Trial Title:
TACE Plus HAIC Combined With Regorafenib for Liver Metastasis of Colorectal Cancer Refractory to Standard Treatment Regimens
NCT ID:
NCT06071052
Condition:
Liver Metastasis Colon Cancer
Conditions: Official terms:
Neoplasm Metastasis
Colonic Neoplasms
Liver Neoplasms
Conditions: Keywords:
Liver Metastasis Colon Cancer
Transcatheter arterial chemoembolization
perfusion chemotherapy
Regofinib
Study type:
Interventional
Study phase:
N/A
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
TACE and HAIC Combined With Regorafenib
Description:
TACE and HAIC Combined With Regorafenib for Liver Metastasis of Colorectal Cancer who
failed the second line treatment regimens
Arm group label:
TACE and HAIC Combined With Regorafenib for Liver Metastasis of Colorectal Cancer
Summary:
Liver metastasis is the main reason that affects the survival rates of patients with
colorectal cancer (CRLM), and is also the main cause of death of those patients.
Especially after the failure of first-line or second-line system treatment, the prognosis
of those patients is extremely poor, with the median OS of only 3.5 months. Even in
combination with molecular targeted drugs such as cetuximab or bevacizumab, the median
tumor-free survival period is only 4.8-6.8 months, and OS is only 11-15 months. When they
have disease progression, treatment is currently a difficult clinical problem. Regofinib
is a new targeted drug for the third-line treatment of advanced colorectal cancer in
recent years. However, in the prospective multicenter clinical study, compared with the
placebo group, the extended OS is only 1.4 months, which is not so satisfactory. How to
improve the survival of these advanced patients with drug resistance is an important
clinical problem to be solved urgently. Minimally invasive local treatment may be a
promising way to solve this problem. Transcatheter arterial chemoembolization (TACE) and
hepatic artery infusion chemotherapy (HAIC) are currently the most widely used methods in
clinical practice. In theory, TACE combined with HAIC can control small metastasis and
embolic residual lesions. The combination of TACE and HAIC can improve the curative
effect. Whether the combination of TACE, HAIC and Regofinib can be expected to achieve
the effect of 1+1+1>3 in CRLM patients who have failed the previous second-line
chemotherapy remains unknown. Therefore, the purpose of this study is to explore the
safety and clinical efficacy of irinotecan-loaded drug-eluting beads-TACE (DEBIRI-TACE)
combined with HAIC and Regofinib in the treatment of patients with CRLM who failed
standard treatment regimens.
Detailed description:
Colorectal cancer is one of the most common tumors worldwide, with an annual incidence
rate ranking the first in gastrointestinal tract tumors and the third in all malignant
tumors in Europe and the United States, the second in gastrointestinal tract tumors and
the fourth in all malignant tumors in China, featuring an continuously increasing
incidence rate year by year. The liver is the most common site of hematogenous metastasis
in colorectal cancer, and about 50% of patients develop liver metastasis during the
disease process, at least over 60% of which will die of liver metastasis. Related
epidemiological studies have shown that about 25% of colorectal cancer patients are
diagnosed with liver metastasis, while another 15% to 25% of patients develop liver
metastasis after radical primary lesions, and the vast majority (80%-90%) of liver
metastases can't obtain curative resection. Liver metastasis is the main influencing
factor of survival and the leading cause of death in CRC patients. The median survival of
the untreated patients with focal liver metastases was only 6.9 months, and the 5-year
survival rate of the unresectable patients reached nearly 0.
Surgical resection of primary lesions and liver metastases is the preferred method for
curing colorectal liver metastases (CLRM), but only 10%-20% of patients are considered
suitable for surgical resection of metastasis at initial diagnosis. The standard
first-line chemotherapy for FOLFOX or XELOX was used for unresectable CLRM, and the
median PFS was about 7.0-12.3 months, while the OS was about 15.0-29.8 months. However,
after the failure of the first-line or second-line system treatment, the patient
prognosis was extremely poor, with a median natural survival of only 3.5 months. Even
with molecular targeted drugs such as cetusimab or bevacizumab, the median PFS was only
4.8-6.8 months, while the OS was only 11-15 months. Treatment for these patients remains
the existing clinical difficulty. Regefenib is a new targeted drug for third-line
treatment of advanced colorectum, which, as a small-molecule multi-target kinase
inhibitor, affects angiogenesis, proliferation, and microenvironment by inhibiting tumor
angiogenesis, proliferation, and other targets such as VEGFR1, VEGFR2, VEGFR3, TIE2, Kit,
RET, PDGFR, FGFRl, etc. It is now the treatment method recommended for the treatment of
the third-line and above CLRM in the major domestic and foreign guidelines such as the
National Comprehensive Cancer Network (NCCN), the European Society of Medical Oncology
(ESMO), and the Chinese Clinical Cancer Congress (CSCO), etc. The prospective multicenter
clinical study CORRECT trial compared the efficacy of regorofenib and placebo in patients
with metastatic colorectal cancer above the second line, with the median OS in the
regorofenib group significantly better than that in the placebo group (6.4 months vs. 5.0
months, HR=0.77), which established the recommended position of regorofenib in the
third-line CLRM. However, the extended OS was also only 1.4 month, which was not
satisfactory. To this end, improvement of the survival rate of such advanced
drug-resistant CLRM patients becomes an important clinical issue that requires immediate
attention.
