FULIRI Plus Targeted Therapy for First-line Conversion Therapy of Colorectal Cancer Liver Metastases.

Official title

A Phase II Clinical Study of FULIRI Regimen Chemotherapy Combined With Targeted Therapy for First-line Conversion Treatment of Colorectal Cancer Liver Metastases.

Overview

This study is a single-center, prospective, randomized, single-arm phase II clinical trial designed to evaluate the safety and efficacy of FULIRI chemotherapy regimen combined with targeted therapy (bevacizumab/cetuximab) as first-line conversion therapy for colorectal cancer with liver metastases. Eligible patients with colorectal cancer and liver metastases, after signing informed consent, received FULIRI chemotherapy combined with bevacizumab/cetuximab targeted therapy. Efficacy was assessed after every four treatment cycles, followed by multidisciplinary team (MDT) discussion regarding potential surgical resection, ablation, or stereotactic radiotherapy. The primary endpoint was the objective response rate (ORR), and secondary endpoints included: disease control rate (DCR), R0 resection rate of liver metastases, progression-free survival (PFS), 3-year/5-year survival rates, and the incidence of acute toxicities of any grade and grades 3/4.

Detailed description

Irinotecan (IRI, also known as CPT-11) is an important component in chemotherapy for metastatic colorectal cancer. It induces single-strand DNA damage and blocks DNA replication. After traditional irinotecan administration, both the parent drug and its active metabolite SN-38 exist in two forms: active lactone and carboxylate. The lactone ring structure is unstable in neutral and alkaline solutions. Under physiological pH conditions, the active lactone rapidly hydrolyzes and becomes inactive as a carboxylate, thus reducing its efficacy, which limits its clinical application. The most significant adverse events in patients receiving irinotecan treatment are diarrhea, nausea, vomiting, and neutropenia; in patients receiving irinotecan monotherapy, the main causes of treatment-related death are neutropenic infection, grade 4 diarrhea, and fatigue. Shijiazhuang Pharmaceutical Group's first generic irinotecan liposome is a new formulation that improves upon traditional irinotecan. It encapsulates the active substance irinotecan in liposomes, utilizing the enhanced permeability and retention (EPR) effect to specifically target the tumor area. This increases the affinity of the drug to cancer cells, overcomes drug resistance, reduces the dosage, improves efficacy, and reduces toxic side effects, thereby mitigating the limitations of irinotecan in clinical use.

Currently, there is a lack of research data on irinotecan liposome combined with 5-FU/LV and targeted therapy in patients with advanced metastatic colorectal cancer. Because irinotecan liposome cannot directly replace the dosage of conventional irinotecan, we are conducting a phase II clinical study for first-line conversion therapy in patients with colorectal cancer liver metastases. This study aims to explore the safety and efficacy of irinotecan liposome combined with 5-FU/LV + bevacizumab or cetuximab, thus providing more treatment options for patients with advanced metastatic colorectal cancer.

Interventions

• Drug FULIRI combination targeted therapy
  Chemotherapy regimen FULIRI: Irinotecan liposome 70 mg/m2; leucovorin CF 400 mg/m2, d1, iv drop; 5-FU 400 mg/m2, d1, iv drop; 5-FU 2400 mg/m2, d1, CIV 46-48h; repeated every 2 weeks. Combined targeted therapy: Based on tumor gene analysis results, investigators may choose to combine bevacizumab (5 mg/kg, iv drop, d1) or cetuximab (500 mg/m2, iv drop, d1), repeated every 2 weeks.

