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

Sponsor

Sun Yat-sen University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05727163

Collaborator

(none)

194

Enrollment

Location

Arms

53.1

Anticipated Duration (Months)

3.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Metastatic	Drug: Dexamethasone Drug: Anisodamine Drug: Oxaliplatin Drug: Leucovorin Drug: Fluorouracil Drug: Irinotecan Drug: Bevacizumab Drug: Oxaliplatin Drug: Leucovorin Drug: Fluorouracil	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

194 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jul 29, 2022

Anticipated Primary Completion Date :

Dec 31, 2026

Anticipated Study Completion Date :

Dec 31, 2026

Arms and Interventions

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
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: (UGT28 7/7, UGT6 A/A, UGT28 6/7 and UGT6 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: 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

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:

Drug: Irinotecan

150 mg/m2 intravenously

Drug: Bevacizumab

5 mg/kg intravenously

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: 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:

Outcome Measures

Primary Outcome Measures

Objective Remission Rate (ORR) [Assessed up to 48 months]
As assessed by the investigators using RECIST v1.1 criteria

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed colorectal adenocarcinoma
Imaging or pathological confirmation of liver metastases
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.
Patients with mutated RAS and BrafV600E
No previous treatment for liver metastases, including chemotherapy, surgery, radiotherapy, transarterial chemoembolization (TACE) and targeted therapy
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)
Normal hematological function (platelets >90×109/L; white blood cells >3×109/L; neutrophils >1.5×109/L)
Serum bilirubin ≤ 1.5 times the upper limit of normal value (ULN), transaminases ≤ 5 times ULN
No ascites, normal coagulation function, albumin ≥35g/L
Liver function Child-Push grade A
Serum creatinine less than upper limit of normal (ULN) or calculated creatinine clearance >50 ml/min (using Cockcroft-Gault formula)
ECOG score 0-1
Life expectancy > 3 months
Signed written informed consent

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

Presence of any extrahepatic metastases and/or primary tumor not amenable to radical surgical resection
Development of liver metastases within 1 year after completion of adjuvant chemotherapy with FOLFOX or XELOX
Severe arterial embolism or ascites
Bleeding tendency or coagulation disorder
Hypertensive crisis or hypertensive encephalopathy
Severe uncontrolled systemic complications such as infections or diabetes mellitus
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
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)
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)
Treatment using any investigational drug within the last 28 days prior to the study
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
History of allergy to any of the drugs in the study
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
Unable or unwilling to comply with the study protocol
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