Timely addition of minimally invasive local treatment is considered a promising way to
solve this problem, and the interventional route of chemotherapy and embolization is one
of the most used clinical methods. Given that liver metastases of colorectal cancer are
mainly supplied by the hepatic artery (90% to 95%), while the normal liver parenchyma is
mainly provided by the portal vein, an anatomical basis and clinical basis are provided
for the local intervention of the transhepatic artery, including transcatheter arterial
chemoembolization (TACE), and hepatic artery infusion chemotherapy (HAIC), etc. These
attempts can effectively control the intrahepatic tumor load, and achieve the goal of
prolonging patient survival, which have been widely used in clinical practice. The 2020
edition of the Chinese Guidelines for the Diagnosis and Comprehensive Treatment of Liver
Metastasis in Colorectal Cancer clearly states that HAIC or TACE can be used on
refractory patients with liver metastases mainly, large tumor load and insignificant drug
treatment effect, or those who cannot tolerate systemic treatment [4]. Both the 2016 ESMO
and 2021 NCCN colorectal guidelines also stipulate that TACE or HAIC can be performed on
CRLM patients with poor chemotherapy efficacy in conditional hospitals, or used for
clinical research. Among them, irinotecan-loaded drug-eluting beads-TACE (DEBIRI-TACE) is
a classic interventional treatment for CLRM, which can embolize the tumor blood vessels,
block the tumor blood supply, and make the slow and continuous release of
chemotherapeutic drugs in the tumor microcirculation, thereby improving the curative
effect. Several prospective studies have demonstrated the superiority of DEBIRI-TACE
efficacy to systemic chemotherapy or conventional lipiodol TACE on CLRM patients without
increasing the toxic side phase. For patients with bowel cancer liver metastases who have
failed standard chemotherapy, the implementation of DEBIRI-TACE achieves a median PFS up
to 5 months and a median OS up to 8 months. DEBIRI-TACE is even effective and safe for
colorectal cancer liver metastases subject to the failure of irinotecan systemic
chemotherapy, which provides basis for CLRM above the second line.
However, it is difficult for TACE to achieve complete tumor necrosis as a non-radical
treatment mode, and its induced ischemic damage will lead to the upregulation of
angiogenesis-related molecules, thus subsequently promoting tumor growth, invasion, and
metastasis. In this case, the combination of regorofenib with TACE can both enhance the
tumor reduction effect and inhibit the TACE-induced angiogenic effect as well as tumor
growth by complementing each other. In addition, it was reported that the adverse
reactions caused by regofinil were mainly fatigue, hand and foot syndrome, and diarrhea,
etc., while the abdominal pain, nausea, vomiting and fever above the adverse reactions
caused by DEBIRI-TACE were the most common. Adverse effects of these two approaches had
no obvious overlapping effects, indicating the safety and feasibility of the combination
of TACE with Regofenib, which was confirmed in a recently-published retrospective study.
An analysis over 76 CLRM patients who had failed previous chemotherapy found that
compared with single regorofenib monotherapy, DEBIRI-TACE combined with single achieved a
higher local response rate (ORR 35.3% vs 7.1%, P = 0.002; DCR 76.5% vs 47.6%, P = 0.011),
and a longer median PFS (7.6 vs 4.1 months, P <0.001) and OS (15.7 vs 9.2 months, P
<0.001), and the side reaction was equivalent (P> 0.05). The above results further
validate the important potential of local interventional therapy combined with regofenib
in the posterior treatment of CRLM. It is an important clinical problem worth further
exploration to further improve the curative effect on this basis for the benefit of more
patients.
Different from the TACE vascular embolization effect, HAIC has the advantage to directly
deliver high doses of chemotherapeutic drugs to the blood supply branch of the hepatic
artery tumor, which can increase the local drug concentration and reduce the systemic
side reactions, gradually making it an effective treatment for unresectable CRLM.
Besides, it has been shown that even after the failure of systemic chemotherapy regimen,
the same chemotherapy regimen is still effective, and the overall survival can be
extended to 7.7-19 months. In a phase II clinical study from Sloan Catherine Cancer
Memorial Hospital, 65% of the enrolled CRLM patients were on second-or third-line
therapy, with an ORR of 76% with 5-Fu and systemic chemotherapy with or without
bevacizumab, and about 47% of initially-unresectable patients were converted to
resectable ones, with a median OS of 38 months. In a European multicenter study (OPTILIV)
published in 2016, all enrolled patients received overline systemic therapy and combined
systemic cetuximab with arterial perfusion (oxaliplatin, irinotecan and 5-Fu), and 29.7%
of these patients were converted to resectable ones, with a median OS of 35.2 months
after resection. The above studies suggest that HAIC can still obtain a high response
rate and resection rate as a powerful complementary method after systemic treatment
failure.