Primary outcome measures

• Objective Response Rate (ORR) [Time frame: 1 year]

Secondary outcome measures (4)

• Disease Control Rate (DCR) [Time frame: 3 years]
• R0 resection rate of liver metastases [Time frame: 1 year]
• Progression-free survival (PFS) [Time frame: 3 years]
• Overall survival (OS) [Time frame: 3/5 years]

Eligibility criteria

Inclusion criteria

\- (1) Age 18-75 years; (2) Histologically confirmed colorectal adenocarcinoma; (3) Synchronous liver metastasis of colorectal cancer, or liver metastasis occurring after curative surgery for colorectal cancer, and no prior systemic anti-tumor treatment (including but not limited to systemic chemotherapy, molecular targeted therapy, immunotherapy, biological therapy, and other investigational drugs) after diagnosis of liver metastasis; (4) Liver metastasis deemed unresectable by MDT assessment, or potentially resectable but with a CRS score ≥3; (5) For patients who have received neoadjuvant or adjuvant therapy for colorectal cancer, the date of first diagnosis of liver metastasis must be at least 6 months after the last dose of neoadjuvant or adjuvant therapy; (6) At least one measurable target lesion on CT scan, assessable according to RECIST v1.1 criteria; (7) ECOG performance status 0-2; (8) Good organ function, without severe comorbidities of the heart, liver, lungs, kidneys, brain, etc.; (9) Blood routine: HGB ≥90 g/L, WBC >3.5 × 10\^9/L (NEU ≥1.5 × 10\^9/L), PLT ≥90 × 10\^9/L; Liver function: ALT or AST ≤2.5 times the upper limit of normal (ULN); Bilirubin ≤1.5 × ULN; Renal function: serum creatinine ≤1.5 × ULN; (10) Female subjects of childbearing potential must have a negative serum pregnancy test within 7 days before starting the study medication and be willing to use a medically approved highly effective contraceptive method during the study and for 3 months after the last dose of study medication; male subjects with partners of childbearing potential must agree to use effective contraception during the study and for 3 months after the last dose of study medication.

(11) The subject has given informed consent and signed the informed consent form, and is willing and able to comply with the planned visits, study treatment, laboratory tests, and other study procedures.

Exclusion criteria

• (1) Pathological diagnosis reveals the presence of neuroendocrine tumor, squamous cell carcinoma, or adenosquamous carcinoma components; (2) Presence of conditions requiring emergency treatment, such as bowel obstruction, bowel perforation, or bleeding; (3) Presence of multiple metastases in sites other than the liver (excluding localized lung metastases (≤2) or localized retroperitoneal lymph node metastases, provided the investigator assesses that the patient has a chance of achieving NED status); (4) Patients with known microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) who are deemed suitable for immunotherapy with immune checkpoint inhibitors by the investigator; (5) Previous treatment with irinotecan; (6) Underweight (Body Mass Index \[BMI\] < 18 kg/m2); (7) Concurrent or previous history of other malignancies besides cervical carcinoma in situ and basal cell carcinoma of the skin; (8) Concurrent severe infection or active pulmonary tuberculosis; (9) History of immunodeficiency, including HIV positive, or other acquired or congenital immunodeficiency diseases, or history of organ transplantation; (10) Patients with hepatitis B, if hepatitis B DNA exceeds 1000 copies/mL, should be excluded; patients with hepatitis C, if hepatitis C RNA is positive, should be excluded; (11) Received surgery or other anti-tumor treatments (including chemotherapy, radiotherapy, investigational treatments, etc.) within 4 weeks prior to enrollment; (12) Concurrent severe gastrointestinal dysfunction (> Grade I according to NCI-CTCAE v5.0, such as intestinal inflammation or diarrhea); (13) Presence of conditions within the past 6 months that contraindicate targeted therapy, such as arterial embolism, severe bleeding, or bowel perforation (excluding bleeding caused by surgery); (14) Concurrent severe or uncontrolled systemic diseases, including but not limited to hypertension (systolic blood pressure consistently above 150 mmHg, diastolic blood pressure consistently above 95 mmHg), diabetes, heart disease, etc.; (15) Patients who cannot tolerate this study or who may be allergic to the medications used in this study; (16) Patients with cognitive impairment or co-existing severe mental disorders, who are judged by the investigator to have poor adherence to chemotherapy; or other situations deemed unsuitable for participation in clinical research by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Zhongnan Hospital of Wuhan University — Wuhan

Identifiers

NCT: NCT07515963 · 2025073

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