of charge.
All data and treatment must be verifiable: in order to ensure the reliability of the study
data, all observations and findings should be verifiable. Quality control will be used in
every stage of the study to ensure the reliability of all data and the accuracy of the
research procedure. The main investigator should ensure that the researchers comply with the
test plan, confirm the accuracy of the data and the completeness of the record report, and
ensure that informed consent from all subjects is obtained before the study begins. Any
breach or deviation shall be reported to the ethics committee in a timely manner. If
necessary, the research team will formulate standard operation procedures, and implement
quality control procedures in all links of research and data processing to ensure the
specification and reliability of research implementation and data operation.The clinical
research will formulate corresponding data security monitoring plan according to the risk.
All adverse events were recorded in detail, properly handled and tracked until they were
properly resolved or stable, and serious adverse events and unexpected events were timely
reported to ethics committee, competent department, sponsor and drug regulatory department
according to regulations; main researchers conducted cumulative review on all adverse events
on a regular basis, and convened a meeting of researchers to assess the risk of the study
when necessary And benefit from it; Statistical analysis was performed by a specially
assigned person (blind method). Statistical software SPSS V16.0 was used to analyze the data.
The continuous variables were analyzed by unpaired Student's t test or Mann Whitney U test.
The counting data were analyzed by chi square or Fisher's exact test. P < 0.05 was considered
to be statistically significant.
