Trial Title:
Fruquintinib With or Without HAI-FOLFOX for Refractory Colorectal Cancer
NCT ID:
NCT06441565
Condition:
Colorectal Cancer
Conditions: Official terms:
Colorectal Neoplasms
Oxaliplatin
Fluorouracil
Conditions: Keywords:
Colorectal cancer
Hepatic Arterial Infusion Chemotherapy
Randomized Clinical Study
Progression Free Surivival
Safety Profile
Study type:
Interventional
Study phase:
Phase 2/Phase 3
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Participants will be randomly assigned in a 1:1 ratio to either the fruquintinib
monotherapy group (control group) or the fruquintinib plus HAI-FOLFOX treatment group
(experimental group)
Primary purpose:
Treatment
Masking:
None (Open Label)
Masking description:
Open label
Intervention:
Intervention type:
Drug
Intervention name:
Fruquintinib
Description:
A treatment cycle of 4 weeks, with 4 mg orally once daily for 3 weeks, followed by a
1-week break
Arm group label:
Fruquintinib monotherapy group (control group)
Arm group label:
Fruquintinib plus HAI-FOLFOX treatment group (experimental group)
Other name:
Fruzaqla
Intervention type:
Drug
Intervention name:
Fluorouracil
Description:
2.8 g/m² (400mg bolus + 2.4g/m² continuous infusion) given every 2 weeks through hepatic
arterial infusion
Arm group label:
Fruquintinib plus HAI-FOLFOX treatment group (experimental group)
Other name:
5-FU
Intervention type:
Drug
Intervention name:
Oxaliplatin
Description:
85 mg/m² given every 2 weeks through hepatic arterial infusion
Arm group label:
Fruquintinib plus HAI-FOLFOX treatment group (experimental group)
Other name:
L01XA03
Summary:
The objective of this clinical trial is to evaluate the efficacy and safety of combining
fruquintinib with hepatic artery infusion (HAI)-FOLFOX in the treatment of refractory
colorectal cancer with liver metastasis.
Detailed description:
Colorectal cancer (CRC) is the third most common cancer globally, accounting for
approximately 10% of all cancer cases, and is the second leading cause of cancer-related
deaths worldwide. Significant advancements have been made in treating metastatic
colorectal cancer (mCRC) over the past two decades, primarily due to continuous
improvements in first-line treatment regimens. However, treatment options are relatively
limited for patients with mCRC who do not respond to standard first-line treatments or
who develop chemotherapy resistance. Approved second-line treatments include regorafenib,
fruquintinib, and TAS-102, but their reported efficacy and overall survival (OS) rates
are not ideal.
Fruquintinib is a novel small-molecule anticancer drug classified as a quinazoline,
acting as a potent and highly selective inhibitor of vascular endothelial growth factor
receptor (VEGFR) tyrosine kinase. Preclinical and clinical studies conducted in China and
the United States have demonstrated significant anticancer activity of fruquintinib in
solid tumors. The prospective randomized controlled clinical study FRESCO-2 showed that
fruquintinib significantly improved median OS (7.4 months vs. 4.8 months; P < 0.001) and
median progression-free survival (PFS) (3.7 months vs. 1.8 months; P < 0.001) compared to
the placebo group. These results are consistent with previous FRESCO study findings.
Although these studies provide strong evidence for fruquintinib in treating refractory
mCRC patients, the overall improvement in survival is limited, with a 6-month PFS rate of
only about 20% (FRESCO: 19.3%, FRESCO-2: 22.7%). Thus, there is a need for new
second-line treatment options to further enhance efficacy and survival in refractory mCRC
patients.
Recent studies have shown that combining fruquintinib with paclitaxel as a second-line
therapy demonstrates good efficacy and safety in advanced gastric cancer patients.
Additionally, fruquintinib combined with sintilimab has shown some antitumor activity,
particularly in mCRC patients with pMMR status. Therefore, combining fruquintinib with
other anticancer drugs might offer a new treatment direction for refractory mCRC.
Liver metastasis is the most common form of metastasis in colorectal cancer. Normal liver
tissue primarily receives blood supply from the portal vein, while colorectal cancer
liver metastases mainly receive blood from the hepatic artery. This dual blood supply
characteristic has led to the development of hepatic artery infusion (HAI), a treatment
method delivering high concentrations of chemotherapy drugs directly to liver metastases,
minimizing toxicity to normal liver tissue and surrounding organs. For mCRC patients with
chemotherapy resistance and liver-dominant metastasis, treatments such as yttrium-90
resin microsphere selective internal radiation therapy (Y-90 SIRT) are recommended by
NCCN guidelines, although Y-90 SIRT is not yet widely available domestically.
Fluorouracil (5-FU) and floxuridine (FUDR) are the most commonly used drugs for hepatic
artery infusion chemotherapy (HAIC), with high first-pass metabolism rates and short
half-lives, suitable for HAI. Studies have reported that HAIC combined with systemic
chemotherapy shows high efficacy (76%) and a conversion surgery rate of 47% in mCRC
patients who have undergone multiple lines of treatment. Cercek et al. found that mCRC
patients resistant to at least three standard systemic treatments (n = 57) benefited from
HAI-FUDR, with partial response (PR) and stable disease (SD) rates of 33% and 54%,
respectively. However, many countries, including China, no longer produce FUDR
injections, necessitating the search for alternative drugs or combinations for HAIC.
