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

FOLFOX Via Hepatic Artery Infusion Chemotherapy (HAI) Plus Systemic Irinotecan With or Without Bevacizumab Versus Systemic FOLFOXIRI With or Without Bevacizumab in Patients With Initially Unresectable RAS-mutated Colorectal Cancer With Liver Metastases: A Prospective, Randomized, Controlled Clinical Study

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer Metastatic
• Intervention / Treatment: Drug: Dexamethasone; Drug: Anisodamine; Drug: Oxaliplatin; Drug: Leucovorin; Drug: Fluorouracil; Drug: Irinotecan; Drug: Bevacizumab; Drug: Oxaliplatin; Drug: Leucovorin; Drug: Fluorouracil

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.

• Study Type: Interventional
• Enrollment (Estimated): 194
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Li Yuhong; Phone Number: +86 020-87342487; Email: liyh@sysucc.org.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Sun Yat-sen University Cancer Center
      • Contact: Yuhong Li, MD; Phone Number: +86 020-87342487; Email: liyh@sysucc.org.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (Patients meeting any of the following criteria will be excluded from the study):

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Dexamethasone; 25mg via HAI (Pre-chemotherapy); Drug: Anisodamine; 10 mg via HAI (Pre-chemotherapy); Other Names: 654-2; Drug: Oxaliplatin; 85 mg/m2 via HAI over 3 hours; Drug: Leucovorin; 200 mg/m2 via HAI; Drug: Fluorouracil; 400 mg/m2 via HAI and 2.4g/m2 via HAI over 48 hours; Other Names: FU; Drug: Irinotecan; 150 mg/m2 intravenously; Drug: Bevacizumab; 5 mg/kg intravenously; Drug: Oxaliplatin; 85 mg/m2 intravenously over 3 hours; Drug: Leucovorin; 200 mg/m2 intravenously; Drug: Fluorouracil; 400 mg/m2 intravenously + 2400 mg/m2 continuous intravenous infusion over 46 hours; Other Names: FU
Active Comparator: 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.	Drug: Oxaliplatin; 85 mg/m2 via HAI over 3 hours; Drug: Leucovorin; 200 mg/m2 via HAI; Drug: Fluorouracil; 400 mg/m2 via HAI and 2.4g/m2 via HAI over 48 hours; Other Names: FU; Drug: Irinotecan; 150 mg/m2 intravenously; Drug: Bevacizumab; 5 mg/kg intravenously; Drug: Oxaliplatin; 85 mg/m2 intravenously over 3 hours; Drug: Leucovorin; 200 mg/m2 intravenously; Drug: Fluorouracil; 400 mg/m2 intravenously + 2400 mg/m2 continuous intravenous infusion over 46 hours; Other Names: FU

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Remission Rate (ORR)	As assessed by the investigators using RECIST v1.1 criteria	Assessed up to 48 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Depth of Response (DpR)	The investigators evaluate the maximum tumor regression to baseline tumor ratio to determine the depth of tumor regression (DpR) and calculate the median value.	Assessed up to 48 months
R0 surgical resection rate	Defined as the proportion of patients who achieved complete resection (pathologically determined R0 resection) after treatment	Assessed up to 48 months
No evidence of disease rate (NED)	Proportion of treated patients who achieve no evidence of disease	Assessed up to 48 months
Progression Free Survival (PFS)	The length of time during and after the treatment of the disease, that a patient lives with the disease without its aggravation	Assessed up to 48 months
Overall Survival (OS)	The length of time from the start of treatment that patients diagnosed are still alive	Assessed up to 48 months
Recurrence Free Survival in resectable patients	Defined as the time from complete resection of liver metastases or NED to the development of disease recurrence or death	Assessed up to 48 months
Safety (including chemotherapy-related adverse events, catheterization-related adverse events, surgical complications, etc.)	Number of patients with adverse events and severity according to NCI CTCAE v3.0	Assessed up to 48 months

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: October 24, 2022
• First Submitted That Met QC Criteria: February 3, 2023
• First Posted (Actual): February 14, 2023

Study Record Updates

• Last Update Posted (Actual): May 30, 2025
• Last Update Submitted That Met QC Criteria: May 24, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: FOLFOX; Systemic Chemotherapy; FOLFOXIRI; Colorectal liver metastasis; Hepatic Artery Infusion Chemotherapy; RAS-mutation; Initially unresectable colon cancer
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Sensory System Agents; Analgesics, Non-Narcotic; Analgesics; Neurotransmitter Agents; Anti-Arrhythmia Agents; Anti-Inflammatory Agents, Non-Steroidal; Micronutrients; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Antioxidants; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Free Radical Scavengers; Antidotes; Vitamin B Complex; Vitamins; Vasodilator Agents; Anti-Ulcer Agents; Parasympatholytics; Oxaliplatin; Bevacizumab; Irinotecan; Dexamethasone; Fluorouracil; Leucovorin; Levoleucovorin; Anisodamine
• Other Study ID Numbers: New Triumph

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No