Theoretically, HAIC combined with TACE can control small metastases and embolic residual
lesions, and their combination can complement each other and improve the efficacy.
Indeed, as early as 2014, Japanese scholars had reported several cases of TACE combined
with HAIC for successfully treating liver metastases of gastric cancer. Recently, this
interventional combination model has also been successively reported in primary liver
cancer. A study involving 83 patients with middle and advanced HCC reported that the TACE
and local response rate, conversion resection rate, PFS and OS in the HAIC group were
better than the TACE group alone, and had a comparable grade 3 / 4 adverse reaction rate;
another study also demonstrated the efficiency and feasibility of TACE combined with HACI
and sorafenib in advanced liver cancer, with more than 50% of the 66 patients ith HCC
achieving a PFS for 6 months, and the side reactions could be tolerated. However, in
CLRM, only one retrospective study explored the efficacy of 162 patients receiving TACE
and HAIC after chemotherapy failure, and found that the total median OS in the combined
treatment group could be up to 29.5 months (calculated from the definite diagnosis) and
15.6 months (calculated from the first TACE and HAIC), with a DCR reaching 75%. For
severe adverse reactions, 15 patients (9.26%) had grade 3 / 4 myelosuppression, and one
(0.62%) was subject to liver abscess, having recovered after drainage. The above evidence
suggests the important potential of the TACE combined with HAIC in the posterior
treatment of CRLM. Further explorations should be made upon the efficiency of the
combination of the TACE, HAIC and regofenib treatment in CRLM patients subject to
previous second-line chemotherapy failure, as well as the achievement of the effect of 1
+ 1 + 1> 3.
CalliSpheres drug-eluting beads is a new drug-carrying microsphere independently
developed with independent intellectual property rights in China, and has obtained the
national invention patent. The product is produced with water-soluble and non-toxic
polymer biomaterials with no side effect after chemical modification, featuring a
microsphere shape uniform in size, smooth surface, good blood suspension, variable
elasticity and compressibility, high drug loading speed, large load, long slow release
time, the capability of absorbing a variety of chemotherapy drugs, and many other
characteristics. The instructions for using CalliSpheres include loading irinotecan
methods and indications, and the treatment of CLRM has been reported in some clinical
studies.
This study aims to explore the clinical efficacy and safety of CalliSpheres drug-eluting
beads loaded with irinotecan combined with HAIC and Regorafenib in the treatment of liver
metastasis in colorectal cancer after previous chemotherapy failure, so as to find a more
effective posterior treatment plan for liver metastasis in intestinal cancer.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Patients aged 18-75 years old, gender unlimited;
2. Patients with liver metastasis of colorectal cancer by pathological histology or
clinical diagnosis (refer to the Guidelines for the Diagnosis and Comprehensive
Treatment of Liver metastasis of Colorectal Cancer, 2016 Edition), those who were
mainly exposed to liver metastasis with large tumor load and suffered from no clear
extrahepatic metastasis;
3. Patients with a liver area tumor no more than 5 tumor nodules, and a nodule size no
more than10cm;
4. Patients subject to the failure of previous chemotherapy regimen containing
irinotecan or oxaliplatin after at least six cycles of systemic chemotherapy; they
cannot undergo surgery or refuse surgery;
5. Patients with liver tumor who did not receive interventional treatment (TACE,
ablation, iodine particle treatment, etc.) within one year;
6. Patients with an expected survival period longer than 3 months;
7. Patients with favorable liver function (7 points for Child-Pugh A or B);
8. Patients with a physical fitness ECOG no more than one point;
9. Patients who understood and signed the Informed Consent Form.
Exclusion Criteria:
1. Patients with distant metastases except the liver;
2. Patients subject to the treatment of TACE, ablation or iodine particles within one
year;
3. Patients with obvious artero / venous fistula and cancer plugs in the main portal
vein;
4. Patients who had suffered from or were currently developing other malignant tumors
(except for the cured basal or squamous cell skin carcinoma or cervical carcinoma in
situ);
5. Patients whose white blood cells were less than 3,000 cell / mm3, or platelet count
less than 50,000 / mm3;
6. Patients subject to renal insufficiency (creatinine> 2 mg/L);
7. Patients whose AST and / or ALT was / were more than 5 times the upper limit of
normal;
8. Patients with poor coagulation function, an INR larger than 1.5, or currently
subject to anticoagulant therapy or known hemorrhagic disease;
9. Patients with a history of major disease with heart, kidney, bone marrow, or lung,
and central nervous system involvement;
10. Patients requiring antibiotic treatment due to recent infections;
11. Patients subject to comorbidities or social environment that could prevent them from
following the study plan or even endanger their safety.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
the first affiliated hospital, Sun-Yat sen university
Address:
City:
Guangzhou
Zip:
510000
Country:
China
Start date:
November 1, 2023
Completion date:
November 1, 2024
Lead sponsor:
Agency:
First Affiliated Hospital, Sun Yat-Sen University
Agency class:
Other
Source:
First Affiliated Hospital, Sun Yat-Sen University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06071052