Compared to systemic oxaliplatin chemotherapy, hepatic artery infusion chemotherapy with
oxaliplatin has a high hepatic extraction rate of 0.47 and good safety. A phase II
clinical study using oxaliplatin HAIC combined with intravenous 5-FU as first-line
treatment showed an objective response rate (ORR) of 64% and a median OS of 27 months in
patients with unresectable CRLM. Another study by the same team found that oxaliplatin
HAIC had a disease control rate of 87% (n = 39) in CRLM patients who had previously
received FOLFIRI or FOLFOX treatments, with 62% achieving partial response, suggesting
that oxaliplatin-based HAIC could overcome resistance to previous oxaliplatin-containing
systemic therapies. Due to these promising results, several prospective randomized
clinical studies are currently underway, such as the phase II SULTAN study investigating
oxaliplatin HAIC combined with systemic FOLFIRI as salvage therapy in patients with
unresectable localized mCRC after systemic chemotherapy induction. Recent retrospective
studies and randomized clinical trials have confirmed that HAI-FOLFOX alone or in
combination with other drugs significantly improves the prognosis of patients with
advanced hepatocellular carcinoma. Our previous retrospective analysis of 21 patients
with recurrent, unresectable CRLM after multiple lines of treatment, who received
oxaliplatin + 5-FU (FOLFOX) or FUDR HAIC with or without systemic chemotherapy, showed an
ORR of 28.6%, with 7 patients successfully undergoing conversion surgery. The median PFS
was 6.3 months, with a 6-month PFS rate of 61.9%. However, due to the limited sample size
and retrospective design of our study, caution is needed when generalizing these results.
To address the limitations of previous studies and provide more robust evidence, this
prospective randomized clinical study will investigate the synergistic effects of
combining fruquintinib with HAI-FOLFOX. The aim is to determine whether this combination
improves the efficacy in CRLM patients who have progressed after standard systemic
chemotherapy compared to fruquintinib monotherapy. By systematically observing a larger
patient sample, we hope to understand the potential advantages of this treatment regimen
in improving PFS, ORR, and OS. This prospective study will provide valuable insights into
the potential clinical benefits of fruquintinib combined with HAI-FOLFOX, paving the way
for new treatment strategies and advancing personalized treatment for patients with
refractory metastatic colorectal cancer.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Aged between 18 and 75 years.
- Histologically confirmed colorectal adenocarcinoma.
- Radiologically or pathologically confirmed liver metastasis.
- At least one measurable lesion (per RECIST v1.1 criteria).
- No extrahepatic metastasis confirmed by CT, MRI, or PET/CT (if necessary). Patients
with minimal extrahepatic metastatic burden (defined as the presence of lung
metastasis and/or lymph node metastasis with lung lesion diameter not exceeding 1
cm, and lymph node metastasis with the longest diameter less than 2 cm) can be
included.
- Disease progression within 3 months or intolerance to standard treatment with
fluoropyrimidine, irinotecan, oxaliplatin combined with targeted therapy (including
bevacizumab and cetuximab (RAS/BRAF wild-type)), with previous oxaliplatin-induced
neurotoxicity < Grade 2.
- Normal hematologic function (platelets >90×10^9/L; white blood cells >3×10^9/L;
neutrophils >1.5×10^9/L).
- Serum bilirubin ≤1.5 times the upper limit of normal (ULN), transaminases ≤5 times
ULN, alkaline phosphatase ≤2.5 times ULN, no ascites, coagulation function:
prothrombin time (PT) ≤1.5 ULN; international normalized ratio (INR) ≤1.5 ULN;
activated partial thromboplastin time (APTT) ≤1.5 ULN, albumin ≥35 g/L.
- Child-Pugh grade A liver function.
- Serum creatinine less than ULN, or calculated creatinine clearance >50 ml/min (using
Cockcroft-Gault formula).
- ECOG performance status 0-1.
- Expected survival >3 months.
- Signed written informed consent.
- Willing and able to undergo follow-up until death or study completion/termination.
Exclusion Criteria:
- Severe arterial embolism.
- Bleeding tendency or coagulation disorders.
- Hypertensive crisis or hypertensive encephalopathy.
- Severe uncontrolled systemic complications such as infection or diabetes.
- Clinically significant cardiovascular diseases such as cerebrovascular accident
(within 6 months prior to enrollment), myocardial infarction (within 6 months prior
to enrollment), uncontrolled hypertension despite appropriate medical therapy,
unstable angina, congestive heart failure (NYHA Class 2-4), or arrhythmias requiring
medication.
- History or physical examination indicative of central nervous system diseases (e.g.,
primary brain tumors, uncontrolled seizures, any history of brain metastasis or
stroke).
- Other malignancies within the past 5 years (except for radically treated basal cell
carcinoma of the skin and/or carcinoma in situ of the cervix).
- Received any investigational drug treatment within 28 days prior to the study.
- Residual toxicity from previous chemotherapy (excluding alopecia), such as
peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0), if considering an
oxaliplatin-containing regimen.
- Allergy to any of the study drugs.
- Pregnant or breastfeeding women.
- Women of childbearing potential not using or refusing to use effective non-hormonal
contraception (intrauterine device, barrier method combined with spermicide, or
sterilization) or men with reproductive potential.
- Inability or unwillingness to comply with the study protocol.
- Presence of any other diseases, functional impairment due to metastatic lesions, or
findings on physical examination suggesting a contraindication to the use of the
study drugs or putting the participant at high risk for treatment-related
complications.
Gender:
All
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Sun Yat-sen University Cancer Center
Address:
City:
Guangzhou
Zip:
510060
Country:
China
Status:
Recruiting
Contact:
Last name:
Yu-hong Li, MD, Ph D
Phone:
87342487
Phone ext:
020
Email:
liyh@sysucc.org.cn
Investigator:
Last name:
Yu-hong Li, MD, Ph D
Email:
Principal Investigator
Start date:
May 24, 2024
Completion date:
December 30, 2029
Lead sponsor:
Agency:
Sun Yat-sen University
Agency class:
Other
Source:
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/NCT06441565
