FOLFOX Via HAI Plus Intravenous Irinotecan With or Without Bevacizumab Versus Systemic FOLFOXIRI With or Without Bevacizumab in Initially Unresectable RAS-mutated CRLM Patients

NCT ID: NCT05727163

Last Updated: 2025-05-30

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 194 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-07-29
• Study Completion Date: 2026-12-31

Brief Summary

This prospective, randomized, controlled clinical study aims to evaluate the objective remission rate of FOLFOX hepatic artery infusion chemotherapy (HAI) in combination with systemic irinotecan with or without bevacizumab versus systemic intravenous FOLFOXIRI with or without bevacizumab in initially unresectable RAS-mutated colorectal cancer patients with liver metastases.

Detailed Description

PRIMARY OBJECTIVES:

The goal of this prospective, randomized, controlled clinical trial is to evaluate the objective remission rate (ORR) of FOLFOX hepatic artery infusion chemotherapy (HAI) in combination with irinotecan with or without bevacizumab systemic intravenous chemotherapy versus systemic intravenous FOLFOXIRI with or without bevacizumab in initially unresectable RAS-mutated colorectal cancer patients with liver metastases.

SECONDARY OBJECTIVES:

To assess and compare the depth of response (DpR), R0 surgical resection rate, No evidence of disease (NED) rate, progression-free survival (PFS), overall survival (OS), recurrence-free survival (RFS) in resectable patients and safety (chemotherapy-related adverse events, catheterization-related adverse events, surgical complications, etc.) between the two intervention groups.

OUTLINE:

Patients in the HAI group receive FOLFOX via hepatic artery infusion chemotherapy plus intravenous irinotecan with or without bevacizumab every 14 days, while patients in the systemic group receive intravenous FOLFOXIRI regimen with or without bevacizumab every 14 days. Patients will receive a maximum of 12 cycles in total (before and after surgery) unless there is disease progression, unacceptable toxicity, or if the patient withdraws from the study.

Conditions

Colorectal Cancer Metastatic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

HAI group

FOLFOX given via Hepatic Artery Infusion (HAI) in Combination With intravenous Irinotecan With or Without Bevacizumab.

Dexamethasone 25 mg via HAI (Pre-chemotherapy) Anisodamine (654-2) 10 mg HAI (Pre-chemotherapy) Oxaliplatin 85 mg/m2 via HAI over 3 hours Leucovorin 200 mg/m2 via HAI FU 400 mg/m2 via HAI FU 2.4g/m2 via HAI over 48 hours Irinotecan 150 mg/m2 intravenously Bevacizumab 5 mg/kg intravenously

The above regimen was given on Day 1 and repeated after 14 days. Patients will typically receive a maximum of 12 courses (preoperative and/or postoperative) unless disease progression is detected, intolerable adverse effects, or the patient refuses further treatment.

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

25mg via HAI (Pre-chemotherapy)

Anisodamine

Intervention Type: DRUG

10 mg via HAI (Pre-chemotherapy)

Oxaliplatin

Intervention Type: DRUG

85 mg/m2 via HAI over 3 hours

Leucovorin

Intervention Type: DRUG

200 mg/m2 via HAI

Fluorouracil

Intervention Type: DRUG

400 mg/m2 via HAI and 2.4g/m2 via HAI over 48 hours

Irinotecan

Intervention Type: DRUG

150 mg/m2 intravenously

Bevacizumab

Intervention Type: DRUG

5 mg/kg intravenously

Systemic Chemotherapy group

Systemic FOLFOXIRI With or Without Bevacizumab

Irinotecan 150mg/m2 intravenously Oxaliplatin 85 mg/m2 intravenously over 3 hours Leucovorin 200 mg/m2 intravenously FU 400 mg/m2 intravenously 5-FU 2400 mg/m2 continuous intravenous infusion over 46 hours Bevacizumab 5 mg/kg intravenously

Note: (UGT*28 7/7, UGT*6 A/A, UGT*28 6/7 and UGT*6 A/G patients, Irinotecan dosage was reduced to 130 mg/m2)

The above regimen was given on Day 1 and repeated after 14 days. Patients will typically receive a maximum of 12 courses (preoperative and/or postoperative) unless disease progression is detected, intolerable adverse effects, or the patient refuses further treatment.

