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

Colorectal Cancer Metastatic Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05727163
• Other study ID #: New Triumph
• Status: Recruiting
• Phase: Phase 2
• Start date: July 29, 2022
• Est. completion date: December 31, 2026

Study information

• Verified date: March 2024
• Source: Sun Yat-sen University
• Contact: Li Yuhong
• Phone: 020-87342487
• Email: liyh[@]sysucc.org.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 194
• Est. completion date: December 31, 2026
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Cancer Metastatic
• Colorectal Neoplasms

Intervention

Drug:
• Dexamethasone
25mg via HAI (Pre-chemotherapy)
• Anisodamine
10 mg via HAI (Pre-chemotherapy)
• Oxaliplatin
85 mg/m2 via HAI over 3 hours
• Leucovorin
200 mg/m2 via HAI
• Fluorouracil
400 mg/m2 via HAI and 2.4g/m2 via HAI over 48 hours
• Irinotecan
150 mg/m2 intravenously
• Bevacizumab
5 mg/kg intravenously
• Oxaliplatin
85 mg/m2 intravenously over 3 hours
• Leucovorin
200 mg/m2 intravenously
• Fluorouracil
400 mg/m2 intravenously + 2400 mg/m2 continuous intravenous infusion over 46 hours

Locations

Country	Name	City	State
China	Sun Yat-sen University Cancer Center	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-sen University

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Remission Rate (ORR)	As assessed by the investigators using RECIST v1.1 criteria	Assessed up to 48 months
Secondary	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
Secondary	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
Secondary	No evidence of disease rate (NED)	Proportion of treated patients who achieve no evidence of disease	Assessed up to 48 months
Secondary	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
Secondary	Overall Survival (OS)	The length of time from the start of treatment that patients diagnosed are still alive	Assessed up to 48 months
Secondary	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
Secondary	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