Group Type: ACTIVE_COMPARATOR

Irinotecan

Intervention Type: DRUG

150 mg/m2 intravenously

Bevacizumab

Intervention Type: DRUG

5 mg/kg intravenously

Oxaliplatin

Intervention Type: DRUG

85 mg/m2 intravenously over 3 hours

Leucovorin

Intervention Type: DRUG

200 mg/m2 intravenously

Fluorouracil

Intervention Type: DRUG

400 mg/m2 intravenously + 2400 mg/m2 continuous intravenous infusion over 46 hours

Interventions

Dexamethasone

25mg via HAI (Pre-chemotherapy)

Intervention Type: DRUG

Anisodamine

10 mg via HAI (Pre-chemotherapy)

Intervention Type: DRUG

Oxaliplatin

85 mg/m2 via HAI over 3 hours

Intervention Type: DRUG

Leucovorin

200 mg/m2 via HAI

Intervention Type: DRUG

Fluorouracil

400 mg/m2 via HAI and 2.4g/m2 via HAI over 48 hours

Intervention Type: DRUG

Irinotecan

150 mg/m2 intravenously

Intervention Type: DRUG

Bevacizumab

5 mg/kg intravenously

Intervention Type: DRUG

Oxaliplatin

85 mg/m2 intravenously over 3 hours

Intervention Type: DRUG

Leucovorin

200 mg/m2 intravenously

Intervention Type: DRUG

Fluorouracil

400 mg/m2 intravenously + 2400 mg/m2 continuous intravenous infusion over 46 hours

Intervention Type: DRUG

Other Intervention Names

654-2; FU; FU

Eligibility Criteria

Inclusion Criteria

1. Histologically confirmed colorectal adenocarcinoma

2. Imaging or pathological confirmation of liver metastases

3. The multidisciplinary team determined that the liver metastases were unresectable, defined as (i) ≥5 metastases; (ii) inability to perform R0 resection; (iii) insufficient volume of liver expected to remain after resection; (iv) failure to preserve all 3 hepatic veins after resection, failure to ensure that blood flow to and from the liver and bile ducts can be preserved, and failure to preserve 2 adjacent liver segments. If any of the above criteria are met, it can be considered as initially unresectable liver metastases.

4. Patients with mutated RAS and BrafV600E

5. No previous treatment for liver metastases, including chemotherapy, surgery, radiotherapy, transarterial chemoembolization (TACE) and targeted therapy

6. No extrahepatic metastases confirmed by CT, MRI, or PET/CT (if necessary) (consider enrollment if there is a lung or lymph node lesion less than 10 mm and metastases are difficult to identify)

7. Normal hematological function (platelets >90×109/L; white blood cells >3×109/L; neutrophils >1.5×109/L)

8. Serum bilirubin ≤ 1.5 times the upper limit of normal value (ULN), transaminases ≤ 5 times ULN

9. No ascites, normal coagulation function, albumin ≥35g/L

10. Liver function Child-Push grade A

11. Serum creatinine less than upper limit of normal (ULN) or calculated creatinine clearance >50 ml/min (using Cockcroft-Gault formula)

12. ECOG score 0-1

13. Life expectancy > 3 months

14. Signed written informed consent

Exclusion Criteria

1. Presence of any extrahepatic metastases and/or primary tumor not amenable to radical surgical resection

2. Development of liver metastases within 1 year after completion of adjuvant chemotherapy with FOLFOX or XELOX

3. Severe arterial embolism or ascites

4. Bleeding tendency or coagulation disorder

5. Hypertensive crisis or hypertensive encephalopathy

6. Severe uncontrolled systemic complications such as infections or diabetes mellitus

7. Clinically significant cardiovascular disease such as cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), uncontrolled hypertension despite appropriate medication, unstable angina pectoris, congestive heart failure (NYHA class 2-4), arrhythmias requiring medication

8. History or physical examination revealing a central nervous system disease (e.g., primary brain tumor, epilepsy not manageable by standard therapy, presence of brain metastases, or history of stroke)

9. Previous malignancy within the last 5 years (except post-radical surgery basal cell carcinoma of the skin and/or carcinoma in situ of the cervix)

10. Treatment using any investigational drug within the last 28 days prior to the study

11. Any residual toxicity from prior chemotherapy (except alopecia), such as peripheral neuropathy ≥ NCI CTC v3.0 grade 2, will not be considered for treatment with oxaliplatin-containing regimens

12. History of allergy to any of the drugs in the study

13. Women of childbearing potential (<2 years after last menstruation) or men of childbearing potential who are not using or have refused to use an effective non-hormonal contraceptive (IUD, barrier method combined with spermicidal gel or sterilization) during pregnancy and lactation

14. Unable or unwilling to comply with the study protocol

15. Presence of any other disease, dysfunction due to metastatic lesions, or suspicious medical findings that suggest a possible contraindication to the use of the study drug or that would place the patient at risk of treatment-related complications

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sun Yat-sen University

OTHER

Sponsor Role: lead

Responsible Party

Yuhong Li

Clinical Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, China

Site Status: RECRUITING

Countries

China

Central Contacts

Li Yuhong

Role: CONTACT

liyh@sysucc.org.cn

020-87342487 ext. +86

Facility Contacts

Yuhong Li, MD

Role: primary

liyh@sysucc.org.cn

020-87342487 ext. +86

Other Identifiers

New Triumph

Identifier Type: -

Identifier Source: org_study_id